Sjogren's Syndrome
Conditions
Brief summary
The present study will examine the role of circulating RNA complexed with autoantibodies and immune complexes and its role in activation of inflammatory pathways in patients with primary Sjogren's syndrome. The study will be conducted in a subset of Sjogren's patients who have elevated levels of autoantibodies and a pattern of elevated interferon-stimulated gene expression in blood cells. A number of biochemical and clinical parameters will be analyzed to determine the potential therapeutic utility of nuclease therapy in Sjogren's syndrome.
Detailed description
This is a multi-center, double-blind, placebo-controlled study to evaluate the impact of 8 intravenous infusions of RSLV-132 in 28 patients with primary Sjogren's syndrome. Each of the subjects will be randomized 3:1 (active:placebo) and will receive 8 infusions of 10 mg/kg of RSLV-132 or placebo as follows on days: • 1, 8, 15, 29, 43, 57, 71, and 85 Potential subjects will be screened to assess their eligibility to enter the study within 60 days prior to study entry (i.e., prior to Baseline visit). Following Baseline evaluations on Day 1, subjects will receive their first infusion of RSLV-132 or placebo. Subjects will return to the research unit for follow-up visits as described in Appendix A. Dose selection rationale: The dose level was chosen based on safety and tolerability data from Protocol 132-02 (multiple ascending dose study in SLE patients). Additionally, in a 6-month toxicology study in cynomolgus monkeys, 50 mg/kg of RSLV-132 was administered by IV infusion weekly. No dose-limiting toxicity was noted, therefore the No Observed Adverse Effect Level is at least 50 mg/kg, providing at least a 5-fold safety margin for this study. RSLV-132 shall be prepared for each subject from individual stock vials provided by Sponsor. Details of dilution, dose preparation, and administration instructions will be provided in the Study Drug Reference Guide. The dose for each individual shall be based on the subject's body weight.
Interventions
DRUGRSLV-132
RNase Fc fusion protein
DRUGPlacebo
Placebo
Sponsors
University Hospital Birmingham
Newcastle-upon-Tyne Hospitals NHS Trust
Resolve Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Meet 4 of 6 criteria of 2002 American-European Consensus Group (AECG) criteria for Primary Sjogren's Syndrome 2. Presence of anti Ro autoantibodies 3. Presence of interferon signature
Exclusion criteria
1. Use fo hydroxychloroquine within 30 days of baseline 2. Use of cyclophosphamide within 180 days of baseline 3. Use of oral corticosteroids greater than 10 mg/day 4. Known IgG4-related disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Blood Cell Gene Expression | Day 1 and Day 99 | Interferon gene expression (mean log2 fold change from baseline to Day 99). The of expression of three IFN-inducible genes (HERC5, EPSTI1, CMPK2) was measured by qPCR to assess the IFN signature status (the altered pattern of gene expression) of Sjögren's syndrome patients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| EULAR ESSDAI Total Score. | Days 1, 29, 57, 85 and 99 | Clinical disease activity: Change from Baseline to Day 99 in European League Against Rheumatism Sjögren's Syndrome Disease Activity Index Total Scores (imputed values with last observation carried forward). The scale ranges from 0 to 123. A higher score means more disease activity (worse outcome). |
Countries
United Kingdom
Participant flow
Recruitment details
Participants were recruited between 12 December 2016 and 01 February 2018. Participants were recruited from the Investigator's medical clinics.
Pre-assignment details
Participants were randomized in a 3:1 ratio to either RSLV-132 or placebo. A total of 22 participants were randomised to RSLV-2 and 8 to placebo. Two participants randomized to RSLV-2 were withdrawn prior to the start of study treatment, one withdrew consent and one was found not to meet the eligibility criteria.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo
Placebo: Placebo | 8 |
| RSLV-132 Experimental drug
RSLV-132: RNase Fc fusion protein | 20 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo | RSLV-132 | Total |
|---|---|---|---|
| Age, Continuous | 59.6 years STANDARD_DEVIATION 8.8 | 56.5 years STANDARD_DEVIATION 12.9 | 57.4 years STANDARD_DEVIATION 11.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 19 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Score | 5.1 Scores on a scale STANDARD_DEVIATION 4.1 | 5.0 Scores on a scale STANDARD_DEVIATION 4.6 | 5.1 Scores on a scale STANDARD_DEVIATION 4.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 19 Participants | 26 Participants |
| Region of Enrollment United Kingdom | 8 participants | 20 participants | 28 participants |
| Sex: Female, Male Female | 8 Participants | 20 Participants | 28 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 20 |
| other Total, other adverse events | 8 / 8 | 20 / 20 |
| serious Total, serious adverse events | 0 / 8 | 1 / 20 |
Outcome results
Primary
Blood Cell Gene Expression
Interferon gene expression (mean log2 fold change from baseline to Day 99). The of expression of three IFN-inducible genes (HERC5, EPSTI1, CMPK2) was measured by qPCR to assess the IFN signature status (the altered pattern of gene expression) of Sjögren's syndrome patients.
