E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
refractory carcinoid syndrome |
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E.1.1.1 | Medical condition in easily understood language |
A complex of symptoms due to a carcinoid tumor producing too many hormones, which cause multiple symptoms like diarrhea, flushing, urgent need for a bowel movement. |
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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 | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10007270 |
E.1.2 | Term | Carcinoid syndrome |
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 of the study is to confirm that at least 1 or more dose groups of telotristat etiprate compared to placebo is effective in reducing the number of daily bowel movements (BMs) from baseline averaged over the 12-week double-blind portion (Treatment Period) of the trial in patients not adequately controlled by current SSA therapy.
The primary safety objective is to assess the overall safety
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E.2.2 | Secondary objectives of the trial |
To assess the effects of telotristat etiprate versus placebo over the 12-week double-blind portion of the study in patients who are not adequately controlled by current SSA therapy as determined by:
•Change from baseline in urinary 5-hydroxyindoleacetic acid (5HIAA) levels at week 12
•Change from baseline in the number of cutaneous flushing episodes averaged across all time points
•Change from baseline in abdominal pain averaged across all time points
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
pharmacogenomic research
populational pharmacokinetics |
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E.3 | Principal inclusion criteria |
1.Patients ≥18 years of age at the time of the Screening visit
2.Histopathologically-confirmed, well-differentiated metastatic NET with extent documented by computed tomography (CT), magnetic resonance imaging (MRI), or radionuclide imaging
3.A documented history of CS, and currently experiencing an average of ≥4 bowel movements per day during the Run-in Period. Confirmation of eligibility will be determined by measuring the mean number of BM
4.Currently receiving a stable-dose SSA therapy. For the purposes of this study, stable-dose SSA therapy is defined as long acting release (LAR) or Depot SSA therapy or a continuous subcutaneous infusion via a pump. Patients must have been receiving the same dose level and frequency for at least 3 months prior to entering the Run-in Period.
5.Minimum dose of LAR or Depot SSA therapy (higher dose or more frequent intervals will exceed minimum dose). SSA therapy must be approved for use in CS in the patient’s country of residence or prescribers’ country of practice.
a.Octreotide LAR at 30 mg every 4 weeks
b.Lanreotide Depot at 120 mg every 4 weeks
c.Patients who cannot tolerate SSA therapy at a level indicated above will be allowed to enter at their highest tolerated dose
6.Patients of childbearing potential must agree to use an adequate method of contraception (defined as having a failure rate of <1% per year) during the study and for 12 weeks after the Follow-up visit. Adequate methods of contraception for patients or partner include condoms with spermicide gel, diaphragm with spermicide gel, coil (intrauterine device), surgical sterilization, vasectomy, oral contraceptive pill, depot progesterone injections, progesterone implant, and abstinence during the study and for 12 weeks after the Follow-up Visit.
a. Childbearing potential is defined as those who have not undergone surgical sterilization, or those who are not considered postmenopausal. Postmenopause is defined as absence of menstruation for at least 2 years. If necessary, follicle-stimulating hormone (FSH) results >50 IU/L at Screening are confirmatory in the absence of a clear postmenopausal history.
7.Ability and willingness to provide written informed consent prior to participation in any study-related procedure |
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E.4 | Principal exclusion criteria |
Patients who meet any of the following criteria will be excluded from participating in the study:
1.Presence of diarrhea attributed to any condition(s) other than CS (including, but not limited to fat malabsorption or bile acid malabsorption)
2.Presence of more than 12 watery BM per day associated with volume contraction, dehydration, or hypotension compatible with a “pancreatic cholera”-type clinical syndrome, as judged by the Investigator
3.Positive stool examination for enteric pathogens, pathogenic ova or parasites, or Clostridium difficile at Screening
4.Karnofsky Performance Status ≤60%
5.Clinical laboratory values for hematology (at Screening):
a.Absolute neutrophil count (ANC) ≤1500 cells/mm3; or
b.Platelets ≤75,000 cells/mm3; or
c.Hemoglobin (Hgb) ≤9 g/dL for males and ≤8 g/dL for females
6.Hepatic laboratory values (at Screening) such that:
a.Aspartate transaminase (AST), or alanine aminotransferase (ALT):
•≥5.5 x upper limit of normal (ULN) if patient has documented history of hepatic metastases; or
•≥2.5 x ULN if patient does not have documented history of hepatic metastases
b.Total bilirubin >1.5 x ULN (unless patient has a documented history of Gilbert’s Syndrome); or
c.Alkaline phosphatase (ALP) ≥5 x ULN, if total bilirubin is >ULN
•No upper limit on the ALP value if the total bilirubin is ≤ULN
7.Serum creatinine ≥1.5 x ULN
8.Treatment with any tumor directed therapy including, but not limited to: interferon, chemotherapy, mTOR inhibitors ≤4 weeks prior to Screening; or hepatic embolization, radiotherapy, radiolabelled SSA, and/or tumor debulking ≤12 weeks prior to Screening
9.Major surgery defined as procedures requiring general anesthesia or major regional anesthesia within 8 weeks prior to Screening
10.A history of short bowel syndrome (SBS)
11.Pregnant or nursing (lactating) women
12.Positive pregnancy test
13.Life expectancy <12 months from the Screening visit
14.Presence of any clinically significant findings at Screening medical history, or physical examination (relative to patient population) that, in the Investigator’s or Medical Monitor's opinion, would compromise patient safety or the outcome of the study
15.Any other clinically significant laboratory abnormality at Screening that would compromise patient safety or the outcome of the study
16.Clinically significant cardiac arrhythmia, bradycardia or tachycardia that would compromise patient safety or the outcome of the study.
17.A history of substance or alcohol abuse within 2 years prior to Screening
18.Administration of any investigational agent within 30 days of Screening or investigational therapeutic protein or antibody within 90 days prior to Screening
19.Previous exposure to telotristat etiprate
20.Patients who are currently committed to an institution by virtue of an order issued either by judicial or administrative authorities
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the change from baseline in the number of daily BMs averaged over the 12 week double blind portion (Treatment Period) of the trial.
Safety endpoints are as follows:
•Incidence of TEAEs, suspected adverse reaction, AEs leading to discontinuation from the study, SAEs, and deaths
•Actual and change from baseline in clinical laboratory results
•Actual and change from baseline in vital signs results
•Actual and change from baseline in physical examinations
•Actual and change from baseline in ECG findings
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
at each visit and the final analysis will be done at the end of the study |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints include:
•Change from baseline in urinary 5-HIAA levels at week 12
•Change from baseline in the number of cutaneous flushing episodes averaged across all time points
•Change from baseline in abdominal pain averaged across all time points
•Proportion of patients with durable response, defined as the proportion of responders with ≥30% reduction in daily number of BMs for ≥50% of time over the double-blind portion of the study
•Change in the frequency of rescue short-acting SSA used to treat bowel-related carcinoid syndrome-symptoms
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
at each visit and the final analysis will be done at the end of the study |
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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 | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
there is a 12-week double-blind treatment phase and then for 36 weeks open label treatment phase |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
two different doses of LX1606 |
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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
| 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 | 45 |
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 |
Australia |
Belgium |
Brazil |
Canada |
France |
Germany |
Ireland |
Israel |
Italy |
Netherlands |
Spain |
Sweden |
Ukraine |
United Kingdom |
United States |
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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 | 8 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |