Pasireotide can induce sustained decreases in urinary cortisol and provide clinical benefit in patients with Cushing’s disease: results from an open-ended, open-label extension trial

This open-label study was a planned extension to a 12-month, multicenter, randomized, Phase III study (Clinicaltrials.gov, NCT00434148) [9]. Patients who were eligible for entry into the core study were adults (≥18 years of age) with confirmed de novo, persistent or recurrent Cushing’s disease. Cushing’s disease was defined by a mean 24-h UFC level (calculated from four UFC samples collected within 14 days) ≥1.5 times the upper limit of normal (ULN; 145 nmol/24 h [52.5 μg/24 h]), a morning plasma ACTH level ≥5 ng/L (1.1 nmol/L), and a confirmed pituitary source of Cushing’s syndrome. Key exclusion criteria were tumor compression of the optic chiasm causing visual-field defects, pituitary irradiation within the previous 10 years, mitotane treatment within the previous 6 months, symptomatic cholelithiasis, a glycated hemoglobin (HbA_1c) level >8 %, and de novo Cushing’s disease in patients who were surgical candidates. Patients with a mean UFC level ≤ ULN at month 12 or those considered, at the discretion of the investigator, to be achieving significant clinical benefit from pasireotide were eligible for entry into the extension.

The study was approved by the independent ethics committee, research ethics board or institutional review board at each center and complied with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, the Declaration of Helsinki and local laws. All patients provided written informed consent. All researchers had full access to all of the data in the study.

At the beginning of the core study (i.e., core baseline), 162 patients were randomly assigned to receive subcutaneous (sc) pasireotide at a dose of 600 µg (n = 82) or 900 µg (n = 80) twice daily (bid). Patients with a mean UFC level ≤2 × ULN and not exceeding the baseline level at month 3 continued to receive their randomly assigned dose; all others had a dose increase of 300 μg bid. At month 6, patients entered an open-label phase until month 12; during this phase, dose increases of 300 µg bid were permitted in patients with UFC > ULN. Patients entering the open-ended extension continued, without interruption to treatment, on the same dose of pasireotide they were receiving at the end of the 12-month core study. During the extension, the dose could be increased by 300 µg bid at any time if UFC was higher than the ULN. The maximum permitted dose of pasireotide was 1,200 µg bid. In the event of drug-related adverse events (AEs), dose reductions of 300 µg bid were allowed.

During the extension, UFC, fasting serum cortisol and plasma ACTH levels were measured at 3-month intervals. The UFC level was calculated as the mean value from two consecutive 24-h urine samples; patients were considered to have controlled (UFC ≤ ULN), partially controlled (UFC > ULN but ≥50 % decrease from core baseline), or uncontrolled (UFC > ULN without a ≥50 % decrease from core baseline) UFC. Patients with a missing mean UFC value were considered to be uncontrolled at the corresponding time point; patients who discontinued treatment were considered to be uncontrolled at all subsequent time points.

UFC level was determined by high-performance liquid chromatography [Alliance^® 2795 High Throughput System, Waters Corp, Milford, MA, USA; normal UFC range 30–145 nmol/24 h (10.8–52.5 μg/24 h)], as described previously [12]. All samples were analyzed by central laboratories (Eurofins Medinet BV, Breda, The Netherlands; CRL Medinet Inc, Lenexa, KS, USA; and Eurofins Technology Services [Suzhou] Co Ltd, Suzhou, China). Pre-dose blood samples were tested for serum cortisol (assay: ADVIA Centaur^® CP Immunoassay System, Siemens Healthcare Diagnostics Inc, Tarrytown, NY, USA) and plasma ACTH (assay: Immulite^® 2000 ACTH kit, DPC, Los Angeles, CA, USA).

Systolic and diastolic blood pressure, body weight, body mass index (BMI), and total and low-density lipoprotein (LDL) cholesterol levels were assessed at 3-month intervals during the extension. At each visit, hematological and blood biochemical measurements (including fasting blood glucose and HbA_1c levels) and urinalysis were performed. Patient diabetic status was defined as normal glucose tolerance (HbA_1c < 5.7 %), pre-diabetes (HbA_1c ≥5.7 to <6.5 %), and diabetes (HbA_1c ≥ 6.5 %); patients with HbA_1c levels ≥8 % were considered to have poorly controlled diabetes. AEs were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 [13]. All medications, other than study drug, administered during the study were recorded; however, dose information for concomitant medications was not recorded during the study.

Analysis of mean UFC, serum cortisol, plasma ACTH, and clinical signs was performed for those patients who had evaluable measurements at the specific time point; for calculations of mean change, only those patients who had evaluable measurements at both core baseline and the specific time point were included. All randomized patients who received at least one dose of pasireotide (n = 162) were included in the analysis of safety and AEs, unless otherwise stated. The 24-month data cut-off for AE analysis occurred when the last ongoing patient reached 24 months’ pasireotide treatment (25 March 2011). As such, a number of patients included in the safety analysis received >24 months of pasireotide treatment. The study was not powered to detect statistically significant differences between dose groups, and these comparisons were not performed.

Seventy-eight of the 162 patients (48.1 %) who entered the core study completed 12 months’ pasireotide treatment (39 patients each in both the 600 and 900 µg bid groups). Of these 78 patients, 58 entered the optional extension phase; the reasons why patients chose not to enter the extension were not consistently recorded. Demographics and characteristics for the 58 patients who entered the extension (26 and 32 patients in the 600 and 900 µg bid groups, respectively) are shown in Table 1. The mean total duration of treatment from core baseline up to the 24-month data cut-off for those all patients who received ≥1 dose of pasireotide (n = 162) was 14 months (range 0–50) and for those who entered the extension phase (n = 58) was 27 months (range 12–50); 53, 46, 41, and 40 patients completed 15, 18, 21, and 24 months’ treatment, respectively, while 10 patients received ≥36 months’ treatment. The mean daily dose of pasireotide for patients randomized to the 600 and 900 µg arms was 1,185 and 1,739 μg for months 0–6, 1,420 and 1,813 μg for months 6–12, 1,509 and 1,766 μg for months 12–18, and 1,500 and 1,620 μg for months 18–24.

Marked improvements in clinical signs of Cushing’s disease were observed during the 24-month study; these effects were observed by month 12 and were sustained until month 24 (Fig. 3). Mean changes from core baseline following 12 months of pasireotide treatment for those patients who entered the extension were: systolic blood pressure, −8.4 mmHg (95 % CI −12.3 to −4.5; −5.6 % change); diastolic blood pressure, −4.0 mmHg (95 % CI −6.9 to −1.2; −3.6 % change); weight, −7.7 kg (95 % CI −9.3 to −6.1; −9.1 % change); and BMI, −2.8 kg/m² (95 % CI −3.4 to −2.3; −9.1 % change). Further improvements in several clinical signs were observed following extended pasireotide treatment; mean changes from core baseline at 24 months were: systolic blood pressure, −11.3 mmHg (95 % CI −15.0 to −7.5; −8.2 % change); diastolic blood pressure, −7.2 mmHg (95 % CI −10.4 to −3.9; −7.6 % change); weight, −8.7 kg (95 % CI −11.1 to −6.2; −9.6 % change); and BMI −3.2 kg/m² (95 % CI −4.0 to −2.3; −9.6 % change). Mean changes from core baseline in total and LDL cholesterol levels were −0.6 mmol/L (95 % CI −0.8 to −0.3; −8.5 % change) and −0.4 mmol/L (95 % CI −0.7 to −0.2; −10.4 % change), respectively, at month 12 and −0.4 mmol/L (95 % CI −0.8 to −0.1; −5.8 % change) and −0.3 mmol/L (95 % CI −0.6 to 0.0; −3.0 % change), respectively, at month 24.

Of the patients who entered the open-ended extension, 46.6 % (27/58) had discontinued the study prior to the 24-month data cut-off: 12 because of consent withdrawal, 10 because of an unsatisfactory therapeutic effect, and five because of AEs. Overall, 98.1 % (159/162) of patients who received at least one dose of pasireotide reported at least one AE, regardless of study-drug relationship, from core baseline until the 24-month data cut-off. Of these patients, 48.4 % experienced AEs with a maximum grade of 1 or 2 (based on CTCAE criteria). The most frequently observed AEs were gastrointestinal disorders, which were reported in 81.5 % of patients. The most common AEs suspected to be study drug related were diarrhea (55.6 %), nausea (48.1 %), hyperglycemia (38.9 %), and cholelithiasis (31.5 %) (Table 2); 11.7 % and 8.6 % of patients experienced grade 3 or 4 hyperglycemia and diabetes mellitus, respectively. Newly occurring AEs during the extension phase that were suspected to be drug related included cholelithiasis (n = 3), diabetes mellitus, nausea, fatigue, diarrhea (n = 2 each), headache and elevated alanine transaminase (n = 1 each). No new safety issues were identified after the first 12-month data cut-off. Serious AEs (SAEs) were reported by 25.9 % (42/162) of patients who received at least one dose of pasireotide; two patients who did not have an SAE up to the core study data cut-off subsequently experienced ≥1 SAE. There were no deaths throughout the entire study.

Thirty-six patients (62.1 %) received antihypertensive medication at some stage during the core study or extension. Of the 28 patients who were not receiving antihypertensive medication at core baseline, six received ≥1 antihypertensive agent at some stage during the core study or extension; eight of the 30 patients who were receiving antihypertensive medication at core baseline received ≥1 additional agent. Thirty-five patients (60.3 %) received antidiabetic medication at some stage during the core study or extension. Of the 50 patients who were not receiving antidiabetic medication at core baseline, at least one antidiabetic medication was initiated in 27 patients; five of the eight patients who were receiving antidiabetic medication at core baseline received ≥1 additional agent during the core study or extension. Only one of 24 patients who did not receive any antidiabetic medication during the core study initiated an antidiabetic treatment during the extension phase. One additional patient had an increase in the number of antidiabetic medications they received during the extension phase compared with the core study.

Mean fasting plasma glucose and HbA_1c levels increased soon after initiation of pasireotide therapy; peak fasting glucose levels were achieved by month 1 and stabilized thereafter. Mean HbA_1c increased from 5.8 % at core baseline to 7.2 % and 6.8 % following 12 and 24 months’ treatment, respectively (Fig. 4a); for the 58 patients who entered the extension, mean HbA_1c was similar at month 24 compared with extension baseline (6.8 vs. 7.0 %). Similarly, mean fasting plasma glucose increased from 97.8 mg/dL at core baseline to 117.7 mg/dL at month 12 and then remained stable until month 24 (119.5 mg/dL) (Fig. 4b); for the 58 patients who entered the extension, mean fasting plasma glucose was similar at month 24 compared with extension baseline (119.5 vs. 113.1 mg/dL).

For those patients who did not receive antidiabetic medication during the 24-month study period, 21 had baseline and post-baseline HbA_1c measurements; 61.9 % (13/21) of these patients had a last available HbA_1c level indicating a worse diabetic status than at core baseline. Two patients had missing values at core baseline. Further details can be found in the Supplementary Appendix.

Most patients had an increase in HbA_1c relative to baseline at some point after initiation of pasireotide treatment. At baseline, 49.4 % (80/162) of patients had normal HbA_1c levels (HbA_1c <5.7 %); 76.3 % (61/80) of these patients had last available HbA_1c levels in a category indicating a worse diabetic status than at core baseline (Table 3). Overall, 16.0 % (26/162) of patients had baseline HbA_1c levels in the diabetic range (HbA_1c ≥6.5 %). Of the patients who had baseline HbA_1c levels in the diabetic range and ≥1 post-baseline measurement, all had at least one post-baseline value indicating poorly controlled diabetes (HbA_1c levels ≥ 8 %; data not shown) and a last available value indicating diabetes mellitus or poorly controlled diabetes (Table 3).