Proof of Concept Study to Evaluate the Efficacy and Safety of BMS-931699 (Lulizumab) or BMS-986142 in Primary Sjögren's Syndrome

A Phase II, Randomized, Multi-Center, Double-Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of BMS-931699 (Lulizumab) or BMS-986142 in Subjects With Moderate to Severe Primary Sjögren's Syndrome

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02843659

Enrollment

Registered

2016-07-26

Start date

2016-10-18

Completion date

2017-07-24

Last updated

2018-10-04

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Sjögren's Syndrome

Brief summary

The primary objective of this study is to evaluate the efficacy of treatment with either lulizumab or BMS-986142 versus placebo in subjects with moderate to severe primary Sjögren's syndrome as measured by the change from baseline in ESSDAI at Week 12 between active treatment arms (lulizumab or BMS-986142, respectively) and the placebo arm.

Interventions

DRUGBMS-931699

Specified dose on specified days

DRUGBMS-986142

Specified dose on specified days

DRUGPlacebo

Specified dose on specified days

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 70 Years

Healthy volunteers

Inclusion criteria

For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: * Subjects diagnosed or classified as having moderate to severe primary Sjögren's Syndrome based on the 2016 ACR-EULAR Sjögren's Syndrome Classification Criteria for at least 16 weeks prior to screening * ESSDAI ≥ 5 including disease activity (any score \> 0) in at least one of the following domains: Glandular, Articular, Hematological, Biological, Lymphadenopathy * Positive anti-SS-A/Ro and/or anti-SS-B/La autoantibody * Unstimulated whole saliva secretion \> 0.01 ml/min * Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug and must not be pregnant or breastfeeding. Male and female subjects must be willing to adhere to protocol-mandated highly effective contraception for the duration of the study and for the protocol-specified follow up period. Hormone-based contraceptive methods are not permitted

Exclusion criteria

* Secondary Sjögren's syndrome or the presence of any other systemic autoimmune disease (eg, RA, SLE, multiple sclerosis, vasculitis) * Very severe primary Sjögren's syndrome or severe complications of primary Sjögren's syndrome at the time of the screening visit * Active systemic or latent bacterial (including tuberculosis), viral or fungal infection, evidence of current or chronic Hepatitis B or C infection, or HIV infection * Any significant concurrent medical condition at the time of screening or baseline visit * Use of methotrexate, cyclophosphamide, cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil (MMF) or leflunomide within 12 weeks of screening visit * Previous treatment with biologics therapies either marketed or in development within 6 months prior to screening visit * Treatment started or an unstable dose of hydroxychloroquine within 8 weeks of screening visit * Oral corticosteroids \> 10 mg/day within 14 days of dosing (Day 1), corticosteroid therapy ≥ 1 mg/kg during the 4 weeks preceding enrollment, or intravenous, intramuscular or intra-articular corticosteroids within 4 weeks of screening visit Other protocol defined inclusion/

Design outcomes

Primary

Measure	Time frame	Description
Mean Change From Baseline in ESSDAI	At baseline and week 12	The ESSDAI is a clinical index that measures Sjogren's syndrome disease activity. A physician scores the disease activity level of twelve organ-specific domains in 3 or 4 levels according to their severity. For example, for no disease activity the domain score equals 0 and for high disease activity the domain score equals 3 or 4. Each domain is assigned a weight between 1 and 6, and the domain score is multiplied by the domain weight. The sum of the weighted domain scores is the overall score, which can range from 0 to 123. A higher score indicates more disease activity. Change from baseline was computed as the value at Week 24 minus the baseline value. A negative value in change from baseline indicates an improvement and a positive value indicates worsening

Secondary

Measure	Time frame	Description
Mean Change From Baseline in ESSPRI Score at Week 4, Week 8, and Week 12.	At baseline, week 4, week 8, and week 12	ESSPRI, also known as EULAR Sjogren's Syndrome Patient Reported Index, measures subjective symptoms of dryness, pain and fatigue. It uses 0-10 numerical scales, one for each domain. The weight of the domains is identical, and the final score is the mean score of the 3 domains.
Proportion of Subjects With a > = 3 Point Improvement From Baseline in ESSDAI at Week 12	At week 12	The ESSDAI is a clinical index that measures Sjogren's syndrome disease activity. A physician scores the disease activity level of twelve organ-specific domains in 3 or 4 levels according to their severity. For example, for no disease activity the domain score equals 0 and for high disease activity the domain score equals 3 or 4. Each domain is assigned a weight between 1 and 6, and the domain score is multiplied by the domain weight. The sum of the weighted domain scores is the overall score, which can range from 0 to 123. A higher score indicates more disease activity. Change from baseline was computed as the value at Week 24 minus the baseline value. A negative value in change from baseline indicates an improvement and a positive value indicates worsening
Proportion of Subjects With Both >= 3 Points Improvement in ESSDAI and >= 1 Point Improvement in ESSPRI From Baseline at Week 12	At week 12	The ESSDAI is a clinical index that measures Sjogren's syndrome disease activity. A physician scores the disease activity level of twelve organ-specific domains in 3 or 4 levels according to their severity. For example, for no disease activity the domain score equals 0 and for high disease activity the domain score equals 3 or 4. Each domain is assigned a weight between 1 and 6, and the domain score is multiplied by the domain weight. The sum of the weighted domain scores is the overall score, which can range from 0 to 123. A higher score indicates more disease activity. Change from baseline was computed as the value at Week 24 minus the baseline value. A negative value in change from baseline indicates an improvement and a positive value indicates worsening
Proportions of Subjects With >=1 Point of Improvement From Baseline in ESSPRI	At week 12	ESSPRI, also known as EULAR Sjogren's Syndrome Patient Reported Index, measures subjective symptoms of dryness, pain and fatigue. It uses 0-10 numerical scales, one for each domain. The weight of the domains is identical, and the final score is the mean score of the 3 domains
Mean Change in Baseline in ESSPRI Individual Component of Dryness	At baseline, week 4, week 8, and week 12	ESSPRI, also known as EULAR Sjogren's Syndrome Patient Reported Index, measures subjective symptoms of dryness, pain and fatigue. It uses 0-10 numerical scales, one for each domain. The weight of the domains is identical, and the final score is the mean score of the 3 domains
Mean Change in Baseline in ESSPRI Individual Component of Fatigue	At baseline, week 4, week 8, and week 12	ESSPRI, also known as EULAR Sjogren's Syndrome Patient Reported Index, measures subjective symptoms of dryness, pain and fatigue. It uses 0-10 numerical scales, one for each domain. The weight of the domains is identical, and the final score is the mean score of the 3 domains
Mean Change in Baseline in ESSPRI Individual Component of Pain	At baseline, week 4, week 8, and week 12	ESSPRI, also known as EULAR Sjogren's Syndrome Patient Reported Index, measures subjective symptoms of dryness, pain and fatigue. It uses 0-10 numerical scales, one for each domain. The weight of the domains is identical, and the final score is the mean score of the 3 domains
Mean Change From Baseline in Unstimulated Salivary Flow Rate	At baseline, week 4, week 8, and week 12	Serum and saliva biomarkers (collected from samples obtained during unstimulated and stimulated salivary flow assessments) were measured to determine the potential PD effect of BMS-931699 and BMS-986142 on disease-related protein analytes. These assessments included, but were not limited to, the detection of cytokines and other protein analytes by immunoassays and/or mass spectrometry proteomic profiling.
Mean Change From Baseline in Stimulated Salivary Flow Rate	At baseline, week 4, week 8, and week 12	Serum and saliva biomarkers (collected from samples obtained during unstimulated and stimulated salivary flow assessments) were measured to determine the potential PD effect of BMS-931699 and BMS-986142 on disease-related protein analytes. These assessments included, but were not limited to, the detection of cytokines and other protein analytes by immunoassays and/or mass spectrometry proteomic profiling.
Mean Change From Baseline in ESSDAI Scores at Week 4 and Week 8	At baseline, week 4 and week 8	The ESSDAI is a clinical index that measures Sjogren's syndrome disease activity. A physician scores the disease activity level of twelve organ-specific domains in 3 or 4 levels according to their severity. For example, for no disease activity the domain score equals 0 and for high disease activity the domain score equals 3 or 4. Each domain is assigned a weight between 1 and 6, and the domain score is multiplied by the domain weight. The sum of the weighted domain scores is the overall score, which can range from 0 to 123. A higher score indicates more disease activity. Change from baseline was computed as the value at Week 24 minus the baseline value. A negative value in change from baseline indicates an improvement and a positive value indicates worsening
Mean Change From Baseline in Schrimer's Test	At baseline, week 4, week 8, and week 12	The test (without anaesthesia) was performed by placing a narrow calibrated filter-paper strip in the inferior cul-de-sac of each eye. Aqueous tear production was measured by the length in millimeters that the strip wets during the 5 minute test period
Mean Change From Baseline in the Tear Break-up Time Test	At baseline, week 4, week 8, and week 12	Determined by instilling fluorescein dye and evaluating the stability of the pre-corneal tear film. After several blinks, the tear film is examined using a broad beam of the slit-lamp (biomicroscope) with a cobalt blue filter. The TBUT, defined as the time in seconds between the subjects's last blink and the first appearance of a random dry spot on the corneal surface, is measured 3 times and the mean value is recorded.
Mean Change From Baseline in Numeric Rating Scale (NRS) for Mouth, Eye and Vaginal Dryness	At baseline, at week 2, week 4, week 6, week 8, week 10, week 12, and week 18	The Numeric Rating Scale (NRS-11) is an 11-point scale for patient self-reporting of pain. 0 = No Pain, 1-3 = Mild Pain(nagging, annoying, interfering little with ADLs), 4-6 = Moderate Pain (interferes significantly with ADLs), 7-10 = Severe Pain (disabling; unable to perform ADLs)
Mean Change From Baseline in Subject Global Assessment of Disease Activity (SubGDA)	At baseline, week 2, week 4, week 6, week 8, week 10, week 12, and week 18	The subjects overall assessment of disease activity from 0-10 cm VAS scale with 0 being no disease and 10 cm being most severe disease
Mean Change Form Baseline in Physician Global Assessment of Disease Activity (phyGDA)	At baseline, week 2, week 4, week 6, week 8, week 10, week 12, and week 18	The investigator's or physician's overall assessment of disease activity from 0-10 cm VAS scale with 0 being no disease and 10 cm being most severe disease.
Mean Change From Baseline in Short Form-36 (SF-36)	At baseline, week 4, week 8, week 12, and week 18	First, precoded numeric values are recoded per the scoring key given in Table 1. Note that all items are scored so that a high score defines a more favorable health state. In addition, each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively. Scores represent the percentage of total possible score achieved. In step 2, items in the same scale are averaged together to create the 8 scale scores. Table 2 lists the items averaged together to create each scale. Items that are left blank(missing data) are not taken into account when calculating the scale scores. Hence, scale scores represent the average for all items in the scale that the respondent answered
Mean Change From Baseline in Female Sexual Function Index (FSFI)	At baseline, week 4, week 8, week 12, and week 18	The Female Sexual Function Index (FSFI), a 19-item questionnaire, has been developed as a brief, multidimensional self-report instrument for assessing the key dimensions of sexual function in women
Mean Change From Baseline in Work Participation and Activity Impairment Questionnaire (WPAI)	At baseline, week 4, week 8, week 12, and week 18	Affords calculation of 4 scales to measure the impact of IBD on different domains of impairment in work or other activities: absenteeism, presenteeism (impairment at work), productivity loss (overall work impairment), activity impairment
Mean Change From Baseline in Ocular Surface Staining	At baseline, week 4, week 8, and week 12	The test was performed by instillation of fluorescein dye and either lissamine green or Rose bengal dye to stain the cornea and conjunctiva, respectively. After instilling the dye, the ocular surface was examined through a slit lamp (biomicroscope).

Countries

Australia, Chile, Colombia, Italy, Mexico, Peru, Poland, Puerto Rico, Russia, South Africa, United States

Participant flow

Pre-assignment details

45 subjects enrolled, 18 subjects were randomized/treated. 15 subjects didn't complete the treatment period. The study was terminated and the remaining 15 randomized subjects who had not yet completed the double-blind period entered the follow-up period. Of the 15 subjects who entered the follow-up period, 12 did not complete the follow-up period

Participants by arm

Arm	Count
BMS-931699/Lulizumab Injection (12.5mg/vial, 12.5mg/mL) for subcutaneous (SC)	5
BMS-986142 50 mg Tablet (Round) or 150 mg Tablet (Oval) For oral administration, 350 mg	6
Placebo For BMS-986142 50 mg tablet (round) or 150 mg tablet	7
Total	18

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Administrative Reason by Sponsor	4	5	4
Overall Study	Adverse Event	0	1	0
Overall Study	Subject Withdrew Consent	0	0	1

Baseline characteristics

Characteristic	BMS-931699/Lulizumab Injection	BMS-986142 50 mg Tablet (Round) or 150 mg Tablet (Oval)	Placebo	Total
Age, Continuous	49.2 Years STANDARD_DEVIATION 11.34	51.2 Years STANDARD_DEVIATION 8.77	52.6 Years STANDARD_DEVIATION 13.3	51.2 Years STANDARD_DEVIATION 11.41
Race/Ethnicity, Customized American Indian or Alaska Native	0 participants	0 participants	0 participants	0 participants
Race/Ethnicity, Customized Asian	0 participants	0 participants	0 participants	0 participants
Race/Ethnicity, Customized Black or African American	0 participants	0 participants	0 participants	0 participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 participants	0 participants	0 participants	0 participants
Race/Ethnicity, Customized Other	1 participants	2 participants	0 participants	3 participants
Race/Ethnicity, Customized White	4 participants	4 participants	7 participants	15 participants
Sex: Female, Male Female	5 Participants	6 Participants	7 Participants	18 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 7	0 / 5	0 / 6
other Total, other adverse events	2 / 7	4 / 5	4 / 6
serious Total, serious adverse events	0 / 7	0 / 5	1 / 6

Outcome results

Primary

Mean Change From Baseline in ESSDAI

The ESSDAI is a clinical index that measures Sjogren's syndrome disease activity. A physician scores the disease activity level of twelve organ-specific domains in 3 or 4 levels according to their severity. For example, for no disease activity the domain score equals 0 and for high disease activity the domain score equals 3 or 4. Each domain is assigned a weight between 1 and 6, and the domain score is multiplied by the domain weight. The sum of the weighted domain scores is the overall score, which can range from 0 to 123. A higher score indicates more disease activity. Change from baseline was computed as the value at Week 24 minus the baseline value. A negative value in change from baseline indicates an improvement and a positive value indicates worsening

Time frame: At baseline and week 12