| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 19.0 |
| 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 |
|
| 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 evaluate the overall efficacy of the treatment regimen of pasireotide alone or in combination with cabergoline in patients with Cushing's disease |
|
| E.2.2 | Secondary objectives of the trial |
Assess the changes in mUFC from baseline to study end at each scheduled visit where UFC is measured
Assess overall efficacy of pasireotide alone or in combination with cabergoline as measured by normal mUFC levels at each scheduled visit |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Written informed consent obtained prior to any screening procedures.
2.Adult patients with confirmed diagnosis of ACTH-dependent Cushing's disease
3.Patients with de novo Cushing's disease can be included only if they are not considered candidates for pituitary surgery
4.Male or female patients aged 18 years or greater
5.Karnofsky performance status ≥ 60
6.Patients on medical treatment for Cushing's disease following washout periods
7. Patients who meet any one of the following criteria:
• They are naïve to pasireotide
• They have received pasireotide in the past and have been discontinued because of lack of efficacy (2 weeks of washout prior to screening for patients treated with pasireotide subcutaneously and 12 weeks of washout prior to screening for patients treated with pasireotide LAR)
• Patients who are on maximal tolerated dose but have not achieved biochemical control
8.Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, if they are using highly effective methods of contraception during dosing and for 30 days after stopping study
medication.
9.Male participants in the trial must agree to use a condom during intercourse, and not to father a child during the study and for the period of 30 days following stopping of the study treatment. |
|
| E.4 | Principal exclusion criteria |
1.Patients with compression of the optic chiasm causing any visual field defect that requires surgical intervention
2.Diabetic patients with poor glycemic control as evidenced by HbA1c >8%
3.Patients with risk factors for torsade de pointes, i.e. patients with a baseline QTcF >450 ms in males, and > 460 ms in females. hypokalemia, hypomagnesaemia, uncontrolled hypothyroidism, family history of long QT syndrome, or concomitant medications known to prolong QT interval
4.Patients with clinically significant valvular disease
5.Patients with Cushing's syndrome due to ectopic ACTH secretion
6.Patients with hypercortisolism secondary to adrenal tumors or nodular (primary) bilateral adrenal hyperplasia
7.Patients who have a known inherited syndrome as the cause for hormone over-secretion (i.e. Carney Complex, McCune-Albright syndrome, MEN-1)
8.Patients who are hypothyroid and not on adequate replacement therapy
9.Patients with symptomatic cholelithiasis
10.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
11.Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis, or patients with ALT/AST > 2 X ULN, serum bilirubin >2.0 X ULN
12.Patients with serum creatinine >2.0 X ULN
13.Patients with WBC <3 X 10e9/L; Hb 90% < LLN; PLT <100 X 10e9/L
14.Patients who have a history of alcohol or drug abuse in the 6 month period prior to receiving pasireotide
15.Patients who have participated in any clinical investigation with an investigational drug within 1 month prior to dosing
16.Patients with active malignant disease within the last five years (with the exception of basal cell carcinoma or carcinoma in situ of the cervix)
17.Patients with the presence of active or suspected acute or chronic uncontrolled infection
18.Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will be unable to complete the entire study
19.Patients with presence of Hepatitis B surface antigen (HbsAg)
20.Patients with presence of Hepatitis C antibody test (anti-HCV)
21.Patients with severe hepatic impairment (Child Pugh C) and hypersensitivity to pasireotide or cabergoline
22.Patients with lung, pericardial, and retroperitoneal fibrosis; gastroduodenal ulcer or digestive haemorrhage, galactose intolerance, Parkinson's disease, uncontrolled hypertension and Raynaud's syndrome.
23.Pregnant or nursing (lactating) women where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL).
24.Patients with end-stage renal failure and/or hemodialysis |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of patients who attain mUFC ≤ 1.0 x ULN at week 35 with pasireotide alone or in combination with cabergoline |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Percentage change in mUFC from baseline to study end at each scheduled visit when UFC is measured
2. Proportion of patients attain mUFC ≤ 1.0 x ULN as assessed at each scheduled visit when UFC is measured
3. Proportion of patients who attain mUFC ≤ 1.0 x ULN or have at least 50% reduction from baseline in mUFC as assessed at each scheduled visit when UFC is measured |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| at weeks 0, 4, 8, 13, 17, 22, 26, 31, 35 |
|
| 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 | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| 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 | No |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Bulgaria |
| Colombia |
| France |
| Germany |
| Greece |
| Hungary |
| India |
| Italy |
| Malaysia |
| Mexico |
| Netherlands |
| Spain |
| Turkey |
| United States |
| Venezuela, Bolivarian Republic of |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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