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Study to Compare a Dose of Telotristat Etiprate in Subjects With Renal Impairment With Matched Subjects With Normal Renal Function

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ClinicalTrials.gov Identifier: NCT03442725
Recruitment Status : Completed
First Posted : February 22, 2018
Last Update Posted : December 21, 2018
Sponsor:
Information provided by (Responsible Party):
Ipsen

Brief Summary:

Renal excretion is a minor elimination route of telotristat etiprate. So this trial is intended to assess the drug behaviour in subjects with decreased renal function.

This is a staged study with Part B contingent upon the results of Part A. Part A will enrol a total of 16 subjects, eight with severely impaired renal function and eight healthy subjects. Part B with enrol a total of 16 subjects, eight subjects in each additional renal function group, i.e. mildly impaired renal function group and moderately impaired group.


Condition or disease Intervention/treatment Phase
Renal Impairment Drug: Telotristat etiprate Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 16 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: A Phase I, Open-label Study to Compare the Pharmacokinetics of Telotristat Ethyl and Its Metabolite in Subjects With Impaired Renal Function to Healthy Subjects With Normal Renal Function After a Single Dose of Telotristat Etiprate
Actual Study Start Date : February 9, 2018
Actual Primary Completion Date : April 27, 2018
Actual Study Completion Date : May 13, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Tests

Arm Intervention/treatment
Severely decreased renal function group
Subjects will receive a single oral 250-mg tablet dose of Telotristat etiprate (Xermelo® 250 mg) on day 1 under fed conditions (i.e. between 15 minutes before and 1 hour after the meal or snack).
Drug: Telotristat etiprate
Oral administration of 1 tablet of Xermelo® containing telotristat etiprate equivalent to 250 mg telotristat ethyl.
Other Name: Xermelo®

Normal renal function group
Subjects will receive a single oral 250-mg tablet dose of Telotristat etiprate (Xermelo® 250 mg) on day 1 under fed conditions (i.e. between 15 minutes before and 1 hour after the meal or snack).
Drug: Telotristat etiprate
Oral administration of 1 tablet of Xermelo® containing telotristat etiprate equivalent to 250 mg telotristat ethyl.
Other Name: Xermelo®

Mildly decreased renal function group
Subjects will receive a single oral 250-mg tablet dose of Telotristat etiprate (Xermelo® 250 mg) on day 1 under fed conditions (i.e. between 15 minutes before and 1 hour after the meal or snack).
Drug: Telotristat etiprate
Oral administration of 1 tablet of Xermelo® containing telotristat etiprate equivalent to 250 mg telotristat ethyl.
Other Name: Xermelo®

Moderately decreased renal function group
Subjects will receive a single oral 250-mg tablet dose of Telotristat etiprate (Xermelo® 250 mg) on day 1 under fed conditions (i.e. between 15 minutes before and 1 hour after the meal or snack).
Drug: Telotristat etiprate
Oral administration of 1 tablet of Xermelo® containing telotristat etiprate equivalent to 250 mg telotristat ethyl.
Other Name: Xermelo®




Primary Outcome Measures :
  1. Cmax of total telotristat ethyl, its active metabolite (telotristat) and the inactive metabolite LP-951757 [ Time Frame: From day 1 (pre-dose) up to day 4, 72hours (post-dose) ]
    Cmax (Maximum plasma concentration)

  2. AUCinf of total telotristat ethyl, its active metabolite (telotristat) and the inactive metabolite LP-951757 [ Time Frame: From day 1 (pre-dose) up to day 4, 72hours (post-dose) ]
    AUC (Area under the concentration-time curve) from 0 to infinity

  3. AUC0-tlast of total telotristat ethyl, its active metabolite (telotristat) and the inactive metabolite LP-951757 [ Time Frame: From day 1 (pre-dose) up to day 4, 72hours (post-dose) ]
    AUC from 0 to the last quantifiable concentration

  4. tmax of total telotristat ethyl, its active metabolite (telotristat) and the inactive metabolite LP-951757 [ Time Frame: From day 1 (pre-dose) up to day 4, 72hours (post-dose) ]
    tmax (Time to maximum plasma concentration)

  5. t1/2 of total telotristat ethyl, its active metabolite (telotristat) and the inactive metabolite LP-951757 [ Time Frame: From day 1 (pre-dose) up to day 4, 72hours (post-dose) ]
    t1/2 (Apparent terminal elimination rate constant)

  6. λz of total telotristat ethyl, its active metabolite (telotristat) and the inactive metabolite LP-951757 [ Time Frame: From day 1 (pre-dose) up to day 4, 72hours (post-dose) ]
    λz (Apparent first order terminal elimination rate constant)

  7. CL/F of total telotristat ethyl, its active metabolite (telotristat) and the inactive metabolite LP-951757 [ Time Frame: From day 1 (pre-dose) up to day 4, 72hours (post-dose) ]
    CL/F (Apparent total clearance from plasma)

  8. Vz/F of total telotristat ethyl, its active metabolite (telotristat) and the inactive metabolite LP-951757 [ Time Frame: From day 1 (pre-dose) up to day 4, 72hours (post-dose) ]
    Vz/F (Apparent volume of distribution)

  9. fu of total telotristat ethyl, its active metabolite (telotristat) and the inactive metabolite LP-951757 [ Time Frame: From day 1 (pre-dose) up to day 4, 72hours (post-dose) ]
    fu (Unbound plasma fraction)

  10. Amount of unchanged telotristat ethyl and its active metabolite (telotristat) excreted in urine (Ae) (where possible). [ Time Frame: Day -1, day 1 (pre-dose) up to day 4, 72 hours (post-dose) ]
    Ae (Amount of unchanged drug excreted in urine)

  11. Cmax of ratio active metabolite (telotristat)/telotristat ethyl and the ratio active metabolite (telotristat)/[telotristat ethyl + active metabolite (telotristat)] [ Time Frame: From day 1 (pre-dose) up to day 4, 72hours (post-dose) ]
  12. AUC of ratio active metabolite (telotristat)/telotristat ethyl and the ratio active metabolite (telotristat)/[telotristat ethyl + active metabolite (telotristat)] [ Time Frame: From day 1 (pre-dose) up to day 4, 72hours (post-dose) ]
  13. Cmax of unbound telotristat ethyl and its active metabolite (telotristat) derived from the mean fraction fu [ Time Frame: From day 1 (pre-dose) up to day 4, 72hours (post-dose) ]
  14. AUCinf of unbound telotristat ethyl and its active metabolite (telotristat) derived from the mean fraction fu [ Time Frame: From day 1 (pre-dose) up to day 4, 72hours (post-dose) ]
    Area under the concentration-time curve (AUC) from 0 to infinity

  15. AUC0-tlast of unbound telotristat ethyl and its active metabolite (telotristat) derived from the mean fraction fu [ Time Frame: From day 1 (pre-dose) up to day 4, 72hours (post-dose) ]
    AUC from 0 to the last quantifiable concentration

  16. CL/F of unbound telotristat ethyl and its active metabolite (telotristat) derived from the mean fraction fu [ Time Frame: From day 1 (pre-dose) up to day 4, 72hours (post-dose) ]
    CL/F (Apparent total clearance from plasma)

  17. Vz/F of unbound telotristat ethyl and its active metabolite (telotristat) derived from the mean fraction fu [ Time Frame: From day 1 (pre-dose) up to day 4, 72hours (post-dose) ]
    Vz/F (Apparent volume of distribution)

  18. fu unbound plasma fraction will be determined (where possible) for telotristat ethyl, its active metabolite (telotristat) and the inactive metabolite LP-951757 [ Time Frame: From day 1 up to 3 hours (post-dose) ]

Secondary Outcome Measures :
  1. Safety and tolerability of telotristat ethyl by assessing Adverse Events (AEs) [ Time Frame: From screening (day -56 to -2) to end of study (up to day 15) ]
    Assessed in subjects with impaired renal function and healthy control subjects with normal renal function.

  2. Safety and tolerability of telotristat ethyl by assessing change from baseline in clinical laboratory test results [ Time Frame: Screening (day -56 to -2), day -1, day 2, day 4 and end of study (up to day 15) ]
    Assessed in subjects with impaired renal function and healthy control subjects with normal renal function.

  3. Safety and tolerability of telotristat ethyl by assessing vital signs [ Time Frame: Screening (day -56 to -2), day -1, day 2, day 4 and end of study (up to day 15) ]
    Assessed in subjects with impaired renal function and healthy control subjects with normal renal function.

  4. Safety and tolerability of telotristat ethyl by assessing ECG measurements [ Time Frame: Screening (day -56 to -2), day -1, day 2, day 4 and end of study (up to day 15) ]
    Assessed in subjects with impaired renal function and healthy control subjects with normal renal function.

  5. Safety and tolerability of telotristat ethyl by assessing concomitant medication usage [ Time Frame: From screening (day -56 to -2) to end of study (up to day 15) ]
    Assessed in subjects with impaired renal function and healthy control subjects with normal renal function.

  6. Percentages of drug bound and drug unbound determined (where possible) for telotristat ethyl, its active metabolite (telotristat) and the inactive metabolite LP-951757 [ Time Frame: Day 1: 0.5, 1, 2, 3 hours post-dose ]
    Assessed in subjects with impaired renal function and healthy control subjects with normal renal function.

  7. Determination of the amount excreted in urine (where possible) for telotristat ethyl and its active metabolite (telotristat). [ Time Frame: Day -1 (pre-dose) two 4-hour interval collections, Day 1 (post-dose) 0-4h, 4-8h, 8-12h, 12-24h, 24-48h, 48-72h ]
    Assessed in subjects with impaired renal function and healthy control subjects with normal renal function.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

All subjects:

  • Provision of written informed consent prior to any study related procedure.
  • Men and women enrolling in the study must be at least 18 years of age at the time of giving informed consent.
  • Women of childbearing potential must agree to use an adequate double-barrier method of contraception during the study and for 30 days after discharge.
  • Men must agree to use an adequate, double barrier method of contraception during the study and for 30 days after discharge.

