E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cushing’s disease |
Cushingova choroba |
|
E.1.1.1 | Medical condition in easily understood language |
Cushing's disease |
Cushingova choroba |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
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 document the safety of pasireotide s.c. in patients with CD |
|
E.2.2 | Secondary objectives of the trial |
To document:
-the efficacy of pasireotide s.c. in normalizing UFC at Week 12 and 24, separately
- the efficacy of pasireotide s.c. in achieving at least 50% reduction of UFC from baseline at Week 12 and 24, separately
- the changes in clinical signs and symptoms
- the changes in patient-reported outcome questionnaires (CushingQoL and WPAI-GH)
- the effects of pasireotide s.c. on the GH/IGF-I axis
Other secondary objectives may apply
Other secondary objectives may apply |
|
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.Male or female patients aged 18 years or greater
3.Patients with confirmed diagnosis of Cushing’s disease as evidenced by
•mean urinary free cortisol of three 24-hour urine samples collected during the 2-week screening period above the upper limit of the laboratory normal range
•morning plasma ACTH within the normal or above normal range
•either MRI confirmation of pituitary adenoma (greater than or equal to 0.6 cm), or inferior petrosal sinus gradient >3 after CRH stimulation for those patients with a microadenoma less than 0.6 cm*, or for patients who have had prior pituitary surgery, histopathology 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)
4.Patients with de novo Cushing’s disease must not be considered as candidates for pituitary surgery (i.e. poor surgical candidates, surgically unapproachable tumors, patients with no visible pituitary tumor, patients who refuse to have surgical treatment)
5.Karnofsky performance status >60 (i.e. requires occasional assistance, but is able to care for most of this personal needs)
6.For patients on previous medical treatment for Cushing’s disease the following washout periods must be completed before screening assessments are performed
•Inhibitors of steroidogenesis (ketoconazole, metyrapone, rosiglitazone): 1 week
•Dopamine agonists (bromocriptine, cabergoline): 4 weeks
•Mitotane: 6 months
•Octreotide LAR and Lanreotide autogel: 8 weeks
•Lanreotide SR: 4 weeks
•Octreotide (immediate release formulation): 1 week |
|
E.4 | Principal exclusion criteria |
Patients eligible for this study must not meet any of the following criteria:
1.Radiotherapy of the pituitary <4 weeks before screening or patient who has not recovered from side effects
2.Patients with compression of the optic chiasm causing acute clinically significant visual field defect
3.Patients with Cushing’s syndrome due to ectopic ACTH secretion
4.Patients with hypercortisolism secondary to adrenal tumors or nodular (primary) bilateral adrenal hyperplasia
5.Patients who have a known inherited syndrome as the cause for hormone over secretion (i.e. Carney Complex, McCune-Albright syndrome, MEN-1)
6.Patients with a diagnosis of glucocorticoid-remedial aldosteronism (GRA)
7.Patients who have undergone major surgery within 1 month prior to screening
8.Patients with known gallbladder or bile duct disease, acute or chronic pancreatitis (patients with asymptomatic cholelithiasis and asymptomatic bile duct dilation can be included)
9.Diabetic patients whose blood glucose is poorly controlled as evidenced by HbA1C >8%
10.Patients who have clinically significant impairment in cardiovascular function or are at risk thereof, as evidenced by
•congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, clinically significant bradycardia, high grade AV block, history of acute MI less than one year prior to study entry
•QTcF >450 msec at screening
•History of syncope or family history of idiopathic sudden death
•Risk factors for Torsades de Pointes such as uncorrected hypokalemia, uncorrected hypomagnesemia, cardiac failure
•Concomitant disease(s) that could prolong the QT interval such as autonomic neuropathy (caused by diabetes or Parkinson's disease), HIV,cirrhosis, uncontrolled hypothyroidism, concomitant medication(s) with known risk for TdPOther protocol-defined inclusion/exclusion criteria may apply |
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E.5 End points |
E.5.1 | Primary end point(s) |
The proportion of patients having a drug-related adverse event that is recorded as grade 3 or 4 or as a serious adverse event. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Week 0, 1, 2, 3, 4, 8, 12, 16, 20, 24, 36, 48 |
|
E.5.2 | Secondary end point(s) |
The secondary end points are:
•proportion of patients with mean UFC ≤ ULN at Week 12 and 24, separately
•proportion of patients achieving a reduction of mean UFC ≥ 50% from baseline at Week 12 and 24, separately
•change from baseline to Week 12 and 24 in clinical signs and symptoms
•change from baseline to Week 12 and 24 in CushingQoL and WPAI-GH scores
•change from baseline to Week 12 and 24 in GH and IGF-I separately
Other secondary endpoints may apply. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Baseline, week 12, 24 and 48
• Baseline, week 12, 24 and 48
• Baseline, week 12, 24 and 48
• Baseline, week 12, 24 and 48
• Baseline, week 12, 24 and 48 |
|
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 | No |
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 | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Patient Reported Outcomes (PRO) |
|
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 | 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 | No |
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 | 1 |
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 |
Brazil |
Czech Republic |
Greece |
Korea, Republic of |
Romania |
Russian Federation |
Spain |
Thailand |
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
|
Patients will be treated until the drug is approved for commercial use and reimbursed in each respective country or until 31 December 2015 , whichever occurs first. |
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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 | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |