| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10011651 |
| E.1.2 | Term | Cushing's disease |
| E.1.2 | System Organ Class | 100000004860 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the efficacy of two Pasireotide LAR regimens (starting doses of 10 mg and 30 mg followed by up-titration if needed or continuation of the same dose) independently in patients with Cushing’s disease after 7 months of treatment regardless of up titration at Month 4 |
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| E.2.2 | Secondary objectives of the trial |
Key Secondary: To assess the efficacy of Pasireotide LAR 10 mg and 30 mg doses independently in patients with Cushing’s disease after 7 months of treatment who did not up titrate the dose of pasireotide at month 4.
Other secondary: Refer to Study protocol |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Written informed consent obtained prior to any screening procedures
2. Adult patients with confirmed diagnosis of ACTH-dependant Cushing’s disease as evidenced by all of the following:
a. The mean of three 24-hour urine samples collected within 2 weeks ≥ 1.5 x ULN and ≤ 5x ULN (as determined by the central lab of this study)
b. Morning plasma ACTH within the normal or above normal range
c. Confirmation of pituitary origin of excess ACTH by at least one of the following three:
I. History of MRI confirmation of pituitary adenoma (greater than 6 mm) with positive dynamic test (e.g. CRH or high dose dexamethasone suppression test)
Or
II. History of inferior petrosal sinus sampling in patients with a tumor less or equal than 6 mm that meet any of the following criteria with either CRH or DDAVP (desmopressin) stimulation:
• Central to peripheral ACTH ratio ≥ 2 at baseline, or
• Central to peripheral ACTH ratio ≥ 3 after stimulation by either CRH or DDAVP (desmopressin)
Or
III. Prior pituitary surgery with histopathology confirming an ACTH staining adenoma
3. Patients with de novo Cushing’s disease can be included only if they are not considered candidates for pituitary surgery (e.g. poor surgical candidates, surgically unapproachable tumors, patients who refuse to have surgical treatment)
4. Confirmation that pseudo-Cushing’s is excluded for patients with mUFC ≤ 3 x ULN (local lab analysis is sufficient) by at least 2 of 3 tests being abnormal (low-dose dexamethasone suppression test, dexamethasone-CRH test or late salivary or serum cortisol), unless there is histopathologic evidence for an ACTH staining pituitary tumor.
5. Male or female patients aged 18 years or greater
6. Karnofsky performance status ≥ 60 (i.e. requires occasional assistance, but is able to care for most of their personal needs)
7. For patients on medical treatment for Cushing’s disease the following washout periods must be completed before screening assessments are performed
a. Inhibitors of steroidogenesis (ketoconazole, metyrapone): 1 week
b. Pituitary directed agents: Dopamine agonists (bromocriptine, cabergoline) and PPARĪ³ agonists (rosiglitazone or pioglitazone): 4 weeks
c. Octreotide LAR, Lanreotide SR and Lanreotide autogel: 14 weeks
d. Octreotide (immediate release formulation): 1 week
e. Progesterone receptor antagonist (mifepristone): 4 weeks
8. Patients with a known history of impaired fasting glucose or DM may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the study and adjusted as necessary. |
|
| E.4 | Principal exclusion criteria |
Patients eligible for this study must not meet any of the following criteria:
1. Patients who are considered candidates for surgical treatment at the time of study entry
2. Patients who have received pituitary irradiation within the last ten years prior to visit 1
3. Patients who have had any previous pasireotide treatment
4. Patients who have been treated with mitotane during the last 6 months prior to Visit 1
5. Patients with compression of the optic chiasm causing any visual field defect that requires surgical intervention
6. Diabetic patients on antihyperglycemic medications with poor glycemic control as evidenced by HbA1c >8%
7. Patients with risk factors for torsade de pointes, i.e. patients with a baseline QTcF >470 ms, hypokalemia, hypomagnesemia, uncontrolled hypothyroidism, family history of long QT syndrome, or concomitant medications known to prolong QT interval
8. History of HIV infection, including a positive HIV test result (Elisa and Western blot). An HIV test will not be required, however, previous medical history will be reviewed
9. Patients with Cushing’s syndrome due to ectopic ACTH secretion
10. Patients with hypercortisolism secondary to adrenal tumors or nodular (primary) bilateral adrenal hyperplasia
11. Patients who have a known inherited syndrome as the cause for hormone over secretion (i.e. Carney Complex, McCune-Albright syndrome, MEN-1)
12. Patients with a diagnosis of glucocorticoid-remedial aldosteronism (GRA)
13. Patients who are hypothyroid and have clinical symptoms of hypothyroidism despite adequate replacement therapy
14. Patients who have undergone major surgery within 1 month prior to starting the study
15. Patients with symptomatic cholelithiasis
16. Patients with abnormal coagulation (PT or PTT elevated by 30% above normal limits)
17. Patients receiving anticoagulants that affect PT or PTT
18. Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, clinically significant bradycardia, advanced heart block, history of acute MI less than one year prior to study entry or clinically significant impairment in cardiovascular function
19. Patients with liver disease such as cirrhosis, chronic active hepatitis B or C, or patients with ALT/AST more than 2 X ULN, serum bilirubin >1.5 X ULN
20. Patients with serum creatinine >2.0 X ULN,
21. Patients with WBC <3 X 109/L; Hgb 90% < LLN; PLT <100 X 109/L
22. 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of patients that attain a mUFC ≤ 1.0 x ULN at Month 7 regardless of dose titration |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Key secondary endpoint: Proportion of patients that attain a mUFC ≤ 1.0 x ULN at Month 7 and had not had a dose increase at Month 4.
For Other endpoint: refer to study protocol |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Randomization to different doses of pasireotide |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Different dose of the same product |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| China |
| Japan |
| Argentina |
| Brazil |
| Thailand |
| Turkey |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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