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Repetitive transcranial magnetic stimulation (rTMS) in autism spectrum disorder: protocol for a multicentre randomised controlled clinical trial ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2020-046830
Article Type: Protocol
Date Submitted by the 11-Nov-2020 Author:
Complete List of Authors: Enticott, Peter; Deakin University School of Psychology Barlow, Karen; The University of Queensland Child Health Research Centre, Child Health Research Centre; Children's Health Queensland Hospital and Health Service Hickie, Ian; The University of Sydney Brain and Mind Centre, Brain and Mind Centre Licari, Melissa; Telethon Kids Institute Rogasch, Nigel; The University of Adelaide Adelaide Medical School; South Australian Health and Medical Research Institute Middeldorp, Christel; The University of Queensland Child Health Research Centre; Children's Health Queensland Hospital and Health Service
Clark, Scott; The University of Adelaide Adelaide Medical School http://bmjopen.bmj.com/ Vallence, Ann-Maree; Murdoch University, School of Psychology and Exercise Sciences; Murdoch University, Centre for Molecular Medicine and Innovative Therapeutics Boulton, Kelsie; The University of Sydney Brain and Mind Centre Guastella, Adam; The University of Sydney Brain and Mind Centre, Clinical Research Unit Whitehouse, Andrew; Telethon Kids Institute; Cooperative Research Centre for Living With Autism
Galletly, Cherrie; The University of Adelaide Adelaide Medical School on September 27, 2021 by guest. Protected copyright. Alvares, Gail; Telethon Kids Institute Fujiyama, Hakuei; Murdoch University, School of Psychology and Exercise Sciences Heussler, Helen; The University of Queensland Child Health Research Centre, Child Development; Children's Health Queensland Hospital and Health Service, Centre fro Children's Health Research Craig, Jeffrey; Deakin University School of Medicine, School of Psychology Kirkovski, Melissa; Deakin University School of Psychology Mills, Natalie; The University of Adelaide Adelaide Medical School Rinehart, Nicole; Deakin University School of Psychology Donaldson, Peter; Deakin University School of Psychology Ford, Talitha; Deakin University School of Psychology Caeyenberghs, Karen; Deakin University School of Psychology, School of Psychology Albein-Urios, Natalia; Deakin University School of Psychology, School of Psychology Bekkali, Soukayna; Deakin University School of Psychology
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 57 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 1 2 3 Fitzgerald , Paul; Monash University Central Clinical School; Epworth 4 HealthCare, Epworth Centre for Innovation in Mental Health 5 6 Child & adolescent psychiatry < PSYCHIATRY, Developmental neurology 7 Keywords: & neurodisability < PAEDIATRICS, Paediatric neurology < PAEDIATRICS, 8 Neurophysiology < NEUROLOGY 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
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1 2 3
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Repetitive transcranial magnetic stimulation (rTMS) in autism spectrum disorder: protocol 7 for a multicentre randomised controlled clinical trial 8 9 10 11 Peter G. Enticott*, School of Psychology, Deakin University, Geelong, Australia 12 Karen Barlow, Child Health Research Centre, The University of Queensland, South Brisbane, Australia; 13 Children’s Health Queensland Hospital and Health Service, Herston, Queensland 14 Ian Hickie, Brain and Mind Centre, University of Sydney, Camperdown, Australia 15 Melissa K. Licari, Research Fellow, Telethon Kids Institute, The University of Western Australia, 16 Nedlands, Australia 17 18 Nigel C. Rogasch, AdelaideFor Medical peer School, The review University of Adelaide, only Adelaide, Australia; South Australian 19 Health and Medical Research Institute (SAHMRI), Adelaide, Australia 20 Christel M Middeldorp, Child Health Research Centre, The University of Queensland, South Brisbane, 21 Australia; Children’s Health Queensland Hospital and Health Service, Herston, Queensland 22 Scott Clark, Adelaide Medical School, The University of Adelaide, Adelaide, Australia 23 Ann-Maree Vallence, School of Psychology and Exercise Sciences, Murdoch University, Murdoch, Australia; 24 Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Australia 25 Brain and Mind Centre, University of Sydney, Camperdown, Australia 26 Kelsie A. Boulton, 27 Adam Guastella, Brain and Mind Centre, University of Sydney, Camperdown, Australia 28 Andrew J. O. Whitehouse, Telethon Kids Institute, The University of Western Australia, Nedlands, 29 Australia; Cooperative Research Centre for Living with Autism, St Lucia, Queensland, Australia 30 Cherrie Galletly, Adelaide Medical School, The University of Adelaide, Adelaide, Australia 31 Gail Alvares, Telethon Kids Institute, The University of Western Australia, Nedlands, Australia 32 33 Hakuei Fujiyama, School of Psychology and Exercise Sciences, Murdoch University, Murdoch, Australia 34 Helen Heussler, Child Health Research Centre, The University of Queensland, South Brisbane, Australia; 35 Children’s Health Queensland Hospital and Health Service, Herston, Queensland
36 Jeffrey Craig, School of Medicine, Deakin University, Geelong, Australia http://bmjopen.bmj.com/ 37 Melissa Kirkovski, School of Psychology, Deakin University, Geelong, Australia 38 39 Natalie T. Mills, Adelaide Medical School, The University of Adelaide, Adelaide, Australia 40 Nicole J. Rinehart, School of Psychology, Deakin University, Geelong, Australia 41 Peter H. Donaldson, School of Psychology, Deakin University, Geelong, Australia 42 Talitha C. Ford, School of Psychology, Deakin University, Geelong, Australia 43 Karen Caeyenberghs, School of Psychology, Deakin University, Geelong, Australia 44 on September 27, 2021 by guest. Protected copyright. 45 Natalia Albein-Urios, School of Psychology, Deakin University, Geelong, Australia 46 Soukayna Bekkali, School of Psychology, Deakin University, Geelong, Australia 47 Paul B. Fitzgerald, Central Clinical School, Monash University; Epworth Centre for Innovation in Mental 48 Health, Epworth HealthCare, Camberwell, Australia 49 50 51 52 Word count (excluding title page, abstract, references, figures and tables): 3,553 53 54 *Correspondence to: Peter G. Enticott, School of Psychology, Deakin University, 221 55 Burwood Hwy, Burwood, Victoria, 3125, Australia. 56 57 Email: [email protected] 58 59 v1, 26 October 2020 60
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1 2 3 ABSTRACT
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Introduction 7 8 There are no well-established biomedical treatments for the core symptoms of autism 9 spectrum disorder (ASD). A small number of studies suggest that repetitive transcranial 10 11 magnetic stimulation (rTMS), a non-invasive brain stimulation technique, may improve 12 clinical and cognitive outcomes in ASD. We describe here the protocol for a funded 13 multicentre randomised controlled clinical trial to investigate whether a course of rTMS to 14 the right temporoparietal junction (rTPJ), which has demonstrated abnormal brain 15 16 activation in ASD, can improve social communication in adolescents and young adults with 17 ASD. 18 For peer review only 19 Methods and analysis 20 21 22 This study will evaluate the safety and efficacy of a four-week course of intermittent theta 23 burst stimulation (iTBS, a variant of rTMS) in ASD. Participants meeting criteria for DSM-5 24 ASD (n = 150, aged 14-40 years) will receive 20 sessions of either active iTBS (600 pulses) or 25 sham iTBS (in which a sham coil mimics the sensation of iTBS, but no active stimulation is 26 27 delivered) to the rTPJ. Participants will undergo a range of clinical, cognitive, epi/genetic, 28 and neurophysiological assessments before and at multiple time points up to six months 29 after iTBS. Safety will be assessed via a structured questionnaire and adverse event 30 reporting. The study will be conducted from November 2020 to October 2024. 31 32 33 Ethics and dissemination 34 35 The study was approved by the Human Research Ethics Committee of Monash Health 36 (Melbourne, Australia) under Australia’s National Mutual Acceptance scheme. The trial is http://bmjopen.bmj.com/ 37 38 registered (prospectively) at the Australian New Zealand Clinical Trials Registry (ANZCTR) 39 ACTRN12620000890932p, will be conducted according to Good Clinical Practice, and 40 findings will be written up for scholarly publication. 41 42 43
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1 2 3 Strengths and limitations of this study
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 This multisite randomised controlled trial will be the largest trial of rTMS in ASD to date 7 8 rTMS will be applied to rTPJ, a cortical region that has demonstrated abnormal 9 10 activation in ASD and forms a major hub of the “social brain” subnetwork 11 12 Participants will undergo structural MRI scans, with rTMS coil position determined via 13 individualised neuronavigation 14 15 16 Adolescent and young adult participants will receive rTMS interventions as outpatients, 17 and complete a comprehensive range of clinical, neuropsychological, and 18 neurophysiologicalFor assessments peer review only 19 20 21 A limitation of the study is the use of only a sham control condition, rather than an 22 additional “active control” site to determine whether effects are specific to rTPJ (rather 23 than a general effect of brain stimulation) 24 25 26 27 28 29 30 31 32 33 34 35
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1 2 3 INTRODUCTION
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Autism spectrum disorder (ASD) is a neurodevelopmental disorder that impacts a range of 7 domains, including social communication, behaviour, cognition, emotion regulation, and 8 sensorimotor function1. Core symptoms of ASD include social interaction and 9 communication problems, and restricted and repetitive behaviours. Comorbid 10 11 neurodevelopmental disorders (e.g., attention deficit hyperactivity disorder [ADHD]) and 12 psychiatric disorders (e.g., depression, anxiety) are very common2 3, with the latter often 13 associated with the core social communicative difficulties4 5. 14 15 6 16 Despite the high prevalence of ASD (1 in 59 ), few clinical interventions target core 17 symptoms beyond early-middle childhood. ASD diagnosis typically occurs by the age of 4-6 18 years6, and early, intensiveFor interventionpeer throughoutreview these only years is associated with the best 19 outcomes for individuals with ASD and their families7. Unfortunately, there is little clinical 20 support available for adolescents and young adults with ASD, who often continue to 21 22 experience social communication symptoms that result in barriers to education, 23 employment, and community participation. As noted, this group also experiences extremely 24 poor mental health that is much worse than the general population; for instance, lifetime 25 depression and anxiety rates are estimated at 37% and 42%, respectively2. 26 27 28 Non-invasive brain stimulation (NIBS) has emerged as a novel, safe, and efficacious 29 intervention for a range of brain-based disorders. These techniques allow non-invasive 30 modulation of specific brain regions via electromagnetic or electrical stimulation. The most 31 common of these is repetitive transcranial magnetic stimulation (rTMS), which is now widely 32 8 33 used as an intervention for treatment-resistant major depressive disorder . It has also been 34 established as an intervention for other neurological disorders, including migraine and 35 obsessive-compulsive disorder9 10.
36 http://bmjopen.bmj.com/ 37 38 rTMS is administered via a plastic-coated metallic coil that is held against the scalp. This coil 39 emits focal, time-varying electromagnetic pulses, which induce electrical current in 40 superficial cortical tissue, thus stimulating neurons in the local region. Depending on the 41 frequency and strength of pulses administered, rTMS can be used to either enhance cortical 42 excitability (i.e., upregulate neural activity), or decrease cortical excitability (i.e., 43 downregulate neural activity) in the stimulated region. This is particularly useful when 44 on September 27, 2021 by guest. Protected copyright. 45 targeting regions (or nodes) of brain networks known to be either underactive or overactive 46 in particular conditions. For instance, high-frequency (excitatory) rTMS has been used to 47 stimulate underactive left dorsolateral prefrontal cortex (DLPFC) in treatment-resistant 48 11 49 depression , while low-frequency (inhibitory) rTMS has been used to downregulate 12 50 excessive activity in left auditory cortex in schizophrenia and supplementary motor area 51 (SMA) in Tourette’s disorder13. Importantly, rTMS also influences broader brain networks 52 that involve the stimulated region14 15, and this is thought to contribute to its clinical 53 efficacy. Here we will stimulate the right temporoparietal junction (rTPJ), a key node for 54 16 55 social cognition, which is a typical area of difficulty among individuals with ASD . 56 57 The brain functions as a set of interconnected networks disseminating neuronal information 58 across a broad range of distributed areas 17. From a neurobiological perspective, ASD is 59 60 commonly understood as a disorder of synaptic plasticity and neural connectivity, leading to
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1 2 3 abnormalities in brain network connectivity between brain regions. These appear to be
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 mediated by disruptions in both excitatory (e.g., glutamatergic) and inhibitory (e.g., 18 19 6 GABAergic) processes . There are also well-documented abnormalities in local “node” 7 activity, particularly within networks that comprise the so-called “social brain,” including 8 rTPJ20 21. Indeed, the rTPJ shows consistent differences in activation between those with and 9 without ASD16 20-22, while meta-analysis demonstrates reduced rTPJ functional connectivity 10 23 11 in ASD . Accordingly, rTMS to this region has the potential to modulate local and regional 12 brain activity within networks implicated in the core social symptoms of ASD. 13 14 rTMS is considered a very safe and tolerable technique. It is typically administered by an 15 16 experienced clinician (nurse or physician), and patients are monitored throughout and at 17 the completion of rTMS administration. Clinical researchers have established a detailed set 18 of safety guidelines,For and when peer rTMS is administered review within only guideline parameters serious 19 adverse effects are exceedingly rare24 25. NIBS (including rTMS) is also considered very safe 20 for paediatric populations, with a recent study showing no adverse effects across 382 21 26 22 children aged 0-18 years . 23 24 Previously, NIBS has been used to investigate the neuropathophysiology of ASD27-30. More 25 recently, several research groups (including ours) have investigated whether rTMS could 26 31-33 27 have clinical utility as an intervention in ASD., These studies (see systematic reviews ) 28 indicate that: low-frequency stimulation of the DLPFC can reduce repetitive behaviours, 29 improve neurophysiological markers of perception, and reduce irritability; low-frequency 30 SMA stimulation can improve movement-related cortical potentials, and; low-frequency 31 stimulation of the premotor cortex can improve sensorimotor integration. While promising, 32 33 these studies are hampered by small sample sizes a lack of an appropriate control condition 34 (placebo or sham stimulation), and moderate-to-high risk of bias31. 35
36 At present, only two placebo-controlled randomised controlled trials (RCTs) have been http://bmjopen.bmj.com/ 37 38 conducted, both of which were double-blind. The first demonstrated that two weeks of 39 daily, high-frequency rTMS to bilateral dorsomedial prefrontal cortex (dmPFC), compared to 40 sham rTMS, improved self-report social relating symptoms in adults with ASD (n = 28) one- 41 month after intervention completion34. A recent study demonstrated that four weeks of 42 high-frequency stimulation of bilateral DLPFC did not improve executive function in 43 adolescents and young adults with ASD (n = 40)35. There was, however, evidence for a 44 on September 27, 2021 by guest. Protected copyright. 45 beneficial effect of rTMS for those with lower adaptive functioning at baseline. While 46 providing preliminary, placebo-controlled support for rTMS in ASD, these studies are limited 47 by small sample size. 48 49 50 Rationale/Justification 51 52 A recent international “consensus statement” provides recommendations for future rTMS 53 research in ASD36. Considering the clinical heterogeneity of ASD, there is agreement that 54 55 “large, multisite, double-blind, placebo-controlled trials with carefully selected 56 neurobiological targets and outcome measures” are required. It is also necessary to 57 understand variability in the response to rTMS that can lead to an individualised therapeutic 58 approach (i.e., personalised medicine approach). These include demographic (e.g., age, sex), 59 60 clinical (e.g., disorder severity, cognitive/symptom profile), neurobiological (e.g., cortical
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1 2 3 thickness, structural and functional connectivity), and genetic/epigenetic factors.
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 Accordingly, we will conduct a large-scale, multi-site investigation of the safety and efficacy 6 of rTMS in ASD that involves (a) feasible and tolerable stimulation paradigms, (b) a carefully 7 selected neurobiological target and mode of stimulation, and (c) rigorous methodological 8 approaches, including individualised stereotactic neuronavigation, an appropriate control 9 condition, and efficacious double blinding. If successful, this trial will establish a first 10 11 biomedical intervention to improve social communicative symptoms in adolescents and 12 young adults diagnosed with ASD, and inform on factors associated with intervention 13 response, with anticipated benefits in mental health, quality of life, and social participation. 14 15 16 Research Hypotheses 17 18 In ASD, active rTMSFor to rTPJ, whenpeer compared review to sham rTMS, only will be associated with: 19 20 1. Improved social communication, measured using the Social Responsiveness Scale – 21 nd 22 2 Edition (SRS-2) (evident one-month after end of rTMS, maintained at three- and 23 six-months) (primary outcome); 24 2. Improved social cognitive performance, measured using face processing/face 25 emotion processing neuropsychological tasks (evident immediately after rTMS, 26 27 maintained at one-, three-, and six-months); 28 3. Improved quality of life, measured using the Personal Wellbeing Index (evident one- 29 month after rTMS, maintained at three- and six-months); 30 4. Acceptable tolerability and safety (as measured by a structured interview and 31 adverse event reporting). 32 33 34 METHODS AND ANALYSIS 35
36 Study Design and Participants http://bmjopen.bmj.com/ 37 38 39 This is a four-year multicentre Australian study to assess the safety and efficacy of a four- 40 week course of rTMS to improve social communication in adolescents and young adults 41 diagnosed with ASD. It will be a parallel group (between-subjects), double-blind, placebo- 42 controlled RCT. Participants will be 150 individuals meeting criteria for DSM-51 ASD and 43 aged between 14-40 years. They will be recruited through existing research participant 44 on September 27, 2021 by guest. Protected copyright. 45 databases, the Australian Autism Biobank37, and advertisements in local clinics, 46 advocacy/support groups, and via social media. The research team will also engage popular 47 media, both locally and nationally, to promote recruitment. 48 49 50 The study will be overseen by a Research Management Group, which comprises the ten 51 Chief Investigators, Study Coordinator, and Site Coordinators. They will meet monthly via 52 videoconference for the duration of the trial. There will be 30 participants enrolled at each 53 of the cities involved (Brisbane, Sydney, Melbourne, Adelaide, Perth). Participants will 54 55 undergo 20 intervention sessions (one per weekday for four consecutive weeks) of either 56 active or sham (i.e., placebo) rTMS. Participants will be assessed before and up to 6 months 57 after intervention and in accordance with Good Clinical Practice (GCP). Assessments will 58 evaluate social communication, neuropsychological function, quality of life, safety, and 59 60 tolerability. There will be five primary intervention sites within Australia (Brisbane, Sydney,
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1 2 3 Melbourne, Adelaide, Perth) and additional local sites to support recruitment, assessment,
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 genetic analysis, and neuroimaging. These will include both University and hospital sites. 6 Written informed consent will be obtained from participants (or their parent/guardian in 7 the case of minors, aged 14-17 years) by a local Chief Investigator or Site Coordinator. 8 Model participant Information and consent forms for parents/guardians and adult 9 participants are provided as Supplemental Material. 10 11 12 Patient and Public Involvement 13 14 The research team have engaged in extensive consultation with community groups in recent 15 16 years, including multiple community forums on rTMS). We have also consulted with autism 17 organisations when preparing advertisements and other study-related communications. 18 While participants wereFor not peerdirectly involved review in the design only of this specific trial, throughout 19 the study we will engage a range of community and advocacy groups in the implementation 20 of the research, and health service partners to ensure rapid translation of our research 21 22 findings to clinical practice. For instance, the Telethon Kids Institute (Western Australia) 23 have established a community reference group with whom they regularly consult for 24 consumer involvement, and this group will also be engaged for the current trial. 25 26 27 rTMS Protocol 28 29 Participants will receive standard intermittent theta burst stimulation (iTBS) to the rTPJ each 30 consecutive weekday for a four-week period (20 sessions). They will undergo either active 31 iTBS or sham iTBS, where a “sham coil” is used to mimic the appearance, sound, and 32 33 sensation of rTMS, but without delivering electromagnetic stimulation. 34 35 Participants will undergo 3T T1 magnetic resonance imaging (MRI) prior to the first rTMS 36 session, and stereotactic neuronavigation will be used to determine the site of stimulation http://bmjopen.bmj.com/ 37 38 (MNI coordinates x = 56, y = -56, z = 18; see Figure 1). 39 40 All stimulation will be administered via a Magstim Rapid2 stimulator (The Magstim Company 41 Ltd., Wales, UK). A staff member trained in rTMS will deliver all rTMS interventions. A visual 42 resting motor threshold (i.e., visual observation of muscle activation following TMS pulse) 43 will be determined at the right hemisphere/left hand prior to the first rTMS session. Each 44 on September 27, 2021 by guest. Protected copyright. 45 iTBS is delivered with the following stimulation parameters: 46 47 • Burst pattern: 3 pulses delivered at 50 Hz 48 49 • Train duration: Bursts repeated 5 times per second (5 Hz) for 2 seconds (10 bursts) 50 • Intensity: 70% of resting motor threshold 51 • Inter-train interval: 8 seconds 52 • Total time: 200 seconds (3 minutes, 20 seconds) 53 • Total trains: 20 54 55 • Total bursts: 200 56 • Total pulses: 600 57 58 <
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1 2 3
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 Participants will be monitored by study staff for at least five minutes after each intervention 6 session. They can then leave the facility and go about their normal daily activities, including 7 driving. The participant will be administered the Non-invasive Brain Stimulation Post- 8 Stimulation Interview at the end of each week of rTMS intervention (i.e., after the Friday 9 session) to determine the presence/intensity of any side-effects. For child participants (aged 10 11 14-17 years), this interview will be conducted with both the parent/guardian and the child. 12 13 Inclusion and Exclusion Criteria 14 15 16 Inclusion Criteria 17 Aged 14-40 years 18 Meets criteriaFor for ASD peer based on DSM-5review criteria (clinician only reported), and confirmed 19 via Autism Diagnostic Observation Schedule – Second Edition (ADOS-2) 20 21 English-language fluency/proficiency 22 23 Exclusion Criteria 24 History of seizure/s or epilepsy 25 26 History of severe (traumatic) brain injury 27 Contraindication to MRI (e.g., claustrophobia, metal implants) 28 Formal verbal intelligence quotient VIQ assessment <55, as determined by Wechsler 29 Abbreviated Scale of Intelligence (WASI-2) 30 31 Comorbid neurological or psychiatric diagnosis not commonly associated with ASD 32 (e.g., psychosis) 33 Unstable medical condition 34 Unstable medication regimen, or medication contraindicated for TMS 35 36 Pregnancy or current breastfeeding http://bmjopen.bmj.com/ 37 Substance use/abuse disorder 38 Concurrent intervention targeting social communication 39 40 Evidence of significant epileptiform activity on electroencephalogram (EEG) (e.g., 41 seizures on EEG, runs of epileptiform discharges) 42 43 Outcome Measures
44 on September 27, 2021 by guest. Protected copyright. 45 46 Data collection and study timings are presented in Table 1. Participants are assessed prior to 47 rTMS (T0), and at four points after rTMS: T1 (immediately after rTMS), T2 (one-month after 48 completion of rTMS), T3 (three-months after completion of rTMS), and T4 (six-months after 49 completion of rTMS). 50 51 nd 52 The primary outcome measure is the Social Responsiveness Scale – 2 Edition (SRS-2; 53 School-Age AutoScore Form for Parent/Guardian [parent/guardian report]/Adult AutoScore 54 Form for Informant [informant report]) Total T-score, while the primary outcome point will 55 be at 1-month after completion of rTMS (T1) compared with pre-rTMS (T0). For adult 56 57 participants, an informant (parent/relative/friend) will complete the SRS-2 with respect to 58 the participant. 59 60
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1 2 3 Secondary outcomes encompass a range of clinical, neuropsychological, neurophysiological,
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 and biological measures. Clinical measures include: Conners 3 (parent/guardian 6 report)/Conners Adult ADHD Rating Scales (CAARS) (informant report and adult self-report); 7 Aberrant Behaviour Checklist – Second Edition (ABC-2) (parent/guardian/informant report); 8 Behaviour Rating Scale of Executive Function, Second Edition (BRIEF)/ Behaviour Rating 9 Scale of Executive Function – Adult Version (BRIEF-A) (parent/guardian/informant report 10 11 and adult self-report); World Health Organization Disability Assessment Schedule 2.0 12 (WHODAS 2.0) (parent/guardian/informant report); Depression, Anxiety and Stress Scale 13 (DASS) (self-report); and Personal Wellbeing Index (PWI) (self-report). 14 15 16 Neuropsychological measures include: Reading the Mind in the Eyes Test (RMET); Benton 17 Facial Recognition Test (BFRT); Cambridge Face Memory Test (CFMT); NIH Cognition 18 Toolbox; and WorkingFor Memory peer Assessment. review only 19 20 Neurophysiological measures include: resting-state electroencephalography (EEG); and face 21 22 processing event-related potentials (ERP). 23 24 Finally, a buccal swab will be administered both before and after the course of rTMS, which 25 will allow an investigation of genetic and epigenetic predictors of intervention response, 26 27 and potential epigenetic changes following rTMS. 28 29 <
44 on September 27, 2021 by guest. Protected copyright. 45 Upon enrolment, participants will be allocated a unique study identification code. Their 46 name will not appear with the research data collected. All data will be stored in REDCap39 47 and on secure network locations governed by Deakin University. All Chief Investigators will 48 49 have access to the final trial dataset. Any information obtained in connection with this 50 research project that can identify a participant will remain confidential. Where a participant 51 elects to withdraw from the study, we will retain and use any data collected prior to 52 withdrawal. 53 54 55 Random effects linear mixed models will be used to ensure the inclusion of participants who 56 have missing data, including those that withdraw from the study. Specifically, this will 57 involve a between-subjects factor (rTMS condition: active vs. placebo) and a within-subjects 58 factor (time of assessment: pre vs. post vs. one-month vs. three-months vs. six-months), 59 60 with participant and site entered as random effects. We will examine rTMS safety by
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1 2 3 exploring descriptive statistics arising from the structured questionnaire related to the
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 development of possible side-effects. An interim analysis will be performed at the mid-point 6 of data collection for possible trial futility. 7 8 Exploratory analyses will be undertaken to investigate factors, including genetic variants and 9 structural/functional neuroimaging (e.g., diffusion MRI, resting-state functional MRI), that 10 11 influence intervention response, and to investigate epigenetic changes following rTMS. We 12 will use linear mixed models to determine the effect of rTMS on SRS-2 score, but with 13 additional independent variables (e.g., age, sex, cognitive ability, ADOS-2 symptom severity, 14 rTPJ structural and functional connectivity within the social brain subnetwork, polygenic risk 15 40 16 score [PRS] for ASD ). 17 18 Epigenetic variationFor refers to peer variation in review chromatin structure, only which is associated with 19 variation in gene expression. In contrast to DNA, epigenetic variation can change over time, 20 for example following treatment41. Accordingly, we will compare epigenetic variation for 21 22 DNA samples collected before and after rTMS and investigate any associations with 23 intervention response. (See Supplemental Material for a statement on Biological 24 Specimens.) 25 26 27 At the conclusion of the project, all electronic and hard copy data will be archived within 28 Deakin University (Information and Records Services). Electronic data will be retained on 29 secure Deakin University servers and archived in REDCap, but also transferred to physical 30 hard drives for archival storage. As some hard copy data will be stored at each site (e.g., 31 signed consent forms, clinical files used during rTMS intervention), these will be securely 32 33 couriered to Deakin University for archiving. Each site will be required to delete any 34 electronic data that may remain at their site. As this is a clinical trial involving child 35 participants, data will be retained indefinitely. Any published work from this study will be 36 accompanied by publicly available deidentified data through the Open Science Framework http://bmjopen.bmj.com/ 37 38 (osf.io). The research team, including both Chief Investigators and Associate Investigators, 39 all have the opportunity to conduct secondary analyses. This will be negotiated with the 40 trial’s Research Management Group, which comprises the ten Chief Investigators. Data may 41 also be shared with external (national and international) collaborators to obtain larger 42 sample sizes, which are often necessary to achieve the statistical power necessary to 43 analyse biomarker data. This could include specific research projects or online data 44 on September 27, 2021 by guest. Protected copyright. 45 repositories, which may be accessed and used by external researchers. 46 47 Blinding 48 49 50 This is a double-blind study; accordingly, participants (and their parents/guardians, where 51 relevant) and the testing researchers/statisticians will be blinded to intervention condition. 52 The individual administering rTMS must select the appropriate coil (i.e., active or sham) and 53 will therefore not be blinded, but this individual will not conduct any of the assessment or 54 55 be involved in the statistical analyses. Unblinding may occur in the event of an adverse 56 event. At the conclusion of the final assessment (T4), participants will be unblinded as to 57 their intervention condition by a member of the research team who is not blinded. Those 58 who were allocated to the sham rTMS intervention will be offered the opportunity to 59 60 undergo the real rTMS intervention.
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1 2 3 Table 1. 4 5 6 Data Collection and Study Timings 7 8 9 10 Visits Pre-enrolment T0 Tx T1 T2 T3 T4 11 12 For peer review only 13 14 Screening X X 15 http://bmjopen.bmj.com/ 16 Written informed consent X 17 18 Randomisation X 19 20 Demographics X X 21 22 Medical History X X 23 on September 27, 2021 by guest. Protected copyright. 24 25 Neuroimaging (MRI) X 26 27 Clinical EEG X 28 29 Buccal Swab X X 30 31 ADOS-2 X 32 33 WASI-2 X 34 35 rTMS intervention (active/sham) X 36 37 NIBS:PSI X 38 39 SRS-2 X X X X X 40 41 42 11 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 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-2020-046830 on 7 July 2021. Downloaded from
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1 2 3 4 Conners-3/CAARS X X X X X 5 6 ABC-2 X X X X X 7 8 BRIEF/BRIEF-A X X X X X 9 10 DASS X X X X X 11 12 PWI ForX peer reviewX XonlyX X 13 14 WHODAS 2.0 X X X X X 15 http://bmjopen.bmj.com/ 16 NIH Cognition Toolbox X X X X 17 18 RMET X X X X 19 20 BFRT X X X X 21 22 CFMT X X X X 23 on September 27, 2021 by guest. Protected copyright. 24 25 Working Memory X X X X 26 27 rsEEG X X 28 29 FP-ERP X X 30 31 Notes: T0: Pre-rTMS; T1: week following rTMS; T2: one-month after completion of rTMS; T3: three-months after completion of rTMS; T4: six-months after completion of nd nd 32 rTMS; MRI: magnetic resonance imaging; ADOS-2: Autism Diagnostic Observation Schedule, 2 Edition; WASI-2: Wechsler Abbreviated Scale of Intelligence, 2 Edition; nd 33 rTMS: repetitive transcranial magnetic stimulation; NIBS:PSI: Non-invasive Brain Stimulation Post-stimulation Interview; SRS-2: Social Responsiveness Scale, 2 Edition; nd 34 CAARS: Conners Adult ADHD Rating Scales; ABC-2: Aberrant Behaviour Checklist, 2 Edition; BRIEF: Brief Rating Inventory of Executive Function; BRIEF-A: Brief Rating 35 Inventory of Executive Function – Adult Version; DASS: Depression Anxiety Stress Scale; PWI: Personal Wellbeing Index; WHODAS 2.0: World Health Organisation Disability 36 Assessment Schedule; NIH: National Institutes of Health; RMET: Reading the Mind in the Eyes Test; BFRT: Benton Facial Recognition Test; CFMT: Cambridge Face Memory 37 Test; rsEEG: resting-state electroencephalography; FP-ERP: face-processing event-related potentials. 38 39 40 41 42 12 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 15 of 57 BMJ Open
1 2 3 Safety
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Participants will undergo extensive screening to ensure that they meet safety criteria for 7 undergoing rTMS25. For child participants, a parent or legal guardian will complete the 8 screening. Participants will undergo EEG prior to their first rTMS session, and this will be 9 reviewed by the trial neurologist. Any participants demonstrating evidence of runs of 10 11 epileptiform discharges, as assessed by the study neurologist, will be withdrawn from the 12 study. At the beginning of their first session, participants (or their parent/guardian for child 13 participants) will again be screened to ensure that they can undergo rTMS. 14 15 16 A data safety monitoring board (DSMB) will be formed. This DSMB will comprise three 17 senior clinical researchers independent to the current project. The DSMB will meet twice 18 per year to review theFor conduct peer of the trial review and monitor study only data. They will also review any 19 serious adverse events in a mid-trial safety analysis and on an ad hoc basis. Terms of 20 reference will be based on advice from the National Health and Medical Research Council’s 21 22 Data Safety Monitoring Boards documentation. 23 24 Adverse events will be reported to the relevant Human Research Ethics Committees (HREC) 25 immediately, and no later than 72 hours after the event. Depending on the nature and 26 27 severity of the event, it may be necessary to also report to other regulatory bodies (e.g., 28 Therapeutic Goods Administration) and suspend or terminate the trial. Should an individual 29 suffer harm from trial participation, they will receive medical treatment required to treat 30 the injury or complication, free of charge, as a public patient in any Australian public 31 hospital. 32 33 34 ETHICS AND DISSEMINATION 35
36 This study has been approved by the Monash Health Human Research Ethics Committee http://bmjopen.bmj.com/ 37 38 (Melbourne, Australia; RES-20-0000-606A) under the National Mutual Acceptance scheme, 39 which allows for mutual scientific and ethic acceptance across Australian jurisdictions and 40 institutions. We will engage a range of community and advocacy groups in the 41 implementation of the study, and health service partners to ensure rapid translation of our 42 research findings to clinical practice. 43
44 on September 27, 2021 by guest. Protected copyright. 45 The health outcomes of this study will be provided within 12 months of the trial’s 46 completion, initially through a freely accessible preprint and an open-access peer-reviewed 47 journal publication. Authorship will be determined according to the standards outlined in 48 49 the National Health and Medical Research Council’s Australian Code for the Responsible 50 Conduct of Research. Chief Investigators will also present the study findings at relevant 51 scientific conferences and autism advocacy/support group community forums. The research 52 team will also engage in more extensive public outreach and disseminate study findings 53 widely through appropriate channels (e.g., study website, social media, news outlets). These 54 55 dissemination pathways will also involve contributing to clinical guidelines (and direct 56 engagement with healthcare providers). 57 58 Participants will be sent a plain language summary detailing the study results at the 59 60 completion of the trial. This summary will be written as a lay summary and in a manner
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1 2 3 accessible to participants and their families. A child version will also be sent to
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 parents/guardians to share with their child. The summary will contain no identifying 6 information and provide only group level results. 7 8 This project involves the collection of a large number of measures (e.g., clinical, 9 neuropsychological, neuroimaging, genetic/epigenetic) and it is expected that the Chief 10 11 Investigators will conduct further exploratory analyses on these data. This might include, for 12 example, examining neuroimaging and genetic predictors of response to rTMS intervention 13 and characterising epigenetic changes following rTMS. 14 15 16 TRIAL STATUS 17 18 At the time of submissionFor recruitment peer has review not commenced. only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43
44 on September 27, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 AUTHORS’ CONTRIBUTIONS
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 PE, KB, IH, ML, NR, CM, SC, AV, KB, AG, HH, JC, MK, PD, and PF contributed to the design of 7 the study. 8 PGE, KB, ML, NR, CM, SC, AV, KB, AW, GA, MK, PD, TF, KC, NA, SB, and PF contributed to the 9 writing of the manuscript. 10 11 All authors approved the final draft of the manuscript. 12 13 FUNDING 14 15 16 This project has been funded by the National Health and Medical Research Council (NHMRC) 17 under the Medical Research Future Fund (MRFF) Neurological Disorders 2020 scheme 18 (Application ID: APP1199298).For peer review only 19 20 PROJECT REGISTRATION 21 22 23 This project has been prospectively registered on the Australian New Zealand Clinical Trials 24 Registry (ANZCTR; ACTRN12620000890932p). 25 26 27 COMPETING INTERESTS 28 29 There are no competing interests to declare. 30 31 TRIAL SPONSOR 32 33 34 Deakin University 35
36 Contact: Prof. Peter G. Enticott http://bmjopen.bmj.com/ 37 38 221 Burwood Hwy, Burwood 39 Victoria, 3125, AUSTRALIA 40 41 ROLE OF SPONSOR AND STUDY 42 43 This is an investigator-initiated study funded by the Australian Government, who provided 44 on September 27, 2021 by guest. Protected copyright. 45 peer review but have had no other involvement in the trial. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 REFERENCES 6 7 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 8 5th ed. Arlington, VA: American Psychiatric Association 2013. 9 2. Hollocks MJ, Lerh JW, Magiati I, et al. Anxiety and depression in adults with autism 10 11 spectrum disorder: A systematic review and meta-analysis. Psychological Medicine 12 2019;49(4):559-72. doi: 10.1017/S0033291718002283 13 3. Rau S, Skapek MF, Tiplady K, et al. Identifying comorbid ADHD in autism: Attending to the 14 inattentive presentation. Research in Autism Spectrum Disorders 2020;69 doi: 15 16 10.1016/j.rasd.2019.101468 17 4. Day TC, McNaughton KA, Naples AJ, et al. Self-reported social impairments predict 18 depressive disorderFor inpeer adults with review autism spectrum only disorder. Autism 2019 doi: 19 10.1177/1362361319857375 20 5. van Steensel FJA, Bögels SM, Perrin S. Anxiety Disorders in Children and Adolescents with 21 22 Autistic Spectrum Disorders: A Meta-Analysis. Clinical Child and Family Psychology 23 Review 2011;14(3):302-17. doi: 10.1007/s10567-011-0097-0 24 6. Baio J, Wiggins L, Christensen DL, et al. Prevalence of Autism Spectrum Disorder Among 25 Children Aged 8 Years — Autism and Developmental Disabilities Monitoring 26 27 Network, 11 Sites, United States, 2014. MMWR Surveillance Summaries 2018;67(SS- 28 6):1-23. doi: http://dx.doi.org/10.15585/mmwr.ss6706a1 29 7. Landa RJ. Efficacy of early interventions for infants and young children with, and at risk 30 for, autism spectrum disorders. International Review of Psychiatry 2018;30(1):25-39. 31 doi: 10.1080/09540261.2018.1432574 32 33 8. George MS, Lisanby SH, Avery D, et al. Daily left prefrontal transcranial magnetic 34 stimulation therapy for major depressive disorder: A sham-controlled randomized 35 trial. Archives of General Psychiatry 2010;67(5):507-16. doi: 36 10.1001/archgenpsychiatry.2010.46 http://bmjopen.bmj.com/ 37 38 9. Feng Y, Zhang B, Zhang J, et al. Effects of Non-invasive Brain Stimulation on Headache 39 Intensity and Frequency of Headache Attacks in Patients With Migraine: A 40 Systematic Review and Meta-Analysis. Headache 2019;59(9):1436-47. doi: 41 10.1111/head.13645 42 10. Rapinesi C, Kotzalidis GD, Ferracuti S, et al. Brain stimulation in obsessive-compulsive 43 disorder (OCD): A systematic review. Current Neuropharmacology 2019;17(8):787- 44 on September 27, 2021 by guest. Protected copyright. 45 807. doi: 10.2174/1570159X17666190409142555 46 11. Luber BM, Davis S, Bernhardt E, et al. Using neuroimaging to individualize TMS 47 treatment for depression: Toward a new paradigm for imaging-guided intervention. 48 49 NeuroImage 2017;148:1-7. doi: 10.1016/j.neuroimage.2016.12.083 50 12. Blumberger DM, Fitzgerald PB, Mulsant BH, et al. Repetitive transcranial magnetic 51 stimulation for refractory symptoms in schizophrenia. Current Opinion in Psychiatry 52 2010;23(2):85-90. doi: 10.1097/YCO.0b013e3283366657 53 13. Hsu CW, Wang LJ, Lin PY. Efficacy of repetitive transcranial magnetic stimulation for 54 55 Tourette syndrome: A systematic review and meta-analysis. Brain Stimulation 56 2018;11(5):1110-18. doi: 10.1016/j.brs.2018.06.002 57 14. Tik M, Hoffmann A, Sladky R, et al. Towards understanding rTMS mechanism of action: 58 Stimulation of the DLPFC causes network-specific increase in functional connectivity. 59 60
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1 2 3 NeuroImage 2017;162:289-96. doi:
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 https://doi.org/10.1016/j.neuroimage.2017.09.022 6 15. Caeyenberghs K, Duprat R, Leemans A, et al. Accelerated intermittent theta burst 7 stimulation in major depression induces decreases in modularity: A connectome 8 analysis. Netw Neurosci 2018;3(1):157-72. doi: 10.1162/netn_a_00060 9 16. Lombardo MV, Chakrabarti B, Bullmore ET, et al. Specialization of right temporo-parietal 10 11 junction for mentalizing and its relation to social impairments in autism. Neuroimage 12 2011;56(3):1832-8. doi: 10.1016/j.neuroimage.2011.02.067 [published Online First: 13 2011/03/02] 14 17. Bullmore E, Sporns O. The economy of brain network organization. Nat Rev Neurosci 15 16 2012;13(5):336-49. doi: 10.1038/nrn3214 17 18. Coghlan S, Horder J, Inkster B, et al. GABA system dysfunction in autism and related 18 disorders: FromFor synapse peer to symptoms. review Neuroscience only & Biobehavioral Reviews 19 2012;36(9):2044-55. doi: https://doi.org/10.1016/j.neubiorev.2012.07.005 20 19. Hull JV, Dokovna LB, Jacokes ZJ, et al. Resting-State Functional Connectivity in Autism 21 22 Spectrum Disorders: A Review. Frontiers in Psychiatry 2017;7(205) doi: 23 10.3389/fpsyt.2016.00205 24 20. Patriquin MA, DeRamus T, Libero LE, et al. Neuroanatomical and neurofunctional 25 markers of social cognition in autism spectrum disorder. Human Brain Mapping 26 27 2016;37(11):3957-78. doi: 10.1002/hbm.23288 [published Online First: 2016/06/23] 28 21. Philip RC, Dauvermann MR, Whalley HC, et al. A systematic review and meta-analysis of 29 the fMRI investigation of autism spectrum disorders. Neuroscience and 30 Biobehavioral Reviews 2012;36(2):901-42. doi: 10.1016/j.neubiorev.2011.10.008 31 [published Online First: 2011/11/22] 32 33 22. Kirkovski M, Enticott PG, Hughes ME, et al. Atypical Neural Activity in Males But Not 34 Females with Autism Spectrum Disorder. Journal of Autism and Developmental 35 Disorders 2016;46(3):954-63. doi: 10.1007/s10803-015-2639-7 [published Online 36 First: 2015/11/02] http://bmjopen.bmj.com/ 37 38 23. Wang W, Liu J, Shi S, et al. Altered Resting-State Functional Activity in Patients With 39 Autism Spectrum Disorder: A Quantitative Meta-Analysis. Frontiers in Neurology 40 2018;9:556. doi: 10.3389/fneur.2018.00556 [published Online First: 2018/08/09] 41 24. Lerner AJ, Wassermann EM, Tamir DI. Seizures from transcranial magnetic stimulation 42 2012–2016: Results of a survey of active laboratories and clinics. Clinical 43 Neurophysiology 2019;130(8):1409-16. doi: 10.1016/j.clinph.2019.03.016 44 on September 27, 2021 by guest. Protected copyright. 45 25. Rossi S, Hallett M, Rossini PM, et al. Safety, ethical considerations, and application 46 guidelines for the use of transcranial magnetic stimulation in clinical practice and 47 research. Clinical Neurophysiology 2009;120(12):2008-39. doi: 48 49 10.1016/j.clinph.2009.08.016 50 26. Zewdie E, Ciechanski P, Kuo H, et al. Safety and tolerability of transcranial magnetic and 51 direct current stimulation in children: Prospective single center evidence from 3.5 52 million stimulations. Brain Stimulation 2019 doi: 53 https://doi.org/10.1016/j.brs.2019.12.025 54 55 27. Cole EJ, Barraclough NE, Enticott PG. Investigating Mirror System (MS) Activity in Adults 56 with ASD When Inferring Others’ Intentions Using Both TMS and EEG. Journal of 57 Autism and Developmental Disorders 2018;48(7):2350-67. doi: 10.1007/s10803-018- 58 3492-2 59 60
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1 2 3 28. Enticott PG, Kennedy HA, Rinehart NJ, et al. GABAergic activity in autism spectrum
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 disorders: An investigation of cortical inhibition via transcranial magnetic 6 stimulation. Neuropharmacology 2013;68:202-09. doi: 7 10.1016/j.neuropharm.2012.06.017 8 29. Enticott PG, Kennedy HA, Rinehart NJ, et al. Mirror neuron activity associated with social 9 impairments but not age in autism spectrum disorder. Biological Psychiatry 10 11 2012;71(5):427-33. doi: 10.1016/j.biopsych.2011.09.001 12 30. Kirkovski M, Rogasch NC, Saeki T, et al. Single Pulse Transcranial Magnetic Stimulation- 13 Electroencephalogram Reveals No Electrophysiological Abnormality in Adults with 14 High-Functioning Autism Spectrum Disorder. Journal of Child and Adolescent 15 16 Psychopharmacology 2016;26(7):606-16. doi: 10.1089/cap.2015.0181 17 31. Barahona-Corrêa JB, Velosa A, Chainho A, et al. Repetitive Transcranial Magnetic 18 Stimulation Forfor Treatment peer of Autism review Spectrum Disorder: only A Systematic Review and 19 Meta-Analysis. Frontiers in Integrative Neuroscience 2018;12 doi: 20 10.3389/fnint.2018.00027 21 22 32. Enticott PG, Kirkovski M, Oberman LM. Transcranial magnetic stimulation in autism 23 spectrum disorder. In: Oberman LM, Enticott PG, eds. Neurotechnology and brain 24 stimulation in pediatric psychiatric and neurodevelopmental disorders. London, UK: 25 Elsevier 2019. 26 27 33. Oberman LM, Enticott PG, Casanova MF, et al. Transcranial magnetic stimulation in 28 autism spectrum disorder: Challenges, promise, and roadmap for future research. 29 Autism Research 2016;9(2):184-203. doi: 10.1002/aur.1567 30 34. Enticott PG, Fitzgibbon BM, Kennedy HA, et al. A double-blind, randomized trial of deep 31 Repetitive Transcranial Magnetic Stimulation (rTMS) for autism spectrum disorder. 32 33 Brain Stimulation 2014;7(2):206-11. doi: 10.1016/j.brs.2013.10.004 34 35. Ameis SH, Blumberger DM, Croarkin PE, et al. Treatment of Executive Function Deficits 35 in Autism Spectrum Disorder with Repetitive Transcranial Magnetic Stimulation: A 36 double-blind, sham-controlled, pilot trial. Brain Stimulation: Basic, Translational, and http://bmjopen.bmj.com/ 37 38 Clinical Research in Neuromodulation 2020;13:539-47. doi: 39 10.1016/j.brs.2020.01.007 40 36. Cole EJ, Enticott PG, Oberman LM, et al. The Potential of Repetitive Transcranial 41 Magnetic Stimulation for Autism Spectrum Disorder: A Consensus Statement. 42 Biological Psychiatry 2019;85(4):e21-e22. doi: 10.1016/j.biopsych.2018.06.003 43 37. Alvares GA, Dawson PA, Dissanayake C, et al. Study protocol for the Australian autism 44 on September 27, 2021 by guest. Protected copyright. 45 biobank: an international resource to advance autism discovery research. BMC 46 Pediatr 2018;18(1):284. doi: 10.1186/s12887-018-1255-z 47 38. Kenjo Y, Antoku Y, Akazawa K, et al. An easily customized, random allocation system 48 49 using the minimization method for multi-institutional clinical trials. Comput Methods 50 Programs Biomed 2000;62(1):45-9. doi: 10.1016/s0169-2607(99)00047-4 [published 51 Online First: 2000/03/04] 52 39. Harris PA, Taylor R, Minor BL, et al. The REDCap consortium: Building an international 53 community of software platform partners. J Biomed Informatics 2019;95 doi: 54 55 10.1016/j.jbi.2019.103208 56 40. Grove J, Ripke S, Als TD, et al. Identification of common genetic risk variants for autism 57 spectrum disorder. Nature Genetics 2019;51(3):431-44. doi: 10.1038/s41588-019- 58 0344-8 59 60
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1 2 3 41. Kular L, Kular S. Epigenetics applied to psychiatry: Clinical opportunities and future
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 challenges. Psychiatry Clin Neurosci 2018;72(4):195-211. doi: 10.1111/pcn.12634 6 [published Online First: 2018/01/03] 7 8 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
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44 on September 27, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39
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1 2 3 Insert Header with institution’s name or institution’s letterhead
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Participant Information Sheet/Consent Form 7 Interventional Study - Adult providing own consent 8 9 [Insert site name] 10 11 Does repetitive transcranial magnetic stimulation 12 (rTMS), compared to sham rTMS, improve social 13 Title 14 communication in adolescents and young adults 15 with autism spectrum disorder (ASD)? 16 Short Title MRFF TBS-ASD 17 Protocol Number v2, 11/09/2020 18 Project Sponsor For peer reviewDeakin University only 19 20 Coordinating Principal Investigator Prof. Peter Enticott 21 22 23 Prof. Paul Fitzgerald, A/Prof. Karen Barlow, Prof. 24 Ian Hickie, Dr Melissa Licari, Dr Nigel Rogasch, 25 Prof. Christel Middeldorp, Dr Scott Clark, Dr Ann- 26 Maree Vallence, Dr Kelsie Boulton, Prof. Adam 27 Associate Investigator(s) Guastella, Prof. Andrew Whitehouse, Prof. 28 Cherrie Galletly, Dr Gail Alvares, Dr Hakuei 29 Fujiyama, A/Prof. Helen Heussler, A/Prof. Jeffrey 30 Craig, Dr Melissa Kirkovski, Dr Natalie Mills, Prof. 31 Nicole Rinehart, Dr Peter Donaldson, Dr Talitha 32 Ford, Prof. Karen Caeyenberghs 33 34 Location [Insert site-specific location] 35
36 http://bmjopen.bmj.com/ 37 38 39 Part 1 What does my participation involve? 40 41 1 Introduction 42 43 You are invited to take part in this research project. This is because you have been diagnosed
44 with autism spectrum disorder (ASD). The research project is testing a new treatment for ASD. on September 27, 2021 by guest. Protected copyright. 45 The new treatment is called repetitive transcranial magnetic stimulation (rTMS). 46 47 This Participant Information Sheet/Consent Form tells you about the research project. It 48 explains the tests and treatments involved. Knowing what is involved will help you decide if you 49 want to take part in the research. 50 51 Please read this information carefully. Ask questions about anything that you don’t understand 52 53 or want to know more about. Before deciding whether or not to take part, you might want to talk 54 about it with a relative, friend or your local doctor. 55 56 Participation in this research is voluntary. If you don’t wish to take part, you don’t have to. 57 58 If you decide you want to take part in the research project, you will be asked to sign the consent 59 section. By signing it you are telling us that you: 60 • Understand what you have read • Consent to take part in the research project
Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 1 of 11 [Site Name] Site MasterFor peer Participant review Informationonly - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date] Local governance version [Date] (Site PI use only) BMJ Open Page 24 of 57
1 2 • Consent to have the tests and treatments that are described 3 • Consent to the use of your personal and health information as described.
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 You will be given a copy of this Participant Information and Consent Form to keep. 6 7 2 What is the purpose of this research? 8 9 Many individuals with ASD experience difficulty with social functioning; for example, in 10 understanding what other people are thinking or feeling. This may cause significant distress and 11 lead to difficulties and anxiety in social situations. There are very few treatment options for 12 improving abilities related to social functioning in ASD. 13 14 The aim of this project is to determine whether rTMS can be used to improve social function. 15 16 rTMS is a safe and non-invasive means of stimulating nerve cells in a particular part of the brain 17 via the administration of brief magnetic pulses. rTMS has been developed as a treatment for 18 major depressive disorder,For and peer we have previously review found that only rTMS can benefit social aspects 19 of ASD. 20 21 In this study we will stimulate a region of the brain that is involved in social understanding and 22 social communication. This region is called the right temporoparietal junction, or rTPJ. 23 24 Some participants will receive the real form of rTMS, while others will receive a sham or placebo 25 form. The sham or placebo form mimics the feeling of rTMS, but no brain stimulation is 26 delivered. You will not know which one you receive until the end of your involvement in the 27 study. Those who received the sham or placebo form will be given the opportunity to undergo 28 the real rTMS treatment at the end of their involvement in the study. 29 30 150 people (aged 14-40 years) will take part in this study, which is being conducted throughout 31 Australia. There are sites in Brisbane, Sydney, Melbourne, Adelaide, and Perth. Participants will 32 be recruited from around Australia, but primarily the greater metropolitan regions within these 33 five cities. 34 35 rTMS is an experimental treatment. This means that it is not an approved treatment for ASD in 36 http://bmjopen.bmj.com/ 37 Australia or elsewhere. 38 39 This research has been initiated by the study investigator, Prof. Peter Enticott (Deakin 40 University, Melbourne). This research has been funded by the National Health and Medical 41 Research Council (NHMRC) of Australian through a Medical Research Future Fund grant 42 (MRFF RCRDUN Neurological Disorders 2020; Application APP1199298). 43
44 on September 27, 2021 by guest. Protected copyright. 45 3 What does participation in this research involve? 46 47 You will be participating in a randomised controlled research project. Sometimes we do not 48 know which treatment is best for treating a condition. To find out we need to compare different 49 treatments. We put people into groups and give each group a different treatment (in this case, 50 real rTMS vs. sham/placebo rTMS). The results are compared to see if one is better. To try to 51 make sure the groups are the same, each participant is put into a group by chance (random). 52 53 This is a double-blind study. This means that neither you nor your study doctor will know which 54 55 treatment you are receiving (in this case, real rTMS or sham/placebo rTMS). However, in certain 56 circumstances your study doctor can find out which treatment you are receiving. Participants will 57 be randomly allocated to either the real rTMS or sham/placebo rTMS condition. As mentioned, 58 those allocated to the sham or placebo form will be given the opportunity to undergo the real 59 rTMS treatment at the end of their involvement in the study. 60 This research project has been designed to make sure the researchers interpret the results in a fair and appropriate way and avoids study doctors or participants jumping to conclusions. Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 2 of 11 [Site Name] Site MasterFor peer Participant review Informationonly - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date] Local governance version [Date] (Site PI use only) Page 25 of 57 BMJ Open
1 2 3 If you decide to take part in this project, you will be asked to take part in a number of interviews
4 and procedures over the course of approximately eight months. These are outlined below. BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Prior to completing the study, we will need to determine your eligibility to take part in the study. 7 We will do this by asking you questions (either over the phone or via email) about your health. 8 We will also ask you to provide a letter or report confirming your diagnosis of ASD; if you are not 9 able to provide this, we will seek permission (via the consent form) to contact your doctor or 10 psychologist directly to confirm your diagnosis. 11 12 Assessment Session One: The first assessment will take place at [site-specific location]. It will 13 take approximately three hours, but you will be given regular breaks throughout the session. 14 15 We will begin by asking you some questions about your health, which will help to confirm your 16 eligibility to take part in the study. We will then ask some questions about yourself that are 17 relevant to ASD. This will include, for example, what you enjoy doing and how much you like 18 For peer review only 19 being with other people. We will also ask you to have someone who knows you well (e.g., a 20 parent, sibling, spouse, or close friend) complete a series of questionnaires. You can nominate 21 this person and we will ask that they agree to complete these questionnaires now and another 22 four times during the study. 23 24 You will then complete a short cognitive assessment, which involves solving puzzles and 25 describing what different words mean. 26 27 Finally, you will undergo electroencephalography (EEG), which involves wearing an “electrode 28 cap” to measure the electrical activity of your brain, or your “brainwaves.” The electrode cap 29 feels similar to a swimming cap. It will also feel a little damp, as we need to put a small amount 30 of gel or saline into the cap to ensure that we get accurate recordings. For most of the EEG you 31 will simply rest while sitting in a chair, but you will also complete a short task on a computer that 32 involves looking at different objects (e.g., faces, household furniture, butterflies). 33 34 Assessment Session Two: Around one-week after “Assessment Session One” you will then 35 undergo a magnetic resonance imaging (MRI) brain scan at [site-specific location]. The MRI 36 http://bmjopen.bmj.com/ brain scan takes around 45-60 minutes, during which you will be asked to lie still in an MRI 37 38 scanner. (Please note that with preparation time you attend the MRI facility for up to two hours.) 39 MRI is a routinely performed, painless ways of examining brain structure and activity. We will 40 use the MRI to accurately place the rTMS device, and ensure that we are stimulating the correct 41 brain region. The MRI procedure may also help us better understand how the treatment works 42 and to determine who is likely to respond to treatment and why. 43
44 Assessment Session Three: During the same week of “Assessment Session Two,” you will on September 27, 2021 by guest. Protected copyright. 45 attend a two-hour assessment session at [site-specific location]. Here we will ask you questions 46 about yourself, some of which are relevant to ASD, while others relate to your mood, 47 concentration, stress, and your satisfaction with life. We will also ask you to complete some 48 cognitive tasks on a computer/tablet. These tasks measure your memory, attention, and 49 understanding of other people’s emotions. We will also ask you to provide a sample for genetic 50 analysis; this will involve having a cotton swab rubbed against the inside of your cheek. These 51 genetic analyses are conducted to investigate whether people with certain genetic profiles 52 respond better to the intervention. You will not receive any health information from these genetic 53 analyses, and they are not considered to be clinically informative. 54 55 rTMS Intervention (4 weeks): The week after “Assessment Session Three” you will begin the 56 57 rTMS intervention, which involves attending [site-specific location] and receiving rTMS for 3 58 minutes, 20 seconds each consecutive weekday for a four-week period (20 rTMS sessions in 59 total). 60 You will have your first rTMS session on the Monday after “Assessment Session Three.” At the beginning of the first session we will administer transcranial magnetic stimulation (TMS) to the Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 3 of 11 [Site Name] Site MasterFor peer Participant review Informationonly - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date] Local governance version [Date] (Site PI use only) BMJ Open Page 26 of 57
1 2 area of the brain that controls the muscles in your hand. This will measure how excitable your 3 brain is and is used to help us determine the personalised settings that will be used for your
4 rTMS treatments. This takes approximately 10 minutes and is not uncomfortable, although you BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 may feel some twitches in the muscle of your hand while the TMS is occurring. 6 7 During each rTMS session you will be awake, alert, and aware of what is happening at all times. 8 During rTMS a coil will be placed against the head, through which rTMS is administered. This is 9 connected to a machine that sends an electrical current through the coil. The current produces a 10 magnetic field that is very focused and is able to stimulate electrical activity in nerves below the 11 coil. These are usually nerve cells in the outer layers of the brain. The sensations associated 12 with rTMS are mild, and most people describe it as a “tapping” sensation on their head. During a 13 rTMS procedure you will hear clicking sounds as the current passes through the coil. You will 14 wear earplugs so that this noise doesn’t disturb you. 15 16 Including setup time, each subsequent treatment session should only take approximately 10 17 minutes. At the end of each treatment week (i.e., on the Friday session) we will ask you a 18 For peer review only 19 number of questions about your experience of RTMS, and whether you feel you have 20 experienced any side effects. 21 22 Assessment Session Four: The week after your last rTMS session, you will attend another 23 two-hour assessment session at [site-specific location]. Here we will again ask you questions 24 about yourself, some of which are relevant to ASD, while others relate to your mood, 25 concentration, stress, and satisfaction with life. We will also again ask you to complete some 26 cognitive tasks on a computer/tablet and to provide another sample (cheek swab) for genetic 27 analysis. 28 29 Assessment Session Five: One-month after your last rTMS session, you will attend another 30 two-hour assessment session at [site-specific location]. This session will be identical to 31 Assessment Session Four. 32 33 Assessment Session Six: Three-months after your last rTMS session, you will attend a one- 34 hour assessment session at [site-specific location]. This session will be identical to Assessment 35 Session Five except that you will not complete the computerised cognitive tasks. 36 http://bmjopen.bmj.com/ 37 38 Assessment Session Seven: Six-months after your last rTMS session, you will attend a final 39 two-hour assessment session at [site-specific location]. This session will be identical to 40 Assessment Session Five. Following the assessment, you will be unblinded; that is, a member 41 of the research team will tell you which treatment condition you received (i.e., real or 42 sham/placebo). If you received the real treatment, your involvement in the study will conclude. If 43 you received the sham/placebo condition, you will be given the opportunity to receive the real
44 treatment and can liaise with research staff to determine when you would like to undergo this on September 27, 2021 by guest. Protected copyright. 45 four-week treatment. 46 47 There are no costs associated with participating in this research project. All treatments, tests, 48 and medical care required as part of the research project will be provided to you free of charge. 49 50 You will not be paid for your participation in this research, but you will be reimbursed $200 to 51 contribute towards costs that you incur as a result of participating in this research project (e.g., 52 travel). If you complete only part of the study and then decide to withdraw, you will be 53 reimbursed a proportion of this amount based on the proportion of the study completed. 54 55 Please note that no study procedures will be performed until consent has been obtained. 56 57 58 It is desirable that your local doctor be advised of your decision to participate in this research 59 project. If you have a local doctor, we strongly recommend that you inform them of your 60 participation in this research project.
Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 4 of 11 [Site Name] Site MasterFor peer Participant review Informationonly - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date] Local governance version [Date] (Site PI use only) Page 27 of 57 BMJ Open
1 2 The research will be monitored by an independent Data Safety Monitoring Board, who will meet 3 twice per year and review the conduct of the trial, monitor study data, and review any serious
4 adverse events that might arise throughout the trial. BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 4 What do I have to do? 7 8 You will be able to continue taking your usual medication if you participate in this study, but you 9 will need to inform us of any changes to this medication that occur during your participation in 10 the study. 11 12 There are several reasons why you may not be able to take part in this study. These include: 13 14 The presence of metal anywhere in the head (except the mouth) 15 16 A history of seizure or epilepsy, or evidence of significant seizure activity as assessed by 17 EEG 18 A history of seriousFor head peer injury review only 19 The presence of certain implanted medical devices (e.g., cardiac pacemaker, medication 20 pumps) 21 Serious heart disease (as there is an increased risk of serious injury in the event of a 22 seizure) 23 24 Being deemed unsuitable to undergo MRI (e.g., due to presence of metal in the body) 25 Unstable medical condition 26 Unstable medication regime 27 Certain medications 28 Substance use disorder 29 Undergoing another current treatment for social communication 30 Employment as a professional driver or machine operator (as the event of a seizure may 31 affect employment) 32 Pregnancy (female participants for whom child-bearing is a possibility will be required to 33 undergo a urine screen) 34 35 Certain neurological or psychiatric diagnoses (i.e., those not commonly associated with
36 ASD, such as psychosis) http://bmjopen.bmj.com/ 37 A measured verbal intelligence quotient (IQ) of less than 55 38 39 5 Other relevant information about the research project 40 41 This study is only taking place in Australia. There will be 150 participants in this study, with 30 42 taking part in each of the five cities involved: Brisbane, Sydney, Melbourne, Adelaide, and 43 Perth. There are a total of 14 organisations involved, including Universities, hospitals, and
44 medical centres. This study is a follow-on study from our previous trials of rTMS in ASD, which on September 27, 2021 by guest. Protected copyright. 45 have taken place at Monash University, Deakin University, The Alfred hospital, and the Epworth 46 Camberwell. 47 48 6 Do I have to take part in this research project? 49 50 Participation in any research project is voluntary. If you do not wish to take part, you do not have 51 52 to. If you decide to take part and later change your mind, you are free to withdraw from the 53 project at any stage. 54 55 If you do decide to take part, you will be given this Participant Information and Consent Form to 56 sign and you will be given a copy to keep. 57 58 Your decision whether to take part or not to take part, or to take part and then withdraw, will not 59 affect your routine treatment, your relationship with those treating you, or your relationship with 60 [site-specific Institution/s].
7 What are the possible benefits of taking part? Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 5 of 11 [Site Name] Site MasterFor peer Participant review Informationonly - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date] Local governance version [Date] (Site PI use only) BMJ Open Page 28 of 57
1 2 3 We cannot guarantee or promise that you will receive any benefits from this research; however,
4 possible benefits include an improvement in social understanding and functioning, including an BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 increased ability to accurately infer what other people are thinking or feeling. 6 7 8 What are the possible risks and disadvantages of taking part? 8 9 Repetitive Transcranial Magnetic Stimulation (rTMS) 10 11 Medical treatments often cause side effects. You may have none, some, or all of the effects 12 listed below, and they may be mild, moderate, or severe. If you have any of these side effects, 13 or are worried about them, talk with your study doctor. Your study doctor will also be looking out 14 for side effects. 15 16 There may be side effects that the researchers do not expect or do not know about and that 17 may be serious. Tell your study doctor immediately about any new or unusual symptoms that 18 For peer review only 19 you get. 20 21 Many side effects go away shortly after treatment ends. However, sometimes side effects can 22 be serious, long lasting, or permanent. If a severe side effect or reaction occurs, your study 23 doctor may need to stop your treatment. Your study doctor will discuss the best way of 24 managing any side effects with you. 25 26 Noise: The clicking noise made by the coil may be uncomfortable. You will wear 27 earplugs during treatment to minimise any discomfort. 28 29 Headache: A headache can occur during rTMS and is thought to affect approximately 30 3% or 3 in 100 participants. It is thought to be caused by stimulation of nerves in the 31 scalp. If you were to experience such a headache, it will respond quickly to simple pain 32 medication such as aspirin, ibuprofen, or paracetamol. 33 34 Scalp Sensation: During the treatment itself, you might feel a tapping or twitching 35 sensation on your scalp as the magnetic pulse stimulates muscles in your scalp as it 36 http://bmjopen.bmj.com/ passes into the brain. This sensation varies between people from very soft to quite 37 38 strong. If you find it uncomfortable, we will use a lower stimulation intensity and only 39 increase it as you find it tolerable. 40 41 Seizure: The main concern associated with rTMS is its potential to induce a fit or 42 seizure. This risk is extremely low, but is increased for those with a history of seizure 43 activity (where a seizure resulting from rTMS affects about 2% or 2 in 100 such
44 individuals). If you have ever experienced a seizure, or if your EEG shows evidence of on September 27, 2021 by guest. Protected copyright. 45 epileptiform activity, you will not be able to take part in this study. Investigators using 46 rTMS have developed safety guidelines to minimise the risk of seizure. The rTMS we 47 provide is well within what is considered to be safe. It is important to note that 48 experiencing a seizure induced by rTMS has never led to the development of epilepsy or 49 increased the probability of having subsequent unprovoked seizures. There will always 50 be medically trained staff available when you have rTMS. Staff will monitor you and 51 know how to treat a seizure should one occur. 52 53 The effects of rTMS on the unborn child and on the newborn baby are not known. Because of 54 this, it is important that research project participants are not pregnant or breast-feeding and do 55 not become pregnant during the course of the research project. You must not participate in the 56 57 research if you are pregnant or trying to become pregnant, or breast-feeding. If you are female 58 and child-bearing is a possibility, you will be required to undergo a urinal pregnancy test prior to 59 commencing rTMS. This test will be processed by a female member of the research staff. 60 If you do become pregnant whilst participating in the research project, you should advise research staff immediately. The researchers will withdraw you from the research project and Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 6 of 11 [Site Name] Site MasterFor peer Participant review Informationonly - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date] Local governance version [Date] (Site PI use only) Page 29 of 57 BMJ Open
1 2 advise on further medical attention should this be necessary. You must not continue in the 3 research if you become pregnant.
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 Your ability to drive or use public transport will not be impaired following rTMS. 6 7 It is also possible that there are unknown risks of rTMS. 8 9 Magnetic Resonance Imaging (MRI) 10 11 MRI stands for magnetic resonance imaging. An MRI scanner is a machine that uses 12 electromagnetic radiation (radio waves) in a strong magnetic field to take clear pictures of the 13 inside of the body. Electromagnetic radiation is not the same as ionising radiation used, for 14 example, in X-rays. The pictures taken by the machine are called MRI scans. 15 16 There are no proven long-term risks related to MRI scans as used in this research project. MRI 17 is considered to be safe when performed at a centre with appropriate procedures. However, the 18 For peer review only 19 magnetic attraction for some metal objects can pose a safety risk, so it is important that metal 20 objects are not taken into the scanner room. 21 22 We will thoroughly examine you to make sure there is no reason for you not to have the scan. 23 You must tell us if you have metal implanted in your body, such as a pacemaker or metal pins. 24 25 The MRI scanner is shaped like a narrow tunnel. Foam cushioning and Velcro straps are used 26 to keep your head relatively still during scanning. While the mask, cushions, and straps are 27 restraining, they should not be uncomfortable. Some people may experience claustrophobia 28 while having an MRI scan. Please let us know if you have experienced claustrophobia in the 29 past. The MRI scanner is noisy, so you will wear ear plugs and headphones to reduce the noise. 30 We will be able to see you and communicate with you during the scanning, and you will be able 31 to stop the machine at any time by pushing a button. If you become uncomfortable during the 32 session, we can pause or stop the scanning. 33 34 The scans we are taking are for research purposes. They are not intended to be used like scans 35 taken for a full clinical examination. The scans will not be used to help diagnose, treat, or 36 http://bmjopen.bmj.com/ manage a particular condition. A specialist will look at your MRI scans for features relevant to 37 38 the research project. On rare occasions, the specialist may find an unusual feature that could 39 have a significant risk to your health. If this happens, we will contact you to talk about the 40 findings. We cannot guarantee that we will find any/all unusual features. There may be wider 41 implications from abnormal findings (e.g., for future applications for some kinds of insurance). 42 43 Other
44 on September 27, 2021 by guest. Protected copyright. 45 We will ask you if you have used illegal drugs. That information will be stored in a re-identifiable 46 (or coded) format. In the event that the researchers are required to disclose that information, it 47 may be used against you in legal proceedings or otherwise. 48 49 If you become upset or distressed as a result of your participation in the research, the study 50 doctor will be able to arrange for counselling or other appropriate support. Any counselling or 51 support will be provided by qualified staff who are not members of the research project team. 52 This counselling will be provided free of charge. 53 54 9 What will happen to my test samples? 55 56 57 You will be asked to provide additional consent for the collection of your tissue (i.e., cheek 58 swab) during the research project. As noted, these samples are collected to allow us to 59 investigate whether certain genetic profiles are associated with a better response to the rTMS 60 intervention. We will only conduct these analyses at a group level. You will not receive any health information (e.g., genetic disease predisposition) from these genetic analyses, and they are not considered to be clinically informative. Your genetic material and information, where Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 7 of 11 [Site Name] Site MasterFor peer Participant review Informationonly - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date] Local governance version [Date] (Site PI use only) BMJ Open Page 30 of 57
1 2 identified or potentially identifiable, will not be released for other uses without your prior consent, 3 unless required by law.
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 Samples of your tissue obtained for the purpose of this research project will be transferred to 6 the Institute for Molecular Bioscience, University of Queensland, who will charge a fee to the 7 research team to recover some of the costs of storing and administering the tissue samples. 8 The University of Queensland will not transfer or sell your samples to any third party. 9 10 10 What if new information arises during this research project? 11 12 Sometimes during the course of a research project, new information becomes available about 13 the treatment that is being studied. If this happens, your study doctor will tell you about it and 14 discuss with you whether you want to continue in the research project. If you decide to 15 withdraw, your study doctor will make arrangements for your regular health care to continue. If 16 you decide to continue in the research project you will be asked to sign an updated consent 17 form. 18 For peer review only 19 20 Also, on receiving new information, your study doctor might consider it to be in your best 21 interests to withdraw you from the research project. If this happens, your study doctor will 22 explain the reasons and arrange for your regular health care to continue. 23 24 11 Can I have other treatments during this research project? 25 26 Whilst you are participating in this research project, you can continue to take the medications or 27 treatments you have been taking for your condition or for other reasons. It is important to tell the 28 research staff about any treatments or medications you may be taking, including over-the- 29 counter medications, vitamins or herbal remedies, acupuncture, or other alternative treatments. 30 You should also tell the study staff about any changes to these during your participation in the 31 research project. 32 33 Because this trial is assessing the effect of rTMS on social communication, you cannot 34 participate if you are also undergoing any other treatment or intervention for social 35 communication. This includes interventions delivered by psychologists. 36 http://bmjopen.bmj.com/ 37 38 12 What if I withdraw from this research project? 39 40 If you decide to withdraw from the project, please notify a member of the research team before 41 you withdraw. This notice will allow that person or the research supervisor to discuss any health 42 risks or special requirements linked to withdrawing. 43
44 If you do withdraw your consent during the research project, the study doctor and relevant study on September 27, 2021 by guest. Protected copyright. 45 staff will not collect additional personal information from you, although personal information 46 already collected will be retained to ensure that the results of the research project can be 47 measured properly and to comply with law. You should be aware that data collected up to the 48 time you withdraw will form part of the research project results. If you do not want the 49 researchers to do this, you must tell them before you join the research project. 50 51 13 Could this research project be stopped unexpectedly? 52 53 This research project may be stopped unexpectedly for a variety of reasons. These may include 54 reasons such as: 55 56 57 • Unacceptable side effects 58 • The drug/treatment/device being shown not to be effective 59 • The drug/treatment/device being shown to work and not need further testing 60 • Decisions made by local regulatory/health authorities.
14 What happens when the research project ends? Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 8 of 11 [Site Name] Site MasterFor peer Participant review Informationonly - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date] Local governance version [Date] (Site PI use only) Page 31 of 57 BMJ Open
1 2 3 You will be sent a summary of the main findings when the project has been completed. This is a
4 4-year study and it is expected that study results will be available by late 2024. Your data will BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 then be securely archived at Deakin University. 6 7 Please note that rTMS will not be available from the research sites after completing the study. It 8 may be approved for future use in ASD, but this will depend on the results from the current 9 study. 10 11 Part 2 How is the research project being conducted? 12 13 14 15 What will happen to information about me? 15 16 By signing the consent form, you consent to the study doctor and relevant research staff 17 collecting and using personal information about you for the research project. Any information 18 obtained in connectionFor with this peer research projectreview that can identify only you will remain confidential. 19 Upon enrolment in the trial you will be allocated a unique study identification code. Your name 20 will not appear with the research data that we collect from you and it will only be possible to re- 21 identify your data using the study code. Only the research team will know which code identifies 22 which participant. Your information will only be used for the purpose of this research project and 23 future research projects, and it will only be disclosed with your permission, except as required 24 by law. 25 26 Information about you may be obtained from your health records held at this and other health 27 services for the purpose of this research. By signing the consent form, you agree to the study 28 team accessing health records if they are relevant to your participation in this research project. 29 30 Your health records and any information obtained during the research project are subject to 31 inspection (for the purpose of verifying the procedures and the data) by the relevant authorities 32 33 and authorised representatives of the Sponsor, Deakin University, the institution relevant to this 34 Participant Information Sheet, [Name of institution], or as required by law. By signing the 35 Consent Form, you authorise release of, or access to, this confidential information to the
36 relevant study personnel and regulatory authorities as noted above. http://bmjopen.bmj.com/ 37 38 It is anticipated that the results of this research project will be published and/or presented in a 39 variety of forums. In any publication and/or presentation, information will be provided in such a 40 way that you cannot be identified, except with your permission. We will only present group-level 41 findings (e.g., average scores across the group) and no individual data will be reported. 42 43 In accordance with relevant Australian and/or [Name of state/territory] privacy and other relevant
44 laws, you have the right to request access to your information collected and stored by the on September 27, 2021 by guest. Protected copyright. 45 research team. You also have the right to request that any information with which you disagree 46 be corrected. Please contact the study team member named at the end of this document if you 47 would like to access your information. 48 49 Any information obtained for the purpose of this research project and for future research that 50 can identify you will be treated as confidential and securely stored. It will be disclosed only with 51 52 your permission, or as required by law. 53 54 It is expected that deidentified data from this study will be made available to other researchers 55 via online data repositories. You will not be able to be identified in these repositories. It is also 56 possible that the research team will use your data from this research project for future studies, 57 but again you will not be able to be identified. 58 59 16 Complaints and compensation 60 If you suffer any injuries or complications as a result of this research project, you should contact the study team as soon as possible and you will be assisted with arranging appropriate medical Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 9 of 11 [Site Name] Site MasterFor peer Participant review Informationonly - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date] Local governance version [Date] (Site PI use only) BMJ Open Page 32 of 57
1 2 treatment. If you are eligible for Medicare, you can receive any medical treatment required to 3 treat the injury or complication, free of charge, as a public patient in any Australian public
4 hospital. BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 If you have complaints about your treatment by members of staff working on this research 7 project, you should contact the person nominated in Section 19 below. If you have complaints 8 about any of the ethical aspects of this study, you can contact the local reviewing HREC 9 Executive Officer nominated in Section 19 below. Complaints about clinical trials can also be 10 directed to the Office of the Australian Information Commissioner. 11 12 17 Who is organising and funding the research? 13 14 This research project is being conducted by a team of researchers led by Prof. Peter Enticott 15 from Deakin University, Victoria. It is funded through a Medical Research Future Fund grant 16 from the National Health and Medical Research Council to Prof. Enticott and the research team. 17 18 For peer review only 19 No member of the research team will receive a personal financial benefit from your involvement 20 in this research project (other than their ordinary wages). 21 22 18 Who has reviewed the research project? 23 24 All research in Australia involving humans is reviewed by an independent group of people called 25 a Human Research Ethics Committee (HREC). The ethical aspects of this research project 26 have been approved by the HREC of Monash Health and [Name of institutions]. 27 28 This project will be carried out according to the National Statement on Ethical Conduct in 29 Human Research (2018). This statement has been developed to protect the interests of people 30 who agree to participate in human research studies. 31 32 19 Further information and who to contact 33 34 The person you may need to contact will depend on the nature of your query. 35
36 http://bmjopen.bmj.com/ If you want any further information concerning this project or if you have any medical problems 37 38 that may be related to your involvement in the project (for example, any side effects), you can 39 contact your site’s principal study doctor on [phone number] or any of the following people: 40 41 Study contact person 42 Name [Name] 43 Position [Position]
44 Telephone [Phone number] on September 27, 2021 by guest. Protected copyright. 45 Email [Email address] 46 47 Clinical contact person 48 49 Name [Name] 50 Position [Position] 51 Telephone [Phone number] 52 Email [Email address] 53 54 For matters relating to research at the site at which you are participating, the details of the local 55 site complaints person are: 56 57 Complaints contact person 58 Name [Name] 59 Position [Position] 60 Telephone [Phone number] Email [Email address] Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 10 of 11 [Site Name] Site MasterFor peer Participant review Informationonly - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date] Local governance version [Date] (Site PI use only) Page 33 of 57 BMJ Open
1 2 3 If you have any complaints about any aspect of the project, the way it is being conducted or any
4 questions about being a research participant in general, then you may contact: BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Reviewing HREC approving this research and HREC Executive Officer details 7 8 Reviewing HREC name Monash Health 9 HREC Executive Officer Ms Deborah Dell 10 Telephone (03) 9594 4605 11 Email [email protected] 12 13 Local HREC Office contact (Single Site - Research Governance Officer) 14 Name [Name] 15 Position [Position] 16 17 Telephone [Phone number] 18 Email For[Email peer address] review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43
44 on September 27, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 11 of 11 [Site Name] Site MasterFor peer Participant review Informationonly - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date] Local governance version [Date] (Site PI use only) BMJ Open Page 34 of 57
1 2 Consent Form - Adult providing own consent 3 Does repetitive transcranial magnetic stimulation 4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from (rTMS), compared to sham rTMS, improve social 5 Title 6 communication in adolescents and young adults 7 with autism spectrum disorder (ASD)? 8 Short Title MRFF RTMS-ASD 9 10 Protocol Number v2, 11/09/2020 11 Project Sponsor Deakin University 12 Coordinating Principal Investigator Prof. Peter Enticott 13 14 Prof. Paul Fitzgerald, A/Prof. Karen Barlow, Prof. 15 Ian Hickie, Dr Melissa Licari, Dr Nigel Rogasch, 16 Prof. Christel Middeldorp, Dr Scott Clark, Dr Ann- 17 Maree Vallence, Dr Kelsie Boulton, Prof. Adam 18 Associate Investigator(s)For peer Guastella,review Prof. Andrew only Whitehouse, Prof. 19 Cherrie Galletly, Dr Gail Alvares, Dr Hakuei 20 Fujiyama, A/Prof. Helen Heussler, A/Prof. Jeffrey 21 Craig, Dr Melissa Kirkovski, Dr Natalie Mills, Prof. 22 Nicole Rinehart, Dr Peter Donaldson, Dr Talitha 23 Ford, Prof. Karen Caeyenberghs 24 25 Location [Location where the research will be conducted] 26 27 28 Consent Agreement 29 I have read the Participant Information Sheet. 30 I understand the purposes, procedures and risks of the research described in the project. 31 32 I give permission for my doctors, other health professionals, hospitals or laboratories outside 33 this hospital to release information to [Name of Institution] concerning my condition and 34 treatment for the purposes of this project. I understand that such information will remain 35 confidential. 36 http://bmjopen.bmj.com/ 37 38 I have had an opportunity to ask questions and I am satisfied with the answers I have received. 39 I freely agree to participate in this research project as described and understand that I am free 40 to withdraw at any time during the study without affecting my future health care. 41 42 I understand that I will be given a signed copy of this document to keep. 43
44 I agree for my anonymous study data to be shared with other researchers, including those on September 27, 2021 by guest. Protected copyright. 45 outside [Name of Institution] and outside Australia, for future studies. 46 47 48 I agree to my anonymised data being made available through online repositories and to the use 49 of my data in any future research. 50 51 Declaration by Participant – for participants who have read the information 52 53 Name of Participant (please print) ______54 55 Signature ______Date ______56 57 58 59 60
Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 1 of 2 [Site Name] Site Master Participant Information Sheet/Consent Form [Date] Local governance versionFor peer [Date] review (Site only PI use- http://bmjopen.bmj.com/site/about/guidelines.xhtml only) Page 35 of 57 BMJ Open
1 Declaration by Study Doctor/Senior Researcher† 2 I have given a verbal explanation of the research project, its procedures and risks and I believe 3 that the participant has understood that explanation.
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 Name of Study Doctor/ 6 Senior Researcher† (please print) 7 8 9 Signature Date 10 † A senior member of the research team must provide the explanation of, and information concerning, the research 11 project. 12 Note: All parties signing the consent section must date their own signature. 13 14 I consent to the storage and use of tissue samples (cheek swabs) taken from me for use, as 15 described in the relevant section of the Participant Information Sheet, for: 16 • This specific research project 17 • Other research that is closely related to this research project 18 • Any future research.For peer review only 19 20 By signing this consent section, I agree to the use of my tissue samples for genetic testing, as 21 outlined in the relevant Section of the Participant Information Sheet. 22 23 24 Name of Participant (please print) 25 26 Signature Date 27 28 29 30 Name of Study Doctor/ 31 Senior Researcher† (please print) 32 33 34 Signature Date 35 † A senior member of the research team must provide the explanation of and information concerning the research 36 project. http://bmjopen.bmj.com/ 37 Note: All parties signing the consent section must date their own signature. 38 39 40 41 42 43
44 on September 27, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 2 of 2 [Site Name] Site Master Participant Information Sheet/Consent Form [Date] Local governance versionFor peer [Date] review (Site only PI use- http://bmjopen.bmj.com/site/about/guidelines.xhtml only) BMJ Open Page 36 of 57
1 2 Form for Withdrawal of Participation - Adult providing own consent 3
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Does repetitive transcranial magnetic stimulation 7 (rTMS), compared to sham rTMS, improve social Title 8 communication in adolescents and young adults 9 with autism spectrum disorder (ASD)? 10 11 Short Title MRFF RTMS-ASD 12 Protocol Number v2, 11/09/2020 13 Project Sponsor Deakin University 14 15 Coordinating Principal Investigator Prof. Peter Enticott 16 Prof. Paul Fitzgerald, A/Prof. Karen Barlow, Prof. 17 Ian Hickie, Dr Melissa Licari, Dr Nigel Rogasch, 18 For peer Prof.review Christel Middeldorp, only Dr Scott Clark, Dr Ann- 19 20 Maree Vallence, Dr Kelsie Boulton, Prof. Adam 21 Associate Investigator(s) Guastella, Prof. Andrew Whitehouse, Prof. 22 Cherrie Galletly, Dr Gail Alvares, Dr Hakuei 23 Fujiyama, A/Prof. Helen Heussler, A/Prof. Jeffrey 24 Craig, Dr Melissa Kirkovski, Dr Natalie Mills, Prof. 25 Nicole Rinehart, Dr Peter Donaldson, Dr Talitha 26 Ford, Prof. Karen Caeyenberghs 27 28 Location [Location where the research will be conducted] 29 30 Declaration by Participant 31 32 I wish to withdraw from participation in the above research project and understand that such 33 withdrawal will not affect my routine treatment, my relationship with those treating me or my 34 relationship with [Institution]. 35
36 http://bmjopen.bmj.com/ 37 Name of Participant (please print) 38 39 Signature Date 40 41 42 Description of circumstances where communicated verbally: 43
44 on September 27, 2021 by guest. Protected copyright. 45 46 47 Declaration by Study Doctor/Senior Researcher† 48 49 I have given a verbal explanation of the implications of withdrawal from the research project and 50 I believe that the participant has understood that explanation. 51 52 53 Name of Study Doctor/ † 54 Senior Researcher (please print) 55 56 Signature Date 57 58 † A senior member of the research team must provide the explanation of and information concerning withdrawal from 59 the research project. 60 Note: All parties signing the consent section must date their own signature. Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 1 of 1 [Site Name] Site Master Participant Information Sheet/Consent Form [Date] Local governance version [Date] (Site PI use only) For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 37 of 57 BMJ Open
1 2 3 Insert Header with institution’s name or institution’s letterhead
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Participant Information Sheet/Consent Form 7 Interventional Study - Parent/Guardian consenting on behalf of participant 8 9 [Insert site name] 10 11 Does repetitive transcranial magnetic stimulation 12 (rTMS), compared to sham rTMS, improve social 13 Title 14 communication in adolescents and young adults 15 with autism spectrum disorder (ASD)? 16 Short Title MRFF TBS-ASD 17 Protocol Number v2, 11/09/2020 18 Project Sponsor For peer reviewDeakin University only 19 20 Coordinating Principal Investigator Prof. Peter Enticott 21 22 23 Prof. Paul Fitzgerald, A/Prof. Karen Barlow, Prof. 24 Ian Hickie, Dr Melissa Licari, Dr Nigel Rogasch, 25 Prof. Christel Middeldorp, Dr Scott Clark, Dr Ann- 26 Maree Vallence, Dr Kelsie Boulton, Prof. Adam 27 Associate Investigator(s) Guastella, Prof. Andrew Whitehouse, Prof. 28 Cherrie Galletly, Dr Gail Alvares, Dr Hakuei 29 Fujiyama, A/Prof. Helen Heussler, A/Prof. Jeffrey 30 Craig, Dr Melissa Kirkovski, Dr Natalie Mills, Prof. 31 Nicole Rinehart, Dr Peter Donaldson, Dr Talitha 32 Ford, Prof. Karen Caeyenberghs 33 34 Location [Insert site-specific location] 35
36 http://bmjopen.bmj.com/ 37 38 39 Part 1 What does the child’s participation involve? 40 41 1 Introduction 42 43 This is an invitation for the child in your care to take part in this research project because they
44 have been diagnosed with autism spectrum disorder (ASD). The research project is testing a on September 27, 2021 by guest. Protected copyright. 45 new treatment for ASD. The new treatment is called repetitive transcranial magnetic stimulation 46 (rTMS). 47 48 This Participant Information Sheet/Consent Form tells you about the research project. It 49 explains the tests and treatments involved. Knowing what is involved will help you decide if you 50 want your child to take part in the research. 51 52 53 Please read this information carefully. Ask questions about anything that you don’t understand 54 or want to know more about. Before deciding whether or not your child can take part, you might 55 want to talk about it with a relative, friend or your child’s local doctor. 56 57 Participation in this research is voluntary. If you do not wish your child to take part, they do not 58 have to. Your child will receive the best possible care whether or not they take part. 59 60 If you decide you want your child to take part in the research project, you will be asked to sign the consent section. By signing it you are telling us that you: • Understand what you have read Master Parent/Guardian Participant Information Sheet/Consent Form 11/09/2020 Page 1 of 11 [Site Name] Site MasterFor peer Participant review onlyInformation - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date] Local governance version [Date] (Site PI use only) BMJ Open Page 38 of 57
1 2 • Consent to your child taking part in the research project 3 • Consent for your child to have the tests and treatments that are described
4 • Consent to the use of your child’s personal and health information as described. BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 You will be given a copy of this Participant Information and Consent Form to keep. 7 8 2 What is the purpose of this research? 9 10 Many individuals with ASD experience difficulty with social functioning; for example, in 11 understanding what other people are thinking or feeling. This may cause significant distress and 12 lead to difficulties and anxiety in social situations. There are very few treatment options for 13 improving abilities related to social functioning in ASD. 14 15 The aim of this project is to determine whether rTMS can be used to improve social function. 16 rTMS is a safe and non-invasive means of stimulating nerve cells in a particular part of the brain 17 via the administration of brief magnetic pulses. rTMS has been developed as a treatment for 18 For peer review only 19 major depressive disorder, and we have previously found that rTMS can benefit social aspects 20 of ASD. 21 22 In this study we will stimulate a region of the brain that is involved in social understanding and 23 social communication. This region is called the right temporoparietal junction, or rTPJ. 24 25 Some participants will receive the real form of rTMS, while others will receive a sham or placebo 26 form. The sham or placebo form mimics the feeling of rTMS, but no brain stimulation is 27 delivered. You will not know which one your child receives until the end of your involvement in 28 the study. Those who received the sham or placebo form will be given the opportunity to 29 undergo the real rTMS treatment at the end of their involvement in the study. 30 31 150 people (aged 14-40 years) will take part in this study, which is being conducted throughout 32 Australia. There are sites in Brisbane, Sydney, Melbourne, Adelaide, and Perth. Participants will 33 be recruited from around Australia, but primarily the greater metropolitan regions within these 34 five cities. 35
36 http://bmjopen.bmj.com/ rTMS is an experimental treatment. This means that it is not an approved treatment for ASD in 37 38 Australia or elsewhere. 39 40 This research has been initiated by the study investigator, Prof. Peter Enticott (Deakin 41 University, Melbourne). This research has been funded by the National Health and Medical 42 Research Council (NHMRC) of Australian through a Medical Research Future Fund grant 43 (MRFF RCRDUN Neurological Disorders 2020; Application APP1199298).
44 on September 27, 2021 by guest. Protected copyright. 45 46 3 What does participation in this research involve? 47 48 Your child will be participating in a randomised controlled research project. Sometimes we do 49 not know which treatment is best for treating a condition. To find out we need to compare 50 different treatments. We put people into groups and give each group a different treatment (in 51 this case, real RTMS vs. sham/placebo RTMS). The results are compared to see if one is 52 better. To try to make sure the groups are the same, each participant is put into a group by 53 chance (random). 54 55 This is a double-blind study. This means that it will not be known which of the treatments your 56 57 child is receiving (in this case, real rTMS or sham/placebo rTMS); the study doctor will also not 58 know. However, in certain circumstances your study doctor can find out which treatment your 59 child is receiving. Participants will be randomly allocated to either the real rTMS or 60 sham/placebo RTMS condition. As mentioned, those allocated to the sham or placebo form will be given the opportunity to undergo the real rTMS treatment at the end of their involvement in the study. Master Parent/Guardian Participant Information Sheet/Consent Form 11/09/2020 Page 2 of 11 [Site Name] Site MasterFor peer Participant review onlyInformation - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date] Local governance version [Date] (Site PI use only) Page 39 of 57 BMJ Open
1 2 3 This research project has been designed to make sure the researchers interpret the results in a
4 fair and appropriate way and avoids study doctors or participants jumping to conclusions. BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 If you decide that your child can participate in this research project, you and your child will be 7 asked to take part in a number of interviews and procedures over the course of approximately 8 eight months. These are outlined below. You (or another parent/guardian of the child) must 9 attend each session with your child. 10 11 Prior to completing the study, we will need to determine your child’s eligibility to take part in the 12 study. We will do this by asking you questions (either over the phone or via email) about their 13 health. We will also ask you to provide a letter or report confirming your child’s diagnosis of 14 ASD; if you are not able to provide this, we will seek permission (via the consent form) to 15 contact your child’s doctor or psychologist directly to confirm their diagnosis. 16 17 Assessment Session One: The first assessment will take place at [site-specific location]. It will 18 For peer review only 19 take approximately three hours, but your child will be given regular breaks throughout the 20 session. 21 22 We will begin by asking you some questions about your child’s health, which will help to confirm 23 their eligibility to take part in the study. We will then ask you some questions about your child 24 that are relevant to ASD. This will include, for example, what they enjoy doing and how much 25 they like being with other people. 26 27 Your child will complete a short cognitive assessment, which involves solving puzzles and 28 describing what different words mean. 29 30 Finally, your child will undergo electroencephalography (EEG), which involves wearing an 31 “electrode cap” to measure the electrical activity of their brain, or their “brainwaves.” The 32 electrode cap feels similar to a swimming cap. It will also feel a little damp, as we need to put a 33 small amount of gel or saline into the cap to ensure that we get accurate recordings. For most of 34 the EEG your child will simply rest while sitting in a chair, but your child will also complete a 35 short task on a computer that involves looking at different objects (e.g., faces, household 36 http://bmjopen.bmj.com/ furniture, butterflies). 37 38 39 Assessment Session Two: Around one-week after “Assessment Session One” your child will 40 then undergo a magnetic resonance imaging (MRI) brain scan at [site-specific location]. The 41 MRI brain scan takes around 45-60 minutes, during which they will be asked to lie still in an MRI 42 scanner. (Please note that with preparation time you attend the MRI facility for up to two hours.) 43 MRI is a routinely performed, painless ways of examining brain structure and activity. We will
44 use the MRI to accurately place the rTMS device and ensure that we are stimulating the correct on September 27, 2021 by guest. Protected copyright. 45 brain region. The MRI procedure may also help us better understand how the treatment works 46 and to determine who is likely to respond to treatment and why. 47 48 Assessment Session Three: During the same week of “Assessment Session Two,” you and 49 your child will attend a two-hour assessment session at [site-specific location]. Here we will ask 50 you questions about your child, some of which are relevant to ASD, while others relate to their 51 concentration and behaviour. Your child will also be asked some questions about their mood, 52 stress, and satisfaction with life. We will also ask your child to complete some cognitive tasks on 53 a computer/tablet. These tasks measure their memory, attention, and understanding of other 54 people’s emotions. We will also ask your child to provide a sample for genetic analysis; this will 55 involve them having a cotton swab rubbed against the inside of their cheek. These genetic 56 57 analyses are conducted to investigate whether people with certain genetic profiles respond 58 better to the intervention. You will not receive any health information from these genetic 59 analyses, and they are not considered to be clinically informative. 60 rTMS Intervention (4 weeks): The week after “Assessment Session Three” your child will begin the rTMS intervention, which involves attending [site-specific location] and receiving rTMS Master Parent/Guardian Participant Information Sheet/Consent Form 11/09/2020 Page 3 of 11 [Site Name] Site MasterFor peer Participant review onlyInformation - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date] Local governance version [Date] (Site PI use only) BMJ Open Page 40 of 57
1 2 for 3 minutes, 20 seconds each consecutive weekday for a four-week period (20 RTMS 3 sessions in total).
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 Your child will have their first rTMS session on the Monday after “Assessment Session Three.” 6 At the beginning of the first session we will administer transcranial magnetic stimulation (TMS) 7 to the area of the brain that controls the muscles in their hand. This will measure how excitable 8 their brain is and is used to help us determine the personalised settings that will be used for 9 their rTMS treatments. This takes approximately 10 minutes and is not uncomfortable, although 10 they may feel some twitches in the muscle of their hand while the TMS is occurring. 11 12 During each rTMS session your child will be awake, alert, and aware of what is happening at all 13 times. During rTMS a coil will be placed against their head, through which rTMS is administered. 14 This is connected to a machine that sends an electrical current through the coil. The current 15 produces a magnetic field that is very focused and is able to stimulate electrical activity in 16 nerves below the coil. These are usually nerve cells in the outer layers of the brain. The 17 sensations associated with rTMS are mild, and most people describe it as a “tapping” sensation 18 For peer review only 19 on their head. During an rTMS procedure, your child will hear clicking sounds as the current 20 passes through the coil. Your child will wear earplugs so that this noise doesn’t disturb them. 21 22 Including setup time, each subsequent treatment session should only take approximately 10 23 minutes. At the end of each treatment week (i.e., on the Friday session) we will ask you and 24 your child a number of questions about their experience of RTMS, and whether you feel that 25 they have experienced any side effects. 26 27 Assessment Session Four: The week after your child’s last RTMS session, you and your child 28 will attend another two-hour assessment session at [site-specific location]. Here we will again 29 ask you questions about your child, some of which are relevant to ASD, while others relate to 30 their concentration and behaviour. Your child will also be asked some questions about their 31 mood, stress, and satisfaction with life. We will also again ask your child to complete some 32 cognitive tasks on a computer/tablet and to provide another sample (cheek swab) for genetic 33 analysis. 34 35 Assessment Session Five: One-month after your child’s last RTMS session, you and your 36 http://bmjopen.bmj.com/ child will attend another two-hour assessment session at [site-specific location]. This session 37 38 will be identical to Assessment Session Four. 39 40 Assessment Session Six: Three-months after your child’s last RTMS session, you and your 41 child will attend a one-hour assessment session at [site-specific location]. This session will be 42 identical to Assessment Session Five except that your child will not complete the computerised 43 cognitive tasks.
