E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acromegaly is characterized by chronic hypersecretion of growth hormone (GH), clinical features comprise structural and functional changes occurring in practically all organs. Cardiovascular disease is the main reason for morbidity and increased mortality. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10000599 |
E.1.2 | Term | Acromegaly |
E.1.2 | System Organ Class | 10014698 - Endocrine disorders |
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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 |
The primary objective is to compare the proportion of patients with a reduction of mean GH level to < 2.5μg/L and the normalization of IGF-1 to within normal limits (age and sex related) between the two treatment groups at 12 months. |
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E.2.2 | Secondary objectives of the trial |
assess the effect of pasireotide LAR vs. octreotide LAR on:
•reduction of GH to <2.5 µg/L alone, normalization of IGF-1 alone, tumor volume, all at 12 months
•proportion of patients with reduction of mean GH level to <2.5 μg/L and normalization of IGF-1 to within normal limits (age and sex related) at months 6 and 9
• change from baseline in mean GH at 12 months
• time to first achievement of mean GH <2.5 μg/L and on normalization of IGF-1 to within normal limits (age and sex related)
•symptoms of acromegaly, specifically: ring size, headache, fatigue, perspiration, paresthesias, osteoarthralgia at 12 months
•health related QoL at 12 months
•PRL levels at 12 months
•duration of response for patients achieving reduction of mean GH level to <2.5 μg/L and normalization of IGF-1 to within normal limits (age and sex related) at month 12
Compare overall safety and tolerability at 12 months. Assess pasireotide and octreotide plasma exposure (trough concentrations)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female patients of at least 18 years of age
2. Patients with active acromegaly demonstrated by
• a lack of suppression of GH nadir to <1 μg/L after an oral tolerance test with 75 g of glucose (not applicable for diabetic patients) or a mean GH concentration of a 5-point profile within a 2 hour time period of > 5 μg/L
• elevated circulating IGF-1 concentration (age and sex adjusted)
3. a) Patients who have undergone one or more pituitary surgeries but have not been treated medically or b) de-novo patients presenting with a visible pituitary adenoma on MRI and who refuse pituitary surgery or for whom pituitary surgery is contraindicated
4. Patients with a known history or new diagnosis of impaired fasting glucose or diabetes mellitus may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary (see Section 6.6.3)
5. Patients for whom written informed consent to participate in the study has been obtained. prior to any study related activity |
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E.4 | Principal exclusion criteria |
1. Patients who are being or were treated with octreotide, lanreotide, dopamine agonists or GH antagonists with the exception of a single dose of short-acting octreotide or short–acting dopamine agonists. In case of a single dose of short-acting octreotide, the dose should not be used to predict the response to the octreotide treatment. The single dose of short acting octreotide or short-acting dopamine agonists should not be administered in the 3 days prior to randomization.
2. De-novo patients having a visible adenoma on MRI
3. Patients who have received pasireotide prior to randomization
4. Patients with compression of the optic chiasm causing any visual field defect
5. Patients who require a surgical intervention for relief of signs or symptoms associated with tumor compression for whom surgical intervention is indicated
6. Patients who have undergone major surgery/surgical therapy for any cause in the 1 month prior to visit 1
7. Patients who have received radiotherapy (except for pituitary irradiation) for any reason within 4 weeks of visit 1 must have recovered from any side effect of radiotherapy
8. Patients who have received pituitary irradiation within the last ten years prior to visit 1
9. Patients who are hypothyroid and not adequately treated with stable doses of thyroid hormone replacement therapy
10. Diabetic patients on antidiabetic medications whose fasting blood glucose is poorly controlled as evidenced by HbA1c >8%
11. Patients with symptomatic cholelithiasis
12. Patients with abnormal coagulation (PT and/or APTT elevated by 30% above normal limits) or patients receiving anticoagulants that affect PT (prothrombin time) or APTT (activated partial thromboplastin time)
13. Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, ventricular fibrillation, clinically significant
bradycardia, advanced heart block or a history of acute myocardial infarction within the six months preceding enrollment
14. Patients with risk factors for torsade de pointes, i.e. patients with a baseline QTc > 450 ms, hypokalemia, hypomagnesemia, hypocalcemia, family history of long QT syndrome, or receiving a concomitant medication known to prolong QT interval
15. Patients with confirmed central hypothyroidism, central hypoadrenalism and diabetes insipidus, unless they are adequately treated with stable doses of hormone replacement therapy for a minimum of 3 months prior to study entry (first dose of study medication). Patients with confirmed central hypogonadism unless they are adequately treated with stable doses of hormone replacement therapy for a minimum of 3 months prior to study entry (first dose of study medication) except in cases where hormone replacement therapy is not indicated.
16. Patients with liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis, or patients with ALT and/or AST more than 2 x ULN, serum creatinine > 2.0 x ULN, serum bilirubin > 2 x ULN, serum albumin < 0.67 x LLN
17. Patients with WBC <3 x 109/L; Hgb < 90%LLN; PLT <100 x 109/L
18. Patients who have any current or prior medical condition that may 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
19. Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method of birth control. Female patients must use one contraception method and the partner should use a condom. If oral contraception is used, female patient must have been practicing this method for at least 2 months prior to the enrollment and must agree to continue the oral contraceptive until 3 months after the last study drug administration. Male patients sexually active are required to use condoms until 3 month after the last study drug administration as a precautionary measure (available data do not suggest any increased reproductive risk with the study drugs)
20. 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
21. Patients who have participated in any clinical investigation with an investigational drug within 1 month prior to first dosing
22. Known hypersensitivity to somatostatin analogues or any other component of the pasireotide LAR or octreotide LAR formulations
23. Patients with active malignant disease within the last five years (with the exception of basal cell carcinoma or carcinoma in situ of the cervix)
24. Patients with the presence of active or suspected acute or chronic uncontrolled infection
25. Patients with a history of non-compliance to medical regimens or considered potentially unreliable or unable to complete the entire study
26. Patients with history of alcohol or drug abuse in the 6 month period prior to receiving the study drug |
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E.5 End points |
E.5.1 | Primary end point(s) |
The proportion of patients with a reduction of mean GH level to <2.5 μg/L and
the normalization of IGF-1 to within normal limits (age and sex related) at the
end of the 12-month period. |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | 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 | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 50 |
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 | Information not present in EudraCT |
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 |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 7 |
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 | 7 |