E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cushing’s disease |
Ziekte van Cushing |
|
E.1.1.1 | Medical condition in easily understood language |
Cushing’s disease |
Ziekte van Cushing |
|
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 | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10011651 |
E.1.2 | Term | Cushing's disease |
E.1.2 | System Organ Class | 10014698 - Endocrine disorders |
|
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 |
Veiligheid van pasireotide s.c. in patienten met de ziekte van Cushing documenteren. |
|
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 |
Documenteren van:
- Effectiviteit van pasireotide s.c. in het normaliseren van UFC (vrij cortisol in de urine) bij 12 en bij 24 weken (separaat).
- effectiviteit van pasireotide s.c. in het bereiken van tenminste 50% reductie van UFC gerekend vanaf de beginwaarde, op 12 of 24 weken.
- Veranderingen in klinische tekenen en symptomen
- Veranderingen in patient gerapporteerde uitkomst vragenlijsten (CushingQoL en WPAI-GH)
- Effecten van pasireotide s.c. op de GH/IGF as.
|
|
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 formula): 1 week |
1. geschreven toestemming voor screening
2. mannelijke of vrouwelijke patienten, 18 jaar of ouder
3. Patienten met bevestigde diagnose van Cushing's bewezen door:
Gemiddelde vrije cortisol in de urine boven de bovenste limiet van normaal van 3 24 uurs verzamelingen van urine monsters gedurende de twee weken screening periode.
Ochtend plasma ACTA waarden binnen of boven de normaal waarde
Of MRI bevestiging van een hypofyse adenoom (groter dan of gelijk aan 0,6 cm), of inferior petrosal sinus gradient > 3 na CRH stimulatie voor die patienten die een microadenoom hebben van minder dan 0,6 cm, of voor patienten met eerdere hypofyse chirurgie, histopathologie die een ACTH gekleurd adenoom aantoont. (als IPSS al eerder zonder CRH is gedaan is een centraal to perifere pre-stimulatie gradient> 2 noodzakelijk. Al IPSS nog niet eeerder is gedaan is deze met CRH stimulatie noodzakelijk).
4. patienten met de novo cushing moeten niet beschouwd worden als candidaten voor hypofyse operatie (dus slechte operatie kandidaten, operatief moeilijk benaderbare tumoren, patienten zonder zichtbare tumor, patienten die geen operatie willen).
5. Karnofsky schaal > 60 (heeft behoefte aan wat ondersteuning maar is in staat de meeste persoonlijke behoeften zelf te doen).
6. Voor patienten die eerder medicatie voor cushing gekregen hebben geldt de volgende periode zonder medicatie voordat met screening kan worden begonnen:
Remmers van steroid (ketoconazole, metyrapone, rosiglitazone): 1 week
Dopamine agonisten (bromocriptine, cabergoline): 4 weken
Mitotane: 6 maanden
Octreotide LAR en lanreotide autogel: 8 weken
Lanreotide SR: 4 weken
Octreotide (formule voor onmiddelijke afgifte): 1 week. |
|
E.4 | Principal exclusion 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 symptomatic cholelithiasis
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) known to increase the QT interval
11.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
12.Patients who have any current or prior medical condition that can interfere with the conduct of the study or the evaluation of its results, such as
•History of immunocompromise, including a positive HIV test result (Elisa and Western blot). An HIV test will not be required, however, previous medical history will be reviewed
•Presence of active or suspected acute or chronic uncontrolled infection
•History of alcohol abuse in the 6 month period prior to screening
13.Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method of birth control. If a woman is participating in the trial then one form of contraception is sufficient (pill or diaphragm) and the partner should use a condom. If oral contraception is used in addition to condoms, the patient must have been practicing this method for at least two months prior to screening and must agree to continue the oral contraceptive throughout the course of the study and for 3 months after the study has ended. Male patients who are sexually active are required to use condoms during the study and for three month afterwards as a precautionary measure (available data do not suggest any increased reproductive risk with the study drugs)
14.Patients who have participated in any clinical investigation with an investigational drug within 1 month prior to screening or patients who have previously been treated with pasireotide
15.Known hypersensitivity to somatostatin analogues
16.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 |
1.radiotherapie van de hypofyse minder dan 4 weken voor de screening of patienten die nog last hebben van bijwerkingen hiervan.
2.Patienten met druk op de optische Chiasm dat acuut klinisch significante gezichtsveld defecten veroorzaakt.
3.Patienten met Cushing’s syndroom door ectopische ACTH uitscheiding
4.Patientens 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 symptomatic cholelithiasis
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) known to increase the QT interval
11.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
12.Patients who have any current or prior medical condition that can interfere with the conduct of the study or the evaluation of its results, such as
•History of immunocompromise, including a positive HIV test result (Elisa and Western blot). An HIV test will not be required, however, previous medical history will be reviewed
•Presence of active or suspected acute or chronic uncontrolled infection
•History of alcohol abuse in the 6 month period prior to screening
13.Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method of birth control. If a woman is participating in the trial then one form of contraception is sufficient (pill or diaphragm) and the partner should use a condom. If oral contraception is used in addition to condoms, the patient must have been practicing this method for at least two months prior to screening and must agree to continue the oral contraceptive throughout the course of the study and for 3 months after the study has ended. Male patients who are sexually active are required to use condoms during the study and for three month afterwards as a precautionary measure (available data do not suggest any increased reproductive risk with the study drugs)
14.Patients who have participated in any clinical investigation with an investigational drug within 1 month prior to screening or patients who have previously been treated with pasireotide
15.Known hypersensitivity to somatostatin analogues
16.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 |
|
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 |
|
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 |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | 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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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
| 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 77 |
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 |
Brazil |
Czech Republic |
Egypt |
Germany |
Greece |
Hungary |
Korea, Republic of |
Netherlands |
Romania |
Spain |
Thailand |
|
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 becomes commercially available in each respective country or up to one year after FPFV in each respective country, whichever occurs first. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |