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A global shortage of neonatal and pediatric antibiotic trials.

Journal: BMJ Open

ManuscriptFor ID peerbmjopen-2017-016293 review only

Article Type: Research

Date Submitted by the Author: 07-Feb-2017

Complete List of Authors: Thompson, Georgina; St George's University of London, Infection and Immunity; University of Exeter Medical School Barker, Charlotte; St George's University of London, Infection and Immunity; University College London Institute of Child Health Folgori, Laura; St George's University of London, Paediatric Infectious Diseases Research Group Bielicki, Julia; St George's University London, Division of Clinical Sciences; University of Basel Children's Hospital Bradley, John; University of California San Diego School of Medicine, Department of Pediatrics Lutsar, Irja; University of Tartu, Department of Medical Microbiology sharland, mike; St George's University of London, Infection and Immunity; St Georges Hospital, Paedaitric Infectious Diseases Unit http://bmjopen.bmj.com/ Primary Subject Paediatrics Heading:

Secondary Subject Heading: Infectious diseases

Paediatric infectious disease & immunisation < PAEDIATRICS, INFECTIOUS Keywords: DISEASES, PAEDIATRICS

on September 28, 2021 by guest. Protected copyright.

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1 2 3 A global shortage of neonatal and pediatric antibiotic trials. 4 1,2 1,3,4 1 1,5 6,7 8 1, 4 5 G. Thompson , C. Barker , L. Folgori , J. Bielicki , J. Bradley , I. Lutsar , M. Sharland 6

7 1 8 Paediatric Infectious Diseases Research Group, Institute for Infection and Immunity, St George's University 9 of London, London, UK 10 2 University of Exeter, Exeter, UK 11 3 12 Inflammation, Infection and Rheumatology Section, UCL Great Ormond Street Institute of Child Health, 30 13 Guilford Street, London, UK 14 4 15 St George’s UniversityFor Hospitals peer NHS Foundation review Trust, Blackshaw Road, only London, UK 16 5 Paediatric Pharmacology and Pharmacometrics, University of Basel Children’s Hospital, Basel, Switzerland 17 6 Department of Pediatrics, School of Medicine, University of California San Diego, CA, United States 18 7 19 Rady Children’s Hospital San Diego, San Diego, CA, United States 20 8 Department of Medical Microbiology, University of Tartu, Tartu, Estonia 21

22 23 24 25 Corresponding author 26 Georgina Thompson 27 Paediatric Infectious Diseases Research Group 28 29 St George's, University of London 30 Jenner Wing, Level 2, Room 2.216F, Mail Point J2C 31

London SW17 0RE http://bmjopen.bmj.com/ 32 33 Telephone: 07880325494 34 Email: [email protected] 35 36 37 38 Word count: 2607 39 40 on September 28, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 2 of 17

1 2 3 ABSTRACT 4 Objectives: There have been few clinical trials (CTs) on antibiotics which inform neonatal and 5 6 pediatric drug labelling. Consequently, the rate of unlicensed and off-label prescribing in pediatrics 7 8 remains high. This remains a major concern, particularly in neonates. It is unclear whether the 9 current pediatric antibiotic research pipeline is adequate to inform optimal drug dosing. Using 10 11 ClinicalTrials.gov registry, this review aims to establish the current global status of antibiotic CTs in 12 children up to 18 years of age. 13 14 Results: Only 76 registered open CTs of antibiotics in children were identified globally; 23 (30%) 15 were recruiting newbornsFor (only peer 8 (11%) included review preterm neonates), only 52 (68%) infants and toddlers, 16 17 58 (76%) children, and 54 (71%) adolescents. The majority of registered trials were late phase (10 18 (15%) Phase 3 and 23 (35%) Phase 4/pharmacovigilance). Two-thirds were sponsored by non-profit 19 20 organisations, with few sponsored by pharmaceutical companies (50 (66%) vs. 26 (34%) 21 respectively). A greater proportion of non-profit funded trials were efficacy-based strategic trials (n= 22 23 34, 68%), in comparison to industry-led trials, which were most often focused on safety or 24 pharmacokinetic data (n=17, 65%). Our search revealed that 2 of the 37 antibiotics listed on the 25 26 May 2016 Pew Charitable Trusts antibiotic development pipeline, currently being studied in adults, 27 appear to be recruiting in open pediatric CTs. 28 29 Conclusions: This review highlights that there are currently very few pediatric antibiotic CTs being 30 conducted globally (especially in neonates). There is striking disparity noted between antibiotic drug 31 32 development programmes involving adults and children. http://bmjopen.bmj.com/ 33

34 35 Strengths and limitations of this study 36 37 • A narrative literature review of registered clinical trials in children. 38 • Explicit reproducible methodology. 39

40 • Search strategy limited to ClinicalTrials.gov and EudraCT. Entirety of clinical research in this on September 28, 2021 by guest. Protected copyright. 41 field might not have been captured. 42 43 • Search strategy also limited to open clinical trials. Active but not yet recruiting trials were not 44 captured. 45 46 47 48 INTRODUCTION 49 50 With the persistence of widespread unlicensed and off-label prescribing in pediatrics – as high as 51 11.4% and 46.5% respectively – the paucity of clinical research involving children that which is 52 53 conducted to inform optimal drug dosing, licensing and labelling remains a problem.[1] For certain 54 medicines, drug efficacy can be extrapolated from adult data provided that the pathology and 55 56 pharmacology (including drug exposure) are the same, or sufficiently similar in children as in 57 adults.[2,3] Advances in modelling and simulation mean smaller focussed studies can now be 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 3 of 17 BMJ Open

1 2 3 performed to help obtain regulatory approval for most medicines, including antimicrobials.[4] 4 Although differences in drug pharmacokinetics (PK) in neonates and children can lead to adverse 5 6 reactions that are not seen in adult populations, these are very rare and extrapolation of safety data 7 8 into the pediatric population can further reduce the need for complex study designs.[5] 9 10 11 Since antibiotics are the most commonly prescribed medicines in children, it is important to improve 12 our currently limited understanding of their pharmacokinetic profiles to help determine optimal drug 13 14 dosing and ultimately to improve patient outcomes.[6] Suboptimal antibiotic dosing, including both 15 under- or over-dosing,For can leadpeer to toxicity orreview failure to meet therapeutic only targets, which not only 16 17 contributes to treatment failure, but may also drive antimicrobial resistance through encouragement 18 of selection pressures on drug-resistant strains of bacteria.[7] In the last decade several initiatives 19 20 have been established to encourage pediatric medicines research, thus bridge the gap between 21 adult and pediatric drug development plans. Such initiatives include the Pediatric Regulation 22 23 (Pediatric Investigation Plans (PIPs), introduced by the European Medicines Agency (EMA),[8] and 24 Pediatric Study Plans (PSPs), by the U.S. Food and Drug Administration (FDA).[9] Despite this, 25 26 there remain limited advances in the development of antibiotics for this population.[10] 27 28 29 The global status of clinical research on antibiotics in pediatrics is currently unknown. Using 30 registered records of clinical trials (CTs) on ClinicalTrials.gov, this review aims (i) to summarise the 31 32 current global status of registered antibiotic research in children and neonates, and (ii) to stimulate http://bmjopen.bmj.com/ 33 discussion and collaboration among the relevant stakeholders on the neglect of antibiotic research 34 35 in pediatrics. 36 37 38 39

40 METHODS on September 28, 2021 by guest. Protected copyright. 41 Data sources 42 th 43 The ClinicalTrials.gov registry (last accessed 8 November 2016) is an international platform for the 44 registration of CTs. It is a web-based registry, developed in 2000 by the National Institute of Health 45 46 (NIH) and the FDA, to which trials from 50 states and 163 countries around the world are registered. 47 All information provided for each trial is updated periodically by the trial’s sponsoring organisation. 48 49 The database has a specific child filter, which uses a key word paradigm to select all registered 50 trials recruiting patients/participants up to 18 years of age. 51 52 53 Study selection 54 55 Our records were identified using suitable key word searches, in which the search terms were 56 (antimicrobial* OR antibiotic* OR antiinfective agent*) AND Child AND Open Studies. All identified 57 58 trials were filtered manually using inclusion and exclusion criteria. Interventional and observational 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 4 of 17

1 2 3 trials on antimicrobials recruiting children up to 18 years of age were considered eligible for 4 inclusion. No specific temporal filter was applied since only open or ongoing clinical trials were of 5 6 interest. The following records, which were not investigating one or more antibiotics, were excluded: 7 8 trials of antifungals, antivirals, antiprotozoal, antimycotics, pro- or pre- biotics, antiseptics, topical or 9 inhalational treatments, prophylactic antibiotics, investigating alternative use for antibiotics (for 10 11 example as anti-inflammatory agents), and trials involving pregnant women or cystic fibrosis, 12 tuberculosis, HIV, febrile neutropenia, and malaria patients. 13 14 15 All eligible recordsFor were identified peer via manual review filtering by GT CB, LFonly and MS. 16 17 18 Data extraction 19 20 The following information was collected from the included records: unique NCT number, recruitment 21 status, study design, trial phase, study sponsor, age group and sex eligibility, clinical indication, 22 23 geographic region of recruitment, antibiotic being investigated, and endpoint classification. 24 Outcomes were categorised as safety, efficacy or PK. Economic setting (based on geographic 25 26 region of recruitment) was classified using The World Bank classification.[11] 27 28 29 The specific class of antibiotic studied in each trial was identified and classified using the World 30 Health Organisation (WHO) ATC/DDD index.[12] To investigate whether novel antibiotics are being 31 32 studied in pediatric and neonatal populations (as well as in adults), the antibiotics currently studied http://bmjopen.bmj.com/ 33 in children were compared with the Pew Charitable Trusts Antibiotics Currently in Clinical 34 35 Development pipeline, which identifies novel antibiotics currently under development for the U.S. 36 37 market.[13] 38 39

40 on September 28, 2021 by guest. Protected copyright. 41 RESULTS 42 43 Our search identified 1056 records. 603 records were excluded on title because they were studies 44 not involving an antimicrobial. 453 records were investigating one or more antimicrobials and 45 46 recruiting children below 18 years of age. Among the 195 trials investigating antibiotics, 76 fulfilled 47 our inclusion and exclusion criteria and were included in the final analysis. Reasons for exclusion 48 49 are summarised in Figure 1. 50 51 All 76 CTs identified were open as of 8th November 2016, and 63 (83%) of these were recognised 52 53 as recruiting participants on this date (Table 1). All trials stated recruitment of both male and female 54 participants. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 5 of 17 BMJ Open

1 2 3 Table 1. Characteristics of clinical trials. 4 5 Number of 6 Characteristic Category studies, n (%) 7 a 8 Age group Preterm neonates 1 (1) 9 Neonates (total) 23 (30) 10 Infants and toddlers 52 (68) 11 Children 58 (76) 12 Adolescents 54 (71) 13 Recruitment status Recruiting 63 (83) 14 Not yet recruiting 13 (17) 15 StudyFor design peerInterventional review only 66 (87) 16 Observational 10 (13) 17 Trial phaseb Phase 1 10 (15) 18 Phase 1-2 1 (2) 19 Phase 2 9 (14) 20 Phase 2-3 3 (5) 21 Phase 3 10 (15) 22 23 Phase 4 23 (39) 24 Not specified 10 (15) 25 Sponsor Industry 26 (34) 26 Non-profit 50 (66) 27 Geographic region Africa 8 (11) 28 Asia 16 (21) 29 Europe 22 (29) 30 Latin America 6 (8) 31 North America 34 (45) http://bmjopen.bmj.com/ 32 Oceania 5 (7) 33 Antibiotic class J01A Tetracycline 4 (5) 34 J01C Beta-lactam, Penicillin 25 (33) 35 J01D Other Beta-lactam 22 (29) 36 J01E Sulfonamides and trimethoprim 7 (9) 37 J01F Macrolide, Lincosamide, Streptogramin 14 (18) 38 39 J01G Aminoglycoside 2 (3)

40 J01M Quinolone 8 (11) on September 28, 2021 by guest. Protected copyright. c 41 J01X Other 21 (28) 42 J01 Not specified 2 (3) 43 44 Totals for Age group, Geographic region, and Antibiotic class do not add up to total number of clinical trials (76) as some trials contributed to more than one sub group. 45 a 46 7 further trials mentioned inclusion of preterm babies in the inclusion criteria. b Trial phase % based on percentage of interventional trials. 47 c J01X includes glycopeptides, polymixins, imidazole derivatives, and nitrofuran. 48

49 50 51 52 Age group 53 On review of the age of participants being recruited, only 23 of the 76 trials (30%) were recruiting 54 55 newborns (0 to 28 days). 1 of these 23 trials focused solely on recruiting preterm newborns (a 56 further 7 CTs mentioned inclusion of preterm newborns in inclusion criteria). Of the remaining 57 58 records, 52 (68%) were recruiting infants and toddlers (28 days to 23 months), 58 (76%) children (2 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 6 of 17

1 2 3 to 11 years), and 54 (71%) adolescents (11 up to 18 years). 29 (38%) trials did not focus solely on 4 the recruitment of children or neonates, with age ranges also spanning across adult populations. 5 6 7 8 Study type 9 Interventional trials were most frequently identified (n=66, 87%) with only 10 (13%) observational 10 11 trials noted. Of the interventional trials, the majority were in the later stages of development; 10 12 (13%) in Phase 1, 1 (2%) between Phase 1 and 2, 9 (14%) in Phase 2, 3 (5%) between Phase 2 13 14 and 3, 10 (15%) in Phase 3 and 23 (35%) in Phase 4. Phase 4 is defined as CTs occurring after an 15 antibiotic has beenFor approved peer in children. In 10review (15%) of cases, a trialonly phase had not been specified. 16 17 18 Sponsor and Endpoint Classification 19 20 Of the antibiotic clinical trials identified in our search, two-thirds (n=50, 66%) were sponsored by 21 non-profit organisations (being University, Hospital or government funded), with many fewer trials 22 23 sponsored by Industry (n=26, 34%). The endpoint classification of the majority of trials (n=43, 57%) 24 was reported as efficacy (Table 2). A greater proportion (n=34, 68%) of non-profit studies measured 25 26 the efficacy of the drugs as the primary endpoint, with less emphasis on collection of PK or safety 27 data (n=16, 32%). In comparison pharmaceutical-led trials focussed on early PK and safety studies 28 29 over the drug’s efficacy (n=17, 65% vs. n=9, 35% respectively). 30

31 32 http://bmjopen.bmj.com/ 33 Table 2. Clinical trial endpoint classification of identified clinical trials stratified by trial sponsor. 34 35 Endpoint classification determined by planned primary outcomes. 36 37 Endpoint classification Industry Non-profit Total (%) 38 39 Efficacy 9 34 43 (57)

40 on September 28, 2021 by guest. Protected copyright. 41 Safety 10 2 12 (16) 42 43 PK 7 14 21 (28) 44 45 46 47 Geographic region 48 Of the 76 antibiotic trials identified, the most frequently recruiting geographic region was North 49 50 America (n=34, 45%). 22 (29%) trials recruiting in Europe and 16 (21%) in Asia were identified, 6 51 (8%) in Latin America, 8 (11%) in Africa, and 5 (7%) in Oceania. The great majority of trials were 52 53 recruiting in High Income Countries (HICs) (n=54, 71%), with fewer trials recruiting in Low Income 54 Countries (LICs) (n=4, 5%), Lower Middle Income Countries (LMICs) (n=4, 5%), Upper Middle 55 56 Income Countries (UMICs) (n=11, 14%) or a combination of UMICs and HICs (n=3, 4%). 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 7 of 17 BMJ Open

1 2 3 Indication 4 The most common treatment indications investigated in the 76 antibiotic trials were Lower 5 6 Respiratory Tract Infection (n=12, 16%) and Sepsis (n=11, 14%), followed by Upper Respiratory 7 8 Tract Infection (n=8, 11%), Intra-abdominal Infection (IAI) (n=8, 11%), Urinary Tract Infection (UTI) 9 (n=7, 9%), complicated Skin and Soft Tissue Infection (cSSTI) (n=6, 8%), CNS infection (n=3, 4%), 10 11 and Bone and Joint infection (n=1, 1%) (Table 3). 18 (24%) trials were investigations of unspecified 12 bacterial infections and these were mainly phase 1 PK studies. 13 14 15 Antibiotic classFor peer review only 16 The majority of antibiotics (n=47, 62%) being investigated were beta-lactams, followed by other 17 18 antibiotic classes (J01X, including vancomycin, telavancin and dalbavancin) (n=21, 28%). 19 Macrolides or lincosamides (J01F) were the next most commonly studied antibiotic classes (n=14, 20 21 18%). Very few of the records reported investigations of tetracyclines (J01A) (n=4, 5%), 22 Sulphonamides and trimethoprim (J01E) (n=7, 9%), aminoglycosides (J01G) (n=2, 3%), or 23 24 quinolones (J01M) (n=8, 11%). 2 CTs (3%) did not specify the class of antibiotic being investigated. 25 16 (21%) trials were investigating more than one antibiotic; these trials counted towards more than 26 27 one J01 category. The breakdown of J01 categories is described in Figure 1. 28 29 30 Antibiotic pipeline 31 Of the 37 antibiotics listed on the most recent May 2016 edition of the Pew Charitable Trusts 32 http://bmjopen.bmj.com/ th 33 Antibiotic Pipeline (last accessed 10 June 2016),[13] as noted by the EMA Opinions and Decisions 34 on Pediatric Investigation Plans, 5 had an agreed PIP: Imipenem/Cilastatin+Relebactam, Cadazolid, 35 th 36 Carbavance (Meropenem+Vaborbactam), Eravacycline, and Solithromycin.[8] As of 8 November 37 2016, our search found that only 2 of the 37 antibiotics listed on the Pew antibiotic pipeline 38 39 (Carbavance and Solithromycin) was being investigated in 1 and 2 on-going CTs in pediatric 40 patients, respectively (Table 4). A PIP was agreed for Carbavance in 2015 for treatment of Gram- on September 28, 2021 by guest. Protected copyright. 41 42 negative infections, and for Solithromycin in 2016 for the treatment of gonococcal infection, and 43 later for treatment of anthrax, tularaemia, and bacterial pneumonia. PIPs were established in 2015 44 45 for treatment of urinary tract infection and complicated intra-abdominal infection with Eravacycline, 46 and in 2016 for treatment of Clostridium difficile infection with Cadazolid and of Gram-negative 47 48 bacterial infection with Imipenem/Cilastin+Relebactam.[14] Despite this, we could not identify any 49 50 registered trials of these antibiotics in our search. 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from - - Page 8 of 17

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on September 28, 2021 by guest. Protected copyright. Debiopharm Debiopharm SA International MicuRx MicuRx Inc. Pharmaceuticals Astrazeneca PLC PLC Astrazeneca PLC Allergan Tetraphase Tetraphase Inc. Pharmaceuticals Theravance Biopharma Biopharma Theravance Inc. Legochem Biosciences Biosciences Legochem Inc. Meiji Seika Pharma Co. Co. Pharma Seika Meiji Pharmaceuticals Fedora For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml For peer review only Phase 1 1 Phase Phase 2 2 Phase Phase 2 2 Phase Phase 1 1 Phase Pharmaceuticals Basilea Phase 1 1 Phase Ltd. Wockhardt infection Bacterial Phase 1 1 Phase Phase 1 1 Phase Phase 1 1 Phase Ltd. Wockhardt infection Bacterial Phase 1 1 Phase Phase 1 1 Phase Inc. Crestone Debio 1450 1450 Debio MRX – 1 1 – MRX Aztreonam – Avibactam Avibactam – Aztreonam 2 Phase TP – 271 271 – TP Zidebactam+Cefepime Zidebactam+Cefepime 1 Phase Ltd. Wockhardt VAP HAP, cUTI, WCK 771 771 WCK WCK 2349 2349 WCK TD – 1607 1607 – TD LCB01 – 0371 – 0371 LCB01 CRS3123 CRS3123 BAL30072 BAL30072 OP0595 OP0595 Page 9 of 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from ------Page 10 of 17 ------

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difficile http://bmjopen.bmj.com/ BMJ Open cUTI, cIAI, HAP, VAP, bacteraemia, bacteraemia, VAP, HAP, cIAI, cUTI, pyelonephritis CAP, cUTI, acute skin infections skin acute cUTI, CAP, Clostridium Clostridium cUTI, cIAI, HAP, VAP, acute acute VAP, HAP, cIAI, cUTI, pyelonephritis CAP, HAP, VAP, acute skin infection, infection, skin acute VAP, HAP, CAP, joint infections prosthetic osteomyelitis, CAP, cUTI, acute skin infection infection skin acute cUTI, CAP, CAP, uncomplicated urogenital urogenital uncomplicated CAP, urethritis gonorrhea, cUTI, HAP, VAP, cIAI, catheter- cIAI, VAP, HAP, cUTI, infection bloodstream associated Acute skin infection, prosthetic joint joint prosthetic infection, Acute skin infection HAP, acute skin infection infection skin acute HAP, on September 28, 2021 by guest. Protected copyright. Rempex Rempex Inc. Pharmaceuticals Melinta Therapeutics Therapeutics Melinta Inc. Actelion Actelion Ltd. Pharmaceuticals Nabriva Therapeutics Therapeutics Nabriva AC Paratek Paratek Inc. Pharmaceuticals For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml For peer review only Phase 3 3 Phase Phase 3 3 Phase Inc. Merck & Co. Phase 3 3 Phase Inc. Cempra Phase 3 3 Phase Phase 3 3 Phase Inc. Pharma Tetraphase and cIAI cUTI Phase 3 3 Phase Phase 3 3 Phase Inc. Cempra Phase 3 3 Phase Inc. Achaogen Phase 3 3 Phase Phase 3 3 Phase PLC Motif Bio target carbapenem enterobacteriacaeresistant hospital-acquiredHAP, pneumonia; VAP,ventilator-acquired pneumonia;cUTI, complicated Urinary Tract Infection; CAP, Community-acquired pneumonia; cIAI, complicated Intra-abdominalInfection. a Solithromycin Solithromycin Plazomicin Plazomicin Eravacycline Eravacycline Delafloxacin (Baxdela) (Baxdela) Delafloxacin 3 Phase Carbavance Carbavance (Meropenem+Vaborbactam) Taksta (fusidic acid) acid) (fusidic Taksta Cadazolid Cadazolid Iclaprim Iclaprim Imipenem / / Imipenem Cilastatin+Relebactam Lefamulin Lefamulin Omadacycline Omadacycline Page 11 of 17 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 12 of 17

1 2 3 DISCUSSION 4 Our search on ClinicalTrials.gov identified 76 clinical trials investigating one or more antibiotics 5 6 recruiting children between 0 and 18 years of age. This is low in comparison to the number of on- 7 8 going trials in adults, with children representing around a quarter of the global population.[15,16] A 9 review of completed CTs in the U.S. between 2000 and 2010 identified a total of 4078 adult trials 10 11 compared to just 294 that had recruited children.[17] In our study, the lack of trials recruiting 12 neonates is striking. Just 23 of the 76 trials identified were recruiting neonates, and remarkably just 13 14 8 CTs globally were recruiting preterm neonates. There are broadly two types of pediatric trials 15 being conductedFor globally. Either peer pharmaceutical-led review Phase 1/2 PK only and safety trials (n=17) being 16 17 conducted in the HIC setting, or investigator led, often pragmatic, late phase efficacy trials in the 18 LMIC setting (n=34), with a greater proportion of the on-going trials sponsored by non-profit 19 20 organisations than industry (66% compared to 34%). As of April 2016, there were 17 agreed 21 antibiotic PIPs agreed by the EMA,[8] covering a range of indications, most commonly cSSTI, 22 23 complicated IAI (cIAI), and complicated UTI (cUTI).[14] In contrast, treatments for respiratory and 24 systemic infections, the most common indications in pediatrics, do not appear to currently being 25 26 evaluated.[18] Although the introduction of PIPs on the whole has encouraged the study of 27 medicines in children, the range of infectious indications covered therefore does not match the 28 29 burden of disease in this age group. Thirty-seven antibiotics are currently being developed in adults, 30 yet to our knowledge just 2 of these are being studied in children. However, some classes of 31 32 antibiotics that may be of higher risk for children (tetracyclines and fluoroquinolones) may not be http://bmjopen.bmj.com/ 33 pursued as aggressively for pediatric approvals by either industry or regulatory agencies. The 34 35 substantial lag time is a real concern, particularly for new antibiotics against resistant Gram- 36 37 negative pathogens, although there is some value in generating substantial safety data in adults 38 prior to exposing children and newborn infants to potentially toxic new agents. However, Gram- 39

40 negative sepsis is a growing problem in neonates, with a significant increase in the proportion of on September 28, 2021 by guest. Protected copyright. 41 multi-resistant Gram-negative pathogens.[19] 42 43 44 In 2013, a similar review of European pediatric clinical trials identified 31 trials of antibiotics 45 46 approved by the EMA in 2000 that were recruiting children in Europe (compared to the 22 trials we 47 found to be now recruiting in this region). They similarly found a very small proportion of neonatal 48 49 trials (just 2 of 31), as well as a greater proportion of efficacy-based trials.[10] In 2012, a review of 50 interventional trials registered with ClinicalTrials.gov between 2007 and 2010 found that only 17% 51 52 had recruited children below 18 years of age.[20] A similar review of antimicrobial CTs conducted in 53 the U.S. between 2000 and 2012 reported that just 5% had recruited only children compared to the 54 55 74% that had recruited only adults, and that, as we have found, the trials were sponsored primarily 56 by non-profit organisations (60% compared to 30% by industry).[17] In our search of global trials, 57 58 39% of registered CTs reported collection of PK data in comparison to a similar review in 2009 of 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 13 of 17 BMJ Open

1 2 3 PK research on medicines for children that reported 24% of registered CTs would be collecting PK 4 data.[21] Collection of PK data is particularly important in neonates where developmental 5 6 differences in physiology lead to significant changes in drug PK, which puts them at increased risk 7 8 of adverse drug reactions.[3,22] Furthermore, off-label and unlicensed prescribing is at its greatest 9 in neonatal populations (61% and 22% respectively)[14]. A recent review noted a striking lack of 10 11 harmonisation in study design and outcomes among completed and on-going neonatal and pediatric 12 antibiotic CTs which may make translation of trial data into clinical guidance more difficult.[23] 13 14 15 The search strategyFor used has peer some limitations. review Since the search wasonly limited to clinical trials 16 17 registered to ClinicalTrials.gov, it is possible that a number of open or on-going trials registered with 18 alternative platforms (for example ICTRP) will have been missed. Together with ClinicalTrials.gov 19 20 these could help to establish the entirety of current clinical research in this field. We did however 21 search EudraCT, and found no further studies to those captured on ClinicalTrials.gov. Our search 22 23 was also limited to open CTs, which means that active but not yet recruiting trials were not 24 captured, as well as those that had closed to recruitment previously. The information recorded for 25 26 each trial registered with ClinicalTrials.gov is updated by the trial investigators, and therefore relies 27 on them to periodically update the registry. On occasion, information such as recruitment status 28 29 might not be updated in real time. 30

31 32 Concerns around the growing threat of antimicrobial resistance have prompted a number of new http://bmjopen.bmj.com/ 33 initiatives. In 2016, the EMA published the first draft of the Concept Paper to propose the 34 35 development of an Addendum to the guideline on the evaluation of new anti-bacterial products for 36 37 treatment of bacterial infections in children.[24] At the same time, the Clinical Trials Transformation 38 Initiative (CTTI) is currently focused on the identification of key barriers in the conduct of pediatric 39

40 antibacterial CTs, which hamper their successful implementation into clinical practice.[25] Recent on September 28, 2021 by guest. Protected copyright. 41 evidence states that overall, antibiotic CTs make up less than 1% of all registered pediatric CTs, 42 43 and that trial completion is slow, with an average time to completion of around two years.[26] 44 45 46 47 CONCLUSIONS 48 49 A number of issues contribute to the difficulties in conducting pediatric antibiotic clinical trials. The 50 lack of regulatory guidance, vulnerability of this population, issues with informed consent and 51 52 assent, and lack of research-experienced hospital personnel all present challenges in study design, 53 delivery and recruitment. Delays in the initial start-up of CTs in pediatrics due to pediatric-specific 54 55 protocol issues and complicated ethical approval continue to discourage both academic and 56 pharmaceutical interest. The limited data presented here suggests that the dismal state of ongoing 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 14 of 17

1 2 3 pediatric antibiotic trials is still continuing. Earlier collaboration between academic research 4 networks and pharmaceutical companies is now vital to accelerate progress. 5 6 7 8 9 ACKNOWLEDGEMENTS 10 11 Contributors MS, CB, GT, LF and JB designed the study, GT and CB conducted the search, IL and 12 JB commented on study design and assisted with drafting the paper. 13 14 Funding This research received no specific grant from any funding agency in the public, 15 commercial or not-for-profitFor sectors.peer review only 16 17 Conflict of interest None declared. 18 Data sharing statement Dataset is available on request. 19 20 21 22 23 REFERENCES 24 1. Corny J, Lebel D, Bailey B et al. Unlicensed and Off-Label Drug Use in Children Before and 25 26 After Pediatric Governmental Initiatives. J Pediatr Pharmacol Ther. 2015;20(4):316–28. 27 2. European Medicines Agency. Concept paper on extrapolation of efficacy and safety in 28 29 medicine development. 30 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/04/WC5 31 32 00142358.pdf. (accessed May 2016) http://bmjopen.bmj.com/ 33 3. Kearns GL, Abdel-Rahman SM, Alander SW et al. Developmental pharmacology--drug 34 35 disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157– 36 37 67. 38 4. Dunne J, Rodriguez WJ, Murphy MD et al. Extrapolation of Adult Data and Other Data in 39

40 Pediatric Drug-Development Programs. Pediatrics. 2011; on September 28, 2021 by guest. Protected copyright. 41 http://pediatrics.aappublications.org/content/early/2011/10/20/peds.2010-3487.abstract 42 43 (accessed June 2016) 44 5. The World Health Organisation. WHO Promoting Safety of Medicines for Children. 2007; 45 46 http://www.who.int/medicines/publications/essentialmedicines/Promotion_safe_med_childre 47 ns.pdf (accessed October 2016) 48 49 6. van der Meer JW, Gyssens IC. Quality of antimicrobial drug prescription in hospital. Clin 50 Microbiol Infect. 2001;7:12–5. 51 52 7. Theuretzbacher U, Van Bambeke F, Cantón R et al. Reviving old antibiotics. Internet J 53 Antimicrob Chemother. 2015; 54 55 http://jac.oxfordjournals.org/content/early/2015/06/10/jac.dkv157.abstract (accessed June 56 2016) 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 15 of 17 BMJ Open

1 2 3 8. European Medicines Agency. EMA Opinions and decisions on Paediatric Investigation 4 Plans. 2016; 5 6 http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/pip_search.jsp&mid 7 8 =WC0b01ac058001d129. (accessed June 2016) 9 9. Guidance for industry. Pediatric Study Plans: Content of and Process for Submitting Initial 10 11 Pediatric Study Plans and Amended Initial Pediatric Study Plans. 12 http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/u 13 14 cm360507.pdf. (accessed June 2016) 15 10. GarazzinoFor S, Lutsar I,peer Bertaina C et al.review New antibiotics for paediatriconly use: a review of a 16 17 decade of regulatory trials submitted to the European Medicines Agency from 2000--why 18 aren’t we doing better? Int J Antimicrob Agents. 2013;42(2):99–118. 19 20 11. The World Bank. The World Bank list of economies. 2015; 21 http://siteresources.worldbank.org/DATASTATISTICS/Resources/CLASS.XLS (accessed 22 23 October 2016) 24 12. The World Health Organisation. WHO ATC/DDD Index. 2016; 25 26 http://www.whocc.no/atc_ddd_index/. (accessed March 2016) 27 13. The Pew Charitable Trusts. Antibiotics Currently in Clinical Development. 2016; 28 29 http://www.pewtrusts.org/~/media/assets/2016/05/antibiotics-currently-in-clinical- 30 development.pdf?la=en. (accessed May 2016) 31 32 14. Lutsar I. Often neglegted: paediatric drug development - a regulatory and clinical view. In http://bmjopen.bmj.com/ 33 Amsterdam, Netherlands; 2016. (S219 - Symposium lecture.). 34 35 15. Ceci A, Felisi M, Baiardi P et al. Medicines for children licensed by the European Medicines 36 37 Agency (EMEA): the balance after 10 years. Eur J Clin Pharmacol. 2006;62(11):947–52. 38 16. Ruperto N, Eichler I, Herold R. A European Network of Paediatric Research at the European 39

40 Medicines Agency (Enpr-EMA). Arch Dis Child. 2012;97:185–88. on September 28, 2021 by guest. Protected copyright. 41 17. Stockmann C, Sherwin CMT, Ampofo K et al. Characteristics of antimicrobial studies 42 43 registered in the USA through ClinicalTrials.Gov. Int J Antimicrob Agents. 2013;42(2):161–6. 44 18. Versporten A, Bielicki J, Drapier N et al. The Worldwide Antibiotic Resistance and 45 46 Prescribing in European Children (ARPEC) point prevalence survey: developing hospital- 47 quality indicators of antibiotic prescribing for children. J Antimicrob Chemother. 48 49 2016;71(4):1106–17. 50 19. Bielicki JA, Lundin R, Sharland M. Antibiotic Resistance Prevalence in Routine Bloodstream 51 52 Isolates from Children’s Hospitals Varies Substantially from Adult Surveillance Data in 53 Europe. Pediatr Infect Dis J. 2015;34(7):734–41. 54 55 20. Califf RM, Zarin DA, Kramer JM et al. Characteristics of clinical trials registered in 56 ClinicalTrials.gov, 2007-2010. JAMA. 2012;307(17):1838–47. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 16 of 17

1 2 3 21. Viergever RF, Rademaker CMA, Ghersi D. Pharmacokinetic research in children: an 4 analysis of registered records of clinical trials. BMJ Open. 2011;1(1):e000221. 5 6 22. Roberts JK, Stockmann C, Constance JE et al. Pharmacokinetics and pharmacodynamics of 7 8 antibacterials, antifungals, and antivirals used most frequently in neonates and infants. Clin 9 Pharmacokinet. 2014;53(7):581–610. 10 11 23. Folgori L, Bielicki J, Ruiz B, et al. Harmonisation in study design and outcomes in paediatric 12 antibiotic clinical trials: a systematic review. Lancet Infect Dis. 2016;16(9):e178-89. 13 14 24. European Medicines Agency. Concept paper on an addendum to the guideline on the 15 evaluationFor of medicinal peer products indicated review for treatment of bacterialonly infections to address 16 17 paediatric-specific clinical data requirements. 18 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/04/WC5 19 20 00205026.pdf. (accessed July 2016) 21 25. Clinical Trials Transformation Initiative. https://www.ctti-clinicaltrials.org/projects/pediatric- 22 23 trials. (accessed July 2016) 24 26. Clinical Trials Transformation Initiative. AACT database. https://www.ctti- 25 26 clinicaltrials.org/aact-database. (accessed January 2017) 27 28 29 30 31 32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 28, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 17 of 17 BMJ Open

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 Figure 1. Flow chart. Clinical trial selection process.

29 195x118mm (150 x 150 DPI) 30 31 32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 28, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open

A global shortage of neonatal and pediatric antibiotic trials: a narrative review.

ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2017-016293.R1

Article Type: Research

Date Submitted by the Author: 09-Jun-2017

Complete List of Authors: Thompson, Georgina; St George's University of London, Infection and Immunity; University of Exeter Medical School Barker, Charlotte; St George's University of London, Infection and Immunity; University College London Institute of Child Health Folgori, Laura; St George's University of London, Paediatric Infectious Diseases Research Group Bielicki, Julia; St George's University London, Division of Clinical Sciences; University of Basel Children's Hospital Bradley, John; University of California San Diego School of Medicine, Department of Pediatrics Lutsar, Irja; University of Tartu, Department of Medical Microbiology sharland, mike; St George's University of London, Infection and Immunity; St Georges Hospital, Paedaitric Infectious Diseases Unit http://bmjopen.bmj.com/

Primary Subject Paediatrics Heading:

Secondary Subject Heading: Infectious diseases

Paediatric infectious disease & immunisation < PAEDIATRICS, INFECTIOUS Keywords: DISEASES, PAEDIATRICS on September 28, 2021 by guest. Protected copyright.

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 1 of 40 BMJ Open

1 2 3 A global shortage of neonatal and pediatric antibiotic trials: a narrative 4 5 review. 6 1,2 1,3,4 1 1,5 6,7 8 1, 4 7 G. Thompson , C. Barker , L. Folgori , J. Bielicki , J. Bradley , I. Lutsar , M. Sharland 8

9 1 10 Paediatric Infectious Diseases Research Group, Institute for Infection and Immunity, St George's University 11 of London, London, UK 12 2 University of Exeter, Exeter, UK 13 3 14 Inflammation, Infection and Rheumatology Section, UCL Great Ormond Street Institute of Child Health, 30 15 Guilford Street, London,For UK peer review only 16 4 St George’s University Hospitals NHS Foundation Trust, Blackshaw Road, London, UK 17 18 5 Paediatric Pharmacology and Pharmacometrics, University of Basel Children’s Hospital, Basel, Switzerland 19 6 Department of Pediatrics, School of Medicine, University of California San Diego, CA, United States 20 7 21 Rady Children’s Hospital San Diego, San Diego, CA, United States 22 8 Department of Medical Microbiology, University of Tartu, Tartu, Estonia 23

24 25 26 Corresponding author 27 28 Georgina Thompson 29 Paediatric Infectious Diseases Research Group 30 31 St George's, University of London 32 Jenner Wing, Level 2, Room 2.216F, Mail Point J2C http://bmjopen.bmj.com/ 33 London SW17 0RE 34 35 Telephone: 07880325494 36 Email: [email protected] 37 38 39

40 on September 28, 2021 by guest. Protected copyright. Word count: 2764 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 2 of 40

1 2 3 ABSTRACT 4 Objectives: There have been few clinical trials (CTs) on antibiotics which inform neonatal and 5 6 pediatric drug labelling. Consequently, the rate of unlicensed and off-label prescribing in pediatrics 7 remains high. This remains a major concern, particularly in neonates. It is unclear whether the 8 9 current pediatric antibiotic research pipeline is adequate to inform optimal drug dosing. Using 10 11 ClinicalTrials.gov registry, this review aims to establish the current global status of antibiotic CTs in 12 children up to 18 years of age. 13 14 Results: Only 76 registered open CTs of antibiotics in children were identified globally; 23 (30%) 15 were recruiting newbornsFor (only peer 8 (11%) included review preterm neonates), only 52 (68%) infants and toddlers, 16 17 58 (76%) children, and 54 (71%) adolescents. The majority of registered trials were late phase (10 18 (15%) Phase 3 and 23 (35%) Phase 4/pharmacovigilance). Two-thirds were sponsored by non-profit 19 20 organisations, with few sponsored by pharmaceutical companies (50 (66%) vs. 26 (34%) 21 respectively). A greater proportion of non-profit funded trials were efficacy-based strategic trials (n= 22 23 34, 68%), in comparison to industry-led trials, which were most often focused on safety or 24 pharmacokinetic data (n=17, 65%). Our search revealed that 2 of the 37 antibiotics listed on the 25 26 May 2016 Pew Charitable Trusts antibiotic development pipeline, currently being studied in adults, 27 appear to be recruiting in open pediatric CTs. 28 29 Conclusions: This review highlights that there are currently very few pediatric antibiotic CTs being 30 conducted globally (especially in neonates). There is striking disparity noted between antibiotic drug 31 32 development programmes involving adults and children. http://bmjopen.bmj.com/ 33

34 35 Strengths and limitations of this study 36 37 • A narrative literature review of registered clinical trials in children. 38 • Explicit reproducible methodology. 39

40 • Search strategy limited to ClinicalTrials.gov and EudraCT. Entirety of clinical research in this on September 28, 2021 by guest. Protected copyright. 41 field might not have been captured. 42 43 • Search strategy also limited to open clinical trials. Active but not yet recruiting trials were not 44 captured. 45 46 47 48 INTRODUCTION 49 50 With the persistence of widespread unlicensed and off-label prescribing in pediatrics – as high as 51 11.4% and 46.5% respectively – the paucity of clinical research involving children that which is 52 53 conducted to inform optimal drug dosing, licensing and labelling remains a problem.[1] For certain 54 medicines, drug efficacy can be extrapolated from adult data provided that the pathology and drug 55 56 exposure are the same, or sufficiently similar in children as in adults.[2,3] Advances in modelling 57 and simulation mean smaller focussed studies can now be performed to help obtain regulatory 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 3 of 40 BMJ Open

1 2 3 approval for most medicines, including antimicrobials.[4] Although differences in drug 4 pharmacokinetics (PK) in neonates and children can lead to adverse reactions that are not seen in 5 6 adult populations, these are very rare and extrapolation of safety data into the pediatric population 7 can further reduce the need for complex study designs.[5] Suboptimal antibiotic dosing, including 8 9 under- and over-dosing, can lead to toxicity, treatment failure, and may drive antimicrobial 10 11 resistance by encouraging selection pressures on drug-resistant strains of bacteria.[6] 12 13 14 Since antibiotics are the most commonly prescribed medicines in children, it is important to improve 15 our currently limitedFor understanding peer of their PKreview profiles to help determine only optimal drug dosing and 16 17 ultimately to improve patient outcomes.[7] In the last decade several initiatives have been 18 established to encourage pediatric medicines research, thus bridge the gap between adult and 19 20 pediatric drug development plans. Such initiatives include the Pediatric Regulation (Pediatric 21 Investigation Plans (PIPs), introduced by the European Medicines Agency (EMA),[8] and Pediatric 22 23 Study Plans (PSPs), by the U.S. Food and Drug Administration (FDA).[9] Despite this, there remain 24 limited advances in the development of antibiotics for this population.[10] 25 26 27 The global status of clinical research on antibiotics in pediatrics is currently unknown. Using 28 29 registered records of clinical trials (CTs) on ClinicalTrials.gov, this review aims (i) to summarise the 30 current global status of registered antibiotic research in children and neonates, and (ii) to stimulate 31 32 discussion and collaboration among the relevant stakeholders on the neglect of antibiotic research http://bmjopen.bmj.com/ 33 in pediatrics. 34 35 36 37 METHODS 38 Data sources 39 th 40 The ClinicalTrials.gov registry (last accessed 8 November 2016) is an international platform for the on September 28, 2021 by guest. Protected copyright. 41 registration of CTs. It is a web-based registry, developed in 2000 by the National Institute of Health 42 43 (NIH) and the FDA, to which trials from 50 states and 163 countries around the world are registered. 44 All information provided for each trial is updated periodically by the trial’s sponsoring organisation. 45 46 The database has a specific child filter, which uses a key word paradigm to select all registered 47 trials recruiting patients/participants up to 18 years of age. 48 49 50 We were not able to capture all studies being planned in neonates, infants, and children by 51 52 pharmaceutical companies in compliance with legislation that mandates studies of any drugs under 53 investigation in adults that may have clinical utility in children. Discussions between companies and 54 55 regulatory agencies are confidential, limiting our ability to fully understand the impact of the PIPs 56 and PSP’s noted above on antimicrobial compounds under development. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 4 of 40

1 2 3 Study selection 4 Our records were identified using suitable key word searches, in which the final search terms were 5 6 (antimicrobial* OR antibiotic* OR antiinfective agent*) AND Child AND Open Studies. All identified 7 trials were filtered manually using inclusion and exclusion criteria. Interventional and observational 8 9 trials on antimicrobials recruiting children up to 18 years of age were considered eligible for 10 11 inclusion. No specific temporal filter was applied since only open or ongoing clinical trials were of 12 interest. The following records, which were not investigating one or more antibiotics, were excluded: 13 14 trials of antiseptics, antifungals, antiprotozoals, antivirals, and pro- or pre- biotics. The following 15 records, which wereFor investigating peer an antibiotic review were excluded: trials only involving tuberculosis, malaria, 16 17 cystic fibrosis, HIV, febrile neutropenic patients, topical or inhalational treatments, prophylactic 18 antibiotics, or records investigating alternative use for antibiotics (for example as an anti- 19 20 inflammatory agent). 21 22 23 The searches were conducted by GT. All eligible records were identified via manual filtering by GT 24 CB, LF and MS, and any disagreements regarding inclusion and exclusion of records were resolved 25 26 through discussion. 27 28 29 Data extraction 30 The following information was collected from the included records: unique NCT number, recruitment 31 32 status, study design, trial phase, study sponsor, age group and sex eligibility, clinical indication, http://bmjopen.bmj.com/ 33 geographic region of recruitment, antibiotic being investigated, and endpoint classification. 34 35 Outcomes were categorised as safety, efficacy or PK. Economic setting (based on geographic 36 37 region of recruitment) was classified using The World Bank classification, where Low Income 38 Countries (LICs) are defined as those with $1,025 or less gross national income per capita, Lower 39

40 Middle Income Countries (LMICs) $1,026 – 4,035, Upper Middle Income Countries (UMICs) $4,036 on September 28, 2021 by guest. Protected copyright. 41 – 12,475, and High Income Countries (HICs) $12,476 or more.[11] 42 43 44 The specific class of antibiotic studied in each trial was identified and classified using the World 45 46 Health Organisation (WHO) ATC/DDD index.[12] To investigate whether novel antibiotics are being 47 studied in pediatric and neonatal populations (as well as in adults), the antibiotics currently studied 48 49 in children were compared with the Pew Charitable Trusts Antibiotics Currently in Clinical 50 Development pipeline, which identifies novel antibiotics currently under development for the U.S. 51 52 market.[13] 53 54 55 RESULTS 56 Our search identified 1056 records. 603 records were excluded on title because they were studies 57 58 not involving an antimicrobial. 453 records were investigating one or more antimicrobials and 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 5 of 40 BMJ Open

1 2 3 recruiting children below 18 years of age. Among the 195 trials investigating antibiotics, 76 fulfilled 4 our inclusion and exclusion criteria and were included in the final analysis. Reasons for exclusion 5 6 are summarised in Figure 1. Details of included studies can be found in Supplementary file 1. 7

8 th 9 All 76 CTs identified were open as of 8 November 2016, and 63 (83%) of these were recognised 10 as recruiting participants on this date (Table 1). All trials stated recruitment of both male and female 11 12 participants. 13 14 15 Table 1. CharacteristicsFor of clinicalpeer trials. review only 16 Number of Characteristic Category 17 studies, n (%) 18 Age group Preterm neonates 1 (1)a 19 Neonates (total) 23 (30) 20 Infants and toddlers 52 (68) 21 Children 58 (76) 22 23 Adolescents 54 (71) 24 Recruitment status Recruiting 63 (83) 25 Not yet recruiting 13 (17) 26 Study design Interventional 66 (87) 27 Observational 10 (13) 28 Trial phaseb Phase 1 10 (15) 29 Phase 1-2 1 (2) 30 Phase 2 9 (14) 31 Phase 2-3 3 (5) http://bmjopen.bmj.com/ 32 Phase 3 10 (15) 33 Phase 4 23 (39) 34 Not specified 10 (15) 35 Sponsor Industry 26 (34) 36 Non-profit 50 (66) 37 Geographic region Africa 8 (11) 38 39 Asia 16 (21)

40 Europe 22 (29) on September 28, 2021 by guest. Protected copyright. 41 Latin America 6 (8) 42 North America 34 (45) 43 Oceania 5 (7) 44 Antibiotic class J01A Tetracycline 4 (5) 45 J01C Beta-lactam, Penicillin 25 (33) 46 J01D Other Beta-lactam 22 (29) 47 J01E Sulfonamides and trimethoprim 7 (9) 48 J01F Macrolide, Lincosamide, Streptogramin 14 (18) 49 J01G Aminoglycoside 2 (3) 50 J01M Quinolone 8 (11) 51 J01X Other antibiotic classesc 21 (28) 52 J01 Not specified 2 (3) 53

54 Totals for Age group, Geographic region, and Antibiotic class do not add up to total number of clinical trials 55 (76) as some trials contributed to more than one sub group. 56 a 7 further trials mentioned inclusion of preterm babies in the inclusion criteria. 57 b Trial phase % based on percentage of interventional trials. 58 c J01X includes glycopeptides, polymixins, imidazole derivatives, and nitrofuran 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 6 of 40

1 2 3 4 Age group 5 6 Twenty three of the 76 trials (30%) were recruiting newborns (0 to 28 days). One of these 23 trials 7 focused solely on recruiting preterm newborns (a further 7 CTs mentioned inclusion of preterm 8 9 newborns in inclusion criteria). Of the remaining records, 52 (68%) were recruiting infants and 10 toddlers (28 days to 23 months), 58 (76%) children (2 to 11 years), and 54 (71%) adolescents (11 11 12 up to 18 years). 29 (38%) trials did not focus solely on the recruitment of children or neonates, with 13 age ranges also spanning across adult populations. 14 15 For peer review only 16 Study type 17 18 Interventional trials were most frequently identified (n=66, 87%) with only 10 (13%) observational 19 trials noted. Of the interventional trials, the majority were in the later stages of development; 10 20 21 (13%) in Phase 1, 1 (2%) between Phase 1 and 2, 9 (14%) in Phase 2, 3 (5%) between Phase 2 22 and 3, 10 (15%) in Phase 3 and 23 (35%) in Phase 4. In 10 (15%) cases, a trial phase had not been 23 24 specified. 25

26 27 Sponsor and Endpoint Classification 28 29 Fifty (66%) trials were sponsored by non-profit organisations (being university, hospital or 30 government funded), and 26 sponsored by industry (34%). The endpoint classification of the 31 32 majority of trials (n=43, 57%) was reported as efficacy (Table 2). A greater proportion (n=34, 68%) http://bmjopen.bmj.com/ 33 of non-profit studies measured the efficacy of the drugs as the primary endpoint, with less emphasis 34 35 on collection of PK or safety data (n=16, 32%). In comparison pharmaceutical-led trials focussed on 36 early PK and safety studies over the drug’s efficacy (n=17, 65% vs. n=9, 35% respectively). 37 38 39 Table 2. Clinical trial endpoint classification of identified clinical trials stratified by trial sponsor. 40 Endpoint classification determined by planned primary outcomes. on September 28, 2021 by guest. Protected copyright. 41 42 Endpoint classification Industry Non-profit Total (%) 43 44 45 Efficacy 9 34 43 (57) 46 Safety 10 2 12 (16) 47 48 PK 7 14 21 (28) 49 50 51 52 Geographic region 53 54 The most frequently recruiting geographic region was North America (n=34, 45%). 22 (29%) trials 55 recruiting in Europe and 16 (21%) in Asia were identified, 6 (8%) in Latin America, 8 (11%) in Africa, 56 57 and 5 (7%) in Oceania. Most trials were recruiting in HICs (n=54, 71%), with fewer trials recruiting in 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 7 of 40 BMJ Open

1 2 3 LICs (n=4, 5%), LMICs (n=4, 5%), UMICs (n=11, 14%) or a combination of UMICs and HICs (n=3, 4 4%). 5 6 7 Indication 8 9 The most common treatment indications investigated were Lower Respiratory Tract Infection (n=12, 10 11 16%) and Sepsis (n=11, 14%), followed by Upper Respiratory Tract Infection (n=8, 11%), Intra- 12 abdominal Infection (IAI) (n=8, 11%), Urinary Tract Infection (UTI) (n=7, 9%), complicated Skin and 13 14 Soft Tissue Infection (cSSTI) (n=6, 8%), CNS infection (n=3, 4%), and Bone and Joint infection 15 (n=1, 1%) (TableFor 3). peer review only 16 17 18 Antibiotic class 19 The majority of antibiotics (n=47, 62%) being investigated were beta-lactams, followed by other 20 21 antibiotic classes (J01X, including vancomycin, telavancin and dalbavancin) (n=21, 28%). 22 Macrolides or lincosamides (J01F) were the next most commonly studied antibiotic classes (n=14, 23 24 18%). Very few of the records reported investigations of tetracyclines (J01A) (n=4, 5%), 25 Sulphonamides and trimethoprim (J01E) (n=7, 9%), aminoglycosides (J01G) (n=2, 3%), or 26 27 quinolones (J01M) (n=8, 11%). 2 CTs (3%) did not specify the class of antibiotic being investigated. 28 29 16 (21%) trials were investigating more than one antibiotic; these trials counted towards more than 30 one J01 category. The breakdown of J01 categories, as per WHO ATC/DDD classification,[12] is 31 32 described in Table 1. http://bmjopen.bmj.com/ 33 34 Antibiotic pipeline 35 36 Of the 37 antibiotics listed on the most recent May 2016 edition of the Pew Charitable Trusts 37 Antibiotic Pipeline (last accessed 10th June 2016),[13] as noted by the EMA Opinions and Decisions 38 39 on Pediatric Investigation Plans, 5 had an agreed PIP: Imipenem/Cilastatin+Relebactam, Cadazolid, 40 Carbavance (Meropenem+Vaborbactam), Eravacycline, and Solithromycin.[8] As of 8th November on September 28, 2021 by guest. Protected copyright. 41 42 2016, our search found that only 2 of the 37 antibiotics listed on the Pew antibiotic pipeline 43 (Carbavance and Solithromycin) was being investigated in 1 and 2 on-going CTs in pediatric 44 45 patients, respectively (Table 4). A PIP was agreed for Carbavance in 2015 for treatment of Gram- 46 negative infections, and for Solithromycin in 2016 for the treatment of gonococcal infection, and 47 48 later for treatment of anthrax, tularaemia, and bacterial pneumonia. PIPs were agreed in 2015 for 49 50 treatment of urinary tract infection and complicated intra-abdominal infection with Eravacycline, and 51 in 2016 for treatment of Clostridium difficile infection with Cadazolid and of Gram-negative bacterial 52 53 infection with Imipenem/Cilastin+Relebactam.[14] Despite this, we could not identify any registered 54 trials of these antibiotics in our search. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 8 of 40

1 1 8 8 6 6 7 7 7 7 4 5 5 14 11 11 63 63 - - open open clinical clinical trials in trials children children Number of Number - -

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3 (4) 3 (1) 1 6 (8) (8) 6 7 (9) (9) 7 8 (11) (11) 8 8 (11) (11) 8 11 (14) (14) 11 18 (24) 18 (16) 12 Total (%) (%) Total

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Phase Phase Manufacturer Phase 1 1 Phase Pharma Ltd. MGB For peer review only 1 Phase Ltd. Wockhardt infection Bacterial Sepsis CNS infection CNS Comparison of antibiotic development pipeline in adults and children. Adapted from Pew Charitable Trusts “Antibiotics currently in currently “Antibiotics Trusts Charitable Pew from Adapted children. adultsand in pipeline development antibiotic of Comparison Antibiotic Antibiotic Urinary Tract Infection Tract Urinary Clinical indication of identified clinical trials stratified by age group being recruited. recruited. being group age by stratified trials clinical identified of indication Clinical Indication Indication Upper Respiratory Tract Respiratory Upper Bone and Joint Infection Joint and Bone Intra-abdominal Infection Intra-abdominal refers to total number of andpreterm neonates.term Skin and Soft Tissue Infection Tissue Soft and Skin

MGB – BP – 3 – BP 3 – MGB WCK 4873 4873 WCK a 4. Table Table 3. Table

clinical development” pipeline (last accessed October 2016).[13] October (last accessed pipeline development” clinical

Age Age dogroup nottotals add up to total number of clinical trials (76) trialsas some contributed to more than group.age one Unspecified Bacterial Infection Bacterial Unspecified Lower Respiratory Tract Infection Tract Respiratory Lower 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from ------

✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ infection infection difficile http://bmjopen.bmj.com/ BMJ Open (systemic) (systemic) VAP, bacteraemia bacteraemia VAP, CAP CAP Bacterial infection infection Bacterial Clostridium Clostridium Multidrug resistant gram gram resistant Multidrug negatives Bacterial infection infection Bacterial cIAI cIAI Acute skin infection infection skin Acute Acute skin infection, HAP, HAP, infection, skin Acute on September 28, 2021 by guest. Protected copyright. MicuRx MicuRx Inc. Pharmaceuticals Tetraphase Tetraphase Inc. Pharmaceuticals Theravance Theravance Inc. Biopharma Legochem Legochem Inc. Biosciences Basilea Basilea Pharmaceuticals Meiji Seika Pharma Pharma Seika Meiji Co. Fedora Pharmaceuticals Astrazeneca PLC PLC Astrazeneca PLC Allergan For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Phase 1 1 Phase Phase 2 2 Phase Phase 1 1 Phase Phase 1 1 Phase Ltd. Wockhardt infection Bacterial Phase 1 1 Phase Phase 1 1 Phase Ltd. Wockhardt infection Bacterial Phase 1 1 Phase Phase 1 1 Phase For 1 Phase Inc. Crestone peer review only MRX – 1 – MRX 1 TP – 271 271 – TP Zidebactam+Cefepime Zidebactam+Cefepime 1 Phase Ltd. Wockhardt VAP HAP, cUTI, WCK 771 771 WCK WCK 2349 2349 WCK TD – 1607 – 1607 TD LCB01 – 0371 0371 – LCB01 CRS3123 CRS3123 BAL30072 BAL30072 OP0595 OP0595 Aztreonam – Avibactam Avibactam – Aztreonam 2 Phase Page 9 of 40 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 10 of 40 ------

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spp difficile infection infection http://bmjopen.bmj.com/ BMJ Open osteomyelitis osteomyelitis (systemic) (systemic) associated osteomyelitis osteomyelitis associated Staphylococcus Staphylococcus Clostridium Clostridium Prevent recurrent Clostridium Clostridium recurrent Prevent difficile CAP, acute skin infection, infection, skin acute CAP, foot diabetic cUTI, cIAI, acute skin skin acute cIAI, cUTI, pyelonephritis infection, Bacterial infection infection Bacterial Pseudomonas spp. spp. Pseudomonas lower VAP, associated tract infection, respiratory bronchiectasis Uncomplicated gonorrhoea gonorrhoea Uncomplicated cUTI, CAP, uncomplicated uncomplicated CAP, cUTI, gonorrhoea urogenital Acute skin infection, infection, skin Acute Acute skin infection infection skin Acute Acute skin infection, infection, skin Acute

on September 28, 2021 by guest. Protected copyright. Summet Summet Inc. Therapeutics Nanotherapeutics Nanotherapeutics Inc. TaiGen TaiGen Co. Biotechnology Ltd. MerLion MerLion Pte Pharmaceuticals Ltd. Crystal Genomics Genomics Crystal Inc. Cellceutix Cellceutix Corporation Entasis Therapeutics Therapeutics Entasis Inc. Debiopharm Debiopharm SA International AstraZeneca PLC PLC AstraZeneca PLC Allergan For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Phase 2 2 Phase Phase 2 2 Phase Ltd. Polyphor Phase 2 2 Phase PLC GlaxoSmithKline Phase 2 2 Phase Phase 2 2 Phase Phase 2 2 Phase Phase 2 2 Phase Phase 2 2 Phase Phase 2 2 Phase For peer review only 2 Phase Ridinilazole Ridinilazole Ramoplanin Ramoplanin Nemonoxacin Nemonoxacin Geptidacin Geptidacin Finafloxacin Finafloxacin CG400549 CG400549 Ceftaroline+Avibactam Ceftaroline+Avibactam 2 Phase Brilacidin Brilacidin P0L7080 P0L7080 ETX0914 ETX0914 Debio 1450 1450 Debio 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from ------1 1

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http://bmjopen.bmj.com/ BMJ Open cUTI prosthetic joint infection joint infection prosthetic Clostridium Clostridium cUTI, HAP, VAP, cIAI, cIAI, VAP, HAP, cUTI, catheter-associated infection bloodstream cIAI and cUTI cUTI and cIAI cUTI, cIAI, HAP, VAP, acute acute VAP, HAP, cIAI, cUTI, pyelonephritis CAP, cUTI, acute skin skin acute cUTI, CAP, infection HAP, VAP, cUTI, cUTI, VAP, HAP, infection bloodstream CAP CAP CAP, HAP, VAP, acute skin skin acute VAP, HAP, CAP, osteomyelitis, infection, joint infections prosthetic cUTI, cIAI, HAP, VAP, febrile febrile VAP, HAP, cIAI, cUTI, bacteraemia, neutropenia, pyelonephritis acute Acute skin infections, CAP, CAP, infections, skin Acute Acute skin infection, infection, skin Acute on September 28, 2021 by guest. Protected copyright. Pharmaceuticals Ltd. Ltd. Pharmaceuticals Tetraphase Pharma Pharma Tetraphase Inc. Melinta Therapeutics Therapeutics Melinta Inc. Nabriva Therapeutics Therapeutics Nabriva Paratek Paratek Inc. Pharmaceuticals Dong Wha Dong Co. Pharmaceuticals Ltd. Rempex Rempex Inc. Pharmaceuticals Actelion Actelion AC AC For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Phase 3 3 Phase Inc. & Co. Merck Phase 3 3 Phase Phase 3 3 Phase PLC Bio Motif infection skin acute HAP, Phase 3 3 Phase Inc. Shionogi Phase 3 3 Phase Phase 3 3 Phase Phase 3 3 Phase Phase 3 3 Phase Phase 3 3 Phase Inc. Achaogen Phase 3 3 Phase

For peer review only Plazomicin Plazomicin Eravacycline Eravacycline Delafloxacin (Baxdela) (Baxdela) Delafloxacin 3 Phase Carbavance Carbavance (Meropenem+Vaborbactam) Taksta (fusidic acid) acid) (fusidic Taksta 3 Phase Inc. Cempra Cadazolid Cadazolid Iclaprim Iclaprim Imipenem / / Imipenem Cilastatin+Relebactam Lefamulin Lefamulin Omadacycline Omadacycline S – 649266 649266 S – Zabofloxacin Zabofloxacin Page 11 of 40 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 12 of 40 2 2

✓

✓ http://bmjopen.bmj.com/ BMJ Open CAP, uncomplicated uncomplicated CAP, gonorrhea, urogenital urethritis on September 28, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Phase 3 3 Phase Inc. Cempra For peer review only target carbapenem enterobacteriacaeresistant hospital-acquiredHAP, pneumonia; VAP,ventilator-acquired pneumonia;cUTI, complicated Urinary Tract Infection; CAP, Community-acquired pneumonia; cIAI, complicated Intra-abdominalInfection. a Solithromycin Solithromycin 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 13 of 40 BMJ Open

1 2 3 DISCUSSION 4 Our search on ClinicalTrials.gov identified 76 clinical trials investigating one or more antibiotics 5 6 recruiting children between 0 and 18 years of age. This is low in comparison to the number of on- 7 going trials in adults, with children representing around a quarter of the global population.[15,16] A 8 9 review of completed CTs in the U.S. between 2000 and 2010 identified a total of 4078 adult trials 10 11 compared to just 294 that had recruited children.[17] In our study, the lack of trials recruiting 12 neonates is striking. Just 23 of the 76 trials identified were recruiting neonates, and remarkably just 13 14 8 CTs globally were recruiting preterm neonates. There are broadly two types of pediatric trials 15 being conductedFor globally. Either peer pharmaceutical-led review Phase 1/2 PK only and safety trials (n=17) being 16 17 conducted in the HIC setting, or investigator led, often pragmatic, late phase efficacy trials in the 18 LMIC setting (n=34), with a greater proportion of the on-going trials sponsored by non-profit 19 20 organisations than industry (66% compared to 34%). The rarity of bacterial infections in children, 21 and the ethical and practical barriers to running paediatric trials likely act as deterrents to 22 23 pharmaceutical interest, resulting in academic investigators focusing on the larger efficacy trials. As 24 of April 2016, there were 17 antibiotic PIPs agreed by the EMA,[8] covering a range of indications, 25 26 most commonly cSSTI, complicated IAI (cIAI), and complicated UTI (cUTI).[14] In contrast, 27 treatments for respiratory and systemic infections, the most common indications in pediatrics, are 28 29 not currently being evaluated.[18] Although the introduction of PIPs on the whole has encouraged 30 the study of medicines in children, the range of infectious indications covered therefore does not 31 32 match the burden of disease in this age group. Thirty-seven antibiotics are currently being http://bmjopen.bmj.com/ 33 developed in adults, yet to our knowledge just 2 of these are being studied in children. However, 34 35 some classes of antibiotics that may be of higher risk for children (tetracyclines and 36 37 fluoroquinolones) may not be pursued as aggressively for pediatric approvals by either industry or 38 regulatory agencies due to well-recognized issues of toxicity, particularly relevant in situations for 39

40 which safer alternative therapy is widely available. The substantial lag time between the submission on September 28, 2021 by guest. Protected copyright. 41 date (for PIP or waiver) and declared date of completion of PK studies in adults is a real concern, 42 43 particularly for new antibiotics against resistant Gram-negative pathogens, although there is some 44 value in generating substantial safety data in adults prior to exposing children and newborn infants 45 46 to potentially toxic new agents. However, Gram-negative sepsis is a growing problem in neonates, 47 with a significant increase in the proportion of multi-resistant Gram-negative pathogens.[19] 48 49 50 In 2013, a similar review of European pediatric clinical trials identified 31 trials of antibiotics 51 52 approved for adults by the EMA in 2000 that were recruiting children in Europe (compared to the 22 53 trials we found to be now recruiting in this region). They included both published and ongoing trials, 54 55 which likely accounts for the higher number of trials reported. They similarly found a very small 56 proportion of neonatal trials (just 2 of 31), as well as a greater proportion of efficacy-based trials.[10] 57 58 In 2012, a review of interventional trials registered with ClinicalTrials.gov between 2007 and 2010 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 14 of 40

1 2 3 found that only 17% had recruited children below 18 years of age.[20] A similar review of 4 antimicrobial CTs conducted in the U.S. between 2000 and 2012 reported that just 5% had recruited 5 6 only children compared to the 74% that had recruited only adults, and that, as we have found, the 7 trials were sponsored primarily by non-profit organisations (60% compared to 30% by industry).[17] 8 9 In our search of global trials, 39% of registered CTs reported collection of PK data in comparison to 10 11 a similar review in 2009 of PK research on medicines for children that reported 24% of registered 12 CTs would be collecting PK data.[21] Collection of PK data is particularly important in neonates 13 14 where developmental differences in physiology lead to significant changes in drug PK, which puts 15 them at increasedFor risk of adverse peer drug reactions.[3,22] review Furthermore, only off-label and unlicensed 16 17 prescribing is at its greatest in neonatal populations (61% and 22% respectively)[14]. A recent 18 review noted a striking lack of harmonisation in study design and outcomes among completed and 19 20 on-going neonatal and pediatric antibiotic CTs which may make translation of trial data into clinical 21 guidance more difficult.[23] 22 23 24 The search strategy used has some limitations. Since the search was limited to clinical trials 25 26 registered to ClinicalTrials.gov, it is possible that a number of open or on-going trials registered with 27 alternative platforms (for example, the WHO International Clinical Trials Registry Platform [ICTRP]) 28 29 will have been missed. Together with ClinicalTrials.gov these could help to establish the entirety of 30 current clinical research in this field. We did however search EudraCT, and found no further studies 31 32 to those captured on ClinicalTrials.gov. Our search was also limited to open CTs, which means that http://bmjopen.bmj.com/ 33 active but not yet recruiting trials were not captured, as well as those that had closed to recruitment 34 35 previously. The information recorded for each trial registered with ClinicalTrials.gov is updated by 36 37 the trial investigators, and therefore relies on them to periodically update the registry. On occasion, 38 information such as recruitment status might not be updated in real time. 39

40 on September 28, 2021 by guest. Protected copyright. 41 Concerns around the growing threat of antimicrobial resistance have prompted a number of new 42 43 initiatives. In 2016, the EMA published the first draft of the Concept Paper to propose the 44 development of an Addendum to the guideline on the evaluation of new anti-bacterial products for 45 46 treatment of bacterial infections in children.[24] At the same time, the Clinical Trials Transformation 47 Initiative (CTTI) is currently focused on the identification of key barriers in the conduct of pediatric 48 49 antibacterial CTs, which hamper their successful implementation into clinical practice.[25] Recent 50 evidence states that overall, antibiotic CTs make up less than 1% of all registered pediatric CTs, 51 52 and that trial completion is slow, with an average time to completion of around two years.[26] There 53 are a number of specific areas where there is potential for harmonisation and simplification in the 54 55 design and conduct of paediatric antibiotic CTs. Standardisation of the inclusion and exclusion 56 criteria for specific Clinical Infection Syndromes, and an improved bridging of safety and efficacy 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 15 of 40 BMJ Open

1 2 3 data from other age groups, would allow improved comparison between studies, and potentially 4 more simplified design of CTs, both of which will improve their conduct and efficiency in children. 5 6 7

8 9 CONCLUSIONS 10 11 A number of issues contribute to the difficulties in conducting pediatric antibiotic clinical trials. The 12 lack of regulatory guidance, vulnerability of this population, issues with informed consent and 13 14 assent, and lack of research-experienced hospital personnel all present challenges in study design, 15 delivery and recruitment.For Delays peer in the initial review start-up of CTs in pediatrics only due to pediatric-specific 16 17 protocol issues and complicated ethical approval continue to discourage both academic and 18 pharmaceutical interest. The limited data presented here suggests that the dismal state of ongoing 19 20 pediatric antibiotic trials is still continuing. Earlier collaboration between academic research 21 networks and pharmaceutical companies is now vital to accelerate progress. 22 23 24 25 26 ACKNOWLEDGEMENTS 27 Contributors MS, CB, GT, LF and JB designed the study, GT conducted the search, IL and JB 28 29 commented on study design and assisted with drafting the paper. 30 Funding This research received no specific grant from any funding agency in the public, 31 32 commercial or not-for-profit sectors. http://bmjopen.bmj.com/ 33 Conflict of interest None declared. 34 35 Data sharing statement Full dataset is available on request. 36 37 38 39

40 REFERENCES on September 28, 2021 by guest. Protected copyright. 41 1. Corny J, Lebel D, Bailey B et al. Unlicensed and Off-Label Drug Use in Children Before and 42 43 After Pediatric Governmental Initiatives. J Pediatr Pharmacol Ther. 2015;20(4):316–28. 44 2. European Medicines Agency. Concept paper on extrapolation of efficacy and safety in 45 46 medicine development. 47 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/04/WC5 48 49 00142358.pdf. (accessed May 2016) 50 3. Kearns GL, Abdel-Rahman SM, Alander SW et al. Developmental pharmacology--drug 51 52 disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157– 53 67. 54 55 4. Dunne J, Rodriguez WJ, Murphy MD et al. Extrapolation of Adult Data and Other Data in 56 Pediatric Drug-Development Programs. Pediatrics. 2011; 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 16 of 40

1 2 3 http://pediatrics.aappublications.org/content/early/2011/10/20/peds.2010-3487.abstract 4 (accessed June 2016) 5 6 5. The World Health Organisation. WHO Promoting Safety of Medicines for Children. 2007; 7 http://www.who.int/medicines/publications/essentialmedicines/Promotion_safe_med_childre 8 9 ns.pdf (accessed October 2016) 10 11 6. Theuretzbacher U, Van Bambeke F, Cantón R et al. Reviving old antibiotics. Internet J 12 Antimicrob Chemother. 2015; 13 14 http://jac.oxfordjournals.org/content/early/2015/06/10/jac.dkv157.abstract (accessed June 15 2016) For peer review only 16 17 7. van der Meer JW, Gyssens IC. Quality of antimicrobial drug prescription in hospital. Clin 18 Microbiol Infect. 2001;7:12–5. 19 20 8. European Medicines Agency. EMA Opinions and decisions on Paediatric Investigation 21 Plans. 2016; 22 23 http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/pip_search.jsp&mid 24 =WC0b01ac058001d129. (accessed June 2016) 25 26 9. Guidance for industry. Pediatric Study Plans: Content of and Process for Submitting Initial 27 Pediatric Study Plans and Amended Initial Pediatric Study Plans. 28 29 http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/u 30 cm360507.pdf. (accessed June 2016) 31 32 10. Garazzino S, Lutsar I, Bertaina C et al. New antibiotics for paediatric use: a review of a http://bmjopen.bmj.com/ 33 decade of regulatory trials submitted to the European Medicines Agency from 2000--why 34 35 aren’t we doing better? Int J Antimicrob Agents. 2013;42(2):99–118. 36 37 11. The World Bank. The World Bank list of economies. 2015; 38 http://siteresources.worldbank.org/DATASTATISTICS/Resources/CLASS.XLS (accessed 39

40 October 2016) on September 28, 2021 by guest. Protected copyright. 41 12. The World Health Organisation. WHO ATC/DDD Index. 2016; 42 43 http://www.whocc.no/atc_ddd_index/. (accessed March 2016) 44 13. The Pew Charitable Trusts. Antibiotics Currently in Clinical Development. 2016; 45 46 http://www.pewtrusts.org/~/media/assets/2016/05/antibiotics-currently-in-clinical- 47 development.pdf?la=en. (accessed May 2016) 48 49 14. Lutsar I. Often neglegted: paediatric drug development - a regulatory and clinical view. In 50 Amsterdam, Netherlands; 2016. (S219 - Symposium lecture.). 51 52 15. Ceci A, Felisi M, Baiardi P et al. Medicines for children licensed by the European Medicines 53 Agency (EMEA): the balance after 10 years. Eur J Clin Pharmacol. 2006;62(11):947–52. 54 55 16. Ruperto N, Eichler I, Herold R. A European Network of Paediatric Research at the European 56 Medicines Agency (Enpr-EMA). Arch Dis Child. 2012;97:185–88. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 17 of 40 BMJ Open

1 2 3 17. Stockmann C, Sherwin CMT, Ampofo K et al. Characteristics of antimicrobial studies 4 registered in the USA through ClinicalTrials.Gov. Int J Antimicrob Agents. 2013;42(2):161–6. 5 6 18. Versporten A, Bielicki J, Drapier N et al. The Worldwide Antibiotic Resistance and 7 Prescribing in European Children (ARPEC) point prevalence survey: developing hospital- 8 9 quality indicators of antibiotic prescribing for children. J Antimicrob Chemother. 10 11 2016;71(4):1106–17. 12 19. Bielicki JA, Lundin R, Sharland M. Antibiotic Resistance Prevalence in Routine Bloodstream 13 14 Isolates from Children’s Hospitals Varies Substantially from Adult Surveillance Data in 15 Europe. ForPediatr Infect peer Dis J. 2015;34(7):734–41. review only 16 17 20. Califf RM, Zarin DA, Kramer JM et al. Characteristics of clinical trials registered in 18 ClinicalTrials.gov, 2007-2010. JAMA. 2012;307(17):1838–47. 19 20 21. Viergever RF, Rademaker CMA, Ghersi D. Pharmacokinetic research in children: an 21 analysis of registered records of clinical trials. BMJ Open. 2011;1(1):e000221. 22 23 22. Roberts JK, Stockmann C, Constance JE et al. Pharmacokinetics and pharmacodynamics of 24 antibacterials, antifungals, and antivirals used most frequently in neonates and infants. Clin 25 26 Pharmacokinet. 2014;53(7):581–610. 27 23. Folgori L, Bielicki J, Ruiz B, et al. Harmonisation in study design and outcomes in paediatric 28 29 antibiotic clinical trials: a systematic review. Lancet Infect Dis. 2016;16(9):e178-89. 30 24. European Medicines Agency. Concept paper on an addendum to the guideline on the 31 32 evaluation of medicinal products indicated for treatment of bacterial infections to address http://bmjopen.bmj.com/ 33 paediatric-specific clinical data requirements. 34 35 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/04/WC5 36 37 00205026.pdf. (accessed July 2016) 38 25. Clinical Trials Transformation Initiative. https://www.ctti-clinicaltrials.org/projects/pediatric- 39

40 trials. (accessed July 2016) on September 28, 2021 by guest. Protected copyright. 41 26. Clinical Trials Transformation Initiative. AACT database. https://www.ctti- 42 43 clinicaltrials.org/aact-database. (accessed January 2017) 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 18 of 40

1 2 3 LIST OF FIGURES 4

5 6 Figure 1. Flow chart. Clinical trial selection process. 7

8 9 Table 1. Characteristics of clinical trials. 10 11 12 Table 2. Clinical trial endpoint classification of identified clinical trials stratified by trial sponsor. 13 Endpoint classification determined by planned primary outcomes. 14 15 Table 3. ClinicalFor indication ofpeer identified clinical review trials stratified by ageonly group being recruited. 16 17 18 Table 4. Comparison of antibiotic development pipeline in adults and children. Adapted from Pew 19 Charitable Trusts “Antibiotics currently in clinical development” pipeline (last accessed October 20 2016).[13] 21 22 23 24 25 26 27 28 29 30 31 32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 28, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 19 of 40 BMJ Open

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 http://bmjopen.bmj.com/ 32 Figure 1. Flow Chart. Clinical trial selection process. 33 34 254x190mm (300 x 300 DPI) 35 36 37 38 39

40 on September 28, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

BMJ Open Page 20 of 40 DATASET 1 2 A B C D 3 1 NCT Number Title Recruitment Study Results 4 2 NCT02539407 Population Pharmacokinetics of Anti-infectives in Critically Ill Children Recruiting No Results Available 5 6 3 NCT02935374 Effect of Antimicrobial Treatment of Acute Otitis Media on the Intestinal Microbiome in ChildrenNot yet recruiting No Results Available 7 4 NCT02899143 Short-course Antimicrobial Therapy in Sepsis Recruiting No Results Available 8 5 NCT01595529 The SCOUT Study: Short Course Therapy for Urinary Tract Infections in Children Recruiting No Results Available 9 10 6 NCT02380352 Short-course Antimicrobial Therapy for Paediatric Respiratory Infections Not yet recruiting No Results Available 11 7 NCT02891915 Trial to Evaluate Beta-Lactam Antimicrobial Therapy of Community Acquired Pneumonia in ChildrenFor peer review onlyRecruiting No Results Available 12 8 NCT02746276 Optimising Antibiotic Treatment for Sick Malnourished Children Recruiting No Results Available 13 9 NCT02917551 BALANCE on the Wards: A Pilot RCT Not yet recruiting No Results Available 14 15 10 NCT01243437 A Clinical Trial to Evaluate the Safety and Efficacy of Ciprofloxacin in the Treatment of Plague in Humanshttp://bmjopen.bmj.com/ Recruiting No Results Available 16 11 NCT02635191 Tailored Therapy for Helicobacter Pylori in Children Recruiting No Results Available 17 12 NCT01522105 Daptomycin in Pediatric Patients With Bacterial Meningitis Recruiting No Results Available 18 19 13 NCT02456974 Antibiotic Dosing in Pediatric Intensive Care Recruiting No Results Available 20 14 NCT00579956 A Randomized Double Blinded Comparison of Ceftazidime and Meropenem in Severe MelioidosisRecruiting No Results Available 21 15 NCT00545961 Middle Meatal Bacteriology During Acute Respiratory Infection in Children Not yet recruiting No Results Available 22 16 NCT01431326 Pharmacokinetics of Understudied Drugs Administered to Children Per Standard of Care Recruiting No Results Available 23 on September 28, 2021 by guest. Protected copyright. 24 17 NCT02475876 PK of Clindamycin and Trimethoprim-sulfamethoxazole in Infants and Children Recruiting No Results Available 25 18 NCT01420341 Co-trimoxazole as Maintenance Therapy for Meliodosis Recruiting No Results Available 26 19 NCT02266706 Pharmacokinetic and Safety Study of Ceftolozane/Tazobactam in Pediatric Participants Receiving Antibiotic Therapy for Proven or Suspected Gram-negative Infection or for Peri-operative Prophylaxis (MK-7625A-010)Recruiting No Results Available 27 28 20 NCT00867789 Antibiotics Versus Placebo in the Treatment of Abscesses in the Emergency Department Recruiting No Results Available 29 21 NCT02879981 A Safety Study of Balsamic Bactrim in Pediatric Participants With Acute Bronchitis Not yet recruiting No Results Available 30 22 NCT01269541 MESS-study MRSA Eradication Study SkÌ´ne Recruiting No Results Available 31 23 NCT02276482 Study of Tedizolid Phosphate in Adolescents With Complicated Skin and Soft Tissue Infection (cSSTI) (MK-1986-012)Recruiting No Results Available 32 33 24 NCT02663596 Safety and TDM of Continuous Infusion Vancomycin Through Continuous Renal Replacement Therapy SolutionNot yet recruiting No Results Available 34 25 NCT02555059 Special Drug Use Investigation of Ciproxan Injection in Pediatrics Recruiting No Results Available 35 26 NCT02297815 Comparative Effectiveness of Antibiotics for Respiratory Infections Recruiting No Results Available 36 37 27 NCT02224040 Typhoid Fever: Combined vs. Single Antibiotic Therapy Recruiting No Results Available 38 28 NCT02775968 Population Pharmacokinetics of Cephalosporins and Macrolides in Chinese Children With Community Acquired PneumoniaNot yet recruiting No Results Available 39 29 NCT02687906 Dose-finding, Pharmacokinetics, Safety, and Tolerability of Meropenem-Vaborbactam in Pediatric Subjects With Serious Bacterial InfectionsRecruiting No Results Available 40 30 NCT02783859 Hospitalised Pneumonia With Extended Treatment (HOPE) Study Recruiting No Results Available 41 42 31 NCT01994993 Antibiotic Safety (SCAMP) Recruiting No Results Available 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 A B C D 3 32 NCT02258763 Trial on the Ideal Duration of Oral Antibiotics in Children With Pneumonia Recruiting No Results Available 4 33 NCT02688790 Study Evaluate the PK Profile of Dalbavancin in Hospitalized Infants and Neonates Patients With Known or Suspected Bacterial InfectionRecruiting No Results Available 5 6 34 NCT00323219 Oral Moxifloxacin Versus Cefazolin and Oral Probenecid in the Management of Skin and Soft Tissue Infections in the Emergency DepartmentRecruiting No Results Available 7 35 NCT02750761 A Study of Oral and Intravenous (IV) Tedizolid Phosphate in Hospitalized Participants, Ages 2 to <12 Years, With Confirmed or Suspected Bacterial Infection (MK-1986-013)Recruiting No Results Available 8 36 NCT02466438 Safety and Pharmacokinetics of Piperacillin-tazobactam Extended Infusion in Infants and Children (PIP-TAZO)Recruiting No Results Available 9 10 37 NCT02260102 Temocillin Pharmacokinetics in Paediatrics Not yet recruiting No Results Available 11 38 NCT02694458 Comparison of Two Dosage Adjustment Strategies of Vancomycin in ChildrenFor peer review onlyRecruiting No Results Available 12 39 NCT01540838 Slow Initial beta-lactam Infusion With High-dose Paracetamol to Improve the Outcomes of Childhood Bacterial MeningitisRecruiting No Results Available 13 40 NCT00368498 A Trial to Evaluate the Loading Dose Required to Achieve Therapeutic Serum Teicoplanin Concentration TimelyRecruiting No Results Available 14 15 41 NCT01785641 Single Versus Combined Antibiotic Therapy for Bacterial Peritonitis in CAPD Patients http://bmjopen.bmj.com/ Recruiting No Results Available 16 42 NCT02554383 Efficacy of Antibiotics in Children With Acute Sinusitis: Which Subgroups Benefit? Recruiting No Results Available 17 43 NCT01265173 Comparison of Efficacy of Cefotaxime, Ceftriaxone, and Ciprofloxacin for the Treatment of Spontaneous Bacterial Peritonitis in Patients With Liver CirrhosisRecruiting No Results Available 18 19 44 NCT02335905 Ceftaroline for Treatment of Hematogenously Acquired Staphylococcus Aureus Osteomyelitis in ChildrenRecruiting No Results Available 20 45 NCT02922686 Penicillin for the Emergency Department Outpatient Treatment of CELLulitis Not yet recruiting No Results Available 21 46 NCT02848820 Initial Non-operative Treatment Strategy Versus Appendectomy Treatment Strategy for Simple Appendicitis in ChildrenNot yet recruiting No Results Available 22 47 NCT02475733 Evaluation of Safety,Pharmacokinetics and Efficacy of CAZ-AVI With Metronidazole in Childern Aged 3 Months to 18 Years Old With Complicated Intra-abdominal Infections (cIAIs).Recruiting No Results Available 23 on September 28, 2021 by guest. Protected copyright. 24 48 NCT02372461 Randomized Trial of Amoxicillin Versus Placebo for (Fast Breathing) Pneumonia Recruiting No Results Available 25 49 NCT01553006 Study of Cefditoren Pivoxil in Treatment of Childhood With Acute Rhinosinusitis Recruiting No Results Available 26 50 NCT02527681 Pharmacokinetics and Safety of Ceftobiprole in Neonates and Infants up to 3 Months Treated With Systemic AntibioticsRecruiting No Results Available 27 28 51 NCT02210169 RCT of Continuous Versus Intermittent Infusion of Vancomycin in Neonates Recruiting No Results Available 29 52 NCT02497781 Evaluation of Safety, Pharmacokinetics and Efficacy of Ceftazidime and Avibactam (CAZ-AVI ) Compared With Cefepime in Children From 3 Months to Less Than 18 Years of Age With Complicated Urinary Tract Infections (cUTIs)Recruiting No Results Available 30 53 NCT02814916 Dalbavancin for the Treatment of Acute Bacterial Skin and Skin Structure Infections in Children, Known or Suspected to be Caused by Susceptible Gram-positive Organisms, Including MRSANot yet recruiting No Results Available 31 54 NCT02210325 Efficacy and Safety Study of Oral Solithromycin Compared to Intramuscular Ceftriaxone Plus Oral Azithromycin in the Treatment of Patients With GonorrheaRecruiting No Results Available 32 33 55 NCT02801370 Phase 3 Study of OTO-201 in Acute Otitis Externa Recruiting No Results Available 34 56 NCT02760420 3 Days Amoxicillin Versus Placebo for Fast Breathing Childhood Pneumonia in Malawi Recruiting No Results Available 35 57 NCT02678195 3 Days Versus 5 Days Amoxicillin for Chest-indrawing Childhood Pneumonia in Malawi Recruiting No Results Available 36 37 58 NCT02605122 Safety and Efficacy of Solithromycin in Adolescents and Children With Community-acquired Bacterial PneumoniaRecruiting No Results Available 38 59 NCT02570490 Oral Sodium Fusidate (CEM-102) Versus Oral Linezolid for the Treatment of Acute Bacterial Skin and Skin Structure InfectionsRecruiting No Results Available 39 60 NCT02443285 Is Spontaneous Bacterial Peritonitis Still Responding to 3rd Generation Cephalosporins? Recruiting No Results Available 40 61 NCT02334124 Comparing the Intravenous Treatment of Skin Infections in Children, Home Versus Hospital Recruiting No Results Available 41 42 62 NCT02218372 A Study to Investigate the Safety and Efficacy of Fidaxomicin (Oral Suspension or Tablets) and Vancomycin (Oral Liquid or Capsules) in Pediatric Subjects With Clostridium Difficile-associated Diarrhea (CDAD)Recruiting No Results Available 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 A B C D 3 63 NCT01032499 Open and Comparative Study to Measure Tolerability and Efficacy of Taro Elixir Not yet recruiting No Results Available 4 64 NCT02598362 Pharmacokinetics of Ciprofloxacin in Pediatric Patients Recruiting No Results Available 5 6 65 NCT02878031 Community Case Management of Chest Indrawing Pneumonia Recruiting No Results Available 7 66 NCT02790996 Neonatal Vancomycin Trial Not yet recruiting No Results Available 8 67 NCT02712307 Study of 5 and 10 Days Treatment With Penicillin Against Sore Throat Caused by Streptococci Recruiting No Results Available 9 10 68 NCT02424734 Safety, Tolerability and Efficacy of Ceftaroline in Paediatrics With Late-Onset Sepsis Recruiting No Results Available 11 69 NCT02134301 Open-Label, Dose-Finding, Pharmacokinetics, Safety and Tolerability Study of Oritavancin in Pediatric Patients With Suspected or Confirmed Bacterial InfectionsFor peer review onlyRecruiting No Results Available 12 70 NCT02013141 An Open-Label Study of the Pharmacokinetics of a Single Dose of Telavancin in Pediatric Subjects Aged 1 to 17 YearsRecruiting No Results Available 13 71 NCT01427842 Dose Enhancement of Vancomycin IN Everyday Patients Recruiting No Results Available 14 15 72 NCT01278017 The Role of Short-course Ceftriaxone Therapy in the Treatment of Severe Nontyphoidal Salmonella Enterocolitishttp://bmjopen.bmj.com/ Recruiting No Results Available 16 73 NCT00988026 Safety and Efficacy Comparison of Minocycline Microgranules Versus Lymecycline in the Treatment of Mild to Moderate AcneRecruiting No Results Available 17 74 NCT02288234 Telavancin Observational Use Registry (TOUR) Recruiting No Results Available 18 19 75 NCT01304459 Vancomycin Serum Concentrations in Pediatric Oncology Patients Under Intensive Care Recruiting No Results Available 20 76 NCT01173575 Assessment of the Efficacy of FOSFOMYCIN in Patients With Bacterial Infection Recruiting No Results Available 21 77 NCT01778634 Trial of Intravenous Azithromycin to Eradicate Ureaplasma Respiratory Tract Infection in Preterm Infants (AZIPIII)Recruiting No Results Available 22

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1 2 E F 3 1 Indication Infection category 4 2 Proven or suspected infection (in patients on PICU) 9 5 6 3 Acute Otitis Media 3 7 4 Sepsis 8 8 5 Urinary Tract Infections (UTI) 7 9 10 6 Community-acquired Pneumonia (CAP) 4 11 7 Pneumonia For peer review4 only 12 8 Proven or suspected infection in patients with malnutrition 9 13 9 Bacteremia 8 14 15 10 Plague 8 http://bmjopen.bmj.com/ 16 11 Helicobacter Pylori Infection 7 17 12 Meningitis 1 18 19 13 Proven or suspected bacterial infection (Pharmacokinetics) 9 20 14 Melioidosis 8 21 15 Acute Respiratory Infection|Sinusitis 3 22 16 Various infections (including nosocomial Pneumonia, CAP, Acute Bacterial Exacerbation of Chronic Bronchitis, cSSSI, Uncomplicated SSSI, cUTI, Acute Pyelonephritis, uUTI, Bacterial Septicemia, Plague, Acute Bacterial Sinusitis, Bacterial Meningitis)Various 23 on September 28, 2021 by guest. Protected copyright. 24 17 Bacterial Infections 9 25 18 Meliodosis 8 26 19 Proven or Suspected Gram-negative Bacterial Infection 9 27 28 20 Abscess 1 29 21 Bronchitis 4 30 22 Throatcarriers of MRSA 3 31 23 Acute Skin and Soft Tissue infections (aSSTIs) 2 32 33 24 Proven or suspected bacterial infection (in CRRT patients) 9 34 25 Cystitis / Pyelonephritis 7 35 26 Acute Upper Respiratory Tract Infections (ARTIs) 3 36 37 27 Typhoid Fever 8 38 28 Community Acquired Pneumonia (CAP) 4 39 29 Bacterial Infections 9 40 30 Pneumonia 4 41 42 31 Complicated Intra Abdominal Infections (cIAIs) 6 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 E F 3 32 Pneumonia 4 4 33 Bacterial Infections 9 5 6 34 Cellulitis 2 7 35 Gram-Positive Bacterial Infections 9 8 36 Infection 9 9 10 37 Urinary Tract Infection or suspected Cholangitis 7 11 38 Methicillin-resistant Staphylococcal InfectionsFor peer review9 only 12 39 Bacterial Meningitis 1 13 40 Staphylococcal Infections 9 14 15 41 Peritonitis (in CAPD patients) 6 http://bmjopen.bmj.com/ 16 42 Acute Sinusitis (Respiratory Tract Infections) 3 17 43 SBP in patients with Liver Cirrhosis 6 18 19 44 Hematogenously Acquired Staphylococcus Aureus Osteomyelitis 5 20 45 Cellulitis or Wound Infection 8 21 46 Appendicitis 6 22 47 Complicated Intra-abdominal Infections (cIAIs) 6 23 on September 28, 2021 by guest. Protected copyright. 24 48 Pneumonia (fast-breathing) 4 25 49 Rhinosinusitis 3 26 50 Bacterial Infections 9 27 28 51 Sepsis 8 29 52 Complicated Urinary Tract Infections (cUTIs) 7 30 53 Methicillin-Resistant Staphylococcus Aureus Skin Infection 2 31 54 Uncomplicated Urogenital Gonorrhea 7 32 33 55 Acute Otitis Externa 3 34 56 Pneumonia 4 35 57 Pneumonia 4 36 37 58 Community-acquired Bacterial Pneumonia 4 38 59 Acute Bacterial Skin and Skin Structure Infections 2 39 60 Primary Bacterial Peritonitis 6 40 61 Cellulitis 8 41 42 62 Clostridium Difficile-associated Diarrhea (CDAD) 6 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 E F 3 63 Acne Vulgaris II or III Degree 2 4 64 Urinary Tract Infection or Pyelonephritis 7 5 6 65 Pneumonia 4 7 66 Late Onset Neonatal Sepsis 8 8 67 Tonsillitis 3 9 10 68 Late-onset Sepsis 8 11 69 Gram Positive Bacterial InfectionsFor peer review9 only 12 70 Gram-Positive Bacterial Infections 9 13 71 Vancomycin Therapy 9 14 15 72 Diarrhea 6 http://bmjopen.bmj.com/ 16 73 Mild to Moderate Acne 2 17 74 Hospital Acquired Bacterial Pneumonia (HAP), Complicated Skin and Skin Structure Infections (cSSSI), Ventilator Associated Bacterial Pneumonia (VAP), Gram Positive InfectionVarious 18 19 75 Infection 9 20 76 Bacterial Infection 9 21 77 Eradicate ureaplasma respiratory tract infection from preterm infants4 22

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1 2 G H I J 3 1 Interventions Antibiotic class (J01 code) Gender Age 4 2 Antiinfectives (beta-lactam, aminoglycoside, glycopeptide, fluoroquinolone, daptomycin, rifampin, trimethoprim, sulfamethoxazole, clarithromycin)Various Both Up to 18 Years 5 6 3 Amoxicillin, Amoxicillin-Potassium Clavulanate, Macrolide Various Both 6 Months to 7 Years 7 4 Antibiotic J01 Both Up to 18 years 8 5 Trimethoprim sulfamethoxazole, cefixime, or cephalexin Various Both 2 Months to 10 Years 9 10 6 Amoxicillin J01C Both 6 Months to 10 Years 11 7 Amoxicillin, Amoxicillin-clavulanate, CefdinirFor peer reviewVarious onlyBoth 6 Months to 71 Months 12 8 Ceftriaxone, Metronidazole J01D Both 2 Months to 59 Months 13 9 7 days vs 14 days of adequate antibiotic treatment J01 Both Up to 18 years 14 15 10 Ciprofloxacin, doxyxcycline Various Bothhttp://bmjopen.bmj.com/ 8 Years and older 16 11 Tailored vs standard therapy (Amoxicillin, Clarithromycin, Metronidazole, Rabeprazole, Esomeprazole, Omeprazole)Various Both 4 Years to 18 Years 17 12 Daptomycin J01X Both 3 Months to 16 Years 18 19 13 Amoxicillin-clavulanate, Piperacilline-tazobactam, Vancomycin Various Both Up to 16 Years 20 14 Meropenem, Ceftazidime J01D Both 15 Years and older 21 15 Amoxicillin clavulanate acid J01C Both 6 Years to 13 Years 22 16 Various drugs (Ceftazidime, Ciprofloxacin, Clindamycin, Doxycycline, Levofloxacin, Meropenem)Various Both Up to 18 years 23 on September 28, 2021 by guest. Protected copyright. 24 17 Clindamycin, Trimethoprim-sulfamethoxazole Various Both 1 Month to 16 Years 25 18 Co-trimoxazole J01E Both 15 Years and older 26 19 Ceftolozane/Tazobactam J01D Both Up to 17 Years 27 28 20 Trimethoprim-sulfamethoxazole J01E Both 3 Months to 17 Years 29 21 Guaifenesin, Sulfamethoxazole trimethoprim J01E Both 4 Years to 14 Years 30 22 Systemic Rifampin and Clindamycine/Trimehoprimsulfa, or Topical mupirocinVarious Both 5 Years and older 31 23 Tedizolid Phophate J01X Both 12 Years to 18 Years 32 33 24 Vancomycin J01X Both Up to 18 years 34 25 Ciprofloxacin J01F Both Up to 14 Years 35 26 Antibiotics (Amoxicillin-clavulanate, azithromycin, cefdinir, cefprozil, cefuroxime axetil, ceftriaxone, cefadroxil)Various Both 6 Months to 18 Years 36 37 27 Ceftriaxone, Ceftriaxone/azithromycin, Azithromycin, Azithromycin/cefiximeVarious Both 2 Years to 80 Years 38 28 Cephalosporins and Macrolides Various Both 1 Year to 18 Years 39 29 Carbavance J01D Both Up to 17 Years 40 30 Amoxicillin-clavulanic Acid J01C Both 3 Months to 5 Years 41 42 31 Ampicillin/metronidazole/gentamicin/clindamycin/Piperacillin-tazobactam combinationsVarious Both Up to 120 Days 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 G H I J 3 32 Amoxicillin-Potassium Clavulanate J01C Both 3 Months to 59 Months 4 33 Dalbavancin J01X Both Up to 28 Days 5 6 34 Cefazolin/Moxifloxacin Various Both Up to 18 Years 7 35 Tedizolid Phosphate J01X Both 2 Years to 11 Years 8 36 Piperacillin-tazobactam J01C Both 2 Months to 6 Years 9 10 37 Temocillin J01C Both 6 Months to 3 Years 11 38 Vancomycin For peer reviewJ01X onlyBoth 1 Month to 16 Years 12 39 Beta-lactam J01C Both 2 Months to 15 Years 13 40 Teicoplanin J01X Both 16 Years and older 14 15 41 Ceftazidime/ciprofloxacin, Ceftazidime, Cefazolin/gentamicin, Cefazolin Various Bothhttp://bmjopen.bmj.com/ 15 Years and older 16 42 Amoxicillin-clavulanate J01C Both 2 Years to 11 Years 17 43 Cefotaxime, Ceftriaxone, Ciprofloxacin Various Both 16 Years and older 18 19 44 Ceftaroline Fosamil J01D Both 1 Year to 17 Years 20 45 Flucloxacillin, Phenoxymethylpenicillin J01C Both 16 Years and older 21 46 Augmentin/Gentamicin, Appendectomy J01C Both 7 Years to 17 Years 22 47 Ceftazidime-avibactam, Meropenem, Metronidazole Various Both 3 Months to 18 Years 23 on September 28, 2021 by guest. Protected copyright. 24 48 Amoxicillin J01C Both 2 Months to 59 Months 25 49 Cefditoren pivoxil J01D Both 1 Year to 15 Years 26 50 Ceftobiprole J01D Both Up to 3 Months 27 28 51 Vancomycin J01X Both Up to 90 Days 29 52 Ceftazidime-avibactam, Cefepime J01D Both 3 Months to 18 Years 30 53 Dalbavancin single dose J01X Both 3 Months to 17 Years 31 54 Solithromycin, Ceftriaxone, Azithromycin Various Both 15 Years and older 32 33 55 Ciprofloxacin J01M Both 6 Months and older 34 56 Amoxicillin J01C Both 2 Months to 59 Months 35 57 Amoxicillin J01C Both 2 Months to 59 Months 36 37 58 Solithromycin J01F Both 2 Months to 17 Years 38 59 Sodium fusidate, Linezolid J01X Both 12 Years and older 39 60 Cefotaxime, Ceftriaxone J01D Both Up to 18 Years 40 61 Ceftriaxone, Flucloxacillin Various Both 6 Months to 18 Years 41 42 62 Fidaxomicin, Vancomycin J01X Both Up to 17 Years 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 G H I J 3 63 Taro Elixir J01A Both 14 Years and older 4 64 Ciprofloxacin J01M Both 3 Months to 17 Years 5 6 65 Amoxicillin J01C Both 2 Months to 59 Months 7 66 Vancomycin J01X Both Up to 90 Days 8 67 Phenoxymethylpenicillin J01C Both 6 Years and older 9 10 68 Ceftaroline Fosamil J01D Both Up to 59 Days 11 69 Oritavancin For peer reviewJ01X onlyBoth Up to 18 Years 12 70 Telavancin J01X Both 1 Year to 17 Years 13 71 Vancomycin J01X Both 16 Years and older 14 15 72 Ceftriaxone J01D Bothhttp://bmjopen.bmj.com/ 3 Months to 18 Years 16 73 Minocycline, Lymecycline J01A Both 14 Years to 30 Years 17 74 Telavancin J01X Both Up to 18 Years 18 19 75 Vancomycin J01X Both Up to 18 Years 20 76 Fosfomycin J01X Both Up to 18 Years 21 77 Azithromycin J01F Both 0 to 72 hours 22

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1 2 K L M N O 3 1 Age group Estimated enrollment Location Income class Geographic region 4 2 8 1850 France High income Europe 5 6 3 9 150 Finland High income Europe 7 4 8 320 Italy High income Europe 8 5 9 746 United States High income North America 9 10 6 9 270 Canada High income North America 11 7 9 For400 United States peer reviewHigh income onlyNorth America 12 8 9 80 Kenya Lower middle income Africa 13 9 8 50 Canada High income North America 14 15 10 11 200 Uganda Low income Africa http://bmjopen.bmj.com/ 16 11 11 200 China Upper middle income Asia 17 12 10 5 Switzerland High income Europe 18 19 13 8 200 Belgium High income Europe 20 14 5 750 Thailand Upper middle income Asia 21 15 11 120 Finland High income Europe 22 16 8 3000 Various (United States, Canada, Israel, Singapore, United Kingdom)High income International 23 on September 28, 2021 by guest. Protected copyright. 24 17 10 54 United States High income North America 25 18 5 800 Thailand Upper middle income Asia 26 19 8 36 United States High income North America 27 28 20 10 200 United States High income North America 29 21 11 50 Peru Upper middle income Latin America 30 22 11 69 Sweden High income North America 31 23 5 162 Various (United States, Argentina, Bulgaria, Chile, Czech Republic, Georgia, Germany, Latvia, Lithuania, Panama, Poland, Slovenia, South Africa, Spain)Upper middle to High income International 32 33 24 8 10 United States High income North America 34 25 8 45 Japan High income Asia 35 26 10 117000 United States High income North America 36 37 27 11 120 Nepal Low income Asia 38 28 10 750 China Upper middle income Asia 39 29 8 56 United States High income North America 40 30 9 314 Various (Australia, Malaysia) High income Oceania 41 42 31 6 284 Various (United States, Canada)High income North America 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 K L M N O 3 32 9 300 Malaysia Upper middle income Asia 4 33 2 24 United States High income North America 5 6 34 8 390 Canada High income North America 7 35 4 32 United States High income North America 8 36 9 141 Canada High income North America 9 10 37 9 45 Belgium High income Europe 11 38 10 For100 France peer reviewHigh income onlyEurope 12 39 10 400 Angola Upper middle income Africa 13 40 5 20 Taiwan, China High income Asia 14 15 41 5 300 Thailand Upper middle income Asia http://bmjopen.bmj.com/ 16 42 4 688 United States High income North America 17 43 5 261 Republic of Korea High income Asia 18 19 44 10 18 United States High income North America 20 45 5 414 Ireland High income Europe 21 46 11 334 Netherlands High income Europe 22 47 10 102 Various (United States, Argentina, Chile, Czech Republic, Greece, Hungary, Poland, Romania, Russian Federation, Spain, Taiwan, Turkey) Upper middle to High income International 23 on September 28, 2021 by guest. Protected copyright. 24 48 9 2500 Pakistan Lower middle income Asia 25 49 10 120 Thailand Upper middle income Asia 26 50 6 45 Various (Belgium, Germany, Lithuania)High income Europe 27 28 51 6 200 Australia High income Oceania 29 52 10 102 Various (United States, Czech Republic, Greece, Hungary, Republic of Korea, Poland, Romania, Russian Federation, Taiwan, Turkey)Upper middle to High income International 30 53 10 300 United States High income North America 31 54 5 300 Various (United States, Australia)High income International 32 33 55 10 500 Various (United States, Canada)High income North America 34 56 9 2000 Malawi Low income Africa 35 57 9 2000 Malawi Low income Africa 36 37 58 10 400 Various (United States, Bulgaria, Hungary, Spain)High income International 38 59 5 712 Various (United States, Puerto Rico)High income International 39 60 8 100 Egypt Lower middle income Africa 40 61 10 188 Australia High income Oceania 41 42 62 8 144 Various (United States, Belgium, Canada, France, Germany, Hungary, Italy, Poland, Romania, Slovakia, Spain)High income International 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 K L M N O 3 63 5 120 Brazil Upper middle income Latin America 4 64 10 20 Belgium High income Europe 5 6 65 9 308 Nigeria Lower middle income Africa 7 66 6 300 Various (United Kingdom, France, Italy, Greece, Estonia)High income Europe 8 67 11 432 Sweden High income Europe 9 10 68 7 24 Various (United States, Hungary, Italy, Lithuania, Spain)High income International 11 69 8 For60 United States peer reviewHigh income onlyNorth America 12 70 10 32 United States High income North America 13 71 5 100 Australia High income Oceania 14 15 72 10 200 Taiwan, China High income Asia http://bmjopen.bmj.com/ 16 73 5 168 Mexico High income North America 17 74 8 1000 United States High income North America 18 19 75 8 50 Brazil Upper middle income Latin America 20 76 8 200 Various (Austria, Germany) High income Europe 21 77 1 180 United States High income North America 22

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1 2 P Q R S T 3 1 Collaborators Sponsor Study Types Phase Endpoint classification 4 2 Assistance Publique - Hopitaux de Paris Hospital Observational Not applicable Pharmacokinetics 5 6 3 University of Oulu|Oulu University Hospital University Interventional Phase 4 Efficacy 7 4 Ospedale Santa Maria delle Croci Hospital Interventional Phase 2 Safety/Efficacy 8 5 Children's Hospital of Philadelphia|Children's Hospital of Pittsburgh|University of Pennsylvania|Westat|National Institute of Allergy and Infectious Diseases (NIAID)Hospital Interventional Phase 2 Safety/Efficacy 9 10 6 Hamilton Health Sciences Corporation|Children's Hospital of Eastern OntarioHospital Interventional Phase 4 Safety/Efficacy 11 7 National Institute of Allergy and Infectious Diseases (NIAID)For peerNIH Interventional reviewPhase 4 onlyEfficacy 12 8 University of Oxford|KEMRI Wellcome Trust Research Program, Kenya|Centre for Research in Therapeutic Sciences, Strathmore University, Nairobi Kenya|University College, London|Centre for Microbiology Research, Kenya Medical Research Institute|Centre for Clinical Research, Kenya Medical Research InstituteUniversity Interventional Phase 2 Pharmacokinetics 13 9 Sunnybrook Health Sciences Centre Hospital Interventional Not specified Efficacy 14 15 10 Centers for Disease Control and Prevention|MRC/UVRI Uganda Research Unit on Aids|Ministry of Health, UgandaCDC Interventional Phase 2 Safety/Efficacyhttp://bmjopen.bmj.com/ 16 11 Beijing Children's Hospital Hospital Interventional Phase 4 Safety/Efficacy 17 12 University Hospital Inselspital, Berne Hospital Interventional Phase 1 Pharmacokinetics 18 19 13 University Hospital, Ghent|University Hospital, Antwerp|Queen Fabiola Children's University Hospital, BrusselsHospital Observational Not applicable Pharmacokinetics 20 14 University of Oxford|Mahidol University|Wellcome TrustUniversity Interventional Not specified Efficacy 21 15 Oulu University Hospital University Interventional Phase 4 Safety/Efficacy 22 16 Daniel Benjamin|Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)|The EMMES Corporation|OpAns, LLC|Duke UniversityUniversity Observational Not applicable Pharmacokinetics 23 on September 28, 2021 by guest. Protected copyright. 24 17 Michael Cohen-Wolkowiez|Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)|Duke UniversityUniversity Interventional Phase 1 Pharmacokinetics 25 18 Khon Kaen University University Interventional Not specified Efficacy 26 19 Cubist Pharmaceuticals LLC Industry Interventional Phase 1 Pharmacokinetics 27 28 20 Children's Mercy Hospital Kansas City|Blue Cross Blue ShieldHospital Interventional Not specified Efficacy 29 21 Hoffmann-La Roche Industry Observational Not applicable Safety 30 22 Region Skane Hospital Interventional Not specified Efficacy 31 23 Cubist Pharmaceuticals LLC Industry Interventional Phase 3 Safety 32 33 24 Drexel University|The Center for Pediatric Pharmacotherapy, LLCUniversity Interventional Phase 1 Safety 34 25 Bayer Industry Observational Not applicable Safety/Efficacy 35 26 Children's Hospital of Philadelphia Hospital Observational Not applicable Safety/Efficacy 36 37 27 Sheba Medical Center Hospital Interventional Phase 4 Efficacy 38 28 Beijing Children's Hospital Hospital Observational Not applicable Pharmacokinetics 39 29 Rempex Pharmaceuticals (a wholly owned subsidiary of The Medicines Company)|Department of Health and Human ServicesIndustry Interventional Phase 1 Safety 40 30 Menzies School of Health Research|Griffith University|Sarawak General Hospital|University of Malaya|The University of Queensland|Queensland University of Technology|Nanyang Technological UniversityUniversity Interventional Phase 4 Safety/Efficacy 41 42 31 Michael Cohen-Wolkowiez|The EMMES Corporation|Duke UniversityUniversity Interventional Phase 2-3 Safety 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 P Q R S T 3 32 University of Malaya|Menzies School of Health ResearchUniversity Interventional Phase 4 Efficacy 4 33 Durata Therapeutics Inc., an affiliate of Allergan plcIndustry Interventional Phase 1 Pharmacokinetics 5 6 34 University of British Columbia University Interventional Phase 3 Efficacy 7 35 Merck Sharp & Dohme Corp. Industry Interventional Phase 1 Pharmacokinetics 8 36 St. Justine's Hospital Hospital Interventional Phase 1 Pharmacokinetics 9 10 37 Universit̩ Catholique de Louvain University Interventional Phase 4 Pharmacokinetics 11 38 Assistance Publique - H̫pitaux de ParisFor peerHospital Interventional reviewNot specified onlyPharmacokinetics 12 39 Helsinki University|Foundation for Paediatric Research, FinlandUniversity Interventional Phase 4 Safety/Efficacy 13 40 National Taiwan University Hospital University Interventional Phase 4 Pharmacokinetics 14 15 41 Chulalongkorn University University Interventional Not specified Efficacy http://bmjopen.bmj.com/ 16 42 University of Pittsburgh|National Institute of Allergy and Infectious Diseases (NIAID)University Interventional Phase 3 Safety/Efficacy 17 43 Korea University University Interventional Phase 4 Efficacy 18 19 44 Baylor College of Medicine|Forest Laboratories University Interventional Phase 1-2 Safety/Efficacy 20 45 Royal College of Surgeons, Ireland|Health Research Board, IrelandUniversity Interventional Phase 4 Efficacy 21 46 Ramon Gorter|ZonMw: The Netherlands Organisation for Health Research and Development|VU University Medical Center|Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)University Interventional Phase 4 Efficacy 22 47 AstraZeneca|PRA Health Sciences Industry Interventional Phase 2 Safety/Efficacy 23 on September 28, 2021 by guest. Protected copyright. 24 48 Aga Khan University University Interventional Not specified Efficacy 25 49 Thammasat University University Interventional Phase 4 Safety/Efficacy 26 50 Basilea Pharmaceutica Industry Interventional Phase 1 Pharmacokinetics 27 28 51 Murdoch Childrens Research Institute|Royal Children's Hospital|Mercy Hospital for Women, AustraliaUniversity Interventional Not specified Pharmacokinetics 29 52 AstraZeneca|PRA Health Sciences Industry Interventional Phase 2 Safety/Efficacy 30 53 Durata Therapeutics Inc., an affiliate of Allergan plcIndustry Interventional Phase 3 Safety/Efficacy 31 54 Cempra Inc|National Institute of Allergy and Infectious Diseases (NIAID)Industry Interventional Phase 3 Efficacy 32 33 55 Otonomy, Inc. Industry Interventional Phase 3 Efficacy 34 56 Save the Children|University of North Carolina|University of WashingtonHealth OrganisationInterventional Phase 4 Efficacy 35 57 Save the Children|University of North Carolina|University of WashingtonHealth OrganisationInterventional Phase 4 Efficacy 36 37 58 Cempra Inc Industry Interventional Phase 2-3 Safety/Efficacy 38 59 Cempra Inc Industry Interventional Phase 3 Safety/Efficacy 39 60 Tanta University University Interventional Phase 3 Efficacy 40 61 Murdoch Childrens Research Institute University Interventional Not specified Efficacy 41 42 62 Astellas Pharma Europe B.V.|Merck Sharp & Dohme Corp.|Astellas Pharma IncIndustry Interventional Phase 3 Safety/Efficacy 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 P Q R S T 3 63 Laboratorios Goulart S.A. Industry Interventional Phase 3 Safety/Efficacy 4 64 University Hospital, Ghent|Universitair Ziekenhuis BrusselUniversity Interventional Phase 4 Pharmacokinetics 5 6 65 Malaria Consortium|World Health Organization Health OrganisationInterventional Phase 4 Safety 7 66 PENTA Foundation|St George's, University of London|Institut National de la SantÌ© Et de la Recherche MÌ©dicale, France|University of Tartu|Consorzio per Valutazioni Biologiche e Farmacologiche|University of Liverpool|Therakind limited|Bambino GesÌ_ Hospital and Research Institute|Servicio Madrile̱o de Salud, Madrid, Spain|Aristotle University Of Thessaloniki|University of Edinburgh|SYNAPSE Research Management Partners S.L|European CommissionHealth OrganisationInterventional Phase 2 Safety/Efficacy 8 67 Sigvard M̦lstad|Public Health Agency of SwedenUniversity Interventional Phase 4 Safety/Efficacy 9 10 68 AstraZeneca|PRA Health Sciences Industry Interventional Phase 2-3 Safety/Efficacy 11 69 The Medicines Company For peerIndustry Interventional reviewPhase 1 onlyPharmacokinetics 12 70 Theravance Biopharma Antibiotics, Inc. Industry Interventional Phase 4 Pharmacokinetics 13 71 The Canberra Hospital Hospital Interventional Phase 2 Pharmacokinetics 14 15 72 Chang Gung Memorial Hospital Hospital Interventional Phase 4 Efficacy http://bmjopen.bmj.com/ 16 73 Darier Industry Interventional Phase 4 Safety/Efficacy 17 74 Theravance Biopharma Antibiotics, Inc. Industry Observational Not applicable Safety/Efficacy 18 19 75 Grupo de Apoio ao Adolescente e a Crianca com CancerHospital Observational Not applicable Pharmacokinetics 20 76 Infectopharm Arzneimittel GmbH|J&P Medical Research Ltd.|Sandoz GmbHIndustry Observational Not applicable Efficacy 21 77 University of Maryland University Interventional Phase 2 Safety/Efficacy 22

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1 2 U V W X Y Z AA AB 3 1 Primary outcome variable PK data collected First ReceivedStart Date Completion DateLast UpdatedLast Verified Results First Received 4 2 PK PK study design July 2, 2015 Sep-15 Dec-18 September 14, 2016Sep-16 No Study Results Posted 5 6 3 Efficacy No PK data September 28, 2016Oct-16 null October 12, 2016 Oct-16 No Study Results Posted 7 4 Efficacy No PK data September 8, 2016Sep-16 null September 13, 2016Sep-16 No Study Results Posted 8 5 Efficacy No PK data May 8, 2012 May-12 Apr-18 June 27, 2016 Jun-16 No Study Results Posted 9 10 6 Efficacy No PK data March 2, 2015 Mar-16 May-18 March 24, 2016 Mar-16 No Study Results Posted 11 7 Efficacy No PK dataFor peerSeptember 1, 2016 reviewOct-16 Mar-19 October 13, 2016 onlyOct-16 No Study Results Posted 12 8 PK PK study design April 4, 2016 Apr-16 Sep-16 April 25, 2016 Apr-16 No Study Results Posted 13 9 Efficacy No PK data September 23, 2016Oct-16 Dec-17 September 26, 2016Sep-16 No Study Results Posted 14 15 10 Efficacy No PK data November 17, 2010Dec-10 null September 10, 2012http://bmjopen.bmj.com/ Sep-12 No Study Results Posted 16 11 Efficacy No PK data November 25, 2015Mar-14 Jul-16 December 16, 2015Nov-15 No Study Results Posted 17 12 PK Primary PK data January 26, 2012 Apr-12 Apr-18 December 10, 2015Dec-15 No Study Results Posted 18 19 13 PK PK study design May 18, 2015 May-12 null November 17, 2015Nov-15 No Study Results Posted 20 14 Efficacy No PK data December 18, 2007Dec-07 Sep-10 June 3, 2008 Aug-07 No Study Results Posted 21 15 Efficacy No PK data October 17, 2007 Nov-07 Dec-09 October 18, 2007 Oct-07 No Study Results Posted 22 16 PK PK study design August 17, 2011 Nov-11 Feb-17 February 4, 2016 Feb-16 No Study Results Posted 23 on September 28, 2021 by guest. Protected copyright. 24 17 PK PK study design June 12, 2015 Nov-15 Dec-17 August 1, 2016 Aug-16 No Study Results Posted 25 18 Efficacy No PK data August 18, 2011 Aug-11 Dec-20 August 30, 2016 Aug-16 No Study Results Posted 26 19 PK PK study design September 22, 2014Sep-14 Nov-16 October 31, 2016 Oct-16 No Study Results Posted 27 28 20 Efficacy No PK data March 23, 2009 Mar-09 Oct-12 June 21, 2011 Jun-11 No Study Results Posted 29 21 Safety No PK data August 23, 2016 Aug-16 Dec-16 September 1, 2016Sep-16 No Study Results Posted 30 22 Efficacy No PK data January 3, 2011 Mar-11 Jun-15 May 25, 2015 May-15 No Study Results Posted 31 23 Safety Secondary PK data October 9, 2014 Mar-15 Jan-18 October 31, 2016 Oct-16 No Study Results Posted 32 33 24 Safety Primary PK data January 12, 2016 Jan-17 Dec-18 September 8, 2016Sep-16 No Study Results Posted 34 25 Safety No PK data September 18, 2015Jul-16 Sep-18 October 19, 2016 Oct-16 No Study Results Posted 35 26 Efficacy No PK data November 17, 2014Jan-14 Jul-17 May 6, 2016 May-16 No Study Results Posted 36 37 27 Efficacy No PK data August 21, 2014 Aug-13 Aug-15 August 26, 2014 Aug-14 No Study Results Posted 38 28 PK PK study design May 11, 2016 Aug-16 Oct-22 May 17, 2016 May-16 No Study Results Posted 39 29 Safety Primary PK data February 17, 2016 Jul-16 Sep-19 October 6, 2016 Oct-16 No Study Results Posted 40 30 Efficacy No PK data May 5, 2016 Jun-16 Dec-20 October 7, 2016 Oct-16 No Study Results Posted 41 42 31 Safety No PK data November 18, 2013Dec-13 Sep-17 August 1, 2016 Aug-16 No Study Results Posted 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 U V W X Y Z AA AB 3 32 Efficacy No PK data September 23, 2014Nov-14 Dec-18 December 20, 2015Dec-15 No Study Results Posted 4 33 PK PK study design February 18, 2016 Apr-16 May-17 October 19, 2016 Oct-16 No Study Results Posted 5 6 34 Efficacy No PK data May 8, 2006 Jan-04 Dec-13 February 6, 2012 Feb-12 No Study Results Posted 7 35 PK PK study design April 1, 2016 May-16 Feb-18 October 21, 2016 Oct-16 No Study Results Posted 8 36 PK PK study design June 2, 2015 Jan-16 Dec-17 April 18, 2016 Apr-16 No Study Results Posted 9 10 37 PK PK study design October 1, 2014 Oct-16 Oct-17 October 24, 2016 Oct-16 No Study Results Posted 11 38 PK PK study designFor peerFebruary 24, 2016 reviewFeb-16 Feb-17 March 8, 2016 onlyMar-16 No Study Results Posted 12 39 Efficacy No PK data February 23, 2012 Feb-12 Jul-17 February 19, 2016 Feb-16 No Study Results Posted 13 40 PK PK study design August 23, 2006 Jun-06 Dec-07 August 23, 2006 Aug-06 No Study Results Posted 14 15 41 Efficacy No PK data January 30, 2013 Dec-12 Dec-13 February 6, 2013http://bmjopen.bmj.com/ Feb-13 No Study Results Posted 16 42 Efficacy No PK data September 8, 2015Feb-16 Sep-20 October 3, 2016 Oct-16 No Study Results Posted 17 43 Efficacy No PK data December 22, 2010Apr-07 Apr-16 April 8, 2014 Apr-14 No Study Results Posted 18 19 44 Safety Secondary PK data December 31, 2014Jan-15 Jan-20 June 24, 2016 Jun-16 No Study Results Posted 20 45 Efficacy No PK data August 9, 2016 Dec-16 Dec-19 September 30, 2016Jul-16 No Study Results Posted 21 46 Efficacy No PK data July 24, 2016 Dec-16 Dec-20 July 26, 2016 Jul-16 No Study Results Posted 22 47 Safety Secondary PK data May 25, 2015 Jul-15 Oct-17 October 21, 2016 Oct-16 No Study Results Posted 23 on September 28, 2021 by guest. Protected copyright. 24 48 Efficacy No PK data November 4, 2014Nov-14 Jul-17 June 3, 2016 Jun-16 No Study Results Posted 25 49 Efficacy No PK data February 17, 2012 Jan-12 Sep-12 March 13, 2012 Mar-12 No Study Results Posted 26 50 PK PK study design August 5, 2015 Aug-14 Jun-17 October 20, 2016 Oct-16 No Study Results Posted 27 28 51 PK PK study design August 5, 2014 Sep-14 Sep-17 March 17, 2016 Mar-16 No Study Results Posted 29 52 Safety Secondary PK data June 16, 2015 Sep-15 Oct-17 October 21, 2016 Oct-16 No Study Results Posted 30 53 Efficacy No PK data June 8, 2016 Jun-16 Jul-18 June 23, 2016 Jun-16 No Study Results Posted 31 54 Efficacy No PK data August 1, 2014 Aug-14 Apr-17 September 20, 2016Sep-16 No Study Results Posted 32 33 55 Efficacy No PK data June 13, 2016 Jun-16 Nov-16 June 13, 2016 Jun-16 No Study Results Posted 34 56 Efficacy No PK data May 1, 2016 Jun-16 Sep-18 June 10, 2016 Jun-16 No Study Results Posted 35 57 Efficacy No PK data February 3, 2016 Mar-16 null June 10, 2016 Jun-16 No Study Results Posted 36 37 58 Safety No PK data November 10, 2015Mar-16 Jan-18 September 14, 2016Sep-16 No Study Results Posted 38 59 Efficacy No PK data October 5, 2015 Nov-15 Feb-17 October 5, 2016 Oct-16 No Study Results Posted 39 60 Efficacy No PK data May 11, 2015 Jan-15 Dec-16 May 9, 2016 May-16 No Study Results Posted 40 61 Efficacy No PK data January 4, 2015 Jan-15 Jan-17 March 16, 2016 Mar-16 No Study Results Posted 41 42 62 Efficacy No PK data August 11, 2014 Oct-14 Feb-17 June 17, 2016 Jun-16 No Study Results Posted 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 U V W X Y Z AA AB 3 63 Efficacy No PK data December 14, 2009May-10 Oct-10 March 18, 2010 Dec-09 No Study Results Posted 4 64 PK PK study design November 4, 2015 Apr-15 Apr-16 November 4, 2015Nov-15 No Study Results Posted 5 6 65 Safety No PK data August 17, 2016 Oct-16 Jul-17 October 3, 2016 Oct-16 No Study Results Posted 7 66 Efficacy Secondary PK data April 7, 2016 Jul-16 Mar-18 May 31, 2016 May-16 No Study Results Posted 8 67 Efficacy No PK data March 4, 2016 Sep-15 Oct-16 October 4, 2016 Oct-16 No Study Results Posted 9 10 68 Safety Secondary PK data February 23, 2015 Aug-15 Oct-17 October 14, 2016 Oct-16 No Study Results Posted 11 69 PK PK study designFor peerMay 7, 2014 reviewMay-14 Dec-16 November 4, 2015 onlyNov-15 No Study Results Posted 12 70 PK PK study design December 11, 2013Dec-14 Aug-16 June 24, 2016 Jun-16 No Study Results Posted 13 71 PK PK study design August 31, 2011 Aug-11 Jul-12 September 1, 2011Aug-11 No Study Results Posted 14 15 72 Efficacy No PK data November 25, 2010Aug-10 Jul-12 January 14, 2011http://bmjopen.bmj.com/ Nov-10 No Study Results Posted 16 73 Efficacy No PK data September 30, 2009Jun-09 Apr-10 September 30, 2009Sep-09 No Study Results Posted 17 74 Efficacy No PK data November 5, 2014Nov-14 Sep-18 June 29, 2016 Jun-16 No Study Results Posted 18 19 75 PK Primary PK data February 24, 2011 Jan-11 null March 21, 2012 Mar-12 No Study Results Posted 20 76 Efficacy No PK data July 29, 2010 Aug-10 null February 5, 2016 Feb-16 No Study Results Posted 21 77 Efficacy Secondary PK data January 22, 2013 Jul-13 Dec-21 May 28, 2015 May-15 No Study Results Posted 22

