Efficacy and Safety of Relamorelin in Diabetics With Symptoms of Gastroparesis: A Randomized, Placebo-Controlled Study

Abstract

Background & Aims Gastroparesis is a complication of diabetes with few treatment options. Relamorelin (also called RM-131) is a selective, prokinetic agonist of ghrelin. We aimed to evaluate efficacy of relamorelin on symptoms and gastric emptying (GE) in a 12-week, phase 2B study of diabetic patients with moderate to severe gastroparesis symptoms (DG). Methods We performed a study of 393 patients with DG (37.7% male; 9.9% with type 1 diabetes; median age, 58.2 years [range 20–76]; median body mass index, 31.4 kg/m2 [range, 18.2–60.1]; HbA1c level, 7.6%, [range, 5.2–11.0]). All participants had 13C-spirulina GE breath test T1/2 values of 79 min or more (with 89.8% delayed relative to 90th %ile of normal, 85.75 minutes), recent vomiting, and gastroparesis cardinal symptom index-daily diary scores of 2.6 or more. Patients were randomly assigned to groups given placebo (n=104) or relamorelin (10 μg [n=98], 30 μg [n=109], or 100 μg [n=82] twice daily) for 12 weeks, following a 2-week, single-blind, placebo run-in period. Patient-reported outcomes were determined from DG Symptom Severity daily e-diaries, in which patients recorded vomiting frequency and symptom scores (nausea, abdominal pain, postprandial fullness, and bloating) on a 0–10 scale. Endpoints were change from baseline in vomiting frequency, composite DG Symptom Severity score, GE, and safety. We performed longitudinal, mixed-effects model analysis using repeated measures, with baseline and baseline-by-week interaction values as covariates. Results Patients given relamorelin had a 75% reduction in vomiting frequency compared to baseline, but this difference was not significant compared with the placebo group. All 4 symptoms of DG (composite or individual symptoms) were significantly reduced over the 12-week study period in all 3 relamorelin dose groups, compared to the placebo group (all P<.05, based on longitudinal analysis over 12 weeks). Relamorelin significantly accelerated GE from baseline compared with placebo (by 12%, P<.05 for the 10 and 30 μg groups; P=.051 for the 100 μg group). Dose-related worsening of glycemic control was noted in 14.5% of patients who received relamorelin; some required insulin or other diabetes drug dosage adjustments. Conclusions In a phase 2B randomized trial of patients with moderate to severe DG, relamorelin significantly reduced core symptoms of DG and overall composite score compared to placebo, accelerated GE, and was generally safe and well tolerated.

Reproducibility of gastric emptying assessed with scintigraphy in patients with upper GI symptoms

“…In this study, the inter‐individual COV (40%) was greater than the intra‐individual COV (20%) for the GE t 1/2 . In the phase 2 trial of relamorelin for gastroparesis, a 10% reduction in GE measured with the GE breath test was clinically significant . With an inter‐individual COV of 40%, it is estimated that 231 subjects will be necessary to detect an effect size of 10% between two treatments with 80% power and a 2‐sided α level of 0.05.…”

The Role of GI Peptides in Functional Dyspepsia and Gastroparesis: A Systematic Review

“…The orally administered TZP-102 showed promising results in phase 2a, but this was not confirmed in phase 2b (52,53). Relamorelin, an injectable ghrelin receptor agonist, showed efficacy in diabetic gastroparesis patients with active vomiting symptoms in two placebo-controlled phase 2 studies and is being evaluated in phase 3 studies (54,55).…”

Cardiovascular safety of prokinetic agents: A focus on drug‐induced arrhythmias

“…101 At present, the synthetic ghrelin receptor agonist, relamorelin (RM-131), has entered phase III clinical trials. [102][103][104] Importantly, these agents are not extensively metabolized by CYP3A family members, exhibit minimal affinity for hERG/K v 11.1, and have not been associated with overt QTc prolongation. 105 Thus, ghrelin receptor agonists appear to have favorable cardiovascular safety profiles.…”

“…However, the possibility exists that safety concerns, including cardiac arrhythmias driven by non-hERG/K v 11.1 mechanisms such as PI3K inhibition, could still emerge during the analysis of phase III and early postmarketing surveillance data. Nevertheless, due to a paucity of agents to treat gastroparesis and the efficacy demonstrated in recent phase IIb trials, 104 the FDA has granted a fast track review of relamorelin, and optimism surrounds the prospect that the first ghrelin receptor agonist could be approved for clinical use in the near future.…”