E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
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 who are pasireotide untreated at screening
(Group1)
• To evaluate the efficacy of pasireotide in combination with cabergoline in patients treated with pasireotide at screening but still with uncontrolled mUFC (Group 2) |
|
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 in Group 1 and Group 2 patients, separately.
Assess overall efficacy of pasireotide alone or in combination with cabergoline as measured by normal mUFC levels at each scheduled visit in Group 1 and Group 2, separately. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria for Group 1:
1. Adult patients with confirmed diagnosis of ACTH-dependent Cushing’s disease
2. Patients with de novo Cushing’s disease can be included only if they are not considered candidates for pituitary surgery
3. Male or female patients aged 18 years or greater
4. Karnofsky performance status ≥ 60 (i.e. requires occasional assistance, but is able to care for most of their personal
needs)
5.Patients on medical treatment for Cushing’s disease the following washout periods must be completed before
screening assessments are performed
6.Patients have been on pasireotide in the past but discontinued
because of lack of efficacy are also allowed to enter Group 1. Patients treated with pasireotide subcutaneously must have been discontinued from the treatment for at least 4 weeks before
screening. Patients treated with pasireotide LAR must have been
discontinued from the treatment for at least 12 weeks before screening.
7.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.
Inclusion criteria for Group 2:
1. Adult patients with confirmed diagnosis of ACTH-dependent
Cushing’s disease
2.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)
3.Patients currently treated with maximal tolerated doses of
pasireotide for at least 8 weeks at the time of screening but have not achieved biochemical control. These patients will
enter the study starting combination therapy.
4.Women of child-bearing potential, if they are using highly effective methods of contraception during dosing
and for 30 days after stopping study medication. |
|
E.4 | Principal exclusion criteria |
Exclusion criteria for Group 1 and Group 2:
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 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
8. 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
9. Patients with serum creatinine >2.0 X ULN
10. Patients with WBC <3 X 10e9/L; Hb 90% < LLN; PLT <100 X 10e9/L
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
mUFC :
- Proportion of patients who attain mUFC ≤ 1.0 x ULN at week 35 with pasireotide alone
or in combination with cabergoline in Group 1
- Proportion of patients who attain a mUFC ≤ 1.0 x ULN at week 17 with pasireotide with combination of cabergoline in Group 2 |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
at week 35 for group 1
at week 17 for group 2
|
|
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 for group 1
|
|
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.8.5 | 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 |
Belgium |
Bulgaria |
France |
Greece |
Italy |
Argentina |
Australia |
Brazil |
Colombia |
Germany |
Hungary |
India |
Malaysia |
Spain |
Venezuela, Bolivarian Republic of |
Mexico |
Turkey |
United Kingdom |
United States |
|
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 | 3 |
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 | 3 |
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 |