Maintenance of Acromegaly Control in Patients Switching From Injectable Somatostatin Receptor Ligands to Oral Octreotide

Abstract

Purpose: The phase 3 CHIASMA OPTIMAL trial (NCT03252353) evaluated efficacy and safety of oral octreotide capsules (OOCs) in patients with acromegaly who previously demonstrated biochemical control while receiving injectable somatostatin receptor ligands (SRLs).

Methods: In this double-blind study, patients (N = 56) stratified by prior SRL dose were randomly assigned 1:1 to OOC or placebo for 36 weeks. The primary end point was maintenance of biochemical control at the end of treatment (mean insulin-like growth factor 1 [IGF-1] ≤ 1.0 × upper limit of normal [ULN]; weeks 34 and 36). Time to loss of IGF-1 response and proportion requiring reversion to injectable SRLs were assessed as broader control measures.

Results: Mean IGF-1 measurements were 0.80 and 0.97 × ULN for OOC and 0.84 and 1.69 × ULN for placebo, at baseline and end of treatment, respectively. Mean growth hormone (GH) changed from 0.66 to 0.60 ng/mL for OOCs and 0.90 to 2.57 ng/mL for placebo. Normalization of IGF-1 levels (≤ 1.0 × ULN) was maintained in 58.2% for OOCs vs 19.4% for placebo (P = .008); GH levels were maintained (< 2.5 ng/mL) in 77.7% for OOC vs 30.4% for placebo (P = .0007). Median time to loss of response (IGF-1 > 1.0 or ≥ 1.3 × ULN definitions) for patients receiving placebo was 16 weeks; for patients receiving OOCs, it was not reached for both definitions during the 36-week trial (P < .0001). Of the patients in the OOC group, 75% completed the trial on oral therapy. The OOC safety profile was consistent with previous SRL experience.

Conclusions: OOCs may be an effective therapy for patients with acromegaly who previously were treated with injectable SRLs.

Keywords: oral octreotide; IGF-1; acromegaly; growth hormone; somatostatin analogues; somatostatin receptor ligands.

Figure 1.

Study design for the CHIASMA OPTIMAL trial, including screening, DPC period, and OLE. DPC, double-blind placebo-controlled; IGF-1, insulin-like growth factor 1; OLE, open-label extension; OOC, oral octreotide capsules; SRL, somatostatin receptor ligand; SV, screening visit.

Figure 2.

Patient disposition for all patients screened for the CHIASMA OPTIMAL trial. AE, adverse event; OOC, oral octreotide capsules.

Figure 3.

Mean levels of insulin-like growth factor 1 (IGF-1) and growth hormone (GH) at baseline and end of treatment. A, The observed mean IGF-1 change from baseline to end of DPC treatment is shown in the OOC group and the placebo group. B, The observed mean change in GH from baseline to end of DPC treatment is shown in the OOC group and the placebo group. GH levels were assessed every 30 (±5) minutes for 2 hours: at the first SV from time 0 to 2 hours (prior to SRL administration, if planned), at baseline from time 0 to 2 hours (prior to study medication), at week 36/EOT, and at all other visits in OLE, 2 to 4 hours after study medication administration. Displayed error bars show the SE. DPC, double-blind placebo-controlled; EOT, end of treatment; OOC, oral octreotide capsules; SRL, somatostatin receptor ligand; ULN, upper limit of normal.

Figure 4.

Proportion of patients who had biochemical response at the end of double-blind placebo-controlled (DPC) treatment. The proportion of patients in the OOC and the placebo groups who maintained their A, IGF-1 and B, GH response at the end of the DPC period. Adjusted proportions were obtained from an exact logistic regression model including covariates for treatment group, baseline SRL dose (low vs medium or high) and baseline IGF-I level (< median, ≥ median). GH, growth hormone; IGF-1, insulin-like growth factor 1; OOC, oral octreotide capsule; SRL, somatostatin receptor ligand; ULN, upper limit of normal.