Additionally, for subjects with renal impaired function:

  • Clinical diagnosis of renal impaired function that has been stable for more than 3 months prior to dosing
  • Renal impaired function classified as mild, moderate, or severe.
  • Under stable medication regimen, i.e. not starting new therapy(ies) or significant changing dosage(s) within at least 1 month prior to dosing, as determined by the investigator.
  • Stable and appropriately managed relative to chronic diseases (e.g. diabetes, hypertension) as determined by medical history, physical examination, ECGs, and clinical laboratory tests.

Additionally, for healthy subjects with normal renal function:

  • Each subject will be demographically-matched to one of the subjects with severely impaired renal function for gender, age (± 10 years), BMI (± 20%).
  • Clinical laboratory test results must be strictly within the normal laboratory reference ranges for urea, creatinine, protein, and albumin.

Exclusion Criteria:

All subjects:

  • Existence of any surgical or medical condition that, in the judgment of the investigator, might interfere with the absorption, distribution, metabolism, or excretion of telotristat etiprate (including bariatric surgery, or any other gastrointestinal surgery, excepting appendectomy and hernia repair, which are acceptable).
  • History of any major surgery within six months or anticipated surgery prior to Day-1.
  • Patients with hereditary problems of galactose intolerance (lactase deficiency or glucose-galactose malabsorption).
  • History of any active infection within 30 days prior to Day-1, if deemed clinically significant by the investigator.
  • Positive hepatitis panel results (including hepatitis B surface antigen and hepatitis virus C ribonucleic acid).
  • Positive results for human immunodeficiency virus, or who has received diagnosis for acquired immunodeficiency syndrome.
  • Positive urine screen for drugs of abuse (not including cotinine).
  • Consumption of alcohol within 48 hours prior to Day-1 (as confirmed by alcohol breath screen) and for the duration of the confinement period.
  • Smoking more than ten cigarettes per day or equivalent; unable or unwilling to refrain from smoking and tobacco use for two hours prior to dosing and four hours after dose administration.
  • Consumption of caffeine- and/or xanthine-containing products (e.g. cola, coffee, tea, chocolate) on Day-1 until 24 hours postdose.
  • Consumption of grapefruit, Seville oranges, and grapefruit- or Seville orange-containing products within 72 hours prior to Day-1 and for the duration of the confinement period.
  • Use of any medication (prescription or over-the-counter), Chinese herbal medications or herbal tea, energy drinks, herbal products (e.g. St. John's wort, garlic), or supplements/supra therapeutic doses of vitamins within 14 days prior to Day-1 and up to Day 4 after dosing, apart from those approved by the investigator.
  • Women who are breastfeeding or are planning to become pregnant during the study.

Additionally, for renal impaired subjects:

  • Clinically significant physical (e.g. oedema in heavy subjects with renal impaired function), laboratory, or ECG findings (apart from those parameters which are related to impaired renal function or underlying disease e.g. diabetes, hypertension) that, in the opinion of the investigator, may interfere with any aspect of the study conduct or interpretation of the results.
  • Glycated haemoglobin A1c ≥ 9%.

Additionally, for healthy subjects with normal renal function:

  • Clinically significant illness or disease including cardiac, pulmonary, hepato-biliary, gastrointestinal, or endocrinology, or cancer within the last 5 years (except localised or in situ non-melanoma skin cancer), as determined by medical history, physical examination, laboratory tests, and 12-lead ECGs.
  • Clinically significant physical, laboratory, or ECG findings that, in the opinion of the investigator, may interfere with any aspect of the study conduct or interpretation of the results.
  • History of renal disease.
  • History of alcohol or drug abuse within 2 years prior to screening.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03442725


Locations
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Belgium
A.T.C. s.a., Clinical Pharmacology Unit, CHU Sart-Tilman
Liège, Belgium, B-4000
Germany
CRS Clinical Research Services Kiel GmbH
Kiel, Germany, D-24105
Moldova, Republic of
ARENSIA Exploratory Medicine Phase I Unit, Republican Clinical Hospital
Chisinau, Moldova, Republic of, MD-2025
Romania
ARENSIA Unit in Spitalul de Nefrologie
Bucharest, Romania
Sponsors and Collaborators
Ipsen
Investigators
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Study Director: Ipsen Medical Director Ipsen

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Responsible Party: Ipsen
ClinicalTrials.gov Identifier: NCT03442725     History of Changes
Other Study ID Numbers: D-FR-01017-002
2017-003948-20 ( EudraCT Number )
First Posted: February 22, 2018    Key Record Dates
Last Update Posted: December 21, 2018
Last Verified: December 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Renal Insufficiency
Kidney Diseases
Urologic Diseases