44 on September 27, 2021 by guest. Protected copyright. 45 Assessment Session Seven: Six-months after your child’s last RTMS session, you and your 46 child will attend a final two-hour assessment session at [site-specific location]. This session will 47 be identical to Assessment Session Four. Following the assessment you will be unblinded; that 48 is, a member of the research team will tell you and your child which treatment condition your 49 child received (i.e., real or sham/placebo). If your child received the real treatment, you and your 50 child’s involvement in the study will conclude. If your child received the sham/placebo condition, 51 your child will be given the opportunity to receive the real treatment. You can liaise with 52 research staff to determine when you would like your child to undergo this four-week treatment. 53 54 There are no costs associated with participating in this research project. All treatments, tests, 55 and medical care required as part of the research project will be provided to your child free of 56 57 charge. 58 59 You will not be paid for you and your child’s participation in this research, but you will be 60 reimbursed $200 to contribute towards costs that you incur as a result of participating in this research project (e.g., travel). If you complete only part of the study and then decide to
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1 2 withdraw, you will be reimbursed a proportion of this amount based on the proportion of the 3 study completed.
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 Please note that no study procedures will be performed until consent has been obtained. 6 7 It is desirable that your child’s local doctor be advised of your decision for your child to 8 participate in this research project. If you have a local doctor, we strongly recommend that you 9 inform them of your child’s participation in this research project. 10 11 The research will be monitored by an independent Data Safety Monitoring Board, who will meet 12 twice per year and review the conduct of the trial, monitor study data, and review any serious 13 adverse events that might arise throughout the trial. 14 15 4 What does the child have to do? 16 17 Your child will be able to continue taking their usual medication if they participate in this study, 18 For peer review only 19 but you will need to inform us of any changes to this medication that occur during their 20 participation in the study. 21 22 There are several reasons why your child may not be able to take part in this study. These 23 include: 24 25 The presence of metal anywhere in the head (except the mouth) 26 A history of seizure or epilepsy, or evidence of significant seizure activity as assessed by 27 EEG 28 A history of serious head injury 29 30 The presence of certain implanted medical devices (e.g., cardiac pacemaker, medication 31 pumps) 32 Serious heart disease (as there is an increased risk of serious injury in the event of a 33 seizure) 34 Being deemed unsuitable to undergo MRI (e.g., due to presence of metal in the body) 35 Unstable medical condition 36 Unstable medication regime http://bmjopen.bmj.com/ 37 Certain medications 38 39 Substance use disorder 40 Undergoing another current treatment for social communication 41 Employment as a professional driver or machine operator (as the event of a seizure may 42 affect employment) 43 Pregnancy (female participants for whom child-bearing is a possibility will be required to
44 undergo a urine screen) on September 27, 2021 by guest. Protected copyright. 45 Certain neurological or psychiatric diagnoses (i.e., those not commonly associated with 46 ASD, such as psychosis) 47 A measured verbal intelligence quotient (IQ) of less than 55 48 49 5 Other relevant information about the research project 50 51 52 This study is only taking place in Australia. There will be 150 participants in this study, with 30 53 taking part in each of the five cities involved: Brisbane, Sydney, Melbourne, Adelaide, and 54 Perth. There are a total of 14 organisations involved, including Universities, hospitals, and 55 medical centres. This study is a follow-on study from our previous trials of rTMS in ASD, which 56 have taken place at Monash University, Deakin University, The Alfred hospital, and the Epworth 57 Camberwell. 58 59 6 Does the child have to take part in this research project? 60
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1 2 Participation in any research project is voluntary. If you do not wish for the child to take part, 3 they do not have to. If you decide that they can take part and later change your mind, you are
4 free to withdraw the child from the project at any stage. BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 If you do decide that the child can take part, you will be given this Participant Information and 7 Consent Form to sign and you will be given a copy to keep. If your child has the capacity to 8 provide informed consent, they may also sign the consent form. 9 10 Your decision that the child can or cannot take part, or that they can take part and then be 11 withdrawn, will not affect their routine treatment, relationship with those treating them, or their 12 relationship with [site-specific Institution/s]. 13 14 7 What are the possible benefits of taking part? 15 16 We cannot guarantee or promise that your child will receive any benefits from this research; 17 however, possible benefits include an improvement in social understanding and functioning, 18 For peer review only 19 including an increased ability to accurately infer what other people are thinking or feeling. 20 21 8 What are the possible risks and disadvantages of taking part? 22 23 Repetitive Transcranial Magnetic Stimulation (rTMS) 24 25 Medical treatments often cause side effects. Your child may have none, some, or all of the 26 effects listed below, and they may be mild, moderate, or severe. If your child has any of these 27 side effects, or you are worried about them, talk with your study doctor. Your child’s study doctor 28 will also be looking out for side effects. 29 30 There may be side effects that the researchers do not expect or do not know about and that 31 may be serious. Tell your study doctor immediately about any new or unusual symptoms that 32 your child gets. 33 34 Many side effects go away shortly after treatment ends. However, sometimes side effects can 35 be serious, long lasting, or permanent. If a severe side effect or reaction occurs, your study 36 http://bmjopen.bmj.com/ doctor may need to stop your child’s treatment. The child’s study doctor will discuss the best 37 38 way of managing any side effects with you. 39 40 Noise: The clicking noise made by the coil may be uncomfortable. Your child will wear 41 earplugs during treatment to minimise any discomfort. 42 43 Headache: A headache can occur during rTMS and is thought to affect approximately
44 3% or 3 in 100 participants. It is thought to be caused by stimulation of nerves in the on September 27, 2021 by guest. Protected copyright. 45 scalp. If your child were to experience such a headache, it will respond quickly to simple 46 pain medication such as aspirin, ibuprofen, or paracetamol. 47 48 Scalp Sensation: During the treatment itself, your child might feel a tapping or twitching 49 sensation on their scalp as the magnetic pulse stimulates muscles in their scalp as it 50 passes into the brain. This sensation varies between people from very soft to quite 51 strong. If your child finds it uncomfortable, we will use a lower stimulation intensity and 52 only increase it as they find it tolerable. 53 54 Seizure: The main concern associated with rTMS is its potential to induce a fit or 55 seizure. This risk is extremely low, but is increased for those with a history of seizure 56 57 activity (where a seizure resulting from rTMS affects about 2% or 2 in 100 such 58 individuals). If your child has ever experienced a seizure, or if their EEG shows evidence 59 of epileptiform activity, they will not be able to take part in this study. Investigators using 60 rTMS have developed safety guidelines to minimise the risk of seizure. The RTMS we provide is well within what is considered to be safe. It is important to note that experiencing a seizure induced by rTMS has never led to the development of epilepsy or Master Parent/Guardian Participant Information Sheet/Consent Form 11/09/2020 Page 6 of 11 [Site Name] Site MasterFor peer Participant review onlyInformation - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date] Local governance version [Date] (Site PI use only) Page 43 of 57 BMJ Open
1 2 increased the probability of having subsequent unprovoked seizures. There will always 3 be medically trained staff available when your child has rTMS. Staff will monitor your
4 child and know how to treat a seizure should one occur. BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 The effects of rTMS on the unborn child and on the newborn baby are not known. Because of 7 this, it is important that research project participants are not pregnant or breast-feeding and do 8 not become pregnant during the course of the research project. Individuals must not participate 9 in the research if they are pregnant or trying to become pregnant, or breast-feeding. If your child 10 is female and child-bearing is a possibility, they will be required to undergo a urinal pregnancy 11 test prior to commencing rTMS. This test will be processed by a female member of the research 12 staff. 13 14 If a participant becomes pregnant whilst participating in the research project, they should advise 15 research staff immediately. The researchers will withdraw them from the research project and 16 advise on further medical attention should this be necessary. An individual must not continue in 17 the research if they become pregnant. 18 For peer review only 19 20 The ability to drive or use public transport will not be impaired following rTMS. 21 22 It is also possible that there are unknown risks of rTMS. 23 24 Magnetic Resonance Imaging (MRI) 25 26 MRI stands for magnetic resonance imaging. An MRI scanner is a machine that uses 27 electromagnetic radiation (radio waves) in a strong magnetic field to take clear pictures of the 28 inside of the body. Electromagnetic radiation is not the same as ionising radiation used, for 29 example, in X-rays. The pictures taken by the machine are called MRI scans. 30 31 There are no proven long-term risks related to MRI scans as used in this research project. MRI 32 is considered to be safe when performed at a centre with appropriate procedures. However, the 33 magnetic attraction for some metal objects can pose a safety risk, so it is important that metal 34 objects are not taken into the scanner room. 35
36 http://bmjopen.bmj.com/ We will thoroughly examine your child to make sure there is no reason for them not to have the 37 38 scan. You must tell us if your child has metal implanted in their body, such as a pacemaker or 39 metal pins. 40 41 The MRI scanner is shaped like a narrow tunnel. Foam cushioning and Velcro straps are used 42 to keep your child’s head relatively still during scanning. While the mask, cushions and straps 43 are restraining, they should not be uncomfortable. Some people may experience claustrophobia
44 while having an MRI scan. Please let us know if your child has experienced claustrophobia in on September 27, 2021 by guest. Protected copyright. 45 the past. The MRI scanner is noisy, so your child will wear ear plugs and headphones to reduce 46 the noise. We will be able to see your child and communicate with them during the scanning, 47 and they will be able to stop the machine at any time by pushing a button. If they become 48 uncomfortable during the session, we can pause or stop the scanning. 49 50 The scans we are taking are for research purposes. They are not intended to be used like scans 51 taken for a full clinical examination. The scans will not be used to help diagnose, treat, or 52 manage a particular condition. A specialist will look at your child’s MRI scans for features 53 relevant to the research project. On rare occasions, the specialist may find an unusual feature 54 that could have a significant risk to your child’s health. If this happens, we will contact you to talk 55 about the findings. We cannot guarantee that we will find any/all unusual features. There may 56 57 be wider implications from abnormal findings (e.g., for future applications for some kinds of 58 insurance). 59 60 Other
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1 2 We will ask you and your child if they have used illegal drugs. That information will be stored in 3 a re-identifiable (or coded) format. In the event that the researchers are required to disclose that
4 information, it may be used against them in legal proceedings or otherwise. BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 If you or your child become upset or distressed as a result of your participation in the research, 7 the study doctor will be able to arrange for counselling or other appropriate support. Any 8 counselling or support will be provided by qualified staff who are not members of the research 9 project team. This counselling will be provided free of charge. 10 11 9 What will happen to the child’s test samples? 12 13 You will be asked to provide additional consent for the collection of your child’s tissue (i.e., 14 cheek swab) during the research project. As noted, these samples are collected to allow us to 15 investigate whether certain genetic profiles are associated with a better response to the rTMS 16 intervention. We will only conduct these analyses at a group level. You will not receive any 17 health information (e.g., genetic disease predisposition) from these genetic analyses, and they 18 For peer review only 19 are not considered to be clinically informative. Your child’s genetic material and information, 20 where identified or potentially identifiable, will not be released for other uses without your prior 21 consent, unless required by law. 22 23 Samples of your child’s tissue obtained for the purpose of this research project will be 24 transferred to the Institute for Molecular Bioscience, University of Queensland, who will charge a 25 fee to the research team to recover some of the costs of storing and administering the tissue 26 samples. The University of Queensland will not transfer or sell your child’s samples to any third 27 party. 28 29 10 What if new information arises during this research project? 30 31 Sometimes during the course of a research project, new information becomes available about 32 the treatment that is being studied. If this happens, your child’s study doctor will tell you about it 33 and discuss with you whether you want your child to continue in the research project. If you 34 decide to withdraw your child from the study, your child’s study doctor will make arrangements 35 for their regular health care to continue. If you decide to continue your child’s involvement in the 36 http://bmjopen.bmj.com/ research project you will be asked to sign an updated consent form. 37 38 39 Also, on receiving new information, your child’s study doctor might consider it to be in your 40 child’s best interests to withdraw them from the research project. If this happens, your child’s 41 study doctor will explain the reasons and arrange for your regular health care to continue. 42 43 11 Can the child have other treatments during this research project?
44 on September 27, 2021 by guest. Protected copyright. 45 Whilst your child is participating in this research project, they can continue to take the 46 medications or treatments they have been taking for their condition or for other reasons. It is 47 important to tell the research staff about any treatments or medications your child is taking, 48 including over-the-counter medications, vitamins or herbal remedies, acupuncture, or other 49 alternative treatments. You should also tell the study staff about any changes to these during 50 your child’s participation in the research project. 51 52 Because this trial is assessing the effect of rTMS on social communication, your child cannot 53 participate if they are also undergoing any other treatment or intervention for social 54 communication. This includes interventions delivered by psychologists. 55 56 57 12 What if I withdraw the child from this research project? 58 59 If you decide to withdraw your child from the project, please notify a member of the research 60 team before you withdraw. This notice will allow that person or the research supervisor to discuss any health risks or special requirements linked to withdrawing.
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1 2 If you do withdraw your consent for your child’s participation during the research project, the 3 study doctor and relevant study staff will not collect additional personal information from you or
4 your child, although personal information already collected will be retained to ensure that the BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 results of the research project can be measured properly and to comply with law. You should be 6 aware that data collected up to the time you withdraw your child will form part of the research 7 project results. If you do not want them to do this, you must tell the researchers before your 8 child joins the research project. 9 10 13 Could this research project be stopped unexpectedly? 11 12 This research project may be stopped unexpectedly for a variety of reasons. These may include 13 reasons such as: 14 15 • Unacceptable side effects 16 • The drug/treatment/device being shown not to be effective 17 • The drug/treatment/device being shown to work and not need further testing 18 For peer review only 19 • Decisions made by local regulatory/health authorities. 20 21 14 What happens when the research project ends? 22 23 You will be sent a summary of the main findings when the project has been completed. This is a 24 4-year study and it is expected that study results will be available by late 2024. Your child’s data 25 will then be securely archived at Deakin University. 26 27 Please note that RTMS will not be available from the research sites after completing the study. 28 It may be approved for future use in ASD, but this will depend on the results from the current 29 study. 30 31 Part 2 How is the research project being conducted? 32 33 34 15 What will happen to information about my child? 35
36 By signing the consent form, you consent to the study doctor and relevant research staff http://bmjopen.bmj.com/ 37 collecting and using personal information about your child for the research project. Any 38 information obtained in connection with this research project that can identify your child will 39 remain confidential. Upon enrolment in the trial your child will be allocated a unique study 40 identification code. Your child’s name will not appear with the research data that we collect from 41 you and them, and it will only be possible to re-identify your child’s data using the study code. 42 Only the research team will know which code identifies which participant. Your child’s 43 information will only be used for the purpose of this research project and future research
44 projects, and it will only be disclosed with your permission, except as required by law. on September 27, 2021 by guest. Protected copyright. 45 46 Information about your child may be obtained from your child’s health records held at this and 47 other health services for the purpose of this research. By signing the consent form, you agree to 48 the study team accessing your child’s health records if they are relevant to your child’s 49 participation in this research project. 50 51 52 Your child’s health records and any information obtained during the research project are subject 53 to inspection (for the purpose of verifying the procedures and the data) by the relevant 54 authorities and authorised representatives of the Sponsor, Deakin University, the institution 55 relevant to this Participant Information Sheet, [Name of institution], or as required by law. By 56 signing the Consent Form, you authorise release of, or access to, this confidential information to 57 the relevant study personnel and regulatory authorities as noted above. 58 59 It is anticipated that the results of this research project will be published and/or presented in a 60 variety of forums. In any publication and/or presentation, information will be provided in such a way that your child cannot be identified, except with your permission. We will only present
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1 2 group-level findings (e.g., average scores across the group) and no individual data will be 3 reported.
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 In accordance with relevant Australian and/or [Name of state/territory] privacy and other relevant 6 laws, you have the right to request access to your child’s information collected and stored by the 7 research team. You also have the right to request that any information with which you disagree 8 be corrected. Please contact the study team member named at the end of this document if you 9 would like to access your child’s information. 10 11 Any information obtained for the purpose of this research project and for future research that 12 can identify your child will be treated as confidential and securely stored. It will be disclosed 13 only with your permission, or as required by law. 14 15 It is expected that deidentified data from this study will be made available to other researchers 16 via online data repositories. Your child will not be able to be identified in these repositories. It is 17 also possible that the research team will use your child’s data from this research project for 18 For peer review only 19 future studies, but again they will not be able to be identified. 20 21 16 Complaints and compensation 22 23 If your child suffer any injuries or complications as a result of this research project, you should 24 contact the study team as soon as possible and you will be assisted with arranging appropriate 25 medical treatment. If you are eligible for Medicare, you can receive any medical treatment 26 required to treat the injury or complication, free of charge, as a public patient in any Australian 27 public hospital. 28 29 If you have complaints about you or your child’s treatment by members of staff working on this 30 research project, you should contact the person nominated in Section 19 below. If you have 31 complaints about any of the ethical aspects of this study, you can contact the local reviewing 32 HREC Executive Officer nominated in Section 19 below. Complaints about clinical trials can 33 also be directed to the Office of the Australian Information Commissioner. 34 35 17 Who is organising and funding the research? 36 http://bmjopen.bmj.com/ 37 38 This research project is being conducted by a team of researchers led by Prof. Peter Enticott 39 from Deakin University, Victoria. It is funded through a Medical Research Future Fund grant 40 from the National Health and Medical Research Council to Prof. Enticott and the research team. 41 42 No member of the research team will receive a personal financial benefit from your child’s 43 involvement in this research project (other than their ordinary wages).
44 on September 27, 2021 by guest. Protected copyright. 45 18 Who has reviewed the research project? 46 47 All research in Australia involving humans is reviewed by an independent group of people called 48 a Human Research Ethics Committee (HREC). The ethical aspects of this research project 49 have been approved by the HREC of Monash Health and [Name of institutions]. 50 51 This project will be carried out according to the National Statement on Ethical Conduct in 52 Human Research (2018). This statement has been developed to protect the interests of people 53 who agree to participate in human research studies. 54 55 19 Further information and who to contact 56 57 58 The person you may need to contact will depend on the nature of your query. 59 60 If you want any further information concerning this project or if your child has any medical problems that may be related to their involvement in the project (for example, any side effects),
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1 2 you can contact your site’s principal study doctor on [phone number] or any of the following 3 people:
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 Study contact person 6 Name [Name] 7 Position [Position] 8 Telephone [Phone number] 9 Email [Email address] 10 11 Clinical contact person 12 13 Name [Name] 14 Position [Position] 15 Telephone [Phone number] 16 Email [Email address] 17 18 For matters relating toFor research peer at the site reviewat which you are onlyparticipating, the details of the local 19 site complaints person are: 20 21 Complaints contact person 22 Name [Name] 23 24 Position [Position] 25 Telephone [Phone number] 26 Email [Email address] 27 28 If you have any complaints about any aspect of the project, the way it is being conducted or any 29 questions about being a research participant in general, then you may contact: 30 31 Reviewing HREC approving this research and HREC Executive Officer details 32 33 Reviewing HREC name Monash Health 34 HREC Executive Officer Ms Deborah Dell 35 Telephone (03) 9594 4605
36 Email [email protected] http://bmjopen.bmj.com/ 37 38 Local HREC Office contact (Single Site - Research Governance Officer) 39 40 Name [Name] 41 Position [Position] 42 Telephone [Phone number] 43 Email [Email address]
44 on September 27, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 Consent Form - Adult providing own consent 3 Does repetitive transcranial magnetic stimulation 4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from (rTMS), compared to sham rTMS, improve social 5 Title 6 communication in adolescents and young adults 7 with autism spectrum disorder (ASD)? 8 Short Title MRFF RTMS-ASD 9 10 Protocol Number v2, 11/09/2020 11 Project Sponsor Deakin University 12 Coordinating Principal Investigator Prof. Peter Enticott 13 14 Prof. Paul Fitzgerald, A/Prof. Karen Barlow, Prof. 15 Ian Hickie, Dr Melissa Licari, Dr Nigel Rogasch, 16 Prof. Christel Middeldorp, Dr Scott Clark, Dr Ann- 17 Maree Vallence, Dr Kelsie Boulton, Prof. Adam 18 Associate Investigator(s)For peer Guastella,review Prof. Andrew only Whitehouse, Prof. 19 Cherrie Galletly, Dr Gail Alvares, Dr Hakuei 20 Fujiyama, A/Prof. Helen Heussler, A/Prof. Jeffrey 21 Craig, Dr Melissa Kirkovski, Dr Natalie Mills, Prof. 22 Nicole Rinehart, Dr Peter Donaldson, Dr Talitha 23 Ford, Prof. Karen Caeyenberghs 24 25 Location [Location where the research will be conducted] 26 27 28 Consent Agreement 29 I have read the Participant Information Sheet or someone has read it to me in a language that I 30 understand. 31 32 I understand the purposes, procedures and risks of the research described in the project. 33 I give permission for the child’s doctors, other health professionals, hospitals or laboratories 34 outside this hospital to release information to [Name of Institution] concerning the child’s 35 disease and treatment for the purposes of this project. I understand that such information will 36 http://bmjopen.bmj.com/ 37 remain confidential. 38 39 I have had an opportunity to ask questions and I am satisfied with the answers I have received. 40 I freely agree to the child participating in this research project as described and understand that 41 I am free to withdraw them at any time during the research project without affecting their future 42 43 health care.
44 on September 27, 2021 by guest. Protected copyright. 45 I freely agree to participate in this research project as described (e.g., completion of 46 questionnaires) and understand that I am free to withdraw at any time during the study without 47 affecting my future health care. 48 49 I understand that I will be given a signed copy of this document to keep. 50 51 I agree for my child’s anonymous study data to be shared with other researchers, including 52 those outside [Name of Institution] and outside Australia, for future studies. 53 54 I agree to my child’s anonymised data being made available through online repositories and to 55 the use of my data in any future research. 56 57 58 59 60
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1 Declaration by Parent/Guardian – for Parent/Guardian who has read the information 2 3
4 Name of Child (please print) BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Name of Parent/Guardian (please print) 7 8 Signature of Parent/Guardian Date 9 10 11 Declaration by Young Person – for participants under the age of 18 who have capacity to 12 provide informed consent 13 14 15 16 Name of Young Person (please print) 17 18 Signature of YoungFor Person peer review only Date 19 20 21 22 Declaration by Study Doctor/Senior Researcher† 23 I have given a verbal explanation of the research project, its procedures and risks and I believe 24 that the participant has understood that explanation. 25 26 Name of Study Doctor/ 27 Senior Researcher† (please print) 28 29 30 Signature Date 31 † A senior member of the research team must provide the explanation of, and information concerning, the research 32 project. 33 Note: All parties signing the consent section must date their own signature. 34 35
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1 I consent to the storage and use of tissue samples (cheek swabs) taken from my child for use, 2 as described in the relevant section of the Participant Information Sheet, for: 3 • This specific research project
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from • Other research that is closely related to this research project 5 6 • Any future research. 7 By signing this consent section, I agree to the use of my child’s tissue samples for genetic 8 testing, as outlined in the relevant Section of the Participant Information Sheet. 9 10 11 12 Name of Child (please print) 13 14 Name of Parent/Guardian (please print) 15 16 Signature of Parent/Guardian Date 17 18 For peer review only 19 20 21 Name of Young Person (please print) 22 23 Signature of Young Person Date 24 25 26 27 Name of Study Doctor/ 28 Senior Researcher† (please print) 29 30 Signature Date 31 32 † A senior member of the research team must provide the explanation of and information concerning the research 33 project. 34 Note: All parties signing the consent section must date their own signature. 35
36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43
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1 2 Form for Withdrawal of Participation - Parent/Guardian consenting on 3 behalf of participant
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 Does repetitive transcranial magnetic stimulation 6 (rTMS), compared to sham rTMS, improve social Title 7 communication in adolescents and young adults 8 with autism spectrum disorder (ASD)? 9 10 Short Title MRFF RTMS-ASD 11 Protocol Number v2, 11/09/2020 12 Project Sponsor Deakin University 13 14 Coordinating Principal Investigator Prof. Peter Enticott 15 16 Prof. Paul Fitzgerald, A/Prof. Karen Barlow, Prof. 17 Ian Hickie, Dr Melissa Licari, Dr Nigel Rogasch, 18 For peer Prof.review Christel Middeldorp, only Dr Scott Clark, Dr Ann- 19 Maree Vallence, Dr Kelsie Boulton, Prof. Adam 20 Associate Investigator(s) Guastella, Prof. Andrew Whitehouse, Prof. 21 Cherrie Galletly, Dr Gail Alvares, Dr Hakuei 22 Fujiyama, A/Prof. Helen Heussler, A/Prof. Jeffrey 23 Craig, Dr Melissa Kirkovski, Dr Natalie Mills, Prof. 24 Nicole Rinehart, Dr Peter Donaldson, Dr Talitha 25 Ford, Prof. Karen Caeyenberghs 26 27 Location (where CPI/PI will recruit) [Location where the research will be conducted] 28 29 Declaration by Participant 30 31 32 I wish to withdraw from participation in the above research project and understand that such 33 withdrawal will not affect my routine treatment, my relationship with those treating me or my 34 relationship with [Institution]. 35
36 Name of Child (please print) http://bmjopen.bmj.com/ 37 38 Name of Parent/Guardian (please print) 39 40 Signature of Parent/Guardian Date 41 42 43
44 on September 27, 2021 by guest. Protected copyright. 45 Name of Young Person (please print) 46 47 Signature of Young Person Date 48 49 50 Description of circumstances where communicated verbally: 51 52 53 54 55 ***Continued on next page*** 56 57 58 59 60
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1 Declaration by Study Doctor/Senior Researcher† 2 I have given a verbal explanation of the implications of withdrawal from the research project and 3 I believe that the participant has understood that explanation.
