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Cadazolid / ACT-179811 Clostridium Difficile-Associated Diarrhea Protocol AC-061A303

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Cadazolid / ACT-179811 Clostridium Difficile-Associated Diarrhea Protocol AC-061A303 NCT03105479 Cadazolid / ACT-179811 Clostridium difficile-associated diarrhea Protocol AC-061A303 A prospective, multicenter study to investigate the pharmacokinetics, safety, and efficacy of cadazolid versus vancomycin in pediatric subjects with Clostridium difficile- associated diarrhea LIST OF AMENDMENTS (Summary of changes) Document History: - Original Version 14 July 2015 - Global Amendments Amendment 1 (non-substantial) 05 November 2015 Amendment 2 (substantial) 27 October 2016 Amendment 3 (substantial) 01 March 2017 Confidentiality statement Property of Actelion Pharmaceuticals Ltd. May not be used, divulged, published or otherwise disclosed without the consent of Actelion Pharmaceuticals Ltd. NCT03105479 Amendment 1 (non-substantial amendment), 05 November 2015 This amendment was made before protocol submission to any IRBs/IECs. Amendment 2 (substantial amendment), 27 October 2016 Main reason for this Amendment: To align the global protocol with the European Medical Agency's decision on the cadazolid Paediatric Investigation Plan and with the FDA's requirements (as described below) Description of change(s) Amended protocol sections Inclusion of neonates and infants below 6 months of age Sections 1.3, 2.1, 3.1, 3.1.1, 3.2, 4.1, 4.2 & 4.3 Figure 1 The age cohort of subjects from 2 to < 12 years to be split Sections 3.1.1, 3.2, 4.1 & 10.5.1 into two new cohorts: subjects from 6 to < 12 years and Figure 1 from 2 to < 6 years resulting in a minor increase in sample size from 194 to 200 participants Study timelines to be shortened by enrolling subjects in Part Section 3.1.2 B of the study as soon as dosing recommendations are Figure 1, Figure 3 available for respective age groups based on Part A Addition of an Independent Data Monitoring Committee to Sections 3.1.1, 3.2, 3.4 & 8.3 review the data and make recommendations as to further dosing in the subsequent age cohorts or strata Part B of the study to be blinded to an efficacy assessor Sections 3.1.2, 3.3.2, 5.1.5 & 7.2.3.3 Palatability/acceptability to be studied in all subjects Sections 2.4, 6.4.1, 7.4 & 10.3.5.7 Addition of a lower strength of oral cadazolid (50 mg) Section 5.1.1, 5.1.3 &5.16 Table 1 Amendment 3 (substantial amendment), 01 March 2017 Main reason for this Amendment: To address agreed changes in the response to Voluntary Harmonization Procedure (VHP) list of grounds for non-acceptance, dated 10 February 2017. The key requested modifications to the protocol included: Description of change(s) Amended protocol sections Classification of the study as a Phase 2/3 instead of Phase Title page, Section 3.1 3, as the study includes a preliminary dose-finding part and a subsequent part assessing safety and efficacy Addition of a separate summary section of known Section 1.2.3 potential risks and benefits for Cadazolid Updates of the exclusion criteria by adding the following Section 4.4 criteria: - Exclusion of subjects with hypersensitivity to cadazolid and to any of the excipients of vancomycin); - Exclusion of subjects with mental disorders Clarification on the effectiveness of double-barrier Section 4.5.2 NCT03105479 contraception methods and on the variability of acceptance of such contraception measures between concerned countries To clearly indicate that patients must be discontinued Section 5.1.8, 5.2.5 & 6.1.1.2 from the study in case of recognized fulminant or life- threatening Clostridium difficile-associated diarrhea Cadazolid / ACT-179811 Clostridium difficile-associated diarrhea Protocol AC-061A303 A prospective, multicenter study to investigate the pharmacokinetics, safety, and efficacy of cadazolid versus vancomycin in pediatric subjects with Clostridium difficile-associated diarrhea NCT Number: NCT03105479 EudraCT Number: 2015-004805-17 Document version, Date: Final Version 4, 01 March 2017 Document History: - Original Version 14 July 2015 - Global Amendments Amendment 1 05 November 2015 (non-substantial) Amendment 2 27 October 2016 (substantial) Amendment 3 01 March 2017 (substantial) Confidentiality statement Property of Actelion Pharmaceuticals Ltd. May not be used, divulged, published or otherwise disclosed without the consent of Actelion Pharmaceuticals Ltd. TPL-000052_v10 Cadazolid / ACT-179811 EudraCT 2015-004805-17 Clostridium difficile-associated diarrhea Doc No D-17.162 Protocol AC-061A303 Confidential Final Version 4 1 March 2017, page 2/117 SPONSOR CONTACT DETAILS SPONSOR ACTELION Pharmaceuticals Ltd Gewerbestrasse 16 CH-4123 Allschwil Switzerland +41 61 565 65 65 Clinical Trial Physician Contact details of the Clinical Trial Physician can be found in the Investigator Site File MEDICAL HOTLINE Site-specific toll telephone numbers and toll-free Toll phone number: [number] numbers for the Medical Hotline can be found in the Investigator Site File ACTELION CONTRIBUTORS TO THE PROTOCOL Clinical Trial Scientist BSc Clinical Trial Statistician MSc Clinical Trial Physician MD, MSc Clinical Trial Pharmacologist PhD Drug Safety Physician MD Cadazolid / ACT-179811 EudraCT 2015-004805-17 Clostridium difficile-associated diarrhea Doc No D-17.162 Protocol AC-061A303 Confidential Final Version 4 1 March 2017, page 3/117 CONTRACT RESEARCH ORGANIZATIONS INFORMATION CENTRAL LABORATORY CENTRAL RANDOMIZATION MONITORING A list of site-specific contact details for Contract Research Organizations (CROs) can be found in the Investigator Site File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adazolid / ACT-179811 EudraCT 2015-004805-17 Clostridium difficile-associated diarrhea Doc No D-17.162 Protocol AC-061A303 Confidential Final Version 4 1 March 2017, page 5/117 INVESTIGATOR SIGNATURE PAGE Treatment name / number Cadazolid / ACT-179811 Indication Clostridium difficile-associated diarrhea Protocol number, study title AC-061A303, A prospective, multicenter study to investigate the pharmacokinetics, safety, and efficacy of cadazolid versus vancomycin in pediatric subjects with Clostridium difficile-associated diarrhea I agree to the terms and conditions relating to this study as defined in this protocol, the Case Report Form (CRF), and any other protocol-related documents. I fully understand that any changes instituted by the investigator(s) without previous agreement with the sponsor would constitute a protocol deviation, including any ancillary studies or procedures performed on study subjects (other than those procedures necessary for the wellbeing of the subjects). I agree to conduct this study in accordance with the Declaration of Helsinki principles, International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, and applicable regulations and laws. I will obtain approval by an independent ethics committee or institutional review board (IEC/IRB) prior to study start and signed informed consent from all parents/ legally designated representatives of the subjects included in this pediatric study. If an amendment to the protocol is necessary, I will obtain approval by an IEC/IRB and ensure approval by regulatory authorities has been obtained before the implementation of changes described in the amendment, and I will re-consent the subjects (if applicable). I will allow direct access to source documents and study facilities to sponsor representative(s), particularly Clinical Research Associate(s) (CRA[s]) and auditor(s), and agree to inspection by regulatory authorities or IEC/IRB representative(s). I will ensure that the study treatment(s) supplied by the sponsor is/are being used only as described in this protocol. I will ensure that all subjects or legally designated representatives have understood the nature, objectives, benefits, implications, risks and inconveniences for participating in this study. During the conduct of the study, I will constantly monitor the risk/benefit balance for an individual subject. I confirm herewith that the sponsor is allowed to enter and utilize my professional contact details and function in an electronic database for internal purposes and for submission to health authorities worldwide. Country Site Town Date Signature number Principal Investigator Cadazolid / ACT-179811 EudraCT 2015-004805-17 Clostridium difficile-associated diarrhea Doc No D-17.162 Protocol AC-061A303 Confidential Final Version 4 1 March 2017, page 6/117 TABLE OF CONTENTS TABLE OF CONTENTS .....................................................................................................6 LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................13 SUBSTANTIAL GLOBAL AMENDMENT 3 .................................................................16 PROTOCOL SYNOPSIS AC-061A303 ............................................................................19 PROTOCOL ......................................................................................................................34 1 BACKGROUND .........................................................................................................34 1.1 Clostridium difficile-associated diarrhea ......................................................34 1.1.1 Introduction .......................................................................................34
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