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Single Ascending Dose Study of PBI-4547 in Healthy Subjects

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: NCT04068259
Recruitment Status : Terminated (PK data from first 3 cohorts does not support study continuation.There was no safety concerns)
First Posted : August 28, 2019
Last Update Posted : June 19, 2020
Sponsor:
Collaborator:
Syneos Health
Information provided by (Responsible Party):
ProMetic Pharma SMT Limited

Brief Summary:
This study will evaluate the safety, tolerability, and pharmacokinetics (PK) of PBI-4547 in healthy adult participants.

Condition or disease Intervention/treatment Phase
Healthy Subjects Drug: PBI-4547 Other: Placebo Phase 1

Detailed Description:

This is a first-in-human, single-ascending dose study of PBI-4547 in healthy adult participants. PBI-4547 is a synthetic ligand of G protein-coupled receptor (GPR)40 and GPR84, which have been reported to play a role in fibrosis in various animal models as well as in tissue culture.

A total of 40 healthy adult participants will sequentially receive 1 of 5 doses of PBI-4547 (Dose1, 2, 3, 4 or 5) or matching placebo, with each cohort of 8 participants randomized in a 3:1 ratio to receive PBI-4547 or matching placebo.

A food-effect cohort will be added after review of the PK results of at least the first dose, and the following 2 doses, if needed. In this cohort participants will initially receive the study drug under fasting conditions (Period 1) followed by the same dose after the ingestion of a high-fat meal (Period 2) after a 14-day washout period.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 1, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses of PBI-4547 in Healthy Subjects
Actual Study Start Date : September 5, 2019
Actual Primary Completion Date : October 8, 2019
Actual Study Completion Date : October 8, 2019

Arm Intervention/treatment
Experimental: Cohort 1, Dose 1 of PBI-4547 or Placebo
Dose 1 of PBI-4547 or matching Placebo tablets by mouth
Drug: PBI-4547
PBI-4547 tablet

Other: Placebo
Placebo tablet

Experimental: Cohort 2, Dose 2 of PBI-4547 or Placebo
Dose 2 of PBI-4547 or matching Placebo tablets by mouth
Drug: PBI-4547
PBI-4547 tablet

Other: Placebo
Placebo tablet

Experimental: Cohort 3, Dose 3 of PBI-4547 or Placebo
Dose 3 of PBI-4547 or matching Placebo tablets by mouth
Drug: PBI-4547
PBI-4547 tablet

Other: Placebo
Placebo tablet

Experimental: Cohort 4, Dose 4 of PBI-4547 or Placebo
Dose 4 of PBI-4547 or matching Placebo tablets by mouth
Drug: PBI-4547
PBI-4547 tablet

Other: Placebo
Placebo tablet

Experimental: Cohort 5, Dose 5 of PBI-4547 or Placebo
Dose 5 of PBI-4547 or matching Placebo tablets by mouth
Drug: PBI-4547
PBI-4547 tablet

Other: Placebo
Placebo tablet




Primary Outcome Measures :
  1. Number of participants with treatment-emergent adverse events (TEAEs) [ Time Frame: 5-6 days ]
    TEAE is any untoward medical occurrence in a subject who has been administered a pharmaceutical product or not, which does not necessarily have a causal relationship with this treatment.

  2. Number of participants with clinically significant laboratory evaluation findings [ Time Frame: 5-6 days ]
    Laboratory tests for hematology, serum chemistry and urinalysis will be performed upon admission, at discharge, and at the follow-up visit (5 ± 1 day post-dose).

  3. Number of participants with clinically significant electrocardiogram (ECG) Findings [ Time Frame: 5-6 days ]
    Triplicate ECG will be performed upon admission, pre-dose, and approximately 1, 2, 8, and 24 hours post-dose, and at the follow-up visit (5 ± 1 day post-dose). Subjects will be continuously monitored using a Holter monitor from approximately 1 hour pre-dose until approximately 24 hours post-dose.

  4. Number of participants with clinically significant vital sign findings [ Time Frame: 5-6 days ]
    Vital signs include blood pressure, heart rate, respiratory rate, and oral body temperature will be measured upon admission, before discharge from the clinic and at the follow-up visit (5 ± 1 day post-dose).

  5. Number of participants with physical examination findings [ Time Frame: 5-6 days ]
    Brief physical examination will be conducted upon admission and at discharge. A complete physical examination will be conducted at screening and follow-up visit.


Secondary Outcome Measures :
  1. AUC0-t for PBI-4547 [ Time Frame: 48 hours ]
    Area under the concentration-time curve from time zero to the last non-zero concentration

  2. AUC0-inf for PBI-4547 [ Time Frame: 48 hours ]
    Area under the concentration-time curve from time zero to infinity (extrapolated)

  3. Cmax for PBI-4547 [ Time Frame: 48 hours ]
    Maximum observed concentration

  4. Residual area for PBI-4547 [ Time Frame: 48 hours ]
    Residual area calculated as 100*(1- AUC0-t / AUC0-inf)

  5. Tmax for PBI-4547 [ Time Frame: 48 hours ]
    Time of observed Cmax

  6. T1/2 el for PBI-4547 [ Time Frame: 48 hours ]
    Elimination half-life

  7. Kel for PBI-4547 [ Time Frame: 48 hours ]
    Elimination rate constant

  8. Rkel for PBI-4547 [ Time Frame: 48 hours ]
    Accumulation factor based on elimination rate constant

  9. MRT for PBI-4547 [ Time Frame: 48 hours ]
    Mean residence time

  10. Cl/F for PBI-4547 [ Time Frame: 48 hours ]
    Total body clearance, calculated as Dose/AUC0-inf;Cl/F normalized for subject body weight in kg will be calculated

  11. Vd/F for PBI-4547 [ Time Frame: 48 hours ]
    Apparent volume of distribution, calculated as Dose/(Kel x AUC0-inf). Vd/F normalized for subject body weight in kg will be calculated

  12. AUC0-t for PBI-4547 under fed condition [ Time Frame: 48 hours ]
    Area under the concentration-time curve from time zero to the last non-zero concentration after a high-fat diet

  13. AUC0-inf for PBI-4547 under fed condition [ Time Frame: 48 hours ]
    Area under the concentration-time curve from time zero to infinity (extrapolated) after a high-fat diet

  14. Cmax for PBI-4547 under fed condition [ Time Frame: 48 hours ]
    Maximum observed concentration after a high-fat diet

  15. Tmax for PBI-4547 under fed condition [ Time Frame: 48 hours ]
    Time of observed Cmax after a high-fat diet



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 to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy male participants or non-childbearing potential female participants, ≥18 and ≤55 years.
  • Body mass index > 18.5 and < 30.0 kg/m^2, and body weight ≥ 50.0 kg for male participants and ≥ 45.0 kg for female participants.
  • Continuous non-smoker who has not used tobacco or nicotine-containing products for at least 3 months prior to screening.
  • Male participants with a pregnant partner must agree to use a condom from the first dosing until at least 90 days after study drug administration.
  • Male participants must be willing not to donate sperm until 90 days after study drug administration.

Exclusion Criteria:

  • Any clinically significant abnormality or abnormal laboratory test results.
  • An estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m^2.
  • Positive urine drug screen and history of significant drug abuse.
  • History of significant allergic reactions to any drug.
  • Use of any drugs known to induce or inhibit hepatic drug metabolism.
  • Positive pregnancy test or breast-feeding participant.
  • Clinically significant abnormalities in ECG, blood pressure, and heart rate at screening.
  • History of significant alcohol abuse or regular use of alcohol.
  • Use of medication other than topical products without significant systemic absorption.
  • Donation of plasma.

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): NCT04068259


Locations
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Canada, Quebec
Syneos Health
Montréal, Quebec, Canada, H3X 2H9
Canada
Syneos Health
Québec, Canada, G1P 0A2
Sponsors and Collaborators
ProMetic Pharma SMT Limited
Syneos Health
Investigators
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Study Director: John Moran, MD Prometic Pharma SMT Ltd.
Principal Investigator: Richard Larouche, MD Syneos Health
Publications:
Leduc M, Grouix B, Tremblay M, GervaisL, Sarra-Bournet F, Felton X, Simard J, Leblond FA, Laurin P and Gagnon L. PBI-4547 Improves Glucose Metabolism and Insulin Resistance, and Reduces Liver Damage in a High-Fat Diet Mouse Model of Obesity and Metabolic Syndrome. Diabetes 2018 Jul; 67(Supplement 1).
Gagnon L, Laverdure A, Sarra-Bournet F, Cloutier M, Felton A, Treemblay M, Richard J, Gervais L, Laurin P, Leblond FA and Grouix B. PBI-4547 Reverses Diabetes and Metabolic Syndrome through Regulation of Lipid/Glucose Metabolism, ß-Oxidation and Fibrosis in Liver, and White Adipose Tissue in ob/ob Mice. Diabetes 2018 Jul; 67(Supplement 1).
Sarra-Bournet F, Grouix B, Hince K, Felton A, Tremblay M, Abbott S, Duceppe JS, Zacharie B, Laurin P, Gagnon G. PBI-4547 decreases hepatic stellate cell activation via AMPK signaling pathway, and reduces fibrosis in carbon tetrachloride (CCL4)-induced hepatic fibrosis model. Journal of Hepatology 2018, 68:S365-S604.

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Responsible Party: ProMetic Pharma SMT Limited
ClinicalTrials.gov Identifier: NCT04068259    
Other Study ID Numbers: PBI-4547-CT-9-01
180271 ( Other Identifier: Syneos Health )
First Posted: August 28, 2019    Key Record Dates
Last Update Posted: June 19, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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