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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03442725
Recruitment Status : Completed
First Posted : February 22, 2018
Results First Posted : September 13, 2019
Last Update Posted : April 8, 2020
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
Experimental: 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®

Active Comparator: 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®

Experimental: 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®

Experimental: 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. Maximum Plasma Concentration (Cmax) of Total Telotristat Ethyl, LP-778902 and LP-951757 [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours) ]

    Blood samples were collected to determine plasma levels of telotristat ethyl, its active metabolite LP-778902 (also known as telotristat) and the inactive metabolite LP-951757 using a validated, specific and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalytical method with a lower limit of quantitation (LOQ) of 0.5 nanograms (ng)/mL for telotristat ethyl and 2 ng/mL for LP-778902 and LP-951757.

    Cmax was determined using non-compartmental analysis.


  2. Time to Maximum Observed Plasma Concentration (Tmax) of Total Telotristat Ethyl, LP-778902 and LP-951757 [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours) ]

    Blood samples were collected to determine plasma levels of telotristat ethyl, its active metabolite LP-778902 (also known as telotristat) and the inactive metabolite LP-951757 using a validated, specific and sensitive LC-MS/MS bioanalytical method with a LOQ of 0.5 ng/mL for telotristat ethyl and 2 ng/mL for LP-778902 and LP-951757.

    Tmax was determined using non-compartmental analysis.


  3. Apparent Terminal Elimination Half-Life (t1/2) of Total Telotristat Ethyl, LP-778902 and LP-951757 [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours) ]

    Blood samples were collected to determine plasma levels of telotristat ethyl, its active metabolite LP-778902 (also known as telotristat) and the inactive metabolite LP-951757 using a validated, specific and sensitive LC-MS/MS bioanalytical method with a LOQ of 0.5 ng/mL for telotristat ethyl and 2 ng/mL for LP-778902 and LP-951757.

    T1/2 was determined using non-compartmental analysis.


  4. Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Total Telotristat Ethyl, LP-778902 and LP-951757 [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours) ]

    Blood samples were collected to determine plasma levels of telotristat ethyl, its active metabolite LP-778902 (also known as telotristat) and the inactive metabolite LP-951757 using a validated, specific and sensitive LC-MS/MS bioanalytical method with a LOQ of 0.5 ng/mL for telotristat ethyl and 2 ng/mL for LP-778902 and LP-951757.

    AUC0-inf was determined using non-compartmental analysis.


  5. Area Under the Plasma Concentration-Time Curve From Time 0 to Time Corresponding to the Last Quantifiable Concentration (AUC0-tlast) of Total Telotristat Ethyl, LP-778902 and LP-951757 [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours) ]

    Blood samples were collected to determine plasma levels of telotristat ethyl, its active metabolite LP-778902 (also known as telotristat) and the inactive metabolite LP-951757 using a validated, specific and sensitive LC-MS/MS bioanalytical method with a LOQ of 0.5 ng/mL for telotristat ethyl and 2 ng/mL for LP-778902 and LP-951757.

    AUC0-tlast was determined using non-compartmental analysis.


  6. Apparent First Order Terminal Elimination Rate Constant (λz) of Total Telotristat Ethyl, LP-778902 and LP-951757 [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours) ]

    Blood samples were collected to determine plasma levels of telotristat ethyl, its active metabolite LP-778902 (also known as telotristat) and the inactive metabolite LP-951757 using a validated, specific and sensitive LC-MS/MS bioanalytical method with a LOQ of 0.5 ng/mL for telotristat ethyl and 2 ng/mL for LP-778902 and LP-951757.

    λz was determined using non-compartmental analysis.


  7. Apparent Total Clearance From Plasma (CL/F) of Total Telotristat Ethyl [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours) ]

    Blood samples were collected to determine plasma levels of telotristat ethyl using a validated, specific and sensitive LC-MS/MS bioanalytical method with a LOQ of 0.5 ng/mL.

    CL/F was determined using non-compartmental analysis.


