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Drug-drug Interaction Study Between KD025, Itraconazole, Rifampicin, Rabeprazole and Omeprazole in Healthy Volunteers

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ClinicalTrials.gov Identifier: NCT03530995
Recruitment Status : Recruiting
First Posted : May 21, 2018
Last Update Posted : October 15, 2018
Sponsor:
Collaborator:
Quotient Sciences
Information provided by (Responsible Party):
Kadmon Corporation, LLC

Brief Summary:
This is a single centre, two-part, non-randomised, open label study in healthy male subjects.

Condition or disease Intervention/treatment Phase
Drug Drug Interaction Autoimmune Diseases Fibrotic Disease Drug: KD025 Drug: Itraconazole Drug: Rabeprazole Drug: Rifampicin Drug: Omeprazole Phase 1

Detailed Description:

Part 1: In each study period, subjects will receive a single dose of KD025 Tablet, in the fed state. Additionally, in order to assess the effects of inhibition and induction of CYP3A4 and the elevation of gastric pH on KD025 exposure, subjects will receive multiple doses of perpetrator drugs in Periods 2 to 4; a strong CYP3A4 inhibitor, itraconazole, in Period 2; a proton pump inhibitor, rabeprazole, in Period 3; and a strong CYP3A4 inducer, rifampicin, in Period 4.

Part 2: In period 1, subjects will receive a single dose of KD025 Tablet, in the fed state. In period 2, in order to assess the effects of inhibition and induction of CYP3A4 and the elevation of gastric pH on KD025 exposure, subjects will receive multiple doses of a proton pump inhibitor, omeprazole.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 78 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Two-Part, Non-Randomised
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: A Two-Part, Non-Randomised, Open Label Study to Evaluate the Effect of Itraconazole, Rifampicin, Rabeprazole, and Omeprazole on the Pharmacokinetics of KD025
Actual Study Start Date : April 28, 2018
Estimated Primary Completion Date : March 15, 2019
Estimated Study Completion Date : June 15, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Drug Reactions

Arm Intervention/treatment
Experimental: Part 1, Period 1
Drug: KD025 Subjects will receive KD025 200 mg single dose on Day 1
Drug: KD025
Development candidate
Other Name: SLx-2119

Experimental: Part 1, Period 2
Drug: itraconazole Subjects will receive itraconazole 200 mg QD on Day 1 through Day 7 Drug: KD025 Subjects will receive KD025 200 mg + itraconazole 200 mg QD on Day 8 Subjects will receive itraconazole 200 mg QD on Day 9
Drug: KD025
Development candidate
Other Name: SLx-2119

Drug: Itraconazole
Perpetrator drug

Experimental: Part 1, Period 3
Drug: rabeprazole Subjects will receive rabeprazole 20 mg BID on Day 1 through Day 3 Drug: KD025 Subjects will receive KD025 200 mg + rabeprazole 20 mg QD on Day 4
Drug: KD025
Development candidate
Other Name: SLx-2119

Drug: Rabeprazole
Perpetrator drug

Experimental: Part 1, Period 4
Drug: rifampicin Subjects will receive rifampicin 600 mg QD on Day 1 through Day 9 Drug: KD025 Subjects will receive KD025 200 mg on Day 10
Drug: KD025
Development candidate
Other Name: SLx-2119

Drug: Rifampicin
Perpetrator drug

Experimental: Part 2, Period 1
Drug: KD025 Subjects will receive KD025 200 mg BID on Day 1
Drug: KD025
Development candidate
Other Name: SLx-2119

Experimental: Part 2, Period 2
Drug: omeprazole Subjects will receive omeprazole 20 mg QD on Day 1 through Day 3 Drug: KD025 Subjects will receive KD025 200 mg BID + omeprazole 20 mg QD on Day 4
Drug: KD025
Development candidate
Other Name: SLx-2119

Drug: Omeprazole
Perpetrator drug




Primary Outcome Measures :
  1. Change in KD025 PK parameter Cmax when administered with itraconazole [ Time Frame: 45 days ]
    A comparison of the PK profile of KD025 Tablets when co-administered with itraconazole compared to when administered alone, by assessing the peak plasma concentration (Cmax) for KD025 and metabolites KD025m1 and KD025m2

  2. Change in KD025 parameter AUC when administered with itraconazole [ Time Frame: 45 days ]
    A comparison of the PK profile of KD025 Tablets when co-administered with itraconazole compared to when administered alone, by assessing the area under the plasma concentration versus time curve (AUC) for KD025 and metabolites KD025m1 and KD025m2

  3. Change in KD025 PK parameter Cmax when administered with rabeprazole [ Time Frame: 45 days ]
    A comparison of the PK profile of KD025 Tablets when co-administered with rabeprazole compared to when administered alone, by assessing the peak plasma concentration (Cmax) for KD025 and metabolites KD025m1 and KD025m2

  4. Change in KD025 parameter AUC when administered with rabeprazole [ Time Frame: 45 days ]
    A comparison of the PK profile of KD025 Tablets when co-administered with rabeprazole compared to when administered alone, by assessing the area under the plasma concentration versus time curve (AUC) for KD025 and metabolites KD025m1 and KD025m2

  5. Change in KD025 PK parameter Cmax when administered with rifampicin [ Time Frame: 45 days ]
    A comparison of the PK profile of KD025 Tablets when co-administered with rifampicin compared to when administered alone, by assessing the peak plasma concentration (Cmax) for KD025 and metabolites KD025m1 and KD025m2

