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 |
To compare the proportion of patients achieving biochemical control defined as mean GH levels < 2.5 µg/L and normalization of sex- and age-adjusted IGF-1 at 24 weeks with pasireotide LAR 40 mg and pasireotide LAR 60 mg separately versus continuing the same treatment with octreotide LAR 30 mg or lanreotide ATG 120 mg. |
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E.2.2 | Secondary objectives of the trial |
Key Secondary: To compare the effect of pasireotide LAR (40mg and 60 mg seperately) versus continuing the same treatment on the proportion of patients achieving normalization of sex- and age-adjusted IGF-1 at 24 weeks.
Secondary:
To assess the effect of pasireotide LAR (40 mg and 60 mg separately) vs continuing the same treatment on the proportion of patients achieving:
•biochemical control defined as mean GH levels < 2.5 µg/L and normalization of sex- and age-adjusted IGF-1 at 12 weeks,
•GH levels < 2.5 µg/L at 12 and 24 weeks,
•normal, sex- and age-adjusted IGF-1 at 12 weeks,
•GH levels < 1 µg/L and normal, sex- and age-adjusted IGF-1 at 12 and 24 weeks,
•GH levels < 1 µg/L at 12 and 24 weeks,
•a tumor volume reduction > 25% assessed by pituitary MRI at 24 weeks,
see protocol |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Male and female patients ≥ 18 years of age
•Patients with written informed consent prior to any study related activity
•Patients with inadequately controlled acromegaly as defined by
•a mean GH concentration of a 5-point profile over a 2-hour period > 2.5 µg/L
and
•sex- and age adjusted IGF-1 > 1.3 x upper limit of normal (ULN)
•Patients treated with maximum indicated doses of octreotide LAR or lanreotide ATG for at least 6 months prior to Visit 1 (Screening). The maximum indicated dose for octreotide LAR is 30 mg and for lanreotide ATG is 120 mg
•Patients with diagnosis of pituitary micro- or macro adenoma. Patients can have been previously submitted to surgery
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E.4 | Principal exclusion criteria |
•Patients who have received pasireotide (SOM 230) prior to enrolment
•Concomitant treatment with GHR-antagonist or dopamine agonists unless concomitant treatment was discontinued 8 weeks prior to Visit 1 (Screening) (8-week wash-out period)
•Patients with compression of the optic chiasm causing acute clinically significant visual field defects
•Patients who require a surgical intervention for relief of any sign or symptom associated with tumor compression
•Patients who have received pituitary irradiation within 10 years prior to Visit 1 (Screening)
•Patients who have undergone major surgery/surgical therapy for
any cause within 4 weeks prior to Visit 1 (Screening)
•Patients who are hypothyroid and not adequately treated with a stable dose of thyroid hormone replacement therapy
•Diabetic patients whose blood glucose is poorly controlled as evidenced by HbA1C >8% at Visit 1 (Screening). Patients with a known history of impaired fasting glucose or diabetes mellitus with HbA1c<8% may be included; however, blood glucose and anti diabetic treatment must be monitored closely throughout the trial and adjusted as necessary
• Patients with known gallbladder or bile duct disease, acute or chronic pancreatitis (patients with asymptomatic cholelithiasis and asymptomatic bile duct dilation can be included)
•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)
•Patients who have congestive heart failure (NYHA Class III or
IV), unstable angina, sustained ventricular tachycardia,
ventricular fibrillation, advanced heart block or a history of acute myocardial infarction within the 6 months preceding Visit 1 (Screening)
•Screening or baseline (predose) QTcF > 450 msec
•History of syncope or family history of idiopathic sudden death
•Sustained or clinically significant cardiac arrhythmias
•Risk factors for Torsades de Pointes such as uncorrected hypokalemia, uncorrected hypomagnesemia, cardiac failure, clinically significant/symptomatic bradycardia or high-grade AV block.
•Concomitant disease(s) that could prolong the QT interval such as autonomic neuropathy (caused by diabetes or Parkinson’s disease), HIV, cirrhosis, uncontrolled hypothyroidism or cardiac failure
•Concomitant medication(s) known to increase the QT interval
•Patients with liver disease or history of liver disease such as cirrhosis, chronic active hepatitis B or C or chronic persistent hepatitis, or patients with ALT and/or AST more than 2 x ULN, total serum bilirubin > 1.5 x ULN, serum albumin < 0.67 x LLN
•Patients with serum creatinine > 2.0 x ULN
•Patients with WBC <3 x 109/L; Hgb < 90% LLN; PLT <100 x 109/L
•Patients with any current or prior medical condition that, in the judgment of the investigator may interfere with the conduct of the study or the evaluation of the study results
•History of immunocompromise, including a positive HIV test
result (ELISA and Western blot). A HIV test will not be required;
however, previous medical history will be reviewed
•Known hypersensitivity to somatostatin analogues or any other
component of pasireotide LAR
•Patients with active malignant disease within the last five years (with the exception of basal cell carcinoma or carcinoma in situ
of the cervix)
•Patients with the presence of active or suspected acute or
chronic uncontrolled infection
•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 Visit 1 (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)
•Participants in investigational drug study 30 days before Visit 1 (Screening). Patients must have recovered from all side effects of other investigational therapy.
•History of non-compliance to medical regimens, or patient who is considered potentially unreliable, or any circumstance at the time of study inclusion that would preclude completion of the entire study or the required follow up
•Patients who have a history of or current alcohol or drug misuse/abuse in the 12 month period prior to Visit 1 (Screening)
• Presence of Hepatitis B surface antigen (HbsAg)
• Presence of Hepatitis C antibody test (anti-HCV) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy endpoint
The proportion of patients with a reduction of mean GH levels to < 2.5 µg/L and normalization of sex- and age-adjusted IGF-1 at 24 weeks
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E.5.2 | Secondary end point(s) |
The endpoint for the key secondary objective is:
• the proportion of patients achieving normalization of sex- and age-adjusted IGF-1 at 24 weeks.
The secondary end points are:
•the proportion of patients achieving biochemical control defined as mean GH levels < 2.5 μg/L and normalization of sex- and age-adjusted IGF-1 at 12 weeks,
•the proportion of patients achieving GH levels < 2.5 μg/L at 12 and 24 weeks,
•the proportion of patients achieving normal IGF-1 (sex- and age-adjusted) at 12 and 24 weeks,
•the proportion of patients achieving GH levels < 1 μg/L and normal, sex- and age-adjusted IGF-1 at 12 and 24 weeks,
•the proportion of patients achieving GH levels < 1 μg/L at 12 and 24 weeks,
•the proportion of patients achieving a tumor volume reduction > 25% assessed by pituitary MRI at24 weeks,
•the percent change in tumor volume assessed by pituitary MRI from baseline to 24 weeks,
•the change from baseline in clinical signs/symptoms of acromegaly (ring size; headache, fatigue, perspiration, paresthesias and osteoarthralgia according to a five-point score scale),
•the change from baseline in health related QoL as measured by the AcroQoL (acromegaly health related QoL),
•the PK levels of pasireotide LAR 40 mg and pasireotide LAR 60 mg. |
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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 | Yes |
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 | Yes |
E.8.1.3 | Single blind | Information not present in EudraCT |
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.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 39 |
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 |
Israel |
Mexico |
United States |
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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
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
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 | 6 |