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A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Treatment With Sirukumab (CNTO 136) in Patients With Active Lupus Nephritis.

ABSTRACT: To assess the efficacy and safety of sirukumab, an anti-interleukin-6 monoclonal antibody, for the treatment of patients with active lupus nephritis (LN).Patients with class III or class IV LN (as determined by renal biopsy within 14 months of randomization) who had persistent proteinuria (>0.5 gm/day) despite receiving immunosuppressive therapy and who were being treated with stable doses of a renin-angiotensin system blocker were randomized (5:1) to receive treatment with sirukumab at a dose of 10 mg/kg intravenously (n?=?21) or placebo (n?=?4) every 4 weeks through week 24. The primary end point was the percent reduction in proteinuria (measured as the protein-to-creatinine [P:C] ratio in a 12-hour urine collection) from baseline to week 24.Twenty-five patients were enrolled, of whom 19 (76.0%) completed treatment through week 24 and 6 (24.0%) discontinued the study agent early, with 5 of the 6 discontinuing due to adverse events. At week 24, the median percent change in proteinuria from baseline to week 24 in sirukumab-treated patients was 0.0% (95% confidence interval -61.8, 39.6). In contrast, the 4 placebo-treated patients showed an increase in proteinuria (median percent reduction -43.3%) at week 24. Of note, a subset of 5 sirukumab-treated patients had ?50% improvement in their P:C ratio through week 28. In the sirukumab group, 47.6% of patients experienced ?1 serious adverse event through week 40; most were infection-related. No deaths or malignancies occurred. No serious adverse events were observed in the 4 placebo-treated patients.This proof-of-concept study did not demonstrate the anticipated efficacy nor did it demonstrate an acceptable safety profile for sirukumab treatment in this population of patients with active LN receiving concomitant immunosuppressive treatment.

SUBMITTER: Rovin BH

PROVIDER: S-EPMC5129491 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Treatment With Sirukumab (CNTO 136) in Patients With Active Lupus Nephritis.

Rovin Brad H BH van Vollenhoven Ronald F RF Aranow Cynthia C Wagner Carrie C Gordon Robert R Zhuang Yanli Y Belkowski Stanley S Hsu Benjamin B

Arthritis & rheumatology (Hoboken, N.J.) 20160901 9

<h4>Objective</h4>To assess the efficacy and safety of sirukumab, an anti-interleukin-6 monoclonal antibody, for the treatment of patients with active lupus nephritis (LN).<h4>Methods</h4>Patients with class III or class IV LN (as determined by renal biopsy within 14 months of randomization) who had persistent proteinuria (>0.5 gm/day) despite receiving immunosuppressive therapy and who were being treated with stable doses of a renin-angiotensin system blocker were randomized (5:1) to receive tr ...[more]

PMID: 27110697

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Project description:ObjectiveVoclosporin, a novel calcineurin inhibitor approved for the treatment of adults with lupus nephritis (LN), improved complete renal response rates in patients with LN in a phase 2 trial. This study aimed to evaluate the efficacy and safety of voclosporin for the treatment of LN.MethodsThis multicenter, double-blind, randomized phase 3 trial was done in 142 hospitals and clinics across 27 countries. Patients with a diagnosis of systemic lupus erythematosus and LN, according to the American College of Rheumatology criteria, who had undergone a kidney biopsy within 2 years that showed class III, IV, or V (alone or in combination with class III or IV) were eligible for this study. Patients were randomly assigned (1:1) to receive oral voclosporin (23.7 mg twice daily) or a placebo, on a background of mycophenolate mofetil (1 g twice daily) and rapidly tapered low-dose oral steroids, by use of an interactive web response system. The primary endpoint was complete renal response at 52 weeks, defined as a composite of urine protein creatinine ratio of 0.5 mg/mg or less, stable renal function (defined as estimated glomerular filtration rate [eGFR] ≥60 ml/min/1.73m2 or no confirmed decrease from baseline in eGFR of > 20%), no administration of rescue medication, and no more than 10 mg prednisone equivalent per day for 3 or more consecutive days or 7 or more days during Week 44 through Week 52 (just before the primary endpoint assessment). Safety was also assessed. Efficacy analysis was by intention to treat, and safety analysis was by randomized patients receiving at least one dose of study treatment.ResultsBetween April 13, 2017, and October 10, 2019, 179 patients were assigned to the voclosporin group and 178 were assigned to the placebo group. The primary endpoint of complete renal response at Week 52 was achieved in significantly more patients in the voclosporin group than in the placebo group (73 [41%] of 179 patients vs 40 [23%] of 178 patients; odds ratio, 2.65; 95% confidence interval [CI] 1.64-4.27; P < 0·0001). The adverse event profile was balanced between the two groups; serious adverse events occurred in 37 (21%) of 178 patients in the voclosporin group and 38 (21%) of 178 patients in the placebo group. The most frequent serious adverse event involving infection was pneumonia, occurring in seven (4%) patients in the voclosporin group and in eight (4%) patients in the placebo group. A total of six patients died during the study or study follow-up period (one [<1%] patient in the voclosporin group and five [3%] patients in the placebo group). None of the events leading to death were considered by the investigators to be related to the study treatments.ConclusionVoclosporin in combination with mycophenolate mofetil (MMF) and low-dose steroids led to a clinically and statistically superior complete renal response rate versus MMF and low-dose steroids alone, with a comparable safety profile. This finding is an important advancement in the treatment of patients with active LN.

Project description:IntroductionWe assessed the efficacy and safety of repository corticotropin injection (RCI; Acthar® Gel) for persistently active systemic lupus erythematosus (SLE) despite use of moderate-dose glucocorticoids.MethodsThis multicenter, double-blind, randomized, placebo-controlled study enrolled patients ≥ 18 years with active SLE and moderate to severe rash and/or arthritis despite stable glucocorticoid doses (7.5-30 mg/day prednisone equivalent) and antimalarials for ≥ 4 weeks and/or immunosuppressants for ≥ 8 weeks before screening. Stable glucocorticoid doses were required through week 16 with optional taper from weeks 16 to 24. Patients were randomized (1:1) to 80 U RCI subcutaneously or placebo every other day to week 4, then twice weekly to week 24. Endpoints included the proportion of SLE Responder Index (SRI)-4 responders at week 16; changes from baseline to week 16 in 28 Swollen Joint Count/Tender Joint Count (28 SJC/TJC) and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI)-Activity score; and changes from baseline to week 24 in inflammatory cytokines. Safety was assessed by adverse events.ResultsIn the modified intention-to-treat population (RCI, n = 84; placebo, n = 85), the proportion of SRI-4 responders at week 16 was not significantly different between groups (RCI, 47.6%; placebo, 43.5%; OR [95% CI] 1.2 [0.6 to 2.2]; p = 0.5762). RCI treatment resulted in a reduction from baseline to week 16 in 28 SJC/TJC and CLASI-Activity score and from baseline to week 8 in a proliferation-inducing ligand cytokine. Post hoc analyses demonstrated a greater proportion of BILAG-based Combined Lupus Assessment responders for RCI than placebo at weeks 4, 12, and 20 and greater SRI-4 response in RCI-treated patients with baseline SLE Disease Activity Index-2000 ≥ 10 and CLASI-Activity ≥ 11. No new safety signals were identified.ConclusionsDespite failure to achieve the primary endpoint, these results support the utility of RCI for treating persistently active SLE.Trial registrationClinicalTrials.gov identifier NCT02953821.

Project description:IntroductionFibromyalgia is a chronic disorder characterized by widespread pain and tenderness. Prior trials have demonstrated the efficacy of pregabalin for the relief of fibromyalgia symptoms, and it is approved for the treatment of fibromyalgia in the United States. However, prior to this study, there has not been a large-scale efficacy trial in patients with fibromyalgia in Japan.MethodsThis randomized, double-blind, multicenter, placebo-controlled trial was conducted at 44 centers in Japan to assess the efficacy and safety of pregabalin for the symptomatic relief of pain in fibromyalgia patients. Patients aged ≥18 years who had met the criteria for fibromyalgia were randomized to receive either pregabalin, starting at 150 mg/day and increasing to a maintenance dose of 300 or 450 mg/day, or placebo, for 15 weeks. The primary efficacy endpoint was mean pain score at final assessment. Secondary endpoints included Patient Global Impression of Change (PGIC) together with measures of sleep, physical functioning and quality of life.ResultsA total of 498 patients (89% female) were randomized to receive either pregabalin (n = 250) or placebo (n = 248). Pregabalin significantly reduced mean pain score at final assessment (difference in mean change from baseline, compared with placebo -0.44; P = 0.0046) and at every week during the study (P <0.025). Key secondary endpoints were also significantly improved with pregabalin treatment compared with placebo, including PGIC (percentage reporting symptoms "very much improved" or "much improved", 38.6% vs 26.7% with placebo; P = 0.0078); pain visual analog scale (difference in mean change from baseline, compared with placebo -6.19; P = 0.0013); Fibromyalgia Impact Questionnaire total score (-3.33; P = 0.0144); and quality of sleep score (-0.73; P <0.0001). Treatment was generally well tolerated, with somnolence and dizziness the most frequently reported adverse events.ConclusionsThis trial demonstrated that pregabalin, at doses of up to 450 mg/day, was effective for the symptomatic relief of pain in Japanese patients with fibromyalgia. Pregabalin also improved measures of sleep and functioning and was well tolerated. These data indicate that pregabalin is an effective treatment option for the relief of pain and sleep problems in Japanese patients with fibromyalgia.Trial registrationClinicalTrials.gov: NCT00830167.

Project description:BackgroundType 2 diabetes mellitus (T2DM) is characterized by systemic metabolic abnormalities and the development of micro- and macrovascular complications, resulting in a shortened life expectancy. A recent cardiovascular (CV) safety trial, the EMPA-REG OUTCOME trial, showed that empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, markedly reduced CV death and all-cause mortality and hospitalization for heart failure in patients with T2DM and established CV disease (CVD). SGLT2 inhibitors are known to not only decrease plasma glucose levels, but also favorably modulate a wide range of metabolic and hemodynamic disorders related to CV pathways. Although some experimental studies revealed a beneficial effect of SGLT2 inhibitors on atherosclerosis, there is a paucity of clinical data showing that they can slow the progression of atherosclerosis in patients with T2DM. Therefore, the EMBLEM trial was designed to investigate whether empagliflozin treatment can improve endothelial function, which plays a pivotal role in the pathogenesis of atherosclerosis, in patients with T2DM and established CVD.MethodsThe EMBLEM trial is an ongoing, prospective, multicenter, placebo-controlled double-blind randomized, investigator-initiated clinical trial in Japan. A total of 110 participants with T2DM (HbA1c range 6.0-10.0%) and with established CVD will be randomized (1:1) to receive either empagliflozin 10 mg once daily or a placebo. The primary endpoint of the trial is change in the reactive hyperemia (RH)-peripheral arterial tonometry-derived RH index at 24 weeks from baseline. For comparison of treatment effects between the treatment groups, the baseline-adjusted means and their 95% confidence intervals will be estimated by analysis of covariance adjusted for the following allocation factors: HbA1c (<7.0 or ≥7.0%), age (<65 or ≥65 years), systolic blood pressure (<140 or ≥140 mmHg), and current smoking status (nonsmoker or smoker). Key secondary endpoints include the change from baseline for other vascular-related markers such as arterial stiffness, sympathetic nervous activity, and parameters of cardiac and renal function. Importantly, serious adverse effects independently on the causal relationship to the trial drugs and protocol will be also evaluated throughout the trial period.DiscussionEMBLEM is the first trial to assess the effect of empagliflozin on endothelial function in patients with T2DM and established CVD. Additionally, mechanisms associating empagliflozin-mediated actions with endothelial function and other CV markers will be evaluated. Thus, the trial is designed to elucidate potential mechanisms by which empagliflozin protects CV systems and improves CV outcomes. Trial registration Unique Trial Number, UMIN000024502 ( https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000028197 ).

Dataset Information

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Treatment With Sirukumab (CNTO 136) in Patients With Active Lupus Nephritis.

Publications

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Treatment With Sirukumab (CNTO 136) in Patients With Active Lupus Nephritis.

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