Safety: To assess the safety and tolerability of BMS-986165 in LNEfficacy: Efficacy: To evaluate the efficacy of BMS 986165 compared with placebo with regard to proteinuria SecondaryEfficacy - To evaluate the efficacy of BMS-986165 with regard to…
ID
Source
Brief title
Condition
- Renal disorders (excl nephropathies)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Efficacy Endpoint
• AEs, vital signs, ECGs, and laboratory abnormalities from baseline through
Week 52
• Percentage change from baseline in 24 hour UPCR at Week 24
Secondary outcome
• 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 <= 0.75 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
Background summary
Lupus nephritis is one of the most serious manifestations of systemic lupus
erythematosus (SLE) but the prognosis for patients with LN has not
substantially improved since the 1980s.2 BMS-986165 is a novel, oral, selective
tyrosine kinase 2 (TYK2) inhibitor with a
unique mechanism of action distinct from other kinase inhibitors that has shown
efficacy in subjects with autoimmune diseases and in murine models of SLE and
LN.3-5 This study is designed to assess whether add-on therapy with BMS-986165
might improve renal function in subjects who
do not adequately respond to initial treatment with MMF.
Study objective
Safety: To assess the safety and tolerability of BMS-986165 in LN
Efficacy: Efficacy: To evaluate the efficacy of BMS 986165 compared with
placebo with regard to proteinuria
Secondary
Efficacy - To evaluate the efficacy of BMS-986165 with regard to measures of
renal function and SLE activity
Study design
This is a 3-part, multicenter, randomized, double-blind study in which eligible
subjects will be assessed for renal response after having received a total of
at least 12 weeks (but <= 24 weeks) of treatment with MMF at a target dose of
1.5 to 3.0 g/day. Subjects will receive 12 weeks of target-dose MMF in Part A
of the study if they have not been taking target-dose MMF at screening.
Subjects who have been taking target-dose MMF for >= 1 day but < 12 weeks at
screening will continue to receive target-dose MMF in Part A until they reach
12 weeks of total MMF treatment. Subjects who have been taking target-dose MMF
for >= 12 weeks but <= 24 weeks at screening will enter the study at Visit A4 to
immediately be assessed for renal response and entry into Part B.
Subjects with an inadequate renal response to MMF may be randomized to blinded
study treatment with one of two doses of BMS 986165 or placebo as add-on
therapy to MMF in Part B. Inadequate response is defined as < 50% reduction in
24 hour UPCR from the pre-MMF value and a 24 hour UPCR >= 1.0 mg/mg. Randomized
subjects will continue taking open-label MMF with or without corticosteroids.
Randomization will be stratified by baseline UPCR < 3.0 mg/mg versus >= 3.0
mg/mg and the total cumulative intravenous (IV) corticosteroid
(methylprednisolone or parenteral equivalent) dose given in the 16 weeks before
randomization (< 250 mg versus >= 250 mg).
Subjects who meet the criteria to continue in Part B but do not meet the
randomization criteria may continue in Part B on open-label MMF with or without
corticosteroids and will have the same assessments in Part B as randomized
subjects. These nonrandomized subjects will exit the study at the end of Part B.
Corticosteroids are permitted but not required in this study. Subjects who are
taking corticosteroids will have their dose tapered (if possible) during Part B.
In Part B, all (randomized and nonrandomized) subjects will be evaluated at
study visits every 4 weeks through Week 52. At the end of Part B, if the
investigator considers it potentially beneficial to continue therapy with study
treatment, randomized subjects may continue to receive blinded study treatment
in the LTE Period for 52 additional weeks. Subjects will continue to be
evaluated every 4 weeks for the first 12 weeks of the LTE Period (through Week
64), then every 10 weeks through Week 104. Subjects randomized to placebo
during the initial 52 week Blinded Treatment Period will be rerandomized to
blinded BMS-986165 3 mg BID or 6 mg BID during the LTE Period, while subjects
initially randomized to BMS 986165 during the 52-week Blinded Treatment Period
will continue their Part B assigned dose in the LTE Period.
Optional renal biopsies may be performed at Week 52 and Week 104, as well as at
the end of treatment for subjects who discontinue early if discontinuation
occurs after Week 24 of Part B. After the last treatment visit (Week 52, Week
104, or early discontinuation), subjects will attend a final end-of-study visit
at the end of a 28-day follow-up period.
Intervention
Subjects who are eligible to continue in Part B of the study will continue
open-label MMF with or without corticosteroids. Subjects who also meet the
randomization criteria will be randomized in a double-blind manner to add-on
therapy with one of the following:
• 3 mg BMS 986165 twice daily (BID)
• 6 mg BMS 986165 BID
• Placebo BID
.
Study burden and risks
BMS-986165
VERY COMMON - May affect more than 1 in 10 people (>10%)
• Headache
COMMON - May affect up to 1 in 10 people (1-10%)
• Mouth/Throat/Stomach/intestine: cold sore, canker sore, toothache, throat
inflammation, sore throat, stomach or intestine inflammation, nausea, vomiting,
stomach pain, diarrhea, indigestion or heartburn
• Nose: stuffy nose, common cold or flu-like feeling
• Skin: rash, acne, itching, hives, skin infection
• Nervous system: dizziness, sleepiness
• Muscles/joints: joint pain, back pain
• Kidneys/bladder: urinary infection
• Changes in the blood: increase in muscle enzyme in the blood
• Other: allergic reaction
Mycophenolate mofetil (MMF)
The most common side effects seen with mycophenolate mofetil are:
• diarrhea
• vomiting
• pain
• stomach area pain
• swelling of the lower legs, ankles and feet
• high blood pressure
Serious side effect seen with mycophenolate mofetil are:
• Low blood cell counts including:
• white blood cells, especially neutrophils (neutrophils fight against
bacterial infections)
• red blood cells (red blood cells carry oxygen to your body tissues)
• platelets (platelets help with blood clotting)
Stomach and intestinal bleeding can happen in people who take high doses of
mycophenolate mofetil. Taking mycophenolate mofetil can increase the risk of
getting certain cancers such as lymphoma, and other cancers, especially skin
cancer.
In some patients who have immunosuppression, mycophenolate mofetil may cause an
infection of the brain, called PML that may cause death. Immunosuppression is
the partial or complete suppression of the immune response of a person.
An overview of the risks and discomforts can be found in the ICF in Appendix D.
Chaussée de la Hulpe 185
Brussels 1170
BE
Chaussée de la Hulpe 185
Brussels 1170
BE
Listed location countries
Age
Inclusion criteria
1) 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
2) SLE Disease Characteristics
a. Meets the SLICC criteria for SLE (see APPENDIX 5)
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) (see APPENDIX 12):
i. N/A per Revised Protocol 10
ii. N/A per Revised Protocol 10
iii. If a biopsy was done within <= 6 months before screening,
sites/laboratories have the option of providing at least one of the following
samples: Renal fresh biopsy; renal historical biopsy (Formalin Fixed Paraffin
Embedded block); renal archival slides; or digital image slides (refer to the
Arkana laboratory manual for further details)
iv. If a biopsy has not been done within 6 months before screening and the
subject meets all other eligibility criteria, a biopsy will be performed as
part of the study
c. N/A per Revised Protocol 10
d. 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
3) Medications for SLE/Concomitant Medications
a. N/A per Revised Protocol 10
b. If subjects are taking an angiotensin-converting enzyme (ACE) inhibitor,
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
c. 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
d. 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)
4) 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 as follows:
i. WOCBP:
a. Per the MMF prescribing information, subjects taking MMF must use acceptable
contraception (see options in APPENDIX 4) 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
ii. 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
Exclusion criteria
See Synopsis enclosed
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-004142-42-NL |
| ClinicalTrials.gov | NCT03943147 |
| CCMO | NL69457.068.19 |