  8. Apparent Volume of Distribution (Vd/F) of Total Telotristat Ethyl [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours) ]

    Blood samples were collected to determine plasma levels of telotristat ethyl using a validated, specific and sensitive LC-MS/MS bioanalytical method with a LOQ of 0.5 ng/mL.

    Vd/F was determined using non-compartmental analysis.


  9. Percentage of Unbound Plasma Fraction (fu) of Total Telotristat Ethyl, LP-778902 and LP-951757 [ Time Frame: Day 1 (0.5, 1, 2 and 3 hours post-dose) ]
    Plasma protein binding was assessed using equilibrium dialysis followed by LC-MS/MS for determination of unbound drug concentrations. The plasma protein binding of telotristat ethyl, LP-778902 and LP-951757 was assessed and the percentage of fu was calculated as the mean over time of the mean of the available replicates.

  10. Cmax for the Unbound Fraction (Cmaxu) of Unbound Telotristat Ethyl, LP-778902 and LP-951757 [ Time Frame: Day 1 (0.5, 1, 2 and 3 hours post-dose) ]
    Cmaxu of unbound telotristat ethyl and its active metabolite LP-778902 (also known as telotristat) and the inactive metabolite LP-951757 was calculated using the unbound fraction fu (defined for each subject as the mean over all time points of the mean of fu) and determined using non-compartmental analysis.

  11. AUC0-inf for the Unbound Fraction (AUC0-infu) of Unbound Telotristat Ethyl, LP-778902 and LP-951757 [ Time Frame: Day 1 (0.5, 1, 2 and 3 hours post-dose) ]
    AUC0-infu of unbound telotristat ethyl and its active metabolite LP-778902 (also known as telotristat) and the inactive metabolite LP-951757 was calculated using the unbound fraction fu (defined for each subject as the mean over all time points of the mean of fu) and determined using non-compartmental analysis.

  12. AUC0-tlast for the Unbound Fraction (AUC0-tlastu) of Unbound Telotristat Ethyl, LP-778902 and LP-951757 [ Time Frame: Day 1 (0.5, 1, 2 and 3 hours post-dose) ]
    AUC0-tlastu of unbound telotristat ethyl and its active metabolite LP-778902 (also known as telotristat) and the inactive metabolite LP-951757 was calculated using the unbound fraction fu (defined for each subject as the mean over all time points of the mean of fu) and determined using non-compartmental analysis.

  13. Metabolic Ratios (MR) of Cmax (LP-778902/Telotristat Ethyl) [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours), Day 2 (24 hours), Day 3 (48 hours) and Day 4 (72 hours) ]

    The following MRs of Cmax were calculated:

    MRCmax = (Cmax LP-778902)/(Cmax telotristat ethyl)

    MRCmaxTotal = (Cmax LP-778902)/(Cmax LP-778902+Cmax telotristat ethyl)

    The ratios were also normalised by molecular weight (MW) of the metabolites (telotristat ethyl: MW=575 grams/mole (g/mol) and LP-778902: MW=547 g/mol). Both the normalised and not normalised ratios are presented.



Secondary Outcome Measures :
  1. Amount of Unchanged Telotristat Ethyl and LP-778902 Excreted in Urine. [ Time Frame: Day 1 (predose and 0 to 4 hours, 4 to 8 hours, 8 to 12 hours, 12 to 24 hours post-dose), Day 2 (24 to 48 hours post-dose), Day 3 (48 to 72 hours post-dose) ]
    For assessment of urine PK parameters, the amount of unchanged telotristat ethyl and its active metabolite LP-778902 (also known as telotristat) excreted in urine was determined.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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
  Study Documents (Full-Text)

Documents provided by Ipsen:
Statistical Analysis Plan  [PDF] June 4, 2018
Study Protocol  [PDF] December 20, 2017

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Responsible Party: Ipsen
ClinicalTrials.gov Identifier: NCT03442725    
Other Study ID Numbers: D-FR-01017-002
2017-003948-20 ( EudraCT Number )
First Posted: February 22, 2018    Key Record Dates
Results First Posted: September 13, 2019
Last Update Posted: April 8, 2020
Last Verified: March 2020

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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