Time frame: Day 1 and Day 99
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Blood Cell Gene Expression | Module M5.12 | -0.0572555 log 2 fold change | Standard Error 0.09889587 |
| Placebo | Blood Cell Gene Expression | Module M3.4 | -0.0301788 log 2 fold change | Standard Error 0.1362689 |
| Placebo | Blood Cell Gene Expression | Module M1.2 | -0.0291486 log 2 fold change | Standard Error 0.1151235 |
| RSLV-132 All | Blood Cell Gene Expression | Module M5.12 | 0.02757946 log 2 fold change | Standard Error 0.1279434 |
| RSLV-132 All | Blood Cell Gene Expression | Module M1.2 | 0.1330903 log 2 fold change | Standard Error 0.09136563 |
| RSLV-132 All | Blood Cell Gene Expression | Module M3.4 | 0.08489987 log 2 fold change | Standard Error 0.08673372 |
| RSLV-132 Responders | Blood Cell Gene Expression | Module M3.4 | 0.1576311 log 2 fold change | Standard Error 0.1801423 |
| RSLV-132 Responders | Blood Cell Gene Expression | Module M1.2 | 0.2509076 log 2 fold change | Standard Error 0.1862489 |
| RSLV-132 Responders | Blood Cell Gene Expression | Module M5.12 | 0.0378753 log 2 fold change | Standard Error 0.1228119 |
| RSLV-132 Non-responders | Blood Cell Gene Expression | Module M5.12 | 0.0227104 log 2 fold change | Standard Error 0.1733785 |
| RSLV-132 Non-responders | Blood Cell Gene Expression | Module M3.4 | 0.0409229 log 2 fold change | Standard Error 0.08639682 |
| RSLV-132 Non-responders | Blood Cell Gene Expression | Module M1.2 | 0.06726222 log 2 fold change | Standard Error 0.06520814 |
Comparison: Module M1.2 Placebo versus RSLV-132 Allp-value: 0.0000496t-test, 2 sided
Comparison: Module M3.4 Placebo versus RSLV-132 Allp-value: 0.0000103t-test, 2 sided
Comparison: Module M5.12 Placebo versus RSLV-132 Allp-value: 0.0004398t-test, 2 sided
Comparison: Module 1.2 Placebo versus RSLV-132 Respondersp-value: 0.0000068t-test, 2 sided
Comparison: Module M3.4 Placebo versus RSLV-132 Respondersp-value: 2e-7t-test, 2 sided
Comparison: Module 5.12 Placebo versus RSLV-132 Respondersp-value: 0.0000926t-test, 2 sided
Comparison: Module M1.2 Placebo versus RSLV-132 Non-respondersp-value: 0.001545t-test, 2 sided
Comparison: Module M3.4 Placebo versus RSLV-132 Non-respondersp-value: 0.0004632t-test, 2 sided
Comparison: Module M5.12p-value: 0.009696t-test, 2 sided
Secondary
EULAR ESSDAI Total Score.
Clinical disease activity: Change from Baseline to Day 99 in European League Against Rheumatism Sjögren's Syndrome Disease Activity Index Total Scores (imputed values with last observation carried forward). The scale ranges from 0 to 123. A higher score means more disease activity (worse outcome).
Time frame: Days 1, 29, 57, 85 and 99
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | EULAR ESSDAI Total Score. | -2.5 Scores on a scale | Standard Deviation 4.3 |
| RSLV-132 All | EULAR ESSDAI Total Score. | 0.0 Scores on a scale | Standard Deviation 3.8 |
Comparison: Mean difference in change from baseline (95% CI)p-value: 0.1895% CI: [-6.34, 1.34]t-test, 2 sided