E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
kidney inflammation caused by lupus (lupus nephritis) |
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E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10025140 |
E.1.2 | Term | Lupus nephritis |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Safety: To assess the safety and tolerability of BMS-986165 in LN Efficacy: To evaluate the efficacy of BMS-986165 compared with placebo with regard to proteinuria |
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E.2.2 | Secondary objectives of the trial |
Efficacy – To evaluate the efficacy of BMS-986165 with regard to measures of renal function and SLE activity |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Signed Written Informed Consent a. Willing to participate in the study and have the ability to give informed consent b. Willing and able to complete all study-specific procedures and visits
SLE Disease Characteristics a. Meets the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) criteria for SLE b. Renal biopsy confirming a histologic diagnosis of active LN ISN/RPS Classes III (A or A/C), IV-S (A or A/C), or IV-G (A or A/C); or Class V (in combination with Class III or IV) c. UPCR ≥ 1.5 mg/mg (for subjects with biopsies taken ≤ 6 months prior to screening) or UPCR ≥ 1 mg/mg (for subjects with biopsies taken ≤ 3 months prior to screening) assessed with a 24-hour urine specimen
Medications for SLE/Concomitant Medications a. If subjects are taking an angiotensin converting enzyme inhibitor (ACE), angiotensin receptor blocker (ARB), or antimalarial drug, the dose must be stable for at least 4 weeks before randomization into part B with no anticipated changes in dosage in Part B b. Required discontinuation periods for other immunomodulatory drugs or biologic drugs must be met as outlined in APPENDIX 7. If a specific drug is not listed, consult the PRA medical monitor for guidance; usual discontinuation periods are 4 weeks or 5 half-lives, whichever is longer c. It is allowed but not required for prospective subjects to have been taking MMF for ≤ 24 weeks at the time of screening. The suggested target dose is 1.5 to 2.0 g/day (maximum 3.0 g/day) unless limited by toxicity or intolerance (refer to Section 6.1 for further details regarding individual target dose)
Age and Reproductive Status a. Men and women aged 18 (or local age of majority) to 75 years inclusive at the time of screening b. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of beta-human chorionic gonadotropin) at screening, within 24 hours before the first dose of MMF in Part A, and before the first dose of blinded study treatment in Part B. c. Women must not be breastfeeding d. The contraception requirements for MMF are stricter than those for BMS-986165; therefore the requirements for MMF (see APPENDIX 4) must be followed throughout study participation and for a period of time after the final dose of MMF or blinded study treatment 1. WOCBP: a. Per the MMF prescribing information, subjects taking MMF must use acceptable contraception throughout the study and continue for at least 6 weeks after the final dose of MMF b. Subjects must be counseled that MMF may reduce the effectiveness of oral contraceptives, and use of additional barrier contraceptive methods is required 2. Men who are sexually active with WOCBP: a. Subjects must inform any and all partners of their participation in the study and the need to use contraception during the man’s study participation and for at least 90 days after his last dose of MMF b. Per the MMF prescribing information, male subjects taking MMF must continue to use effective contraception and should not donate sperm for at least 90 days after the final dose of MMF |
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E.4 | Principal exclusion criteria |
Target Disease a. Pure ISN/RPS Class V membranous LN b. Screening estimated glomerular filtration rate (eGFR; calculated using the MDRD equation) ≤ 30 mL/minute/1.73 m2 c. History of kidney transplantation or planned transplantation during the study d. End-stage renal disease e. Autoimmune diseases other than SLE, with the exception of secondary Sjögren’s syndrome, celiac disease, and stable Hashimoto’s thyroiditis f. SLE overlap syndromes such as mixed connective tissue disease or coexisting scleroderma or rheumatoid arthritis g. Antiphospholipid Syndrome (APS): h. Active or unstable lupus neuropsychiatric manifestations, including but not limited to any condition defined by British Isles Lupus Assessment Group (BILAG) A criteria, with the exception of subjects with mononeuritis multiplex and polyneuropathy, which are allowed with the approval of CRS. i. Dialysis within 12 months before screening or plans for dialysis within 6 months after enrollment