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1 2 AC AD AE AF AG 3 1 Primary Completion DateURL 4 2 Jul-18 https://ClinicalTrials.gov/show/NCT02539407 5 6 3 Dec-18 https://ClinicalTrials.gov/show/NCT02935374 7 4 Sep-18 https://ClinicalTrials.gov/show/NCT02899143 8 5 Apr-18 https://ClinicalTrials.gov/show/NCT01595529 9 10 6 Feb-18 https://ClinicalTrials.gov/show/NCT02380352 11 7 Jan-19 https://ClinicalTrials.gov/show/NCT02891915For peer review only 12 8 Sep-16 https://ClinicalTrials.gov/show/NCT02746276 13 9 Aug-17 https://ClinicalTrials.gov/show/NCT02917551 14 15 10 Jun-13 https://ClinicalTrials.gov/show/NCT01243437 http://bmjopen.bmj.com/ 16 11 Mar-16 https://ClinicalTrials.gov/show/NCT02635191 17 12 Dec-16 https://ClinicalTrials.gov/show/NCT01522105 18 19 13 Dec-17 https://ClinicalTrials.gov/show/NCT02456974 20 14 Sep-10 https://ClinicalTrials.gov/show/NCT00579956 21 15 null https://ClinicalTrials.gov/show/NCT00545961 22 16 Feb-17 https://ClinicalTrials.gov/show/NCT01431326 23 on September 28, 2021 by guest. Protected copyright. 24 17 Nov-17 https://ClinicalTrials.gov/show/NCT02475876 25 18 Dec-20 https://ClinicalTrials.gov/show/NCT01420341 26 19 Nov-16 https://ClinicalTrials.gov/show/NCT02266706 27 28 20 Sep-12 https://ClinicalTrials.gov/show/NCT00867789 29 21 Dec-16 https://ClinicalTrials.gov/show/NCT02879981 30 22 Jun-15 https://ClinicalTrials.gov/show/NCT01269541 31 23 Jan-18 https://ClinicalTrials.gov/show/NCT02276482 32 33 24 Dec-18 https://ClinicalTrials.gov/show/NCT02663596 34 25 Sep-17 https://ClinicalTrials.gov/show/NCT02555059 35 26 Apr-17 https://ClinicalTrials.gov/show/NCT02297815 36 37 27 Dec-14 https://ClinicalTrials.gov/show/NCT02224040 38 28 Aug-22 https://ClinicalTrials.gov/show/NCT02775968 39 29 Aug-19 https://ClinicalTrials.gov/show/NCT02687906 40 30 Dec-19 https://ClinicalTrials.gov/show/NCT02783859 41 42 31 Apr-17 https://ClinicalTrials.gov/show/NCT01994993 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 AC AD AE AF AG 3 32 Dec-17 https://ClinicalTrials.gov/show/NCT02258763 4 33 May-17 https://ClinicalTrials.gov/show/NCT02688790 5 6 34 Dec-12 https://ClinicalTrials.gov/show/NCT00323219 7 35 Feb-18 https://ClinicalTrials.gov/show/NCT02750761 8 36 Dec-17 https://ClinicalTrials.gov/show/NCT02466438 9 10 37 Sep-17 https://ClinicalTrials.gov/show/NCT02260102 11 38 Jun-16 https://ClinicalTrials.gov/show/NCT02694458For peer review only 12 39 Feb-17 https://ClinicalTrials.gov/show/NCT01540838 13 40 null https://ClinicalTrials.gov/show/NCT00368498 14 15 41 Dec-13 https://ClinicalTrials.gov/show/NCT01785641 http://bmjopen.bmj.com/ 16 42 Sep-20 https://ClinicalTrials.gov/show/NCT02554383 17 43 Mar-16 https://ClinicalTrials.gov/show/NCT01265173 18 19 44 Jan-17 https://ClinicalTrials.gov/show/NCT02335905 20 45 Dec-19 https://ClinicalTrials.gov/show/NCT02922686 21 46 Dec-20 https://ClinicalTrials.gov/show/NCT02848820 22 47 Oct-17 https://ClinicalTrials.gov/show/NCT02475733 23 on September 28, 2021 by guest. Protected copyright. 24 48 May-17 https://ClinicalTrials.gov/show/NCT02372461 25 49 Aug-12 https://ClinicalTrials.gov/show/NCT01553006 26 50 Mar-17 https://ClinicalTrials.gov/show/NCT02527681 27 28 51 Sep-17 https://ClinicalTrials.gov/show/NCT02210169 29 52 Oct-17 https://ClinicalTrials.gov/show/NCT02497781 30 53 Apr-18 https://ClinicalTrials.gov/show/NCT02814916 31 54 Apr-17 https://ClinicalTrials.gov/show/NCT02210325 32 33 55 Nov-16 https://ClinicalTrials.gov/show/NCT02801370 34 56 Aug-18 https://ClinicalTrials.gov/show/NCT02760420 35 57 Aug-18 https://ClinicalTrials.gov/show/NCT02678195 36 37 58 Dec-17 https://ClinicalTrials.gov/show/NCT02605122 38 59 Feb-17 https://ClinicalTrials.gov/show/NCT02570490 39 60 Dec-16 https://ClinicalTrials.gov/show/NCT02443285 40 61 Jan-17 https://ClinicalTrials.gov/show/NCT02334124 41 42 62 Feb-17 https://ClinicalTrials.gov/show/NCT02218372 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 AC AD AE AF AG 3 63 Jul-10 https://ClinicalTrials.gov/show/NCT01032499 4 64 Feb-16 https://ClinicalTrials.gov/show/NCT02598362 5 6 65 Mar-17 https://ClinicalTrials.gov/show/NCT02878031 7 66 Dec-17 https://ClinicalTrials.gov/show/NCT02790996 8 67 Oct-16 https://ClinicalTrials.gov/show/NCT02712307 9 10 68 Oct-17 https://ClinicalTrials.gov/show/NCT02424734 11 69 Dec-16 https://ClinicalTrials.gov/show/NCT02134301For peer review only 12 70 Aug-16 https://ClinicalTrials.gov/show/NCT02013141 13 71 Jul-12 https://ClinicalTrials.gov/show/NCT01427842 14 15 72 Jun-11 https://ClinicalTrials.gov/show/NCT01278017 http://bmjopen.bmj.com/ 16 73 Feb-10 https://ClinicalTrials.gov/show/NCT00988026 17 74 Jun-18 https://ClinicalTrials.gov/show/NCT02288234 18 19 75 null https://ClinicalTrials.gov/show/NCT01304459 20 76 Dec-16 https://ClinicalTrials.gov/show/NCT01173575 21 77 Dec-19 https://clinicaltrials.gov/ct2/show/NCT01778634 22

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A global shortage of neonatal and pediatric antibiotic trials: a narrative review.

ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2017-016293.R2

Article Type: Research

Date Submitted by the Author: 25-Jul-2017

Complete List of Authors: Thompson, Georgina; St George's University of London, Infection and Immunity; University of Exeter Medical School Barker, Charlotte; St George's University of London, Infection and Immunity; University College London Institute of Child Health Folgori, Laura; St George's University of London, Paediatric Infectious Diseases Research Group Bielicki, Julia; St George's University London, Division of Clinical Sciences; University of Basel Children's Hospital Bradley, John; University of California San Diego School of Medicine, Department of Pediatrics Lutsar, Irja; University of Tartu, Department of Medical Microbiology sharland, mike; St George's University of London, Infection and Immunity; St Georges Hospital, Paedaitric Infectious Diseases Unit http://bmjopen.bmj.com/

Primary Subject Paediatrics Heading:

Secondary Subject Heading: Infectious diseases

Paediatric infectious disease & immunisation < PAEDIATRICS, INFECTIOUS Keywords: DISEASES, PAEDIATRICS on September 28, 2021 by guest. Protected copyright.

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1 2 3 A global shortage of neonatal and pediatric antibiotic trials: rapid review. 4 1,2 1,3,4 1 1,5 6,7 8 1, 4 5 G. Thompson , C.I.S. Barker , L. Folgori , J.A. Bielicki , J. Bradley , I. Lutsar , M. Sharland 6

7 1 8 Paediatric Infectious Diseases Research Group, Institute for Infection and Immunity, St George's University 9 of London, London, UK 10 2 University of Exeter, Exeter, UK 11 3 12 Inflammation, Infection and Rheumatology Section, UCL Great Ormond Street Institute of Child Health, 30 13 Guilford Street, London, UK 14 4 15 St George’s UniversityFor Hospitals peer NHS Foundation review Trust, Blackshaw Road, only London, UK 16 5 Paediatric Pharmacology and Pharmacometrics, University of Basel Children’s Hospital, Basel, Switzerland 17 6 Department of Pediatrics, School of Medicine, University of California San Diego, CA, United States 18 7 19 Rady Children’s Hospital San Diego, San Diego, CA, United States 20 8 Department of Medical Microbiology, University of Tartu, Tartu, Estonia 21

22 23 24 25 Corresponding author 26 Georgina Thompson 27 Paediatric Infectious Diseases Research Group 28 29 Institute for Infection and Immunity 30 St George's, University of London 31

Jenner Wing, Level 2, Room 2.216F, Mail Point J2C http://bmjopen.bmj.com/ 32 33 London SW17 0RE 34 Telephone: 020 8725 5382 35 36 Email: [email protected] 37 38

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40 Word count: 2392 on September 28, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 2 of 40

1 2 3 ABSTRACT 4 Objectives: There have been few clinical trials (CTs) on antibiotics which inform neonatal and 5 6 pediatric drug labelling. The rate of unlicensed and off-label prescribing in pediatrics remains high. 7 It is unclear whether the current neonatal and pediatric antibiotic research pipeline is adequate to 8 9 inform optimal drug dosing. Using the ClinicalTrials.gov registry, this review aims to establish the 10 11 current global status of antibiotic CTs in children up to 18 years of age. 12 Results: 76 registered open CTs of antibiotics in children were identified globally; 23 (30%) were 13 14 recruiting newborns (8 of which (11%) included preterm neonates), 52 (68%) infants and toddlers, 15 58 (76%) children,For and 54 (71%)peer adolescents. review The majority of registered only trials were late phase (10 16 17 (15%) Phase 3 and 23 (35%) Phase 4/pharmacovigilance). Two-thirds were sponsored by non-profit 18 organisations (n=50, 66%), compared to 26 (34%) by pharmaceutical companies. A greater 19 20 proportion of non-profit funded trials were efficacy-based strategic trials (n= 34, 68%), in comparison 21 to industry-led trials, which were most often focused on safety or pharmacokinetic data (n=17, 65%). 22 23 Only 2 of the 37 antibiotics listed on the May 2016 Pew Charitable Trusts antibiotic development 24 pipeline, currently being studied in adults, appear to be currently recruiting in open pediatric CTs. 25 26 Conclusions: This review highlights that very few pediatric antibiotic CTs are being conducted 27 globally, especially in neonates. There is a striking disparity noted between antibiotic drug 28 29 development programmes in adults and children. 30

31 32 Strengths and limitations of this study http://bmjopen.bmj.com/ 33 34 • A narrative literature review of registered clinical trials in children. 35 • Explicit reproducible methodology. 36 37 • Search strategy limited to ClinicalTrials.gov and EudraCT. Entirety of clinical research in this 38 field might not have been captured. 39

40 • Search strategy was limited to open clinical trials. Active but not yet recruiting trials were not on September 28, 2021 by guest. Protected copyright. 41 captured. 42 43 44 45 46 INTRODUCTION 47 48 Widespread unlicensed and off-label prescribing in pediatrics persists – as high as 11% and 46%, 49 50 respectively – yet the paucity of clinical research involving children that is conducted to inform 51 optimal drug dosing, licensing and labelling remains a problem.[1] For certain medicines, drug 52 53 efficacy can be extrapolated from adult data provided that the pathology and drug exposure are the 54 same, or sufficiently similar in children as in adults.[2,3]. Although differences in drug 55 56 pharmacokinetics (PK) in neonates and children can lead to adverse reactions that are not seen in 57 adult populations, these are very rare.[4] Suboptimal antibiotic dosing, including under- and over- 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 3 of 40 BMJ Open

1 2 3 dosing, can lead to toxicity, treatment failure, and may drive antimicrobial resistance by encouraging 4 selection pressures on drug-resistant strains of bacteria.[5] 5 6 7 Since antibiotics are the medicines most commonly prescribed for children, it is important to 8 9 maximize our understanding of their PK profiles to help determine optimal drug dosing and 10 11 ultimately to improve outcomes.[6] In the last decade several initiatives have been established to 12 encourage pediatric medicines research, bridging the gap between adult and pediatric drug 13 14 development plans. Such initiatives include the Pediatric Regulation (Pediatric Investigation Plans 15 (PIPs), introducedFor by the European peer Medicines review Agency (EMA),[7] andonly Pediatric Study Plans (PSPs), 16 17 by the U.S. Food and Drug Administration (FDA)).[8] Despite this, there have been few advances in 18 antibiotic development for this population.[9] 19 20 21 The global status of clinical research on antibiotics in pediatrics is unknown. Using registered 22 23 records of clinical trials (CTs) on ClinicalTrials.gov, this review aims (i) to summarise the current 24 global status of registered antibiotic research in children and neonates, and (ii) to stimulate 25 26 discussion and collaboration among the relevant stakeholders on the neglect of antibiotic research 27 in children. 28 29 30 METHODS 31 32 Data sources http://bmjopen.bmj.com/ 33 The ClinicalTrials.gov registry (last accessed 8th November 2016) is an international platform for the 34 35 registration of CTs. It is a web-based registry, developed in 2000 by the National Institutes of Health 36 37 (NIH) and the FDA, to which trials from 50 states and 163 countries around the world are registered. 38 Information provided for each trial is updated periodically by the trial’s sponsoring organisation. The 39

40 database has a specific child filter, which uses a key word paradigm to select all registered trials on September 28, 2021 by guest. Protected copyright. 41 recruiting patients/participants up to 18 years of age. 42 43 44 45 46 Study selection 47 Our records were identified using suitable key word searches, in which the final search terms were 48 49 (antimicrobial* OR antibiotic* OR anti-infective agent*) AND Child AND Open Studies. All identified 50 trials were filtered manually using inclusion and exclusion criteria. Interventional and observational 51 52 trials on antimicrobials recruiting children up to 18 years of age were considered eligible for 53 inclusion. No specific temporal filter was applied since only open or ongoing clinical trials were of 54 55 interest. The following records, which were not investigating one or more antibiotics, were excluded: 56 trials of antiseptics, antifungals, antiprotozoals, antivirals, and pro- or pre- biotics. The following 57 58 records, which were investigating an antibiotic were excluded: trials involving tuberculosis, malaria, 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 4 of 40

1 2 3 cystic fibrosis, HIV, febrile neutropenic patients, topical or inhalational treatments, prophylactic 4 antibiotics, or records investigating alternative use for antibiotics (for example as an anti- 5 6 inflammatory agent). 7

8 9 The searches were conducted by GT. All eligible records were identified via manual filtering by GT 10 11 CB, LF and MS, and any disagreements regarding inclusion and exclusion of records were resolved 12 through discussion. 13 14 15 Data extractionFor peer review only 16 17 The following information was collected from the included records: unique NCT number, recruitment 18 status, study design, trial phase, study sponsor, age group and sex eligibility, clinical indication, 19 20 geographic region of recruitment, antibiotic being investigated, and endpoint classification. 21 Outcomes were categorised as safety, efficacy or PK. Economic setting (based on geographic 22 23 region of recruitment) was classified using The World Bank classification to differentiate between 24 Low Income Countries (LICs), Lower Middle Income Countries (LMICs), Upper Middle Income 25 26 Countries (UMICs), and High Income Countries (HICs).[10] 27 28 29 The specific class of antibiotic studied in each trial was identified and classified using the World 30 Health Organisation (WHO) ATC/DDD index.[11] To investigate whether novel antibiotics are being 31 32 studied in pediatric populations, the antibiotics currently studied in children were compared with the http://bmjopen.bmj.com/ 33 Pew Charitable Trusts Antibiotics Currently in Clinical Development pipeline, which identifies novel 34 35 antibiotics currently under development for the U.S. market.[12] 36 37 38 39

40 on September 28, 2021 by guest. Protected copyright. 41 RESULTS 42 43 Our search identified 1056 records. 603 records were excluded on title because they were studies 44 not involving an antimicrobial. 453 records were investigating one or more antimicrobials and 45 46 recruiting children below 18 years of age. Among the 195 trials investigating antibiotics, 76 fulfilled 47 our inclusion and exclusion criteria and were included in the final analysis. Reasons for exclusion 48 49 are summarised in Figure 1. Details of included studies can be found in Supplementary file 1. 50 51 All 76 CTs identified were open as of 8th November 2016, and 63 (83%) of these were recognised 52 53 as recruiting participants on this date (Table 1). All trials were recruiting both male and female 54 participants. 55 56 57 Table 1. Characteristics of clinical trials. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 5 of 40 BMJ Open

1 2 3 Number of Characteristic Category 4 studies, n (%) 5 Age group Preterm neonates 1 (1)a 6 Neonates (total) 23 (30) 7 Infants and toddlers 52 (68) 8 Children 58 (76) 9 Adolescents 54 (71) 10 Recruitment status Recruiting 63 (83) 11 Not yet recruiting 13 (17) 12 13 Study design Interventional 66 (87) Observational 10 (13) 14 b 15 TrialFor phase peerPhase 1 review only 10 (15) 16 Phase 1-2 1 (2) 17 Phase 2 9 (14) 18 Phase 2-3 3 (5) 19 Phase 3 10 (15) 20 Phase 4 23 (39) 21 Not specified 10 (15) 22 Sponsor Industry 26 (34) 23 Non-profit 50 (66) 24 Geographic region Africa 8 (11) 25 Asia 16 (21) 26 Europe 22 (29) 27 Latin America 6 (8) 28 29 North America 34 (45) 30 Oceania 5 (7) 31 Antibiotic class J01A Tetracycline 4 (5) 32 J01C Beta-lactam, Penicillin 25 (33) http://bmjopen.bmj.com/ 33 J01D Other Beta-lactam 22 (29) 34 J01E Sulfonamides and trimethoprim 7 (9) 35 J01F Macrolide, Lincosamide, Streptogramin 14 (18) 36 J01G Aminoglycoside 2 (3) 37 J01M Quinolone 8 (11) 38 J01X Other antibiotic classesc 21 (28) 39 J01 Not specified 2 (3) 40 on September 28, 2021 by guest. Protected copyright. 41 Totals for Age group, Geographic region, and Antibiotic class do not add up to total number of clinical trials 42 (76) as some trials contributed to more than one sub group. 43 a 7 further trials mentioned inclusion of preterm babies in the inclusion criteria. 44 b Trial phase % based on percentage of interventional trials. c 45 J01X includes glycopeptides, polymyxins, imidazole and nitrofuran derivatives. 46 47 48 49 Age group 50 51 Only 23 of the 76 trials (30%) were recruiting newborns (0 to 28 days). One of these 23 trials 52 focused solely on recruiting preterm newborns (a further 7 CTs mentioned inclusion of preterm 53 54 newborns in inclusion criteria). Of the remaining records, 52 (68%) were recruiting infants and 55 toddlers (28 days to 23 months), 58 (76%) children (2 to 11 years), and 54 (71%) adolescents (11 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 6 of 40

1 2 3 up to 18 years). 29 (38%) trials did not focus solely on the recruitment of children or neonates, with 4 age ranges also spanning across adult populations. 5 6 7 Study type 8 9 Interventional trials were most frequently identified (n=66, 87%) with only 10 (13%) observational 10 11 trials noted. Of the interventional trials, the majority were in the later stages of development; 10 12 (13%) in Phase 1, 1 (2%) between Phase 1 and 2, 9 (14%) in Phase 2, 3 (5%) between Phase 2 13 14 and 3, 10 (15%) in Phase 3 and 23 (35%) in Phase 4. In 10 (15%) cases, a trial phase was not 15 specified. For peer review only 16 17 18 Sponsor and Endpoint Classification 19 20 Fifty trials (66%) were sponsored by non-profit organisations (being university, hospital or 21 government funded), and 26 sponsored by industry (34%). The endpoint classification of the 22 23 majority of trials (n=43, 57%) was reported as efficacy (Table 2). A greater proportion (n=34, 68%) 24 of non-profit studies measured the efficacy of the drugs as the primary endpoint, with less emphasis 25 26 on collection of PK or safety data (n=16, 32%). In comparison pharmaceutical-led trials focussed on 27 early PK and safety studies over drug efficacy (n=17, 65% vs. n=9, 35% respectively). 28 29 30 Table 2. Clinical trial endpoint classification of identified clinical trials stratified by trial sponsor. 31

Endpoint classification determined by planned primary outcomes. http://bmjopen.bmj.com/ 32

33 34 Endpoint classification Industry Non-profit Total (%) 35 36 Efficacy 9 34 43 (57) 37 38 Safety 10 2 12 (16) 39 PK 7 14 21 (28) 40 on September 28, 2021 by guest. Protected copyright. 41 42 43 44 Geographic region 45 The most frequently recruiting geographic region was North America (n=34, 45%). 22 (29%) trials 46 47 recruiting in Europe and 16 (21%) in Asia were identified, 6 (8%) in Latin America, 8 (11%) in Africa, 48 and 5 (7%) in Oceania. Most trials were recruiting in HICs (n=54, 71%), with fewer trials recruiting in 49 50 LICs (n=4, 5%), LMICs (n=4, 5%), UMICs (n=11, 14%) or a combination of UMICs and HICs (n=3, 51 4%). 52 53 54 Indication 55 56 The most common treatment indications investigated were lower respiratory tract infection (n=12, 57 16%) and sepsis (n=11, 14%), followed by upper respiratory tract infection (n=8, 11%), intra- 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 7 of 40 BMJ Open

1 2 3 abdominal infection (IAI) (n=8, 11%), urinary tract infection (UTI) (n=7, 9%), complicated skin and 4 soft tissue infection (cSSTI) (n=6, 8%), CNS (central nervous system) infection (n=3, 4%), and bone 5 6 and joint infection (n=1, 1%) (Table 3). 7 8 9 Antibiotic class 10 The majority of antibiotics being investigated were beta-lactams (n=47, 62%), followed by other 11 12 antibiotic classes (J01X, including vancomycin, telavancin and dalbavancin) (n=21, 28%), and 13 macrolides or lincosamides (J01F) (n=14, 18%). Very few trials were investigating tetracyclines 14 15 (J01A) (n=4, 5%),For sulphonamides peer and trimethoprim review (J01E) (n=7, 9%),only aminoglycosides (J01G) 16 (n=2, 3%), or quinolones (J01M) (n=8, 11%). 2 CTs (3%) did not specify the class of antibiotic being 17 18 investigated. 16 (21%) trials were investigating more than one antibiotic; these trials counted 19 towards more than one J01 category. The breakdown of J01 categories, as per WHO ATC/DDD 20 21 classification,[11] is described in Table 1. 22 23 24 Antibiotic pipeline 25 Of the 37 antibiotics listed in the May 2016 edition of the Pew Charitable Trusts Antibiotic Pipeline 26 th 27 (last accessed 10 June 2016),[12] as noted by the EMA Opinions and Decisions on Pediatric 28 Investigation Plans, 5 had an agreed PIP: Imipenem/Cilastatin+Relebactam, Cadazolid, 29 th 30 Carbavance (Meropenem+Vaborbactam), Eravacycline, and Solithromycin.[8] As of 8 November 31

2016, our search found that only 2 of these 37 antibiotics listed (Carbavance and Solithromycin) http://bmjopen.bmj.com/ 32 33 were currently being investigated in 1 and 2 on-going CTs in pediatric patients, respectively (Table 34 4). A PIP was agreed for Carbavance in 2015 for treatment of Gram-negative infections, and for 35 36 Solithromycin in 2016 for the treatment of gonococcal infection, and later for treatment of anthrax, 37 tularaemia, and bacterial pneumonia. PIPs were agreed in 2015 for treatment of UTI and 38 39 complicated IAI with Eravacycline, and in 2016 for treatment of Clostridium difficile infection with

40 on September 28, 2021 by guest. Protected copyright. Cadazolid and Gram-negative bacterial infections with Imipenem/Cilastin+Relebactam.[13] Despite 41 42 this, we could not identify any registered trials of these antibiotics in our search. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 8 of 40

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For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

Phase Phase Manufacturer For peer review only 1 Phase Ltd. Wockhardt infection Bacterial Sepsis infection Comparison of antibiotic development pipeline in adults and children. Adapted from Pew Charitable Trusts “Antibiotics currently in currently “Antibiotics Trusts Charitable Pew from Adapted children. adultsand in pipeline development antibiotic of Comparison Antibiotic Antibiotic Urinary Tract Infection Tract Urinary Clinical indication of identified clinical trials stratified by age group being recruited. recruited. being group age by stratified trials clinical identified of indication Clinical Indication Indication Upper Respiratory Tract Respiratory Upper Bone and Joint Infection Joint and Bone Intra-abdominal Infection Intra-abdominal studies conducted usingpreterm neonates exclusively. refers to total number of andpreterm neonates.term CNS (central nervous system) system) nervous (central CNS Skin and Soft Tissue Infection Tissue Soft and Skin

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clinical development” pipeline (last accessed October 2016).[12] 2016).[12] October (last accessed pipeline development” clinical Age Age dogroup nottotals add up to total number of clinical trials (76) trialsas some contributed to more than group.age one Unspecified Bacterial Infection Bacterial Unspecified Lower Respiratory Tract Infection Tract Respiratory Lower 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from ------

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http://bmjopen.bmj.com/ BMJ Open VAP, bacteraemia bacteraemia VAP, CAP CAP Bacterial infection infection Bacterial Clostridium Multidrug resistant Gram Gram resistant Multidrug infections negative Bacterial infection infection Bacterial Clostridium cIAI cIAI Acute skin infection, HAP, HAP, infection, skin Acute on September 28, 2021 by guest. Protected copyright. Tetraphase Tetraphase Inc. Pharmaceuticals Theravance Theravance Inc. Biopharma Legochem Legochem Inc. Biosciences Basilea Basilea Pharmaceuticals Meiji Seika Pharma Pharma Seika Meiji Co. Fedora Pharmaceuticals Astrazeneca PLC PLC Astrazeneca PLC Allergan For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Phase 1 1 Phase Pharma Ltd. MGB Phase 1 1 Phase Phase 1 1 Phase Phase 1 1 Phase Ltd. Wockhardt infection Bacterial Phase 1 1 Phase Phase 1 1 Phase Ltd. Wockhardt infection Bacterial Phase 1 1 Phase Phase 1 1 Phase For 1 Phase peer Inc. Crestone review only TP – 271 271 – TP Zidebactam+Cefepime Zidebactam+Cefepime 1 Phase Ltd. Wockhardt VAP HAP, cUTI, WCK 771 771 WCK WCK 2349 2349 WCK TD – 1607 – 1607 TD LCB01 – 0371 0371 – LCB01 CRS3123 CRS3123 BAL30072 BAL30072 OP0595 OP0595 MGB – BP – 3 – BP 3 – MGB Aztreonam – Avibactam Avibactam – Aztreonam 2 Phase Page 9 of 40 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 10 of 40 ------

✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ . . Clostridium Clostridium spp infection infection http://bmjopen.bmj.com/ BMJ Open osteomyelitis osteomyelitis (systemic) (systemic) Staphylococcus Staphylococcus osteomyelitis associated (systemic) (systemic) Prevent recurrent recurrent Prevent difficile CAP, acute skin infection, infection, skin acute CAP, foot diabetic cUTI, cIAI, acute skin skin acute cIAI, cUTI, pyelonephritis infection, Bacterial infection infection Bacterial Pseudomonas spp. spp. Pseudomonas lower VAP, associated tract infection, respiratory bronchiectasis Uncomplicated gonorrhoea gonorrhoea Uncomplicated cUTI, CAP, uncomplicated uncomplicated CAP, cUTI, gonorrhoea urogenital Acute skin infection, infection, skin Acute Acute skin infection infection skin Acute Acute skin infection, infection, skin Acute Acute skin infection infection skin Acute

on September 28, 2021 by guest. Protected copyright. Nanotherapeutics Nanotherapeutics Inc. TaiGen TaiGen Co. Biotechnology Ltd. MerLion MerLion Pte Pharmaceuticals Ltd. Crystal Genomics Genomics Crystal Inc. Cellceutix Cellceutix Corporation Entasis Therapeutics Therapeutics Entasis Inc. Debiopharm Debiopharm SA International MicuRx MicuRx Inc. Pharmaceuticals AstraZeneca PLC PLC AstraZeneca PLC Allergan For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Phase 2 2 Phase Phase 2 2 Phase Phase 2 2 Phase Ltd. Polyphor Phase 2 2 Phase PLC GlaxoSmithKline Phase 2 2 Phase Phase 2 2 Phase Phase 2 2 Phase Phase 2 2 Phase Phase 2 2 Phase For peer review only 2 Phase Ramoplanin Ramoplanin Nemonoxacin Nemonoxacin Geptidacin Geptidacin Finafloxacin Finafloxacin CG400549 CG400549 Ceftaroline+Avibactam Ceftaroline+Avibactam 2 Phase Brilacidin Brilacidin P0L7080 P0L7080 ETX0914 ETX0914 Debio 1450 1450 Debio MRX – 1 – MRX 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from ------1 1

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http://bmjopen.bmj.com/ BMJ Open cUTI prosthetic joint infection joint infection prosthetic Clostridium cIAI and cUTI cUTI and cIAI cUTI, cIAI, HAP, VAP, acute acute VAP, HAP, cIAI, cUTI, pyelonephritis CAP, cUTI, acute skin skin acute cUTI, CAP, infection HAP, VAP, cUTI, cUTI, VAP, HAP, infection bloodstream CAP CAP Clostridium CAP, HAP, VAP, acute skin skin acute VAP, HAP, CAP, osteomyelitis, infection, joint infections prosthetic cUTI, cIAI, HAP, VAP, febrile febrile VAP, HAP, cIAI, cUTI, bacteraemia, neutropenia, pyelonephritis acute Acute skin infections, CAP, CAP, infections, skin Acute Acute skin infection, infection, skin Acute on September 28, 2021 by guest. Protected copyright. Pharmaceuticals Ltd. Ltd. Pharmaceuticals Tetraphase Pharma Pharma Tetraphase Inc. Melinta Therapeutics Therapeutics Melinta Inc. Nabriva Therapeutics Therapeutics Nabriva Paratek Paratek Inc. Pharmaceuticals Dong Wha Dong Co. Pharmaceuticals Ltd. Summet Summet Inc. Therapeutics Rempex Rempex Inc. Pharmaceuticals Actelion Actelion AC AC For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Phase 3 3 Phase Inc. & Co. Merck Phase 3 3 Phase Phase 3 3 Phase PLC Bio Motif infection skin acute HAP, Phase 3 3 Phase Inc. Shionogi Phase 3 3 Phase Phase 3 3 Phase Phase 3 3 Phase Phase 3 3 Phase Phase 3 3 Phase Phase 2 2 Phase

For peer review only Eravacycline Eravacycline Delafloxacin (Baxdela) (Baxdela) Delafloxacin 3 Phase Carbavance Carbavance (Meropenem+Vaborbactam) Taksta (fusidic acid) acid) (fusidic Taksta 3 Phase Inc. Cempra Cadazolid Cadazolid Iclaprim Iclaprim Imipenem / / Imipenem Cilastatin+Relebactam Lefamulin Lefamulin Omadacycline Omadacycline S – 649266 649266 S – Zabofloxacin Zabofloxacin Ridinilazole Ridinilazole Page 11 of 40 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 12 of 40 - 2 2

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✓ ✓ a a http://bmjopen.bmj.com/ BMJ Open CAP, uncomplicated uncomplicated CAP, gonorrhoea, urogenital urethritis cUTI, HAP, VAP, cIAI, cIAI, VAP, HAP, cUTI, catheter-associated infection bloodstream on September 28, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Phase 3 3 Phase Inc. Cempra Phase 3 3 Phase Inc. Achaogen For peer review only target carbapenem Enterobacteriaceaeresistant pneumonia; VAP, ventilator-acquiredpneumonia. Community-acquiredCAP, pneumonia; cIAI, complicatedIntra-abdominal Infection; UTI, complicated UrinaryInfection; Tract HAP, hospital-acquired a Solithromycin Solithromycin Plazomicin Plazomicin 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 13 of 40 BMJ Open

1 2 3 DISCUSSION 4 Our search identified 76 clinical trials investigating one or more antibiotics recruiting children 5 6 between birth and 18 years of age. This is low in comparison to the number of on-going trials in 7 adults, despite children representing nearly a quarter of the global population.[14,15] A review of 8 9 completed CTs in the U.S. between 2000 and 2010 identified a total of 4078 adult trials compared to 10 11 just 294 that had recruited children.[16] In our study, the lack of trials recruiting neonates is striking. 12 Just 23 of the 76 trials identified were recruiting neonates and just 8 CTs globally were recruiting 13 14 preterm neonates. There are broadly two types of pediatric trials conducted globally: 15 pharmaceutical-ledFor Phase 1/2peer PK and safety review trials (n=17) in the HIC only setting, or investigator-led, 16 17 often pragmatic, late phase efficacy trials in the LMIC setting (n=34), with a greater proportion of on- 18 going trials being sponsored by non-profit organisations over industry (66% compared to 34%). As 19 20 of April 2016, there were 17 antibiotic PIPs agreed by the EMA,[8] covering a range of indications, 21 most commonly cSSTI, complicated IAI (cIAI), and complicated UTI (cUTI).[13] In contrast, 22 23 treatments for respiratory and systemic infections, the most common clinical indications for 24 antibiotics in pediatrics, are not currently being evaluated.[14] Thirty-seven antibiotics are being 25 26 developed in adults, yet to our knowledge just 2 of these are being studied in children. Some 27 classes of antibiotics that may be of higher risk for children (tetracyclines and fluoroquinolones) may 28 29 not be pursued as aggressively for pediatric approvals due to well-recognized issues of toxicity, 30 particularly when safer alternatives are widely available. Given that Gram-negative sepsis is a 31 32 growing problem in neonates, with a significant increase in the proportion of multi-resistant Gram- http://bmjopen.bmj.com/ 33 negative pathogens,[15] the substantial lag time between the submission date (for PIP or waiver) 34 35 and declared completion date of PK studies in adults is a real concern; however, there is value in 36 37 generating substantial safety data in adults prior to exposing children and newborns to potentially 38 toxic new agents. 39

40 on September 28, 2021 by guest. Protected copyright. 41 In 2013, a similar review of European pediatric clinical trials identified 31 trials of antibiotics 42 43 approved for adults by the EMA in 2000 that were recruiting children in Europe (compared to the 22 44 that we identified). They included both published and ongoing trials, which likely accounts for the 45 46 higher number of trials reported. They also found a very small proportion of neonatal trials (2 of 31), 47 as well as a greater proportion of efficacy-based trials.[9] A review of interventional trials registered 48 49 with ClinicalTrials.gov between 2007 and 2010 found that only 17% had recruited children below 18 50 years of age.[17] A similar review of antimicrobial CTs conducted in the U.S. between 2000 and 51 52 2012 reported that just 5% had recruited only children compared to 74% that recruited only adults, 53 and that, as we have found, the trials were sponsored primarily by non-profit organisations (60% 54 55 versus 30% by industry).[16] In our search of global trials, 39% of registered CTs reported collection 56 of PK data in comparison to the 24% identified in a 2009 paediatric PK research review.[18] 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 14 of 40

1 2 3 The search strategy used has clear limitations. Since the search was limited to clinical trials 4 registered with ClinicalTrials.gov, it is possible that other open or on-going trials registered with 5 6 alternative platforms (for example, the WHO International Clinical Trials Registry Platform [ICTRP]) 7 will have been missed. Together with ClinicalTrials.gov these could help to establish the entirety of 8 9 current clinical research in this field. We did however search EudraCT, and found no further studies 10 11 beyond those captured on ClinicalTrials.gov. Our search was also limited to open CTs, thereby 12 missing active but not yet recruiting trials, and those that had already closed to recruitment. The 13 14 information recorded for each trial registered with ClinicalTrials.gov is updated by the trial 15 investigators, andFor therefore reliespeer on them toreview periodically update theonly registry. Occasionally, 16 17 information such as recruitment status might not be updated in real time. 18 19 20 Concerns around the growing threat of antimicrobial resistance have prompted several new 21 initiatives. In 2016, the EMA published a draft Concept Paper to propose the development of an 22 23 Addendum to the guideline on the evaluation of new anti-bacterial products for treatment of bacterial 24 infections in children.[19] At the same time, the Clinical Trials Transformation Initiative (CTTI) is 25 26 currently focused on the identification of key barriers in the conduct of pediatric antibacterial CTs, 27 which hamper their successful implementation into clinical practice.[20] Recent evidence states that 28 29 overall, antibiotic CTs make up less than 1% of all registered pediatric CTs, and that trial completion 30 is slow, with an average time to completion of around two years.[21] There are specific areas where 31 32 the design and conduct of pediatric antibiotic CTs can be harmonized and simplified, such as the http://bmjopen.bmj.com/ 33 standardisation of the inclusion and exclusion criteria for specific Clinical Infection Syndromes, and 34 35 improved bridging of safety and efficacy data from other age groups; these advances could improve 36 37 trial conduct and efficiency in children.[22] 38 39

40 on September 28, 2021 by guest. Protected copyright. 41 CONCLUSIONS 42 43 This review highlights that very few pediatric antibiotic CTs are being conducted globally, 44 particularly in neonates. There is a marked disparity between antibiotic drug development 45 46 programmes in adults and children. Many issues contribute to the difficulties in conducting pediatric 47 antibiotic clinical trials. The lack of regulatory guidance, vulnerability of this population, issues with 48 49 informed consent and assent, and lack of research-experienced hospital personnel all present 50 challenges in study design, delivery and recruitment. Delays in the initial start-up of CTs in children 51 52 due to pediatric-specific protocol issues and complicated ethical approval continue to discourage 53 both academic and pharmaceutical interest. The limited data presented here suggest that the 54 55 dismal state of pediatric antibiotic research continues. Earlier collaboration between global 56 academic research networks and pharmaceutical companies is now vital to accelerate progress. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 15 of 40 BMJ Open

1 2 3 4 ACKNOWLEDGEMENTS 5 6 Contributors MS, CB, GT, LF and JB designed the study, GT conducted the search, IL and JB 7 commented on study design and assisted with drafting the paper. 8 9 Funding This research received no specific grant from any funding agency in the public, 10 11 commercial or not-for-profit sectors. CB was funded as a Clinical Research Fellow by the Global 12 Research in Paediatrics (GRiP) Network of Excellence, part of the European Union’s Seventh 13 14 Framework Programme for research, technological development and demonstration (FP7/2007– 15 2013, grant agreementFor number peer 261060). review only 16 17 Conflict of interest None declared. 18 Data sharing statement Full dataset is available on request. 19 20 21 22 23 REFERENCES 24 1. Corny J, Lebel D, Bailey B et al. Unlicensed and Off-Label Drug Use in Children Before and 25 26 After Pediatric Governmental Initiatives. J Pediatr Pharmacol Ther. 2015;20(4):316–28. 27 2. European Medicines Agency. Concept paper on extrapolation of efficacy and safety in 28 29 medicine development. 30 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/04/WC50 31 32 0142358.pdf. (accessed May 2016) http://bmjopen.bmj.com/ 33 3. Dunne J, Rodriguez WJ, Murphy MD et al. Extrapolation of Adult Data and Other Data in 34 35 Pediatric Drug-Development Programs. Pediatrics. 2011; 36 37 http://pediatrics.aappublications.org/content/early/2011/10/20/peds.2010-3487.abstract 38 (accessed June 2016) 39

40 4. Kearns GL, Abdel-Rahman SM, Alander SW et al. Developmental pharmacology--drug on September 28, 2021 by guest. Protected copyright. 41 disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157–67. 42 43 5. Theuretzbacher U, Van Bambeke F, Cantón R et al. Reviving old antibiotics. Internet J 44 Antimicrob Chemother. 2015; 45 46 http://jac.oxfordjournals.org/content/early/2015/06/10/jac.dkv157.abstract (accessed June 47 2016) 48 49 6. van der Meer JW, Gyssens IC. Quality of antimicrobial drug prescription in hospital. Clin 50 Microbiol Infect. 2001;7:12–5. 51 52 7. European Medicines Agency. EMA Opinions and decisions on Paediatric Investigation Plans. 53 2016; 54 55 http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/pip_search.jsp&mid 56 =WC0b01ac058001d129. (accessed June 2016) 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 16 of 40

1 2 3 8. Guidance for industry. Pediatric Study Plans: Content of and Process for Submitting Initial 4 Pediatric Study Plans and Amended Initial Pediatric Study Plans. 5 6 http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/uc 7 m360507.pdf. (accessed June 2016) 8 9 9. Garazzino S, Lutsar I, Bertaina C et al. New antibiotics for paediatric use: a review of a 10 11 decade of regulatory trials submitted to the European Medicines Agency from 2000--why 12 aren’t we doing better? Int J Antimicrob Agents. 2013;42(2):99–118. 13 14 10. The World Bank. The World Bank list of economies. 2015; 15 http://siteresources.worldbank.org/DATASTATISTICS/Resources/CLASS.XLSFor peer review only (accessed 16 17 October 2016) 18 11. The World Health Organisation. WHO ATC/DDD Index. 2016; 19 20 http://www.whocc.no/atc_ddd_index/. (accessed March 2016) 21 12. The Pew Charitable Trusts. Antibiotics Currently in Clinical Development. 2016; 22 23 http://www.pewtrusts.org/~/media/assets/2016/05/antibiotics-currently-in-clinical- 24 development.pdf?la=en. (accessed May 2016) 25 26 13. Lutsar I. Often neglegted: paediatric drug development - a regulatory and clinical view. In 27 Amsterdam, Netherlands; 2016. (S219 - Symposium lecture.). 28 29 14. Versporten A, Bielicki J, Drapier N et al. The Worldwide Antibiotic Resistance and Prescribing 30 in European Children (ARPEC) point prevalence survey: developing hospital-quality 31 32 indicators of antibiotic prescribing for children. J Antimicrob Chemother. 2016;71(4):1106–17. http://bmjopen.bmj.com/ 33 15. Bielicki JA, Lundin R, Sharland M. Antibiotic Resistance Prevalence in Routine Bloodstream 34 35 Isolates from Children’s Hospitals Varies Substantially from Adult Surveillance Data in 36 37 Europe. Pediatr Infect Dis J. 2015;34(7):734–41. 38 16. Stockmann C, Sherwin CMT, Ampofo K et al. Characteristics of antimicrobial studies 39

40 registered in the USA through ClinicalTrials.Gov. Int J Antimicrob Agents. 2013;42(2):161–6. on September 28, 2021 by guest. Protected copyright. 41 17. Califf RM, Zarin DA, Kramer JM et al. Characteristics of clinical trials registered in 42 43 ClinicalTrials.gov, 2007-2010. JAMA. 2012;307(17):1838–47. 44 18. Viergever RF, Rademaker CMA, Ghersi D. Pharmacokinetic research in children: an analysis 45 46 of registered records of clinical trials. BMJ Open. 2011;1(1):e000221. 47 19. European Medicines Agency. Concept paper on an addendum to the guideline on the 48 49 evaluation of medicinal products indicated for treatment of bacterial infections to address 50 paediatric-specific clinical data requirements. 51 52 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/04/WC50 53 0205026.pdf. (accessed July 2016) 54 55 20. Clinical Trials Transformation Initiative. https://www.ctti-clinicaltrials.org/projects/pediatric- 56 trials. (accessed July 2016) 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 17 of 40 BMJ Open

1 2 3 21. Clinical Trials Transformation Initiative. AACT database. https://www.ctti- 4 clinicaltrials.org/aact-database. (accessed January 2017) 5 6 22. Folgori L, Bielicki J, Ruiz B, et al. Harmonisation in study design and outcomes in paediatric 7 antibiotic clinical trials: a systematic review. Lancet Infect Dis. 2016;16(9):e178-89. 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 28, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 18 of 40

1 2 3 LIST OF FIGURES 4

5 6 Figure 1. Flow chart. Clinical trial selection process. 7

8 9 Table 1. Characteristics of clinical trials. 10 11 12 Table 2. Clinical trial endpoint classification of identified clinical trials stratified by trial sponsor. 13 Endpoint classification determined by planned primary outcomes. 14 15 Table 3. ClinicalFor indication ofpeer identified clinical review trials stratified by ageonly group being recruited. 16 17 18 Table 4. Comparison of antibiotic development pipeline in adults and children. Adapted from Pew 19 Charitable Trusts “Antibiotics currently in clinical development” pipeline (last accessed October 20 2016).[12] 21 22 23 24 25 26 27 28 29 30 31 32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 28, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 19 of 40 BMJ Open

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 http://bmjopen.bmj.com/ 32 Figure 1. Flow Chart. Clinical trial selection process. 33 34 254x190mm (300 x 300 DPI) 35 36 37 38 39

40 on September 28, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

BMJ Open Page 20 of 40 DATASET 1 2 A B C D 3 1 NCT Number Title Recruitment Study Results 4 2 NCT02539407 Population Pharmacokinetics of Anti-infectives in Critically Ill Children Recruiting No Results Available 5 6 3 NCT02935374 Effect of Antimicrobial Treatment of Acute Otitis Media on the Intestinal Microbiome in ChildrenNot yet recruiting No Results Available 7 4 NCT02899143 Short-course Antimicrobial Therapy in Sepsis Recruiting No Results Available 8 5 NCT01595529 The SCOUT Study: Short Course Therapy for Urinary Tract Infections in Children Recruiting No Results Available 9 10 6 NCT02380352 Short-course Antimicrobial Therapy for Paediatric Respiratory Infections Not yet recruiting No Results Available 11 7 NCT02891915 Trial to Evaluate Beta-Lactam Antimicrobial Therapy of Community Acquired Pneumonia in ChildrenFor peer review onlyRecruiting No Results Available 12 8 NCT02746276 Optimising Antibiotic Treatment for Sick Malnourished Children Recruiting No Results Available 13 9 NCT02917551 BALANCE on the Wards: A Pilot RCT Not yet recruiting No Results Available 14 15 10 NCT01243437 A Clinical Trial to Evaluate the Safety and Efficacy of Ciprofloxacin in the Treatment of Plague in Humanshttp://bmjopen.bmj.com/ Recruiting No Results Available 16 11 NCT02635191 Tailored Therapy for Helicobacter Pylori in Children Recruiting No Results Available 17 12 NCT01522105 Daptomycin in Pediatric Patients With Bacterial Meningitis Recruiting No Results Available 18 19 13 NCT02456974 Antibiotic Dosing in Pediatric Intensive Care Recruiting No Results Available 20 14 NCT00579956 A Randomized Double Blinded Comparison of Ceftazidime and Meropenem in Severe MelioidosisRecruiting No Results Available 21 15 NCT00545961 Middle Meatal Bacteriology During Acute Respiratory Infection in Children Not yet recruiting No Results Available 22 16 NCT01431326 Pharmacokinetics of Understudied Drugs Administered to Children Per Standard of Care Recruiting No Results Available 23 on September 28, 2021 by guest. Protected copyright. 24 17 NCT02475876 PK of Clindamycin and Trimethoprim-sulfamethoxazole in Infants and Children Recruiting No Results Available 25 18 NCT01420341 Co-trimoxazole as Maintenance Therapy for Meliodosis Recruiting No Results Available 26 19 NCT02266706 Pharmacokinetic and Safety Study of Ceftolozane/Tazobactam in Pediatric Participants Receiving Antibiotic Therapy for Proven or Suspected Gram-negative Infection or for Peri-operative Prophylaxis (MK-7625A-010)Recruiting No Results Available 27 28 20 NCT00867789 Antibiotics Versus Placebo in the Treatment of Abscesses in the Emergency Department Recruiting No Results Available 29 21 NCT02879981 A Safety Study of Balsamic Bactrim in Pediatric Participants With Acute Bronchitis Not yet recruiting No Results Available 30 22 NCT01269541 MESS-study MRSA Eradication Study SkÌ´ne Recruiting No Results Available 31 23 NCT02276482 Study of Tedizolid Phosphate in Adolescents With Complicated Skin and Soft Tissue Infection (cSSTI) (MK-1986-012)Recruiting No Results Available 32 33 24 NCT02663596 Safety and TDM of Continuous Infusion Vancomycin Through Continuous Renal Replacement Therapy SolutionNot yet recruiting No Results Available 34 25 NCT02555059 Special Drug Use Investigation of Ciproxan Injection in Pediatrics Recruiting No Results Available 35 26 NCT02297815 Comparative Effectiveness of Antibiotics for Respiratory Infections Recruiting No Results Available 36 37 27 NCT02224040 Typhoid Fever: Combined vs. Single Antibiotic Therapy Recruiting No Results Available 38 28 NCT02775968 Population Pharmacokinetics of Cephalosporins and Macrolides in Chinese Children With Community Acquired PneumoniaNot yet recruiting No Results Available 39 29 NCT02687906 Dose-finding, Pharmacokinetics, Safety, and Tolerability of Meropenem-Vaborbactam in Pediatric Subjects With Serious Bacterial InfectionsRecruiting No Results Available 40 30 NCT02783859 Hospitalised Pneumonia With Extended Treatment (HOPE) Study Recruiting No Results Available 41 42 31 NCT01994993 Antibiotic Safety (SCAMP) Recruiting No Results Available 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 A B C D 3 32 NCT02258763 Trial on the Ideal Duration of Oral Antibiotics in Children With Pneumonia Recruiting No Results Available 4 33 NCT02688790 Study Evaluate the PK Profile of Dalbavancin in Hospitalized Infants and Neonates Patients With Known or Suspected Bacterial InfectionRecruiting No Results Available 5 6 34 NCT00323219 Oral Moxifloxacin Versus Cefazolin and Oral Probenecid in the Management of Skin and Soft Tissue Infections in the Emergency DepartmentRecruiting No Results Available 7 35 NCT02750761 A Study of Oral and Intravenous (IV) Tedizolid Phosphate in Hospitalized Participants, Ages 2 to <12 Years, With Confirmed or Suspected Bacterial Infection (MK-1986-013)Recruiting No Results Available 8 36 NCT02466438 Safety and Pharmacokinetics of Piperacillin-tazobactam Extended Infusion in Infants and Children (PIP-TAZO)Recruiting No Results Available 9 10 37 NCT02260102 Temocillin Pharmacokinetics in Paediatrics Not yet recruiting No Results Available 11 38 NCT02694458 Comparison of Two Dosage Adjustment Strategies of Vancomycin in ChildrenFor peer review onlyRecruiting No Results Available 12 39 NCT01540838 Slow Initial beta-lactam Infusion With High-dose Paracetamol to Improve the Outcomes of Childhood Bacterial MeningitisRecruiting No Results Available 13 40 NCT00368498 A Trial to Evaluate the Loading Dose Required to Achieve Therapeutic Serum Teicoplanin Concentration TimelyRecruiting No Results Available 14 15 41 NCT01785641 Single Versus Combined Antibiotic Therapy for Bacterial Peritonitis in CAPD Patients http://bmjopen.bmj.com/ Recruiting No Results Available 16 42 NCT02554383 Efficacy of Antibiotics in Children With Acute Sinusitis: Which Subgroups Benefit? Recruiting No Results Available 17 43 NCT01265173 Comparison of Efficacy of Cefotaxime, Ceftriaxone, and Ciprofloxacin for the Treatment of Spontaneous Bacterial Peritonitis in Patients With Liver CirrhosisRecruiting No Results Available 18 19 44 NCT02335905 Ceftaroline for Treatment of Hematogenously Acquired Staphylococcus Aureus Osteomyelitis in ChildrenRecruiting No Results Available 20 45 NCT02922686 Penicillin for the Emergency Department Outpatient Treatment of CELLulitis Not yet recruiting No Results Available 21 46 NCT02848820 Initial Non-operative Treatment Strategy Versus Appendectomy Treatment Strategy for Simple Appendicitis in ChildrenNot yet recruiting No Results Available 22 47 NCT02475733 Evaluation of Safety,Pharmacokinetics and Efficacy of CAZ-AVI With Metronidazole in Childern Aged 3 Months to 18 Years Old With Complicated Intra-abdominal Infections (cIAIs).Recruiting No Results Available 23 on September 28, 2021 by guest. Protected copyright. 24 48 NCT02372461 Randomized Trial of Amoxicillin Versus Placebo for (Fast Breathing) Pneumonia Recruiting No Results Available 25 49 NCT01553006 Study of Cefditoren Pivoxil in Treatment of Childhood With Acute Rhinosinusitis Recruiting No Results Available 26 50 NCT02527681 Pharmacokinetics and Safety of Ceftobiprole in Neonates and Infants up to 3 Months Treated With Systemic AntibioticsRecruiting No Results Available 27 28 51 NCT02210169 RCT of Continuous Versus Intermittent Infusion of Vancomycin in Neonates Recruiting No Results Available 29 52 NCT02497781 Evaluation of Safety, Pharmacokinetics and Efficacy of Ceftazidime and Avibactam (CAZ-AVI ) Compared With Cefepime in Children From 3 Months to Less Than 18 Years of Age With Complicated Urinary Tract Infections (cUTIs)Recruiting No Results Available 30 53 NCT02814916 Dalbavancin for the Treatment of Acute Bacterial Skin and Skin Structure Infections in Children, Known or Suspected to be Caused by Susceptible Gram-positive Organisms, Including MRSANot yet recruiting No Results Available 31 54 NCT02210325 Efficacy and Safety Study of Oral Solithromycin Compared to Intramuscular Ceftriaxone Plus Oral Azithromycin in the Treatment of Patients With GonorrheaRecruiting No Results Available 32 33 55 NCT02801370 Phase 3 Study of OTO-201 in Acute Otitis Externa Recruiting No Results Available 34 56 NCT02760420 3 Days Amoxicillin Versus Placebo for Fast Breathing Childhood Pneumonia in Malawi Recruiting No Results Available 35 57 NCT02678195 3 Days Versus 5 Days Amoxicillin for Chest-indrawing Childhood Pneumonia in Malawi Recruiting No Results Available 36 37 58 NCT02605122 Safety and Efficacy of Solithromycin in Adolescents and Children With Community-acquired Bacterial PneumoniaRecruiting No Results Available 38 59 NCT02570490 Oral Sodium Fusidate (CEM-102) Versus Oral Linezolid for the Treatment of Acute Bacterial Skin and Skin Structure InfectionsRecruiting No Results Available 39 60 NCT02443285 Is Spontaneous Bacterial Peritonitis Still Responding to 3rd Generation Cephalosporins? Recruiting No Results Available 40 61 NCT02334124 Comparing the Intravenous Treatment of Skin Infections in Children, Home Versus Hospital Recruiting No Results Available 41 42 62 NCT02218372 A Study to Investigate the Safety and Efficacy of Fidaxomicin (Oral Suspension or Tablets) and Vancomycin (Oral Liquid or Capsules) in Pediatric Subjects With Clostridium Difficile-associated Diarrhea (CDAD)Recruiting No Results Available 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 A B C D 3 63 NCT01032499 Open and Comparative Study to Measure Tolerability and Efficacy of Taro Elixir Not yet recruiting No Results Available 4 64 NCT02598362 Pharmacokinetics of Ciprofloxacin in Pediatric Patients Recruiting No Results Available 5 6 65 NCT02878031 Community Case Management of Chest Indrawing Pneumonia Recruiting No Results Available 7 66 NCT02790996 Neonatal Vancomycin Trial Not yet recruiting No Results Available 8 67 NCT02712307 Study of 5 and 10 Days Treatment With Penicillin Against Sore Throat Caused by Streptococci Recruiting No Results Available 9 10 68 NCT02424734 Safety, Tolerability and Efficacy of Ceftaroline in Paediatrics With Late-Onset Sepsis Recruiting No Results Available 11 69 NCT02134301 Open-Label, Dose-Finding, Pharmacokinetics, Safety and Tolerability Study of Oritavancin in Pediatric Patients With Suspected or Confirmed Bacterial InfectionsFor peer review onlyRecruiting No Results Available 12 70 NCT02013141 An Open-Label Study of the Pharmacokinetics of a Single Dose of Telavancin in Pediatric Subjects Aged 1 to 17 YearsRecruiting No Results Available 13 71 NCT01427842 Dose Enhancement of Vancomycin IN Everyday Patients Recruiting No Results Available 14 15 72 NCT01278017 The Role of Short-course Ceftriaxone Therapy in the Treatment of Severe Nontyphoidal Salmonella Enterocolitishttp://bmjopen.bmj.com/ Recruiting No Results Available 16 73 NCT00988026 Safety and Efficacy Comparison of Minocycline Microgranules Versus Lymecycline in the Treatment of Mild to Moderate AcneRecruiting No Results Available 17 74 NCT02288234 Telavancin Observational Use Registry (TOUR) Recruiting No Results Available 18 19 75 NCT01304459 Vancomycin Serum Concentrations in Pediatric Oncology Patients Under Intensive Care Recruiting No Results Available 20 76 NCT01173575 Assessment of the Efficacy of FOSFOMYCIN in Patients With Bacterial Infection Recruiting No Results Available 21 77 NCT01778634 Trial of Intravenous Azithromycin to Eradicate Ureaplasma Respiratory Tract Infection in Preterm Infants (AZIPIII)Recruiting No Results Available 22

23 on September 28, 2021 by guest. Protected copyright. 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 E F 3 1 Indication Infection category 4 2 Proven or suspected infection (in patients on PICU) 9 5 6 3 Acute Otitis Media 3 7 4 Sepsis 8 8 5 Urinary Tract Infections (UTI) 7 9 10 6 Community-acquired Pneumonia (CAP) 4 11 7 Pneumonia For peer review4 only 12 8 Proven or suspected infection in patients with malnutrition 9 13 9 Bacteremia 8 14 15 10 Plague 8 http://bmjopen.bmj.com/ 16 11 Helicobacter Pylori Infection 7 17 12 Meningitis 1 18 19 13 Proven or suspected bacterial infection (Pharmacokinetics) 9 20 14 Melioidosis 8 21 15 Acute Respiratory Infection|Sinusitis 3 22 16 Various infections (including nosocomial Pneumonia, CAP, Acute Bacterial Exacerbation of Chronic Bronchitis, cSSSI, Uncomplicated SSSI, cUTI, Acute Pyelonephritis, uUTI, Bacterial Septicemia, Plague, Acute Bacterial Sinusitis, Bacterial Meningitis)Various 23 on September 28, 2021 by guest. Protected copyright. 24 17 Bacterial Infections 9 25 18 Meliodosis 8 26 19 Proven or Suspected Gram-negative Bacterial Infection 9 27 28 20 Abscess 1 29 21 Bronchitis 4 30 22 Throatcarriers of MRSA 3 31 23 Acute Skin and Soft Tissue infections (aSSTIs) 2 32 33 24 Proven or suspected bacterial infection (in CRRT patients) 9 34 25 Cystitis / Pyelonephritis 7 35 26 Acute Upper Respiratory Tract Infections (ARTIs) 3 36 37 27 Typhoid Fever 8 38 28 Community Acquired Pneumonia (CAP) 4 39 29 Bacterial Infections 9 40 30 Pneumonia 4 41 42 31 Complicated Intra Abdominal Infections (cIAIs) 6 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 E F 3 32 Pneumonia 4 4 33 Bacterial Infections 9 5 6 34 Cellulitis 2 7 35 Gram-Positive Bacterial Infections 9 8 36 Infection 9 9 10 37 Urinary Tract Infection or suspected Cholangitis 7 11 38 Methicillin-resistant Staphylococcal InfectionsFor peer review9 only 12 39 Bacterial Meningitis 1 13 40 Staphylococcal Infections 9 14 15 41 Peritonitis (in CAPD patients) 6 http://bmjopen.bmj.com/ 16 42 Acute Sinusitis (Respiratory Tract Infections) 3 17 43 SBP in patients with Liver Cirrhosis 6 18 19 44 Hematogenously Acquired Staphylococcus Aureus Osteomyelitis 5 20 45 Cellulitis or Wound Infection 8 21 46 Appendicitis 6 22 47 Complicated Intra-abdominal Infections (cIAIs) 6 23 on September 28, 2021 by guest. Protected copyright. 24 48 Pneumonia (fast-breathing) 4 25 49 Rhinosinusitis 3 26 50 Bacterial Infections 9 27 28 51 Sepsis 8 29 52 Complicated Urinary Tract Infections (cUTIs) 7 30 53 Methicillin-Resistant Staphylococcus Aureus Skin Infection 2 31 54 Uncomplicated Urogenital Gonorrhea 7 32 33 55 Acute Otitis Externa 3 34 56 Pneumonia 4 35 57 Pneumonia 4 36 37 58 Community-acquired Bacterial Pneumonia 4 38 59 Acute Bacterial Skin and Skin Structure Infections 2 39 60 Primary Bacterial Peritonitis 6 40 61 Cellulitis 8 41 42 62 Clostridium Difficile-associated Diarrhea (CDAD) 6 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 E F 3 63 Acne Vulgaris II or III Degree 2 4 64 Urinary Tract Infection or Pyelonephritis 7 5 6 65 Pneumonia 4 7 66 Late Onset Neonatal Sepsis 8 8 67 Tonsillitis 3 9 10 68 Late-onset Sepsis 8 11 69 Gram Positive Bacterial InfectionsFor peer review9 only 12 70 Gram-Positive Bacterial Infections 9 13 71 Vancomycin Therapy 9 14 15 72 Diarrhea 6 http://bmjopen.bmj.com/ 16 73 Mild to Moderate Acne 2 17 74 Hospital Acquired Bacterial Pneumonia (HAP), Complicated Skin and Skin Structure Infections (cSSSI), Ventilator Associated Bacterial Pneumonia (VAP), Gram Positive InfectionVarious 18 19 75 Infection 9 20 76 Bacterial Infection 9 21 77 Eradicate ureaplasma respiratory tract infection from preterm infants4 22

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1 2 G H I J 3 1 Interventions Antibiotic class (J01 code) Gender Age 4 2 Antiinfectives (beta-lactam, aminoglycoside, glycopeptide, fluoroquinolone, daptomycin, rifampin, trimethoprim, sulfamethoxazole, clarithromycin)Various Both Up to 18 Years 5 6 3 Amoxicillin, Amoxicillin-Potassium Clavulanate, Macrolide Various Both 6 Months to 7 Years 7 4 Antibiotic J01 Both Up to 18 years 8 5 Trimethoprim sulfamethoxazole, cefixime, or cephalexin Various Both 2 Months to 10 Years 9 10 6 Amoxicillin J01C Both 6 Months to 10 Years 11 7 Amoxicillin, Amoxicillin-clavulanate, CefdinirFor peer reviewVarious onlyBoth 6 Months to 71 Months 12 8 Ceftriaxone, Metronidazole J01D Both 2 Months to 59 Months 13 9 7 days vs 14 days of adequate antibiotic treatment J01 Both Up to 18 years 14 15 10 Ciprofloxacin, doxyxcycline Various Bothhttp://bmjopen.bmj.com/ 8 Years and older 16 11 Tailored vs standard therapy (Amoxicillin, Clarithromycin, Metronidazole, Rabeprazole, Esomeprazole, Omeprazole)Various Both 4 Years to 18 Years 17 12 Daptomycin J01X Both 3 Months to 16 Years 18 19 13 Amoxicillin-clavulanate, Piperacilline-tazobactam, Vancomycin Various Both Up to 16 Years 20 14 Meropenem, Ceftazidime J01D Both 15 Years and older 21 15 Amoxicillin clavulanate acid J01C Both 6 Years to 13 Years 22 16 Various drugs (Ceftazidime, Ciprofloxacin, Clindamycin, Doxycycline, Levofloxacin, Meropenem)Various Both Up to 18 years 23 on September 28, 2021 by guest. Protected copyright. 24 17 Clindamycin, Trimethoprim-sulfamethoxazole Various Both 1 Month to 16 Years 25 18 Co-trimoxazole J01E Both 15 Years and older 26 19 Ceftolozane/Tazobactam J01D Both Up to 17 Years 27 28 20 Trimethoprim-sulfamethoxazole J01E Both 3 Months to 17 Years 29 21 Guaifenesin, Sulfamethoxazole trimethoprim J01E Both 4 Years to 14 Years 30 22 Systemic Rifampin and Clindamycine/Trimehoprimsulfa, or Topical mupirocinVarious Both 5 Years and older 31 23 Tedizolid Phophate J01X Both 12 Years to 18 Years 32 33 24 Vancomycin J01X Both Up to 18 years 34 25 Ciprofloxacin J01F Both Up to 14 Years 35 26 Antibiotics (Amoxicillin-clavulanate, azithromycin, cefdinir, cefprozil, cefuroxime axetil, ceftriaxone, cefadroxil)Various Both 6 Months to 18 Years 36 37 27 Ceftriaxone, Ceftriaxone/azithromycin, Azithromycin, Azithromycin/cefiximeVarious Both 2 Years to 80 Years 38 28 Cephalosporins and Macrolides Various Both 1 Year to 18 Years 39 29 Carbavance J01D Both Up to 17 Years 40 30 Amoxicillin-clavulanic Acid J01C Both 3 Months to 5 Years 41 42 31 Ampicillin/metronidazole/gentamicin/clindamycin/Piperacillin-tazobactam combinationsVarious Both Up to 120 Days 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 G H I J 3 32 Amoxicillin-Potassium Clavulanate J01C Both 3 Months to 59 Months 4 33 Dalbavancin J01X Both Up to 28 Days 5 6 34 Cefazolin/Moxifloxacin Various Both Up to 18 Years 7 35 Tedizolid Phosphate J01X Both 2 Years to 11 Years 8 36 Piperacillin-tazobactam J01C Both 2 Months to 6 Years 9 10 37 Temocillin J01C Both 6 Months to 3 Years 11 38 Vancomycin For peer reviewJ01X onlyBoth 1 Month to 16 Years 12 39 Beta-lactam J01C Both 2 Months to 15 Years 13 40 Teicoplanin J01X Both 16 Years and older 14 15 41 Ceftazidime/ciprofloxacin, Ceftazidime, Cefazolin/gentamicin, Cefazolin Various Bothhttp://bmjopen.bmj.com/ 15 Years and older 16 42 Amoxicillin-clavulanate J01C Both 2 Years to 11 Years 17 43 Cefotaxime, Ceftriaxone, Ciprofloxacin Various Both 16 Years and older 18 19 44 Ceftaroline Fosamil J01D Both 1 Year to 17 Years 20 45 Flucloxacillin, Phenoxymethylpenicillin J01C Both 16 Years and older 21 46 Augmentin/Gentamicin, Appendectomy J01C Both 7 Years to 17 Years 22 47 Ceftazidime-avibactam, Meropenem, Metronidazole Various Both 3 Months to 18 Years 23 on September 28, 2021 by guest. Protected copyright. 24 48 Amoxicillin J01C Both 2 Months to 59 Months 25 49 Cefditoren pivoxil J01D Both 1 Year to 15 Years 26 50 Ceftobiprole J01D Both Up to 3 Months 27 28 51 Vancomycin J01X Both Up to 90 Days 29 52 Ceftazidime-avibactam, Cefepime J01D Both 3 Months to 18 Years 30 53 Dalbavancin single dose J01X Both 3 Months to 17 Years 31 54 Solithromycin, Ceftriaxone, Azithromycin Various Both 15 Years and older 32 33 55 Ciprofloxacin J01M Both 6 Months and older 34 56 Amoxicillin J01C Both 2 Months to 59 Months 35 57 Amoxicillin J01C Both 2 Months to 59 Months 36 37 58 Solithromycin J01F Both 2 Months to 17 Years 38 59 Sodium fusidate, Linezolid J01X Both 12 Years and older 39 60 Cefotaxime, Ceftriaxone J01D Both Up to 18 Years 40 61 Ceftriaxone, Flucloxacillin Various Both 6 Months to 18 Years 41 42 62 Fidaxomicin, Vancomycin J01X Both Up to 17 Years 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 G H I J 3 63 Taro Elixir J01A Both 14 Years and older 4 64 Ciprofloxacin J01M Both 3 Months to 17 Years 5 6 65 Amoxicillin J01C Both 2 Months to 59 Months 7 66 Vancomycin J01X Both Up to 90 Days 8 67 Phenoxymethylpenicillin J01C Both 6 Years and older 9 10 68 Ceftaroline Fosamil J01D Both Up to 59 Days 11 69 Oritavancin For peer reviewJ01X onlyBoth Up to 18 Years 12 70 Telavancin J01X Both 1 Year to 17 Years 13 71 Vancomycin J01X Both 16 Years and older 14 15 72 Ceftriaxone J01D Bothhttp://bmjopen.bmj.com/ 3 Months to 18 Years 16 73 Minocycline, Lymecycline J01A Both 14 Years to 30 Years 17 74 Telavancin J01X Both Up to 18 Years 18 19 75 Vancomycin J01X Both Up to 18 Years 20 76 Fosfomycin J01X Both Up to 18 Years 21 77 Azithromycin J01F Both 0 to 72 hours 22

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1 2 K L M N O 3 1 Age group Estimated enrollment Location Income class Geographic region 4 2 8 1850 France High income Europe 5 6 3 9 150 Finland High income Europe 7 4 8 320 Italy High income Europe 8 5 9 746 United States High income North America 9 10 6 9 270 Canada High income North America 11 7 9 For400 United States peer reviewHigh income onlyNorth America 12 8 9 80 Kenya Lower middle income Africa 13 9 8 50 Canada High income North America 14 15 10 11 200 Uganda Low income Africa http://bmjopen.bmj.com/ 16 11 11 200 China Upper middle income Asia 17 12 10 5 Switzerland High income Europe 18 19 13 8 200 Belgium High income Europe 20 14 5 750 Thailand Upper middle income Asia 21 15 11 120 Finland High income Europe 22 16 8 3000 Various (United States, Canada, Israel, Singapore, United Kingdom)High income International 23 on September 28, 2021 by guest. Protected copyright. 24 17 10 54 United States High income North America 25 18 5 800 Thailand Upper middle income Asia 26 19 8 36 United States High income North America 27 28 20 10 200 United States High income North America 29 21 11 50 Peru Upper middle income Latin America 30 22 11 69 Sweden High income North America 31 23 5 162 Various (United States, Argentina, Bulgaria, Chile, Czech Republic, Georgia, Germany, Latvia, Lithuania, Panama, Poland, Slovenia, South Africa, Spain)Upper middle to High income International 32 33 24 8 10 United States High income North America 34 25 8 45 Japan High income Asia 35 26 10 117000 United States High income North America 36 37 27 11 120 Nepal Low income Asia 38 28 10 750 China Upper middle income Asia 39 29 8 56 United States High income North America 40 30 9 314 Various (Australia, Malaysia) High income Oceania 41 42 31 6 284 Various (United States, Canada)High income North America 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 K L M N O 3 32 9 300 Malaysia Upper middle income Asia 4 33 2 24 United States High income North America 5 6 34 8 390 Canada High income North America 7 35 4 32 United States High income North America 8 36 9 141 Canada High income North America 9 10 37 9 45 Belgium High income Europe 11 38 10 For100 France peer reviewHigh income onlyEurope 12 39 10 400 Angola Upper middle income Africa 13 40 5 20 Taiwan, China High income Asia 14 15 41 5 300 Thailand Upper middle income Asia http://bmjopen.bmj.com/ 16 42 4 688 United States High income North America 17 43 5 261 Republic of Korea High income Asia 18 19 44 10 18 United States High income North America 20 45 5 414 Ireland High income Europe 21 46 11 334 Netherlands High income Europe 22 47 10 102 Various (United States, Argentina, Chile, Czech Republic, Greece, Hungary, Poland, Romania, Russian Federation, Spain, Taiwan, Turkey) Upper middle to High income International 23 on September 28, 2021 by guest. Protected copyright. 24 48 9 2500 Pakistan Lower middle income Asia 25 49 10 120 Thailand Upper middle income Asia 26 50 6 45 Various (Belgium, Germany, Lithuania)High income Europe 27 28 51 6 200 Australia High income Oceania 29 52 10 102 Various (United States, Czech Republic, Greece, Hungary, Republic of Korea, Poland, Romania, Russian Federation, Taiwan, Turkey)Upper middle to High income International 30 53 10 300 United States High income North America 31 54 5 300 Various (United States, Australia)High income International 32 33 55 10 500 Various (United States, Canada)High income North America 34 56 9 2000 Malawi Low income Africa 35 57 9 2000 Malawi Low income Africa 36 37 58 10 400 Various (United States, Bulgaria, Hungary, Spain)High income International 38 59 5 712 Various (United States, Puerto Rico)High income International 39 60 8 100 Egypt Lower middle income Africa 40 61 10 188 Australia High income Oceania 41 42 62 8 144 Various (United States, Belgium, Canada, France, Germany, Hungary, Italy, Poland, Romania, Slovakia, Spain)High income International 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 K L M N O 3 63 5 120 Brazil Upper middle income Latin America 4 64 10 20 Belgium High income Europe 5 6 65 9 308 Nigeria Lower middle income Africa 7 66 6 300 Various (United Kingdom, France, Italy, Greece, Estonia)High income Europe 8 67 11 432 Sweden High income Europe 9 10 68 7 24 Various (United States, Hungary, Italy, Lithuania, Spain)High income International 11 69 8 For60 United States peer reviewHigh income onlyNorth America 12 70 10 32 United States High income North America 13 71 5 100 Australia High income Oceania 14 15 72 10 200 Taiwan, China High income Asia http://bmjopen.bmj.com/ 16 73 5 168 Mexico High income North America 17 74 8 1000 United States High income North America 18 19 75 8 50 Brazil Upper middle income Latin America 20 76 8 200 Various (Austria, Germany) High income Europe 21 77 1 180 United States High income North America 22

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1 2 P Q R S T 3 1 Collaborators Sponsor Study Types Phase Endpoint classification 4 2 Assistance Publique - Hopitaux de Paris Hospital Observational Not applicable Pharmacokinetics 5 6 3 University of Oulu|Oulu University Hospital University Interventional Phase 4 Efficacy 7 4 Ospedale Santa Maria delle Croci Hospital Interventional Phase 2 Safety/Efficacy 8 5 Children's Hospital of Philadelphia|Children's Hospital of Pittsburgh|University of Pennsylvania|Westat|National Institute of Allergy and Infectious Diseases (NIAID)Hospital Interventional Phase 2 Safety/Efficacy 9 10 6 Hamilton Health Sciences Corporation|Children's Hospital of Eastern OntarioHospital Interventional Phase 4 Safety/Efficacy 11 7 National Institute of Allergy and Infectious Diseases (NIAID)For peerNIH Interventional reviewPhase 4 onlyEfficacy 12 8 University of Oxford|KEMRI Wellcome Trust Research Program, Kenya|Centre for Research in Therapeutic Sciences, Strathmore University, Nairobi Kenya|University College, London|Centre for Microbiology Research, Kenya Medical Research Institute|Centre for Clinical Research, Kenya Medical Research InstituteUniversity Interventional Phase 2 Pharmacokinetics 13 9 Sunnybrook Health Sciences Centre Hospital Interventional Not specified Efficacy 14 15 10 Centers for Disease Control and Prevention|MRC/UVRI Uganda Research Unit on Aids|Ministry of Health, UgandaCDC Interventional Phase 2 Safety/Efficacyhttp://bmjopen.bmj.com/ 16 11 Beijing Children's Hospital Hospital Interventional Phase 4 Safety/Efficacy 17 12 University Hospital Inselspital, Berne Hospital Interventional Phase 1 Pharmacokinetics 18 19 13 University Hospital, Ghent|University Hospital, Antwerp|Queen Fabiola Children's University Hospital, BrusselsHospital Observational Not applicable Pharmacokinetics 20 14 University of Oxford|Mahidol University|Wellcome TrustUniversity Interventional Not specified Efficacy 21 15 Oulu University Hospital University Interventional Phase 4 Safety/Efficacy 22 16 Daniel Benjamin|Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)|The EMMES Corporation|OpAns, LLC|Duke UniversityUniversity Observational Not applicable Pharmacokinetics 23 on September 28, 2021 by guest. Protected copyright. 24 17 Michael Cohen-Wolkowiez|Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)|Duke UniversityUniversity Interventional Phase 1 Pharmacokinetics 25 18 Khon Kaen University University Interventional Not specified Efficacy 26 19 Cubist Pharmaceuticals LLC Industry Interventional Phase 1 Pharmacokinetics 27 28 20 Children's Mercy Hospital Kansas City|Blue Cross Blue ShieldHospital Interventional Not specified Efficacy 29 21 Hoffmann-La Roche Industry Observational Not applicable Safety 30 22 Region Skane Hospital Interventional Not specified Efficacy 31 23 Cubist Pharmaceuticals LLC Industry Interventional Phase 3 Safety 32 33 24 Drexel University|The Center for Pediatric Pharmacotherapy, LLCUniversity Interventional Phase 1 Safety 34 25 Bayer Industry Observational Not applicable Safety/Efficacy 35 26 Children's Hospital of Philadelphia Hospital Observational Not applicable Safety/Efficacy 36 37 27 Sheba Medical Center Hospital Interventional Phase 4 Efficacy 38 28 Beijing Children's Hospital Hospital Observational Not applicable Pharmacokinetics 39 29 Rempex Pharmaceuticals (a wholly owned subsidiary of The Medicines Company)|Department of Health and Human ServicesIndustry Interventional Phase 1 Safety 40 30 Menzies School of Health Research|Griffith University|Sarawak General Hospital|University of Malaya|The University of Queensland|Queensland University of Technology|Nanyang Technological UniversityUniversity Interventional Phase 4 Safety/Efficacy 41 42 31 Michael Cohen-Wolkowiez|The EMMES Corporation|Duke UniversityUniversity Interventional Phase 2-3 Safety 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 P Q R S T 3 32 University of Malaya|Menzies School of Health ResearchUniversity Interventional Phase 4 Efficacy 4 33 Durata Therapeutics Inc., an affiliate of Allergan plcIndustry Interventional Phase 1 Pharmacokinetics 5 6 34 University of British Columbia University Interventional Phase 3 Efficacy 7 35 Merck Sharp & Dohme Corp. Industry Interventional Phase 1 Pharmacokinetics 8 36 St. Justine's Hospital Hospital Interventional Phase 1 Pharmacokinetics 9 10 37 Universit̩ Catholique de Louvain University Interventional Phase 4 Pharmacokinetics 11 38 Assistance Publique - H̫pitaux de ParisFor peerHospital Interventional reviewNot specified onlyPharmacokinetics 12 39 Helsinki University|Foundation for Paediatric Research, FinlandUniversity Interventional Phase 4 Safety/Efficacy 13 40 National Taiwan University Hospital University Interventional Phase 4 Pharmacokinetics 14 15 41 Chulalongkorn University University Interventional Not specified Efficacy http://bmjopen.bmj.com/ 16 42 University of Pittsburgh|National Institute of Allergy and Infectious Diseases (NIAID)University Interventional Phase 3 Safety/Efficacy 17 43 Korea University University Interventional Phase 4 Efficacy 18 19 44 Baylor College of Medicine|Forest Laboratories University Interventional Phase 1-2 Safety/Efficacy 20 45 Royal College of Surgeons, Ireland|Health Research Board, IrelandUniversity Interventional Phase 4 Efficacy 21 46 Ramon Gorter|ZonMw: The Netherlands Organisation for Health Research and Development|VU University Medical Center|Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)University Interventional Phase 4 Efficacy 22 47 AstraZeneca|PRA Health Sciences Industry Interventional Phase 2 Safety/Efficacy 23 on September 28, 2021 by guest. Protected copyright. 24 48 Aga Khan University University Interventional Not specified Efficacy 25 49 Thammasat University University Interventional Phase 4 Safety/Efficacy 26 50 Basilea Pharmaceutica Industry Interventional Phase 1 Pharmacokinetics 27 28 51 Murdoch Childrens Research Institute|Royal Children's Hospital|Mercy Hospital for Women, AustraliaUniversity Interventional Not specified Pharmacokinetics 29 52 AstraZeneca|PRA Health Sciences Industry Interventional Phase 2 Safety/Efficacy 30 53 Durata Therapeutics Inc., an affiliate of Allergan plcIndustry Interventional Phase 3 Safety/Efficacy 31 54 Cempra Inc|National Institute of Allergy and Infectious Diseases (NIAID)Industry Interventional Phase 3 Efficacy 32 33 55 Otonomy, Inc. Industry Interventional Phase 3 Efficacy 34 56 Save the Children|University of North Carolina|University of WashingtonHealth OrganisationInterventional Phase 4 Efficacy 35 57 Save the Children|University of North Carolina|University of WashingtonHealth OrganisationInterventional Phase 4 Efficacy 36 37 58 Cempra Inc Industry Interventional Phase 2-3 Safety/Efficacy 38 59 Cempra Inc Industry Interventional Phase 3 Safety/Efficacy 39 60 Tanta University University Interventional Phase 3 Efficacy 40 61 Murdoch Childrens Research Institute University Interventional Not specified Efficacy 41 42 62 Astellas Pharma Europe B.V.|Merck Sharp & Dohme Corp.|Astellas Pharma IncIndustry Interventional Phase 3 Safety/Efficacy 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 P Q R S T 3 63 Laboratorios Goulart S.A. Industry Interventional Phase 3 Safety/Efficacy 4 64 University Hospital, Ghent|Universitair Ziekenhuis BrusselUniversity Interventional Phase 4 Pharmacokinetics 5 6 65 Malaria Consortium|World Health Organization Health OrganisationInterventional Phase 4 Safety 7 66 PENTA Foundation|St George's, University of London|Institut National de la SantÌ© Et de la Recherche MÌ©dicale, France|University of Tartu|Consorzio per Valutazioni Biologiche e Farmacologiche|University of Liverpool|Therakind limited|Bambino GesÌ_ Hospital and Research Institute|Servicio Madrile̱o de Salud, Madrid, Spain|Aristotle University Of Thessaloniki|University of Edinburgh|SYNAPSE Research Management Partners S.L|European CommissionHealth OrganisationInterventional Phase 2 Safety/Efficacy 8 67 Sigvard M̦lstad|Public Health Agency of SwedenUniversity Interventional Phase 4 Safety/Efficacy 9 10 68 AstraZeneca|PRA Health Sciences Industry Interventional Phase 2-3 Safety/Efficacy 11 69 The Medicines Company For peerIndustry Interventional reviewPhase 1 onlyPharmacokinetics 12 70 Theravance Biopharma Antibiotics, Inc. Industry Interventional Phase 4 Pharmacokinetics 13 71 The Canberra Hospital Hospital Interventional Phase 2 Pharmacokinetics 14 15 72 Chang Gung Memorial Hospital Hospital Interventional Phase 4 Efficacy http://bmjopen.bmj.com/ 16 73 Darier Industry Interventional Phase 4 Safety/Efficacy 17 74 Theravance Biopharma Antibiotics, Inc. Industry Observational Not applicable Safety/Efficacy 18 19 75 Grupo de Apoio ao Adolescente e a Crianca com CancerHospital Observational Not applicable Pharmacokinetics 20 76 Infectopharm Arzneimittel GmbH|J&P Medical Research Ltd.|Sandoz GmbHIndustry Observational Not applicable Efficacy 21 77 University of Maryland University Interventional Phase 2 Safety/Efficacy 22

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1 2 U V W X Y Z AA AB 3 1 Primary outcome variable PK data collected First ReceivedStart Date Completion DateLast UpdatedLast Verified Results First Received 4 2 PK PK study design July 2, 2015 Sep-15 Dec-18 September 14, 2016Sep-16 No Study Results Posted 5 6 3 Efficacy No PK data September 28, 2016Oct-16 null October 12, 2016 Oct-16 No Study Results Posted 7 4 Efficacy No PK data September 8, 2016Sep-16 null September 13, 2016Sep-16 No Study Results Posted 8 5 Efficacy No PK data May 8, 2012 May-12 Apr-18 June 27, 2016 Jun-16 No Study Results Posted 9 10 6 Efficacy No PK data March 2, 2015 Mar-16 May-18 March 24, 2016 Mar-16 No Study Results Posted 11 7 Efficacy No PK dataFor peerSeptember 1, 2016 reviewOct-16 Mar-19 October 13, 2016 onlyOct-16 No Study Results Posted 12 8 PK PK study design April 4, 2016 Apr-16 Sep-16 April 25, 2016 Apr-16 No Study Results Posted 13 9 Efficacy No PK data September 23, 2016Oct-16 Dec-17 September 26, 2016Sep-16 No Study Results Posted 14 15 10 Efficacy No PK data November 17, 2010Dec-10 null September 10, 2012http://bmjopen.bmj.com/ Sep-12 No Study Results Posted 16 11 Efficacy No PK data November 25, 2015Mar-14 Jul-16 December 16, 2015Nov-15 No Study Results Posted 17 12 PK Primary PK data January 26, 2012 Apr-12 Apr-18 December 10, 2015Dec-15 No Study Results Posted 18 19 13 PK PK study design May 18, 2015 May-12 null November 17, 2015Nov-15 No Study Results Posted 20 14 Efficacy No PK data December 18, 2007Dec-07 Sep-10 June 3, 2008 Aug-07 No Study Results Posted 21 15 Efficacy No PK data October 17, 2007 Nov-07 Dec-09 October 18, 2007 Oct-07 No Study Results Posted 22 16 PK PK study design August 17, 2011 Nov-11 Feb-17 February 4, 2016 Feb-16 No Study Results Posted 23 on September 28, 2021 by guest. Protected copyright. 24 17 PK PK study design June 12, 2015 Nov-15 Dec-17 August 1, 2016 Aug-16 No Study Results Posted 25 18 Efficacy No PK data August 18, 2011 Aug-11 Dec-20 August 30, 2016 Aug-16 No Study Results Posted 26 19 PK PK study design September 22, 2014Sep-14 Nov-16 October 31, 2016 Oct-16 No Study Results Posted 27 28 20 Efficacy No PK data March 23, 2009 Mar-09 Oct-12 June 21, 2011 Jun-11 No Study Results Posted 29 21 Safety No PK data August 23, 2016 Aug-16 Dec-16 September 1, 2016Sep-16 No Study Results Posted 30 22 Efficacy No PK data January 3, 2011 Mar-11 Jun-15 May 25, 2015 May-15 No Study Results Posted 31 23 Safety Secondary PK data October 9, 2014 Mar-15 Jan-18 October 31, 2016 Oct-16 No Study Results Posted 32 33 24 Safety Primary PK data January 12, 2016 Jan-17 Dec-18 September 8, 2016Sep-16 No Study Results Posted 34 25 Safety No PK data September 18, 2015Jul-16 Sep-18 October 19, 2016 Oct-16 No Study Results Posted 35 26 Efficacy No PK data November 17, 2014Jan-14 Jul-17 May 6, 2016 May-16 No Study Results Posted 36 37 27 Efficacy No PK data August 21, 2014 Aug-13 Aug-15 August 26, 2014 Aug-14 No Study Results Posted 38 28 PK PK study design May 11, 2016 Aug-16 Oct-22 May 17, 2016 May-16 No Study Results Posted 39 29 Safety Primary PK data February 17, 2016 Jul-16 Sep-19 October 6, 2016 Oct-16 No Study Results Posted 40 30 Efficacy No PK data May 5, 2016 Jun-16 Dec-20 October 7, 2016 Oct-16 No Study Results Posted 41 42 31 Safety No PK data November 18, 2013Dec-13 Sep-17 August 1, 2016 Aug-16 No Study Results Posted 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 U V W X Y Z AA AB 3 32 Efficacy No PK data September 23, 2014Nov-14 Dec-18 December 20, 2015Dec-15 No Study Results Posted 4 33 PK PK study design February 18, 2016 Apr-16 May-17 October 19, 2016 Oct-16 No Study Results Posted 5 6 34 Efficacy No PK data May 8, 2006 Jan-04 Dec-13 February 6, 2012 Feb-12 No Study Results Posted 7 35 PK PK study design April 1, 2016 May-16 Feb-18 October 21, 2016 Oct-16 No Study Results Posted 8 36 PK PK study design June 2, 2015 Jan-16 Dec-17 April 18, 2016 Apr-16 No Study Results Posted 9 10 37 PK PK study design October 1, 2014 Oct-16 Oct-17 October 24, 2016 Oct-16 No Study Results Posted 11 38 PK PK study designFor peerFebruary 24, 2016 reviewFeb-16 Feb-17 March 8, 2016 onlyMar-16 No Study Results Posted 12 39 Efficacy No PK data February 23, 2012 Feb-12 Jul-17 February 19, 2016 Feb-16 No Study Results Posted 13 40 PK PK study design August 23, 2006 Jun-06 Dec-07 August 23, 2006 Aug-06 No Study Results Posted 14 15 41 Efficacy No PK data January 30, 2013 Dec-12 Dec-13 February 6, 2013http://bmjopen.bmj.com/ Feb-13 No Study Results Posted 16 42 Efficacy No PK data September 8, 2015Feb-16 Sep-20 October 3, 2016 Oct-16 No Study Results Posted 17 43 Efficacy No PK data December 22, 2010Apr-07 Apr-16 April 8, 2014 Apr-14 No Study Results Posted 18 19 44 Safety Secondary PK data December 31, 2014Jan-15 Jan-20 June 24, 2016 Jun-16 No Study Results Posted 20 45 Efficacy No PK data August 9, 2016 Dec-16 Dec-19 September 30, 2016Jul-16 No Study Results Posted 21 46 Efficacy No PK data July 24, 2016 Dec-16 Dec-20 July 26, 2016 Jul-16 No Study Results Posted 22 47 Safety Secondary PK data May 25, 2015 Jul-15 Oct-17 October 21, 2016 Oct-16 No Study Results Posted 23 on September 28, 2021 by guest. Protected copyright. 24 48 Efficacy No PK data November 4, 2014Nov-14 Jul-17 June 3, 2016 Jun-16 No Study Results Posted 25 49 Efficacy No PK data February 17, 2012 Jan-12 Sep-12 March 13, 2012 Mar-12 No Study Results Posted 26 50 PK PK study design August 5, 2015 Aug-14 Jun-17 October 20, 2016 Oct-16 No Study Results Posted 27 28 51 PK PK study design August 5, 2014 Sep-14 Sep-17 March 17, 2016 Mar-16 No Study Results Posted 29 52 Safety Secondary PK data June 16, 2015 Sep-15 Oct-17 October 21, 2016 Oct-16 No Study Results Posted 30 53 Efficacy No PK data June 8, 2016 Jun-16 Jul-18 June 23, 2016 Jun-16 No Study Results Posted 31 54 Efficacy No PK data August 1, 2014 Aug-14 Apr-17 September 20, 2016Sep-16 No Study Results Posted 32 33 55 Efficacy No PK data June 13, 2016 Jun-16 Nov-16 June 13, 2016 Jun-16 No Study Results Posted 34 56 Efficacy No PK data May 1, 2016 Jun-16 Sep-18 June 10, 2016 Jun-16 No Study Results Posted 35 57 Efficacy No PK data February 3, 2016 Mar-16 null June 10, 2016 Jun-16 No Study Results Posted 36 37 58 Safety No PK data November 10, 2015Mar-16 Jan-18 September 14, 2016Sep-16 No Study Results Posted 38 59 Efficacy No PK data October 5, 2015 Nov-15 Feb-17 October 5, 2016 Oct-16 No Study Results Posted 39 60 Efficacy No PK data May 11, 2015 Jan-15 Dec-16 May 9, 2016 May-16 No Study Results Posted 40 61 Efficacy No PK data January 4, 2015 Jan-15 Jan-17 March 16, 2016 Mar-16 No Study Results Posted 41 42 62 Efficacy No PK data August 11, 2014 Oct-14 Feb-17 June 17, 2016 Jun-16 No Study Results Posted 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 U V W X Y Z AA AB 3 63 Efficacy No PK data December 14, 2009May-10 Oct-10 March 18, 2010 Dec-09 No Study Results Posted 4 64 PK PK study design November 4, 2015 Apr-15 Apr-16 November 4, 2015Nov-15 No Study Results Posted 5 6 65 Safety No PK data August 17, 2016 Oct-16 Jul-17 October 3, 2016 Oct-16 No Study Results Posted 7 66 Efficacy Secondary PK data April 7, 2016 Jul-16 Mar-18 May 31, 2016 May-16 No Study Results Posted 8 67 Efficacy No PK data March 4, 2016 Sep-15 Oct-16 October 4, 2016 Oct-16 No Study Results Posted 9 10 68 Safety Secondary PK data February 23, 2015 Aug-15 Oct-17 October 14, 2016 Oct-16 No Study Results Posted 11 69 PK PK study designFor peerMay 7, 2014 reviewMay-14 Dec-16 November 4, 2015 onlyNov-15 No Study Results Posted 12 70 PK PK study design December 11, 2013Dec-14 Aug-16 June 24, 2016 Jun-16 No Study Results Posted 13 71 PK PK study design August 31, 2011 Aug-11 Jul-12 September 1, 2011Aug-11 No Study Results Posted 14 15 72 Efficacy No PK data November 25, 2010Aug-10 Jul-12 January 14, 2011http://bmjopen.bmj.com/ Nov-10 No Study Results Posted 16 73 Efficacy No PK data September 30, 2009Jun-09 Apr-10 September 30, 2009Sep-09 No Study Results Posted 17 74 Efficacy No PK data November 5, 2014Nov-14 Sep-18 June 29, 2016 Jun-16 No Study Results Posted 18 19 75 PK Primary PK data February 24, 2011 Jan-11 null March 21, 2012 Mar-12 No Study Results Posted 20 76 Efficacy No PK data July 29, 2010 Aug-10 null February 5, 2016 Feb-16 No Study Results Posted 21 77 Efficacy Secondary PK data January 22, 2013 Jul-13 Dec-21 May 28, 2015 May-15 No Study Results Posted 22

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1 2 AC AD AE AF AG 3 1 Primary Completion DateURL 4 2 Jul-18 https://ClinicalTrials.gov/show/NCT02539407 5 6 3 Dec-18 https://ClinicalTrials.gov/show/NCT02935374 7 4 Sep-18 https://ClinicalTrials.gov/show/NCT02899143 8 5 Apr-18 https://ClinicalTrials.gov/show/NCT01595529 9 10 6 Feb-18 https://ClinicalTrials.gov/show/NCT02380352 11 7 Jan-19 https://ClinicalTrials.gov/show/NCT02891915For peer review only 12 8 Sep-16 https://ClinicalTrials.gov/show/NCT02746276 13 9 Aug-17 https://ClinicalTrials.gov/show/NCT02917551 14 15 10 Jun-13 https://ClinicalTrials.gov/show/NCT01243437 http://bmjopen.bmj.com/ 16 11 Mar-16 https://ClinicalTrials.gov/show/NCT02635191 17 12 Dec-16 https://ClinicalTrials.gov/show/NCT01522105 18 19 13 Dec-17 https://ClinicalTrials.gov/show/NCT02456974 20 14 Sep-10 https://ClinicalTrials.gov/show/NCT00579956 21 15 null https://ClinicalTrials.gov/show/NCT00545961 22 16 Feb-17 https://ClinicalTrials.gov/show/NCT01431326 23 on September 28, 2021 by guest. Protected copyright. 24 17 Nov-17 https://ClinicalTrials.gov/show/NCT02475876 25 18 Dec-20 https://ClinicalTrials.gov/show/NCT01420341 26 19 Nov-16 https://ClinicalTrials.gov/show/NCT02266706 27 28 20 Sep-12 https://ClinicalTrials.gov/show/NCT00867789 29 21 Dec-16 https://ClinicalTrials.gov/show/NCT02879981 30 22 Jun-15 https://ClinicalTrials.gov/show/NCT01269541 31 23 Jan-18 https://ClinicalTrials.gov/show/NCT02276482 32 33 24 Dec-18 https://ClinicalTrials.gov/show/NCT02663596 34 25 Sep-17 https://ClinicalTrials.gov/show/NCT02555059 35 26 Apr-17 https://ClinicalTrials.gov/show/NCT02297815 36 37 27 Dec-14 https://ClinicalTrials.gov/show/NCT02224040 38 28 Aug-22 https://ClinicalTrials.gov/show/NCT02775968 39 29 Aug-19 https://ClinicalTrials.gov/show/NCT02687906 40 30 Dec-19 https://ClinicalTrials.gov/show/NCT02783859 41 42 31 Apr-17 https://ClinicalTrials.gov/show/NCT01994993 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 AC AD AE AF AG 3 32 Dec-17 https://ClinicalTrials.gov/show/NCT02258763 4 33 May-17 https://ClinicalTrials.gov/show/NCT02688790 5 6 34 Dec-12 https://ClinicalTrials.gov/show/NCT00323219 7 35 Feb-18 https://ClinicalTrials.gov/show/NCT02750761 8 36 Dec-17 https://ClinicalTrials.gov/show/NCT02466438 9 10 37 Sep-17 https://ClinicalTrials.gov/show/NCT02260102 11 38 Jun-16 https://ClinicalTrials.gov/show/NCT02694458For peer review only 12 39 Feb-17 https://ClinicalTrials.gov/show/NCT01540838 13 40 null https://ClinicalTrials.gov/show/NCT00368498 14 15 41 Dec-13 https://ClinicalTrials.gov/show/NCT01785641 http://bmjopen.bmj.com/ 16 42 Sep-20 https://ClinicalTrials.gov/show/NCT02554383 17 43 Mar-16 https://ClinicalTrials.gov/show/NCT01265173 18 19 44 Jan-17 https://ClinicalTrials.gov/show/NCT02335905 20 45 Dec-19 https://ClinicalTrials.gov/show/NCT02922686 21 46 Dec-20 https://ClinicalTrials.gov/show/NCT02848820 22 47 Oct-17 https://ClinicalTrials.gov/show/NCT02475733 23 on September 28, 2021 by guest. Protected copyright. 24 48 May-17 https://ClinicalTrials.gov/show/NCT02372461 25 49 Aug-12 https://ClinicalTrials.gov/show/NCT01553006 26 50 Mar-17 https://ClinicalTrials.gov/show/NCT02527681 27 28 51 Sep-17 https://ClinicalTrials.gov/show/NCT02210169 29 52 Oct-17 https://ClinicalTrials.gov/show/NCT02497781 30 53 Apr-18 https://ClinicalTrials.gov/show/NCT02814916 31 54 Apr-17 https://ClinicalTrials.gov/show/NCT02210325 32 33 55 Nov-16 https://ClinicalTrials.gov/show/NCT02801370 34 56 Aug-18 https://ClinicalTrials.gov/show/NCT02760420 35 57 Aug-18 https://ClinicalTrials.gov/show/NCT02678195 36 37 58 Dec-17 https://ClinicalTrials.gov/show/NCT02605122 38 59 Feb-17 https://ClinicalTrials.gov/show/NCT02570490 39 60 Dec-16 https://ClinicalTrials.gov/show/NCT02443285 40 61 Jan-17 https://ClinicalTrials.gov/show/NCT02334124 41 42 62 Feb-17 https://ClinicalTrials.gov/show/NCT02218372 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 AC AD AE AF AG 3 63 Jul-10 https://ClinicalTrials.gov/show/NCT01032499 4 64 Feb-16 https://ClinicalTrials.gov/show/NCT02598362 5 6 65 Mar-17 https://ClinicalTrials.gov/show/NCT02878031 7 66 Dec-17 https://ClinicalTrials.gov/show/NCT02790996 8 67 Oct-16 https://ClinicalTrials.gov/show/NCT02712307 9 10 68 Oct-17 https://ClinicalTrials.gov/show/NCT02424734 11 69 Dec-16 https://ClinicalTrials.gov/show/NCT02134301For peer review only 12 70 Aug-16 https://ClinicalTrials.gov/show/NCT02013141 13 71 Jul-12 https://ClinicalTrials.gov/show/NCT01427842 14 15 72 Jun-11 https://ClinicalTrials.gov/show/NCT01278017 http://bmjopen.bmj.com/ 16 73 Feb-10 https://ClinicalTrials.gov/show/NCT00988026 17 74 Jun-18 https://ClinicalTrials.gov/show/NCT02288234 18 19 75 null https://ClinicalTrials.gov/show/NCT01304459 20 76 Dec-16 https://ClinicalTrials.gov/show/NCT01173575 21 77 Dec-19 https://clinicaltrials.gov/ct2/show/NCT01778634 22

23 on September 28, 2021 by guest. Protected copyright. 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open

A global shortage of neonatal and pediatric antibiotic trials: rapid review.

ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2017-016293.R3

Article Type: Research

Date Submitted by the Author: 17-Aug-2017

Complete List of Authors: Thompson, Georgina; St George's University of London, Infection and Immunity; University of Exeter Medical School Barker, Charlotte; St George's University of London, Infection and Immunity; University College London Institute of Child Health Folgori, Laura; St George's University of London, Paediatric Infectious Diseases Research Group Bielicki, Julia; St George's University London, Division of Clinical Sciences; University of Basel Children's Hospital Bradley, John; University of California San Diego School of Medicine, Department of Pediatrics Lutsar, Irja; University of Tartu, Department of Medical Microbiology sharland, mike; St George's University of London, Infection and Immunity; St Georges Hospital, Paedaitric Infectious Diseases Unit http://bmjopen.bmj.com/

Primary Subject Paediatrics Heading:

Secondary Subject Heading: Infectious diseases

Paediatric infectious disease & immunisation < PAEDIATRICS, INFECTIOUS Keywords: DISEASES, PAEDIATRICS on September 28, 2021 by guest. Protected copyright.

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1 2 3 A global shortage of neonatal and pediatric antibiotic trials: rapid review. 4 1,2 1,3,4 1 1,5 6,7 8 1, 4 5 G. Thompson , C. I. Barker , L. Folgori , J. A. Bielicki , J. S. Bradley , I. Lutsar , M. Sharland 6

7 1 8 Paediatric Infectious Diseases Research Group, Institute for Infection and Immunity, St George's University 9 of London, London, UK 10 2 University of Exeter, Exeter, UK 11 3 12 Inflammation, Infection and Rheumatology Section, UCL Great Ormond Street Institute of Child Health, 30 13 Guilford Street, London, UK 14 4 15 St George’s UniversityFor Hospitals peer NHS Foundation review Trust, Blackshaw Road, only London, UK 16 5 Paediatric Pharmacology and Pharmacometrics, University of Basel Children’s Hospital, Basel, Switzerland 17 6 Department of Pediatrics, School of Medicine, University of California San Diego, CA, United States 18 7 19 Rady Children’s Hospital San Diego, San Diego, CA, United States 20 8 Department of Medical Microbiology, University of Tartu, Tartu, Estonia 21

22 23 24 25 Corresponding author 26 Georgina Thompson 27 Paediatric Infectious Diseases Research Group 28 29 St George's, University of London 30 Jenner Wing, Level 2, Room 2.216F, Mail Point J2C 31

London SW17 0RE http://bmjopen.bmj.com/ 32 33 Telephone: 07880325494 34 Email: [email protected] 35 36 37 38 Word count: 2434 39 40 on September 28, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 2 of 40

1 2 3 ABSTRACT 4 Objectives: There have been few clinical trials (CTs) on antibiotics which inform neonatal and 5 6 pediatric drug labelling. The rate of unlicensed and off-label prescribing in pediatrics remains high. 7 It is unclear whether the current neonatal and pediatric antibiotic research pipeline is adequate to 8 9 inform optimal drug dosing. Using the ClinicalTrials.gov registry, this review aims to establish the 10 11 current global status of antibiotic CTs in children up to 18 years of age. 12 Methods: Studies were identified using key word searches of the ClinicalTrials.gov registry, and 13 14 were manually filtered using pre-specified inclusion/exclusion criteria. 15 Results: 76 registeredFor open peer CTs of antibiotics review in children were identified only globally; 23 (30%) were 16 17 recruiting newborns (only 8 (11%) included preterm neonates), 52 (68%) infants and toddlers, 58 18 (76%) children, and 54 (71%) adolescents. The majority of registered trials were late phase (10 19 20 (15%) Phase 3 and 23 (35%) Phase 4/pharmacovigilance). Two-thirds were sponsored by non-profit 21 organisations, compared to pharmaceutical companies (50 (66%) vs. 26 (34%) respectively). A 22 23 greater proportion of non-profit funded trials were efficacy-based strategic trials (n= 34, 68%), in 24 comparison to industry-led trials, which were most often focused on safety or pharmacokinetic data 25 26 (n=17, 65%). Only 2 of the 37 antibiotics listed on the May 2016 Pew Charitable Trusts antibiotic 27 development pipeline, currently being studied in adults, appear to be currently recruiting in open 28 29 pediatric CTs. 30 Conclusions: This review highlights that very few pediatric antibiotic CTs are being conducted 31 32 globally, especially in neonates. There is a striking disparity noted between antibiotic drug http://bmjopen.bmj.com/ 33 development programmes in adults and children. 34 35 36 37 Strengths and limitations of this study 38 • A narrative literature review of registered clinical trials in children. 39

40 • Explicit reproducible methodology. on September 28, 2021 by guest. Protected copyright. 41 • Search strategy limited to ClinicalTrials.gov and EudraCT. Entirety of clinical research in this 42 43 field might not have been captured. 44 • Search strategy was limited to open clinical trials. Active but not yet recruiting trials were not 45 46 captured. 47 48 49 50 INTRODUCTION 51 Widespread unlicensed and off-label prescribing in pediatrics persists – as high as 11.4% and 52 53 46.5%, respectively – yet the paucity of clinical research involving children that is conducted to 54 inform optimal drug dosing, licensing and labelling remains a problem.[1] For certain medicines, 55 56 drug efficacy can be extrapolated from adult data provided that the pathology and drug exposure 57 are the same, or sufficiently similar in children as in adults.[2,3]. Although differences in drug 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 3 of 40 BMJ Open

1 2 3 pharmacokinetics (PK) in neonates and children can lead to adverse reactions that are not seen in 4 adult populations, these are very rare.[4] Suboptimal antibiotic dosing, including under- and over- 5 6 dosing, can lead to toxicity, treatment failure, and may drive antimicrobial resistance by encouraging 7 selection pressures on drug-resistant strains of bacteria.[5] 8 9 10 11 Since antibiotics are the most commonly prescribed medicines in children, it is important to 12 maximize our understanding of their PK profiles to help determine optimal drug dosing and 13 14 ultimately to improve outcomes.[6] In the last decade several initiatives have been established to 15 encourage pediatricFor medicines peer research, bridging review the gap between only adult and pediatric drug 16 17 development plans. Such initiatives include the Pediatric Regulation (Pediatric Investigation Plans 18 (PIPs), introduced by the European Medicines Agency (EMA),[7] and Pediatric Study Plans (PSPs), 19 20 by the U.S. Food and Drug Administration (FDA)).[8] Despite this, there have been few advances in 21 antibiotic development for this population.[9] 22 23 24 The global status of clinical research on antibiotics in pediatrics is unknown. Using registered 25 26 records of clinical trials (CTs) on ClinicalTrials.gov, this review aims (i) to summarise the current 27 global status of registered antibiotic research in children and neonates, and (ii) to stimulate 28 29 discussion and collaboration among the relevant stakeholders on the neglect of antibiotic research 30 in children. 31 32 http://bmjopen.bmj.com/ 33

34 35 METHODS 36 37 Data sources 38 The ClinicalTrials.gov registry (last accessed 8th November 2016) is an international platform for the 39

40 registration of CTs. It is a web-based registry, developed in 2000 by the National Institutes of Health on September 28, 2021 by guest. Protected copyright. 41 (NIH) and the FDA, to which trials from 50 states and 163 countries around the world are registered. 42 43 Information provided for each trial is updated periodically by the trial’s sponsoring organisation. The 44 database has a specific child filter, which uses a key word paradigm to select all registered trials 45 46 recruiting patients/participants up to 18 years of age. 47 48 49 Study selection 50 Our records were identified using suitable key word searches, in which the final search terms were 51 52 (antimicrobial* OR antibiotic* OR anti-infective agent*) AND Child AND Open Studies. All identified 53 trials were filtered manually using inclusion and exclusion criteria. Interventional and observational 54 55 trials on antimicrobials recruiting children up to 18 years of age were considered eligible for 56 inclusion. No specific temporal filter was applied since only open or ongoing clinical trials were of 57 58 interest. The following records, which were not investigating one or more antibiotics, were excluded: 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 4 of 40

1 2 3 trials of antiseptics, antifungals, antiprotozoals, antivirals, and pro- or pre- biotics. The following 4 records, which were investigating an antibiotic were excluded: trials involving tuberculosis, malaria, 5 6 cystic fibrosis, HIV, febrile neutropenic patients, topical or inhalational treatments, prophylactic 7 antibiotics, or records investigating alternative use for antibiotics (for example as an anti- 8 9 inflammatory agent). 10 11 12 The searches were conducted by GT. All eligible records were identified via manual filtering by GT 13 14 CIB, LF and MS, and any disagreements regarding inclusion and exclusion of records were 15 resolved throughFor discussion. peer review only 16 17 18 Data extraction 19 20 The following information was collected from the included records: unique NCT number, recruitment 21 status, study design, trial phase, study sponsor, age group and sex eligibility, clinical indication, 22 23 geographic region of recruitment, antibiotic being investigated, and endpoint classification. 24 Outcomes were categorised as safety, efficacy or PK. Economic setting (based on geographic 25 26 region of recruitment) was classified using The World Bank classification to differentiate between 27 Low Income Countries (LICs), Lower Middle Income Countries (LMICs), Upper Middle Income 28 29 Countries (UMICs), and High Income Countries (HICs).[10] 30

31 32 The specific class of antibiotic studied in each trial was identified and classified using the World http://bmjopen.bmj.com/ 33 Health Organisation (WHO) ATC/DDD index.[11] To investigate whether novel antibiotics are being 34 35 studied in pediatric populations, the antibiotics currently studied in children were compared with the 36 37 Pew Charitable Trusts Antibiotics Currently in Clinical Development pipeline, which identifies novel 38 antibiotics currently under development for the U.S. market.[12] 39

40 on September 28, 2021 by guest. Protected copyright. 41 42 43 RESULTS 44 Our search identified 1056 records. 603 records were excluded on title because they were studies 45 46 not involving an antimicrobial. 453 records were investigating one or more antimicrobials and 47 recruiting children below 18 years of age. Among the 195 trials investigating antibiotics, 76 fulfilled 48 49 our inclusion and exclusion criteria and were included in the final analysis. Reasons for exclusion 50 are summarised in Figure 1. Details of included studies can be found in Supplementary file 1. 51 52 53 All 76 CTs identified were open as of 8th November 2016, and 63 (83%) of these were recognised 54 as recruiting participants on this date (Table 1). All trials stated recruitment of both male and female 55 56 participants. 57

58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 5 of 40 BMJ Open

1 2 3 Table 1. Characteristics of clinical trials. 4 Number of 5 Characteristic Category studies, n (%) 6 a 7 Age group Preterm neonates 1 (1) 8 Neonates (total) 23 (30) 9 Infants and toddlers 52 (68) 10 Children 58 (76) 11 Adolescents 54 (71) 12 Recruitment status Recruiting 63 (83) 13 Not yet recruiting 13 (17) 14 Study design Interventional 66 (87) 15 For peerObservational review only 10 (13) 16 Trial phaseb Phase 1 10 (15) 17 Phase 1-2 1 (2) 18 Phase 2 9 (14) 19 Phase 2-3 3 (5) 20 Phase 3 10 (15) 21 22 Phase 4 23 (39) 23 Not specified 10 (15) 24 Sponsor Industry 26 (34) 25 Non-profit 50 (66) 26 Geographic region Africa 8 (11) 27 Asia 16 (21) 28 Europe 22 (29) 29 Latin America 6 (8) 30 North America 34 (45) 31 Oceania 5 (7) http://bmjopen.bmj.com/ 32 Antibiotic class J01A Tetracycline 4 (5) 33 J01C Beta-lactam, Penicillin 25 (33) 34 J01D Other Beta-lactam 22 (29) 35 J01E Sulfonamides and trimethoprim 7 (9) 36 J01F Macrolide, Lincosamide, Streptogramin 14 (18) 37 38 J01G Aminoglycoside 2 (3) J01M Quinolone 8 (11) 39 c 40 J01X Other antibiotic classes 21 (28) on September 28, 2021 by guest. Protected copyright. 41 J01 Not specified 2 (3) 42 43 Totals for Age group, Geographic region, and Antibiotic class do not add up to total number of clinical trials 44 (76) as some trials contributed to more than one sub group. a 7 further trials mentioned inclusion of preterm babies in the inclusion criteria. 45 b Trial phase % based on percentage of interventional trials. 46 c J01X includes glycopeptides, polymyxins, imidazole and nitrofuran derivatives. 47 48 49 Age group 50 Twenty three of the 76 trials (30%) were recruiting newborns (0 to 28 days). One of these 23 trials 51 52 focused solely on recruiting preterm newborns (a further 7 CTs mentioned inclusion of preterm 53 newborns in inclusion criteria). Of the remaining records, 52 (68%) were recruiting infants and 54 55 toddlers (28 days to 23 months), 58 (76%) children (2 to 11 years), and 54 (71%) adolescents (11 56 57 up to 18 years). 29 (38%) trials did not focus solely on the recruitment of children or neonates, with 58 age ranges also spanning across adult populations. 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 6 of 40

1 2 3 Study type 4 Interventional trials were most frequently identified (n=66, 87%) with only 10 (13%) observational 5 6 trials noted. Of the interventional trials, the majority were in the later stages of development; 10 7 (13%) in Phase 1, 1 (2%) between Phase 1 and 2, 9 (14%) in Phase 2, 3 (5%) between Phase 2 8 9 and 3, 10 (15%) in Phase 3 and 23 (35%) in Phase 4. In 10 (15%) cases, a trial phase was not 10 11 specified. 12 13 14 Sponsor and Endpoint Classification 15 Fifty trials (66%)For were sponsored peer by non-profit review organisations (being only university, hospital or 16 17 government funded), and 26 sponsored by industry (34%). The endpoint classification of the 18 majority of trials (n=43, 57%) was reported as efficacy (Table 2). A greater proportion (n=34, 68%) 19 20 of non-profit studies measured the efficacy of the drugs as the primary endpoint, with less emphasis 21 on collection of PK or safety data (n=16, 32%). In comparison pharmaceutical-led trials focussed on 22 23 early PK and safety studies over the drug’s efficacy (n=17, 65% vs. n=9, 35% respectively). 24 25 26 Table 2. Clinical trial endpoint classification of identified clinical trials stratified by trial sponsor. 27 Endpoint classification determined by planned primary outcomes. 28 29 Endpoint classification Industry Non-profit Total (%) 30 31 Efficacy 9 34 43 (57) 32 http://bmjopen.bmj.com/ 33 Safety 10 2 12 (16) 34 35 PK 7 14 21 (28) 36 37 Geographic region 38 39 The most frequently recruiting geographic region was North America (n=34, 45%). 22 (29%) trials

40 on September 28, 2021 by guest. Protected copyright. 41 recruiting in Europe and 16 (21%) in Asia were identified, 6 (8%) in Latin America, 8 (11%) in Africa, 42 and 5 (7%) in Oceania. Most trials were recruiting in HICs (n=54, 71%), with fewer trials recruiting in 43 44 LICs (n=4, 5%), LMICs (n=4, 5%), UMICs (n=11, 14%) or a combination of UMICs and HICs (n=3, 45 4%). 46 47 48 Indication 49 50 The most common treatment indications investigated were lower respiratory tract infection (n=12, 51 16%) and sepsis (n=11, 14%), followed by upper respiratory tract infection (n=8, 11%), intra- 52 53 abdominal infection (IAI) (n=8, 11%), urinary tract infection (UTI) (n=7, 9%), complicated skin and 54 soft tissue infection (cSSTI) (n=6, 8%), CNS infection (n=3, 4%), and bone and joint infection (n=1, 55 56 1%) (Table 3). 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

1 1 8 8 6 6 7 7 7 7 4 5 5 14 11 11 63 63

1 1 4 4 7 7 5 5 9 9 4 9 9 15 67 67 13 13

1 1 4 4 6 6 5 5 5 5 4 9 9 61 61 15 12 12 toddlers toddlers Children Adolescents Infants and and Infants Age group group Age a a

- 3 3 2 2 3 3 1 1 1 6 6 3 3 30 30 11 http://bmjopen.bmj.com/ BMJ Open

------1 1 1 1 Preterm Preterm neonates neonates Neonates on September 28, 2021 by guest. Protected copyright.

