E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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 |
To evaluate the effect of telotristat etiprate versus placebo over the
double-blind portion of the study on
• The incidence of treatment-emergent adverse events (TEAEs)
• Percent (%) change from Baseline in 24-hour urinary 5-
hydroxyindoleacetic acid (5-HIAA) levels at Week 12 |
|
E.2.2 | Secondary objectives of the trial |
To evaluate the effect of telotristat etiprate versus placebo over the double-blind portion of the study on:
• Change from Baseline in the number of daily bowel movements (BMs) averaged over a 12-week treatment period
• Change from Baseline in stool consistency, as measured by the Bristol Stool Form Scale averaged across all time points
• Change from Baseline in the number of cutaneous flushing episodes
• Change from Baseline in abdominal pain averaged across all time points
• Change from Baseline in the frequency of rescue short-acting, somatostatin analog (SSA) used to treat carcinoid syndrome (CS) symptoms
• Change from Baseline in the number of daily BMs averaged over the 12-week treatment period and at each study week, among patients who are not on an SSA at Baseline
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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 |
Pharmacogenomics Research |
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E.3 | Principal inclusion criteria |
Patients must meet all of the following criteria to be considered
eligible to participate in the study:
1. Patients ≥18 years of age at the time of the Screening visit
2. All patients of reproductive 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 patient or partner include
condoms with spermicidal gel, diaphragm with spermicidal gel, coil
(intrauterine device), surgical sterilization, vasectomy, oraloral
contraceptive pill, depot progesterone injections, progesterone implant,
and abstinence during the study and for 12 weeks after the Follow-up
visit. Note: For females, 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, folliclestimulating
hormone (FSH) results >50 IU/L at Screening are
confirmatory in the absence of a clear postmenopausal history.
3. Histopathologically-confirmed, well-differentiated metastatic (NET
confirmed by computed tomography (CT), magnetic resonance imaging
(MRI), or radionuclide imaging
4. Documented history of CS and meeting 1 of the following 2
criteria:
• If currently receiving LAR/Depot/infusion SSA therapy for the treatment of CS, must
be currently receiving a stable dose, averaging <4 BMs per day, and must have ≥1 of the
following sign/symptoms of CS:
a. Daily stool consistency ≥5 on Bristol Stool Form Scale9 (Appendix D)
for ≥50% of the days during the Run-in, or
b. Average daily flushing frequency of ≥2, or
c. Average daily rating of ≥3 for abdominal pain, or
d. Nausea present ≥20% of days, or
e. u5-HIAA > ULN
• If not currently receiving SSA therapy, must have ≥1 of the following
sign/symptoms of CS:
a. Daily stool consistency ≥5 on Bristol Stool Form Scale9 (Appendix D)
for ≥50% of the days during the Run-in, or
b. Average daily flushing frequency of ≥2, or
c. Average daily rating of ≥3 for abdominal pain, or
d. Nausea present ≥20% of days, or
e. u5-HIAA > ULN, or
f. Currently averaging ≥4 BMs per day
5. Patient is able and willing 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 >12 watery BMs 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% (see Appendix C)
5. Clinical laboratory values for hematology (at Screening):
• Absolute neutrophil count (ANC) ≤1500 cells/mm3; or
• Platelets ≤75,000, cells/mm3; or
• Hemoglobin (Hgb) ≤9 g/dL for males and ≤8 g/dL for females
6. Hepatic laboratory values (at Screening) such that:
• Asparate transaminase (AST) or alanine aminotransferase (ALT):
a. ≥5.5 x ULN if patient has documented history of hepatic metastases,
or
b. ≥2.5 x ULN if patient does not have documented history of hepatic
metastases
• Total bilirubin >1.5 x ULN (unless patient has a documented history of
Gilbert's Syndrome); or
• Alkaline phosphatase (ALP) ≥5 x ULN, if total bilirubin is >ULN
a. 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. Current complaints of constipation or history of chronic or idiopathic
constipation within 2 years prior to Screening
12. Positive pregnancy test or pregnant or nursing (lactating) (female
patients only)
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 (DSM-IV Criteria
for Substance-Related Disorders12) 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. 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 a 12-week treatment period.
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 |
|
E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints include:
• Change from Baseline in stool consistency averaged across all time points
• Change from Baseline in the number of cutaneous flushing episodes
• Change from baseline in abdominal pain averaged across all time points
• Change in the frequency of rescue short-acting SSA is used to treat CS symptoms
• Change from Baseline in the number of daily BMs averaged over the 12-week treatment period and at each study week, among patients who are not on an SSA at Baseline
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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 | No |
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 a 36 week 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 |
|
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 |
Israel |
Italy |
Netherlands |
Spain |
Sweden |
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 |