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: 23 March 2015
• Main ID: EUCTR2006-004111-22-ES
• Date of registration: 11/08/2014
• Prospective Registration: No
• Primary sponsor: Novartis Farmaceútica S.A.
• 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: 05/02/2007
• Target sample size: 162
• 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: yes Other specify the comparator: randomization to different doses of pasireotide Number of treatment arms in the trial: 2

Countries of recruitment

Argentina, Belgium, Brazil, Canada, China, Denmark, Finland, France, Germany, Greece, Hungary, Israel, Italy, Mexico, Poland, Portugal, Spain, Turkey, United Kingdom, United States

Contacts

• Name: Javier Malpesa
• Affiliation: Novartis Farmaceutica S.A.

• Name: Javier Malpesa
• Affiliation: Novartis Farmaceutica S.A.

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 (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.
?[(France only) confirmatory testing with a dexamethasone suppression test is required for all patients with UFC ? 3.0 x ULN for whom IPSS has not been done and for whom no histological proof of an ACTH-staining adenoma is available]
?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 162
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 25

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 < LLN ; 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 disease within the last five years (with

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

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cancer [C04]

Cushing?s disease is a 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 a rare disease associated with severe morbidity and premature mortality and most commonly affects adults aged 20-50, primarily females.
MedDRA version: 17.0 Level: LLT Classification code 10011651 Term: Cushing's disease System Organ Class: 100000004860

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: range
Concentration number: 300-900

Primary Outcome(s)

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

Primary end point(s): The primary efficacy parameter will be the proportion of patients in each independent treatment arm with mean UFC concentrations ? 1.0 X ULN at month 6 of pasireotide treatment. Patients required to be unblinded and to increase the dose at month 3 will be classified as non-responders for the month 6 primary analysis .

Secondary Objective: ? reduction of mean UFC to ? 1.0XULN at months 3 and 12
?time to first response
?the effect of pasireotide s.c. 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
?To assess censor-adjusted response, pooled dose response. the response by dose group at intermediate visits, the effect of pasireotide s.c. on Quality of Life
?To determine the pharmacokinetics of pasireotide
?To identify any patient-related factors that may affect the pharmacokinetics or pharmacodynamics
?To explore potential relationships between pharmacokinetics and pharmacodynamics
?To evaluate the safety and tolerability of pasireotide s.c.
Exploratory
?To evaluate pasireotide 600 ?g s.c. b.i.d. and 900 ?g s.c. b.i.d. dose response
?To evaluate midnight salivary cortisol level relationship with mean UFC and serum cortisol

Timepoint(s) of evaluation of this end point: After 6 months of treatment.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: After 6 months of treatment.

Secondary end point(s): UFC response according to the primary efficacy criteria will be calculated at month 6 regardless of their mean UFC level at month 3.
Secondary efficacy parameters
Reduction of UFC to ? 1.0xULN at month 3 and 12: percent of patients whose mean UFC is ? 1xULN.
Time to first response: time to first mean UFC ? 1.0xULN
Serum cortisol: A predose blood draw for serum cortisol sampling will be taken at every visit (at baseline and every 15 days for the first 3 months, every month thereafter, and at study completion). Procedures for sample drawing, handling, storage and transportation will be provided by the central laboratory.
Plasma ACTH: A predose blood draw for plasma ACTH sampling will be taken at every visit (at baseline and every 15 days for the first 3 months, every month thereafter, and at study completion). Procedures for sample drawing, handling, storage and transportation will be provided by the central laboratory.
Median UFC response: The efficacy variable will be defined as the proportion of patients in each independent treatment arm with ? 1.0 X ULN median UFC at month 6.
The clinical signs and symptoms related to Cushing?s disease will be evaluated at baseline, 3, 6 and 12 months (except body composition and bone mineral density which will be assessed at baseline, 6 and 12 months; [Germany Only -for patients in Germany body composition and bone mineral density will not be determined]
Tumor volume: an MRI scan will be performed at baseline, at 6 and at 12 months.
Censor-adjusted response: Patients discontinuing at or before month 6 for reasons unrelated to efficacy will be considered unobserved and non-responders at all subsequent visits
Pooled UFC response: the pooled percentage of patients in both the pasireotide 600 ?g sc bid and 900 ?g treatment arms meeting the primary efficacy criteria month 6 will be provided.
Response by dose group at intermediate visits
Quality of Life: a quality of life assessment will be performed at baseline, 3, 6 and 12 months.

Secondary ID(s)

2006-004111-22-DK

CSOM230B2305

Source(s) of Monetary Support

Novartis Pharma Services