3 (4) 3 (1) 1 6 (8) (8) 6 7 (9) (9) 7 8 (11) (11) 8 8 (11) (11) 8 11 (14) (14) 11 18 (24) 18 (16) 12 Total (%) (%) Total

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

For peer review only Sepsis CNS infection CNS Urinary Tract Infection Tract Urinary Clinical indication of identified clinical trials stratified by age group being recruited. recruited. being group age by stratified trials clinical identified of indication Clinical Indication Indication Upper Respiratory Tract Respiratory Upper Bone and Joint Infection Joint and Bone Intra-abdominal Infection Intra-abdominal refers to total number of andpreterm neonates.term Skin and Soft Tissue Infection Tissue Soft and Skin

a Table 3. Table

Age Age dogroup nottotals add up to total number of clinical trials (76) trialsas some contributed to more than group.age one Unspecified Bacterial Infection Bacterial Unspecified Lower Respiratory Tract Infection Tract Respiratory Lower Page 7 of 40 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 8 of 40

1 2 3 Antibiotic class 4 The majority of antibiotics being investigated were beta-lactams (n=47, 62%), followed by other 5 6 antibiotic classes (J01X, including vancomycin, telavancin and dalbavancin) (n=21, 28%). 7 Macrolides or lincosamides (J01F) were the next most commonly studied antibiotic classes (n=14, 8 9 18%). Very few trials were investigating of tetracyclines (J01A) (n=4, 5%), Sulphonamides and 10 11 trimethoprim (J01E) (n=7, 9%), aminoglycosides (J01G) (n=2, 3%), or quinolones (J01M) (n=8, 12 11%). 2 CTs (3%) did not specify the class of antibiotic being investigated. 16 (21%) trials were 13 14 investigating more than one antibiotic; these trials counted towards more than one J01 category. 15 The breakdown Forof J01 categories, peer as per WHO review ATC/DDD classification,[11] only is described in Table 1. 16 17 18 Antibiotic pipeline 19 Of the 37 antibiotics listed in the May 2016 edition of the Pew Charitable Trusts Antibiotic Pipeline 20 21 (last accessed 10th June 2016),[12] as noted by the EMA Opinions and Decisions on Pediatric 22 Investigation Plans, 5 had an agreed PIP: Imipenem/Cilastatin+Relebactam, Cadazolid, 23 24 Carbavance (Meropenem+Vaborbactam), Eravacycline, and Solithromycin.[8] As of 8th November 25 2016, our search found that only 2 of these 37 antibiotics listed (Carbavance and Solithromycin) 26 27 were being investigated in 1 and 2 on-going CTs in pediatric patients, respectively (Table 4). A PIP 28 29 was agreed for Carbavance in 2015 for treatment of Gram-negative infections, and for Solithromycin 30 in 2016 for the treatment of gonococcal infection, and later for treatment of anthrax, tularaemia, and 31 32 bacterial pneumonia. PIPs were agreed in 2015 for treatment of UTI and complicated IAI with http://bmjopen.bmj.com/ 33 Eravacycline, and in 2016 for treatment of Clostridium difficile infection with Cadazolid and of Gram- 34 35 negative bacterial infection with Imipenem/Cilastin+Relebactam.[13] Despite this, we could not 36 identify any registered trials of these antibiotics in our search. 37 38 39

40 on September 28, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from ------open open clinical clinical trials in trials children children Number of Number ------drug drug Plan for for Plan Pediatric Pediatric in Children in Children Investigation Investigation development development

✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ Drug Drug in Adults in Adults development development infection infection infection infection difficile difficile Indication Indication http://bmjopen.bmj.com/ BMJ Open VAP, bacteraemia bacteraemia VAP, Bacterial infection infection Bacterial Clostridium Clostridium Multidrug resistant gram gram resistant Multidrug negatives Bacterial infection infection Bacterial Clostridium Clostridium Acute skin infection, HAP, HAP, infection, skin Acute on September 28, 2021 by guest. Protected copyright. Theravance Theravance Inc. Biopharma Legochem Legochem Inc. Biosciences Basilea Basilea Pharmaceuticals Meiji Seika Pharma Pharma Seika Meiji Co. Fedora Pharmaceuticals For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Phase Phase Manufacturer Phase 1 1 Phase Pharma Ltd. MGB Phase 1 1 Phase Phase 1 1 Phase Ltd. Wockhardt infection Bacterial Phase 1 1 Phase Phase 1 1 Phase Ltd. Wockhardt infection Bacterial Phase 1 1 Phase Ltd. Wockhardt infection Bacterial Phase 1 1 Phase Phase 1 1 Phase For peer review 1 Phase Inc. Crestone only Comparison of antibiotic development pipeline in adults and children. Adapted from Pew Charitable Trusts “Antibiotics currently in currently “Antibiotics Trusts Charitable Pew from Adapted children. adults and in pipeline development antibiotic of Comparison Antibiotic Antibiotic WCK 771 771 WCK WCK 2349 2349 WCK TD – 1607 – 1607 TD LCB01 – 0371 0371 – LCB01 CRS3123 CRS3123 BAL30072 BAL30072 OP0595 OP0595 MGB – BP – 3 – BP 3 – MGB WCK 4873 4873 WCK Table 4. Table clinical development” pipeline (last accessed October 2016).[12] 2016).[12] October (last accessed pipeline development” clinical Page 9 of 40 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 10 of 40 ------

✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ . . spp http://bmjopen.bmj.com/ BMJ Open osteomyelitis osteomyelitis (systemic) (systemic) Staphylococcus Staphylococcus osteomyelitis associated (systemic) (systemic) cUTI, cIAI, acute skin skin acute cIAI, cUTI, pyelonephritis infection, Bacterial infection infection Bacterial Pseudomonas spp. spp. Pseudomonas lower VAP, associated tract infection, respiratory bronchiectasis Uncomplicated gonorrhoea gonorrhoea Uncomplicated CAP CAP cIAI cIAI Acute skin infection, infection, skin Acute Acute skin infection infection skin Acute Acute skin infection, infection, skin Acute Acute skin infection infection skin Acute on September 28, 2021 by guest. Protected copyright. MerLion MerLion Pte Pharmaceuticals Ltd. Crystal Genomics Genomics Crystal Inc. Cellceutix Cellceutix Corporation Entasis Therapeutics Therapeutics Entasis Inc. Debiopharm Debiopharm SA International MicuRx MicuRx Inc. Pharmaceuticals Tetraphase Tetraphase Inc. Pharmaceuticals AstraZeneca PLC PLC AstraZeneca PLC Allergan Astrazeneca PLC PLC Astrazeneca PLC Allergan For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Phase 1 1 Phase Phase 2 2 Phase Phase 2 2 Phase Phase 2 2 Phase Ltd. Polyphor Phase 2 2 Phase Phase 2 2 Phase Phase 2 2 Phase For peer 2 Phase review only Finafloxacin Finafloxacin CG400549 CG400549 Ceftaroline+Avibactam Ceftaroline+Avibactam 2 Phase Brilacidin Brilacidin P0L7080 P0L7080 ETX0914 ETX0914 Debio 1450 1450 Debio MRX – 1 – MRX 1 TP – 271 271 – TP Zidebactam+Cefepime Zidebactam+Cefepime 1 Phase Ltd. Wockhardt VAP HAP, cUTI, Aztreonam – Avibactam Avibactam – Aztreonam 2 Phase 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from ------

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✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓

difficile difficile infection infection http://bmjopen.bmj.com/ BMJ Open prosthetic joint infection joint infection prosthetic Clostridium Clostridium cUTI, cIAI, HAP, VAP, acute acute VAP, HAP, cIAI, cUTI, pyelonephritis CAP, cUTI, acute skin skin acute cUTI, CAP, infection HAP, VAP, cUTI, cUTI, VAP, HAP, infection bloodstream CAP CAP Clostridium Clostridium Prevent recurrent Clostridium Clostridium recurrent Prevent difficile CAP, acute skin infection, infection, skin acute CAP, foot diabetic CAP, HAP, VAP, acute skin skin acute VAP, HAP, CAP, osteomyelitis, infection, joint infections prosthetic cUTI, CAP, uncomplicated uncomplicated CAP, cUTI, gonorrhoea urogenital Acute skin infection, infection, skin Acute

on September 28, 2021 by guest. Protected copyright. Pharmaceuticals Ltd. Ltd. Pharmaceuticals Nabriva Therapeutics Therapeutics Nabriva Paratek Paratek Inc. Pharmaceuticals Dong Wha Dong Co. Pharmaceuticals Ltd. Summet Summet Inc. Therapeutics Nanotherapeutics Nanotherapeutics Inc. TaiGen TaiGen Co. Biotechnology Ltd. Actelion Actelion AC AC For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Phase 3 3 Phase Inc. & Co. Merck Phase 3 3 Phase PLC Bio Motif infection skin acute HAP, Phase 3 3 Phase Inc. Shionogi Phase 2 2 Phase PLC GlaxoSmithKline Phase 3 3 Phase Phase 3 3 Phase Phase 3 3 Phase Phase 2 2 Phase Phase 3 3 Phase Phase 2 2 Phase For 2 Phase peer review only Taksta (fusidic acid) acid) (fusidic Taksta 3 Phase Inc. Cempra Cadazolid Cadazolid Iclaprim Iclaprim Imipenem / / Imipenem Cilastatin+Relebactam Lefamulin Lefamulin Omadacycline Omadacycline S – 649266 649266 S – Zabofloxacin Zabofloxacin Ridinilazole Ridinilazole Ramoplanin Ramoplanin Nemonoxacin Nemonoxacin Geptidacin Geptidacin Page 11 of 40 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 12 of 40 - - - 2 2 1 1

- ✓ ✓ ✓ Waiver Waiver granted granted

✓ ✓ ✓ ✓ ✓ a a

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http://bmjopen.bmj.com/ BMJ Open cUTI CAP, uncomplicated uncomplicated CAP, gonorrhoea, urogenital urethritis cUTI, HAP, VAP, cIAI, cIAI, VAP, HAP, cUTI, catheter-associated infection bloodstream cIAI and cUTI cUTI and cIAI cUTI, cIAI, HAP, VAP, febrile febrile VAP, HAP, cIAI, cUTI, bacteraemia, neutropenia, pyelonephritis acute Acute skin infections, CAP, CAP, infections, skin Acute on September 28, 2021 by guest. Protected copyright. Tetraphase Pharma Pharma Tetraphase Inc. Melinta Therapeutics Therapeutics Melinta Inc. Rempex Rempex Inc. Pharmaceuticals For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Phase 3 3 Phase Phase 3 3 Phase Phase 3 3 Phase Inc. Cempra Phase 3 3 Phase Inc. Achaogen

For peer review only target carbapenem enterobacteriaceaeresistant hospital-acquiredHAP, pneumonia; VAP,ventilator-acquired pneumonia;cUTI, complicated Urinary Tract Infection; CAP, Community-acquired pneumonia; cIAI, complicated Intra-abdominalInfection. a Solithromycin Solithromycin Plazomicin Plazomicin Eravacycline Eravacycline Delafloxacin (Baxdela) (Baxdela) Delafloxacin 3 Phase Carbavance Carbavance (Meropenem+Vaborbactam) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 13 of 40 BMJ Open

1 2 3 DISCUSSION 4 Our search identified 76 clinical trials investigating one or more antibiotics recruiting children 5 6 between 0 and 18 years of age. This is low in comparison to the number of on-going trials in adults, 7 despite children representing around a quarter of the global population.[14, 15] A review of 8 9 completed CTs in the U.S. between 2000 and 2010 identified a total of 4078 adult trials compared to 10 11 just 294 that had recruited children.[16] In our study, the lack of trials recruiting neonates is striking. 12 Just 23 of the 76 trials identified were recruiting neonates, and remarkably just 8 CTs globally were 13 14 recruiting preterm neonates. There are broadly two types of pediatric trials conducted globally. 15 Either pharmaceutical-ledFor Phase peer 1/2 PK and review safety trials (n=17) beingonly conducted in the HIC setting, 16 17 or investigator led, often pragmatic, late phase efficacy trials in the LMIC setting (n=34), with a 18 greater proportion of on-going trials being sponsored by non-profit organisations over industry (66% 19 20 compared to 34%).. As of April 2016, there were 17 antibiotic PIPs agreed by the EMA,[8] covering 21 a range of indications, most commonly cSSTI, complicated IAI (cIAI), and complicated UTI 22 23 (cUTI).[13] In contrast, treatments for respiratory and systemic infections, the most common clinical 24 indications for antibiotics in pediatrics, are not currently being evaluated.[14] Thirty-seven antibiotics 25 26 are currently being developed in adults, yet to our knowledge just 2 of these are being studied in 27 children. Some classes of antibiotics that may be of higher risk for children (tetracyclines and 28 29 fluoroquinolones) may not be pursued as aggressively for pediatric approvals due to well- 30 recognized issues of toxicity, particularly when safer alternatives are widely available. Given that 31 32 Gram-negative sepsis is a growing problem in neonates, with a significant increase in the proportion http://bmjopen.bmj.com/ 33 of multi-resistant Gram-negative pathogens,[15] the substantial lag time between the submission 34 35 date (for PIP or waiver) and declared completion date of PK studies in adults is a real concern; 36 37 although, there is value in generating substantial safety data in adults prior to exposing children and 38 newborns to potentially toxic new agents. 39

40 on September 28, 2021 by guest. Protected copyright. 41 In 2013, a similar review of European pediatric clinical trials identified 31 trials of antibiotics 42 43 approved for adults by the EMA in 2000 that were recruiting children in Europe (compared to the 22 44 trials we found recruiting in Europe). They included both published and ongoing trials, which likely 45 46 accounts for the higher number of trials reported. They similarly found a very small proportion of 47 neonatal trials (2 of 31), as well as a greater proportion of efficacy-based trials.[9] A review of 48 49 interventional trials registered with ClinicalTrials.gov between 2007 and 2010 found that only 17% 50 had recruited children below 18 years of age.[17] A similar review of antimicrobial CTs conducted in 51 52 the U.S. between 2000 and 2012 reported that just 5% had recruited only children compared to 74% 53 that recruited only adults, and that, as we have found, the trials were sponsored primarily by non- 54 55 profit organisations (60% versus 30% by industry).[14] In our search of global trials, 39% of 56 registered CTs reported collection of PK data in comparison to a 2009 paediatrc PK research review 57 58 that reported 24% of registered CTs would be collecting PK data.[18] 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 14 of 40

1 2 3 4 The search strategy used has some limitations. Since the search was limited to clinical trials 5 6 registered with ClinicalTrials.gov, it is possible other open or on-going trials registered with 7 alternative platforms (for example, the WHO International Clinical Trials Registry Platform [ICTRP]) 8 9 will have been missed. Together with ClinicalTrials.gov these could help to establish the entirety of 10 11 current clinical research in this field. We did however search EudraCT, and found no further studies 12 beyond those captured on ClinicalTrials.gov. Our search was also limited to open CTs, thereby 13 14 missing active but not yet recruiting trials, and those that had already closed to recruitment. The 15 information recordedFor for each peer trial registered review with ClinicalTrials.gov only is updated by the trial 16 17 investigators, and therefore relies on them to periodically update the registry. Occasionally, 18 information such as recruitment status might not be updated in real time. 19 20 21 Concerns around the growing threat of antimicrobial resistance have prompted several new 22 23 initiatives. In 2016, the EMA published a draft Concept Paper to propose the development of an 24 Addendum to the guideline on the evaluation of new anti-bacterial products for treatment of bacterial 25 26 infections in children.[19] At the same time, the Clinical Trials Transformation Initiative (CTTI) is 27 currently focused on the identification of key barriers in the conduct of pediatric antibacterial CTs, 28 29 which hamper their successful implementation into clinical practice.[20] Recent evidence states that 30 overall, antibiotic CTs make up less than 1% of all registered pediatric CTs, and that trial completion 31 32 is slow, with an average time to completion of around two years.[21] There are specific areas where http://bmjopen.bmj.com/ 33 the design and conduct of pediatric antibiotic CTs can be harmonized and simplified, such as the 34 35 standardisation of the inclusion and exclusion criteria for specific Clinical Infection Syndromes, and 36 37 improved bridging of safety and efficacy data from other age groups; these advances could improve 38 trial conduct and efficiency in children.[22] 39

40 on September 28, 2021 by guest. Protected copyright. 41 42 43 CONCLUSIONS 44 This review highlights that very few pediatric antibiotic CTs are being conducted globally, 45 46 particularly in neonates. There is a marked disparity between antibiotic drug development 47 programmes in adults and children. Many issues contribute to the difficulties in conducting pediatric 48 49 antibiotic clinical trials. The lack of regulatory guidance, vulnerability of this population, issues with 50 informed consent and assent, and lack of research-experienced hospital personnel all present 51 52 challenges in study design, delivery and recruitment. Delays in the initial start-up of CTs in 53 pediatrics due to pediatric-specific protocol issues and complicated ethical approval continue to 54 55 discourage both academic and pharmaceutical interest. The limited data presented here suggest 56 that the dismal state of pediatric antibiotic research continues. Earlier collaboration between global 57 58 academic research networks and pharmaceutical companies is now vital to accelerate progress. 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 15 of 40 BMJ Open

1 2 3 ACKNOWLEDGEMENTS 4 Contributors MS, CIB, GT, LF and JAB designed the study. Searches were conducted by GT. 5 6 Eligible records were identified via manual filtering by GT CIB, LF and MS. IL and JSB commented 7 on study design and assisted with drafting the manuscript. 8 9 Funding This research received no specific grant from any funding agency in the public, 10 11 commercial or not-for-profit sectors. CIB was funded as a Clinical Research Fellow by the Global 12 Research in Paediatrics (GRiP) Network of Excellence, part of the European Union’s Seventh 13 14 Framework Programme for research, technological development and demonstration (FP7/2007– 15 2013, grant agreementFor number peer 261060). review only 16 17 Conflict of interest None declared. 18 Data sharing statement Full dataset is available on request. 19 20 21 22 23 REFERENCES 24 1. Corny J, Lebel D, Bailey B et al. Unlicensed and Off-Label Drug Use in Children Before and 25 26 After Pediatric Governmental Initiatives. J Pediatr Pharmacol Ther. 2015;20(4):316–28. 27 2. European Medicines Agency. Concept paper on extrapolation of efficacy and safety in 28 29 medicine development. 30 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/04/WC50 31 32 0142358.pdf. (accessed May 2016) http://bmjopen.bmj.com/ 33 3. Dunne J, Rodriguez WJ, Murphy MD et al. Extrapolation of Adult Data and Other Data in 34 35 Pediatric Drug-Development Programs. Pediatrics. 2011; 36 37 http://pediatrics.aappublications.org/content/early/2011/10/20/peds.2010-3487.abstract 38 (accessed June 2016) 39

40 4. Kearns GL, Abdel-Rahman SM, Alander SW et al. Developmental pharmacology--drug on September 28, 2021 by guest. Protected copyright. 41 disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157–67. 42 43 5. Theuretzbacher U, Van Bambeke F, Cantón R et al. Reviving old antibiotics. Internet J 44 Antimicrob Chemother. 2015; 45 46 http://jac.oxfordjournals.org/content/early/2015/06/10/jac.dkv157.abstract (accessed June 47 2016) 48 49 6. van der Meer JW, Gyssens IC. Quality of antimicrobial drug prescription in hospital. Clin 50 Microbiol Infect. 2001;7:12–5. 51 52 7. European Medicines Agency. EMA Opinions and decisions on Paediatric Investigation Plans. 53 2016; 54 55 http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/pip_search.jsp&mid 56 =WC0b01ac058001d129. (accessed June 2016) 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 16 of 40

1 2 3 8. Guidance for industry. Pediatric Study Plans: Content of and Process for Submitting Initial 4 Pediatric Study Plans and Amended Initial Pediatric Study Plans. 5 6 http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/uc 7 m360507.pdf. (accessed June 2016) 8 9 9. Garazzino S, Lutsar I, Bertaina C et al. New antibiotics for paediatric use: a review of a 10 11 decade of regulatory trials submitted to the European Medicines Agency from 2000--why 12 aren’t we doing better? Int J Antimicrob Agents. 2013;42(2):99–118. 13 14 10. The World Bank. The World Bank list of economies. 2015; 15 http://siteresources.worldbank.org/DATASTATISTICS/Resources/CLASS.XLSFor peer review only (accessed 16 17 October 2016) 18 11. The World Health Organisation. WHO ATC/DDD Index. 2016; 19 20 http://www.whocc.no/atc_ddd_index/. (accessed March 2016) 21 12. The Pew Charitable Trusts. Antibiotics Currently in Clinical Development. 2016; 22 23 http://www.pewtrusts.org/~/media/assets/2016/05/antibiotics-currently-in-clinical- 24 development.pdf?la=en. (accessed May 2016) 25 26 13. Lutsar I. Often neglegted: paediatric drug development - a regulatory and clinical view. In 27 Amsterdam, Netherlands; 2016. (S219 - Symposium lecture.). 28 29 14. Stockmann C, Sherwin CMT, Ampofo K et al. Characteristics of antimicrobial studies 30 registered in the USA through ClinicalTrials.Gov. Int J Antimicrob Agents. 2013;42(2):161–6. 31 32 15. Versporten A, Bielicki J, Drapier N et al. The Worldwide Antibiotic Resistance and Prescribing http://bmjopen.bmj.com/ 33 in European Children (ARPEC) point prevalence survey: developing hospital-quality 34 35 indicators of antibiotic prescribing for children. J Antimicrob Chemother. 2016;71(4):1106–17. 36 37 16. Bielicki JA, Lundin R, Sharland M. Antibiotic Resistance Prevalence in Routine Bloodstream 38 Isolates from Children’s Hospitals Varies Substantially from Adult Surveillance Data in 39

40 Europe. Pediatr Infect Dis J. 2015;34(7):734–41. on September 28, 2021 by guest. Protected copyright. 41 17. Califf RM, Zarin DA, Kramer JM et al. Characteristics of clinical trials registered in 42 43 ClinicalTrials.gov, 2007-2010. JAMA. 2012;307(17):1838–47. 44 18. Viergever RF, Rademaker CMA, Ghersi D. Pharmacokinetic research in children: an analysis 45 46 of registered records of clinical trials. BMJ Open. 2011;1(1):e000221. 47 19. European Medicines Agency. Concept paper on an addendum to the guideline on the 48 49 evaluation of medicinal products indicated for treatment of bacterial infections to address 50 paediatric-specific clinical data requirements. 51 52 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/04/WC50 53 0205026.pdf. (accessed July 2016) 54 55 20. Clinical Trials Transformation Initiative. https://www.ctti-clinicaltrials.org/projects/pediatric- 56 trials. (accessed July 2016) 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 17 of 40 BMJ Open

1 2 3 21. Clinical Trials Transformation Initiative. AACT database. https://www.ctti- 4 clinicaltrials.org/aact-database. (accessed January 2017) 5 6 22. Folgori L, Bielicki J, Ruiz B, et al. Harmonisation in study design and outcomes in paediatric 7 antibiotic clinical trials: a systematic review. Lancet Infect Dis. 2016;16(9):e178-89. 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 28, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from BMJ Open Page 18 of 40

1 2 3 LIST OF FIGURES 4

5 6 Figure 1. Flow chart. Clinical trial selection process. 7

8 9 Table 1. Characteristics of clinical trials. 10 11 12 Table 2. Clinical trial endpoint classification of identified clinical trials stratified by trial sponsor. 13 Endpoint classification determined by planned primary outcomes. 14 15 Table 3. ClinicalFor indication ofpeer identified clinical review trials stratified by ageonly group being recruited. 16 17 18 Table 4. Comparison of antibiotic development pipeline in adults and children. Adapted from Pew 19 Charitable Trusts “Antibiotics currently in clinical development” pipeline (last accessed October 20 2016).[12] 21 22 23 24 25 26 27 28 29 30 31 32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

40 on September 28, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from Page 19 of 40 BMJ Open

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 http://bmjopen.bmj.com/ 32 Figure 1. Flow Chart. Clinical trial selection process. 33 34 254x190mm (300 x 300 DPI) 35 36 37 38 39

40 on September 28, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

BMJ Open Page 20 of 40 DATASET 1 2 A B C D 3 1 NCT Number Title Recruitment Study Results 4 2 NCT02539407 Population Pharmacokinetics of Anti-infectives in Critically Ill Children Recruiting No Results Available 5 6 3 NCT02935374 Effect of Antimicrobial Treatment of Acute Otitis Media on the Intestinal Microbiome in ChildrenNot yet recruiting No Results Available 7 4 NCT02899143 Short-course Antimicrobial Therapy in Sepsis Recruiting No Results Available 8 5 NCT01595529 The SCOUT Study: Short Course Therapy for Urinary Tract Infections in Children Recruiting No Results Available 9 10 6 NCT02380352 Short-course Antimicrobial Therapy for Paediatric Respiratory Infections Not yet recruiting No Results Available 11 7 NCT02891915 Trial to Evaluate Beta-Lactam Antimicrobial Therapy of Community Acquired Pneumonia in ChildrenFor peer review onlyRecruiting No Results Available 12 8 NCT02746276 Optimising Antibiotic Treatment for Sick Malnourished Children Recruiting No Results Available 13 9 NCT02917551 BALANCE on the Wards: A Pilot RCT Not yet recruiting No Results Available 14 15 10 NCT01243437 A Clinical Trial to Evaluate the Safety and Efficacy of Ciprofloxacin in the Treatment of Plague in Humanshttp://bmjopen.bmj.com/ Recruiting No Results Available 16 11 NCT02635191 Tailored Therapy for Helicobacter Pylori in Children Recruiting No Results Available 17 12 NCT01522105 Daptomycin in Pediatric Patients With Bacterial Meningitis Recruiting No Results Available 18 19 13 NCT02456974 Antibiotic Dosing in Pediatric Intensive Care Recruiting No Results Available 20 14 NCT00579956 A Randomized Double Blinded Comparison of Ceftazidime and Meropenem in Severe MelioidosisRecruiting No Results Available 21 15 NCT00545961 Middle Meatal Bacteriology During Acute Respiratory Infection in Children Not yet recruiting No Results Available 22 16 NCT01431326 Pharmacokinetics of Understudied Drugs Administered to Children Per Standard of Care Recruiting No Results Available 23 on September 28, 2021 by guest. Protected copyright. 24 17 NCT02475876 PK of Clindamycin and Trimethoprim-sulfamethoxazole in Infants and Children Recruiting No Results Available 25 18 NCT01420341 Co-trimoxazole as Maintenance Therapy for Meliodosis Recruiting No Results Available 26 19 NCT02266706 Pharmacokinetic and Safety Study of Ceftolozane/Tazobactam in Pediatric Participants Receiving Antibiotic Therapy for Proven or Suspected Gram-negative Infection or for Peri-operative Prophylaxis (MK-7625A-010)Recruiting No Results Available 27 28 20 NCT00867789 Antibiotics Versus Placebo in the Treatment of Abscesses in the Emergency Department Recruiting No Results Available 29 21 NCT02879981 A Safety Study of Balsamic Bactrim in Pediatric Participants With Acute Bronchitis Not yet recruiting No Results Available 30 22 NCT01269541 MESS-study MRSA Eradication Study SkÌ´ne Recruiting No Results Available 31 23 NCT02276482 Study of Tedizolid Phosphate in Adolescents With Complicated Skin and Soft Tissue Infection (cSSTI) (MK-1986-012)Recruiting No Results Available 32 33 24 NCT02663596 Safety and TDM of Continuous Infusion Vancomycin Through Continuous Renal Replacement Therapy SolutionNot yet recruiting No Results Available 34 25 NCT02555059 Special Drug Use Investigation of Ciproxan Injection in Pediatrics Recruiting No Results Available 35 26 NCT02297815 Comparative Effectiveness of Antibiotics for Respiratory Infections Recruiting No Results Available 36 37 27 NCT02224040 Typhoid Fever: Combined vs. Single Antibiotic Therapy Recruiting No Results Available 38 28 NCT02775968 Population Pharmacokinetics of Cephalosporins and Macrolides in Chinese Children With Community Acquired PneumoniaNot yet recruiting No Results Available 39 29 NCT02687906 Dose-finding, Pharmacokinetics, Safety, and Tolerability of Meropenem-Vaborbactam in Pediatric Subjects With Serious Bacterial InfectionsRecruiting No Results Available 40 30 NCT02783859 Hospitalised Pneumonia With Extended Treatment (HOPE) Study Recruiting No Results Available 41 42 31 NCT01994993 Antibiotic Safety (SCAMP) Recruiting No Results Available 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 A B C D 3 32 NCT02258763 Trial on the Ideal Duration of Oral Antibiotics in Children With Pneumonia Recruiting No Results Available 4 33 NCT02688790 Study Evaluate the PK Profile of Dalbavancin in Hospitalized Infants and Neonates Patients With Known or Suspected Bacterial InfectionRecruiting No Results Available 5 6 34 NCT00323219 Oral Moxifloxacin Versus Cefazolin and Oral Probenecid in the Management of Skin and Soft Tissue Infections in the Emergency DepartmentRecruiting No Results Available 7 35 NCT02750761 A Study of Oral and Intravenous (IV) Tedizolid Phosphate in Hospitalized Participants, Ages 2 to <12 Years, With Confirmed or Suspected Bacterial Infection (MK-1986-013)Recruiting No Results Available 8 36 NCT02466438 Safety and Pharmacokinetics of Piperacillin-tazobactam Extended Infusion in Infants and Children (PIP-TAZO)Recruiting No Results Available 9 10 37 NCT02260102 Temocillin Pharmacokinetics in Paediatrics Not yet recruiting No Results Available 11 38 NCT02694458 Comparison of Two Dosage Adjustment Strategies of Vancomycin in ChildrenFor peer review onlyRecruiting No Results Available 12 39 NCT01540838 Slow Initial beta-lactam Infusion With High-dose Paracetamol to Improve the Outcomes of Childhood Bacterial MeningitisRecruiting No Results Available 13 40 NCT00368498 A Trial to Evaluate the Loading Dose Required to Achieve Therapeutic Serum Teicoplanin Concentration TimelyRecruiting No Results Available 14 15 41 NCT01785641 Single Versus Combined Antibiotic Therapy for Bacterial Peritonitis in CAPD Patients http://bmjopen.bmj.com/ Recruiting No Results Available 16 42 NCT02554383 Efficacy of Antibiotics in Children With Acute Sinusitis: Which Subgroups Benefit? Recruiting No Results Available 17 43 NCT01265173 Comparison of Efficacy of Cefotaxime, Ceftriaxone, and Ciprofloxacin for the Treatment of Spontaneous Bacterial Peritonitis in Patients With Liver CirrhosisRecruiting No Results Available 18 19 44 NCT02335905 Ceftaroline for Treatment of Hematogenously Acquired Staphylococcus Aureus Osteomyelitis in ChildrenRecruiting No Results Available 20 45 NCT02922686 Penicillin for the Emergency Department Outpatient Treatment of CELLulitis Not yet recruiting No Results Available 21 46 NCT02848820 Initial Non-operative Treatment Strategy Versus Appendectomy Treatment Strategy for Simple Appendicitis in ChildrenNot yet recruiting No Results Available 22 47 NCT02475733 Evaluation of Safety,Pharmacokinetics and Efficacy of CAZ-AVI With Metronidazole in Childern Aged 3 Months to 18 Years Old With Complicated Intra-abdominal Infections (cIAIs).Recruiting No Results Available 23 on September 28, 2021 by guest. Protected copyright. 24 48 NCT02372461 Randomized Trial of Amoxicillin Versus Placebo for (Fast Breathing) Pneumonia Recruiting No Results Available 25 49 NCT01553006 Study of Cefditoren Pivoxil in Treatment of Childhood With Acute Rhinosinusitis Recruiting No Results Available 26 50 NCT02527681 Pharmacokinetics and Safety of Ceftobiprole in Neonates and Infants up to 3 Months Treated With Systemic AntibioticsRecruiting No Results Available 27 28 51 NCT02210169 RCT of Continuous Versus Intermittent Infusion of Vancomycin in Neonates Recruiting No Results Available 29 52 NCT02497781 Evaluation of Safety, Pharmacokinetics and Efficacy of Ceftazidime and Avibactam (CAZ-AVI ) Compared With Cefepime in Children From 3 Months to Less Than 18 Years of Age With Complicated Urinary Tract Infections (cUTIs)Recruiting No Results Available 30 53 NCT02814916 Dalbavancin for the Treatment of Acute Bacterial Skin and Skin Structure Infections in Children, Known or Suspected to be Caused by Susceptible Gram-positive Organisms, Including MRSANot yet recruiting No Results Available 31 54 NCT02210325 Efficacy and Safety Study of Oral Solithromycin Compared to Intramuscular Ceftriaxone Plus Oral Azithromycin in the Treatment of Patients With GonorrheaRecruiting No Results Available 32 33 55 NCT02801370 Phase 3 Study of OTO-201 in Acute Otitis Externa Recruiting No Results Available 34 56 NCT02760420 3 Days Amoxicillin Versus Placebo for Fast Breathing Childhood Pneumonia in Malawi Recruiting No Results Available 35 57 NCT02678195 3 Days Versus 5 Days Amoxicillin for Chest-indrawing Childhood Pneumonia in Malawi Recruiting No Results Available 36 37 58 NCT02605122 Safety and Efficacy of Solithromycin in Adolescents and Children With Community-acquired Bacterial PneumoniaRecruiting No Results Available 38 59 NCT02570490 Oral Sodium Fusidate (CEM-102) Versus Oral Linezolid for the Treatment of Acute Bacterial Skin and Skin Structure InfectionsRecruiting No Results Available 39 60 NCT02443285 Is Spontaneous Bacterial Peritonitis Still Responding to 3rd Generation Cephalosporins? Recruiting No Results Available 40 61 NCT02334124 Comparing the Intravenous Treatment of Skin Infections in Children, Home Versus Hospital Recruiting No Results Available 41 42 62 NCT02218372 A Study to Investigate the Safety and Efficacy of Fidaxomicin (Oral Suspension or Tablets) and Vancomycin (Oral Liquid or Capsules) in Pediatric Subjects With Clostridium Difficile-associated Diarrhea (CDAD)Recruiting No Results Available 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 A B C D 3 63 NCT01032499 Open and Comparative Study to Measure Tolerability and Efficacy of Taro Elixir Not yet recruiting No Results Available 4 64 NCT02598362 Pharmacokinetics of Ciprofloxacin in Pediatric Patients Recruiting No Results Available 5 6 65 NCT02878031 Community Case Management of Chest Indrawing Pneumonia Recruiting No Results Available 7 66 NCT02790996 Neonatal Vancomycin Trial Not yet recruiting No Results Available 8 67 NCT02712307 Study of 5 and 10 Days Treatment With Penicillin Against Sore Throat Caused by Streptococci Recruiting No Results Available 9 10 68 NCT02424734 Safety, Tolerability and Efficacy of Ceftaroline in Paediatrics With Late-Onset Sepsis Recruiting No Results Available 11 69 NCT02134301 Open-Label, Dose-Finding, Pharmacokinetics, Safety and Tolerability Study of Oritavancin in Pediatric Patients With Suspected or Confirmed Bacterial InfectionsFor peer review onlyRecruiting No Results Available 12 70 NCT02013141 An Open-Label Study of the Pharmacokinetics of a Single Dose of Telavancin in Pediatric Subjects Aged 1 to 17 YearsRecruiting No Results Available 13 71 NCT01427842 Dose Enhancement of Vancomycin IN Everyday Patients Recruiting No Results Available 14 15 72 NCT01278017 The Role of Short-course Ceftriaxone Therapy in the Treatment of Severe Nontyphoidal Salmonella Enterocolitishttp://bmjopen.bmj.com/ Recruiting No Results Available 16 73 NCT00988026 Safety and Efficacy Comparison of Minocycline Microgranules Versus Lymecycline in the Treatment of Mild to Moderate AcneRecruiting No Results Available 17 74 NCT02288234 Telavancin Observational Use Registry (TOUR) Recruiting No Results Available 18 19 75 NCT01304459 Vancomycin Serum Concentrations in Pediatric Oncology Patients Under Intensive Care Recruiting No Results Available 20 76 NCT01173575 Assessment of the Efficacy of FOSFOMYCIN in Patients With Bacterial Infection Recruiting No Results Available 21 77 NCT01778634 Trial of Intravenous Azithromycin to Eradicate Ureaplasma Respiratory Tract Infection in Preterm Infants (AZIPIII)Recruiting No Results Available 22

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1 2 E F 3 1 Indication Infection category 4 2 Proven or suspected infection (in patients on PICU) 9 5 6 3 Acute Otitis Media 3 7 4 Sepsis 8 8 5 Urinary Tract Infections (UTI) 7 9 10 6 Community-acquired Pneumonia (CAP) 4 11 7 Pneumonia For peer review4 only 12 8 Proven or suspected infection in patients with malnutrition 9 13 9 Bacteremia 8 14 15 10 Plague 8 http://bmjopen.bmj.com/ 16 11 Helicobacter Pylori Infection 7 17 12 Meningitis 1 18 19 13 Proven or suspected bacterial infection (Pharmacokinetics) 9 20 14 Melioidosis 8 21 15 Acute Respiratory Infection|Sinusitis 3 22 16 Various infections (including nosocomial Pneumonia, CAP, Acute Bacterial Exacerbation of Chronic Bronchitis, cSSSI, Uncomplicated SSSI, cUTI, Acute Pyelonephritis, uUTI, Bacterial Septicemia, Plague, Acute Bacterial Sinusitis, Bacterial Meningitis)Various 23 on September 28, 2021 by guest. Protected copyright. 24 17 Bacterial Infections 9 25 18 Meliodosis 8 26 19 Proven or Suspected Gram-negative Bacterial Infection 9 27 28 20 Abscess 1 29 21 Bronchitis 4 30 22 Throatcarriers of MRSA 3 31 23 Acute Skin and Soft Tissue infections (aSSTIs) 2 32 33 24 Proven or suspected bacterial infection (in CRRT patients) 9 34 25 Cystitis / Pyelonephritis 7 35 26 Acute Upper Respiratory Tract Infections (ARTIs) 3 36 37 27 Typhoid Fever 8 38 28 Community Acquired Pneumonia (CAP) 4 39 29 Bacterial Infections 9 40 30 Pneumonia 4 41 42 31 Complicated Intra Abdominal Infections (cIAIs) 6 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 E F 3 32 Pneumonia 4 4 33 Bacterial Infections 9 5 6 34 Cellulitis 2 7 35 Gram-Positive Bacterial Infections 9 8 36 Infection 9 9 10 37 Urinary Tract Infection or suspected Cholangitis 7 11 38 Methicillin-resistant Staphylococcal InfectionsFor peer review9 only 12 39 Bacterial Meningitis 1 13 40 Staphylococcal Infections 9 14 15 41 Peritonitis (in CAPD patients) 6 http://bmjopen.bmj.com/ 16 42 Acute Sinusitis (Respiratory Tract Infections) 3 17 43 SBP in patients with Liver Cirrhosis 6 18 19 44 Hematogenously Acquired Staphylococcus Aureus Osteomyelitis 5 20 45 Cellulitis or Wound Infection 8 21 46 Appendicitis 6 22 47 Complicated Intra-abdominal Infections (cIAIs) 6 23 on September 28, 2021 by guest. Protected copyright. 24 48 Pneumonia (fast-breathing) 4 25 49 Rhinosinusitis 3 26 50 Bacterial Infections 9 27 28 51 Sepsis 8 29 52 Complicated Urinary Tract Infections (cUTIs) 7 30 53 Methicillin-Resistant Staphylococcus Aureus Skin Infection 2 31 54 Uncomplicated Urogenital Gonorrhea 7 32 33 55 Acute Otitis Externa 3 34 56 Pneumonia 4 35 57 Pneumonia 4 36 37 58 Community-acquired Bacterial Pneumonia 4 38 59 Acute Bacterial Skin and Skin Structure Infections 2 39 60 Primary Bacterial Peritonitis 6 40 61 Cellulitis 8 41 42 62 Clostridium Difficile-associated Diarrhea (CDAD) 6 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 E F 3 63 Acne Vulgaris II or III Degree 2 4 64 Urinary Tract Infection or Pyelonephritis 7 5 6 65 Pneumonia 4 7 66 Late Onset Neonatal Sepsis 8 8 67 Tonsillitis 3 9 10 68 Late-onset Sepsis 8 11 69 Gram Positive Bacterial InfectionsFor peer review9 only 12 70 Gram-Positive Bacterial Infections 9 13 71 Vancomycin Therapy 9 14 15 72 Diarrhea 6 http://bmjopen.bmj.com/ 16 73 Mild to Moderate Acne 2 17 74 Hospital Acquired Bacterial Pneumonia (HAP), Complicated Skin and Skin Structure Infections (cSSSI), Ventilator Associated Bacterial Pneumonia (VAP), Gram Positive InfectionVarious 18 19 75 Infection 9 20 76 Bacterial Infection 9 21 77 Eradicate ureaplasma respiratory tract infection from preterm infants4 22