  6. Change in KD025 parameter AUC when administered with rifampicin [ Time Frame: 45 days ]
    A comparison of the PK profile of KD025 Tablets when co-administered with rifampicin compared to when administered alone, by assessing the area under the plasma concentration versus time curve (AUC) for KD025 and metabolites KD025m1 and KD025m2

  7. Change in KD025 parameter Cmax when administered with omeprazole [ Time Frame: 20 days ]
    A comparison of the PK profile of KD025 Tablets when co-administered with omeprazole compared to when administered alone, by assessing the peak plasma concentration (Cmax) for KD025 and metabolites KD025m1 and KD025m2

  8. Change in KD025 parameter AUC when administered with omeprazole [ Time Frame: 20 days ]
    A comparison of the PK profile of KD025 Tablets when co-administered with omeprazole compared to when administered alone, by assessing the area under the plasma concentration versus time curve (AUC) for KD025 and metabolites KD025m1 and KD025m2


Secondary Outcome Measures :
  1. Change in blood pressure from baseline [ Time Frame: 45 days ]
    Individual systolic and diastolic blood pressure including derivations such as change from baseline will be listed.

  2. Change in electrocardiograms from baseline [ Time Frame: 45 days ]
    The arithmetic mean of the triplicate values for each ECG measurement will be computed for each subject at pre-dose and 4 h post-dose on Day 1 of each study period. The arithmetic means will then be used to compute the summary statistics for the observed value and for the change from baseline values.

  3. Total number of treatment emergent adverse events [ Time Frame: 45 days ]
    The number and percentage of subjects exposed to each study drug on each day will be summarised by treatment.

  4. Total number of adverse drug reactions [ Time Frame: 45 days ]
    The number and percentage of subjects exposed to each study drug on each day will be summarised by treatment.

  5. Total number of treatment emergent adverse events leading to subject withdrawal [ Time Frame: 45 days ]
    The number and percentage of subjects exposed to each study drug on each day will be summarised by treatment.

  6. Total number of serious treatment emergent adverse events [ Time Frame: 45 days ]
    The number and percentage of subjects exposed to each study drug on each day will be summarised by treatment.

  7. Total number of treatment emergent adverse events leading to death [ Time Frame: 45 days ]
    The number and percentage of subjects exposed to each study drug on each day will be summarised by treatment.

  8. Total number of severe treatment emergent adverse events [ Time Frame: 45 days ]
    The number and percentage of subjects exposed to each study drug on each day will be summarised by treatment.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Healthy males
  2. Age 18 to 55 years
  3. Good state of health (mentally and physically) as indicated by a comprehensive clinical assessment (detailed medical history and a complete physical examination), ECG and laboratory investigations (haematology, clinical chemistry and urinalysis)
  4. Body weight ≥50 kg
  5. Body mass index of 18.0 to 32.0 kg/m2 or, if outside the range, considered not clinically significant by the investigator
  6. Must be willing and able to communicate and participate in the whole study
  7. Must provide written informed consent
  8. Must adhere to the contraception requirements

Exclusion Criteria:

  1. Subjects who have received any investigational product in a clinical research study within the previous 3 months
  2. Subjects who are study site employees, or immediate family members of a study site or sponsor employee
  3. Subjects with pregnant partners
  4. History of any drug or alcohol abuse in the past 2 years
  5. Regular alcohol consumption in males >21 units per week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 units = 125 mL glass of wine, depending on type)
  6. Current smokers and those who have smoked within the last 12 months. A breath carbon monoxide reading of greater than 10 ppm at screening and admission
  7. Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months
  8. Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening
  9. Clinically significant abnormal biochemistry, haematology or urinalysis as judged by the investigator
  10. Positive drugs of abuse test result at screening and admission
  11. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results
  12. Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance (CLcr) of <80 mL/min using the Cockcroft-Gault equation
  13. History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder, as judged by the investigator
  14. Subject has a history or presence of any of the following:

    • Active gastrointestinal disease requiring therapy
    • Hepatic disease and/or ALT or AST > ULN
    • Renal disease and/or serum creatinine > ULN
    • Other condition known to interfere with the absorption, distribution, metabolism or excretion of drugs
  15. Subjects with a history of cholecystectomy or gall stones
  16. Subject has QT interval corrected using Fridericia's formula (QTcF) intervals >450 msec at screening or admission
  17. Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients; including intolerance to itraconazole, rabeprazole and rifampicin
  18. Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hayfever is allowed unless it is active
  19. Donation or loss of greater than 400 mL of blood within the previous 3 months
  20. Subjects who are taking, or have taken, any prescribed or over-the-counter drug (other than 4 g per day paracetamol) or herbal remedies in the 14 days before investigational product administration.
  21. Failure to satisfy the investigator of fitness to participate for any other reason

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): NCT03530995


Contacts
Contact: Nand Singh, MD +44 (0)115 974 9000 nand.singh@quotientsciences.com

Locations
United Kingdom
Quotient Sciences Ltd Recruiting
Ruddington, Nottingham, United Kingdom, NG11 6JS
Contact: Nand Singh, MD         
Sponsors and Collaborators
Kadmon Corporation, LLC
Quotient Sciences

Responsible Party: Kadmon Corporation, LLC
ClinicalTrials.gov Identifier: NCT03530995     History of Changes
Other Study ID Numbers: KD025-107
First Posted: May 21, 2018    Key Record Dates
Last Update Posted: October 15, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Additional relevant MeSH terms:
Omeprazole
Autoimmune Diseases
Immune System Diseases
Rabeprazole
Itraconazole
Rifampin
Hydroxyitraconazole
Anti-Ulcer Agents
Gastrointestinal Agents
Proton Pump Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP3A Inhibitors
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers