Randomized controlled phase Ib study of ghrelin agonist, RM-131, in type 2 diabetic women with delayed gastric emptying: pharmacokinetics and pharmacodynamics

Abstract

Objective: To investigate the pharmacokinetics (PK), pharmacodynamics, and safety of single-dose RM-131 in type 2 diabetic patients with gastrointestinal cardinal symptoms (GCSI) and previously documented delayed gastric emptying (DGE).

Research design and methods: In a randomized crossover study, 10 female patients received RM-131 (100 μg s.c.) or placebo and underwent scintigraphic gastric emptying (GE) and colonic filling at 6 h (CF6) of a solid-liquid meal administered 30 min postdosing. Adverse events, plasma glucose, and hormonal levels were assessed. GCSI daily diary (GCSI-DD) was completed during treatments. PK was assessed in this cohort and healthy volunteers (HVs).

Results: At screening, HbA(1c) was 7.2 ± 0.4% (SEM) and total GCSI-DD score was 1.32 ± 0.21. RM-131 accelerated GE t(1/2) of solids (P = 0.011); mean difference (Δ) in solid GE t(1/2) was 68.3 min (95% CI 20-117) or 66.1%. There were numerical differences in GE lag time, CF6 solids, and GE t(1/2) liquids (all P < 0.14). With a significant (P < 0.014) order effect, further analysis of the first treatment period (n = 5 per group) confirmed significant RM-131 effects on GE t(1/2) (solids, P = 0.016; liquids, P = 0.024; CF6, P = 0.013). PK was similar in DGE patients and HVs. There were increases in 120-min blood glucose (P = 0.07) as well as 30-90-min area under the curve (AUC) levels of growth hormone, cortisol, and prolactin (all P < 0.02) with single-dose RM-131. Only light-headedness was reported more on RM-131.

Conclusions: RM-131 greatly accelerates the GE of solids in patients with type 2 diabetes and documented DGE. PK is similar in diabetic patients and HVs.

Trial registration: ClinicalTrials.gov NCT01394055.

Figure 1

Effect of RM-131 on main transit measurements (GE, minutes for solids and liquids, and CF6, percent). Top: Data in all 10 patients. Bottom: Analysis of data in period 1 only (n = 5 per group; see text for details). White bars, placebo; black bars, RM-131, 100 μg, treatment. Data are mean ± SEM. P values by the Student paired t test comparing RM-131 vs. placebo above each comparison (top) and by the Student unpaired t test comparing RM-131 vs. placebo (bottom). Published normal data (28) with this meal show t_1/2 solid of median 83 min (IQR 64–103 min).

Figure 2

PK of RM-131, 100 μg, in diabetic gastroparesis patients (yellow triangles) vs. a cohort of three male, nonobese HVs (at 100 μg [blue diamonds]) showing similar PK in diabetic patients and volunteers over the 6-h sampling scheme. The volunteers were studied separately in the RM-131 single ascending dose study (RM-131 Study 001). (A high-quality color representation of this figure is available in the online issue.)