A Phase III, multicenter, randomized study was conducted to evaluate the safety and efficacy of two dose levels of SIGNIFOR over a 6-month treatment period in Cushing's disease patients with persistent or recurrent disease despite pituitary surgery or de novo patients for whom surgery was not indicated or who had refused surgery. 

Patients with a baseline 24-hour urine free cortisol (UFC) >1.5 x ULN were randomized to receive a SIGNIFOR dosage of either 0.6 mg subcutaneous twice a day or 0.9 mg subcutaneous twice a day. After 3 months of treatment, patients with a mean 24-hour UFC ≤ 2.0 x ULN and below or equal to their baseline values continued blinded treatment at the randomized dose until Month 6. Patients who did not meet these criteria were unblinded and the dose was increased by 0.3 mg twice a day. After the initial 6 months in the study, patients entered an additional 6-month open-label treatment period. The dosage could be reduced by 0.3 mg twice a day at any time during the study for intolerability.

A total of 162 patients were enrolled in this study. The majority of patients were female (78%) and had persistent or recurrent Cushing's disease despite pituitary surgery (83%) with a mean age of 40 years. A few patients (4%) in either treatment group received previous pituitary irradiation. The median value of the baseline 24-hour UFC for all patients was 565 nmol/24 hours (normal range 30 to 145 nmol/24 hours). About two-thirds of all randomized patients completed 6 months of treatment.

The primary efficacy endpoint was the proportion of patients who achieved normalization of mean 24-hour UFC levels after 6 months of treatment and did not dose increase during this period.

24-Hour Urinary Free Cortisol Results

At Month 6, the percentages of responders for the primary endpoint were 15% and 26% in the 0.6 mg twice a day and 0.9 mg twice a day groups, respectively (Table 3). The percentages of patients with mUFC ≤ ULN or ≥ 50% reduction from baseline, a less stringent endpoint than the primary endpoint, were 34% in the 0.6 mg twice a day and 41% in the 0.9 mg twice a day groups. Dose increases appeared to have minimal effect on 24-hour UFC response. Mean and median percentage changes in UFC from baseline are presented in Table 3.

SIGNIFOR resulted in a decrease in the mean 24-hour UFC after 1 month of treatment (Figure 1). For patients (n = 78) who stayed in the trial, similar UFC lowering was observed at Month 12.

Figure 1 – Mean (± SE) Urinary Free Cortisol (nmol/24h) at Time Points up to Month 6 by Randomized Dose Group

Note: Only patients who completed 6 months of treatment are included in this analysis (n = 110). The reference line is the ULN for UFC, which is 145 nmol/24hour; +/-Standard errors are displayed.

Other Endpoints

Decreases from baseline for blood pressure were observed at Month 6, including patients who did not receive any anti-hypertensive medication. However, due to the fact that the study allowed initiation of anti-hypertensive medication and dose increases in patients already receiving such medications, the individual contribution of SIGNIFOR or of anti-hypertensive medication adjustments cannot be clearly established.

The mean decreases from baseline at Month 6 for weight, body mass index, and waist circumference were 4.4 kg, 1.6 kg/m2 and 2.6 cm, respectively. Individual patients showed varying degrees of improvement in Cushing's disease manifestations, but because of the variability in response and the absence of a control group in this trial, it is uncertain whether these changes could be ascribed to the effects of SIGNIFOR.