The ghrelin agonist RM-131 accelerates gastric emptying of solids and reduces symptoms in patients with type 1 diabetes mellitus

Abstract

Background & aims: RM-131, a synthetic ghrelin agonist, greatly accelerates gastric emptying of solids in patients with type 2 diabetes and delayed gastric emptying (DGE). We investigated the safety and effects of a single dose of RM-131 on gastric emptying and upper gastrointestinal (GI) symptoms in patients with type 1 diabetes and previously documented DGE.

Methods: In a double-blind cross-over study, 10 patients with type 1 diabetes (age, 45.7 ± 4.4 y; body mass index, 24.1 ± 1.1 kg/m(2)) and previously documented DGE were assigned in random order to receive a single dose of RM-131 (100 μg, subcutaneously) or placebo. Thirty minutes later, they ate a radiolabeled solid-liquid meal containing EggBeaters (ConAgra Foods, Omaha, NE), and then underwent 4 hours of gastric emptying and 6 hours of colonic filling analyses by scintigraphy. Upper GI symptoms were assessed using a daily diary, gastroparesis cardinal symptom index (total GCSI-DD) and a combination of nausea, vomiting, fullness, and pain (NVFP) scores (each rated on a 0-5 scale).

Results: At screening, participants' mean level of hemoglobin A1c was 9.1% ± 0.5%; their total GCSI-DD score was 1.66 ± 0.38 (median, 1.71), and their total NVFP score was 1.73 ± 0.39 (median, 1.9). The t1/2 of solid gastric emptying was 84.9 ± 31.6 minutes when subjects were given RM-131 and 118.7 ± 26.7 when they were given a placebo. The median difference (Δ)was 33.9 minutes (interquartile range [IQR] -12, -49), or -54.7% (IQR, -21%,-110%). RM-131 decreased gastric retention of solids at 1 hour (P = .005) and 2 hours (P = .019). Numeric differences in t1/2 for gastric emptying of liquids, solid gastric emptying lag time, and colonic filling at 6 hours were not significant. Total GCSI-DD scores were 0.79 on placebo (IQR, 0.75, 2.08) and 0.17 on RM-131 (IQR, 0.00, 0.67; P = .026); NVFP scores were lower on RM-131 (P = .041). There were no significant adverse effects.

Conclusions: RM-131 significantly accelerates gastric emptying of solids and reduces upper GI symptoms in patients with type 1 diabetes and documented DGE.

Trial registration: ClinicalTrials.gov NCT01394055.

Keywords: AE; CF6; CRU; Clinical Research Unit; Clinical Trial; DGE; Drug; GCSI-DD; GE; GI; Gastroparesis; IQR; NVFP; Prokinetic; T1DM; T2DM; adverse event; colonic filling at 6 hours; daily diary of gastroparesis cardinal symptom index; delayed gastric emptying; gastric emptying; gastrointestinal; interquartile range; nausea, vomiting fullness, pain; t(1/2); the calculated time point at which 50% of the radiolabeled meal has emptied from the stomach; type 1 diabetes mellitus; type 2 diabetes mellitus.

Conflict of interest statement

Conflicts of interest: This author discloses the following: Michael Camilleri serves on an advisory board for Rhythm Pharmaceuticals, but does not receive any personal remuneration; Dr Camilleri is employed by the Mayo Clinic, which receives compensation on an hourly basis for his work in an advisory capacity. The remaining authors disclose no conflicts.

Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Patient disposition using the consolidated standards of reporting trials (CONSORT) approach. All participants completed all studies, and data were analyzed using intention-to-treat principles.

Figure 2

Changes in GE t1/2 solids by treatment period for each patient (GE, minutes for solids for all 10 patients by treatment period: placebo and RM-131). Data are individual observations for each patient. The published median (83 min) and IQR (64–103 min) from 123 healthy volunteers using the identical radiolabeled meal are presented.

Figure 3

Effect of RM-131 on main transit measurements in all 10 participants (GE, minutes for solids and liquids [upper panel]; percentage GE at 1, 2, and 4 hours, and CF6 at 6 hours [lower panel]). Gray, placebo; white, RM-131 100 μg. Data are median (IQR and range); P values by Wilcoxon signed rank test or paired t test (for GE 1 hour and 2 hour) comparing RM-131 versus placebo. Δ, median percentage difference for each end point. Data were not available for 1 participant for GE 1 hour.

Figure 4

Assessment of GE of solids by scintigraphy in 1 patient showing delayed GE with placebo and normal GE with RM-131 (left panel). GE is shown as the percentage emptied over time for placebo and RM-131 in the same individual (right panel).