A Phase 3, randomized, double-blind, multicenter study was conducted to evaluate the safety and efficacy of two dose regimens of SIGNIFOR LAR over a 12-month treatment period in patients with persistent or recurrent Cushing's disease, or de novo patients who were not considered candidates for pituitary surgery.

The study enrolled 150 patients with a screening mean urinary free cortisol level (mUFC) ≥ 1.5 and ≤ 5 x ULN, who were randomized in a 1:1 ratio to receive a SIGNIFOR LAR starting dose of either 10 mg intramuscularly once every 28 days or 30 mg intramuscularly once every 28 days. Randomization was stratified by values of mUFC at screening (1.5 to < 2 x ULN versus 2 to 5 x ULN, respectively).

After four months of treatment, patients who had a mUFC ≤ 1.5 x ULN continued on the blinded dose to which they were randomized. Patients with a mUFC > 1.5 x ULN at Month 4 had their doses increased in a blinded manner from 10 mg to 30 mg, or from 30 mg to 40 mg, provided there were no tolerability concerns. Additional dose increases were allowed at Month 7 and Month 9 (by one dose level if the mUFC was > 1 x ULN).

Dose reduction by one dose level for tolerability was allowed in a blinded fashion for the first seven months, with a minimum dose level of 5 mg. After the first seven months, blinded down titration of more than one dose level was allowed at any month.

After twelve months of treatment (core phase), patients had the option to enter an extension to continue to receive SIGNIFOR LAR if they benefited from treatment.

The primary efficacy endpoint was the proportion of patients in each arm who were mUFC responders (mUFC ≤ ULN) after seven months of treatment, with or without up-titration at Month 4. The key secondary endpoint was the proportion of patients in each arm who were mUFC responders after seven months of treatment and who did not up-titrate the dose prior to Month 7. The pre-specified boundary of the lower limit of the 95% confidence interval (CI) for efficacy for both the primary and key secondary endpoints was 15%. Patients with missing mUFC assessment at Month 7 were classified as non-responders. Other secondary endpoints included changes from baseline in 24-hour UFC, plasma ACTH, and serum cortisol levels. All analyses were conducted based on the randomized dose groups.

Baseline demographics and disease history were well balanced between the two randomized dose groups and consistent with the epidemiology of the disease. The mean age of patients was approximately 38.5 years with a predominance of female patients (78.7%). The majority of the patients had persistent or recurrent Cushing's disease (82.0%). The median value of the baseline 24-hour mUFC for all patients was 396.9 nmol/24 hours (ULN: 166.5 nmol/24 hours). About three-quarters of all randomized patients completed seven months of treatment, and about two-thirds of all randomized patients completed twelve months of treatment.

The study met the primary efficacy objective for both dose groups. Patients were considered responders if they remained on treatment until at least Month 7 and achieved a Month 7 mUFC ≤ 1 x ULN, regardless of up-titration at Month 4. The proportion of patients with mUFC response at Month 7 was 39.2% (95% CI: 28.0, 51.2) in the 10 mg arm and 40.8% (95% CI: 29.7, 52.7) in the 30 mg arm. The responder rate at Month 12 was 35.1% (26/74) and 25.0% (19/76) in the 10 mg and 30 mg starting dose groups, respectively.

The study met the key secondary efficacy objective for both dose groups. At Month 4, 31/74 (41.9%) and 28/76 (36.8%) patients were up-titrated in the pasireotide LAR 10 mg and 30 mg arms, respectively. When all patients who up-titrated prior to Month 7 were counted as non-responders, Month 7 mUFC response was observed in 25.7% (95% CI: 16.2 to 37.2) and 31.6% (95% CI: 21.4 to 43.3) of patients randomized to pasireotide LAR at a starting dose of 10 mg once every 28 days and 30 mg once every 28 days, respectively.

A secondary efficacy analysis was conducted for the combined proportion of patients who attained mUFC ≤ ULN (controlled) or had at least 50% reduction in mUFC (partially controlled) in the core phase of the study. The combined rate of controlled or partially controlled responders at Month 7 constituted 44.6% and 53.9% of patients randomized to the 10 mg and 30 mg dose groups, respectively (Table 8).

Decreases in median mUFC levels at Month 7 compared to baseline, as measured by overall percentage of reduction, are shown in Table 9. Reductions in serum cortisol and plasma ACTH levels were also observed at Months 7 and 12 for each dose group.