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: 21 August 2017
• Main ID: EUCTR2006-004111-22-GB
• Date of registration: 20/03/2008
• Prospective Registration: No
• 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: 19/03/2008
• 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
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): 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 two 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) or for those patients with a microadenoma (tumor less than 1cm)*
*if IPSS had previously been performed without CRH (eg. with DDAVP), then a central to peripheral pre-stimulation gradien >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 his 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 two years prior to visit 1, as the onset time of the radiation effects can not be determined
•were treated with mitotane during the last 6 months
•with compression of the optic chiasm causing any visual field defect
•with Cushing’s syndrome due to ectopic ACTH secretion
•with hypercortisolism secondary to adrenal tumors or Nodular (primary) bilateral adrenal hyperplasia
•have a known inherited syndrome as the cause for hormone over secretion (i.e. Carney Complex, McCune-Albright syndrome, MEN-1)
•with a diagnosis of glucocorticoid-remedial aldosteronism (GRA)
•are hypothyroid and not on adequate replacement therapy
•have undergone major surgery within 1 month
•with symptomatic cholelithiasis
• Diabetic patients on antidiabetic medications whose fasting blood glucose is poorly controlled as evidenced by HbA1c >8%
•with abnormal coagulation (PT or PTT elevated by 30% above normal limits)
•receiving anticoagulants that affect PT or PTT
•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 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 ULN
•Patients with WBC <3 X 109/L; Hgb •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. An HIV test will not be required, however, previous medical history will be reviewed
• Patients with a history of alcohol or drug abuse in the 6 month period prior to
receiving pasireotide
• Patients who have given a blood donation 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 the presence of active or suspected acute or chronic uncontrolled infection
•Patients with a history of non-compliance to med

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-

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: 600-

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: 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

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 Objective: TO ASSESS
•reduction of mean UFC to = 1.0xULN at month 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 of pasireotide s.c. on tumor volume as evaluated with MRI scanning.
•censor-adjusted response
•pooled dose response
•response by dose group at intermediate visits
•effect on Quality of Life
•the pharmacokinetics of pasireotide after s.c. b.i.d. administration
•patient-related factors that may affect the PK and PD of pasiriotide after s.c. b.i.d. dosing
•explore potential PK/PD relationships after s.c. b.i.d. dosing
•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 parametic and/or nonparametic correlation analysis

Secondary ID(s)

CSOM230B2305

2006-004111-22-DK