| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Systemic Lupus Erythematosus |
|
| E.1.1.1 | Medical condition in easily understood language |
| Systemic Lupus Erythematosus or SLE, is an inflammatory disease caused when the immune system attacks its own tissues. |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10042947 |
| E.1.2 | Term | Systemic lupus erythematosus synd |
| E.1.2 | System Organ Class | 100000017968 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To assess the effect of BMS-986165 on BICLA response at Week 32 in subjects
with SLE |
|
| E.2.2 | Secondary objectives of the trial |
To assess the effect of BMS-986165 on measures of global and organ-specific
SLE clinical response.
To assess the safety and tolerability of BMS-986165.
To assess the PK of BMS-986165 in subjects with SLE.
To assess the effect of BMS-986165 on PD markers.
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Biomarker assessments substudy - a sample will be collected 24 to 72 hours after the first dose for for blood RNA and inflammatory markers - in USA only.
Blood flow cytometry substudy in approximately 120 subjects - in USA only. |
|
| E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent
2) SLE Disease Characteristics
a) Diagnosed ≥ 24 weeks before the screening visit
b) Meets the SLICC classification criteria for SLE9.
c) One of the following: elevated antinuclear antibodies ≥ 1:80 or positive
anti-dsDNA or positive anti-Smith as determined by the central laboratory.
d) Total SLEDAI-2K score ≥ 6 points and clinical SLEDAI-2K score ≥ 4 points with joint
involvement and/or rash
o Lupus headache, alopecia, organic brain syndrome, and mucosal ulcers cannot
count toward the score.
o Clinical SLEDAI-2K excludes laboratory abnormalities such as hematuria, pyuria,
urinary casts, proteinuria, positive anti-dsDNA, decreased complement,
thrombocytopenia, and leukopenia.
e) At least 1 of the following BILAG-based protocol-specific manifestations of SLE:
i) BILAG 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).
Modified BILAG A or B score in the Musculoskeletal body system due to active
polyarthritis.
iii) If only 1 B and no A grade is present in the Mucocutaneous body system or in the
Musculoskeletal body system due to arthritis, then at least 1 B grade must be present
in one of the other body systems, for a total of 2 BILAG B body system grades.
3) Medications for SLE
a) Background therapy is required for ≥ 12 weeks before the screening visit and must be at a
stable dose for ≥ 8 weeks before the screening visit and remain stable until randomization
and throughout study participation. Details for specific medications are as follows:
Immunosuppressants (combinations of these are NOT permitted):
o azathioprine (maximum 200 mg/day)
o 6-mercaptopurine (6-MP)
o methotrexate (MTX; maximum 25 mg/week; dose and route of administration
of MTX may not be changed for 8 weeks before the screening visit and
throughout study participation)
o leflunomide
o mycophenolate mofetil/ mycophenolic acid (MMF). Note: Subjects who are
receiving MMF may participate in the study only if administered as a
maintenance therapy and up to a maximum of 2 g/day (or equivalent); in subjects
of African ancestry, 3 g/day (or equivalent) is acceptable. Treatment may be
interrupted due to neutropenia per the product label.
Antimalarials: chloroquine, hydroxychloroquine, or quinacrine; monotherapy is
permitted.
Required discontinuation periods for other immunomodulatory drugs or biologic drugs (are provided in Appendix 7 of the protocol.
b) CS (prednisone or equivalent) background therapy is permitted but not required. For
subjects taking CS, the dose must be stable for ≥ 2 weeks before the screening visit, cannot
exceed 30 mg/day at screening, and must remain stable until randomization. Prednisone
equivalents are provided in Appendix 6. Further specifications are as follows:
Intramuscular, intra-articular, intrabursal, and intravenous (IV) CS use is prohibited
within 6 weeks before screening.
Topical CS use is permitted, but must follow a stable regimen throughout the study
and cannot be used on an as-needed basis.
Inhaled CS for nonlupus conditions is permitted and will not count against the
maximum CS dose.
Modified-release CS formulations are prohibited.
c) Requirements for subjects who are receiving chronic therapy with NSAIDs (including
marketed cyclooxygenase [COX]-2 inhibitors) are as follows; exceptions or changes may
be possible with approval by the medical monitor:
Doses must be stable for 14 days before the screening visit and must remain stable
until randomization and throughout the study.
No more than 1 oral NSAID may be used (at a stable dose) during the study, and
may be combined with topical NSAIDs.
Use of 1 or more topical NSAIDs is permitted, but must follow a stable regimen
throughout the study.
4) Age and Reproductive Status
a) Males and females, ages 18 to 75 years, inclusive, at the time of screening
b) Women of childbearing potential must have a
negative urine pregnancy test within 24 hours prior to the start of study treatment.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of contraception for the duration
of treatment with study treatment (BMS-986165 or placebo) for a total of 33 days post treatment
completion.
e) WOCBP who are not heterosexually active are exempt from contraceptive requirements,
and still must undergo pregnancy testing as described in this section.
f) Investigators shall counsel WOCBP on the importance of pregnancy prevention and the
implications of an unexpected pregnancy. Investigators shall advise on the use of highly
effective methods of contraception. |
|
| E.4 | Principal exclusion criteria |
1) Target Disease Exceptions
a) Drug-induced SLE
b) Other autoimmune diseases are excluded.
c) SLE overlap syndromes such as scleroderma and mixed connective tissue disease are
excluded.
d) Subjects with a serious thrombotic event within 1 year before the screening visit . Subjects with a history of catastrophic antiphospholipid syndrome or saddle embolism.
e) Active or unstable lupus neuropsychiatric manifestations, including but not limited to any
condition defined by BILAG A criteria.
f) Active, severe lupus nephritis that requires or may require treatment with cytotoxic agents or high-dose CS.
2) Other Medical Conditions and History:
a) Any major illness/condition that will substantially increase the risk to the subject if he or she participates in the study.
b) Any major surgery within the last 30 days before the first dose of study treatment, or any
surgery planned during the study.
c) Cancer or history of cancer or lymphoproliferative disease within 5 years
d) Class III or IV congestive heart failure
e) Acute coronary syndrome and/or any history of significant cerebrovascular disease within 24 weeks of screening
f) Current or recent (within 3 months before randomization) gastrointestinal disease,
including surgery, that could impact the absorption of study treatment
g) Subjects with non-SLE concomitant illness that is likely
to require additional systemic glucocorticosteroid therapy
h) Significant blood loss (> 500 mL) or blood transfusion within 4 weeks of
randomization
i) Inability to tolerate oral medication
j) Inability to undergo venipuncture and/or tolerate venous access
k) Recent (within 6 months of randomization) drug or alcohol abuse.
3) Prior/Concomitant Therapy
a) Inability to comply with restrictions and prohibited treatments or to
comply with discontinuation requirements.
b) Taking more than 1 immunosuppressant.
c) Prior exposure to Tyk2 inhibitors
d) Prior exposure to anifrolumab or rontalizumab
e) Other investigational agents must be discontinued at least 12 weeks or 5 half-lives before
randomization, whichever is longer.
4) Findings Related to Possible Infection
a) Evidence of active or latent tuberculosis (TB):
Positive chest x-ray for evidence of active pulmonary TB within 6 months before
screening
Subjects with negative chest x-ray within 6 months of screening may be
eligible if:
o negative IFN gamma release assay (IGRA)
o positive IGRA and no symptoms of active TB, and have previously (within
5 years) received adequate documented treatment for latent TB
o positive IGRA and no symptoms of active TB, but have NOT previously (within 5 years) received adequate documented treatment; subject must initiate prophylactic treatment per local guidelines and may rescreen after 1 month of treatment
b) Hepatitis C, hepatitis B, or HIV infection as
demonstrated by a positive blood screen for hepatitis C antibody (anti-HCV), hepatitis B
surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), or HIV-1 and -2 antibody.
Subjects vaccinated for hepatitis B (hepatitis B surface antibody [anti-HBs].
c) Currently on any therapy for chronic infection
d) History of congenital or acquired immunodeficiency
e) Known active infection, or any major episode of infection requiring hospitalization or
treatment with parenteral antimicrobial agents within 30 days of randomization, or
completion of oral antimicrobial agents within 2 weeks of randomization
f) Previous history of herpes zoster, herpes simplex, or influenza infection within 12 weeks
of randomization or a history of disseminated/complicated herpes zoster infection
g) Administration of a live vaccine within 90 days or an inactivated vaccine within 30 days
of randomization. Furthermore, live vaccines should not be used during treatment or within the 2 months following last dose, and any other inactivated vaccines should be used according to local
guidelines.
5) Physical and Laboratory Test Findings
a) Clinically significant abnormalities on chest x-ray or ECG
b) Clinically significant abnormalities in laboratory tests:
i) Serum alanine aminotransferase (ALT) > 2× ULN, unless related to lupus
ii) Serum aspartate aminotransferase (AST) > 2× ULN, unless related to lupus
iii) Serum total bilirubin > 1.5× ULN, unless related to lupus
iv) Hemoglobin < 8 g/dL (80 g/L) or, if due to hemolytic anemia related to SLE, < 7 g/dL
(70 g/L)
v) Proteinuria > 3.0 g/day (3000 mg/day) or equivalent level of proteinuria as assessed by
urine protein/creatinine ratio (3 mg/mg or 339 mg/mmol)
vi) Estimated glomerular filtration rate < 30 mL/min
vii) Absolute white blood cell count < 1.2× 103/μL (1.2× 109/L)
viii) Platelet count < 50× 103/μL (50× 109/L)
ix) Abnormal free thyroxine (T4). Those with abnormal free T4 will be excluded unless they have a prior diagnosis of a thyroid disorder and are currently receiving thyroid replacement therapy.
6) History of any significant drug allergy
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Proportion of subjects who achieve BICLA response at Week 32 after treatment
with BMS-986165 or placebo administered on stable background therapy |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy:
- Proportion of subjects who meet response criteria for SLE Responder Index (SRI)(4)
- Proportion of subjects with a Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity score ≥ 10 at baseline who achieve a CLASI response, defined as a decrease of ≥ 50% from baseline CLASI activity score - Change from baseline in the 40-joint count for tender, swollen, and
tender + swollen joints
Safety:
- Number and proportion of subjects experiencing serious adverse events (SAEs), AEs, and abnormalities in laboratory testing, vital signs, and electrocardiograms (ECGs)
Pharmacokinetics:
Trough concentrations of BMS-986165
Pharmacodynamics:
o Change in mean and median interferon-regulated gene (IRG) expression levels
compared to baseline over time and at Week 32
o Change in mean complement (C3, C4) and anti-double-stranded DNA (dsDNA)
levels compared to baseline over time and at Week 32
o Assess the effect of BMS-986165 on measures of global SLE clinical response in
subjects based on IRG status (ie, high versus low IRG signature) at Week 32 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy - Week 32
Safety - Throughout the study
Pharmacokinetics - at Weeks 2, 4, 8, 12, 24, 32, and 48
Pharmacodynamics - Week 32 |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 34 |
| 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 |
| Brazil |
| Bulgaria |
| Colombia |
| France |
| Germany |
| Hungary |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| Peru |
| Poland |
| Romania |
| Russian Federation |
| Taiwan |
| Ukraine |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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