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Name of Study Doctor/ 7 Senior Researcher† (please print) 8 9 Signature Date 10 11 † A senior member of the research team must provide the explanation of and information concerning withdrawal from 12 the research project. 13 Note: All parties signing the consent section must date their own signature. 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43
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1 2 3 BIOLOGICAL SPECIMENS
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Participants will be administered a buccal swab on two occasions, which involves rubbing a 7 cotton bud against the inside of the cheek. These will be collected in person by a member of 8 the research team at each site. Specimens will then be sealed in a DNA/RNA Shield tube and 9 labelled with the participant’s unique study identification code. It will then be transported 10 11 by courier/post to the Institute of Molecular Bioscience, University of Queensland, for 12 extraction, storage, and analysis. 13 14 Numerical data arising from genetic and epigenetic analyses will be sent electronically to 15 16 the research team (Chief Investigators Prof. Enticott and Prof. Middeldorp) and stored in 17 REDCap databases. PDF files containing results will also be stored in REDCap. 18 For peer review only 19 The research team will retain all biospecimens, which will be securely stored at the Institute 20 of Molecular Bioscience, University of Queensland. This will allow the possibility of future 21 22 analyses, particularly to determine genetic and epigenetic factors associated with a clinical 23 response to the TBS intervention. The research team may contribute results from these data 24 to future collaborative projects, which may involve external researchers who are not 25 involved in the current trial. No information that could identify a participant will be shared. 26 27 Participants (and their parent/guardian where necessary) will be asked to provide 28 permission for future biospecimen use as part of the informed consent procedure. 29 30 31 32 33 34 35
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1 2 3
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 7 8 SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and 9 related documents* 10 11 Section/item Item Description Page Number 12 No on which item 13 is reported 14 15 Administrative information 16 17 Title 1 Descriptive title identifying the study design, 1 18 Forpopulation, peer interventions, review and, if applicable, only trial 19 20 acronym 21 22 Trial 2a Trial identifier and registry name. If not yet registered, 2 23 registration name of intended registry 24 25 2b All items from the World Health Organization Trial n/a 26 Registration Data Set 27 28 Protocol 3 Date and version identifier 1 29 version 30 31 Funding 4 Sources and types of financial, material, and other 15 32 33 support 34 35 Roles and 5a Names, affiliations, and roles of protocol contributors 1
36 responsibilitie http://bmjopen.bmj.com/ 5b Name and contact information for the trial sponsor 15 37 s 38 39 5c Role of study sponsor and funders, if any, in study 15 40 design; collection, management, analysis, and 41 42 interpretation of data; writing of the report; and the 43 decision to submit the report for publication, including
44 whether they will have ultimate authority over any of on September 27, 2021 by guest. Protected copyright. 45 these activities 46 47 5d Composition, roles, and responsibilities of the 7, 13 48 49 coordinating centre, steering committee, endpoint 50 adjudication committee, data management team, and 51 other individuals or groups overseeing the trial, if 52 applicable (see Item 21a for data monitoring 53 54 committee) 55 56 Introduction 57 58 59 60
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1 2 Background 6a Description of research question and justification for 4-6 3 and rationale undertaking the trial, including summary of relevant
4 studies (published and unpublished) examining BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 benefits and harms for each intervention 7 8 6b Explanation for choice of comparators 7 9 10 Objectives 7 Specific objectives or hypotheses 6 11 12 Trial design 8 Description of trial design including type of trial (eg, 6-10 13 parallel group, crossover, factorial, single group), 14 allocation ratio, and framework (eg, superiority, 15 equivalence, noninferiority, exploratory) 16 17 18 Methods: Participants,For interventions, peer andreview outcomes only 19 20 Study setting 9 Description of study settings (eg, community clinic, 6 21 academic hospital) and list of countries where data 22 will be collected. Reference to where list of study sites 23 24 can be obtained 25 26 Eligibility 10 Inclusion and exclusion criteria for participants. If 7-8 27 criteria applicable, eligibility criteria for study centres and 28 individuals who will perform the interventions (eg, 29 surgeons, psychotherapists) 30 31 Interventions 11a Interventions for each group with sufficient detail to 7 32 33 allow replication, including how and when they will be 34 administered 35
36 11b Criteria for discontinuing or modifying allocated n/a http://bmjopen.bmj.com/ 37 interventions for a given trial participant (eg, drug 38 dose change in response to harms, participant 39 40 request, or improving/worsening disease) 41 42 11c Strategies to improve adherence to intervention n/a 43 protocols, and any procedures for monitoring 44 adherence (eg, drug tablet return, laboratory tests) on September 27, 2021 by guest. Protected copyright. 45 46 11d Relevant concomitant care and interventions that are 8 47 48 permitted or prohibited during the trial 49 50 Outcomes 12 Primary, secondary, and other outcomes, including 8-9 51 the specific measurement variable (eg, systolic blood 52 pressure), analysis metric (eg, change from baseline, 53 final value, time to event), method of aggregation (eg, 54 55 median, proportion), and time point for each outcome. 56 Explanation of the clinical relevance of chosen 57 efficacy and harm outcomes is strongly recommended 58 59 60
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1 2 Participant 13 Time schedule of enrolment, interventions (including Table 1, 11-12 3 timeline any run-ins and washouts), assessments, and visits
4 for participants. A schematic diagram is highly BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 recommended (see Figure) 7 8 Sample size 14 Estimated number of participants needed to achieve 6 9 study objectives and how it was determined, including 10 clinical and statistical assumptions supporting any 11 sample size calculations 12 13 Recruitment 15 Strategies for achieving adequate participant 7 14 15 enrolment to reach target sample size 16 17 Methods: Assignment of interventions (for controlled trials) 18 For peer review only 19 Allocation: 20 21 Sequence 16a Method of generating the allocation sequence (eg, 9 22 generation computer-generated random numbers), and list of any 23 factors for stratification. To reduce predictability of a 24 random sequence, details of any planned restriction 25 26 (eg, blocking) should be provided in a separate 27 document that is unavailable to those who enrol 28 participants or assign interventions 29 30 Allocation 16b Mechanism of implementing the allocation sequence 9 31 concealme (eg, central telephone; sequentially numbered, 32 33 nt opaque, sealed envelopes), describing any steps to 34 mechanis conceal the sequence until interventions are assigned 35 m
36 http://bmjopen.bmj.com/ 37 Implement 16c Who will generate the allocation sequence, who will 9 38 39 ation enrol participants, and who will assign participants to 40 interventions 41 42 Blinding 17a Who will be blinded after assignment to interventions 10 43 (masking) (eg, trial participants, care providers, outcome 44 assessors, data analysts), and how on September 27, 2021 by guest. Protected copyright. 45 46 17b If blinded, circumstances under which unblinding is 10 47 48 permissible, and procedure for revealing a 49 participant’s allocated intervention during the trial 50 51 Methods: Data collection, management, and analysis 52 53 54 55 56 57 58 59 60
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1 2 Data 18a Plans for assessment and collection of outcome, 8-9 3 collection baseline, and other trial data, including any related
4 methods processes to promote data quality (eg, duplicate BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 measurements, training of assessors) and a 7 description of study instruments (eg, questionnaires, 8 laboratory tests) along with their reliability and validity, 9 if known. Reference to where data collection forms 10 11 can be found, if not in the protocol 12 13 18b Plans to promote participant retention and complete 9 14 follow-up, including list of any outcome data to be 15 collected for participants who discontinue or deviate 16 from intervention protocols 17 18 Data 19 ForPlans forpeer data entry, review coding, security, only and storage, 9-10 19 20 management including any related processes to promote data 21 quality (eg, double data entry; range checks for data 22 values). Reference to where details of data 23 management procedures can be found, if not in the 24 25 protocol 26 27 Statistical 20a Statistical methods for analysing primary and 9 28 methods secondary outcomes. Reference to where other 29 details of the statistical analysis plan can be found, if 30 not in the protocol 31 32 20b Methods for any additional analyses (eg, subgroup 9-10 33 34 and adjusted analyses) 35
36 20c Definition of analysis population relating to protocol 9 http://bmjopen.bmj.com/ 37 non-adherence (eg, as randomised analysis), and any 38 statistical methods to handle missing data (eg, 39 multiple imputation) 40 41 Methods: Monitoring 42 43 Data 21a Composition of data monitoring committee (DMC); 13 44 on September 27, 2021 by guest. Protected copyright. 45 monitoring summary of its role and reporting structure; statement 46 of whether it is independent from the sponsor and 47 competing interests; and reference to where further 48 49 details about its charter can be found, if not in the 50 protocol. Alternatively, an explanation of why a DMC 51 is not needed 52 53 21b Description of any interim analyses and stopping 9 54 guidelines, including who will have access to these 55 56 interim results and make the final decision to 57 terminate the trial 58 59 60
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1 2 Harms 22 Plans for collecting, assessing, reporting, and 13 3 managing solicited and spontaneously reported
4 adverse events and other unintended effects of trial BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 interventions or trial conduct 7 8 Auditing 23 Frequency and procedures for auditing trial conduct, if n/a 9 any, and whether the process will be independent 10 from investigators and the sponsor 11 12 13 Ethics and dissemination 14 Research 24 Plans for seeking research ethics 13 15 16 ethics committee/institutional review board (REC/IRB) 17 approval approval 18 For peer review only 19 Protocol 25 Plans for communicating important protocol 13 20 amendments modifications (eg, changes to eligibility criteria, 21 outcomes, analyses) to relevant parties (eg, 22 23 investigators, REC/IRBs, trial participants, trial 24 registries, journals, regulators) 25 26 Consent or 26a Who will obtain informed consent or assent from 7 27 assent potential trial participants or authorised surrogates, 28 29 and how (see Item 32) 30 31 26b Additional consent provisions for collection and use of Appendix 32 participant data and biological specimens in ancillary 33 studies, if applicable 34 35 Confidentiality 27 How personal information about potential and enrolled 9 36 participants will be collected, shared, and maintained http://bmjopen.bmj.com/ 37 38 in order to protect confidentiality before, during, and 39 after the trial 40 41 Declaration of 28 Financial and other competing interests for principal 15 42 interests investigators for the overall trial and each study site 43
44 Access to 29 Statement of who will have access to the final trial 10 on September 27, 2021 by guest. Protected copyright. 45 data dataset, and disclosure of contractual agreements 46 47 that limit such access for investigators 48 49 Ancillary and 30 Provisions, if any, for ancillary and post-trial care, and 13 50 post-trial care for compensation to those who suffer harm from trial 51 participation 52 53 Dissemination 31a Plans for investigators and sponsor to communicate 13-14 54 policy trial results to participants, healthcare professionals, 55 56 the public, and other relevant groups (eg, via 57 publication, reporting in results databases, or other 58 data sharing arrangements), including any publication 59 restrictions 60
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1 2 31b Authorship eligibility guidelines and any intended use 13 3 of professional writers
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 31c Plans, if any, for granting public access to the full 10, 14 6 protocol, participant-level dataset, and statistical code 7 8 9 Appendices 10 11 Informed 32 Model consent form and other related documentation Appendix 12 consent given to participants and authorised surrogates 13 materials 14 15 Biological 33 Plans for collection, laboratory evaluation, and Appendix 16 specimens storage of biological specimens for genetic or 17 18 Formolecular peer analysis reviewin the current trial only and for future 19 use in ancillary studies, if applicable 20 21 *It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 22 Explanation & Elaboration for important clarification on the items. Amendments to the 23 protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT 24 Group under the Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 Unported” 25 26 license. 27 28 29 30 31 32 33 34 35
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Repetitive transcranial magnetic stimulation (rTMS) in autism spectrum disorder: protocol for a multicentre randomised controlled clinical trial ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2020-046830.R1
Article Type: Protocol
Date Submitted by the 18-Apr-2021 Author:
Complete List of Authors: Enticott, Peter; Deakin University School of Psychology Barlow, Karen; The University of Queensland Child Health Research Centre, Child Health Research Centre; Children's Health Queensland Hospital and Health Service Guastella, Adam; The University of Sydney Brain and Mind Centre, Clinical Research Unit Licari, Melissa; Telethon Kids Institute Rogasch, Nigel; The University of Adelaide Adelaide Medical School; South Australian Health and Medical Research Institute Middeldorp, Christel; The University of Queensland Child Health Research Centre; Children's Health Queensland Hospital and Health Service
Clark, Scott; The University of Adelaide Adelaide Medical School http://bmjopen.bmj.com/ Vallence, Ann-Maree; Murdoch University, School of Psychology and Exercise Sciences; Murdoch University, Centre for Molecular Medicine and Innovative Therapeutics Boulton, Kelsie; The University of Sydney Brain and Mind Centre Hickie, Ian; The University of Sydney Brain and Mind Centre, Brain and Mind Centre Whitehouse, Andrew; Telethon Kids Institute; Cooperative Research Centre for Living With Autism
Galletly, Cherrie; The University of Adelaide Adelaide Medical School on September 27, 2021 by guest. Protected copyright. Alvares, Gail; Telethon Kids Institute Fujiyama, Hakuei; Murdoch University, School of Psychology and Exercise Sciences Heussler, Helen; The University of Queensland Child Health Research Centre, Child Development; Children's Health Queensland Hospital and Health Service, Centre fro Children's Health Research Craig, Jeffrey; Deakin University School of Medicine, School of Psychology Kirkovski, Melissa; Deakin University School of Psychology Mills, Natalie; The University of Adelaide Adelaide Medical School Rinehart, Nicole; Deakin University School of Psychology Donaldson, Peter; Deakin University School of Psychology Ford, Talitha; Deakin University School of Psychology Caeyenberghs, Karen; Deakin University School of Psychology, School of Psychology Albein-Urios, Natalia; Deakin University School of Psychology, School of Psychology Bekkali, Soukayna; Deakin University School of Psychology
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 58 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 1 2 3 Fitzgerald , Paul; Monash University Central Clinical School; Epworth 4 HealthCare, Epworth Centre for Innovation in Mental Health 5 6 Primary Subject Neurology 7 Heading: 8 Secondary Subject Heading: Mental health 9 10 Child & adolescent psychiatry < PSYCHIATRY, Developmental neurology 11 Keywords: & neurodisability < PAEDIATRICS, Paediatric neurology < PAEDIATRICS, 12 Neurophysiology < NEUROLOGY 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
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1 2 3
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1 2 3
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Repetitive transcranial magnetic stimulation (rTMS) in autism spectrum disorder: protocol 7 for a multicentre randomised controlled clinical trial 8 9 10 11 Peter G. Enticott*, School of Psychology, Deakin University, Geelong, Australia 12 Karen Barlow, Child Health Research Centre, The University of Queensland, South Brisbane, Australia; 13 Children’s Health Queensland Hospital and Health Service, Herston, Queensland 14 Adam J. Guastella, Brain and Mind Centre, University of Sydney, Camperdown, Australia 15 Melissa K. Licari, Research Fellow, Telethon Kids Institute, The University of Western Australia, 16 Nedlands, Australia 17 18 Nigel C. Rogasch, AdelaideFor Medical peer School, The review University of Adelaide, only Adelaide, Australia; South Australian 19 Health and Medical Research Institute (SAHMRI), Adelaide, Australia 20 Christel M. Middeldorp, Child Health Research Centre, The University of Queensland, South Brisbane, 21 Australia; Children’s Health Queensland Hospital and Health Service, Herston, Queensland 22 Scott R. Clark, Adelaide Medical School, The University of Adelaide, Adelaide, Australia 23 Ann-Maree Vallence, School of Psychology and Exercise Sciences, Murdoch University, Murdoch, Australia; 24 Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Australia 25 Brain and Mind Centre, University of Sydney, Camperdown, Australia 26 Kelsie A. Boulton, 27 Ian B. Hickie, Brain and Mind Centre, University of Sydney, Camperdown, Australia Andrew J. O. 28 Whitehouse, Telethon Kids Institute, The University of Western Australia, Nedlands, Australia; Cooperative 29 Research Centre for Living with Autism, St Lucia, Queensland, Australia 30 Cherrie Galletly, Adelaide Medical School, The University of Adelaide, Adelaide, Australia 31 Gail Alvares, Telethon Kids Institute, The University of Western Australia, Nedlands, Australia 32 33 Hakuei Fujiyama, School of Psychology and Exercise Sciences, Murdoch University, Murdoch, Australia 34 Helen Heussler, Child Health Research Centre, The University of Queensland, South Brisbane, Australia; 35 Children’s Health Queensland Hospital and Health Service, Herston, Queensland
36 Jeffrey Craig, School of Medicine, Deakin University, Geelong, Australia http://bmjopen.bmj.com/ 37 Melissa Kirkovski, School of Psychology, Deakin University, Geelong, Australia 38 39 Natalie T. Mills, Adelaide Medical School, The University of Adelaide, Adelaide, Australia 40 Nicole J. Rinehart, School of Psychology, Deakin University, Geelong, Australia 41 Peter H. Donaldson, School of Psychology, Deakin University, Geelong, Australia 42 Talitha C. Ford, School of Psychology, Deakin University, Geelong, Australia 43 Karen Caeyenberghs, School of Psychology, Deakin University, Geelong, Australia 44 on September 27, 2021 by guest. Protected copyright. 45 Natalia Albein-Urios, School of Psychology, Deakin University, Geelong, Australia 46 Soukayna Bekkali, School of Psychology, Deakin University, Geelong, Australia 47 Paul B. Fitzgerald, Central Clinical School, Monash University; Epworth Centre for Innovation in Mental 48 Health, Epworth HealthCare, Camberwell, Australia 49 50 51 52 Word count (excluding title page, abstract, references, figures and tables): 4,001 53 54 *Correspondence to: Peter G. Enticott, School of Psychology, Deakin University, 221 55 Burwood Hwy, Burwood, Victoria, 3125, Australia. 56 57 Email: [email protected] 58 59 v2, 13 April 2021 60
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1 2 3 ABSTRACT
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Introduction 7 8 There are no well-established biomedical treatments for the core symptoms of autism 9 spectrum disorder (ASD). A small number of studies suggest that repetitive transcranial 10 11 magnetic stimulation (rTMS), a non-invasive brain stimulation technique, may improve 12 clinical and cognitive outcomes in ASD. We describe here the protocol for a funded 13 multicentre randomised controlled clinical trial to investigate whether a course of rTMS to 14 the right temporoparietal junction (rTPJ), which has demonstrated abnormal brain 15 16 activation in ASD, can improve social communication in adolescents and young adults with 17 ASD. 18 For peer review only 19 Methods and analysis 20 21 22 This study will evaluate the safety and efficacy of a four-week course of intermittent theta 23 burst stimulation (iTBS, a variant of rTMS) in ASD. Participants meeting criteria for DSM-5 24 ASD (n = 150, aged 14-40 years) will receive 20 sessions of either active iTBS (600 pulses) or 25 sham iTBS (in which a sham coil mimics the sensation of iTBS, but no active stimulation is 26 27 delivered) to the rTPJ. Participants will undergo a range of clinical, cognitive, epi/genetic, 28 and neurophysiological assessments before and at multiple time points up to six months 29 after iTBS. Safety will be assessed via a structured questionnaire and adverse event 30 reporting. The study will be conducted from November 2020 to October 2024. 31 32 33 Ethics and dissemination 34 35 The study was approved by the Human Research Ethics Committee of Monash Health 36 (Melbourne, Australia) under Australia’s National Mutual Acceptance scheme. The trial is http://bmjopen.bmj.com/ 37 38 registered (prospectively) at the Australian New Zealand Clinical Trials Registry (ANZCTR) 39 ACTRN12620000890932p, will be conducted according to Good Clinical Practice, and 40 findings will be written up for scholarly publication. 41 42 43
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1 2 3 Strengths and limitations of this study
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 This multisite randomised controlled trial will be the largest trial of rTMS in ASD to date 7 8 rTMS will be applied to rTPJ, a cortical region that has demonstrated abnormal 9 10 activation in ASD and forms a major hub of the “social brain” subnetwork 11 12 Participants will undergo structural MRI scans, with rTMS coil position determined via 13 individualised neuronavigation 14 15 16 Adolescent and young adult participants will receive rTMS interventions as outpatients, 17 and complete a comprehensive range of clinical, neuropsychological, and 18 neurophysiologicalFor assessments peer review only 19 20 21 A limitation of the study is the use of only a sham control condition, rather than an 22 additional “active control” site to determine whether effects are specific to rTPJ (rather 23 than a general effect of brain stimulation) 24 25 26 27 28 29 30 31 32 33 34 35
36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43
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1 2 3 INTRODUCTION
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Autism spectrum disorder (ASD) is a neurodevelopmental disorder that impacts a range of 7 domains, including social communication, behaviour, cognition, emotion regulation, and 8 sensorimotor function1. Core symptoms of ASD include social interaction and 9 communication problems, and restricted and repetitive behaviours. Comorbid 10 11 neurodevelopmental disorders (e.g., attention deficit hyperactivity disorder [ADHD]) and 12 psychiatric disorders (e.g., depression, anxiety) are very common2 3, with the latter often 13 associated with the core social communicative difficulties4 5. 14 15 6 16 Despite the high prevalence of ASD (1 in 59 ), few clinical interventions target core 17 symptoms beyond early-middle childhood. ASD diagnosis typically occurs by the age of 4-6 18 years6, and early, intensiveFor interventionpeer throughoutreview these only years is associated with the best 19 outcomes for individuals with ASD and their families7. Unfortunately, there is little clinical 20 support available for adolescents and young adults with ASD, who often continue to 21 22 experience social communication symptoms that result in barriers to education, 23 employment, and community participation. As noted, this group also experiences extremely 24 poor mental health that is much worse than the general population; for instance, lifetime 25 depression and anxiety rates are estimated at 37% and 42%, respectively2. 26 27 28 Non-invasive brain stimulation (NIBS) has emerged as a novel, safe, and efficacious 29 intervention for a range of brain-based disorders. These techniques allow non-invasive 30 modulation of specific brain regions via electromagnetic or electrical stimulation. The most 31 common of these is repetitive transcranial magnetic stimulation (rTMS), which is now widely 32 8 33 used as an intervention for treatment-resistant major depressive disorder . It has also been 34 established as an intervention for other neurological disorders, including migraine and 35 obsessive-compulsive disorder9 10.
36 http://bmjopen.bmj.com/ 37 38 rTMS is administered via a plastic-coated metallic coil that is held against the scalp. This coil 39 emits focal, time-varying electromagnetic pulses, which induce electrical current in 40 superficial cortical tissue, thus stimulating neurons in the local region. Depending on the 41 frequency and strength of pulses administered, rTMS can be used to either enhance cortical 42 excitability (i.e., upregulate neural activity), or decrease cortical excitability (i.e., 43 downregulate neural activity) in the stimulated region. This is particularly useful when 44 on September 27, 2021 by guest. Protected copyright. 45 targeting regions (or nodes) of brain networks known to be either underactive or overactive 46 in particular conditions. For instance, high-frequency (excitatory) rTMS has been used to 47 stimulate underactive left dorsolateral prefrontal cortex (DLPFC) in treatment-resistant 48 11 49 depression , while low-frequency (inhibitory) rTMS has been used to downregulate 12 50 excessive activity in left auditory cortex in schizophrenia and supplementary motor area 51 (SMA) in Tourette’s disorder13. Importantly, rTMS also influences broader brain networks 52 that involve the stimulated region14 15, and this is thought to contribute to its clinical 53 efficacy. Here we will stimulate the right temporoparietal junction (rTPJ), a key node for 54 16 55 social cognition, which is a typical area of difficulty among individuals with ASD . 56 57 The brain functions as a set of interconnected networks disseminating neuronal information 58 across a broad range of distributed areas 17. From a neurobiological perspective, ASD is 59 60 commonly understood as a disorder of synaptic plasticity and neural connectivity, leading to
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1 2 3 abnormalities in brain network connectivity between brain regions. These appear to be
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 mediated by disruptions in both excitatory (e.g., glutamatergic) and inhibitory (e.g., 18 19 6 GABAergic) processes . There are also well-documented abnormalities in local “node” 7 activity, particularly within networks that comprise the so-called “social brain,” including 8 rTPJ20 21. Indeed, the rTPJ shows consistent differences in activation between those with and 9 without ASD16 20-22, while meta-analysis demonstrates reduced rTPJ functional connectivity 10 23 11 in ASD . Accordingly, rTMS to this region has the potential to modulate local and regional 12 brain activity within networks implicated in the core social symptoms of ASD. 13 14 rTMS is considered a very safe and tolerable technique. It is typically administered by an 15 16 experienced clinician (nurse or physician), and patients are monitored throughout and at 17 the completion of rTMS administration. Clinical researchers have established a detailed set 18 of safety guidelines,For and when peer rTMS is administered review within only guideline parameters serious 19 adverse effects are exceedingly rare24 25. NIBS (including rTMS) is also considered very safe 20 for paediatric populations, with a recent study showing no adverse effects across 382 21 26 22 children aged 0-18 years . 23 24 Previously, NIBS has been used to investigate the neuropathophysiology of ASD27-30. More 25 recently, several research groups (including ours) have investigated whether rTMS could 26 31-33 27 have clinical utility as an intervention in ASD., These studies (see systematic reviews ) 28 indicate that: low-frequency stimulation of the DLPFC can reduce repetitive behaviours, 29 improve neurophysiological markers of perception, and reduce irritability; low-frequency 30 SMA stimulation can improve movement-related cortical potentials, and; low-frequency 31 stimulation of the premotor cortex can improve sensorimotor integration. While promising, 32 33 these studies are hampered by small sample sizes a lack of an appropriate control condition 34 (placebo or sham stimulation), and moderate-to-high risk of bias31. 35
36 At present, only two placebo-controlled randomised controlled trials (RCTs) have been http://bmjopen.bmj.com/ 37 38 conducted, both of which were double-blind. The first demonstrated that two weeks of 39 daily, high-frequency rTMS to bilateral dorsomedial prefrontal cortex (dmPFC), compared to 40 sham rTMS, improved self-report social relating symptoms in adults with ASD (n = 28) one- 41 month after intervention completion34. A recent study demonstrated that four weeks of 42 high-frequency stimulation of bilateral DLPFC did not improve executive function in 43 adolescents and young adults with ASD (n = 40)35. There was, however, evidence for a 44 on September 27, 2021 by guest. Protected copyright. 45 beneficial effect of rTMS for those with lower adaptive functioning at baseline. While 46 providing preliminary, placebo-controlled support for rTMS in ASD, these studies are limited 47 by small sample size. 48 49 50 Rationale/Justification 51 52 A recent international “consensus statement” provides recommendations for future rTMS 53 research in ASD36. Considering the clinical heterogeneity of ASD, there is agreement that 54 55 “large, multisite, double-blind, placebo-controlled trials with carefully selected 56 neurobiological targets and outcome measures” are required. It is also necessary to 57 understand variability in the response to rTMS that can lead to an individualised therapeutic 58 approach (i.e., personalised medicine approach). These include demographic (e.g., age, sex), 59 60 clinical (e.g., disorder severity, cognitive/symptom profile), neurobiological (e.g., cortical
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1 2 3 thickness, structural and functional connectivity), and genetic/epigenetic factors.
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 Accordingly, we will conduct a large-scale, multi-site investigation of the safety and efficacy 6 of rTMS in ASD that involves (a) feasible and tolerable stimulation paradigms, (b) a carefully 7 selected neurobiological target and mode of stimulation, and (c) rigorous methodological 8 approaches, including individualised stereotactic neuronavigation, an appropriate control 9 condition, and efficacious double blinding. If successful, this trial will establish a first 10 11 biomedical intervention to improve social communicative symptoms in adolescents and 12 young adults diagnosed with ASD, and inform on factors associated with intervention 13 response, with anticipated benefits in mental health, quality of life, and social participation. 14 15 16 Research Hypotheses 17 18 In ASD, active rTMSFor to rTPJ, whenpeer compared review to sham rTMS, only will be associated with: 19 20 1. Improved social communication, measured using the Social Responsiveness Scale – 21 nd 22 2 Edition (SRS-2) (evident one-month after end of rTMS, maintained at three- and 23 six-months) (primary outcome); 24 2. Improved social cognitive performance, measured using face processing/face 25 emotion processing neuropsychological tasks (evident immediately after rTMS, 26 27 maintained at one-, three-, and six-months); 28 3. Improved quality of life, measured using the Personal Wellbeing Index (evident one- 29 month after rTMS, maintained at three- and six-months); 30 4. Acceptable tolerability and safety (as measured by a structured interview and 31 adverse event reporting). 32 33 34 METHODS AND ANALYSIS 35
36 Study Design and Participants http://bmjopen.bmj.com/ 37 38 39 This is a four-year multicentre Australian study to assess the safety and efficacy of a four- 40 week course of rTMS to improve social communication in adolescents and young adults 41 diagnosed with ASD. It will be a parallel group (between-subjects), double-blind, placebo- 42 controlled RCT. Participants will be 150 individuals meeting criteria for DSM-51 ASD and 43 aged between 14-40 years. While broad, this age range was selected to ensure the 44 on September 27, 2021 by guest. Protected copyright. 45 feasibility of participant recruitment and to target age groups (i.e., adolescents and young 46 adults) where interventions for ASD are lacking. They will be recruited through existing 47 research participant databases, the Australian Autism Biobank37, and advertisements in local 48 49 clinics, advocacy/support groups, and via social media. The research team will also engage 50 popular media, both locally and nationally, to promote recruitment. 51 52 The study will be overseen by a Research Management Group, which comprises the ten 53 Chief Investigators, Study Coordinator, and Site Coordinators. They will meet monthly via 54 55 videoconference for the duration of the trial. There will be 30 participants enrolled at each 56 of the cities involved (Brisbane, Sydney, Melbourne, Adelaide, Perth). Participants will 57 undergo 20 intervention sessions (one per weekday for four consecutive weeks) of either 58 active or sham (i.e., placebo) rTMS. Participants will be assessed before and up to 6 months 59 60 after intervention and in accordance with Good Clinical Practice (GCP). Assessments will
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1 2 3 evaluate social communication, neuropsychological function, quality of life, safety, and
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 tolerability. There will be five primary intervention sites within Australia (Brisbane, Sydney, 6 Melbourne, Adelaide, Perth) and additional local sites to support recruitment, assessment, 7 genetic analysis, and neuroimaging. These will include both University and hospital sites. 8 Written informed consent will be obtained from participants (or their parent/guardian in 9 the case of minors, aged 14-17 years) by a local Chief Investigator or Site Coordinator. 10 11 Model participant Information and consent forms for parents/guardians and adult 12 participants are provided as Supplemental Material. 13 14 Patient and Public Involvement 15 16 17 The research team have engaged in extensive consultation with community groups in recent 18 years, including multipleFor community peer forums review on rTMS). We only have also consulted with autism 19 organisations when preparing advertisements and other study-related communications. 20 While participants were not directly involved in the design of this specific trial, throughout 21 22 the study we will engage a range of community and advocacy groups in the implementation 23 of the research, and health service partners to ensure rapid translation of our research 24 findings to clinical practice. For instance, the Telethon Kids Institute (Western Australia) 25 have established a community reference group with whom they regularly consult for 26 27 consumer involvement, and this group will also be engaged for the current trial. 28 29 rTMS Protocol 30 31 Participants will receive standard intermittent theta burst stimulation (iTBS) to the rTPJ each 32 33 consecutive weekday for a four-week period (20 sessions). iTBS was chosen as it is an 34 “excitatory” paradigm that has the potential to target the reduced activation and 35 connectivity commonly seen in rTPJ in ASD 16 20 21 23. It can also be administered quickly and 36 at a low intensity, which are important considerations in this clinical population. Participants http://bmjopen.bmj.com/ 37 38 will undergo either active iTBS or sham iTBS, where a “sham coil” is used to mimic the 39 appearance, sound, and sensation of rTMS, but without delivering electromagnetic 40 stimulation. 41 42 Participants will undergo 3T T1 magnetic resonance imaging (MRI) prior to the first rTMS 43 session, and stereotactic neuronavigation will be used to determine the site of stimulation 44 on September 27, 2021 by guest. Protected copyright. 45 (MNI coordinates x = 56, y = -56, z = 18; see Figure 1). 46 47 All stimulation will be administered via a Magstim Rapid2 stimulator (The Magstim Company 48 49 Ltd., Wales, UK). A staff member trained in rTMS will deliver all rTMS interventions. A visual 50 resting motor threshold (i.e., visual observation of muscle activation following TMS pulse) 51 will be determined at the right hemisphere/left hand prior to the first rTMS session. Each 52 iTBS is delivered with the following stimulation parameters: 53 54 55 • Burst pattern: 3 pulses delivered at 50 Hz 56 • Train duration: Bursts repeated 5 times per second (5 Hz) for 2 seconds (10 bursts) 57 • Intensity: 70% of resting motor threshold 58 • Inter-train interval: 8 seconds 59 60 • Total time: 200 seconds (3 minutes, 20 seconds)
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1 2 3 • Total trains: 20
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 • Total bursts: 200 6 • Total pulses: 600 7 8 <
44 Comorbid neurological or psychiatric diagnosis not commonly associated with ASD on September 27, 2021 by guest. Protected copyright. 45 (e.g., psychosis) 46 47 Unstable medical condition 48 Unstable medication regimen, or medication contraindicated for TMS 49 Pregnancy or current breastfeeding 50 Substance use/abuse disorder 51 52 Concurrent intervention targeting social communication 53 Evidence of significant epileptiform activity on electroencephalogram (EEG) (e.g., 54 seizures on EEG, runs of epileptiform discharges) 55 56 57 Outcome Measures 58 59 Data collection and study timings are presented in Table 1. Participants are assessed prior to 60 rTMS (T0), and at four points after rTMS: T1 (immediately after rTMS), T2 (one-month after
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1 2 3 completion of rTMS), T3 (three-months after completion of rTMS), and T4 (six-months after
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 completion of rTMS). 6 7 The primary outcome measure is the Social Responsiveness Scale – 2nd Edition (SRS-2; 8 School-Age AutoScore Form for Parent/Guardian [parent/guardian report]/Adult AutoScore 9 Form for Informant [informant report]) Total T-score, while the primary outcome point will 10 11 be at 1-month after completion of rTMS (T2) compared with pre-rTMS (T0). For adult 12 participants, an informant (parent/relative/friend) will complete the SRS-2 with respect to 13 the participant. 14 15 16 Secondary outcomes encompass a range of clinical, neuropsychological, neurophysiological, 17 and biological measures. Clinical measures include: Conners 3 (parent/guardian 18 report)/Conners AdultFor ADHD peer Rating Scales review (CAARS) (informant only report and adult self-report); 19 Aberrant Behaviour Checklist – Second Edition (ABC-2) (parent/guardian/informant report); 20 Behaviour Rating Scale of Executive Function, Second Edition (BRIEF)/ Behaviour Rating 21 22 Scale of Executive Function – Adult Version (BRIEF-A) (parent/guardian/informant report 23 and adult self-report); World Health Organization Disability Assessment Schedule 2.0 24 (WHODAS 2.0) (parent/guardian/informant report); Depression, Anxiety and Stress Scale 25 (DASS) (self-report); and Personal Wellbeing Index (PWI) (self-report). 26 27 28 Neuropsychological measures include: Reading the Mind in the Eyes Test (RMET); Benton 29 Facial Recognition Test (BFRT); Cambridge Face Memory Test (CFMT); NIH Cognition 30 Toolbox; and Working Memory Assessment. 31 32 33 Neurophysiological measures include: resting-state electroencephalography (EEG); and face 34 processing event-related potentials (ERP). 35
36 The neuropsychological and neurophysiological measures were selected as they are http://bmjopen.bmj.com/ 37 38 38 associated with activation of the target cortical region (e.g., ); while there were additional 39 paradigms that could have been used (e.g., biological motion processing), we were mindful 40 of not overburdening our participants, and selected those that we felt most relevant to our 41 social communication target. 42 43 Finally, a buccal swab will be administered both before and after the course of rTMS, which 44 on September 27, 2021 by guest. Protected copyright. 45 will allow an investigation of genetic and epigenetic predictors of intervention response, 46 and potential epigenetic changes following rTMS. 47 48 49 The various electrophysiological and genetic measures that are being collected are highly 50 exploratory but may help us to understand mechanisms by which rTMS exerts an influence 51 on social communication. 52 53 <
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1 2 3 randomisation procedure (minimisation method) will be performed, adjusting for baseline
4 39 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 characteristics (age, sex, SRS T0 score) , which ensures a balance of conditions across trial 6 sites. Randomisation will be completed by the Chief Investigator, who will provide this 7 information to the intervention clinicians (who are not blinded) via email. 8 9 Statistical Analysis and Data Management 10 11 12 With respect to statistical power, allowing for 10% attrition of our 150 participants, and 13 based on the estimated effect size from our previously published RCT (which revealed a 14 moderate effect of rTMS34), a sample size of n = 135 in a mixed-model (2 groups, 5 time- 15 16 points) will yield power of 0.99 (f = .20, α = 0.01). While this sample size is larger than the 17 minimum suggested by a priori power analysis (n = 64, based on f = .20, α = 0.01, Power = 18 0.95), this will enableFor exploratory peer analysis review to determine demographic, only clinical, 19 neuroimaging, and genetic predictors of treatment response. 20 21 22 Upon enrolment, participants will be allocated a unique study identification code. Their 23 name will not appear with the research data collected. All data will be stored in REDCap40 24 and on secure network locations governed by Deakin University. All Chief Investigators will 25 have access to the final trial dataset. Any information obtained in connection with this 26 27 research project that can identify a participant will remain confidential. Where a participant 28 elects to withdraw from the study, we will retain and use any data collected prior to 29 withdrawal. 30 31 Random effects linear mixed models will be used to ensure the inclusion of participants who 32 33 have missing data, including those that withdraw from the study. Specifically, this will 34 involve a between-subjects factor (rTMS condition: active vs. placebo) and a within-subjects 35 factor (time of assessment: pre vs. post vs. one-month vs. three-months vs. six-months), 36 with participant and site entered as random effects. We will employ an intention to treat http://bmjopen.bmj.com/ 37 38 (ITT) framework for these analyses. We will examine rTMS safety by exploring descriptive 39 statistics arising from the structured questionnaire related to the development of possible 40 side-effects. An interim analysis will be performed at the mid-point of data collection for 41 possible trial futility. The above-mentioned a priori power analysis, where n = 64 is required 42 to detect a moderate effect, suggests that we will be sufficiently powered to detect an 43 effect of rTMS in this interim analysis. 44 on September 27, 2021 by guest. Protected copyright. 45 46 Exploratory analyses will be undertaken to investigate factors, including genetic variants and 47 structural/functional neuroimaging (e.g., diffusion MRI, resting-state functional MRI), that 48 49 influence intervention response, and to investigate epigenetic changes following rTMS. We 50 will use linear mixed models to determine the effect of rTMS on SRS-2 score, but with 51 additional independent variables (e.g., age, sex, cognitive ability, ADOS-2 symptom severity, 52 rTPJ structural and functional connectivity within the social brain subnetwork, polygenic risk 53 score [PRS] for ASD41). 54 55 56 Epigenetic variation refers to variation in chromatin structure, which is associated with 57 variation in gene expression. In contrast to DNA, epigenetic variation can change over time, 58 for example following treatment42. Accordingly, we will compare epigenetic variation for 59 60 DNA samples collected before and after rTMS and investigate any associations with
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1 2 3 intervention response. (See Supplemental Material for a statement on Biological
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 Specimens.) 6 7 At the conclusion of the project, all electronic and hard copy data will be archived within 8 Deakin University (Information and Records Services). Electronic data will be retained on 9 secure Deakin University servers and archived in REDCap, but also transferred to physical 10 11 hard drives for archival storage. As some hard copy data will be stored at each site (e.g., 12 signed consent forms, clinical files used during rTMS intervention), these will be securely 13 couriered to Deakin University for archiving. Each site will be required to delete any 14 electronic data that may remain at their site. As this is a clinical trial involving child 15 16 participants, data will be retained indefinitely. Any published work from this study will be 17 accompanied by publicly available deidentified data through the Open Science Framework 18 (osf.io). The researchFor team, includingpeer both review Chief Investigators only and Associate Investigators, 19 all have the opportunity to conduct secondary analyses. This will be negotiated with the 20 trial’s Research Management Group, which comprises the ten Chief Investigators. Data may 21 22 also be shared with external (national and international) collaborators to obtain larger 23 sample sizes, which are often necessary to achieve the statistical power necessary to 24 analyse biomarker data. This could include specific research projects or online data 25 repositories, which may be accessed and used by external researchers. 26 27 28 Blinding 29 30 This is a double-blind study; accordingly, participants (and their parents/guardians, where 31 relevant) and the testing researchers/statisticians will be blinded to intervention condition. 32 33 The individual administering rTMS must select the appropriate coil (i.e., active or sham) and 34 will therefore not be blinded, but this individual will not conduct any of the assessment or 35 be involved in the statistical analyses. Unblinding may occur in the event of an adverse 36 event. We will assess blinding integrity by asking participants to indicate, at the end of their http://bmjopen.bmj.com/ 37 38 four-week intervention, which condition they believed they received and the confidence (on 39 an 11-point scale) in this judgment. At the conclusion of the final assessment (T4), 40 participants will be unblinded as to their intervention condition by a member of the 41 research team who is not blinded. Those who were allocated to the sham rTMS intervention 42 will be offered the opportunity to undergo the real rTMS intervention. While this will occur 43 after all assessments have been administered, scored, and entered into REDCap, we have 44 on September 27, 2021 by guest. Protected copyright. 45 developed standard operating procedures to minimise the likelihood that assessors will 46 encounter participants completing the open label component. 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 Table 1. 4 5 6 Data Collection and Study Timings 7 8 9 10 Visits Pre-enrolment T0 Tx T1 T2 T3 T4 11 12 For peer review only 13 14 Screening X X 15 http://bmjopen.bmj.com/ 16 Written informed consent X 17 18 Randomisation X 19 20 Demographics X X 21 22 Medical History X X 23 on September 27, 2021 by guest. Protected copyright. 24 25 Neuroimaging (MRI) X 26 27 Clinical EEG X 28 29 Buccal Swab X X 30 31 ADOS-2 X 32 33 WASI-2 X 34 35 rTMS intervention (active/sham) X 36 37 NIBS:PSI X 38 39 SRS-2 X X X X X 40 41 42 12 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 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-2020-046830 on 7 July 2021. Downloaded from
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1 2 3 4 Conners-3/CAARS X X X X X 5 6 ABC-2 X X X X X 7 8 BRIEF/BRIEF-A X X X X X 9 10 DASS X X X X X 11 12 PWI ForX peer reviewX XonlyX X 13 14 WHODAS 2.0 X X X X X 15 http://bmjopen.bmj.com/ 16 NIH Cognition Toolbox X X X X 17 18 RMET X X X X 19 20 BFRT X X X X 21 22 CFMT X X X X 23 on September 27, 2021 by guest. Protected copyright. 24 25 Working Memory X X X X 26 27 rsEEG X X 28 29 FP-ERP X X 30 31 Notes: T0: Pre-rTMS; T1: week following rTMS; T2: one-month after completion of rTMS; T3: three-months after completion of rTMS; T4: six-months after completion of nd nd 32 rTMS; MRI: magnetic resonance imaging; ADOS-2: Autism Diagnostic Observation Schedule, 2 Edition; WASI-2: Wechsler Abbreviated Scale of Intelligence, 2 Edition; nd 33 rTMS: repetitive transcranial magnetic stimulation; NIBS:PSI: Non-invasive Brain Stimulation Post-stimulation Interview; SRS-2: Social Responsiveness Scale, 2 Edition; nd 34 CAARS: Conners Adult ADHD Rating Scales; ABC-2: Aberrant Behaviour Checklist, 2 Edition; BRIEF: Brief Rating Inventory of Executive Function; BRIEF-A: Brief Rating 35 Inventory of Executive Function – Adult Version; DASS: Depression Anxiety Stress Scale; PWI: Personal Wellbeing Index; WHODAS 2.0: World Health Organisation Disability 36 Assessment Schedule; NIH: National Institutes of Health; RMET: Reading the Mind in the Eyes Test; BFRT: Benton Facial Recognition Test; CFMT: Cambridge Face Memory 37 Test; rsEEG: resting-state electroencephalography; FP-ERP: face-processing event-related potentials. 38 39 40 41 42 13 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 16 of 58
1 2 3 Safety
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Participants will undergo extensive screening to ensure that they meet safety criteria for 7 undergoing rTMS25. For child participants, a parent or legal guardian will complete the 8 screening. Participants will undergo EEG prior to their first rTMS session, and this will be 9 reviewed by the trial neurologist. Any participants demonstrating evidence of runs of 10 11 epileptiform discharges, as assessed by the study neurologist, will be withdrawn from the 12 study. At the beginning of their first session, participants (or their parent/guardian for child 13 participants) will again be screened to ensure that they can undergo rTMS. 14 15 16 A data safety monitoring board (DSMB) will be formed. This DSMB will comprise three 17 senior clinical researchers independent to the current project. The DSMB will meet twice 18 per year to review theFor conduct peer of the trial review and monitor study only data. They will also review any 19 serious adverse events in a mid-trial safety analysis and on an ad hoc basis. Terms of 20 reference will be based on advice from the National Health and Medical Research Council’s 21 22 Data Safety Monitoring Boards documentation. 23 24 Adverse events will be reported to the relevant Human Research Ethics Committees (HREC) 25 immediately, and no later than 72 hours after the event. Depending on the nature and 26 27 severity of the event, it may be necessary to also report to other regulatory bodies (e.g., 28 Therapeutic Goods Administration) and suspend or terminate the trial. Should an individual 29 suffer harm from trial participation, they will receive medical treatment required to treat 30 the injury or complication, free of charge, as a public patient in any Australian public 31 hospital. 32 33 34 ETHICS AND DISSEMINATION 35
36 This study has been approved by the Monash Health Human Research Ethics Committee http://bmjopen.bmj.com/ 37 38 (Melbourne, Australia; RES-20-0000-606A) under the National Mutual Acceptance scheme, 39 which allows for mutual scientific and ethic acceptance across Australian jurisdictions and 40 institutions. We will engage a range of community and advocacy groups in the 41 implementation of the study, and health service partners to ensure rapid translation of our 42 research findings to clinical practice. 43
44 on September 27, 2021 by guest. Protected copyright. 45 The health outcomes of this study will be provided within 12 months of the trial’s 46 completion, initially through a freely accessible preprint and an open-access peer-reviewed 47 journal publication. Authorship will be determined according to the standards outlined in 48 49 the National Health and Medical Research Council’s Australian Code for the Responsible 50 Conduct of Research. Chief Investigators will also present the study findings at relevant 51 scientific conferences and autism advocacy/support group community forums. The research 52 team will also engage in more extensive public outreach and disseminate study findings 53 widely through appropriate channels (e.g., study website, social media, news outlets). These 54 55 dissemination pathways will also involve contributing to clinical guidelines (and direct 56 engagement with healthcare providers). 57 58 Participants will be sent a plain language summary detailing the study results at the 59 60 completion of the trial. This summary will be written as a lay summary and in a manner
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1 2 3 accessible to participants and their families. A child version will also be sent to
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 parents/guardians to share with their child. The summary will contain no identifying 6 information and provide only group level results. 7 8 This project involves the collection of a large number of measures (e.g., clinical, 9 neuropsychological, neuroimaging, genetic/epigenetic) and it is expected that the Chief 10 11 Investigators will conduct further exploratory analyses on these data. This might include, for 12 example, examining neuroimaging and genetic predictors of response to rTMS intervention 13 and characterising epigenetic changes following rTMS. 14 15 16 TRIAL STATUS 17 18 At the time of submissionFor recruitment peer has review not commenced. only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43
44 on September 27, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 AUTHORS’ CONTRIBUTIONS
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 PE, KB, AG, ML, NR, CM, SC, AV, KB, IH, CG, HF, HH, JC, MK, NM, PD, and PF contributed to 7 the design of the study. 8 PE, KB, ML, NR, CM, SC, AV, KB, AW, GA, MK, PD, TF, KC, NA, SB, and PF contributed to the 9 writing of the manuscript. 10 11 All authors approved the final draft of the manuscript. 12 13 FUNDING 14 15 16 This project has been funded by the National Health and Medical Research Council (NHMRC) 17 under the Medical Research Future Fund (MRFF) Neurological Disorders 2020 scheme 18 (Application ID: APP1199298).For peer review only 19 20 PROJECT REGISTRATION 21 22 23 This project has been prospectively registered on the Australian New Zealand Clinical Trials 24 Registry (ANZCTR; ACTRN12620000890932p). 25 26 27 COMPETING INTERESTS 28 29 There are no competing interests to declare. 30 31 TRIAL SPONSOR 32 33 34 Deakin University 35
36 Contact: Prof. Peter G. Enticott http://bmjopen.bmj.com/ 37 38 221 Burwood Hwy, Burwood 39 Victoria, 3125, AUSTRALIA 40 41 ROLE OF SPONSOR AND STUDY 42 43 This is an investigator-initiated study funded by the Australian Government, who provided 44 on September 27, 2021 by guest. Protected copyright. 45 peer review but have had no other involvement in the trial. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 REFERENCES 6 7 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 8 5th ed. Arlington, VA: American Psychiatric Association 2013. 9 2. Hollocks MJ, Lerh JW, Magiati I, et al. Anxiety and depression in adults with autism 10 11 spectrum disorder: A systematic review and meta-analysis. Psychological Medicine 12 2019;49(4):559-72. doi: 10.1017/S0033291718002283 13 3. Rau S, Skapek MF, Tiplady K, et al. Identifying comorbid ADHD in autism: Attending to the 14 inattentive presentation. Research in Autism Spectrum Disorders 2020;69 doi: 15 16 10.1016/j.rasd.2019.101468 17 4. Day TC, McNaughton KA, Naples AJ, et al. Self-reported social impairments predict 18 depressive disorderFor inpeer adults with review autism spectrum only disorder. Autism 2019 doi: 19 10.1177/1362361319857375 20 5. van Steensel FJA, Bögels SM, Perrin S. Anxiety Disorders in Children and Adolescents with 21 22 Autistic Spectrum Disorders: A Meta-Analysis. Clinical Child and Family Psychology 23 Review 2011;14(3):302-17. doi: 10.1007/s10567-011-0097-0 24 6. Baio J, Wiggins L, Christensen DL, et al. Prevalence of Autism Spectrum Disorder Among 25 Children Aged 8 Years — Autism and Developmental Disabilities Monitoring 26 27 Network, 11 Sites, United States, 2014. MMWR Surveillance Summaries 2018;67(SS- 28 6):1-23. doi: http://dx.doi.org/10.15585/mmwr.ss6706a1 29 7. Landa RJ. Efficacy of early interventions for infants and young children with, and at risk 30 for, autism spectrum disorders. International Review of Psychiatry 2018;30(1):25-39. 31 doi: 10.1080/09540261.2018.1432574 32 33 8. George MS, Lisanby SH, Avery D, et al. Daily left prefrontal transcranial magnetic 34 stimulation therapy for major depressive disorder: A sham-controlled randomized 35 trial. Archives of General Psychiatry 2010;67(5):507-16. doi: 36 10.1001/archgenpsychiatry.2010.46 http://bmjopen.bmj.com/ 37 38 9. Feng Y, Zhang B, Zhang J, et al. Effects of Non-invasive Brain Stimulation on Headache 39 Intensity and Frequency of Headache Attacks in Patients With Migraine: A 40 Systematic Review and Meta-Analysis. Headache 2019;59(9):1436-47. doi: 41 10.1111/head.13645 42 10. Rapinesi C, Kotzalidis GD, Ferracuti S, et al. Brain stimulation in obsessive-compulsive 43 disorder (OCD): A systematic review. Current Neuropharmacology 2019;17(8):787- 44 on September 27, 2021 by guest. Protected copyright. 45 807. doi: 10.2174/1570159X17666190409142555 46 11. Luber BM, Davis S, Bernhardt E, et al. Using neuroimaging to individualize TMS 47 treatment for depression: Toward a new paradigm for imaging-guided intervention. 48 49 NeuroImage 2017;148:1-7. doi: 10.1016/j.neuroimage.2016.12.083 50 12. Blumberger DM, Fitzgerald PB, Mulsant BH, et al. Repetitive transcranial magnetic 51 stimulation for refractory symptoms in schizophrenia. Current Opinion in Psychiatry 52 2010;23(2):85-90. doi: 10.1097/YCO.0b013e3283366657 53 13. Hsu CW, Wang LJ, Lin PY. Efficacy of repetitive transcranial magnetic stimulation for 54 55 Tourette syndrome: A systematic review and meta-analysis. Brain Stimulation 56 2018;11(5):1110-18. doi: 10.1016/j.brs.2018.06.002 57 14. Tik M, Hoffmann A, Sladky R, et al. Towards understanding rTMS mechanism of action: 58 Stimulation of the DLPFC causes network-specific increase in functional connectivity. 59 60
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1 2 3 28. Enticott PG, Kennedy HA, Rinehart NJ, et al. GABAergic activity in autism spectrum
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1 2 3 41. Grove J, Ripke S, Als TD, et al. Identification of common genetic risk variants for autism
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44 on September 27, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 Insert Header with institution’s name or institution’s letterhead
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Participant Information Sheet/Consent Form 7 Interventional Study - Adult providing own consent 8 9 [Insert site name] 10 11 Does repetitive transcranial magnetic stimulation 12 (rTMS), compared to sham rTMS, improve social 13 Title 14 communication in adolescents and young adults 15 with autism spectrum disorder (ASD)? 16 Short Title MRFF TBS-ASD 17 Protocol Number v2, 11/09/2020 18 Project Sponsor For peer reviewDeakin University only 19 20 Coordinating Principal Investigator Prof. Peter Enticott 21 22 23 Prof. Paul Fitzgerald, A/Prof. Karen Barlow, Prof. 24 Ian Hickie, Dr Melissa Licari, Dr Nigel Rogasch, 25 Prof. Christel Middeldorp, Dr Scott Clark, Dr Ann- 26 Maree Vallence, Dr Kelsie Boulton, Prof. Adam 27 Associate Investigator(s) Guastella, Prof. Andrew Whitehouse, Prof. 28 Cherrie Galletly, Dr Gail Alvares, Dr Hakuei 29 Fujiyama, A/Prof. Helen Heussler, A/Prof. Jeffrey 30 Craig, Dr Melissa Kirkovski, Dr Natalie Mills, Prof. 31 Nicole Rinehart, Dr Peter Donaldson, Dr Talitha 32 Ford, Prof. Karen Caeyenberghs 33 34 Location [Insert site-specific location] 35
36 http://bmjopen.bmj.com/ 37
38 39 Part 1 What does my participation involve? 40 41 1 Introduction 42 43 You are invited to take part in this research project. This is because you have been diagnosed
44 with autism spectrum disorder (ASD). The research project is testing a new treatment for ASD. on September 27, 2021 by guest. Protected copyright. 45 The new treatment is called repetitive transcranial magnetic stimulation (rTMS). 46 47 This Participant Information Sheet/Consent Form tells you about the research project. It 48 explains the tests and treatments involved. Knowing what is involved will help you decide if you 49 want to take part in the research. 50
51 Please read this information carefully. Ask questions about anything that you don’t understand 52 53 or want to know more about. Before deciding whether or not to take part, you might want to talk 54 about it with a relative, friend or your local doctor. 55 56 Participation in this research is voluntary. If you don’t wish to take part, you don’t have to. 57 58 If you decide you want to take part in the research project, you will be asked to sign the consent 59 section. By signing it you are telling us that you: 60 • Understand what you have read • Consent to take part in the research project
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1 2 • Consent to have the tests and treatments that are described 3 • Consent to the use of your personal and health information as described.
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 You will be given a copy of this Participant Information and Consent Form to keep. 6 7 2 What is the purpose of this research? 8 9 Many individuals with ASD experience difficulty with social functioning; for example, in 10 understanding what other people are thinking or feeling. This may cause significant distress and 11 lead to difficulties and anxiety in social situations. There are very few treatment options for 12 improving abilities related to social functioning in ASD. 13
14 The aim of this project is to determine whether rTMS can be used to improve social function. 15 16 rTMS is a safe and non-invasive means of stimulating nerve cells in a particular part of the brain 17 via the administration of brief magnetic pulses. rTMS has been developed as a treatment for 18 major depressive disorder,For and peer we have previously review found that only rTMS can benefit social aspects 19 of ASD. 20 21 In this study we will stimulate a region of the brain that is involved in social understanding and 22 social communication. This region is called the right temporoparietal junction, or rTPJ. 23 24 Some participants will receive the real form of rTMS, while others will receive a sham or placebo 25 form. The sham or placebo form mimics the feeling of rTMS, but no brain stimulation is 26 delivered. You will not know which one you receive until the end of your involvement in the 27 study. Those who received the sham or placebo form will be given the opportunity to undergo 28 the real rTMS treatment at the end of their involvement in the study. 29 30 150 people (aged 14-40 years) will take part in this study, which is being conducted throughout 31 Australia. There are sites in Brisbane, Sydney, Melbourne, Adelaide, and Perth. Participants will 32 be recruited from around Australia, but primarily the greater metropolitan regions within these 33 five cities. 34 35 rTMS is an experimental treatment. This means that it is not an approved treatment for ASD in 36 http://bmjopen.bmj.com/ 37 Australia or elsewhere. 38 39 This research has been initiated by the study investigator, Prof. Peter Enticott (Deakin 40 University, Melbourne). This research has been funded by the National Health and Medical 41 Research Council (NHMRC) of Australian through a Medical Research Future Fund grant 42 (MRFF RCRDUN Neurological Disorders 2020; Application APP1199298). 43
44 on September 27, 2021 by guest. Protected copyright. 45 3 What does participation in this research involve? 46 47 You will be participating in a randomised controlled research project. Sometimes we do not 48 know which treatment is best for treating a condition. To find out we need to compare different 49 treatments. We put people into groups and give each group a different treatment (in this case, 50 real rTMS vs. sham/placebo rTMS). The results are compared to see if one is better. To try to 51 make sure the groups are the same, each participant is put into a group by chance (random). 52
53 54 This is a double-blind study. This means that neither you nor your study doctor will know which 55 treatment you are receiving (in this case, real rTMS or sham/placebo rTMS). However, in certain 56 circumstances your study doctor can find out which treatment you are receiving. Participants will 57 be randomly allocated to either the real rTMS or sham/placebo rTMS condition. As mentioned, 58 those allocated to the sham or placebo form will be given the opportunity to undergo the real 59 rTMS treatment at the end of their involvement in the study. 60 This research project has been designed to make sure the researchers interpret the results in a fair and appropriate way and avoids study doctors or participants jumping to conclusions. Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 2 of 11 [Site Name] Site MasterFor peer Participant review Informationonly - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date]
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1 2 3 If you decide to take part in this project, you will be asked to take part in a number of interviews
4 and procedures over the course of approximately eight months. These are outlined below. BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Prior to completing the study, we will need to determine your eligibility to take part in the study. 7 We will do this by asking you questions (either over the phone or via email) about your health. 8 We will also ask you to provide a letter or report confirming your diagnosis of ASD; if you are not 9 able to provide this, we will seek permission (via the consent form) to contact your doctor or 10 psychologist directly to confirm your diagnosis. 11 12 Assessment Session One: The first assessment will take place at [site-specific location]. It will 13 take approximately three hours, but you will be given regular breaks throughout the session. 14 15 We will begin by asking you some questions about your health, which will help to confirm your 16 eligibility to take part in the study. We will then ask some questions about yourself that are 17 relevant to ASD. This will include, for example, what you enjoy doing and how much you like 18 For peer review only 19 being with other people. We will also ask you to have someone who knows you well (e.g., a 20 parent, sibling, spouse, or close friend) complete a series of questionnaires. You can nominate 21 this person and we will ask that they agree to complete these questionnaires now and another 22 four times during the study. 23 24 You will then complete a short cognitive assessment, which involves solving puzzles and 25 describing what different words mean. 26 27 Finally, you will undergo electroencephalography (EEG), which involves wearing an “electrode 28 cap” to measure the electrical activity of your brain, or your “brainwaves.” The electrode cap 29 feels similar to a swimming cap. It will also feel a little damp, as we need to put a small amount 30 of gel or saline into the cap to ensure that we get accurate recordings. For most of the EEG you 31 will simply rest while sitting in a chair, but you will also complete a short task on a computer that 32 involves looking at different objects (e.g., faces, household furniture, butterflies). 33 34 Assessment Session Two: Around one-week after “Assessment Session One” you will then 35 undergo a magnetic resonance imaging (MRI) brain scan at [site-specific location]. The MRI 36 http://bmjopen.bmj.com/ brain scan takes around 45-60 minutes, during which you will be asked to lie still in an MRI 37 38 scanner. (Please note that with preparation time you attend the MRI facility for up to two hours.) 39 MRI is a routinely performed, painless ways of examining brain structure and activity. We will 40 use the MRI to accurately place the rTMS device, and ensure that we are stimulating the correct 41 brain region. The MRI procedure may also help us better understand how the treatment works 42 and to determine who is likely to respond to treatment and why. 43
44 Assessment Session Three: During the same week of “Assessment Session Two,” you will on September 27, 2021 by guest. Protected copyright. 45 attend a two-hour assessment session at [site-specific location]. Here we will ask you questions 46 about yourself, some of which are relevant to ASD, while others relate to your mood, 47 concentration, stress, and your satisfaction with life. We will also ask you to complete some 48 cognitive tasks on a computer/tablet. These tasks measure your memory, attention, and 49 understanding of other people’s emotions. We will also ask you to provide a sample for genetic 50 analysis; this will involve having a cotton swab rubbed against the inside of your cheek. These 51 genetic analyses are conducted to investigate whether people with certain genetic profiles 52 respond better to the intervention. You will not receive any health information from these genetic 53 analyses, and they are not considered to be clinically informative. 54
55 rTMS Intervention (4 weeks): The week after “Assessment Session Three” you will begin the 56 57 rTMS intervention, which involves attending [site-specific location] and receiving rTMS for 3 58 minutes, 20 seconds each consecutive weekday for a four-week period (20 rTMS sessions in 59 total). 60 You will have your first rTMS session on the Monday after “Assessment Session Three.” At the beginning of the first session we will administer transcranial magnetic stimulation (TMS) to the Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 3 of 11 [Site Name] Site MasterFor peer Participant review Informationonly - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date]
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1 2 area of the brain that controls the muscles in your hand. This will measure how excitable your 3 brain is and is used to help us determine the personalised settings that will be used for your
4 rTMS treatments. This takes approximately 10 minutes and is not uncomfortable, although you BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 may feel some twitches in the muscle of your hand while the TMS is occurring. 6 7 During each rTMS session you will be awake, alert, and aware of what is happening at all times. 8 During rTMS a coil will be placed against the head, through which rTMS is administered. This is 9 connected to a machine that sends an electrical current through the coil. The current produces a 10 magnetic field that is very focused and is able to stimulate electrical activity in nerves below the 11 coil. These are usually nerve cells in the outer layers of the brain. The sensations associated 12 with rTMS are mild, and most people describe it as a “tapping” sensation on their head. During a 13 rTMS procedure you will hear clicking sounds as the current passes through the coil. You will 14 wear earplugs so that this noise doesn’t disturb you. 15 16 Including setup time, each subsequent treatment session should only take approximately 10 17 minutes. At the end of each treatment week (i.e., on the Friday session) we will ask you a 18 For peer review only 19 number of questions about your experience of RTMS, and whether you feel you have 20 experienced any side effects. 21 22 Assessment Session Four: The week after your last rTMS session, you will attend another 23 two-hour assessment session at [site-specific location]. Here we will again ask you questions 24 about yourself, some of which are relevant to ASD, while others relate to your mood, 25 concentration, stress, and satisfaction with life. We will also again ask you to complete some 26 cognitive tasks on a computer/tablet and to provide another sample (cheek swab) for genetic 27 analysis. 28 29 Assessment Session Five: One-month after your last rTMS session, you will attend another 30 two-hour assessment session at [site-specific location]. This session will be identical to 31 Assessment Session Four. 32 33 Assessment Session Six: Three-months after your last rTMS session, you will attend a one- 34 hour assessment session at [site-specific location]. This session will be identical to Assessment 35 Session Five except that you will not complete the computerised cognitive tasks. 36 http://bmjopen.bmj.com/
37 38 Assessment Session Seven: Six-months after your last rTMS session, you will attend a final 39 two-hour assessment session at [site-specific location]. This session will be identical to 40 Assessment Session Five. Following the assessment, you will be unblinded; that is, a member 41 of the research team will tell you which treatment condition you received (i.e., real or 42 sham/placebo). If you received the real treatment, your involvement in the study will conclude. If 43 you received the sham/placebo condition, you will be given the opportunity to receive the real
44 treatment and can liaise with research staff to determine when you would like to undergo this on September 27, 2021 by guest. Protected copyright. 45 four-week treatment. 46 47 There are no costs associated with participating in this research project. All treatments, tests, 48 and medical care required as part of the research project will be provided to you free of charge. 49 50 You will not be paid for your participation in this research, but you will be reimbursed $200 to 51 contribute towards costs that you incur as a result of participating in this research project (e.g., 52 travel). If you complete only part of the study and then decide to withdraw, you will be 53 reimbursed a proportion of this amount based on the proportion of the study completed. 54
55 Please note that no study procedures will be performed until consent has been obtained. 56 57 58 It is desirable that your local doctor be advised of your decision to participate in this research 59 project. If you have a local doctor, we strongly recommend that you inform them of your 60 participation in this research project.
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1 2 The research will be monitored by an independent Data Safety Monitoring Board, who will meet 3 twice per year and review the conduct of the trial, monitor study data, and review any serious
4 adverse events that might arise throughout the trial. BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 4 What do I have to do? 7 8 You will be able to continue taking your usual medication if you participate in this study, but you 9 will need to inform us of any changes to this medication that occur during your participation in 10 the study. 11 12 There are several reasons why you may not be able to take part in this study. These include: 13 14 • The presence of metal anywhere in the head (except the mouth) 15 16 • A history of seizure or epilepsy, or evidence of significant seizure activity as assessed by 17 EEG 18 • A history of seriousFor head peer injury review only 19 • The presence of certain implanted medical devices (e.g., cardiac pacemaker, medication 20 pumps) 21 • Serious heart disease (as there is an increased risk of serious injury in the event of a 22 seizure) 23 24 • Being deemed unsuitable to undergo MRI (e.g., due to presence of metal in the body) 25 • Unstable medical condition 26 • Unstable medication regime 27 • Certain medications 28 • Substance use disorder 29 • Undergoing another current treatment for social communication 30 • Employment as a professional driver or machine operator (as the event of a seizure may 31 affect employment) 32 • Pregnancy (female participants for whom child-bearing is a possibility will be required to 33 undergo a urine screen) 34 35 • Certain neurological or psychiatric diagnoses (i.e., those not commonly associated with
36 ASD, such as psychosis) http://bmjopen.bmj.com/ 37 • A measured verbal intelligence quotient (IQ) of less than 55 38 39 5 Other relevant information about the research project 40 41 This study is only taking place in Australia. There will be 150 participants in this study, with 30 42 taking part in each of the five cities involved: Brisbane, Sydney, Melbourne, Adelaide, and 43 Perth. There are a total of 14 organisations involved, including Universities, hospitals, and
44 medical centres. This study is a follow-on study from our previous trials of rTMS in ASD, which on September 27, 2021 by guest. Protected copyright. 45 have taken place at Monash University, Deakin University, The Alfred hospital, and the Epworth 46 Camberwell. 47 48 6 Do I have to take part in this research project? 49
50 Participation in any research project is voluntary. If you do not wish to take part, you do not have 51 52 to. If you decide to take part and later change your mind, you are free to withdraw from the 53 project at any stage. 54 55 If you do decide to take part, you will be given this Participant Information and Consent Form to 56 sign and you will be given a copy to keep. 57 58 Your decision whether to take part or not to take part, or to take part and then withdraw, will not 59 affect your routine treatment, your relationship with those treating you, or your relationship with 60 [site-specific Institution/s].
7 What are the possible benefits of taking part? Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 5 of 11 [Site Name] Site MasterFor peer Participant review Informationonly - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date]
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1 2 3 We cannot guarantee or promise that you will receive any benefits from this research; however,
4 possible benefits include an improvement in social understanding and functioning, including an BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 increased ability to accurately infer what other people are thinking or feeling. 6 7 8 What are the possible risks and disadvantages of taking part? 8 9 Repetitive Transcranial Magnetic Stimulation (rTMS) 10 11 Medical treatments often cause side effects. You may have none, some, or all of the effects 12 listed below, and they may be mild, moderate, or severe. If you have any of these side effects, 13 or are worried about them, talk with your study doctor. Your study doctor will also be looking out 14 for side effects. 15 16 There may be side effects that the researchers do not expect or do not know about and that 17 may be serious. Tell your study doctor immediately about any new or unusual symptoms that 18 For peer review only 19 you get. 20 21 Many side effects go away shortly after treatment ends. However, sometimes side effects can 22 be serious, long lasting, or permanent. If a severe side effect or reaction occurs, your study 23 doctor may need to stop your treatment. Your study doctor will discuss the best way of 24 managing any side effects with you. 25 26 Noise: The clicking noise made by the coil may be uncomfortable. You will wear 27 earplugs during treatment to minimise any discomfort. 28 29 Headache: A headache can occur during rTMS and is thought to affect approximately 30 3% or 3 in 100 participants. It is thought to be caused by stimulation of nerves in the 31 scalp. If you were to experience such a headache, it will respond quickly to simple pain 32 medication such as aspirin, ibuprofen, or paracetamol. 33 34 Scalp Sensation: During the treatment itself, you might feel a tapping or twitching 35 sensation on your scalp as the magnetic pulse stimulates muscles in your scalp as it 36 http://bmjopen.bmj.com/ passes into the brain. This sensation varies between people from very soft to quite 37 38 strong. If you find it uncomfortable, we will use a lower stimulation intensity and only 39 increase it as you find it tolerable. 40 41 Seizure: The main concern associated with rTMS is its potential to induce a fit or 42 seizure. This risk is extremely low, but is increased for those with a history of seizure 43 activity (where a seizure resulting from rTMS affects about 2% or 2 in 100 such
44 individuals). If you have ever experienced a seizure, or if your EEG shows evidence of on September 27, 2021 by guest. Protected copyright. 45 epileptiform activity, you will not be able to take part in this study. Investigators using 46 rTMS have developed safety guidelines to minimise the risk of seizure. The rTMS we 47 provide is well within what is considered to be safe. It is important to note that 48 experiencing a seizure induced by rTMS has never led to the development of epilepsy or 49 increased the probability of having subsequent unprovoked seizures. There will always 50 be medically trained staff available when you have rTMS. Staff will monitor you and 51 know how to treat a seizure should one occur. 52 53 The effects of rTMS on the unborn child and on the newborn baby are not known. Because of 54 this, it is important that research project participants are not pregnant or breast-feeding and do 55 not become pregnant during the course of the research project. You must not participate in the 56 57 research if you are pregnant or trying to become pregnant, or breast-feeding. If you are female 58 and child-bearing is a possibility, you will be required to undergo a urinal pregnancy test prior to 59 commencing rTMS. This test will be processed by a female member of the research staff. 60 If you do become pregnant whilst participating in the research project, you should advise research staff immediately. The researchers will withdraw you from the research project and Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 6 of 11 [Site Name] Site MasterFor peer Participant review Informationonly - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date]
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1 2 advise on further medical attention should this be necessary. You must not continue in the 3 research if you become pregnant.
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 Your ability to drive or use public transport will not be impaired following rTMS. 6 7 It is also possible that there are unknown risks of rTMS. 8 9 Magnetic Resonance Imaging (MRI) 10 11 MRI stands for magnetic resonance imaging. An MRI scanner is a machine that uses 12 electromagnetic radiation (radio waves) in a strong magnetic field to take clear pictures of the 13 inside of the body. Electromagnetic radiation is not the same as ionising radiation used, for 14 example, in X-rays. The pictures taken by the machine are called MRI scans. 15 16 There are no proven long-term risks related to MRI scans as used in this research project. MRI 17 is considered to be safe when performed at a centre with appropriate procedures. However, the 18 For peer review only 19 magnetic attraction for some metal objects can pose a safety risk, so it is important that metal 20 objects are not taken into the scanner room. 21 22 We will thoroughly examine you to make sure there is no reason for you not to have the scan. 23 You must tell us if you have metal implanted in your body, such as a pacemaker or metal pins. 24 25 The MRI scanner is shaped like a narrow tunnel. Foam cushioning and Velcro straps are used 26 to keep your head relatively still during scanning. While the mask, cushions, and straps are 27 restraining, they should not be uncomfortable. Some people may experience claustrophobia 28 while having an MRI scan. Please let us know if you have experienced claustrophobia in the 29 past. The MRI scanner is noisy, so you will wear ear plugs and headphones to reduce the noise. 30 We will be able to see you and communicate with you during the scanning, and you will be able 31 to stop the machine at any time by pushing a button. If you become uncomfortable during the 32 session, we can pause or stop the scanning. 33 34 The scans we are taking are for research purposes. They are not intended to be used like scans 35 taken for a full clinical examination. The scans will not be used to help diagnose, treat, or 36 http://bmjopen.bmj.com/ manage a particular condition. A specialist will look at your MRI scans for features relevant to 37 38 the research project. On rare occasions, the specialist may find an unusual feature that could 39 have a significant risk to your health. If this happens, we will contact you to talk about the 40 findings. We cannot guarantee that we will find any/all unusual features. There may be wider 41 implications from abnormal findings (e.g., for future applications for some kinds of insurance). 42 43 Other
44 on September 27, 2021 by guest. Protected copyright. 45 We will ask you if you have used illegal drugs. That information will be stored in a re-identifiable 46 (or coded) format. In the event that the researchers are required to disclose that information, it 47 may be used against you in legal proceedings or otherwise. 48 49 If you become upset or distressed as a result of your participation in the research, the study 50 doctor will be able to arrange for counselling or other appropriate support. Any counselling or 51 support will be provided by qualified staff who are not members of the research project team. 52 This counselling will be provided free of charge. 53 54 9 What will happen to my test samples? 55
56 57 You will be asked to provide additional consent for the collection of your tissue (i.e., cheek 58 swab) during the research project. As noted, these samples are collected to allow us to 59 investigate whether certain genetic profiles are associated with a better response to the rTMS 60 intervention. We will only conduct these analyses at a group level. You will not receive any health information (e.g., genetic disease predisposition) from these genetic analyses, and they are not considered to be clinically informative. Your genetic material and information, where Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 7 of 11 [Site Name] Site MasterFor peer Participant review Informationonly - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date]
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1 2 identified or potentially identifiable, will not be released for other uses without your prior consent, 3 unless required by law.
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 Samples of your tissue obtained for the purpose of this research project will be transferred to 6 the Institute for Molecular Bioscience, University of Queensland, who will charge a fee to the 7 research team to recover some of the costs of storing and administering the tissue samples. 8 The University of Queensland will not transfer or sell your samples to any third party. 9 10 10 What if new information arises during this research project? 11 12 Sometimes during the course of a research project, new information becomes available about 13 the treatment that is being studied. If this happens, your study doctor will tell you about it and 14 discuss with you whether you want to continue in the research project. If you decide to 15 withdraw, your study doctor will make arrangements for your regular health care to continue. If 16 you decide to continue in the research project you will be asked to sign an updated consent 17 form. 18 For peer review only 19 20 Also, on receiving new information, your study doctor might consider it to be in your best 21 interests to withdraw you from the research project. If this happens, your study doctor will 22 explain the reasons and arrange for your regular health care to continue. 23 24 11 Can I have other treatments during this research project? 25 26 Whilst you are participating in this research project, you can continue to take the medications or 27 treatments you have been taking for your condition or for other reasons. It is important to tell the 28 research staff about any treatments or medications you may be taking, including over-the- 29 counter medications, vitamins or herbal remedies, acupuncture, or other alternative treatments. 30 You should also tell the study staff about any changes to these during your participation in the 31 research project. 32 33 Because this trial is assessing the effect of rTMS on social communication, you cannot 34 participate if you are also undergoing any other treatment or intervention for social 35 communication. This includes interventions delivered by psychologists. 36 http://bmjopen.bmj.com/
37 38 12 What if I withdraw from this research project? 39 40 If you decide to withdraw from the project, please notify a member of the research team before 41 you withdraw. This notice will allow that person or the research supervisor to discuss any health 42 risks or special requirements linked to withdrawing. 43
44 If you do withdraw your consent during the research project, the study doctor and relevant study on September 27, 2021 by guest. Protected copyright. 45 staff will not collect additional personal information from you, although personal information 46 already collected will be retained to ensure that the results of the research project can be 47 measured properly and to comply with law. You should be aware that data collected up to the 48 time you withdraw will form part of the research project results. If you do not want the 49 researchers to do this, you must tell them before you join the research project. 50 51 13 Could this research project be stopped unexpectedly? 52 53 This research project may be stopped unexpectedly for a variety of reasons. These may include 54 reasons such as: 55
56 57 • Unacceptable side effects 58 • The drug/treatment/device being shown not to be effective 59 • The drug/treatment/device being shown to work and not need further testing 60 • Decisions made by local regulatory/health authorities.
14 What happens when the research project ends? Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 8 of 11 [Site Name] Site MasterFor peer Participant review Informationonly - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date]
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1 2 3 You will be sent a summary of the main findings when the project has been completed. This is a
4 4-year study and it is expected that study results will be available by late 2024. Your data will BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 then be securely archived at Deakin University. 6 7 Please note that rTMS will not be available from the research sites after completing the study. It 8 may be approved for future use in ASD, but this will depend on the results from the current 9 study. 10 11 Part 2 How is the research project being conducted? 12 13 14 15 What will happen to information about me? 15 16 By signing the consent form, you consent to the study doctor and relevant research staff 17 collecting and using personal information about you for the research project. Any information 18 obtained in connectionFor with this peer research projectreview that can identify only you will remain confidential. 19 Upon enrolment in the trial you will be allocated a unique study identification code. Your name 20 will not appear with the research data that we collect from you and it will only be possible to re- 21 identify your data using the study code. Only the research team will know which code identifies 22 which participant. Your information will only be used for the purpose of this research project and 23 future research projects, and it will only be disclosed with your permission, except as required 24 by law. 25 26 Information about you may be obtained from your health records held at this and other health 27 services for the purpose of this research. By signing the consent form, you agree to the study 28 team accessing health records if they are relevant to your participation in this research project. 29 30 Your health records and any information obtained during the research project are subject to 31 inspection (for the purpose of verifying the procedures and the data) by the relevant authorities 32 33 and authorised representatives of the Sponsor, Deakin University, the institution relevant to this 34 Participant Information Sheet, [Name of institution], or as required by law. By signing the 35 Consent Form, you authorise release of, or access to, this confidential information to the
36 relevant study personnel and regulatory authorities as noted above. http://bmjopen.bmj.com/ 37 38 It is anticipated that the results of this research project will be published and/or presented in a 39 variety of forums. In any publication and/or presentation, information will be provided in such a 40 way that you cannot be identified, except with your permission. We will only present group-level 41 findings (e.g., average scores across the group) and no individual data will be reported. 42 43 In accordance with relevant Australian and/or [Name of state/territory] privacy and other relevant
44 laws, you have the right to request access to your information collected and stored by the on September 27, 2021 by guest. Protected copyright. 45 research team. You also have the right to request that any information with which you disagree 46 be corrected. Please contact the study team member named at the end of this document if you 47 would like to access your information. 48 49 Any information obtained for the purpose of this research project and for future research that 50 can identify you will be treated as confidential and securely stored. It will be disclosed only with 51 52 your permission, or as required by law. 53 54 It is expected that deidentified data from this study will be made available to other researchers 55 via online data repositories. You will not be able to be identified in these repositories. It is also 56 possible that the research team will use your data from this research project for future studies, 57 but again you will not be able to be identified. 58 59 16 Complaints and compensation 60 If you suffer any injuries or complications as a result of this research project, you should contact the study team as soon as possible and you will be assisted with arranging appropriate medical Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 9 of 11 [Site Name] Site MasterFor peer Participant review Informationonly - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date]
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1 2 treatment. If you are eligible for Medicare, you can receive any medical treatment required to 3 treat the injury or complication, free of charge, as a public patient in any Australian public
4 hospital. BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 If you have complaints about your treatment by members of staff working on this research 7 project, you should contact the person nominated in Section 19 below. If you have complaints 8 about any of the ethical aspects of this study, you can contact the local reviewing HREC 9 Executive Officer nominated in Section 19 below. Complaints about clinical trials can also be 10 directed to the Office of the Australian Information Commissioner. 11 12 17 Who is organising and funding the research? 13 14 This research project is being conducted by a team of researchers led by Prof. Peter Enticott 15 from Deakin University, Victoria. It is funded through a Medical Research Future Fund grant 16 from the National Health and Medical Research Council to Prof. Enticott and the research team. 17
18 For peer review only 19 No member of the research team will receive a personal financial benefit from your involvement 20 in this research project (other than their ordinary wages). 21 22 18 Who has reviewed the research project? 23 24 All research in Australia involving humans is reviewed by an independent group of people called 25 a Human Research Ethics Committee (HREC). The ethical aspects of this research project 26 have been approved by the HREC of Monash Health and [Name of institutions]. 27 28 This project will be carried out according to the National Statement on Ethical Conduct in 29 Human Research (2018). This statement has been developed to protect the interests of people 30 who agree to participate in human research studies. 31 32 19 Further information and who to contact 33 34 The person you may need to contact will depend on the nature of your query. 35
36 http://bmjopen.bmj.com/ If you want any further information concerning this project or if you have any medical problems 37 38 that may be related to your involvement in the project (for example, any side effects), you can 39 contact your site’s principal study doctor on [phone number] or any of the following people: 40 41 Study contact person 42 Name [Name] 43 Position [Position]
44 Telephone [Phone number] on September 27, 2021 by guest. Protected copyright. 45 Email [Email address] 46 47 Clinical contact person 48 49 Name [Name] 50 Position [Position] 51 Telephone [Phone number] 52 Email [Email address] 53 54 For matters relating to research at the site at which you are participating, the details of the local 55 site complaints person are: 56 57 Complaints contact person 58 Name [Name] 59 Position [Position] 60 Telephone [Phone number] Email [Email address] Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 10 of 11 [Site Name] Site MasterFor peer Participant review Informationonly - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date]
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1 2 3 If you have any complaints about any aspect of the project, the way it is being conducted or any
4 questions about being a research participant in general, then you may contact: BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Reviewing HREC approving this research and HREC Executive Officer details 7 8 Reviewing HREC name Monash Health 9 HREC Executive Officer Ms Deborah Dell 10 Telephone (03) 9594 4605 11 Email [email protected] 12 13 Local HREC Office contact (Single Site - Research Governance Officer) 14 Name [Name] 15 Position [Position] 16 17 Telephone [Phone number] 18 Email For[Email peer address] review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43
44 on September 27, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 Consent Form - Adult providing own consent 3 Does repetitive transcranial magnetic stimulation 4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from (rTMS), compared to sham rTMS, improve social 5 Title 6 communication in adolescents and young adults 7 with autism spectrum disorder (ASD)? 8 Short Title MRFF RTMS-ASD 9 10 Protocol Number v2, 11/09/2020 11 Project Sponsor Deakin University 12 Coordinating Principal Investigator Prof. Peter Enticott 13 14 Prof. Paul Fitzgerald, A/Prof. Karen Barlow, Prof. 15 Ian Hickie, Dr Melissa Licari, Dr Nigel Rogasch, 16 Prof. Christel Middeldorp, Dr Scott Clark, Dr Ann- 17 Maree Vallence, Dr Kelsie Boulton, Prof. Adam 18 Associate Investigator(s)For peer Guastella,review Prof. Andrew only Whitehouse, Prof. 19 Cherrie Galletly, Dr Gail Alvares, Dr Hakuei 20 Fujiyama, A/Prof. Helen Heussler, A/Prof. Jeffrey 21 Craig, Dr Melissa Kirkovski, Dr Natalie Mills, Prof. 22 Nicole Rinehart, Dr Peter Donaldson, Dr Talitha 23 Ford, Prof. Karen Caeyenberghs 24 25 Location [Location where the research will be conducted] 26 27 28 Consent Agreement 29 I have read the Participant Information Sheet. 30 I understand the purposes, procedures and risks of the research described in the project. 31 32 I give permission for my doctors, other health professionals, hospitals or laboratories outside 33 this hospital to release information to [Name of Institution] concerning my condition and 34 treatment for the purposes of this project. I understand that such information will remain 35 confidential. 36 http://bmjopen.bmj.com/ 37 38 I have had an opportunity to ask questions and I am satisfied with the answers I have received.
39 I freely agree to participate in this research project as described and understand that I am free 40 to withdraw at any time during the study without affecting my future health care. 41 42 I understand that I will be given a signed copy of this document to keep. 43 44 I agree for my anonymous study data to be shared with other researchers, including those on September 27, 2021 by guest. Protected copyright. 45 outside [Name of Institution] and outside Australia, for future studies. 46
47 48 I agree to my anonymised data being made available through online repositories and to the use 49 of my data in any future research. 50 51 Declaration by Participant – for participants who have read the information 52 53 Name of Participant (please print) ______54 55 Signature ______Date ______56 57 58 59 60
Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 1 of 2 [Site Name] Site Master Participant Information Sheet/Consent Form [Date]
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1 Declaration by Study Doctor/Senior Researcher† 2 I have given a verbal explanation of the research project, its procedures and risks and I believe 3 that the participant has understood that explanation.
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from
5 Name of Study Doctor/ 6 Senior Researcher† (please print) 7
8 9 Signature Date 10 † A senior member of the research team must provide the explanation of, and information concerning, the research 11 project. 12 Note: All parties signing the consent section must date their own signature. 13 14 I consent to the storage and use of tissue samples (cheek swabs) taken from me for use, as 15 described in the relevant section of the Participant Information Sheet, for: 16 • This specific research project 17 • Other research that is closely related to this research project 18 • Any future researchFor. peer review only 19
20 By signing this consent section, I agree to the use of my tissue samples for genetic testing, as 21 outlined in the relevant Section of the Participant Information Sheet. 22 23 24 Name of Participant (please print) 25 26 Signature Date 27 28 29
30 Name of Study Doctor/ 31 Senior Researcher† (please print) 32 33 34 Signature Date 35 † A senior member of the research team must provide the explanation of and information concerning the research 36 project. http://bmjopen.bmj.com/ 37 Note: All parties signing the consent section must date their own signature. 38 39 40 41 42 43
44 on September 27, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 Form for Withdrawal of Participation - Adult providing own consent 3
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Does repetitive transcranial magnetic stimulation 7 (rTMS), compared to sham rTMS, improve social Title 8 communication in adolescents and young adults 9 with autism spectrum disorder (ASD)? 10 11 Short Title MRFF RTMS-ASD 12 Protocol Number v2, 11/09/2020 13 Project Sponsor Deakin University 14 15 Coordinating Principal Investigator Prof. Peter Enticott
16 Prof. Paul Fitzgerald, A/Prof. Karen Barlow, Prof. 17 Ian Hickie, Dr Melissa Licari, Dr Nigel Rogasch, 18 For peer Prof.review Christel Middeldorp, only Dr Scott Clark, Dr Ann- 19 20 Maree Vallence, Dr Kelsie Boulton, Prof. Adam 21 Associate Investigator(s) Guastella, Prof. Andrew Whitehouse, Prof. 22 Cherrie Galletly, Dr Gail Alvares, Dr Hakuei 23 Fujiyama, A/Prof. Helen Heussler, A/Prof. Jeffrey 24 Craig, Dr Melissa Kirkovski, Dr Natalie Mills, Prof. 25 Nicole Rinehart, Dr Peter Donaldson, Dr Talitha 26 Ford, Prof. Karen Caeyenberghs 27 28 Location [Location where the research will be conducted] 29 30 Declaration by Participant 31 32 I wish to withdraw from participation in the above research project and understand that such 33 withdrawal will not affect my routine treatment, my relationship with those treating me or my 34 relationship with [Institution]. 35 36 http://bmjopen.bmj.com/ 37 Name of Participant (please print) 38 39 Signature Date 40 41 42 Description of circumstances where communicated verbally: 43
44 on September 27, 2021 by guest. Protected copyright. 45 46 47 Declaration by Study Doctor/Senior Researcher† 48 49 I have given a verbal explanation of the implications of withdrawal from the research project and 50 I believe that the participant has understood that explanation. 51 52 53 Name of Study Doctor/ † 54 Senior Researcher (please print) 55 56 Signature Date 57 † 58 A senior member of the research team must provide the explanation of and information concerning withdrawal from 59 the research project. 60 Note: All parties signing the consent section must date their own signature. Master Adult Participant Information Sheet/Consent Form 11/09/2020 Page 1 of 1 [Site Name] Site Master Participant Information Sheet/Consent Form [Date]
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1 2 3 Insert Header with institution’s name or institution’s letterhead
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Participant Information Sheet/Consent Form 7 Interventional Study - Parent/Guardian consenting on behalf of participant 8 9 [Insert site name] 10 11 Does repetitive transcranial magnetic stimulation 12 (rTMS), compared to sham rTMS, improve social 13 Title 14 communication in adolescents and young adults 15 with autism spectrum disorder (ASD)? 16 Short Title MRFF TBS-ASD 17 Protocol Number v2, 11/09/2020 18 Project Sponsor For peer reviewDeakin University only 19 20 Coordinating Principal Investigator Prof. Peter Enticott 21 22 23 Prof. Paul Fitzgerald, A/Prof. Karen Barlow, Prof. 24 Ian Hickie, Dr Melissa Licari, Dr Nigel Rogasch, 25 Prof. Christel Middeldorp, Dr Scott Clark, Dr Ann- 26 Maree Vallence, Dr Kelsie Boulton, Prof. Adam 27 Associate Investigator(s) Guastella, Prof. Andrew Whitehouse, Prof. 28 Cherrie Galletly, Dr Gail Alvares, Dr Hakuei 29 Fujiyama, A/Prof. Helen Heussler, A/Prof. Jeffrey 30 Craig, Dr Melissa Kirkovski, Dr Natalie Mills, Prof. 31 Nicole Rinehart, Dr Peter Donaldson, Dr Talitha 32 Ford, Prof. Karen Caeyenberghs 33 34 Location [Insert site-specific location] 35
36 http://bmjopen.bmj.com/ 37
38 39 Part 1 What does the child’s participation involve? 40 41 1 Introduction 42 43 This is an invitation for the child in your care to take part in this research project because they
44 have been diagnosed with autism spectrum disorder (ASD). The research project is testing a on September 27, 2021 by guest. Protected copyright. 45 new treatment for ASD. The new treatment is called repetitive transcranial magnetic stimulation 46 (rTMS). 47 48 This Participant Information Sheet/Consent Form tells you about the research project. It 49 explains the tests and treatments involved. Knowing what is involved will help you decide if you 50 want your child to take part in the research. 51
52 53 Please read this information carefully. Ask questions about anything that you don’t understand 54 or want to know more about. Before deciding whether or not your child can take part, you might 55 want to talk about it with a relative, friend or your child’s local doctor. 56 57 Participation in this research is voluntary. If you do not wish your child to take part, they do not 58 have to. Your child will receive the best possible care whether or not they take part. 59 60 If you decide you want your child to take part in the research project, you will be asked to sign the consent section. By signing it you are telling us that you: • Understand what you have read Master Parent/Guardian Participant Information Sheet/Consent Form 11/09/2020 Page 1 of 11 [Site Name] Site MasterFor peer Participant review onlyInformation - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date]
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1 2 • Consent to your child taking part in the research project 3 • Consent for your child to have the tests and treatments that are described
4 • Consent to the use of your child’s personal and health information as described. BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 You will be given a copy of this Participant Information and Consent Form to keep. 7 8 2 What is the purpose of this research? 9 10 Many individuals with ASD experience difficulty with social functioning; for example, in 11 understanding what other people are thinking or feeling. This may cause significant distress and 12 lead to difficulties and anxiety in social situations. There are very few treatment options for 13 improving abilities related to social functioning in ASD. 14 15 The aim of this project is to determine whether rTMS can be used to improve social function. 16 rTMS is a safe and non-invasive means of stimulating nerve cells in a particular part of the brain 17 via the administration of brief magnetic pulses. rTMS has been developed as a treatment for 18 For peer review only 19 major depressive disorder, and we have previously found that rTMS can benefit social aspects 20 of ASD. 21 22 In this study we will stimulate a region of the brain that is involved in social understanding and 23 social communication. This region is called the right temporoparietal junction, or rTPJ. 24 25 Some participants will receive the real form of rTMS, while others will receive a sham or placebo 26 form. The sham or placebo form mimics the feeling of rTMS, but no brain stimulation is 27 delivered. You will not know which one your child receives until the end of your involvement in 28 the study. Those who received the sham or placebo form will be given the opportunity to 29 undergo the real rTMS treatment at the end of their involvement in the study. 30 31 150 people (aged 14-40 years) will take part in this study, which is being conducted throughout 32 Australia. There are sites in Brisbane, Sydney, Melbourne, Adelaide, and Perth. Participants will 33 be recruited from around Australia, but primarily the greater metropolitan regions within these 34 five cities. 35
36 http://bmjopen.bmj.com/ rTMS is an experimental treatment. This means that it is not an approved treatment for ASD in 37 38 Australia or elsewhere. 39 40 This research has been initiated by the study investigator, Prof. Peter Enticott (Deakin 41 University, Melbourne). This research has been funded by the National Health and Medical 42 Research Council (NHMRC) of Australian through a Medical Research Future Fund grant 43 (MRFF RCRDUN Neurological Disorders 2020; Application APP1199298).
44 on September 27, 2021 by guest. Protected copyright. 45 46 3 What does participation in this research involve? 47 48 Your child will be participating in a randomised controlled research project. Sometimes we do 49 not know which treatment is best for treating a condition. To find out we need to compare 50 different treatments. We put people into groups and give each group a different treatment (in 51 this case, real RTMS vs. sham/placebo RTMS). The results are compared to see if one is 52 better. To try to make sure the groups are the same, each participant is put into a group by 53 chance (random). 54
55 This is a double-blind study. This means that it will not be known which of the treatments your 56 57 child is receiving (in this case, real rTMS or sham/placebo rTMS); the study doctor will also not 58 know. However, in certain circumstances your study doctor can find out which treatment your 59 child is receiving. Participants will be randomly allocated to either the real rTMS or 60 sham/placebo RTMS condition. As mentioned, those allocated to the sham or placebo form will be given the opportunity to undergo the real rTMS treatment at the end of their involvement in the study. Master Parent/Guardian Participant Information Sheet/Consent Form 11/09/2020 Page 2 of 11 [Site Name] Site MasterFor peer Participant review onlyInformation - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date]
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1 2 3 This research project has been designed to make sure the researchers interpret the results in a
4 fair and appropriate way and avoids study doctors or participants jumping to conclusions. BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 If you decide that your child can participate in this research project, you and your child will be 7 asked to take part in a number of interviews and procedures over the course of approximately 8 eight months. These are outlined below. You (or another parent/guardian of the child) must 9 attend each session with your child. 10 11 Prior to completing the study, we will need to determine your child’s eligibility to take part in the 12 study. We will do this by asking you questions (either over the phone or via email) about their 13 health. We will also ask you to provide a letter or report confirming your child’s diagnosis of 14 ASD; if you are not able to provide this, we will seek permission (via the consent form) to 15 contact your child’s doctor or psychologist directly to confirm their diagnosis. 16
17 Assessment Session One: The first assessment will take place at [site-specific location]. It will 18 For peer review only 19 take approximately three hours, but your child will be given regular breaks throughout the 20 session. 21 22 We will begin by asking you some questions about your child’s health, which will help to confirm 23 their eligibility to take part in the study. We will then ask you some questions about your child 24 that are relevant to ASD. This will include, for example, what they enjoy doing and how much 25 they like being with other people. 26 27 Your child will complete a short cognitive assessment, which involves solving puzzles and 28 describing what different words mean. 29 30 Finally, your child will undergo electroencephalography (EEG), which involves wearing an 31 “electrode cap” to measure the electrical activity of their brain, or their “brainwaves.” The 32 electrode cap feels similar to a swimming cap. It will also feel a little damp, as we need to put a 33 small amount of gel or saline into the cap to ensure that we get accurate recordings. For most of 34 the EEG your child will simply rest while sitting in a chair, but your child will also complete a 35 short task on a computer that involves looking at different objects (e.g., faces, household 36 http://bmjopen.bmj.com/ furniture, butterflies). 37 38 39 Assessment Session Two: Around one-week after “Assessment Session One” your child will 40 then undergo a magnetic resonance imaging (MRI) brain scan at [site-specific location]. The 41 MRI brain scan takes around 45-60 minutes, during which they will be asked to lie still in an MRI 42 scanner. (Please note that with preparation time you attend the MRI facility for up to two hours.) 43 MRI is a routinely performed, painless ways of examining brain structure and activity. We will
44 use the MRI to accurately place the rTMS device and ensure that we are stimulating the correct on September 27, 2021 by guest. Protected copyright. 45 brain region. The MRI procedure may also help us better understand how the treatment works 46 and to determine who is likely to respond to treatment and why. 47 48 Assessment Session Three: During the same week of “Assessment Session Two,” you and 49 your child will attend a two-hour assessment session at [site-specific location]. Here we will ask 50 you questions about your child, some of which are relevant to ASD, while others relate to their 51 concentration and behaviour. Your child will also be asked some questions about their mood, 52 stress, and satisfaction with life. We will also ask your child to complete some cognitive tasks on 53 a computer/tablet. These tasks measure their memory, attention, and understanding of other 54 people’s emotions. We will also ask your child to provide a sample for genetic analysis; this will 55 involve them having a cotton swab rubbed against the inside of their cheek. These genetic 56 57 analyses are conducted to investigate whether people with certain genetic profiles respond 58 better to the intervention. You will not receive any health information from these genetic 59 analyses, and they are not considered to be clinically informative. 60 rTMS Intervention (4 weeks): The week after “Assessment Session Three” your child will begin the rTMS intervention, which involves attending [site-specific location] and receiving rTMS Master Parent/Guardian Participant Information Sheet/Consent Form 11/09/2020 Page 3 of 11 [Site Name] Site MasterFor peer Participant review onlyInformation - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date]
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1 2 for 3 minutes, 20 seconds each consecutive weekday for a four-week period (20 RTMS 3 sessions in total).
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 Your child will have their first rTMS session on the Monday after “Assessment Session Three.” 6 At the beginning of the first session we will administer transcranial magnetic stimulation (TMS) 7 to the area of the brain that controls the muscles in their hand. This will measure how excitable 8 their brain is and is used to help us determine the personalised settings that will be used for 9 their rTMS treatments. This takes approximately 10 minutes and is not uncomfortable, although 10 they may feel some twitches in the muscle of their hand while the TMS is occurring. 11 12 During each rTMS session your child will be awake, alert, and aware of what is happening at all 13 times. During rTMS a coil will be placed against their head, through which rTMS is administered. 14 This is connected to a machine that sends an electrical current through the coil. The current 15 produces a magnetic field that is very focused and is able to stimulate electrical activity in 16 nerves below the coil. These are usually nerve cells in the outer layers of the brain. The 17 sensations associated with rTMS are mild, and most people describe it as a “tapping” sensation 18 For peer review only 19 on their head. During an rTMS procedure, your child will hear clicking sounds as the current 20 passes through the coil. Your child will wear earplugs so that this noise doesn’t disturb them. 21 22 Including setup time, each subsequent treatment session should only take approximately 10 23 minutes. At the end of each treatment week (i.e., on the Friday session) we will ask you and 24 your child a number of questions about their experience of RTMS, and whether you feel that 25 they have experienced any side effects. 26 27 Assessment Session Four: The week after your child’s last RTMS session, you and your child 28 will attend another two-hour assessment session at [site-specific location]. Here we will again 29 ask you questions about your child, some of which are relevant to ASD, while others relate to 30 their concentration and behaviour. Your child will also be asked some questions about their 31 mood, stress, and satisfaction with life. We will also again ask your child to complete some 32 cognitive tasks on a computer/tablet and to provide another sample (cheek swab) for genetic 33 analysis. 34 35 Assessment Session Five: One-month after your child’s last RTMS session, you and your 36 http://bmjopen.bmj.com/ child will attend another two-hour assessment session at [site-specific location]. This session 37 38 will be identical to Assessment Session Four. 39 40 Assessment Session Six: Three-months after your child’s last RTMS session, you and your 41 child will attend a one-hour assessment session at [site-specific location]. This session will be 42 identical to Assessment Session Five except that your child will not complete the computerised 43 cognitive tasks.
44 on September 27, 2021 by guest. Protected copyright. 45 Assessment Session Seven: Six-months after your child’s last RTMS session, you and your 46 child will attend a final two-hour assessment session at [site-specific location]. This session will 47 be identical to Assessment Session Four. Following the assessment you will be unblinded; that 48 is, a member of the research team will tell you and your child which treatment condition your 49 child received (i.e., real or sham/placebo). If your child received the real treatment, you and your 50 child’s involvement in the study will conclude. If your child received the sham/placebo condition, 51 your child will be given the opportunity to receive the real treatment. You can liaise with 52 research staff to determine when you would like your child to undergo this four-week treatment. 53 54 There are no costs associated with participating in this research project. All treatments, tests, 55 and medical care required as part of the research project will be provided to your child free of 56 57 charge. 58 59 You will not be paid for you and your child’s participation in this research, but you will be 60 reimbursed $200 to contribute towards costs that you incur as a result of participating in this research project (e.g., travel). If you complete only part of the study and then decide to
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1 2 withdraw, you will be reimbursed a proportion of this amount based on the proportion of the 3 study completed.
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 Please note that no study procedures will be performed until consent has been obtained. 6 7 It is desirable that your child’s local doctor be advised of your decision for your child to 8 participate in this research project. If you have a local doctor, we strongly recommend that you 9 inform them of your child’s participation in this research project. 10 11 The research will be monitored by an independent Data Safety Monitoring Board, who will meet 12 twice per year and review the conduct of the trial, monitor study data, and review any serious 13 adverse events that might arise throughout the trial. 14 15 4 What does the child have to do? 16
17 Your child will be able to continue taking their usual medication if they participate in this study, 18 For peer review only 19 but you will need to inform us of any changes to this medication that occur during their 20 participation in the study. 21 22 There are several reasons why your child may not be able to take part in this study. These 23 include: 24 25 • The presence of metal anywhere in the head (except the mouth) 26 • A history of seizure or epilepsy, or evidence of significant seizure activity as assessed by 27 EEG 28 • A history of serious head injury 29 30 • The presence of certain implanted medical devices (e.g., cardiac pacemaker, medication 31 pumps) 32 • Serious heart disease (as there is an increased risk of serious injury in the event of a 33 seizure) 34 • Being deemed unsuitable to undergo MRI (e.g., due to presence of metal in the body) 35 • Unstable medical condition 36 • Unstable medication regime http://bmjopen.bmj.com/ 37 • Certain medications 38 39 • Substance use disorder 40 • Undergoing another current treatment for social communication 41 • Employment as a professional driver or machine operator (as the event of a seizure may 42 affect employment) 43 • Pregnancy (female participants for whom child-bearing is a possibility will be required to
44 undergo a urine screen) on September 27, 2021 by guest. Protected copyright. 45 • Certain neurological or psychiatric diagnoses (i.e., those not commonly associated with 46 ASD, such as psychosis) 47 • A measured verbal intelligence quotient (IQ) of less than 55 48 49 5 Other relevant information about the research project 50
51 52 This study is only taking place in Australia. There will be 150 participants in this study, with 30 53 taking part in each of the five cities involved: Brisbane, Sydney, Melbourne, Adelaide, and 54 Perth. There are a total of 14 organisations involved, including Universities, hospitals, and 55 medical centres. This study is a follow-on study from our previous trials of rTMS in ASD, which 56 have taken place at Monash University, Deakin University, The Alfred hospital, and the Epworth 57 Camberwell. 58 59 6 Does the child have to take part in this research project? 60
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1 2 Participation in any research project is voluntary. If you do not wish for the child to take part, 3 they do not have to. If you decide that they can take part and later change your mind, you are
4 free to withdraw the child from the project at any stage. BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 If you do decide that the child can take part, you will be given this Participant Information and 7 Consent Form to sign and you will be given a copy to keep. If your child has the capacity to 8 provide informed consent, they may also sign the consent form. 9 10 Your decision that the child can or cannot take part, or that they can take part and then be 11 withdrawn, will not affect their routine treatment, relationship with those treating them, or their 12 relationship with [site-specific Institution/s]. 13 14 7 What are the possible benefits of taking part? 15 16 We cannot guarantee or promise that your child will receive any benefits from this research; 17 however, possible benefits include an improvement in social understanding and functioning, 18 For peer review only 19 including an increased ability to accurately infer what other people are thinking or feeling. 20 21 8 What are the possible risks and disadvantages of taking part? 22 23 Repetitive Transcranial Magnetic Stimulation (rTMS) 24 25 Medical treatments often cause side effects. Your child may have none, some, or all of the 26 effects listed below, and they may be mild, moderate, or severe. If your child has any of these 27 side effects, or you are worried about them, talk with your study doctor. Your child’s study doctor 28 will also be looking out for side effects. 29 30 There may be side effects that the researchers do not expect or do not know about and that 31 may be serious. Tell your study doctor immediately about any new or unusual symptoms that 32 your child gets. 33 34 Many side effects go away shortly after treatment ends. However, sometimes side effects can 35 be serious, long lasting, or permanent. If a severe side effect or reaction occurs, your study 36 http://bmjopen.bmj.com/ doctor may need to stop your child’s treatment. The child’s study doctor will discuss the best 37 38 way of managing any side effects with you. 39 40 Noise: The clicking noise made by the coil may be uncomfortable. Your child will wear 41 earplugs during treatment to minimise any discomfort. 42 43 Headache: A headache can occur during rTMS and is thought to affect approximately
44 3% or 3 in 100 participants. It is thought to be caused by stimulation of nerves in the on September 27, 2021 by guest. Protected copyright. 45 scalp. If your child were to experience such a headache, it will respond quickly to simple 46 pain medication such as aspirin, ibuprofen, or paracetamol. 47 48 Scalp Sensation: During the treatment itself, your child might feel a tapping or twitching 49 sensation on their scalp as the magnetic pulse stimulates muscles in their scalp as it 50 passes into the brain. This sensation varies between people from very soft to quite 51 strong. If your child finds it uncomfortable, we will use a lower stimulation intensity and 52 only increase it as they find it tolerable. 53 54 Seizure: The main concern associated with rTMS is its potential to induce a fit or 55 seizure. This risk is extremely low, but is increased for those with a history of seizure 56 57 activity (where a seizure resulting from rTMS affects about 2% or 2 in 100 such 58 individuals). If your child has ever experienced a seizure, or if their EEG shows evidence 59 of epileptiform activity, they will not be able to take part in this study. Investigators using 60 rTMS have developed safety guidelines to minimise the risk of seizure. The RTMS we provide is well within what is considered to be safe. It is important to note that experiencing a seizure induced by rTMS has never led to the development of epilepsy or Master Parent/Guardian Participant Information Sheet/Consent Form 11/09/2020 Page 6 of 11 [Site Name] Site MasterFor peer Participant review onlyInformation - http://bmjopen.bmj.com/site/about/guidelines.xhtml Sheet/Consent Form [Date]
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1 2 increased the probability of having subsequent unprovoked seizures. There will always 3 be medically trained staff available when your child has rTMS. Staff will monitor your
4 child and know how to treat a seizure should one occur. BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 The effects of rTMS on the unborn child and on the newborn baby are not known. Because of 7 this, it is important that research project participants are not pregnant or breast-feeding and do 8 not become pregnant during the course of the research project. Individuals must not participate 9 in the research if they are pregnant or trying to become pregnant, or breast-feeding. If your child 10 is female and child-bearing is a possibility, they will be required to undergo a urinal pregnancy 11 test prior to commencing rTMS. This test will be processed by a female member of the research 12 staff. 13 14 If a participant becomes pregnant whilst participating in the research project, they should advise 15 research staff immediately. The researchers will withdraw them from the research project and 16 advise on further medical attention should this be necessary. An individual must not continue in 17 the research if they become pregnant. 18 For peer review only 19 20 The ability to drive or use public transport will not be impaired following rTMS. 21 22 It is also possible that there are unknown risks of rTMS. 23 24 Magnetic Resonance Imaging (MRI) 25 26 MRI stands for magnetic resonance imaging. An MRI scanner is a machine that uses 27 electromagnetic radiation (radio waves) in a strong magnetic field to take clear pictures of the 28 inside of the body. Electromagnetic radiation is not the same as ionising radiation used, for 29 example, in X-rays. The pictures taken by the machine are called MRI scans. 30 31 There are no proven long-term risks related to MRI scans as used in this research project. MRI 32 is considered to be safe when performed at a centre with appropriate procedures. However, the 33 magnetic attraction for some metal objects can pose a safety risk, so it is important that metal 34 objects are not taken into the scanner room. 35
36 http://bmjopen.bmj.com/ We will thoroughly examine your child to make sure there is no reason for them not to have the 37 38 scan. You must tell us if your child has metal implanted in their body, such as a pacemaker or 39 metal pins. 40 41 The MRI scanner is shaped like a narrow tunnel. Foam cushioning and Velcro straps are used 42 to keep your child’s head relatively still during scanning. While the mask, cushions and straps 43 are restraining, they should not be uncomfortable. Some people may experience claustrophobia
44 while having an MRI scan. Please let us know if your child has experienced claustrophobia in on September 27, 2021 by guest. Protected copyright. 45 the past. The MRI scanner is noisy, so your child will wear ear plugs and headphones to reduce 46 the noise. We will be able to see your child and communicate with them during the scanning, 47 and they will be able to stop the machine at any time by pushing a button. If they become 48 uncomfortable during the session, we can pause or stop the scanning. 49 50 The scans we are taking are for research purposes. They are not intended to be used like scans 51 taken for a full clinical examination. The scans will not be used to help diagnose, treat, or 52 manage a particular condition. A specialist will look at your child’s MRI scans for features 53 relevant to the research project. On rare occasions, the specialist may find an unusual feature 54 that could have a significant risk to your child’s health. If this happens, we will contact you to talk 55 about the findings. We cannot guarantee that we will find any/all unusual features. There may 56 57 be wider implications from abnormal findings (e.g., for future applications for some kinds of 58 insurance). 59 60 Other
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1 2 We will ask you and your child if they have used illegal drugs. That information will be stored in 3 a re-identifiable (or coded) format. In the event that the researchers are required to disclose that
4 information, it may be used against them in legal proceedings or otherwise. BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 If you or your child become upset or distressed as a result of your participation in the research, 7 the study doctor will be able to arrange for counselling or other appropriate support. Any 8 counselling or support will be provided by qualified staff who are not members of the research 9 project team. This counselling will be provided free of charge. 10 11 9 What will happen to the child’s test samples? 12 13 You will be asked to provide additional consent for the collection of your child’s tissue (i.e., 14 cheek swab) during the research project. As noted, these samples are collected to allow us to 15 investigate whether certain genetic profiles are associated with a better response to the rTMS 16 intervention. We will only conduct these analyses at a group level. You will not receive any 17 health information (e.g., genetic disease predisposition) from these genetic analyses, and they 18 For peer review only 19 are not considered to be clinically informative. Your child’s genetic material and information, 20 where identified or potentially identifiable, will not be released for other uses without your prior 21 consent, unless required by law. 22 23 Samples of your child’s tissue obtained for the purpose of this research project will be 24 transferred to the Institute for Molecular Bioscience, University of Queensland, who will charge a 25 fee to the research team to recover some of the costs of storing and administering the tissue 26 samples. The University of Queensland will not transfer or sell your child’s samples to any third 27 party. 28 29 10 What if new information arises during this research project? 30 31 Sometimes during the course of a research project, new information becomes available about 32 the treatment that is being studied. If this happens, your child’s study doctor will tell you about it 33 and discuss with you whether you want your child to continue in the research project. If you 34 decide to withdraw your child from the study, your child’s study doctor will make arrangements 35 for their regular health care to continue. If you decide to continue your child’s involvement in the 36 http://bmjopen.bmj.com/ research project you will be asked to sign an updated consent form. 37 38 39 Also, on receiving new information, your child’s study doctor might consider it to be in your 40 child’s best interests to withdraw them from the research project. If this happens, your child’s 41 study doctor will explain the reasons and arrange for your regular health care to continue. 42 43 11 Can the child have other treatments during this research project?
44 on September 27, 2021 by guest. Protected copyright. 45 Whilst your child is participating in this research project, they can continue to take the 46 medications or treatments they have been taking for their condition or for other reasons. It is 47 important to tell the research staff about any treatments or medications your child is taking, 48 including over-the-counter medications, vitamins or herbal remedies, acupuncture, or other 49 alternative treatments. You should also tell the study staff about any changes to these during 50 your child’s participation in the research project. 51 52 Because this trial is assessing the effect of rTMS on social communication, your child cannot 53 participate if they are also undergoing any other treatment or intervention for social 54 communication. This includes interventions delivered by psychologists. 55
56 57 12 What if I withdraw the child from this research project? 58 59 If you decide to withdraw your child from the project, please notify a member of the research 60 team before you withdraw. This notice will allow that person or the research supervisor to discuss any health risks or special requirements linked to withdrawing.
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1 2 If you do withdraw your consent for your child’s participation during the research project, the 3 study doctor and relevant study staff will not collect additional personal information from you or
4 your child, although personal information already collected will be retained to ensure that the BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 results of the research project can be measured properly and to comply with law. You should be 6 aware that data collected up to the time you withdraw your child will form part of the research 7 project results. If you do not want them to do this, you must tell the researchers before your 8 child joins the research project. 9 10 13 Could this research project be stopped unexpectedly? 11 12 This research project may be stopped unexpectedly for a variety of reasons. These may include 13 reasons such as: 14 15 • Unacceptable side effects 16 • The drug/treatment/device being shown not to be effective 17 • The drug/treatment/device being shown to work and not need further testing 18 For peer review only 19 • Decisions made by local regulatory/health authorities. 20 21 14 What happens when the research project ends? 22 23 You will be sent a summary of the main findings when the project has been completed. This is a 24 4-year study and it is expected that study results will be available by late 2024. Your child’s data 25 will then be securely archived at Deakin University. 26 27 Please note that RTMS will not be available from the research sites after completing the study. 28 It may be approved for future use in ASD, but this will depend on the results from the current 29 study. 30 31 Part 2 How is the research project being conducted? 32 33 34 15 What will happen to information about my child? 35
36 By signing the consent form, you consent to the study doctor and relevant research staff http://bmjopen.bmj.com/ 37 collecting and using personal information about your child for the research project. Any 38 information obtained in connection with this research project that can identify your child will 39 remain confidential. Upon enrolment in the trial your child will be allocated a unique study 40 identification code. Your child’s name will not appear with the research data that we collect from 41 you and them, and it will only be possible to re-identify your child’s data using the study code. 42 Only the research team will know which code identifies which participant. Your child’s 43 information will only be used for the purpose of this research project and future research
44 projects, and it will only be disclosed with your permission, except as required by law. on September 27, 2021 by guest. Protected copyright. 45 46 Information about your child may be obtained from your child’s health records held at this and 47 other health services for the purpose of this research. By signing the consent form, you agree to 48 the study team accessing your child’s health records if they are relevant to your child’s 49 participation in this research project. 50
51 52 Your child’s health records and any information obtained during the research project are subject 53 to inspection (for the purpose of verifying the procedures and the data) by the relevant 54 authorities and authorised representatives of the Sponsor, Deakin University, the institution 55 relevant to this Participant Information Sheet, [Name of institution], or as required by law. By 56 signing the Consent Form, you authorise release of, or access to, this confidential information to 57 the relevant study personnel and regulatory authorities as noted above. 58 59 It is anticipated that the results of this research project will be published and/or presented in a 60 variety of forums. In any publication and/or presentation, information will be provided in such a way that your child cannot be identified, except with your permission. We will only present
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1 2 group-level findings (e.g., average scores across the group) and no individual data will be 3 reported.
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 In accordance with relevant Australian and/or [Name of state/territory] privacy and other relevant 6 laws, you have the right to request access to your child’s information collected and stored by the 7 research team. You also have the right to request that any information with which you disagree 8 be corrected. Please contact the study team member named at the end of this document if you 9 would like to access your child’s information. 10 11 Any information obtained for the purpose of this research project and for future research that 12 can identify your child will be treated as confidential and securely stored. It will be disclosed 13 only with your permission, or as required by law. 14 15 It is expected that deidentified data from this study will be made available to other researchers 16 via online data repositories. Your child will not be able to be identified in these repositories. It is 17 also possible that the research team will use your child’s data from this research project for 18 For peer review only 19 future studies, but again they will not be able to be identified. 20 21 16 Complaints and compensation 22 23 If your child suffer any injuries or complications as a result of this research project, you should 24 contact the study team as soon as possible and you will be assisted with arranging appropriate 25 medical treatment. If you are eligible for Medicare, you can receive any medical treatment 26 required to treat the injury or complication, free of charge, as a public patient in any Australian 27 public hospital. 28 29 If you have complaints about you or your child’s treatment by members of staff working on this 30 research project, you should contact the person nominated in Section 19 below. If you have 31 complaints about any of the ethical aspects of this study, you can contact the local reviewing 32 HREC Executive Officer nominated in Section 19 below. Complaints about clinical trials can 33 also be directed to the Office of the Australian Information Commissioner. 34 35 17 Who is organising and funding the research? 36 http://bmjopen.bmj.com/
37 38 This research project is being conducted by a team of researchers led by Prof. Peter Enticott 39 from Deakin University, Victoria. It is funded through a Medical Research Future Fund grant 40 from the National Health and Medical Research Council to Prof. Enticott and the research team. 41 42 No member of the research team will receive a personal financial benefit from your child’s 43 involvement in this research project (other than their ordinary wages).
44 on September 27, 2021 by guest. Protected copyright. 45 18 Who has reviewed the research project? 46 47 All research in Australia involving humans is reviewed by an independent group of people called 48 a Human Research Ethics Committee (HREC). The ethical aspects of this research project 49 have been approved by the HREC of Monash Health and [Name of institutions]. 50 51 This project will be carried out according to the National Statement on Ethical Conduct in 52 Human Research (2018). This statement has been developed to protect the interests of people 53 who agree to participate in human research studies. 54
55 19 Further information and who to contact 56 57 58 The person you may need to contact will depend on the nature of your query. 59 60 If you want any further information concerning this project or if your child has any medical problems that may be related to their involvement in the project (for example, any side effects),
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1 2 you can contact your site’s principal study doctor on [phone number] or any of the following 3 people:
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 Study contact person 6 Name [Name] 7 Position [Position] 8 Telephone [Phone number] 9 Email [Email address] 10
11 12 Clinical contact person 13 Name [Name] 14 Position [Position] 15 Telephone [Phone number] 16 Email [Email address] 17 18 For matters relating toFor research peer at the site reviewat which you are onlyparticipating, the details of the local 19 site complaints person are: 20 21 Complaints contact person 22 23 Name [Name] 24 Position [Position] 25 Telephone [Phone number] 26 Email [Email address] 27 28 If you have any complaints about any aspect of the project, the way it is being conducted or any 29 questions about being a research participant in general, then you may contact: 30 31 Reviewing HREC approving this research and HREC Executive Officer details 32 33 Reviewing HREC name Monash Health 34 HREC Executive Officer Ms Deborah Dell 35 Telephone (03) 9594 4605 36 Email [email protected] http://bmjopen.bmj.com/ 37 38 Local HREC Office contact (Single Site - Research Governance Officer) 39 40 Name [Name] 41 Position [Position] 42 Telephone [Phone number] 43 Email [Email address]
44 on September 27, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 Consent Form - Adult providing own consent 3 Does repetitive transcranial magnetic stimulation 4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from (rTMS), compared to sham rTMS, improve social 5 Title 6 communication in adolescents and young adults 7 with autism spectrum disorder (ASD)? 8 Short Title MRFF RTMS-ASD 9 10 Protocol Number v2, 11/09/2020 11 Project Sponsor Deakin University 12 Coordinating Principal Investigator Prof. Peter Enticott 13 14 Prof. Paul Fitzgerald, A/Prof. Karen Barlow, Prof. 15 Ian Hickie, Dr Melissa Licari, Dr Nigel Rogasch, 16 Prof. Christel Middeldorp, Dr Scott Clark, Dr Ann- 17 Maree Vallence, Dr Kelsie Boulton, Prof. Adam 18 Associate Investigator(s)For peer Guastella,review Prof. Andrew only Whitehouse, Prof. 19 Cherrie Galletly, Dr Gail Alvares, Dr Hakuei 20 Fujiyama, A/Prof. Helen Heussler, A/Prof. Jeffrey 21 Craig, Dr Melissa Kirkovski, Dr Natalie Mills, Prof. 22 Nicole Rinehart, Dr Peter Donaldson, Dr Talitha 23 Ford, Prof. Karen Caeyenberghs 24 25 Location [Location where the research will be conducted] 26 27 28 Consent Agreement 29 I have read the Participant Information Sheet or someone has read it to me in a language that I 30 understand. 31 32 I understand the purposes, procedures and risks of the research described in the project.
33 I give permission for the child’s doctors, other health professionals, hospitals or laboratories 34 outside this hospital to release information to [Name of Institution] concerning the child’s 35 disease and treatment for the purposes of this project. I understand that such information will 36 http://bmjopen.bmj.com/ 37 remain confidential. 38 39 I have had an opportunity to ask questions and I am satisfied with the answers I have received.
40 I freely agree to the child participating in this research project as described and understand that 41 42 I am free to withdraw them at any time during the research project without affecting their future 43 health care.
44 on September 27, 2021 by guest. Protected copyright. 45 I freely agree to participate in this research project as described (e.g., completion of 46 questionnaires) and understand that I am free to withdraw at any time during the study without 47 affecting my future health care. 48 49 I understand that I will be given a signed copy of this document to keep. 50 51 I agree for my child’s anonymous study data to be shared with other researchers, including 52 those outside [Name of Institution] and outside Australia, for future studies. 53 54 I agree to my child’s anonymised data being made available through online repositories and to 55 the use of my data in any future research. 56 57 58 59 60
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1 Declaration by Parent/Guardian – for Parent/Guardian who has read the information 2 3
4 Name of Child (please print) BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Name of Parent/Guardian (please print) 7 8 Signature of Parent/Guardian Date 9
10 11 Declaration by Young Person – for participants under the age of 18 who have capacity to 12 provide informed consent 13 14 15 16 Name of Young Person (please print) 17 18 Signature of YoungFor Person peer review only Date 19
20 21 22 Declaration by Study Doctor/Senior Researcher† 23 I have given a verbal explanation of the research project, its procedures and risks and I believe 24 that the participant has understood that explanation. 25
26 Name of Study Doctor/ 27 † Senior Researcher (please print) 28
29 30 Signature Date 31 † A senior member of the research team must provide the explanation of, and information concerning, the research 32 project. 33 Note: All parties signing the consent section must date their own signature. 34 35 36 ***Continued on next page*** http://bmjopen.bmj.com/ 37 38 39 40 41 42 43
44 on September 27, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 I consent to the storage and use of tissue samples (cheek swabs) taken from my child for use, 2 as described in the relevant section of the Participant Information Sheet, for: 3 • This specific research project
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from • Other research that is closely related to this research project 5 6 • Any future research.
7 By signing this consent section, I agree to the use of my child’s tissue samples for genetic 8 testing, as outlined in the relevant Section of the Participant Information Sheet. 9
10 11 12 Name of Child (please print) 13 14 Name of Parent/Guardian (please print) 15 16 Signature of Parent/Guardian Date 17
18 For peer review only 19 20 21 Name of Young Person (please print) 22 23 Signature of Young Person Date 24 25 26 27 Name of Study Doctor/ † 28 Senior Researcher (please print) 29 30 Signature Date 31 32 † A senior member of the research team must provide the explanation of and information concerning the research 33 project. 34 Note: All parties signing the consent section must date their own signature. 35
36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43
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1 2 Form for Withdrawal of Participation - Parent/Guardian consenting on 3 behalf of participant
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 Does repetitive transcranial magnetic stimulation 6 (rTMS), compared to sham rTMS, improve social Title 7 communication in adolescents and young adults 8 with autism spectrum disorder (ASD)? 9 10 Short Title MRFF RTMS-ASD 11 Protocol Number v2, 11/09/2020 12 Project Sponsor Deakin University 13 14 Coordinating Principal Investigator Prof. Peter Enticott 15 16 Prof. Paul Fitzgerald, A/Prof. Karen Barlow, Prof. 17 Ian Hickie, Dr Melissa Licari, Dr Nigel Rogasch, 18 For peer Prof.review Christel Middeldorp, only Dr Scott Clark, Dr Ann- 19 Maree Vallence, Dr Kelsie Boulton, Prof. Adam 20 Associate Investigator(s) Guastella, Prof. Andrew Whitehouse, Prof. 21 Cherrie Galletly, Dr Gail Alvares, Dr Hakuei 22 Fujiyama, A/Prof. Helen Heussler, A/Prof. Jeffrey 23 Craig, Dr Melissa Kirkovski, Dr Natalie Mills, Prof. 24 Nicole Rinehart, Dr Peter Donaldson, Dr Talitha 25 Ford, Prof. Karen Caeyenberghs 26 27 Location (where CPI/PI will recruit) [Location where the research will be conducted] 28 29 Declaration by Participant 30
31 32 I wish to withdraw from participation in the above research project and understand that such 33 withdrawal will not affect my routine treatment, my relationship with those treating me or my 34 relationship with [Institution]. 35
36 Name of Child (please print) http://bmjopen.bmj.com/ 37 38 Name of Parent/Guardian (please print) 39 40 Signature of Parent/Guardian Date 41 42 43
44 on September 27, 2021 by guest. Protected copyright. 45 Name of Young Person (please print) 46 47 Signature of Young Person Date 48 49 50 Description of circumstances where communicated verbally: 51 52 53 54 55 ***Continued on next page*** 56 57 58 59 60
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1 Declaration by Study Doctor/Senior Researcher† 2 I have given a verbal explanation of the implications of withdrawal from the research project and 3 I believe that the participant has understood that explanation. 4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Name of Study Doctor/ 7 Senior Researcher† (please print) 8 9 Signature Date 10 11 † A senior member of the research team must provide the explanation of and information concerning withdrawal from 12 the research project. 13 Note: All parties signing the consent section must date their own signature. 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43
44 on September 27, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 BIOLOGICAL SPECIMENS
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 Participants will be administered a buccal swab on two occasions, which involves rubbing a 7 cotton bud against the inside of the cheek. These will be collected in person by a member of 8 the research team at each site. Specimens will then be sealed in a DNA/RNA Shield tube and 9 labelled with the participant’s unique study identification code. It will then be transported 10 11 by courier/post to the Institute of Molecular Bioscience, University of Queensland, for 12 extraction, storage, and analysis. 13 14 Numerical data arising from genetic and epigenetic analyses will be sent electronically to 15 16 the research team (Chief Investigators Prof. Enticott and Prof. Middeldorp) and stored in 17 REDCap databases. PDF files containing results will also be stored in REDCap. 18 For peer review only 19 The research team will retain all biospecimens, which will be securely stored at the Institute 20 of Molecular Bioscience, University of Queensland. This will allow the possibility of future 21 22 analyses, particularly to determine genetic and epigenetic factors associated with a clinical 23 response to the TBS intervention. The research team may contribute results from these data 24 to future collaborative projects, which may involve external researchers who are not 25 involved in the current trial. No information that could identify a participant will be shared. 26 27 Participants (and their parent/guardian where necessary) will be asked to provide 28 permission for future biospecimen use as part of the informed consent procedure. 29 30 31 32 33 34 35
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1 2 3
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 7 8 SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and 9 related documents* 10 11 Section/item Item Description Page Number 12 No on which item 13 is reported 14 15 Administrative information 16 17 Title 1 Descriptive title identifying the study design, 1 18 Forpopulation, peer interventions, review and, if applicable, only trial 19 20 acronym 21 22 Trial 2a Trial identifier and registry name. If not yet registered, 2 23 registration name of intended registry 24 25 2b All items from the World Health Organization Trial n/a 26 Registration Data Set 27 28 Protocol 3 Date and version identifier 1 29 version 30 31 Funding 4 Sources and types of financial, material, and other 15 32 33 support 34 35 Roles and 5a Names, affiliations, and roles of protocol contributors 1
36 responsibilitie http://bmjopen.bmj.com/ 5b Name and contact information for the trial sponsor 15 37 s 38 39 5c Role of study sponsor and funders, if any, in study 15 40 design; collection, management, analysis, and 41 42 interpretation of data; writing of the report; and the 43 decision to submit the report for publication, including
44 whether they will have ultimate authority over any of on September 27, 2021 by guest. Protected copyright. 45 these activities 46 47 5d Composition, roles, and responsibilities of the 7, 13 48 49 coordinating centre, steering committee, endpoint 50 adjudication committee, data management team, and 51 other individuals or groups overseeing the trial, if 52 applicable (see Item 21a for data monitoring 53 54 committee) 55 56 Introduction 57 58 59 60
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1 2 Background 6a Description of research question and justification for 4-6 3 and rationale undertaking the trial, including summary of relevant
4 studies (published and unpublished) examining BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 benefits and harms for each intervention 7 8 6b Explanation for choice of comparators 7 9 10 Objectives 7 Specific objectives or hypotheses 6 11 12 Trial design 8 Description of trial design including type of trial (eg, 6-10 13 parallel group, crossover, factorial, single group), 14 allocation ratio, and framework (eg, superiority, 15 equivalence, noninferiority, exploratory) 16 17 18 Methods: Participants,For interventions, peer andreview outcomes only 19 20 Study setting 9 Description of study settings (eg, community clinic, 6 21 academic hospital) and list of countries where data 22 will be collected. Reference to where list of study sites 23 24 can be obtained 25 26 Eligibility 10 Inclusion and exclusion criteria for participants. If 7-8 27 criteria applicable, eligibility criteria for study centres and 28 individuals who will perform the interventions (eg, 29 surgeons, psychotherapists) 30 31 Interventions 11a Interventions for each group with sufficient detail to 7 32 33 allow replication, including how and when they will be 34 administered 35
36 11b Criteria for discontinuing or modifying allocated n/a http://bmjopen.bmj.com/ 37 interventions for a given trial participant (eg, drug 38 dose change in response to harms, participant 39 40 request, or improving/worsening disease) 41 42 11c Strategies to improve adherence to intervention n/a 43 protocols, and any procedures for monitoring 44 adherence (eg, drug tablet return, laboratory tests) on September 27, 2021 by guest. Protected copyright. 45 46 11d Relevant concomitant care and interventions that are 8 47 48 permitted or prohibited during the trial 49 50 Outcomes 12 Primary, secondary, and other outcomes, including 8-9 51 the specific measurement variable (eg, systolic blood 52 pressure), analysis metric (eg, change from baseline, 53 final value, time to event), method of aggregation (eg, 54 55 median, proportion), and time point for each outcome. 56 Explanation of the clinical relevance of chosen 57 efficacy and harm outcomes is strongly recommended 58 59 60
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1 2 Participant 13 Time schedule of enrolment, interventions (including Table 1, 11-12 3 timeline any run-ins and washouts), assessments, and visits
4 for participants. A schematic diagram is highly BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 recommended (see Figure) 7 8 Sample size 14 Estimated number of participants needed to achieve 6 9 study objectives and how it was determined, including 10 clinical and statistical assumptions supporting any 11 sample size calculations 12 13 Recruitment 15 Strategies for achieving adequate participant 7 14 15 enrolment to reach target sample size 16 17 Methods: Assignment of interventions (for controlled trials) 18 For peer review only 19 Allocation: 20 21 Sequence 16a Method of generating the allocation sequence (eg, 9 22 generation computer-generated random numbers), and list of any 23 factors for stratification. To reduce predictability of a 24 random sequence, details of any planned restriction 25 26 (eg, blocking) should be provided in a separate 27 document that is unavailable to those who enrol 28 participants or assign interventions 29 30 Allocation 16b Mechanism of implementing the allocation sequence 9 31 concealme (eg, central telephone; sequentially numbered, 32 33 nt opaque, sealed envelopes), describing any steps to 34 mechanis conceal the sequence until interventions are assigned 35 m
36 http://bmjopen.bmj.com/ 37 Implement 16c Who will generate the allocation sequence, who will 9 38 39 ation enrol participants, and who will assign participants to 40 interventions 41 42 Blinding 17a Who will be blinded after assignment to interventions 10 43 (masking) (eg, trial participants, care providers, outcome 44 assessors, data analysts), and how on September 27, 2021 by guest. Protected copyright. 45 46 17b If blinded, circumstances under which unblinding is 10 47 48 permissible, and procedure for revealing a 49 participant’s allocated intervention during the trial 50 51 Methods: Data collection, management, and analysis 52 53 54 55 56 57 58 59 60
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1 2 Data 18a Plans for assessment and collection of outcome, 8-9 3 collection baseline, and other trial data, including any related
4 methods processes to promote data quality (eg, duplicate BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 measurements, training of assessors) and a 7 description of study instruments (eg, questionnaires, 8 laboratory tests) along with their reliability and validity, 9 if known. Reference to where data collection forms 10 11 can be found, if not in the protocol 12 13 18b Plans to promote participant retention and complete 9 14 follow-up, including list of any outcome data to be 15 collected for participants who discontinue or deviate 16 from intervention protocols 17 18 Data 19 ForPlans forpeer data entry, review coding, security, only and storage, 9-10 19 20 management including any related processes to promote data 21 quality (eg, double data entry; range checks for data 22 values). Reference to where details of data 23 management procedures can be found, if not in the 24 25 protocol 26 27 Statistical 20a Statistical methods for analysing primary and 9 28 methods secondary outcomes. Reference to where other 29 details of the statistical analysis plan can be found, if 30 not in the protocol 31 32 20b Methods for any additional analyses (eg, subgroup 9-10 33 34 and adjusted analyses) 35
36 20c Definition of analysis population relating to protocol 9 http://bmjopen.bmj.com/ 37 non-adherence (eg, as randomised analysis), and any 38 statistical methods to handle missing data (eg, 39 multiple imputation) 40 41 Methods: Monitoring 42 43 Data 21a Composition of data monitoring committee (DMC); 13 44 on September 27, 2021 by guest. Protected copyright. 45 monitoring summary of its role and reporting structure; statement 46 of whether it is independent from the sponsor and 47 competing interests; and reference to where further 48 49 details about its charter can be found, if not in the 50 protocol. Alternatively, an explanation of why a DMC 51 is not needed 52 53 21b Description of any interim analyses and stopping 9 54 guidelines, including who will have access to these 55 56 interim results and make the final decision to 57 terminate the trial 58 59 60
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1 2 Harms 22 Plans for collecting, assessing, reporting, and 13 3 managing solicited and spontaneously reported
4 adverse events and other unintended effects of trial BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 6 interventions or trial conduct 7 8 Auditing 23 Frequency and procedures for auditing trial conduct, if n/a 9 any, and whether the process will be independent 10 from investigators and the sponsor 11 12 13 Ethics and dissemination 14 Research 24 Plans for seeking research ethics 13 15 16 ethics committee/institutional review board (REC/IRB) 17 approval approval 18 For peer review only 19 Protocol 25 Plans for communicating important protocol 13 20 amendments modifications (eg, changes to eligibility criteria, 21 outcomes, analyses) to relevant parties (eg, 22 23 investigators, REC/IRBs, trial participants, trial 24 registries, journals, regulators) 25 26 Consent or 26a Who will obtain informed consent or assent from 7 27 assent potential trial participants or authorised surrogates, 28 29 and how (see Item 32) 30 31 26b Additional consent provisions for collection and use of Appendix 32 participant data and biological specimens in ancillary 33 studies, if applicable 34 35 Confidentiality 27 How personal information about potential and enrolled 9 36 participants will be collected, shared, and maintained http://bmjopen.bmj.com/ 37 38 in order to protect confidentiality before, during, and 39 after the trial 40 41 Declaration of 28 Financial and other competing interests for principal 15 42 interests investigators for the overall trial and each study site 43
44 Access to 29 Statement of who will have access to the final trial 10 on September 27, 2021 by guest. Protected copyright. 45 data dataset, and disclosure of contractual agreements 46 47 that limit such access for investigators 48 49 Ancillary and 30 Provisions, if any, for ancillary and post-trial care, and 13 50 post-trial care for compensation to those who suffer harm from trial 51 participation 52 53 Dissemination 31a Plans for investigators and sponsor to communicate 13-14 54 policy trial results to participants, healthcare professionals, 55 56 the public, and other relevant groups (eg, via 57 publication, reporting in results databases, or other 58 data sharing arrangements), including any publication 59 restrictions 60
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1 2 31b Authorship eligibility guidelines and any intended use 13 3 of professional writers
4 BMJ Open: first published as 10.1136/bmjopen-2020-046830 on 7 July 2021. Downloaded from 5 31c Plans, if any, for granting public access to the full 10, 14 6 protocol, participant-level dataset, and statistical code 7 8 9 Appendices 10 11 Informed 32 Model consent form and other related documentation Appendix 12 consent given to participants and authorised surrogates 13 materials 14 15 Biological 33 Plans for collection, laboratory evaluation, and Appendix 16 specimens storage of biological specimens for genetic or 17 18 Formolecular peer analysis reviewin the current trial only and for future 19 use in ancillary studies, if applicable 20 21 *It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 22 Explanation & Elaboration for important clarification on the items. Amendments to the 23 protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT 24 Group under the Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 Unported” 25 26 license. 27 28 29 30 31 32 33 34 35
36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43
44 on September 27, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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