Other Medical Conditions and History a. Women who are pregnant or breastfeeding b. Screening systolic blood pressure > 150 and/or diastolic blood pressure > 90 mmHg c. BMI ≥ 40 kg/m2 at screening d. Any major illness/condition, evidence of an unstable clinical condition, or symptoms of a severe, progressive, or uncontrolled condition or local active infection/infectious illness that might place the subject at unacceptable risk for participation in this study e. Any major surgery within 30 days before the first dose of study treatment or any surgery planned during the course of the study f. Cancer or history of cancer or lymphoproliferative disease within 5 years before screening g. New York Heart Association (NYHA) Class III or IV congestive heart failure or any recent onset of heart failure resulting in NYHA Class III/IV symptoms h. Acute coronary syndrome and/or any history of significant cerebrovascular disease within 24 weeks before screening i. Serious thrombotic event(s) within 1 year before the screening visit j. Current or recent gastrointestinal disease, including gastrointestinal surgery, that could impact the absorption of oral study treatment k. Non-SLE concomitant illness that is likely to require additional systemic glucocorticosteroid therapy during the study l. Severe, progressive, or uncontrolled kidney, liver, blood, stomach, lung, heart, or brain disease not due to active SLE m. Comorbid conditions requiring systemic corticosteroid use in the 52 weeks before screening n. Poorly controlled or advanced diabetes mellitus, as evidenced by a hemoglobin A1c of ≥ 8.0% at screening, or by active diabetic complications such as diabetic nephropathy o. Evidence of a degree of tubulointerstitial changes that suggest a significant and irreversible decrease in renal function p. Renal disease unrelated to SLE including persistent, non-SLE-related pyuria or hematuria q. Significant blood loss (> 500 mL) or blood transfusion within 4 weeks before randomization r. Inability to tolerate oral medication s. Inability to tolerate venipuncture and/or inadequate venous access t. Recent substance dependence or abus u. Any disease or medical condition that would make the subject unsuitable for this study, would interfere with the interpretation of subject safety or study results, or considered unsuitable by the investigator for any other reason
Findings Related to Possible Infection a. Evidence of active or latent tuberculosis (TB) b. Any of the following hepatitis B (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) serology results at screening c. Currently receiving therapy for chronic infection; medications used for prophylaxis are not exclusionary d. History of congenital or acquired immunodeficiency e. Known active infection, or any major episode of infection f. Administration of a live vaccine or an inactivated vaccine within 30 days before screening g. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection (either suspected or confirmed) within 12 weeks of screening.
Physical Examination and Laboratory Results a. Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, or clinical laboratory determination beyond what is consistent with the target population b. Clinically significant abnormalities on screening chest X-ray or ECG unless due to SLE c. Clinically significant abnormalities in screening laboratory results
Allergies and Adverse Drug Reaction a. History of any significant drug allergy
Other Exclusion Criteria a. Involuntary incarceration such as imprisonment b. Compulsory detention for treatment of psychiatric or physical illness c. Inability to comply with the study protocol
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E.5 End points |
E.5.1 | Primary end point(s) |
Percentage change from baseline in 24-hour UPCR at Week 24 AEs, vital signs, ECGs and laboratory abnormalities from baseline through Week 52 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Percentage change at Week 24 continuous follow up of AEs and laboratory abnormalities from baseline through Week 52
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E.5.2 | Secondary end point(s) |
*PRR at Week 24, defined as ≥ 50% reduction from baseline in 24-hour UPCR * CRR at Week 24, defined as both of the following: - 24-hour UPCR ≤ 0.7 mg/mg - eGFR ≥ 60 mL/min or ≤ 20% decrease from baseline * CRR at Week 52 * CRR + successful CS taper to ≤ 7.5 mg/day at Week 24 * CRR + successful CS taper to ≤ 7.5 mg/day at Week 52 * PRR at Week 52 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
* CRR at Week 24 * CRR at Week 52 * CRR + successful CS taper to ≤ 7.5 mg/day at Week 24 * CRR + successful CS taper to ≤ 7.5 mg/day at Week 52 * PRR at Week 52 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Belgium |
Brazil |
Canada |
China |
Czech Republic |
Germany |
Israel |
Italy |
Korea, Republic of |
Mexico |
Netherlands |
Russian Federation |
Spain |
Sweden |
Taiwan |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |