AMENDED CLINICAL TRIAL PROTOCOL 04

AMENDED CLINICAL TRIAL PROTOCOL 04

Protocol title:

An adaptive phase 3, randomized, double-blind, placebo-controlled study assessing efficacy and safety of sarilumab for hospitalized patients with COVID-19

Protocol number:

EFC16844

Amendment number: 04

Compound number (INN/Trademark):

SAR153191 Sarilumab/Kevzara?

Study phase: Short title:

Phase 3 Sarilumab COVID-19

Sponsor name:

sanofi-aventis Recherche & D?veloppement

Legal registered address:

1 avenue Pierre Brossolette 91385 Chilly Mazarin Cedex France

Monitoring Team's Representative Name and Contact Information

Regulatory agency identifier number(s):

IND:

Not available at the time of protocol preparation

EudraCT:

2020-001162-12

NCT:

NCT04327388

WHO:

U1111-1249-6021

EUDAMED

Not available at the time of protocol preparation

Other:

Not available at the time of protocol preparation

Date:

11-Jun-2020

Total number of pages: 86

Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be

disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written consent of Sanofi (or the concerned affiliated company); `affiliated company' means any corporation, partnership or other entity which at the date

of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with `control' meaning direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity

Based on Template: Sanofi OneDocument Version 2.0, dated 14-OCT-2019

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE CHANGES

DOCUMENT HISTORY

Document

Amended Clinical Trial Protocol 04 Amended Clinical Trial Protocol 03 Amended Clinical Trial Protocol 02 Amended Clinical Trial Protocol 01 Original Protocol

Country/countries impacted by amendment All

All

All

All

All

Date, version

11-Jun-2020, version 1 (electronic 4.0) 29-Apr-2020, version 1 (electronic 3.0) 08-Apr-2020, version 1 (electronic 2.0) 26-Mar-2020, version 1 (electronic 1.0) 18-Mar-2020, version 1 (electronic 1.0)

Amended protocol [04] (11-Jun-2020)

This amended protocol 04 (amendment 04) is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European Union.

OVERALL RATIONALE FOR THE AMENDMENT

The main purpose of the amendment is to close enrollment into the sarilumab 200 mg IV arm while maintaining the original 2:1 ratio of sarilumab 400 mg IV to placebo. This amendment also clarifies instructions and provides additional guidance to investigators regarding follow-up and reporting of adverse events of special interest (AESI).

Protocol amendment summary of changes table

Section # and Name

Section 1.1 Synopsis, Section 1.2 Schema, Section 2.1 Study Rationale, Section 4.1 Overall Design, Section 4.2 Scientific Rationale for Study Design, Section 4.3 Justification for Dose, Section 6.1. Study Interventions administered (Table 3)

Description of Change

Closed enrollment to the sarilumab 200 mg IV arm

Brief Rationale

Based on anticipation of a more favorable benefit-risk profile in the 400 mg arm versus the 200 mg arm, enrollment in the 200 mg arm will be closed upon implementation of amended protocol 04.

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Section # and Name Section 1.3 Schedule of Activities Section 5.2 Section 10.3.1 Definition of AE

Section 10.3.1 Definition of AE

Section 10.3.2.1 Recording and follow-up of AE and/or SAE

Description of Change

Urinalysis and urine culture results, serum IL6, adverse events

E04 was modified to clarify that oral corticosteroids were a type of systemic corticosteroids.

Events meeting the AE definition: Removed: "Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE or SAE.

Events meeting the AE definition: The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE or SAE. Also, "lack of efficacy" or "failure of expected pharmacological action" also constitutes an AE or SAE.

Added tables for assessment of intensity for infusion related reactions, hypersensitivity reactions, and neutropenia. Added guidance for the follow-up of AESIs of ALT increase and Grade 4 Neutropenia.

Brief Rationale The timing of urinalysis, urine culture results, serum IL-6, and adverse events assessments was clarified. No changes were made to the collection schedule. Clarification of definition.

This bullet is duplicated in error. The same information is included in the first bullet.

This bullet is contradictory to the information provided, stating "Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an AE or SAE.

Provide guidance to the investigator.

