A Study of RSLV-132 in Subjects With Primary Sjogren's Syndrome

• Sponsor: Resolve Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03247686
• Collaborator: University Hospital Birmingham (Other), Newcastle-upon-Tyne Hospitals NHS Trust (Other)
• Enrollment: 28
• Locations: 2
• Arms: 2
• Actual Duration (Months): 29.9
• Patients Per Site: 14
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Sjogren's Syndrome	Drug: RSLV-132; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Double-blind, Placebo-controlled Study of RSLV-132 in Subjects With Primary Sjogren's Syndrome
• Actual Study Start Date: Feb 1, 2017
• Actual Primary Completion Date: Jul 15, 2018
• Actual Study Completion Date: Aug 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo	Drug: Placebo; Placebo
Active Comparator: RSLV-132 Experimental drug	Drug: RSLV-132; RNase Fc fusion protein

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Hospitals Birmingham	Birmingham	Edgbaston	United Kingdom	B16 6TT
2	Newcastle upon Tyne Hospitals	Newcastle upon Tyne	Gosforth	United Kingdom	NE3 3HD

Sponsors and Collaborators

• Resolve Therapeutics
• University Hospital Birmingham
• Newcastle-upon-Tyne Hospitals NHS Trust

Investigators

• Study Director: James Posada, Ph.D., Resolve Therapeutics

Study Documents (Full-Text)

• Study Protocol - Apr 19, 2017
• Statistical Analysis Plan - Jul 18, 2018

More Information

Publications

None provided.

• Responsible Party: Resolve Therapeutics
• ClinicalTrials.gov Identifier: NCT03247686
• Other Study ID Numbers: 132-04
• First Posted: Aug 14, 2017
• Last Update Posted: Apr 2, 2021
• Last Verified: Oct 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Sjogren's Syndrome; Syndrome

Study Results

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 Detail	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.

Arm/Group Title	Placebo	RSLV-132
Arm/Group Description	Placebo Placebo: Placebo	Experimental drug RSLV-132: RNase Fc fusion protein
Period Title: Overall Study
STARTED	8	20
COMPLETED	7	18
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Placebo	RSLV-132	Total
Arm/Group Description	Placebo Placebo: Placebo	Experimental drug RSLV-132: RNase Fc fusion protein	Total of all reporting groups
Overall Participants	8	20	28
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.6 (8.8)	56.5 (12.9)	57.4 (11.8)
Sex: Female, Male (Count of Participants)
Female	8 100%	20 100%	28 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 5%	1 3.6%
Not Hispanic or Latino	8 100%	19 95%	27 96.4%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 12.5%	1 5%	2 7.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	7 87.5%	19 95%	26 92.9%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United Kingdom	8 100%	20 100%	28 100%
EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) Total Score (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	5.1 (4.1)	5.0 (4.6)	5.1 (4.4)

Outcome Measures

1. Primary Outcome

Title	Blood Cell Gene Expression
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	RSLV-132 All	RSLV-132 Responders	RSLV-132 Non-responders
Arm/Group Description	Placebo Placebo: Placebo	Experimental drug RSLV-132: RNase Fc fusion protein All participants receiving RSLV-132	Experimental drug RSLV-132: RNase Fc fusion protein Participants receiving RSLV-132 showing a clinically meaningful improvement in two of the three patient reported outcomes	Experimental drug RSLV-132: RNase Fc fusion protein Participants receiving RSLV-132 not showing a clinically meaningful improvement in two of the three patient reported outcomes
Measure Participants	7	20	13	7
Module M1.2	-0.0291486 (0.1151235)	0.1330903 (0.09136563)	0.2509076 (0.1862489)	0.06726222 (0.06520814)
Module M3.4	-0.0301788 (0.1362689)	0.08489987 (0.08673372)	0.1576311 (0.1801423)	0.0409229 (0.08639682)
Module M5.12	-0.0572555 (0.09889587)	0.02757946 (0.1279434)	0.0378753 (0.1228119)	0.0227104 (0.1733785)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, RSLV-132 All
	Comments	Module M1.2 Placebo versus RSLV-132 All
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0000496
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, RSLV-132 All
	Comments	Module M3.4 Placebo versus RSLV-132 All
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0000103
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, RSLV-132 All
	Comments	Module M5.12 Placebo versus RSLV-132 All
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0004398
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, RSLV-132 Responders
	Comments	Module 1.2 Placebo versus RSLV-132 Responders
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0000068
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, RSLV-132 Responders
	Comments	Module M3.4 Placebo versus RSLV-132 Responders
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0000002
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, RSLV-132 Responders
	Comments	Module 5.12 Placebo versus RSLV-132 Responders
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0000926
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, RSLV-132 Non-responders
	Comments	Module M1.2 Placebo versus RSLV-132 Non-responders
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0015450
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, RSLV-132 Non-responders
	Comments	Module M3.4 Placebo versus RSLV-132 Non-responders
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0004632
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Placebo, RSLV-132 Non-responders
	Comments	Module M5.12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0096960
	Comments
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	EULAR ESSDAI Total Score.
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	RSLV-132
Arm/Group Description	Placebo Placebo: Placebo	Experimental drug RSLV-132: RNase Fc fusion protein
Measure Participants	8	20
Mean (Standard Deviation) [Scores on a scale]	-2.5 (4.3)	0.0 (3.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, RSLV-132 All
	Comments	Mean difference in change from baseline (95% CI)
	Type of Statistical Test	Equivalence
	Comments	Two sample t-test with Satterthwaite approximation
Statistical Test of Hypothesis	p-Value	0.180
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.50
	Confidence Interval	(2-Sided) 95%; -6.34 to 1.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	211 days
Adverse Event Reporting Description	Adverse events were collected from the first dose of study treatment until the last telephone contact on Day 211
Arm/Group Title	Placebo		RSLV-132
Arm/Group Description	Placebo Placebo: Placebo		Experimental drug RSLV-132: RNase Fc fusion protein
All Cause Mortality
	Placebo		RSLV-132
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/20 (0%)
Serious Adverse Events
	Placebo		RSLV-132
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		1/20 (5%)
Infections and infestations
Parotitis	0/8 (0%)	0	1/20 (5%)	1
Other (Not Including Serious) Adverse Events
	Placebo		RSLV-132
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/8 (100%)		20/20 (100%)
Cardiac disorders
Atrial Fibrillation	1/8 (12.5%)	1	0/20 (0%)	0
Palpitations	1/8 (12.5%)	1	1/20 (5%)	1
Ear and labyrinth disorders
Tinnitus	1/8 (12.5%)	1	0/20 (0%)	0
Eye disorders
Conjunctival haemorrhage	1/8 (12.5%)	1	0/20 (0%)	0
Conjunctival hyperaemia	1/8 (12.5%)	1	0/20 (0%)	0
Eye pain	1/8 (12.5%)	1	0/20 (0%)	0
Gastrointestinal disorders
Constipation	0/8 (0%)	0	2/20 (10%)	2
Diarrhoea	1/8 (12.5%)	1	1/20 (5%)	1
Dyspepsia	1/8 (12.5%)	1	0/20 (0%)	0
Hiatus hernia	1/8 (12.5%)	1	0/20 (0%)	0
Mouth ulceration	1/8 (12.5%)	1	1/20 (5%)	1
Nausea	1/8 (12.5%)	1	1/20 (5%)	1
Vomiting	1/8 (12.5%)	1	0/20 (0%)	0
General disorders
Catheter site erythema	1/8 (12.5%)	1	0/20 (0%)	0
Fatigue	1/8 (12.5%)	1	6/20 (30%)	7
Oedema peripheral	1/8 (12.5%)	1	1/20 (5%)	1
Infections and infestations
Conjunctivitis	1/8 (12.5%)	1	3/20 (15%)	4
Gastoenteritis viral	1/8 (12.5%)	1	0/20 (0%)	0
Hordeolum	1/8 (12.5%)	1	1/20 (5%)	1
Lower respiratory tract infection	3/8 (37.5%)	3	1/20 (5%)	1
Parotitis	0/8 (0%)	0	1/20 (5%)	1
Upper respiratory tract infection	2/8 (25%)	3	5/20 (25%)	8
Urinary tract infection	0/8 (0%)	0	2/20 (10%)	3
Viral infection	1/8 (12.5%)	1	1/20 (5%)	1
Viral upper respiratory tract infection	1/8 (12.5%)	1	4/20 (20%)	6
Injury, poisoning and procedural complications
Contusion	1/8 (12.5%)	1	0/20 (0%)	0
Head injury	1/8 (12.5%)	1	0/20 (0%)	0
Infusion related reaction	1/8 (12.5%)	2	1/20 (5%)	1
Joint injury	1/8 (12.5%)	1	1/20 (5%)	1
Thermal burn	1/8 (12.5%)	1	0/20 (0%)	0
Investigations
Weight increased	0/8 (0%)	0	2/20 (10%)	2
Metabolism and nutrition disorders
Decreased appetite	1/8 (12.5%)	1	0/20 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/8 (0%)	0	5/20 (25%)	5
Joint swelling	1/8 (12.5%)	1	1/20 (5%)	1
Limb discomfort	1/8 (12.5%)	1	0/20 (0%)	0
Muscle spasms	1/8 (12.5%)	1	2/20 (10%)	2
Osteoarthritis	1/8 (12.5%)	1	1/20 (5%)	1
Pain in extremity	1/8 (12.5%)	1	1/20 (5%)	1
Palindromic rheumatism	1/8 (12.5%)	1	0/20 (0%)	0
Sjogren's syndrome	2/8 (25%)	3	0/20 (0%)	0
Tendonitis	1/8 (12.5%)	1	0/20 (0%)	0
Nervous system disorders
Dizziness	0/8 (0%)	0	2/20 (10%)	2
Headache	1/8 (12.5%)	1	3/20 (15%)	4
Presyncope	1/8 (12.5%)	1	0/20 (0%)	0
Sensorimotor disorder	1/8 (12.5%)	1	0/20 (0%)	0
Tremor	1/8 (12.5%)	1	0/20 (0%)	0
Psychiatric disorders
Mood altered	1/8 (12.5%)	2	0/20 (0%)	0
Sleep disorder	1/8 (12.5%)	1	1/20 (5%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/8 (12.5%)	1	2/20 (10%)	2
Oropharyngeal pain	0/8 (0%)	0	2/20 (10%)	2
Skin and subcutaneous tissue disorders
Dermatitis contact	0/8 (0%)	0	2/20 (10%)	3
Rash	0/8 (0%)	0	2/20 (10%)	2
Rash papular	0/8 (0%)	0	2/20 (10%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.