Long-Term Efficacy and Safety of Once-Monthly Pasireotide in Cushing's Disease

A Phase III Extension Study

Maria Fleseriu; Stephan Petersenn; Beverly M. K. Biller; Pinar Kadioglu; Christophe De Block; Guy T'Sjoen; Marie-Christine Vantyghem; Libuse Tauchmanova; Judi Wojna; Michael Roughton; André Lacroix; John Newell-Price

Disclosures

Clin Endocrinol. 2019;91(6):776-785. 

In This Article

Methods

Patients

This was an optional, open-label extension to a 12-month Phase III core study.[11] Patients could enter the extension if they satisfied the following criteria at the end of the core study: mean urinary free cortisol (mUFC; mean of three 24-hour samples collected within 2 weeks) not exceeding the upper limit of normal (ULN; 166.5 nmol/24 h) and/or considered by the investigator to be receiving significant clinical benefit from long-acting pasireotide; demonstrated acceptable tolerability of pasireotide during the core study; and provided consent to participate in the extension.

Study Design

During the core study, adults with confirmed CD and mUFC of 1.5–5.0 × ULN were randomized to double-blind pasireotide 10 or 30 mg every 28 days; dose titration was permitted based on efficacy/tolerability.[11] Patients who entered the extension continued long-acting pasireotide (without interruption) at the same dose that they received at month 12. Pasireotide dose could be increased (5 to 10 mg, 10 to 20 mg, 30 to 40 mg every 28 days) if mUFC > 1.0 × ULN, providing there was an interval of ≥3 months since last increase. Dose reductions were permitted at any time for tolerability (lowest permitted dose: 5 mg every 28 days).

During the extension, patients received long-acting pasireotide for 12 months, at which point they continued in the study until an option was available to transit to a separate open-label, long-term safety study of long-acting pasireotide (clinicaltrials.gov: NCT01794793; results not presented), which occurred once the last ongoing patient had received 12 months of treatment during the extension. Patients who had received an additional ≥12 months of treatment after the 12-month core phase and had the option to enter the separate open-label, long-term safety study were considered to have completed the extension. The study ended once the last patient had received 12 months of treatment during the extension, and all patients had either transited to the long-term safety study or discontinued treatment.

Assessments and Outcomes During the Extension

Prespecified outcomes of the extension included the following: changes in mUFC, plasma ACTH, and morning serum and late-night salivary cortisol (LNSC); proportion of patients with controlled (≤ULN) or partially controlled (>ULN and ≥50% reduction from baseline) mUFC; change in pituitary tumour volume, clinical signs of hypercortisolism and health-related QoL (Cushing's quality-of-life questionnaire [CushingQoL]); and safety and tolerability of long-acting pasireotide.

During the extension, the following parameters were monitored at 3-month intervals: clinical signs (systolic blood pressure [SBP] and diastolic blood pressure [DBP], body mass index [BMI] and waist circumference), mUFC, morning serum cortisol, LNSC and plasma ACTH. Bone mineral density (BMD; left total hip and lumbar spine [L1-L4]) was measured at 6-month intervals by Lunar or Hologic dual-energy X-ray absorptiometry (DXA) instruments. Patients were scanned on the same DXA instrument for the duration of the study. Pituitary tumour volume was measured at 6-month intervals by magnetic resonance imaging (MRI) and assessed by a central reader.

Safety was assessed by monitoring adverse events (AEs). AEs were defined using the Medical Dictionary for Regulatory Activities version 18.1 and graded according to Common Terminology Criteria for Adverse Events version 3.0. Laboratory assessments, including haematological/blood biochemical measurements (fasting plasma glucose [FPG], glycated haemoglobin [HbA1c], thyroid and liver function tests), vital signs, gallbladder examinations and electrocardiograms, were assessed as described previously.[11]

Statistical Methods

Efficacy and safety data are presented for patients who entered the extension. Analyses were performed once all patients had completed the extension or discontinued treatment. Morning serum cortisol, LNSC, morning plasma ACTH, mUFC and clinical signs were analysed descriptively. Actual/percentage changes were calculated from core study baseline (before pasireotide initiation), and from extension baseline (at end of core study [month 12]) for patients with evaluable assessments at core/extension baseline and the later time point. For the proportions of controlled and partially controlled responders, two-sided 95% confidence intervals (CIs) were calculated. Efficacy data are presented up to month 36 and at each patient's last available assessment. Safety data are presented during the core study (up to month 12) and extension (after month 12 until study end). Definitions of diabetic status (diabetic, prediabetic and normoglycaemic) are included in the Appendix S1.

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