A randomized, double-blind study to assess the safety and efficacy of different dose levels of Pasireotide (SOM230) s.c. over a 6 month treatment period in patients with de novo, persistent or recurrent Cushing’s disease

• Register: EUCTR
• Last refreshed on: 10 July 2015
• Main ID: EUCTR2006-004111-22-GR
• Date of registration: 30/07/2007
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Services AG
• Public title: A randomized, double-blind study to assess the safety and efficacy of different dose levels of Pasireotide (SOM230) s.c. over a 6 month treatment period in patients with de novo, persistent or recurrent Cushing’s disease
• Scientific title: A randomized, double-blind study to assess the safety and efficacy of different dose levels of Pasireotide (SOM230) s.c. over a 6 month treatment period in patients with de novo, persistent or recurrent Cushing’s disease
• Date of first enrolment: 11/12/2007
• Target sample size: 146
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2006-004111-22
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: yes Other trial design description: Randomization to different doses of pasireotide If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no

Countries of recruitment

Belgium, Denmark, Finland, France, Germany, Greece, Hungary, Italy, Portugal, Spain, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
•Male or female patients aged 18 years or greater
•Patients with confirmed diagnosis of ACTH-dependent Cushing’s disease, as evidenced by
(1) mean UFC from four 24-hour urinary collections at least 1.5 times the upper limit of the laboratory normal range collected within 2 weeks;
(2) morning plasma ACTH within the normal or above normal range;
(3) either MRI confirmation of pituitary macroadenoma (greater than or equal to 1 cm) or inferior petrosal sinus gradient >3 after corticotrophin-releasing hormone (CRH) for those patients with a microadenoma (tumor less than 1 cm)*, or for patients who have had prior pituitary surgery, documentation confirming an ACTH staining adenoma.
* if IPSS had previously been performed without CRH (e.g.with DDAVP), then a central to peripheral pre-stimulation gradient > 2 is required. If IPSS had not previously been performed, IPSS with CRH stimulation is required.
•Patients with de novo Cushing’s disease can be included only if they are not considered candidates for pituitary surgery (e.g. poor surgery candidates, surgically unapproachable tumors, patients who refuse to have surgical treatment)
•Confirmatory testing prior to IPSS (low-dose dexamethasone suppression testing or dexamethasone-CRH testing) has to be performed for patients with UFC = 3.0 X ULN and a pituitary microadenoma in order to exclude possible pseudo-Cushing’s syndrome.
•Karnofsky performance status = 60 (i.e. requires occasional assistance, but is able to care for most of this personal needs)
•For patients on medical treatment for Cushing’s disease the following washout periods must be completed before baseline efficacy assessments are performed
•Inhibitors of steroidogenesis – ketoconazole, metyrapone, rosiglitazone: 1 week
•Dopamine agonists - bromocriptine, cabergoline: 4 weeks
•Octreotide LAR and Lanreotide autogel: 8 weeks
•Lanreotide SR: 4 weeks
•Octreotide - immediate release formulation: 1 week
•Patients with a known history of impaired fasting glucose or Diabetes Mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
•Patients who have received pituitary irradiation within the last ten years prior to visit 1, as the onset time of the radiation effects cannot be determined
•Patients who have been treated with mitotane during the last 6 months
•Patients with compression of the optic chiasm causing any visual field defect, in order to exclude patients with a tumor causing chiasma compression requiring surgery
•Patients with Cushing’s syndrome due to ectopic ACTH secretion
•Patients with hypercortisolism secondary to adrenal tumors or Nodular (primary) bilateral adrenal hyperplasia
•Patients who have a known inherited syndrome as the cause for hormone over secretion (i.e. Carney Complex, McCune-Albright syndrome, MEN-1)
•Patients with a diagnosis of glucocorticoid-remedial aldosteronism (GRA)
•Patients who are hypothyroid and not on adequate replacement therapy
•Patients who have undergone major surgery within 1 month
•Patients with symptomatic cholelithiasis
•Diabetic patients on antidiabetic medications whose fasting blood glucose is poorly controlled as evidenced by HbA1C >8%
•Patients with abnormal coagulation (PT or PTT elevated by 30% above normal limits)
•Patients receiving anticoagulants that affect PT or PTT
•Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, symptomatic bradycardia, advanced heart block, history of acute MI less than one year prior to study entry or clinically significant impairment in cardiovascular function.
•Patients with risk factors for torsade de pointes, i.e. patients with a baseline QTc >480 ms, hypokalemia, family history of long QT syndrome, and concomitant medications known to prolong QT interval
•Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis, or patients with ALT/AST more than 2 X ULN, serum creatinine >2.0 X ULN, serum bilirubin >2.0 X ULN, serum albumin < 0.67 X LLN
•Patients with WBC <3 X 109/L; Hgb <13 g/dL for males and <12 g/dL for females; PLT <100 X 109/L
•Patients who have any current or prior medical condition that can interfere with the conduct of the study or the evaluation of its results in the opinion of the investigator or the sponsor’s medical monitor
•Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method for birth control. Female patients must use barrier contraception with condoms. If oral contraception is used, the patient must have been practicing this method for at least two months prior to enrollment and must agree to continue the oral contraceptive throughout the course of the study and for one month after the last dose of study drug. Male patients who are sexually active are required to use condoms during the study and for 1 month afterwards
•History of immunocompromise, including a positive HIV test result (Elisa and Western blot). A HIV test will not be required, however, previous medical history will be reviewed
•Patients who have a history of alcohol or drug abuse in the 6 month period prior to receiving pasireotide
•Patients who have given a blood donation (of 400 ml or more) within 2 months before receiving pasireotide
•Patients who have participated in any clinical investigation with an investigational drug within 1 month prior to dosing and patients who have previously been treated with pasireotide
•Known hypersensitivity to somatostatin analogues
•Patients with active malignant dise

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Cushing’s disease is rare disease that is caused by an adrenocorticotropic hormone (ACTH) secreting pituitary adenoma. The elevated ACTH secreted by these tumors stimulates the adrenal glands to produce excess cortisol, leading to the subsequent development of the clinical signs and symptoms of hypercortisolism. Cushing's disease is associated with severe morbidity and premature mortality and most commonly affects adults aged 20-50, primarily females
MedDRA version: 8.1 Level: LLT Classification code 10011651 Term: Cushing's disease

Intervention(s)

Product Name: pasireotide
Product Code: SOM230B
Pharmaceutical Form: Solution for injection
INN or Proposed INN: pasireotide
CAS Number: 396091-77-3
Current Sponsor code: SOM230 (di-aspartate)
Other descriptive name: Cyclo((diaminoethyl-carbamate)HyPro-Phg-(D)Trp-Lys-Tyr(Bzl)-Phe) di-aspartate
Concentration unit: µg/ml microgram(s)/millilitre
Concentration type: equal
Concentration number: 300-900

Primary Outcome(s)

Main Objective: To assess the efficacy in terms of response to pasireotide 600 µg s.c. b.i.d. and 900 µg s.c. b.i.d. independently in patients with Cushing’s disease as measured by mean UFC = 1.0 X ULN from baseline after 6 months of treatment

Secondary Objective: To assess
•reduction of mean UFC to = 1.0XULN at months 3 and 12
•time to first response
•the effect on plasma ACTH and serum cortisol median UFC response
•improvement in clinical signs
•improvement in clinical symptoms of Cushing’s disease
•the effect on tumor volume (MRI)
•censor-adjusted response
•pooled dose response
•the response by dose group at intermediate visits
•the effect on Quality of Life
•the pharmacokinetics after s.c. b.i.d. administration
•patient-related factors that may affect the pharmacokinetics or pharmacodynamics after s.c. b.i.d. dosing
•potential relationships between pharmacokinetics and pharmacodynamics after s.c. b.i.d. dosing
•the safety and tolerability of pasireotide s.c. in patients with Cushing’s disease
Exploratory
•pasireotide 600 µg s.c. b.i.d. and 900 µg s.c. b.i.d. dose response longitudinally
•midnight salivary cortisol level relationship with mean UFC and cortisol by parametric and/or nonparametric correlation analysis

Primary end point(s): Proportion of patients in each independent treatment arm with <1.0 X ULN at month 6. Patients unblinded at the month 3 assessment will be considered non-responders.

Secondary ID(s)

CSOM230B2305

2006-004111-22-DK