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CTRI Number  CTRI/2020/11/029092 [Registered on: 12/11/2020] Trial Registered Prospectively
Last Modified On: 22/04/2022
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group, Placebo Controlled Trial 
Public Title of Study   Efficacy and safety study comparing SAR442168 to placebo in participants with nonrelapsing secondary progressive multiple sclerosis 
Scientific Title of Study   A Phase 3, randomized, double-blind, efficacy and safety study comparing SAR442168 to placebo in participants with nonrelapsing secondary progressive multiple sclerosis  
Trial Acronym  HERCULES 
Secondary IDs if Any  
Secondary ID  Identifier 
2020-000647-30  EudraCT 
EFC16645 Amendment 01 Version no.1, dated 15May2020  Protocol Number 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name   
Designation   
Affiliation   
Address 




 
Phone    
Fax    
Email    
 
Details of Contact Person
Scientific Query

Modification(s)  
Name  Dr Saket Thaker 
Designation  Senior Medical Advisor and CSU Safety Lead 
Affiliation  Sanofi Healthcare India Private Limited 
Address  Sanofi Healthcare India Private Limited Sanofi House CTS No.117 B L&T Business Park Saki Vihar Road Powai Mumbai

Mumbai
MAHARASHTRA
400072
India 
Phone  912228032528  
Fax    
Email  Saket.Thaker@sanofi.com  
 
Details of Contact Person
Public Query

Modification(s)  
Name  Dr Vishal Patil 
Designation  Clinical Project Leader 
Affiliation  Sanofi Healthcare India Private Limited 
Address  Sanofi Healthcare India Private Limited Sanofi House CTS No.117 B L&T Business Park Saki Vihar Road Powai Mumbai

Mumbai
MAHARASHTRA
400072
India 
Phone  9823088050  
Fax    
Email  Vishal.Patil@Sanofi.com  
 
Source of Monetary or Material Support
Modification(s)  
Sanofi Healthcare India Private Limited, Sanofi House, CTS No.117-B L&T Business Park Saki Vihar Road, Powai Mumbai:400072  
 
Primary Sponsor
Modification(s)  
Name  Sanofi Healthcare India Private Limited 
Address  Sanofi House, CTS No. 117-B, L&T Business Park, Powai, Mumbai – 400072 
Type of Sponsor  Pharmaceutical industry-Global 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     Argentina
Brazil
Canada
France
Germany
India
Netherlands
Portugal
Republic of Korea
Russian Federation
Spain
Switzerland
Ukraine
United Kingdom
United States of America  
Sites of Study
Modification(s)  
No of Sites = 9  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr M V Padma  All India Institute of Medical Sciences (AIIMS) - The Neurosciences (N.S) Centre  Sri Aurobindo Marg, Ansari Nagar, Ansari Nagar East, New Delhi, Delhi 110029, India
South West
DELHI 
9810819167

vasanthapadma123@gmail.com 
Dr Manish Mahajan  Artemis Hospital  Artemis Hospital Sector 51, Gurugram, Haryana 122001, India
Gurgaon
HARYANA 
8557873567

drmanishneurology@gmail.com 
Dr Sanjay Ganpat Ramteke  Brain Clinic Jasleen Hospital  Opp. Big Bazar, Panchsheel Square, Dhantoli, Nagpur 440012, Maharashtra, India
Nagpur
MAHARASHTRA 
919890332286

ssrt95@yahoo.co.in 
Dr Praveen Gupta  Fortis Hospital, Gurgaon  Sec-44, Opp - Huda City Center, Metro Station Gurugram, Haryana-122002
Gurgaon
HARYANA 
9560217602

praveen.Gupta@fortishealthcare.com 
Dr Lekha Pandit  Justice K S Hegde Charitable Hospital, Dept. of Neurology, Mangalore  Dept. of Neurology, Deralakatte, Karnataka 575018, India
Dakshina Kannada
KARNATAKA 
9845084343

panditmng@gmail.com 
Dr Manjunath Netravathi  NIMHANS  P.B. No. 2900, Hosur Rd, Bengaluru, Karnataka 560029, India
Bangalore
KARNATAKA 
9880106662

sundernetra@yahoo.co.in 
Dr L Neeharika Mathukumalli  Nizam’s Institute of Medical Sciences   Department of Neurology, Millennium block, ground floor, Panjagutta, Hyderabad, 500082, Telangana, India
Hyderabad
TELANGANA 
919502653537

drmlneeharika@gmail.com 
Dr Dheeraj Khurana  Postgraduate Institute of Medical Education and Research  Room No. 18, Department of Neurology, Ground Floor, Block A, Nehru Hospital, PGIMER, Sector 12, Chandigarh, Punjab-160012
Chandigarh
CHANDIGARH 
9815066990

dherajk@yahoo.com 
Dr Anshu Rohatgi  Sir Gangaram Hospital  Rajinder Nagar, New Delhi, Delhi 110060, India
Central
DELHI 
9810159046

rohatgianshu@yahoo.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 9  
Name of Committee  Approval Status 
Artemis Health Sciences, Instutional Ethics Committee_Dr. Manish Mahajan  Approved 
Central Ethics Committee Nitte Deemed to be University, University Enclave Medical Sciences Complex Deralakatte_Dr. Lekha Pandit  Approved 
IEC, Fortis Memorial Research Institute_Dr. Praveen Gupta  Approved 
Institute Ethics Committee All India Institute of Medical Sciences_Dr. M V Padma  Approved 
Institutional Ethics Committee Post Graduate Institute of Medical Education and Research_Dr. Dheeraj Khurana  Approved 
Jasleen Hospital’s Ethics Committee, Maharashtra  Approved 
NIMHANS Ethics Committee National Institute of Mental health and Neurosciences_Dr. Netravathi M  Approved 
NIMS Institutional Ethics Committee, NIMS Hospital, Telangana  Submittted/Under Review 
Sir Ganga Ram Hospital Ethics Committee_Dr. Anshu Rohatgi  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  (1) ICD-10 Condition: G35||Multiple sclerosis,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Comparator Agent  Placebo  Unit dose strength(s) 60 mg Dose formulation Tablet Dosage level(s) Once daily Route of administration Oral  
Intervention  SAR442168 60 mg or Placebo matched to SAR442168  Dose formulation Tablet Unit dose strength(s) 60 mg Dosage level(s) Once daily Route of administration: Oral Dose once daily Frequency Once daily Duration of therapy 48 months  
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  60.00 Year(s)
Gender  Both 
Details  Participants are eligible to be included in the study only if all of the following criteria apply:
Age
I 01. The participant must be 18 to 60 years of age, inclusive, at the time of signing the informed consent.

Type of participant and disease characteristics:
I 02. The participant must have been diagnosed with RRMS according to the 2017 revision of the McDonald diagnostic criteria (16).
03. The participant must have a current diagnosis of SPMS in accordance with the clinical course criteria (11) revised in 2013 (10) and endorsed by an Adjudication Committee.
I 04. The participant must have documented evidence of disability progression observed during the 12 months before screening. Eligibility will be analyzed by an Adjudication Committee (to evaluate source data for disability confirmation; details see Section 10.1.5.3).
I 05. Absence of clinical relapses for at least 24 months.
I 06. The participant must have an EDSS score at screening from 3.0 to 6.5 points, inclusive.
I 07. The participant must have, at screening, disease duration from the onset of MS symptoms
of:
<20 years in participants with EDSS scores at screening >5.0;
OR <10 years in participants with EDSS scores at screening ≤5.0
Weight
I 05. Not applicable.

Sex
I 06. Male and /or Female

Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
A) Male participants
Not applicable
B) Female participants
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
Is not a WOCBP
OR
Is a WOCBP and agrees to use an acceptable contraceptive method as described in Appendix 4 of protocol during the intervention period.
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) (Appendix 2 [Section 10.2] of protocol) before the first dose of study intervention.
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
Requirements for pregnancy testing during and after study intervention are located in the SoA (Section 1.3 of the protocol).
Additional requirements for pregnancy testing during and after study intervention are located in Appendix 2 (Section 10.2 of the protocol).
The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy, if allowed by local regulations
See Section 10.8 of protocol for country-specific contraception requirements.
Informed Consent
I 10. The participant is capable of giving signed informed consent as described in Appendix 1 of the protocol which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. In countries where the legal age of majority is above 18 years, a specific ICF must also be signed by the participant’s legally authorized representative (Appendix 1, Section 10.1.3 of the protocol).
 
