| CTRI Number |
CTRI/2020/11/029237 [Registered on: 19/11/2020] Trial Registered Prospectively |
| Last Modified On: |
16/08/2023 |
| Post Graduate Thesis |
No |
| Type of Trial |
Interventional |
|
Type of Study
|
Drug |
| Study Design |
Randomized, Parallel Group, Placebo Controlled Trial |
|
Public Title of Study
|
Relapsing forms of multiple sclerosis (RMS) study of BTK inhibitor SAR442168 (GEMINI 2) |
|
Scientific Title of Study
|
A Phase 3, randomized, double-blind efficacy and safety study comparing SAR442168 to teriflunomide (Aubagio®) in participants with relapsing forms of multiple sclerosis |
| Trial Acronym |
GEMINI 2 |
|
Secondary IDs if Any
|
| Secondary ID |
Identifier |
| 2020-000644-55 |
EudraCT |
| EFC16034 Protocol Amendment 01 Version no.1 dated 07May2020 |
Protocol Number |
|
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Modification(s)
|
| Name |
Dr. J. Dinesh Kumar |
| Designation |
Medical Advisor |
| Affiliation |
Sanofi Healthcare India Private Limited |
| Address |
Sanofi House, CTS No. 117-B, L&T Business Park, Saki Vihar Road, Powai Mumbai 400072, India
Mumbai
MAHARASHTRA
400072
India |
| Phone |
9790753835 |
| Fax |
|
| Email |
DineshKumar.Jeyaprakash@sanofi.com |
|
Details of Contact Person
Scientific Query
Modification(s)
|
| Name |
Dr. J. Dinesh Kumar |
| Designation |
Medical Advisor |
| Affiliation |
Sanofi Healthcare India Private Limited |
| Address |
Sanofi House, CTS No. 117-B, L&T Business Park, Saki Vihar Road, Powai Mumbai 400072, India
Mumbai
MAHARASHTRA
400072
India |
| Phone |
9790753835 |
| Fax |
|
| Email |
DineshKumar.Jeyaprakash@sanofi.com |
|
Details of Contact Person
Public Query
Modification(s)
|
| Name |
Venkateshwar Chaubey |
| Designation |
Clinical Project Leader |
| Affiliation |
Sanofi Healthcare India Private Limited |
| Address |
Sanofi House, CTS No. 117-B, L&T Business Park, Saki Vihar Road, Powai Mumbai 400072, India
Mumbai
MAHARASHTRA
400072
India |
| Phone |
9540013386 |
| Fax |
|
| Email |
Venkateshwar.chaubey@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
|
|
|
Countries of Recruitment
|
United States of America
Argentina
Brazil
France
Germany
Netherlands
Portugal
Switzerland
Ukraine
India
Spain
United Kingdom
Republic of Korea
Russian Federation |
|
Sites of Study
|
| No of Sites = 6 |
| Name of Principal
Investigator |
Name of Site |
Site Address |
Phone/Fax/Email |
| Dr Manish Mahajan |
Artemis Hospital |
Sector 51, Gurugram,
Haryana 122001, India
Gurgaon
HARYANA |
8557873567
drmanishneurology@gmail.com |
| Dr Praveen Gupta |
Fortis Hospital |
Fortis Memorial Research Institute situated at Fortis Memorial Research Institute Fortis Memorial Research Institute Sector-44, Gurugram Haryana - 122002
Gurgaon
HARYANA |
9891907903
praveen.gupta@fortishealthcare.com |
| Dr Thomas Iype |
Government medical college |
Government Medical College, Thiruvananthapuram, Kerala - 695611
Thiruvananthapuram
KERALA |
9446230317
drthomasiypeneuro@gmail.com |
| Dr Manjunath Netravathi |
NIMHANS |
P.B. No. 2900, Hosur Rd, Bengaluru, Karnataka 560029, India
Bangalore
KARNATAKA |
9880106662
sundernetra@yahoo.co.in |
| 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= 6 |
| Name of Committee |
Approval Status |
| Artemis health Sciences Institutional Ethics Committee_Dr. Manish Mahajan |
Approved |
| Human Ethics Committee Government medical college |
Submittted/Under Review |
| IEC, Fortis Memorial Research Institute_Dr. Praveen Gupta |
Approved |
| Instutional Ethics Committee, Post graduate Institute of Medical Education and Research |
Submittted/Under Review |
| NIMHANS Ethics Committee_Dr. Netravathi M |
Approved |
| Sir Ganga Ram Hospital Ethics Committee_Dr. Anshu Rohtagi |
Approved |
|
|
Regulatory Clearance Status from DCGI
|
|
|
Health Condition / Problems Studied
|
| Health Type |
Condition |
| Patients |
(1) ICD-10 Condition: G35||Multiple sclerosis, |
|
|
Intervention / Comparator Agent
|
| Type |
Name |
Details |
| 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
IMP
approximately 36 months duration |
| Comparator Agent |
Teriflunomide 14 mg or Placebo matched to teriflunomide |
Dose formulation Tablet
Unit dose strength(s) 14 mg
Dosage level(s) Once daily
Route of administration Oral
IMP and NIMP IMP
approximately 36 months duration |
|
|
Inclusion Criteria
|
| Age From |
18.00 Year(s) |
| Age To |
55.00 Year(s) |
| Gender |
Both |
| Details |
Age
I 01. The participant must be 18 to 55 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 RMS according to the 2017 revision of the McDonald diagnostic criteria (16).
I 03. The participant has an EDSS score ≤5.5 at the first Screening Visit
I 04. The participant must have at least 1 of the following prior to screening:
≥1 documented relapse within the previous year OR
≥2 documented relapses within the previous 2 years, OR
≥1 documented Gd-enhancing brain lesion on an MRI scan within the previous year.
Note: The initial clinical demyelinating episode of MS should be counted as a relapse for the first 2 criteria
Weight
I 05. Not applicable.
Sex
I 06. Male or Female
Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Male participants wishing to conceive a child and female participants becoming pregnant or wishing to become pregnant must permanently discontinue the study intervention and follow the local teriflunomide label recommendation
A) Male participants
Male participants are eligible to participate if they agree to the following during the intervention period and until the accelerated elimination procedure is performed.
Refrain from donating sperm
Plus either:
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent
OR
Must agree to use contraception/barrier method as detailed below
Agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant
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 apply:
Is not a WOCBP
OR
Is a WOCBP and agrees to use a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, during the intervention period and until the accelerated elimination procedure is completed after the last dose of study intervention
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local regulations) within 24 hours 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.
Additional requirements for pregnancy testing during the study and after study intervention are located in the schedule of activities (SoA)
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 protocol for country-specific contraception requirements
Informed Consent
I 07. The participant must have given written informed consent prior to undertaking any study-related procedure. This includes consent to comply with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. In countries where the legal age of maturity is greater than 18 years, a specific ICF for such legally minor participants must also be signed by the participant’s legally authorized representative
|
|
| ExclusionCriteria |
| Details |
Participants are excluded from the study if any of the following criteria apply:
Medical conditions
E 01. The participant has been diagnosed with PPMS according to the 2017 revision of the
McDonald diagnostic criteria or with nonrelapsing SPMS.
E 02. 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
The participant has received any live (attenuated) vaccine (including but not limited to varicella zoster, oral polio, and nasal influenza) within 2 months before the first treatment visit.
E 03. 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 04. 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 05. Conditions that may predispose the participant to excessive bleeding:
A bleeding disorder or known platelet dysfunction at any time prior to the Screening Visit.
A platelet count <150 000/μL at the Screening Visit.
E 06. Conditions that would adversely affect participation in the study or make the primary efficacy endpoint non-evaluable:
Any malignancy within 5 years prior to the Screening visit (except for effectively treated carcinoma in situ of the cervix or adequately treated non-metastatic squamous or basal cell carcinoma of the skin) will also be exclusionary.
Prior/concomitant therapy
E 07. The participant has received any of the following medications/treatments within the specified time frame before any baseline assessment (no washout is required for interferon beta or glatiramer acetate treatments):
E 08. The participant is receiving strong inducers or inhibitors of cytochrome P450 (CYP) 3A or CYP2C8 hepatic enzymes as listed in Appendix 8A
E 09. The participant is receiving anticoagulant/antiplatelet therapies, including:
Acetylsalicylic acid (aspirin)
Antiplatelet drugs (eg, clopidogrel)
Warfarin (vitamin K antagonist)
Apixaban, edoxaban, rivaroxaban (direct factor Xa inhibitors)
Prior/concurrent clinical study experience
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 had a relapse in the 30 days prior to randomization.
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.
E 15. Participant 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). |
|
|
Method of Generating Random Sequence
|
Computer generated randomization |
|
Method of Concealment
|
Centralized |
|
Blinding/Masking
|
Participant and Investigator Blinded |
|
Primary Outcome
|
| Outcome |
TimePoints |
| Annualized adjudicated relapse rate (ARR) during the study period assessed by confirmed protocol-defined adjudicated relapses |
Study will continue until 162 events are projected to have occurred in the pooled data, to ensure approximately 90% power to detect a 40% risk reduction in 6-month CDW with SAR442168 compared to teriflunomide, based on an assumed 24-month event rate of 12% in the teriflunomide arm. |
|
|
Secondary Outcome
|
| Outcome |
TimePoints |
Time to onset of confirmed disability worsening (CDW), confirmed over at least 6 months, defined as follows:
increase of ≥1.5 points from the baseline Expanded Disability Status Scale (EDSS) score when the baseline score is 0, OR
increase of ≥1.0 point from the baseline EDSS score when the baseline score is 0.5 to ≤5.5, OR
increase of ≥0.5 point from the baseline EDSS score when the baseline score is 5.5
|
at least 6 months |
Time to onset of CDW, assessed by the EDSS score and confirmed over at least 3 months
|
at least 6 months |
|
|
Target Sample Size
|
Total Sample Size="900"
Sample Size from India="50"
Final Enrollment numbers achieved (Total)= "899"
Final Enrollment numbers achieved (India)="26" |
|
Phase of Trial
|
Phase 3 |
|
Date of First Enrollment (India)
|
01/12/2020 |
| Date of Study Completion (India) |
Date Missing |
| Date of First Enrollment (Global) |
15/07/2020 |
| Date of Study Completion (Global) |
Date Missing |
|
Estimated Duration of Trial
|
Years="3"
Months="0"
Days="0" |
Recruitment Status of Trial (Global)
Modification(s)
|
Completed |
| Recruitment Status of Trial (India) |
Completed |
|
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 dose–response
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 Approximately 80 to 85 percent
of MS patients are initially diagnosed with relapsing remitting multiple
sclerosis (RRMS). The current DMTs cannot ensure long-term suppression of
multiple sclerosis (MS) inflammatory activity including relapse and new
magnetic resonance imaging (MRI) lesion control. Therefore, there is still an
unmet need for additional efficacious treatments, especially treatments that
target disease mechanisms CNS behind a closed or partially closed blood-brain
barrier. In addition, 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, primary progressive MS [PPMS] and
secondary progressive MS [SPMS]). 6 In spite of the effectiveness of
approved DMTs in preventing acute relapses, abundant
evidence suggests that innate immunity, and specifically CNS resident microglial
cell activity, is a significant driver of neurodegeneration and disability
accumulation in all forms of MS. 1,2 Even the most recent high-efficacy DMTs mainly
act on adaptive immunity in the periphery with only modest ability to slow
neuroinflammatory and neurodegenerative processes, as demonstrated by recent
studies in progressive MS. 4,5 The modulation of innate immunity has
the potential to curtail smoldering neuroinflammation and other manifestations
of disease progression that remain unaddressed by current, approved therapies
and therefore, MS treatments targeting innate immunity with new modes of action
is of interest. This is particularly important for RRMS constituting the major
subgroup of all MS phenotypes |