Recombinant human relaxin in the treatment of systemic sclerosis with diffuse cutaneous involvement: a randomized, double-blind, placebo-controlled trial

Abstract

Objective: A phase II randomized controlled trial of recombinant human relaxin suggested that a dosage of 25 microg/kg/day was safe and clinically effective in improving skin disease and reducing functional disability in scleroderma (systemic sclerosis; SSc). We undertook a large randomized, double-blind, placebo-controlled clinical trial to compare placebo with 10 microg/kg/day and 25 microg/kg/day recombinant human relaxin, given for 24 weeks in patients with stable, diffuse, moderate-to-severe SSc.

Methods: Men and women ages 18-70 years with diffuse cutaneous SSc (dcSSc) were administered recombinant human relaxin (10 microg/kg/day or 25 microg/kg/day) or placebo for 24 weeks as a continuous subcutaneous infusion. There was a followup safety visit at week 28.

Results: The primary outcome measure, the modified Rodnan skin thickness score, was similar among the 3 groups at baseline and at weeks 4, 12, and 24. Secondary outcomes such as functional disability were similar in all 3 groups, while the forced vital capacity decreased significantly in the relaxin groups. The discontinuation of both doses of relaxin at week 24 led to statistically significant declines in creatinine clearance and serious renal adverse events (defined as doubling of serum creatinine, renal crisis, or grade 3 or 4 essential hypertension) in 7 patients who had received relaxin therapy but in none who had received placebo.

Conclusion: Recombinant relaxin was not significantly better than placebo in improving the total skin score or pulmonary function or in reducing functional disability in patients with dcSSc. In addition, relaxin was associated with serious renal adverse events, the majority of which occurred after stopping the infusion. If relaxin is used therapeutically for any conditions other than scleroderma, close monitoring of blood pressure and renal function must be performed.

Trial profile

Figure 1

Change in modified Rodnan skin score over 24 weeks. Data are presented as box plots, where the boxes represent the 25th to 75^th percentiles, the lines within the boxes represent the median, and the lines outside the boxes represent the minimum to 25th percentile and 75th percentile to maximum values. Despite individual variability at each time point, the MRSS decreased over 24 weeks and there were no statistical differences among the 3 groups during the trial.

Figure 2

Change in creatinine clearance over 24 weeks. Therapy with relaxin was associated with an increase in creatinine clearance during the trial and an abrupt decline after the therapy was discontinued. Data is presented as mean change with bars representing the standard error. *p< 0.05 for comparison of relaxin 25 ug/kg/day vs. placebo, adjusted for baseline value † p< 0.05 for comparison of relaxin 10 ug/kg/day vs. placebo, adjusted for baseline value ‡ p= 0.07 for comparison of relaxin 10 ug/kg/day and 25 ug/kg/day vs. placebo, adjusted for baseline value