Improvement of Severe Fatigue Following Nuclease Therapy in Patients With Primary Sjögren's Syndrome: A Randomized Clinical Trial

Abstract

Objective: To assess the safety and efficacy of RSLV-132, an RNase Fc fusion protein, in a phase II randomized, double-blind, placebo-controlled clinical trial in patients with primary Sjögren's syndrome (SS).

Methods: Thirty patients with primary SS were randomized to receive treatment with RSLV-132 or placebo intravenously once per week for 2 weeks, and then every 2 weeks for 12 weeks. Eight patients received placebo and 20 patients received RSLV-132 at a dose of 10 mg/kg. Clinical efficacy measures included the European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Profile of Fatigue (ProF), and the Digit Symbol Substitution Test (DSST).

Results: Patients randomized to receive RSLV-132 experienced clinically meaningful improvements in the ESSPRI score (P = 0.27), FACIT-F score (P = 0.05), ProF score (P = 0.07), and DSST (P = 0.02) from baseline to day 99, whereas patients who received placebo showed no changes in any of these clinical efficacy measures. This improvement was significantly correlated with increased expression of selected interferon-inducible genes (Pearson's correlations, each P < 0.05).

Conclusion: Administration of RSLV-132 improved severe fatigue, as determined by 4 independent patient-reported measures of fatigue, in patients with primary SS.

Trial registration: ClinicalTrials.gov NCT03247686.

Figure 1

Distribution of patients with primary Sjögren’s syndrome to the randomized treatment groups, with follow‐up. Two subjects did not meet the eligibility criterion requiring serum positivity for anti‐Ro autoantibodies. Eligible patients were randomized to receive RSLV‐132 (10 mg/kg) or placebo, once weekly for 2 weeks and then every 2 weeks for 12 weeks.

Figure 2

Heatmaps showing changes in expression of interferon (IFN)–inducible genes from day 1 to day 99. The log₂ fold change in expression of 3 modules (M1.2, M3.4, and M5.12) of IFN‐inducible genes was assessed in whole blood samples from the placebo group (n = 7) compared to the RSLV‐132 group as a whole (n = 20) (A) or the subgroups of RSLV‐132–treated patients who either achieved a clinical response (R) or did not achieve a clinical response (NR) (B) over the follow‐up.

Figure 3

Secondary end point efficacy measures. Clinical efficacy was assessed as the mean change from baseline in the fatigue component of the European League Against Rheumatism Sjögren’s Syndrome Patient Reported Index (ESSPRI) (A), Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT‐F) (B), and mental fatigue component of the Profile of Fatigue (ProF) (C) in the RSLV‐132 and placebo treatment groups. Groups were compared using separate 1‐way analysis of variance models for each visit, each testing the null hypothesis that the true mean difference between treatment groups was 0 (unadjusted α = 0.05). Between‐group differences were as follows: P = 0.136 in A, P = 0.092 in B, and P = 0.046 in C. Results at each time point are the mean ± SEM.