Octreotide Subcutaneous Depot for Acromegaly: A Randomized, Double-blind, Placebo-controlled Phase 3 Trial, ACROINNOVA 1

Abstract

Context: Acromegaly, characterized by excessive GH and insulin-like growth factor-1 (IGF-1), impacts quality of life (QoL) and mortality. Standard of care (SoC; octreotide long-acting repeatable or lanreotide autogel) treatment typically requires healthcare provider administration. CAM2029, a novel subcutaneous octreotide depot with increased bioavailability using FluidCrystal technology, enables self-administration and room-temperature storage.

Objective: Assess superiority of CAM2029 vs placebo for biochemical control in patients with controlled acromegaly.

Design: 24-week, multinational, randomized, double-blind, phase 3 trial (NCT04076462).

Setting: 45 sites; 10 countries.

Patients: 72 patients on SoC with biochemical control at screening [IGF-1 ≤upper limit of normal (ULN); mean GH <2.5 μg/L].

Interventions: Patients were randomized 2:1 to once-monthly CAM2029 (n = 48) or placebo (n = 24).

Main outcome measures: The primary endpoint was proportion of patients with IGF-1 ≤ULN (week 22/24 mean), with dose-reduced patients classified as nonresponders; first key secondary endpoint was the same, including dose-reduced responders. The second key secondary endpoint was proportion of patients with IGF-1 ≤ULN (week 22/24) and mean GH <2.5 μg/L (week 24).

Results: At week 22/24 (intention-to-treat analysis), CAM2029-treated patients demonstrated superior response rates vs placebo for IGF-1 (72.2% vs 37.5%; risk difference: 34.6, 95% confidence interval: 11.3, 57.9; P = .0018) and combined IGF-1/GH (70.0% vs 37.5%; P = .0035). CAM2029-treated patients had well-controlled symptoms, improved QoL, and treatment satisfaction vs placebo and baseline. CAM2029 was well tolerated; safety was consistent with SoC.

Conclusion: CAM2029 provides a convenient and effective treatment option for acromegaly, with superior biochemical control vs placebo. Symptom control, QoL, and satisfaction were improved from baseline SoC.

Clinical trial registration: NCT04076462 (ClinicalTrials.gov).

Keywords: CAM2029; FluidCrystal; acromegaly; octreotide; randomized controlled trial; somatostatin receptor ligands.

Figure 1.

Patient flow diagram. ^aPatients switched to rescue medication with SoC if they experienced worsening signs and symptoms of acromegaly together with an increase in IGF-1 to ≥1.3 × ULN at 2 consecutive visits. Abbreviations: IGF-1, insulin-like growth factor-1; SoC, standard of care; ULN, upper limit of normal.

Figure 2.

Biochemical control at week 22 and 24 (primary and key secondary efficacy endpoints). Proportion (percentages) of patients with biochemical response at the end of trial. ITT analysis set. ^aPrimary efficacy endpoint; ^bKey secondary efficacy endpoint. P-values are one-sided. Combined estimates from 100 analyses based on imputed dataset. Patients with intercurrent events were regarded as nonresponders independently of their endpoint result; Mantel-Haenszel-type common difference in proportions across strata, stratified by prior treatment (octreotide LAR or lanreotide ATG). In the closed testing procedure, a comparison was eligible for superiority testing only if all previous comparisons, if any, had established superiority at the one-sided significance level of P < .025. Abbreviations: ATG, autogel; CI, confidence interval; IGF-1, insulin-like growth factor-1; ITT, intention-to-treat; LAR, long-acting repeatable; ULN, upper limit of normal.

Figure 3

. Biochemical and symptom control over time. ITT analysis set. (A) Mean IGF-1 values (absolute values as a ratio to the ULN) for all patients in the 2 treatment arms over time; (B) Time to loss of IGF-1 response;^a (C) Mean change in AIS Overall Score from baseline over time.^b Error bars show 95% CIs. ^aTime to loss of response was defined as the earliest time when 2 consecutive IGF-1 measurements were >ULN. For patients categorized as nonresponders at their first and second consecutive measurement, loss of response was reported as day 1. Responders still receiving treatment were censored at week 24. For patients who discontinued treatment or withdrew from the trial, IGF-1 values from the visit following their last injection were used, but any subsequent values were considered missing. Patients who discontinued treatment or withdrew without a confirmed loss of response were censored at their last available IGF-1 measurement; ^bThe AIS completed by the investigator (with the patient) predose at each visit. Abbreviations: AIS, Acromegaly Index of Severity; CI, confidence interval; IGF-1, insulin-like growth factor-1; ITT, intention-to-treat; ULN, upper limit of normal.

Figure 4.

Individual IGF-1/ULN at baseline and at the end of trial. ITT analysis set. Individual IGF-1/ULN at baseline (mean of week −2 and day 1) and at the end of the trial (mean of week 22 and week 24) by actual time of last measurement (final visit was slightly later than week 24 for some patients, often due to COVID-19-related delays). For patients who withdrew or discontinued treatment, the last IGF-1 value before discontinuation was included. ^aOne patient in the CAM2029 arm had a high IGF-1 value at week 22 that subsequently dropped below ULN at week 24. Abbreviations: IGF-1, insulin-like growth factor-1; ITT, intention-to-treat; ULN, upper limit of normal.

Figure 5.

Key patient-reported outcomes. ITT analysis set. At baseline, patients were receiving SoC. Filled circles show results for the CAM2029 arm and open circles the placebo arm. ^aPatients rated overall treatment experience compared to their prior treatment with octreotide LAR or lanreotide ATG from 1 “much worse” to 5 “much better”; ^bCombined estimate from 100 analyses based on imputed dataset. Abbreviations: AcroQoL, Acromegaly Quality of Life questionnaire; ATG, autogel; CI, confidence interval; ITT, intention-to-treat; LAR, long-acting repeatable; LS, least squares; PSS, Patient Satisfaction Scale; SoC, standard of care; TSQM, Treatment Satisfaction Questionnaire for Medication.