Efficacy and Safety of Afimetoran compared with Placebo in Participants with Active Systemic Lupus Erythematosus
Scientific Title of Study
A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, Study to Evaluate the Efficacy and Safety of Afimetoran in Participants with Active Systemic Lupus Erythematosus
Trial Acronym
NIL
Secondary IDs if Any
Secondary ID
Identifier
2019-004021-25
EudraCT
GCT/CT04/FF/2023/38165
DCGI
IM026-024 Protocol amendment 03 dated 24 Feb 2023
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Shilpi Sinha
Designation
Associate Director, Country Head RCO India
Affiliation
Bristol Myers Squibb India Pvt. Ltd.
Address
Bristol Myers Squibb India Pvt. Ltd.
One International Centre, 6th Floor, Tower 1, Senapati Bapat Marg, Elphinstone (W), Mumbai - 400013 (Suburban), MAHARASHTRA,
India
Mumbai (Suburban) MAHARASHTRA 4000013 India
Phone
02266288600
Fax
Email
Shilpi.Sinha@bms.com
Details of Contact Person Scientific Query
Name
Dr Kartik Doshi
Designation
Associate Director, Medical India
Affiliation
Bristol Myers Squibb India Pvt. Ltd.
Address
One International Centre, 6th Floor, Tower 1, Senapati Bapat Marg, Elphinstone (W), Mumbai - 400013 (Suburban), MAHARASHTRA,
India
Mumbai (Suburban) MAHARASHTRA 400013 India
Phone
02266288600
Fax
Email
kartik.doshi@bms.com
Details of Contact Person Public Query
Name
Shilpi Sinha
Designation
Associate Director, Head RCO India
Affiliation
Bristol Myers Squibb India Pvt. Ltd.
Address
One International Centre, 6th Floor, Tower 1, Senapati Bapat Marg, Elphinstone (W), Mumbai - 400013 (Suburban), MAHARASHTRA,
India Bristol Myers Squibb India Pvt. Ltd.
One International Centre, 6th Floor, Tower 1, Senapati Bapat Marg, Elphinstone (W), Mumbai - 400013 (Suburban), MAHARASHTRA,
India Mumbai (Suburban) MAHARASHTRA 4000013 India
Phone
02266288600
Fax
Email
Shilpi.Sinha@bms.com
Source of Monetary or Material Support
BRISTOL MYERS SQUIBB INDIA PRIVATE LIMITED
One International Center, 6th Floor, Tower 1,
Senapati Bapat Marg, Elphinstone (W), Mumbai- 400013
India
Primary Sponsor
Name
BRISTOL MYERS SQUIBB INDIA PRIVATE LIMITED
Address
One International Centre, 6th Floor, Tower 1, Senapati Bapat Marg, Elphinstone (W), Mumbai - 400013, India
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
NIL
NIL
Countries of Recruitment
Argentina Australia Brazil Chile China Colombia France Germany Ireland Japan Mexico Poland Romania Spain Taiwan United Kingdom United States of America
Oral treatment with afimetoran2.5mg QD, 10mgQD, 30mg QD. Treatment period is approximately 48 weeks during blinded placebo-controlled active treatment phase & 52 weeks for Optional Longterm extension phase.
Comparator Agent
Placebo
Oral treatment with placebo QD: Intervention: approximately 48 Weeks during blinded, placebo controlled active treatment period.
Inclusion Criteria
Age From
18.00 Year(s)
Age To
70.00 Year(s)
Gender
Both
Details
1. Diagnosed ≥ 12 weeks before the screening visit and qualify as having SLE, according to the SLE International Collaborating Clinics (SLICC) Classification Criteria at the screening visit
2. Test positive for at least 1 of the following lupus-related autoantibodies as determined by the central lab at the time of screening: antinuclear antibody (ANA) ≥ 1:80, anti–double-stranded deoxyribonucleic acid (dsDNA) antibody, or anti-Smith (Sm) antibody
3. Total hybrid (h)SLEDAI score ≥ 6 points and clinical hSLEDAI score ≥ 4 points with joint involvement and/or rash (score must be confirmed by the lupus expert review panel [LERP])
i. Alopecia and mucosal ulcers do not count toward the points required for eligibility at screening. Active neuropsychiatric SLE is exclusionary for study participation. Thus, points for seizures, psychosis, organic brain syndrome, visual disturbance, cranial neuropathy, lupus headache, and cerebrovascular accident, as defined by the Hybrid SLEDAI, will also not contribute to scoring
ii. Clinical hSLEDAI excludes laboratory abnormalities such as hematuria, pyuria, urinary casts, proteinuria, positive anti-dsDNA, decreased complement, thrombocytopenia, and leukopenia
4. At least 1 of the following BILAG-based protocol-specific manifestations of SLE (must be confirmed by the LERP):
i. BILAG-2004 A or B grade in the Mucocutaneous body system. If a BILAG B grade for Mucocutaneous disease is due to BILAG #6 mild skin eruption, the total score of the erythema and scale components of the CLASI disease activity must be ≥ 3 (excluding mucous membrane ulcerations and nonscarring alopecia).
ii. Modified BILAG-2004 A or B score in the Musculoskeletal body system due to active polyarthritis (see protocol section 6.1 for criteria)
5. Have a PGA score of disease activity on a 0-3 VAS ≥ 1
6. Be using at least 1 background SLE treatment prior to screening, at a stable dose that must be maintained through study completion.
i. Qualifying background treatments include the following: oral systemic corticosteroids (CS); azathioprine; 6-mercaptopurine (6-MP); methotrexate (MTX); leflunomide; MMF; tacrolimus and antimalarials (e.g., chloroquine, hydroxychloroquine, or quinacrine)
ii. Background SLE treatment use is permitted according to specific protocol limits, including maximal dose and minimum duration at stable dose prior to randomization.
iii. Daily CS dose may not exceed 20 mg per day of prednisone or equivalent
iv. For participants whose only background SLE therapy is CS, the dose should be ≥ 10 mg prednisone or equivalent daily.
i) Changes to CS doses are allowed as described in Section 7.7.2.1.
v. If CS are being used (with or without a non-CS SLE treatment), they must be in use for at least 4 weeks and at a stable dose for at least 2 weeks prior to screening.
vi. Background non-CS SLE treatments must be in use for at least 8 weeks and at a stable dose for at least 4 weeks prior to screening.
vii. Required discontinuation periods for other immunomodulatory drugs or biologic drugs are provided in APPENDIX 18 of the protocol. If a drug is not specifically listed, consult the medical monitor for guidance. Usual discontinuation periods are 4 weeks or 5 half-lives whichever is longer.
Inclusion Criteria for LTE
1) Signed Written Informed Consent
i. Participants must have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved written ICF in accordance with regulatory, local, and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal patient care.
ii. Participants must be willing and able to complete all study-specific procedures and visits.
2) Type of Participant and Target Disease Characteristics
i. Completion of study treatment through Week 48.
ii. In the opinion of the investigator, the participant may benefit from continuation in the optional LTE period.
• Note: If any participant had been given prohibited medications during the placebo-controlled treatment period and was continued in the study, participation of these subjects in the LTE must be discussed with the Medical Monitor.
3) Reproductive Status
i. WOCBP must have a negative urine pregnancy test at the initial visit (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadoptropin)
1) If a urine test cannot be confirmed as negative (ie, 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.
2) Women must not be pregnant, lactating, breastfeeding, or planning pregnancy during the LTE period.
3) WOCBP must agree to continue using highly effective (with a failure rate of < 1% per year) method(s) of contraception, preferably with low user dependency as described in APPENDIX 4, during the intervention period and for at least 21 days after the last dose of study intervention, and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the same time period
4) Male participants will be required to always use a latex or other synthetic condom during any sexual activity (eg, vaginal, anal, oral) with WOCBP, even if the participants have undergone a successful vasectomy or if their partner is already pregnant or breastfeeding. Males should continue to use a condom during the intervention period and for at least 21 days after the last dose of study intervention.
5) Male participants must refrain from donating sperm during the intervention period and for at least 21 days after the last dose of study intervention.
6) Breastfeeding partners should be advised to consult their health care providers about using appropriate highly effective contraception during the time the participant is required to use condoms
ExclusionCriteria
Details
1. Participants with active severe lupus nephritis (LN) as assessed by the investigator.
2. Active or unstable neuropsychiatric lupus manifestations defined by the Hybrid SLEDAI.
i. Additionally, participants with active or unstable lupus neuropsychiatric manifestations, including but not limited to any condition defined by BILAG-2004 A criteria, are excluded, with the exception of participants with mononeuritis multiplex and polyneuropathy, who are allowed.
3. Diagnosis of Mixed Connective Tissue Disease for which the predominant diagnosis is not SLE.
i. For example, participants whose prevailing signs and symptoms are consistent with dermatomyositis or systemic sclerosis should be excluded. Alternatively, participants who meet classification criteria for SLE and are treated predominantly as SLE patients, but also have erosive arthritis (i.e., Rhupus), thyroiditis, antiphospholipid syndrome, or polymyositis, should not be systematically excluded. The investigator should consider consultation with the MM to ensure such cases are appropriate for study inclusion.
4. Antiphospholipid Syndrome (APS):
i. The following are exclusionary:
i) Confirmed diagnosis of APS as defined by the revised Sapporo criteria (see APPENDIX 19) if there has been a thrombotic event or pregnancy morbidity within 12 months before screening
ii) History of probable or definite catastrophic APS
ii. The following are not exclusionary:
i) A positive result for antiphospholipid antibodies at screening is not exclusionary provided there is no history of thrombosis or pregnancy mortality in the past 12 months
ii) A thrombotic event more than 12 months before screening is not exclusionary provided the subject is maintained on appropriate anticoagulation therapy (warfarin, low-molecular weight heparin, or newer anticoagulants
iii) A history of APS with a history of pregnancy morbidity more than 12 months before screening is not exclusionary provided the subject is maintained on low-dose aspirin or equivalent
5. Inability to comply with restrictions and prohibited treatments, as listed in Section 7.7: Concomitant Therapy.
6. Current daily Oral CS (prednisone or equivalent) ≥ 20 mg QD. Prednisone equivalents are provided. Further specifications are as follows:
7. Intramuscular, intra-articular, intrabursal, and intravenous (IV) CS use is prohibited within 8 weeks before screening.
8. Inhaled and intranasal CS for nonlupus conditions are permitted and will not count toward the maximum CS dose allowed.
i. Modified-release CS formulations are prohibited.
9. Changes in oral CS dose from 2 weeks prior to screening through initial study drug dosing
10. Current or recent use of biologic agent or other prohibited immunosuppressive medication defined
11. Taking more than 1 immunosuppressant, not including CS or antimalarial drugs.
12. Prior exposure to BMS-986256 or another combined TLR7/8 antagonist
13. Use of topical medications/treatments that could affect the appearance of skin lesions within 2 weeks prior to screening
14. Use of strong CYP3A4 inhibitors
15. Recent exposure to other investigational agents; investigational agents must be discontinued at least 4 weeks or 5 half-lives before screening, whichever is longer.
16. Use of any Chinese traditional medicine intended for use in SLE within 4 weeks of randomization
17. Any major illness/condition or evidence of an unstable clinical condition (eg, renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, immunologic, psychiatric) or active infection/infectious illness that, as determined by the investigator’s clinical judgment, will substantially increase the risk to the participant if he or she participates in the LTE.
i. For participants who test positive or indeterminate on the IGRA at Week 48, participation in the LTE should be discussed with the Medical Monitor
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Centralized
Blinding/Masking
Double Blind Double Dummy
Primary Outcome
Outcome
TimePoints
Proportion of participants who achieve an SRI(4)response at Week48
Week48
Secondary Outcome
Outcome
TimePoints
Proportion of participants:
who achieve an SRI(4) response at Week 24Â
who achieve a BICLA response at Week 24Â
who achieve an LLDAS response at Week 24 and Week 48Â
with a CLASI-A score ≥ 10 at baseline who achieve a CLASI-50 response, defined as a decrease of ≥ 50% from baseline CLASI-A score at Week 24 and Week 48Â
with 6 or more swollen joints and 6 or more tender joints at baseline who achieve a ≥ 50% reduction from baseline in both swollen and tender joints at Week 24 and Week 48
Mean change from baseline in:Â
swollen joint count using the 28-joint count at Week 24 and Week 48 in participants with ≥ 2 swollen joints at baselineÂ
tender joint count using the 28-joint count at Week 24 and Week 48 in participants with ≥ 2 tender joints at baselineÂ
Change from baseline in PGA score of disease activity at Week 24 and Week 48Â
Week 24 & Week 48
Target Sample Size
Total Sample Size="268" Sample Size from India="8" 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 2
Date of First Enrollment (India)
16/03/2024
Date of Study Completion (India)
Applicable only for Completed/Terminated trials
Date of First Enrollment (Global)
11/10/2021
Date of Study Completion (Global)
Applicable only for Completed/Terminated trials
Estimated Duration of Trial
Years="2" Months="1" Days="0"
Recruitment Status of Trial (Global)
Open to Recruitment
Recruitment Status of Trial (India)
Open to Recruitment
Publication Details
N/A
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
The data collected during this study are confidential and proprietary to the Sponsor or designee.
Any publications or abstracts arising from this study must adhere to the publication requirements
set forth in the Clinical Trial Agreement (CTAg) governing [study site or investigator]
participation in the study. These requirements include, but are not limited to, submitting proposed
publications to the Sponsor or designee at the earliest practicable time prior to submission or
presentation and otherwise within the time period set forth in the CTAg.
Scientific publications (such as abstracts, congress podium presentations and posters, and
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the
external authors. No public presentation or publication of any interim results may be made by any
principal investigator, sub-investigator, or any other member of the study staff without the prior
written consent of the Sponsor.
Authorship of publications at BMS is aligned with the criteria of the International Committee of
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for
authorship:
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition
of data (ie, evaluable participants with quality data), analysis, or interpretation of data for the
work (eg, problem solving, advice, evaluation, insights and conclusion); AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions related to
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by BMS
for authorship of the primary publication. Sub-investigators will generally not be considered for
authorship in the primary publication. Geographic representation will also be considered.
Authors will be listed by order of significant contributions (highest to lowest), with the exception
of the last author. Authors in first and last position have provided the most significant contributions
to the work.
For secondary analyses and related publications, author list and author order may vary from
primary to reflect additional contributions.