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1 2 G H I J 3 1 Interventions Antibiotic class (J01 code) Gender Age 4 2 Antiinfectives (beta-lactam, aminoglycoside, glycopeptide, fluoroquinolone, daptomycin, rifampin, trimethoprim, sulfamethoxazole, clarithromycin)Various Both Up to 18 Years 5 6 3 Amoxicillin, Amoxicillin-Potassium Clavulanate, Macrolide Various Both 6 Months to 7 Years 7 4 Antibiotic J01 Both Up to 18 years 8 5 Trimethoprim sulfamethoxazole, cefixime, or cephalexin Various Both 2 Months to 10 Years 9 10 6 Amoxicillin J01C Both 6 Months to 10 Years 11 7 Amoxicillin, Amoxicillin-clavulanate, CefdinirFor peer reviewVarious onlyBoth 6 Months to 71 Months 12 8 Ceftriaxone, Metronidazole J01D Both 2 Months to 59 Months 13 9 7 days vs 14 days of adequate antibiotic treatment J01 Both Up to 18 years 14 15 10 Ciprofloxacin, doxyxcycline Various Bothhttp://bmjopen.bmj.com/ 8 Years and older 16 11 Tailored vs standard therapy (Amoxicillin, Clarithromycin, Metronidazole, Rabeprazole, Esomeprazole, Omeprazole)Various Both 4 Years to 18 Years 17 12 Daptomycin J01X Both 3 Months to 16 Years 18 19 13 Amoxicillin-clavulanate, Piperacilline-tazobactam, Vancomycin Various Both Up to 16 Years 20 14 Meropenem, Ceftazidime J01D Both 15 Years and older 21 15 Amoxicillin clavulanate acid J01C Both 6 Years to 13 Years 22 16 Various drugs (Ceftazidime, Ciprofloxacin, Clindamycin, Doxycycline, Levofloxacin, Meropenem)Various Both Up to 18 years 23 on September 28, 2021 by guest. Protected copyright. 24 17 Clindamycin, Trimethoprim-sulfamethoxazole Various Both 1 Month to 16 Years 25 18 Co-trimoxazole J01E Both 15 Years and older 26 19 Ceftolozane/Tazobactam J01D Both Up to 17 Years 27 28 20 Trimethoprim-sulfamethoxazole J01E Both 3 Months to 17 Years 29 21 Guaifenesin, Sulfamethoxazole trimethoprim J01E Both 4 Years to 14 Years 30 22 Systemic Rifampin and Clindamycine/Trimehoprimsulfa, or Topical mupirocinVarious Both 5 Years and older 31 23 Tedizolid Phophate J01X Both 12 Years to 18 Years 32 33 24 Vancomycin J01X Both Up to 18 years 34 25 Ciprofloxacin J01F Both Up to 14 Years 35 26 Antibiotics (Amoxicillin-clavulanate, azithromycin, cefdinir, cefprozil, cefuroxime axetil, ceftriaxone, cefadroxil)Various Both 6 Months to 18 Years 36 37 27 Ceftriaxone, Ceftriaxone/azithromycin, Azithromycin, Azithromycin/cefiximeVarious Both 2 Years to 80 Years 38 28 Cephalosporins and Macrolides Various Both 1 Year to 18 Years 39 29 Carbavance J01D Both Up to 17 Years 40 30 Amoxicillin-clavulanic Acid J01C Both 3 Months to 5 Years 41 42 31 Ampicillin/metronidazole/gentamicin/clindamycin/Piperacillin-tazobactam combinationsVarious Both Up to 120 Days 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 G H I J 3 32 Amoxicillin-Potassium Clavulanate J01C Both 3 Months to 59 Months 4 33 Dalbavancin J01X Both Up to 28 Days 5 6 34 Cefazolin/Moxifloxacin Various Both Up to 18 Years 7 35 Tedizolid Phosphate J01X Both 2 Years to 11 Years 8 36 Piperacillin-tazobactam J01C Both 2 Months to 6 Years 9 10 37 Temocillin J01C Both 6 Months to 3 Years 11 38 Vancomycin For peer reviewJ01X onlyBoth 1 Month to 16 Years 12 39 Beta-lactam J01C Both 2 Months to 15 Years 13 40 Teicoplanin J01X Both 16 Years and older 14 15 41 Ceftazidime/ciprofloxacin, Ceftazidime, Cefazolin/gentamicin, Cefazolin Various Bothhttp://bmjopen.bmj.com/ 15 Years and older 16 42 Amoxicillin-clavulanate J01C Both 2 Years to 11 Years 17 43 Cefotaxime, Ceftriaxone, Ciprofloxacin Various Both 16 Years and older 18 19 44 Ceftaroline Fosamil J01D Both 1 Year to 17 Years 20 45 Flucloxacillin, Phenoxymethylpenicillin J01C Both 16 Years and older 21 46 Augmentin/Gentamicin, Appendectomy J01C Both 7 Years to 17 Years 22 47 Ceftazidime-avibactam, Meropenem, Metronidazole Various Both 3 Months to 18 Years 23 on September 28, 2021 by guest. Protected copyright. 24 48 Amoxicillin J01C Both 2 Months to 59 Months 25 49 Cefditoren pivoxil J01D Both 1 Year to 15 Years 26 50 Ceftobiprole J01D Both Up to 3 Months 27 28 51 Vancomycin J01X Both Up to 90 Days 29 52 Ceftazidime-avibactam, Cefepime J01D Both 3 Months to 18 Years 30 53 Dalbavancin single dose J01X Both 3 Months to 17 Years 31 54 Solithromycin, Ceftriaxone, Azithromycin Various Both 15 Years and older 32 33 55 Ciprofloxacin J01M Both 6 Months and older 34 56 Amoxicillin J01C Both 2 Months to 59 Months 35 57 Amoxicillin J01C Both 2 Months to 59 Months 36 37 58 Solithromycin J01F Both 2 Months to 17 Years 38 59 Sodium fusidate, Linezolid J01X Both 12 Years and older 39 60 Cefotaxime, Ceftriaxone J01D Both Up to 18 Years 40 61 Ceftriaxone, Flucloxacillin Various Both 6 Months to 18 Years 41 42 62 Fidaxomicin, Vancomycin J01X Both Up to 17 Years 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 G H I J 3 63 Taro Elixir J01A Both 14 Years and older 4 64 Ciprofloxacin J01M Both 3 Months to 17 Years 5 6 65 Amoxicillin J01C Both 2 Months to 59 Months 7 66 Vancomycin J01X Both Up to 90 Days 8 67 Phenoxymethylpenicillin J01C Both 6 Years and older 9 10 68 Ceftaroline Fosamil J01D Both Up to 59 Days 11 69 Oritavancin For peer reviewJ01X onlyBoth Up to 18 Years 12 70 Telavancin J01X Both 1 Year to 17 Years 13 71 Vancomycin J01X Both 16 Years and older 14 15 72 Ceftriaxone J01D Bothhttp://bmjopen.bmj.com/ 3 Months to 18 Years 16 73 Minocycline, Lymecycline J01A Both 14 Years to 30 Years 17 74 Telavancin J01X Both Up to 18 Years 18 19 75 Vancomycin J01X Both Up to 18 Years 20 76 Fosfomycin J01X Both Up to 18 Years 21 77 Azithromycin J01F Both 0 to 72 hours 22

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1 2 K L M N O 3 1 Age group Estimated enrollment Location Income class Geographic region 4 2 8 1850 France High income Europe 5 6 3 9 150 Finland High income Europe 7 4 8 320 Italy High income Europe 8 5 9 746 United States High income North America 9 10 6 9 270 Canada High income North America 11 7 9 For400 United States peer reviewHigh income onlyNorth America 12 8 9 80 Kenya Lower middle income Africa 13 9 8 50 Canada High income North America 14 15 10 11 200 Uganda Low income Africa http://bmjopen.bmj.com/ 16 11 11 200 China Upper middle income Asia 17 12 10 5 Switzerland High income Europe 18 19 13 8 200 Belgium High income Europe 20 14 5 750 Thailand Upper middle income Asia 21 15 11 120 Finland High income Europe 22 16 8 3000 Various (United States, Canada, Israel, Singapore, United Kingdom)High income International 23 on September 28, 2021 by guest. Protected copyright. 24 17 10 54 United States High income North America 25 18 5 800 Thailand Upper middle income Asia 26 19 8 36 United States High income North America 27 28 20 10 200 United States High income North America 29 21 11 50 Peru Upper middle income Latin America 30 22 11 69 Sweden High income North America 31 23 5 162 Various (United States, Argentina, Bulgaria, Chile, Czech Republic, Georgia, Germany, Latvia, Lithuania, Panama, Poland, Slovenia, South Africa, Spain)Upper middle to High income International 32 33 24 8 10 United States High income North America 34 25 8 45 Japan High income Asia 35 26 10 117000 United States High income North America 36 37 27 11 120 Nepal Low income Asia 38 28 10 750 China Upper middle income Asia 39 29 8 56 United States High income North America 40 30 9 314 Various (Australia, Malaysia) High income Oceania 41 42 31 6 284 Various (United States, Canada)High income North America 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 K L M N O 3 32 9 300 Malaysia Upper middle income Asia 4 33 2 24 United States High income North America 5 6 34 8 390 Canada High income North America 7 35 4 32 United States High income North America 8 36 9 141 Canada High income North America 9 10 37 9 45 Belgium High income Europe 11 38 10 For100 France peer reviewHigh income onlyEurope 12 39 10 400 Angola Upper middle income Africa 13 40 5 20 Taiwan, China High income Asia 14 15 41 5 300 Thailand Upper middle income Asia http://bmjopen.bmj.com/ 16 42 4 688 United States High income North America 17 43 5 261 Republic of Korea High income Asia 18 19 44 10 18 United States High income North America 20 45 5 414 Ireland High income Europe 21 46 11 334 Netherlands High income Europe 22 47 10 102 Various (United States, Argentina, Chile, Czech Republic, Greece, Hungary, Poland, Romania, Russian Federation, Spain, Taiwan, Turkey) Upper middle to High income International 23 on September 28, 2021 by guest. Protected copyright. 24 48 9 2500 Pakistan Lower middle income Asia 25 49 10 120 Thailand Upper middle income Asia 26 50 6 45 Various (Belgium, Germany, Lithuania)High income Europe 27 28 51 6 200 Australia High income Oceania 29 52 10 102 Various (United States, Czech Republic, Greece, Hungary, Republic of Korea, Poland, Romania, Russian Federation, Taiwan, Turkey)Upper middle to High income International 30 53 10 300 United States High income North America 31 54 5 300 Various (United States, Australia)High income International 32 33 55 10 500 Various (United States, Canada)High income North America 34 56 9 2000 Malawi Low income Africa 35 57 9 2000 Malawi Low income Africa 36 37 58 10 400 Various (United States, Bulgaria, Hungary, Spain)High income International 38 59 5 712 Various (United States, Puerto Rico)High income International 39 60 8 100 Egypt Lower middle income Africa 40 61 10 188 Australia High income Oceania 41 42 62 8 144 Various (United States, Belgium, Canada, France, Germany, Hungary, Italy, Poland, Romania, Slovakia, Spain)High income International 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 K L M N O 3 63 5 120 Brazil Upper middle income Latin America 4 64 10 20 Belgium High income Europe 5 6 65 9 308 Nigeria Lower middle income Africa 7 66 6 300 Various (United Kingdom, France, Italy, Greece, Estonia)High income Europe 8 67 11 432 Sweden High income Europe 9 10 68 7 24 Various (United States, Hungary, Italy, Lithuania, Spain)High income International 11 69 8 For60 United States peer reviewHigh income onlyNorth America 12 70 10 32 United States High income North America 13 71 5 100 Australia High income Oceania 14 15 72 10 200 Taiwan, China High income Asia http://bmjopen.bmj.com/ 16 73 5 168 Mexico High income North America 17 74 8 1000 United States High income North America 18 19 75 8 50 Brazil Upper middle income Latin America 20 76 8 200 Various (Austria, Germany) High income Europe 21 77 1 180 United States High income North America 22

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1 2 P Q R S T 3 1 Collaborators Sponsor Study Types Phase Endpoint classification 4 2 Assistance Publique - Hopitaux de Paris Hospital Observational Not applicable Pharmacokinetics 5 6 3 University of Oulu|Oulu University Hospital University Interventional Phase 4 Efficacy 7 4 Ospedale Santa Maria delle Croci Hospital Interventional Phase 2 Safety/Efficacy 8 5 Children's Hospital of Philadelphia|Children's Hospital of Pittsburgh|University of Pennsylvania|Westat|National Institute of Allergy and Infectious Diseases (NIAID)Hospital Interventional Phase 2 Safety/Efficacy 9 10 6 Hamilton Health Sciences Corporation|Children's Hospital of Eastern OntarioHospital Interventional Phase 4 Safety/Efficacy 11 7 National Institute of Allergy and Infectious Diseases (NIAID)For peerNIH Interventional reviewPhase 4 onlyEfficacy 12 8 University of Oxford|KEMRI Wellcome Trust Research Program, Kenya|Centre for Research in Therapeutic Sciences, Strathmore University, Nairobi Kenya|University College, London|Centre for Microbiology Research, Kenya Medical Research Institute|Centre for Clinical Research, Kenya Medical Research InstituteUniversity Interventional Phase 2 Pharmacokinetics 13 9 Sunnybrook Health Sciences Centre Hospital Interventional Not specified Efficacy 14 15 10 Centers for Disease Control and Prevention|MRC/UVRI Uganda Research Unit on Aids|Ministry of Health, UgandaCDC Interventional Phase 2 Safety/Efficacyhttp://bmjopen.bmj.com/ 16 11 Beijing Children's Hospital Hospital Interventional Phase 4 Safety/Efficacy 17 12 University Hospital Inselspital, Berne Hospital Interventional Phase 1 Pharmacokinetics 18 19 13 University Hospital, Ghent|University Hospital, Antwerp|Queen Fabiola Children's University Hospital, BrusselsHospital Observational Not applicable Pharmacokinetics 20 14 University of Oxford|Mahidol University|Wellcome TrustUniversity Interventional Not specified Efficacy 21 15 Oulu University Hospital University Interventional Phase 4 Safety/Efficacy 22 16 Daniel Benjamin|Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)|The EMMES Corporation|OpAns, LLC|Duke UniversityUniversity Observational Not applicable Pharmacokinetics 23 on September 28, 2021 by guest. Protected copyright. 24 17 Michael Cohen-Wolkowiez|Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)|Duke UniversityUniversity Interventional Phase 1 Pharmacokinetics 25 18 Khon Kaen University University Interventional Not specified Efficacy 26 19 Cubist Pharmaceuticals LLC Industry Interventional Phase 1 Pharmacokinetics 27 28 20 Children's Mercy Hospital Kansas City|Blue Cross Blue ShieldHospital Interventional Not specified Efficacy 29 21 Hoffmann-La Roche Industry Observational Not applicable Safety 30 22 Region Skane Hospital Interventional Not specified Efficacy 31 23 Cubist Pharmaceuticals LLC Industry Interventional Phase 3 Safety 32 33 24 Drexel University|The Center for Pediatric Pharmacotherapy, LLCUniversity Interventional Phase 1 Safety 34 25 Bayer Industry Observational Not applicable Safety/Efficacy 35 26 Children's Hospital of Philadelphia Hospital Observational Not applicable Safety/Efficacy 36 37 27 Sheba Medical Center Hospital Interventional Phase 4 Efficacy 38 28 Beijing Children's Hospital Hospital Observational Not applicable Pharmacokinetics 39 29 Rempex Pharmaceuticals (a wholly owned subsidiary of The Medicines Company)|Department of Health and Human ServicesIndustry Interventional Phase 1 Safety 40 30 Menzies School of Health Research|Griffith University|Sarawak General Hospital|University of Malaya|The University of Queensland|Queensland University of Technology|Nanyang Technological UniversityUniversity Interventional Phase 4 Safety/Efficacy 41 42 31 Michael Cohen-Wolkowiez|The EMMES Corporation|Duke UniversityUniversity Interventional Phase 2-3 Safety 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 P Q R S T 3 32 University of Malaya|Menzies School of Health ResearchUniversity Interventional Phase 4 Efficacy 4 33 Durata Therapeutics Inc., an affiliate of Allergan plcIndustry Interventional Phase 1 Pharmacokinetics 5 6 34 University of British Columbia University Interventional Phase 3 Efficacy 7 35 Merck Sharp & Dohme Corp. Industry Interventional Phase 1 Pharmacokinetics 8 36 St. Justine's Hospital Hospital Interventional Phase 1 Pharmacokinetics 9 10 37 Universit̩ Catholique de Louvain University Interventional Phase 4 Pharmacokinetics 11 38 Assistance Publique - H̫pitaux de ParisFor peerHospital Interventional reviewNot specified onlyPharmacokinetics 12 39 Helsinki University|Foundation for Paediatric Research, FinlandUniversity Interventional Phase 4 Safety/Efficacy 13 40 National Taiwan University Hospital University Interventional Phase 4 Pharmacokinetics 14 15 41 Chulalongkorn University University Interventional Not specified Efficacy http://bmjopen.bmj.com/ 16 42 University of Pittsburgh|National Institute of Allergy and Infectious Diseases (NIAID)University Interventional Phase 3 Safety/Efficacy 17 43 Korea University University Interventional Phase 4 Efficacy 18 19 44 Baylor College of Medicine|Forest Laboratories University Interventional Phase 1-2 Safety/Efficacy 20 45 Royal College of Surgeons, Ireland|Health Research Board, IrelandUniversity Interventional Phase 4 Efficacy 21 46 Ramon Gorter|ZonMw: The Netherlands Organisation for Health Research and Development|VU University Medical Center|Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)University Interventional Phase 4 Efficacy 22 47 AstraZeneca|PRA Health Sciences Industry Interventional Phase 2 Safety/Efficacy 23 on September 28, 2021 by guest. Protected copyright. 24 48 Aga Khan University University Interventional Not specified Efficacy 25 49 Thammasat University University Interventional Phase 4 Safety/Efficacy 26 50 Basilea Pharmaceutica Industry Interventional Phase 1 Pharmacokinetics 27 28 51 Murdoch Childrens Research Institute|Royal Children's Hospital|Mercy Hospital for Women, AustraliaUniversity Interventional Not specified Pharmacokinetics 29 52 AstraZeneca|PRA Health Sciences Industry Interventional Phase 2 Safety/Efficacy 30 53 Durata Therapeutics Inc., an affiliate of Allergan plcIndustry Interventional Phase 3 Safety/Efficacy 31 54 Cempra Inc|National Institute of Allergy and Infectious Diseases (NIAID)Industry Interventional Phase 3 Efficacy 32 33 55 Otonomy, Inc. Industry Interventional Phase 3 Efficacy 34 56 Save the Children|University of North Carolina|University of WashingtonHealth OrganisationInterventional Phase 4 Efficacy 35 57 Save the Children|University of North Carolina|University of WashingtonHealth OrganisationInterventional Phase 4 Efficacy 36 37 58 Cempra Inc Industry Interventional Phase 2-3 Safety/Efficacy 38 59 Cempra Inc Industry Interventional Phase 3 Safety/Efficacy 39 60 Tanta University University Interventional Phase 3 Efficacy 40 61 Murdoch Childrens Research Institute University Interventional Not specified Efficacy 41 42 62 Astellas Pharma Europe B.V.|Merck Sharp & Dohme Corp.|Astellas Pharma IncIndustry Interventional Phase 3 Safety/Efficacy 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 P Q R S T 3 63 Laboratorios Goulart S.A. Industry Interventional Phase 3 Safety/Efficacy 4 64 University Hospital, Ghent|Universitair Ziekenhuis BrusselUniversity Interventional Phase 4 Pharmacokinetics 5 6 65 Malaria Consortium|World Health Organization Health OrganisationInterventional Phase 4 Safety 7 66 PENTA Foundation|St George's, University of London|Institut National de la SantÌ© Et de la Recherche MÌ©dicale, France|University of Tartu|Consorzio per Valutazioni Biologiche e Farmacologiche|University of Liverpool|Therakind limited|Bambino GesÌ_ Hospital and Research Institute|Servicio Madrile̱o de Salud, Madrid, Spain|Aristotle University Of Thessaloniki|University of Edinburgh|SYNAPSE Research Management Partners S.L|European CommissionHealth OrganisationInterventional Phase 2 Safety/Efficacy 8 67 Sigvard M̦lstad|Public Health Agency of SwedenUniversity Interventional Phase 4 Safety/Efficacy 9 10 68 AstraZeneca|PRA Health Sciences Industry Interventional Phase 2-3 Safety/Efficacy 11 69 The Medicines Company For peerIndustry Interventional reviewPhase 1 onlyPharmacokinetics 12 70 Theravance Biopharma Antibiotics, Inc. Industry Interventional Phase 4 Pharmacokinetics 13 71 The Canberra Hospital Hospital Interventional Phase 2 Pharmacokinetics 14 15 72 Chang Gung Memorial Hospital Hospital Interventional Phase 4 Efficacy http://bmjopen.bmj.com/ 16 73 Darier Industry Interventional Phase 4 Safety/Efficacy 17 74 Theravance Biopharma Antibiotics, Inc. Industry Observational Not applicable Safety/Efficacy 18 19 75 Grupo de Apoio ao Adolescente e a Crianca com CancerHospital Observational Not applicable Pharmacokinetics 20 76 Infectopharm Arzneimittel GmbH|J&P Medical Research Ltd.|Sandoz GmbHIndustry Observational Not applicable Efficacy 21 77 University of Maryland University Interventional Phase 2 Safety/Efficacy 22

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1 2 U V W X Y Z AA AB 3 1 Primary outcome variable PK data collected First ReceivedStart Date Completion DateLast UpdatedLast Verified Results First Received 4 2 PK PK study design July 2, 2015 Sep-15 Dec-18 September 14, 2016Sep-16 No Study Results Posted 5 6 3 Efficacy No PK data September 28, 2016Oct-16 null October 12, 2016 Oct-16 No Study Results Posted 7 4 Efficacy No PK data September 8, 2016Sep-16 null September 13, 2016Sep-16 No Study Results Posted 8 5 Efficacy No PK data May 8, 2012 May-12 Apr-18 June 27, 2016 Jun-16 No Study Results Posted 9 10 6 Efficacy No PK data March 2, 2015 Mar-16 May-18 March 24, 2016 Mar-16 No Study Results Posted 11 7 Efficacy No PK dataFor peerSeptember 1, 2016 reviewOct-16 Mar-19 October 13, 2016 onlyOct-16 No Study Results Posted 12 8 PK PK study design April 4, 2016 Apr-16 Sep-16 April 25, 2016 Apr-16 No Study Results Posted 13 9 Efficacy No PK data September 23, 2016Oct-16 Dec-17 September 26, 2016Sep-16 No Study Results Posted 14 15 10 Efficacy No PK data November 17, 2010Dec-10 null September 10, 2012http://bmjopen.bmj.com/ Sep-12 No Study Results Posted 16 11 Efficacy No PK data November 25, 2015Mar-14 Jul-16 December 16, 2015Nov-15 No Study Results Posted 17 12 PK Primary PK data January 26, 2012 Apr-12 Apr-18 December 10, 2015Dec-15 No Study Results Posted 18 19 13 PK PK study design May 18, 2015 May-12 null November 17, 2015Nov-15 No Study Results Posted 20 14 Efficacy No PK data December 18, 2007Dec-07 Sep-10 June 3, 2008 Aug-07 No Study Results Posted 21 15 Efficacy No PK data October 17, 2007 Nov-07 Dec-09 October 18, 2007 Oct-07 No Study Results Posted 22 16 PK PK study design August 17, 2011 Nov-11 Feb-17 February 4, 2016 Feb-16 No Study Results Posted 23 on September 28, 2021 by guest. Protected copyright. 24 17 PK PK study design June 12, 2015 Nov-15 Dec-17 August 1, 2016 Aug-16 No Study Results Posted 25 18 Efficacy No PK data August 18, 2011 Aug-11 Dec-20 August 30, 2016 Aug-16 No Study Results Posted 26 19 PK PK study design September 22, 2014Sep-14 Nov-16 October 31, 2016 Oct-16 No Study Results Posted 27 28 20 Efficacy No PK data March 23, 2009 Mar-09 Oct-12 June 21, 2011 Jun-11 No Study Results Posted 29 21 Safety No PK data August 23, 2016 Aug-16 Dec-16 September 1, 2016Sep-16 No Study Results Posted 30 22 Efficacy No PK data January 3, 2011 Mar-11 Jun-15 May 25, 2015 May-15 No Study Results Posted 31 23 Safety Secondary PK data October 9, 2014 Mar-15 Jan-18 October 31, 2016 Oct-16 No Study Results Posted 32 33 24 Safety Primary PK data January 12, 2016 Jan-17 Dec-18 September 8, 2016Sep-16 No Study Results Posted 34 25 Safety No PK data September 18, 2015Jul-16 Sep-18 October 19, 2016 Oct-16 No Study Results Posted 35 26 Efficacy No PK data November 17, 2014Jan-14 Jul-17 May 6, 2016 May-16 No Study Results Posted 36 37 27 Efficacy No PK data August 21, 2014 Aug-13 Aug-15 August 26, 2014 Aug-14 No Study Results Posted 38 28 PK PK study design May 11, 2016 Aug-16 Oct-22 May 17, 2016 May-16 No Study Results Posted 39 29 Safety Primary PK data February 17, 2016 Jul-16 Sep-19 October 6, 2016 Oct-16 No Study Results Posted 40 30 Efficacy No PK data May 5, 2016 Jun-16 Dec-20 October 7, 2016 Oct-16 No Study Results Posted 41 42 31 Safety No PK data November 18, 2013Dec-13 Sep-17 August 1, 2016 Aug-16 No Study Results Posted 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 U V W X Y Z AA AB 3 32 Efficacy No PK data September 23, 2014Nov-14 Dec-18 December 20, 2015Dec-15 No Study Results Posted 4 33 PK PK study design February 18, 2016 Apr-16 May-17 October 19, 2016 Oct-16 No Study Results Posted 5 6 34 Efficacy No PK data May 8, 2006 Jan-04 Dec-13 February 6, 2012 Feb-12 No Study Results Posted 7 35 PK PK study design April 1, 2016 May-16 Feb-18 October 21, 2016 Oct-16 No Study Results Posted 8 36 PK PK study design June 2, 2015 Jan-16 Dec-17 April 18, 2016 Apr-16 No Study Results Posted 9 10 37 PK PK study design October 1, 2014 Oct-16 Oct-17 October 24, 2016 Oct-16 No Study Results Posted 11 38 PK PK study designFor peerFebruary 24, 2016 reviewFeb-16 Feb-17 March 8, 2016 onlyMar-16 No Study Results Posted 12 39 Efficacy No PK data February 23, 2012 Feb-12 Jul-17 February 19, 2016 Feb-16 No Study Results Posted 13 40 PK PK study design August 23, 2006 Jun-06 Dec-07 August 23, 2006 Aug-06 No Study Results Posted 14 15 41 Efficacy No PK data January 30, 2013 Dec-12 Dec-13 February 6, 2013http://bmjopen.bmj.com/ Feb-13 No Study Results Posted 16 42 Efficacy No PK data September 8, 2015Feb-16 Sep-20 October 3, 2016 Oct-16 No Study Results Posted 17 43 Efficacy No PK data December 22, 2010Apr-07 Apr-16 April 8, 2014 Apr-14 No Study Results Posted 18 19 44 Safety Secondary PK data December 31, 2014Jan-15 Jan-20 June 24, 2016 Jun-16 No Study Results Posted 20 45 Efficacy No PK data August 9, 2016 Dec-16 Dec-19 September 30, 2016Jul-16 No Study Results Posted 21 46 Efficacy No PK data July 24, 2016 Dec-16 Dec-20 July 26, 2016 Jul-16 No Study Results Posted 22 47 Safety Secondary PK data May 25, 2015 Jul-15 Oct-17 October 21, 2016 Oct-16 No Study Results Posted 23 on September 28, 2021 by guest. Protected copyright. 24 48 Efficacy No PK data November 4, 2014Nov-14 Jul-17 June 3, 2016 Jun-16 No Study Results Posted 25 49 Efficacy No PK data February 17, 2012 Jan-12 Sep-12 March 13, 2012 Mar-12 No Study Results Posted 26 50 PK PK study design August 5, 2015 Aug-14 Jun-17 October 20, 2016 Oct-16 No Study Results Posted 27 28 51 PK PK study design August 5, 2014 Sep-14 Sep-17 March 17, 2016 Mar-16 No Study Results Posted 29 52 Safety Secondary PK data June 16, 2015 Sep-15 Oct-17 October 21, 2016 Oct-16 No Study Results Posted 30 53 Efficacy No PK data June 8, 2016 Jun-16 Jul-18 June 23, 2016 Jun-16 No Study Results Posted 31 54 Efficacy No PK data August 1, 2014 Aug-14 Apr-17 September 20, 2016Sep-16 No Study Results Posted 32 33 55 Efficacy No PK data June 13, 2016 Jun-16 Nov-16 June 13, 2016 Jun-16 No Study Results Posted 34 56 Efficacy No PK data May 1, 2016 Jun-16 Sep-18 June 10, 2016 Jun-16 No Study Results Posted 35 57 Efficacy No PK data February 3, 2016 Mar-16 null June 10, 2016 Jun-16 No Study Results Posted 36 37 58 Safety No PK data November 10, 2015Mar-16 Jan-18 September 14, 2016Sep-16 No Study Results Posted 38 59 Efficacy No PK data October 5, 2015 Nov-15 Feb-17 October 5, 2016 Oct-16 No Study Results Posted 39 60 Efficacy No PK data May 11, 2015 Jan-15 Dec-16 May 9, 2016 May-16 No Study Results Posted 40 61 Efficacy No PK data January 4, 2015 Jan-15 Jan-17 March 16, 2016 Mar-16 No Study Results Posted 41 42 62 Efficacy No PK data August 11, 2014 Oct-14 Feb-17 June 17, 2016 Jun-16 No Study Results Posted 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 U V W X Y Z AA AB 3 63 Efficacy No PK data December 14, 2009May-10 Oct-10 March 18, 2010 Dec-09 No Study Results Posted 4 64 PK PK study design November 4, 2015 Apr-15 Apr-16 November 4, 2015Nov-15 No Study Results Posted 5 6 65 Safety No PK data August 17, 2016 Oct-16 Jul-17 October 3, 2016 Oct-16 No Study Results Posted 7 66 Efficacy Secondary PK data April 7, 2016 Jul-16 Mar-18 May 31, 2016 May-16 No Study Results Posted 8 67 Efficacy No PK data March 4, 2016 Sep-15 Oct-16 October 4, 2016 Oct-16 No Study Results Posted 9 10 68 Safety Secondary PK data February 23, 2015 Aug-15 Oct-17 October 14, 2016 Oct-16 No Study Results Posted 11 69 PK PK study designFor peerMay 7, 2014 reviewMay-14 Dec-16 November 4, 2015 onlyNov-15 No Study Results Posted 12 70 PK PK study design December 11, 2013Dec-14 Aug-16 June 24, 2016 Jun-16 No Study Results Posted 13 71 PK PK study design August 31, 2011 Aug-11 Jul-12 September 1, 2011Aug-11 No Study Results Posted 14 15 72 Efficacy No PK data November 25, 2010Aug-10 Jul-12 January 14, 2011http://bmjopen.bmj.com/ Nov-10 No Study Results Posted 16 73 Efficacy No PK data September 30, 2009Jun-09 Apr-10 September 30, 2009Sep-09 No Study Results Posted 17 74 Efficacy No PK data November 5, 2014Nov-14 Sep-18 June 29, 2016 Jun-16 No Study Results Posted 18 19 75 PK Primary PK data February 24, 2011 Jan-11 null March 21, 2012 Mar-12 No Study Results Posted 20 76 Efficacy No PK data July 29, 2010 Aug-10 null February 5, 2016 Feb-16 No Study Results Posted 21 77 Efficacy Secondary PK data January 22, 2013 Jul-13 Dec-21 May 28, 2015 May-15 No Study Results Posted 22

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1 2 AC AD AE AF AG 3 1 Primary Completion DateURL 4 2 Jul-18 https://ClinicalTrials.gov/show/NCT02539407 5 6 3 Dec-18 https://ClinicalTrials.gov/show/NCT02935374 7 4 Sep-18 https://ClinicalTrials.gov/show/NCT02899143 8 5 Apr-18 https://ClinicalTrials.gov/show/NCT01595529 9 10 6 Feb-18 https://ClinicalTrials.gov/show/NCT02380352 11 7 Jan-19 https://ClinicalTrials.gov/show/NCT02891915For peer review only 12 8 Sep-16 https://ClinicalTrials.gov/show/NCT02746276 13 9 Aug-17 https://ClinicalTrials.gov/show/NCT02917551 14 15 10 Jun-13 https://ClinicalTrials.gov/show/NCT01243437 http://bmjopen.bmj.com/ 16 11 Mar-16 https://ClinicalTrials.gov/show/NCT02635191 17 12 Dec-16 https://ClinicalTrials.gov/show/NCT01522105 18 19 13 Dec-17 https://ClinicalTrials.gov/show/NCT02456974 20 14 Sep-10 https://ClinicalTrials.gov/show/NCT00579956 21 15 null https://ClinicalTrials.gov/show/NCT00545961 22 16 Feb-17 https://ClinicalTrials.gov/show/NCT01431326 23 on September 28, 2021 by guest. Protected copyright. 24 17 Nov-17 https://ClinicalTrials.gov/show/NCT02475876 25 18 Dec-20 https://ClinicalTrials.gov/show/NCT01420341 26 19 Nov-16 https://ClinicalTrials.gov/show/NCT02266706 27 28 20 Sep-12 https://ClinicalTrials.gov/show/NCT00867789 29 21 Dec-16 https://ClinicalTrials.gov/show/NCT02879981 30 22 Jun-15 https://ClinicalTrials.gov/show/NCT01269541 31 23 Jan-18 https://ClinicalTrials.gov/show/NCT02276482 32 33 24 Dec-18 https://ClinicalTrials.gov/show/NCT02663596 34 25 Sep-17 https://ClinicalTrials.gov/show/NCT02555059 35 26 Apr-17 https://ClinicalTrials.gov/show/NCT02297815 36 37 27 Dec-14 https://ClinicalTrials.gov/show/NCT02224040 38 28 Aug-22 https://ClinicalTrials.gov/show/NCT02775968 39 29 Aug-19 https://ClinicalTrials.gov/show/NCT02687906 40 30 Dec-19 https://ClinicalTrials.gov/show/NCT02783859 41 42 31 Apr-17 https://ClinicalTrials.gov/show/NCT01994993 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 AC AD AE AF AG 3 32 Dec-17 https://ClinicalTrials.gov/show/NCT02258763 4 33 May-17 https://ClinicalTrials.gov/show/NCT02688790 5 6 34 Dec-12 https://ClinicalTrials.gov/show/NCT00323219 7 35 Feb-18 https://ClinicalTrials.gov/show/NCT02750761 8 36 Dec-17 https://ClinicalTrials.gov/show/NCT02466438 9 10 37 Sep-17 https://ClinicalTrials.gov/show/NCT02260102 11 38 Jun-16 https://ClinicalTrials.gov/show/NCT02694458For peer review only 12 39 Feb-17 https://ClinicalTrials.gov/show/NCT01540838 13 40 null https://ClinicalTrials.gov/show/NCT00368498 14 15 41 Dec-13 https://ClinicalTrials.gov/show/NCT01785641 http://bmjopen.bmj.com/ 16 42 Sep-20 https://ClinicalTrials.gov/show/NCT02554383 17 43 Mar-16 https://ClinicalTrials.gov/show/NCT01265173 18 19 44 Jan-17 https://ClinicalTrials.gov/show/NCT02335905 20 45 Dec-19 https://ClinicalTrials.gov/show/NCT02922686 21 46 Dec-20 https://ClinicalTrials.gov/show/NCT02848820 22 47 Oct-17 https://ClinicalTrials.gov/show/NCT02475733 23 on September 28, 2021 by guest. Protected copyright. 24 48 May-17 https://ClinicalTrials.gov/show/NCT02372461 25 49 Aug-12 https://ClinicalTrials.gov/show/NCT01553006 26 50 Mar-17 https://ClinicalTrials.gov/show/NCT02527681 27 28 51 Sep-17 https://ClinicalTrials.gov/show/NCT02210169 29 52 Oct-17 https://ClinicalTrials.gov/show/NCT02497781 30 53 Apr-18 https://ClinicalTrials.gov/show/NCT02814916 31 54 Apr-17 https://ClinicalTrials.gov/show/NCT02210325 32 33 55 Nov-16 https://ClinicalTrials.gov/show/NCT02801370 34 56 Aug-18 https://ClinicalTrials.gov/show/NCT02760420 35 57 Aug-18 https://ClinicalTrials.gov/show/NCT02678195 36 37 58 Dec-17 https://ClinicalTrials.gov/show/NCT02605122 38 59 Feb-17 https://ClinicalTrials.gov/show/NCT02570490 39 60 Dec-16 https://ClinicalTrials.gov/show/NCT02443285 40 61 Jan-17 https://ClinicalTrials.gov/show/NCT02334124 41 42 62 Feb-17 https://ClinicalTrials.gov/show/NCT02218372 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2017-016293 on 13 October 2017. Downloaded from

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1 2 AC AD AE AF AG 3 63 Jul-10 https://ClinicalTrials.gov/show/NCT01032499 4 64 Feb-16 https://ClinicalTrials.gov/show/NCT02598362 5 6 65 Mar-17 https://ClinicalTrials.gov/show/NCT02878031 7 66 Dec-17 https://ClinicalTrials.gov/show/NCT02790996 8 67 Oct-16 https://ClinicalTrials.gov/show/NCT02712307 9 10 68 Oct-17 https://ClinicalTrials.gov/show/NCT02424734 11 69 Dec-16 https://ClinicalTrials.gov/show/NCT02134301For peer review only 12 70 Aug-16 https://ClinicalTrials.gov/show/NCT02013141 13 71 Jul-12 https://ClinicalTrials.gov/show/NCT01427842 14 15 72 Jun-11 https://ClinicalTrials.gov/show/NCT01278017 http://bmjopen.bmj.com/ 16 73 Feb-10 https://ClinicalTrials.gov/show/NCT00988026 17 74 Jun-18 https://ClinicalTrials.gov/show/NCT02288234 18 19 75 null https://ClinicalTrials.gov/show/NCT01304459 20 76 Dec-16 https://ClinicalTrials.gov/show/NCT01173575 21 77 Dec-19 https://clinicaltrials.gov/ct2/show/NCT01778634 22

23 on September 28, 2021 by guest. Protected copyright. 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60