E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
metastatic carcinoid tumors whose disease-related symptoms are inadequately controlled by somatostatin analogues |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10007271 |
E.1.2 | Term | Carcinoid tumor |
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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 |
Compare the long term efficacy of pasireotide LAR vs. octreotide LAR in controlling diarrhea and flushing in patients with metastatic carcinoid tumors whose disease-related symptoms are inadequately controlled by the maximum approved doses of somatostatin analogues. |
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E.2.2 | Secondary objectives of the trial |
Key Secondary Objective: • Compare the efficacy of pasireotide LAR vs. octreotide LAR in controlling diarrhea and flushing in patients using a stricter responder definition. Other Secondary Objectives: • Compare the effect of pasireotide LAR vs.. octreotide LAR on the following secondary endpoints: • Improvement in the individual components of the primary endpoints (i.e., change in daily bowel movement and total number of flushing) • Time to symptom response • Duration of symptom response • Time to symptom progression • Objective tumor response (based on RECIST criteria) • Compare the effect of pasireotide LAR vs octreotide LAR on Quality of Life • Assess the overall safety and tolerability of pasireotide LAR vs. octreotide LAR |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Male or female patients aged 18 years or greater. • Patients with histopathologically confirmed (from primary or metastatic lesion biopsy) metastatic carcinoid tumors of the digestive system with extent of disease determined by Computer Tomography (CT) scan or Magnetic Resonance Imaging (MRI). • Symptoms of carcinoid disease, diarrhea and flushing, must be inadequately controlled: Inadequate control: a daily mean of 4 or more bowel movements over a two week period and a total of 5 or more flushing episodes during this period, while receiving at least the highest recommended dose of one of the following somatostatin analogues for at least a 3 month period prior to study entry: • octreotide LAR (30 mg q 28 days) • octreotide s.c. (600 μg total daily dose) • lanreotide Autogel (120 mg q 28 days) • lanreotide SR (30 mg q 14 days) • Patients with measurable or evaluable disease per RECIST criteria • Karnofsky Performance Status ≥ 60 • Patients must observe the following intervals between the last injection of their previous treatment and the first injection of study drug: • Octreotide LAR = 28 days (4 weeks) • Octreotide s.c. = 8 hours • Lanreotide Autogel = 28 days (4 weeks) • Lanreotide SR = 14 days (2 weeks) • Patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary (see Section 6.6.2.1) • Female patients of child bearing potential must have a negative pregnancy test at baseline. • Patients for whom written informed consent to participate in the study has been obtained |
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E.4 | Principal exclusion criteria |
•Patients receiving radiolabeled somatostatin analogue therapy within the 6 months or any cytotoxic chemotherapy or interferon therapy within the 2 months prior to recording baseline symptoms • Patients who have undergone major surgery/surgical therapy for any cause within 1 month or surgical therapy of loco-regional metastases within the last 3 months before recording baseline symptoms • Patients with hepatic artery embolization within the last 6 months (1 month if there are other sites of measurable disease), or patients who have undergone cryoablation or radiofrequency ablation of hepatic metastasis within the last 2 months before recording baseline symptoms • Patients who have received radiotherapy for any reason within the last 4 weeks and must have recovered from any side effects of radiotherapy before recording baseline symptoms • Patients who are unwilling to follow dietary restrictions (see Section 7.4.2.7) within 3 days of urinary 5-HIAA sample collection or require medications that would interfere with urinary 5-HIAA measurement (e.g. Reserpine, mephenesin carbamate, Lugol’s solution) • Patients with known malabsorption syndrome, short bowel or chologenic diarrhea not controlled by specific therapeutic means • Patients who are not biochemically euthyroid • Diabetic patients on antidiabetic medications whose fasting blood glucose is poorly controlled as indicated by HbA1C > 8% • Patients with symptomatic cholelithiasis • 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 • Patients with risk factors for torsades de pointes, i.e. patients with a baseline QTc > 450 ms, potassium <3.0 mmol/L at study entry, magnesium <0.4 mmol/L at study entry, calcium <1.75 mmol/L at study entry, family history of long QT syndrome, and concomitant medications known to prolong the QT interval. If the electrolyte abnormalities are corrected prior to study commencement, the patient may become eligible for the trial. • Patients with liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis with serum bilirubin > 2 X ULN, serum albumin < 0.67 X LLN, and/or ALT or AST more than 2 X ULN for patients without liver metastases or ALT or AST more than 5X ULN for patients with documented liver metastases • Patients with additional 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 or with a 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 • Patients with abnormal coagulation (PT or APTT elevated by 30% above normal limits) • Patients with WBC <2.5 X 109/L; Hgb <10 g/dL; PLT <100 X 109/L • 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 • 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 barrier contraception with condoms. If oral contraception is used in addition to condoms, the patient must have been practicing this method for at least two months prior to enrollment and must agree to continue the oral contraceptive throughout the course of the study, and for three 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). Female partners of these male patients must use a secondary barrier contraception. • Patients who are currently part of or have participated in any clinical investigation with an investigational drug (other then pasireotide) within 1 month prior to dosing • Known hypersensitivity to somatostatin analogues or any component of the pasireotide or octreotide LAR or s.c. formulations (see section 6.1.1) • Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study • Patients who have been previously treated with Pasireotide
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is defined as a combination of the mean number of bowel movements and total number of flushing episodes. All of the following criteria must be met for a patient to be considered a responder: • average of < 4 bowel movements per day, determined as a mean of the last 28 days of the 6 month treatment period • a ≥ 20% reduction in the mean daily number of bowel movements from baseline in the same 28 day period • any reduction in total number of flushing episodes in the same 28 day period divided by 2 compared to the total number of flushing episodes over the 14 day baseline 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 | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
exploratory Biomarker objective |
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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 | Yes |
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) | 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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 47 |
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 | |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |