Long-term safety of long-acting octreotide in patients with diabetic retinopathy: results of pooled data from 2 randomized, double-blind, placebo-controlled phase 3 studies

Abstract

Purpose: Octreotide (OCT) has been successfully used for treatment of acromegaly and neuroendocrine tumors for more than 30 years. However, long-term safety of OCT has not been documented in placebo-controlled setting. This present analysis pooled safety data from two similarly-designed, randomized, and placebo-controlled studies to evaluate long-term safety of long-acting OCT (20, 30 mg); targeted post-hoc analyzes focused on cardiac, hepatic, and renal safety.

Methods: Two studies (NCT00131144, NCT001308450) were conducted in patients with diabetic retinopathy (OCT20 = 191, OCT30 = 348, placebo = 347). In this analysis, patients were stratified based on baseline glomerular filtration rate. Hepatic, cardiac, and renal adverse events (AEs) were identified by standardized MedDRA queries.

Results: Median duration of exposure was >3.5 years. Most common AEs reported with OCT were diarrhea, cholelithiasis, hypoglycemia, nasopharyngitis, and hypertension. Incidence of cardiac events (QT prolongation and arrhythmia) with OCT20 and OCT30 were comparable to placebo (OCT20, RR = 1.11 [95% CI, 0.61-2.03]; OCT30, RR = 1.09 [95% CI, 0.70-1.68]). For ECG findings, changes in QTcF were similar in treatment groups, and outliers did not exceed 480 ms. Incidence of cardiac ischemia was lower with OCT than placebo (OCT20 = 12.6%, OCT30 = 10.6%, placebo = 15.3%). Incidence of liver-related AEs was higher with OCT30 than placebo (RR = 2.04 [95% CI, 1.28-3.26]); incidences were comparable with OCT20 and placebo (RR = 1.50 [95% CI, 0.69-3.25]). Overall incidences of renal AEs were comparable between treatment groups (OCT20 = 5.8%; OCT30 = 6.3%; placebo = 7.2%). Drug-related SAEs were reported more frequently with OCT (OCT20 = 7.9%; OCT30 = 10.1%; placebo = 3.5%); predominantly gallbladder-related, GI-related, and hypoglycemia.

Conclusions: The results from these long-term placebo-controlled studies confirm the established safety profile of long-acting OCT, in particular low risk of cardiac, hepatic and renal toxicity in a high-risk population.

Trial registration: ClinicalTrials.gov NCT00131144 NCT01308450.

Keywords: Cardiac function; Diabetic retinopathy; Hepatic function; Long-term safety; Octreotide; Renal function.

Conflict of interest statement

G.H., M.P., S.S., A.L., P.J., and J.E. are employees of Novartis. R.P. has been Principal investigator of research studies from Novartis, has received research grants from Novartis, Pfizer, Viropharma and IBSA, has been occasional consultant for Novartis, Ipsen, Pfizer, Viropharma, Ferring, and Italfarmaco, has received Fees and Honoraria for presentations from Novartis and Shire. A.C. is a member of the advisory board Novartis Europe and is recipient of unrestricted funds from Ipsen, Novartis, Pfizer, and Serono for research in neuroendocrinology. G.M. declares that she has no competing interests.

Figures

Fig. 1

Forest plot of overall relative risk of incidence of hepatic, renal, and cardiac adverse events (sub-populations defined by renal function and all patients). Incidence calculated as number of subjects with any treatment-emergent AE divided by number of subjects at risk. Mantel-Haenszel estimate adjusted for study as stratification factor is used for RR and 95% confidence interval