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TABLE OF CONTENTS

AMENDED CLINICAL TRIAL PROTOCOL 04 ..............................................................................................1

PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE CHANGES...............................................2

DOCUMENT HISTORY...................................................................................................................................2

OVERALL RATIONALE FOR THE AMENDMENT........................................................................................2

TABLE OF CONTENTS..................................................................................................................................4

LIST OF TABLES ...........................................................................................................................................8

LIST OF FIGURES..........................................................................................................................................8

1

PROTOCOL SUMMARY .................................................................................................................9

1.1

SYNOPSIS ....................................................................................................................................... 9

1.2

SCHEMA ........................................................................................................................................ 15

1.3

SCHEDULE OF ACTIVITIES (SOA)..............................................................................................16

2

INTRODUCTION............................................................................................................................20

2.1

STUDY RATIONALE......................................................................................................................20

2.2

BACKGROUND .............................................................................................................................21

2.3

BENEFIT/RISK ASSESSMENT.....................................................................................................22

3

OBJECTIVES AND ENDPOINTS .................................................................................................24

4

STUDY DESIGN ............................................................................................................................27

4.1

OVERALL DESIGN........................................................................................................................27

4.2 4.2.1

SCIENTIFIC RATIONALE FOR STUDY DESIGN .........................................................................28 Participant input into study design .................................................................................................29

4.3

JUSTIFICATION FOR DOSE ........................................................................................................29

4.4

END OF STUDY DEFINITION.......................................................................................................30

5

STUDY POPULATION ..................................................................................................................31

5.1

INCLUSION CRITERIA..................................................................................................................31

5.2

EXCLUSION CRITERIA ................................................................................................................32

5.3

LIFESTYLE CONSIDERATIONS...................................................................................................34

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5.4

SCREEN FAILURES......................................................................................................................34

6

STUDY INTERVENTION ...............................................................................................................35

6.1

STUDY INTERVENTIONS ADMINISTERED ................................................................................35

6.2

PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 36

6.3

MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING .......................................36

6.4

STUDY INTERVENTION COMPLIANCE ......................................................................................37

6.5

CONCOMITANT THERAPY ..........................................................................................................37

6.6

RESCUE THERAPY ......................................................................................................................38

6.7

INTERVENTION AFTER THE END OF THE STUDY ...................................................................38

7

DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT

DISCONTINUATION/WITHDRAWAL ...........................................................................................39

7.1 7.1.1 7.1.2

DISCONTINUATION OF STUDY INTERVENTION ......................................................................39 Definitive discontinuation ...............................................................................................................39 Temporary discontinuation.............................................................................................................39

7.2

PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY..................................40

7.3

LOST TO FOLLOW UP .................................................................................................................41

8

STUDY ASSESSMENTS AND PROCEDURES ...........................................................................42

8.1 8.1.1 8.1.2 8.1.3

EFFICACY ASSESSMENTS .........................................................................................................42 Clinical data collection ...................................................................................................................42 Oxygen Administration and Oxygenation ......................................................................................43 Body temperature...........................................................................................................................44

8.2 8.2.1 8.2.2 8.2.3 8.2.4

SAFETY ASSESSMENTS .............................................................................................................44 Vital signs .......................................................................................................................................45 Targeted Physical Examination .....................................................................................................45 Electrocardiograms ........................................................................................................................45 Clinical safety laboratory assessments..........................................................................................45

8.3 8.3.1 8.3.2 8.3.3 8.3.4

ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS...........................................................45 Time period and frequency for collecting AE and SAE information ...............................................46 Method of detecting AEs and SAEs...............................................................................................46 Follow-up of AEs and SAEs ...........................................................................................................46 Regulatory reporting requirements for SAEs .................................................................................46

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8.3.5 8.3.6 8.3.7

Pregnancy ......................................................................................................................................47 Adverse event of special interest ...................................................................................................48 Guidelines for reporting product complaints ..................................................................................48

8.4

TREATMENT OF OVERDOSE......................................................................................................49

8.5 8.5.1 8.5.2 8.5.3 8.5.4

PHARMACOKINETICS .................................................................................................................. 49 Sampling times...............................................................................................................................49 Sample handling procedure ...........................................................................................................49 Bioanalytical methods ....................................................................................................................50 Pharmacokinetic parameters .........................................................................................................50

8.6 8.6.1 8.6.2

PHARMACODYNAMICS ...............................................................................................................50 Pharmacodynamic parameters ......................................................................................................50 Assessment methods.....................................................................................................................50

8.7

GENETICS ..................................................................................................................................... 51

8.8

BIOMARKERS ...............................................................................................................................51

8.9

HEALTH ECONOMICS/MEDICAL RESOURCE UTILIZATION AND HEALTH

ECONOMICS .................................................................................................................................51

9

STATISTICAL CONSIDERATIONS ..............................................................................................52

9.1

STATISTICAL HYPOTHESES.......................................................................................................52

9.2

SAMPLE SIZE DETERMINATION.................................................................................................52

9.3

POPULATIONS FOR ANALYSES.................................................................................................52

9.4

9.4.1

9.4.2

9.4.3 9.4.3.1 9.4.3.2

9.4.4

9.4.5 9.4.5.1 9.4.5.2 9.4.5.3

9.4.6 9.4.6.1 9.4.6.2

9.4.7

STATISTICAL ANALYSES ............................................................................................................53

General considerations ..................................................................................................................53

Primary endpoint(s)........................................................................................................................54

Secondary endpoint(s) ...................................................................................................................54 Efficacy ........................................................................................................................................... 54 Safety .............................................................................................................................................55

Tertiary/exploratory endpoint(s) .....................................................................................................56

Other safety analyse(s) ..................................................................................................................56 Vital Signs ......................................................................................................................................56 Laboratory Tests ............................................................................................................................56 Assessment of anti- sarilumab antibodies .....................................................................................57

Pharmacokinetics ........................................................................................................................... 57 Analysis of Drug Concentration Data.............................................................................................57 Analysis of Pharmacodynamic and Exploratory Biomarker Data ..................................................57

Other analyse(s).............................................................................................................................57

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9.5

INTERIM ANALYSES ....................................................................................................................57

9.6

INDEPENDENT DATA MONITORING COMMITTEE (IDMC).......................................................58

10

SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................59

10.1 10.1.1 10.1.2 10.1.3 10.1.4 10.1.5 10.1.6 10.1.7 10.1.8 10.1.9

APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS......59 Regulatory and ethical considerations ...........................................................................................59 Financial disclosure........................................................................................................................60 Informed consent process..............................................................................................................60 Data protection...............................................................................................................................61 Dissemination of clinical study data ...............................................................................................61 Data quality assurance ..................................................................................................................62 Source documents .........................................................................................................................63 Study and site start and closure.....................................................................................................63 Publication policy ...........................................................................................................................64

10.2 APPENDIX 2: CLINICAL LABORATORY TESTS .........................................................................64

10.3 APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................66

10.3.1 Definition of AE ..............................................................................................................................66

10.3.2 Definition of SAE ............................................................................................................................67 10.3.2.1 Recording and follow-up of AE and/or SAE ...................................................................................68

10.3.3 Reporting of SAEs..........................................................................................................................72

10.3.4 Management of Acute Reactions ...................................................................................................73 10.3.4.1 Acute Intravenous Infusion Reactions ...........................................................................................73

10.4 APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY INFORMATION ..............................................................................................................................74

10.5 APPENDIX 5: GENETICS .............................................................................................................76

10.6 APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS ..............................................................76

10.7 APPENDIX 9: ABBREVIATIONS...................................................................................................76

10.8 10.8.1 10.8.2 10.8.3

APPENDIX 10: PROTOCOL AMENDMENT HISTORY ................................................................78 Amended protocol [01] (26 March 2020) .......................................................................................78 Amended protocol [02] (08 April 2020) ..........................................................................................80 Amended protocol [03] (29 April 2020) ..........................................................................................82

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REFERENCES ............................................................................................................................... 84

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LIST OF TABLES

Table 1 - Objectives.......................................................................................................................................24 Table 2 - Endpoints .......................................................................................................................................25 Table 3 - Overview of study interventions administered ...............................................................................35 Table 4 - The NEWS2 Scoring System .........................................................................................................43 Table 5 - Body temperature assessment ......................................................................................................44 Table 6 - Summary of handling procedures for samples for sarilumab and sample for anti-sarilumab antibody .........................................................................................................................................................49 Table 7 - Summary of bioanalytical method for sarilumab ............................................................................50 Table 8 - List of pharmacokinetic parameters and definitions.......................................................................50 Table 9 - Summary of handling procedures for sIL-6 and IL-6 .....................................................................50 Table 10 - Populations for analyses ..............................................................................................................52 Table 11 - Protocol-required laboratory assessments ..................................................................................64 Table 12 - Grading of infusion related reactions (NCI-CTCAE v3) ...............................................................69 Table 13 - Grading of hypersensitivity reactions (NCI-CTCAE v3) ...............................................................69 Table 14 - Grading of neutropenia (NCI-CTCAE v3) ....................................................................................69 Table 15 - Grading System for Adverse Events Not Listed in NCI-CTCAE ..................................................70

LIST OF FIGURES

Figure 1 - Graphical study design .................................................................................................................15

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