 
ExclusionCriteria 
Details  Participants are excluded from the study if any of the following criteria apply:
Medical conditions
E 01. The participant has a history of infection or may be at risk for infection:
A history of T-lymphocyte or T-lymphocyte-receptor vaccination, transplantation (including solid organ, stem cell, and bone marrow transplantation) and/or antirejection therapy.
E 02. The presence of psychiatric disturbance or substance abuse as evidenced by:
A history of any psychiatric disease, behavioral condition, or depression requiring hospitalization within 2 years prior to the Screening Visit
E 03. The following findings obtained during the screening visit considered in the Investigator’s judgment to be clinically significant:
Any screening laboratory values outside normal limits.
Abnormal ECG
E 04. Conditions that may predispose the patient to excessive bleeding:
A bleeding disorder or known platelet dysfunction at any time prior to the Screening Visit
E 05. Conditions that would adversely affect participation in the study or make the primary efficacy endpoint non-evaluable:
A short life expectancy due to pre-existing health condition(s) as determined by their treating neurologist
Prior/concomitant therapy
E 06. A requirement for concomitant treatment that could bias the primary evaluation, such as any of the following medications/treatments within the specified time frame before any randomization assessment (no wash out is required for interferon beta or glatiramer acetate treatments although use is not permitted on or after Day 1):
Prior/concurrent clinical study experience
E 07. The participant is receiving strong inducers or inhibitors of CYP3A or CYP2C8 hepatic enzymes as listed in Section 10.9. of the protocol.
E 08. The participant is receiving anticoagulant/antiplatelet therapies; those that are not permitted to be taken concomitantly with the IMP, include the following:
Acetylsalicylic acid (aspirin)
Antiplatelet drugs (eg, clopidogrel)
E 09. The participant has sensitivity to any of the study interventions, or components thereof, or has a drug or other allergy that, in the opinion of the Investigator, contraindicates participation in the study
E 10. The participant was previously exposed to any BTK inhibitor, including SAR442168.
E 11. The participant has taken other investigational drugs within 3 months or 5 half-lives, whichever is longer, before the screening visit.
Diagnostic assessments
E 12. The participant has a contraindication for MRI, ie, presence of pacemaker, metallic implants in high risk areas (ie, artificial heart valves, aneurysm/vessel clips), presence of metallic material (eg, shrapnel) in high risk areas, known history of allergy to any contrast medium, or history of claustrophobia that would prevent completion of all protocol scheduled MRI
Other exclusions
E 13. Individuals accommodated in an institution because of regulatory or legal order; prisoners or participants who are legally institutionalized.
E 14. Any country-related specific regulation that would prevent the participant from entering the study. See Appendix 8 (Section 10.8) (country-specific requirements).
E 15. The participant is not suitable for participation, whatever the reason, as judged by the Investigator, including medical or clinical conditions, or participants potentially at risk of noncompliance to study procedures or not able to follow the schedule of protocol assessments due to other reasons (exception: participants who are not able to complete electronic clinical outcome assessments may be given paper clinical outcome assessments to complete).
E 16. Participants are employees of the clinical study site or other individuals directly involved in the conduct of the study, or immediate family members of such individuals (in conjunction with Section 1.61 of the International Council for Harmonisation [ICH] - Good Clinical Practice [GCP] Ordinance E6).
E 17. Any other situation during study implementation/course that may raise ethics considerations.
E 18. Deleted in amended protocol 01
Note: a one-time retest at screening may be performed if an abnormal laboratory test value is considered temporary
 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Centralized 
Blinding/Masking   Participant and Investigator Blinded 
Primary Outcome  
Outcome  TimePoints 
Time to onset of 6-month confirmed disability Progression (CDP) defined as follows:
- Increase of ≥1.0 point from the baseline EDSS score when the baseline score is ≤5.0, OR
- Increase of ≥0.5 point when the baseline EDSS score is 5.0
 
6 months 
 
Secondary Outcome  
Outcome  TimePoints 
Time to onset of sustained 20% increase in the 9-HPT for at least 3 months
Time to onset of sustained 20% increase in the T25-FW for at least 3 months
Time to onset of 3-month CDP as assessed by the EDSS score 
6 months 
 
Target Sample Size   Total Sample Size="1290"
Sample Size from India="45" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   Phase 3 
Date of First Enrollment (India)   30/11/2020 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  23/10/2020 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="4"
Months="1"
Days="1" 
Recruitment Status of Trial (Global)
Modification(s)  
Open to Recruitment 
Recruitment Status of Trial (India)  Open to Recruitment 
Publication Details   NIL 
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Response - NO
Brief Summary   SAR442168 is expected to reduce MS relapse rate, disability progression, and underlying central nervous system (CNS) damage through its dual action on adaptive immunity in the periphery and innate immunity and the inflammation process in the CNS. The results from the Phase 2b trial (DRI15928) demonstrated a doseresponse relationship for SAR442168 as evidenced by a reduction in the number of new Gd-enhancing T1-hyperintense brain lesions detected by brain MRI after 12 weeks of treatment. There was an 85% relative reduction in lesions at 12 weeks in the 60 mg dose group as compared with placebo. This was obtained from the negative binomial regression model adjusted for baseline Gd-enhancing T1-hyperintense lesion activity SPMS occurs in more than 50% of patients with relapsing remitting multiple sclerosis (RRMS) within 15 to 20 years. Chronic disability accumulation remains a significant unmet need for people living with MS. Individuals with progressive disease, including SPMS, need therapies to reduce the accumulation of disability. With several drugs approved for active secondary progressive disease, there is still no treatment available for NRSPMS. Evidence of inflammation and presence of activated T and B cells in the brain have been confirmed in primary progressive (PPMS) and SPMS, especially in the early stages.4 Inflammatory activity in RMS has been attenuated to different degrees with a variety of immunomodulatory therapies; however, historically these therapies have shown very little effect on disease activity in people with progressive MS despite the evidence for inflammatory activity. This may relate to conditions in the CNS, especially the integrity of the blood brain barrier (BBB), but also to the potency and mechanism of action of the agents. There is still a significant unmet need for therapies that target neuroinflammation in the CNS with a goal of halting long-term disability and neurodegeneration in all diagnostic categories of MS (i.e. RMS as well as progressive forms of the disease, PPMS and SPMS). 5 Even the most recent high-efficacy disease-modifying therapies act mainly on adaptive immunity in the periphery with only modest or temporary ability to slow neuroinflammatory and neurodegenerative processes and stop disease progression. 6,7 Therefore, development of MS treatments with new modes of action is of interest. 

  
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