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

Sponsor
Kadmon Corporation, LLC (Industry)
Overall Status
Completed
CT.gov ID
NCT03530995
Collaborator
Quotient Sciences (Industry)
73
1
6
10
7.3

Study Details

Study Description

Brief Summary

This is a single-center, 2-part, non-randomized, open-label study of the drug-drug interactions of belumosudil (KD025) with itraconazole, rifampicin, rabeprazole, and omeprazole in healthy male subjects.

Detailed Description

Part 1:

The primary objective of Part 1 of this study is to determine the effect of itraconazole, rifampicin, and rabeprazole on the pharmacokinetics of once daily (QD) orally administered belumosudil in healthy male subjects. Part 1 consists of 4 periods.

In each study period, subjects will receive a single dose of belumosudil, in the fed state. Additionally, in order to assess the effects of inhibition and induction of CYP3A4 and the elevation of gastric pH on belumosudil 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.

Subjects will receive a total of 4 single oral dosses of investigative product (IP), 200 mg belumosudil QD, in the fed state over 4 periods (each lasting 3 days with a minimum washout of 2, 8, and 4 days following completion of Periods 1, 2, and 3, respectively). Subjects also will receive 9 single oral doses of itraconazole 200 mg (QD over 9 days) in Period 2; 7 single oral doses of rabeprazole 20 mg (BID over 3 days followed by QD on 1 day) in Period 3; and 9 single doses of rifampicin 600 mg (QD over 9 days) in Period 4.

A follow-up visit will take place 3 to 5 days post-final discharge.

Part 2:

The primary objective of Part 2 of this study is to determine the effect of omeprazole on the PK of a single-day twice daily (BID; every 12 hours [Q12h]) dose of belumosudil administered orally, in healthy male subjects. Part 2 consists of 2 periods.

In Period 1, subjects will receive a single dose of belumosudil, 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 belumosudil exposure, subjects will receive multiple doses of a proton pump inhibitor, omeprazole.

Subjects will receive a total of 4 single oral doses of IP (200 mg belumosudil, BID [Q12h] on 2 occasions) in the fed state over 2 periods (each lasting 3 days with a minimum washout of 2 days between dosing in Period 1 and the start of dosing with non-IP in Period 2). Subjects will also receive 4 single oral doses of omeprazole 20 mg (QD over 4 days) in Period 2.

A follow-up visit will take place 3 to 5 days post-final discharge.

Study Design

Study Type:
Interventional
Actual Enrollment :
73 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Intervention Model Description:
Two-Part, Non-RandomisedTwo-Part, Non-Randomised
Masking:
None (Open Label)
Primary Purpose:
Basic Science
Official Title:
A 2-Part, Non-randomized, Open-label Study to Evaluate the Effect of Itraconazole, Rifampicin, Rabeprazole, and Omeprazole on the Pharmacokinetics of Belumosudil (KD025)
Actual Study Start Date :
Apr 9, 2018
Actual Primary Completion Date :
Feb 8, 2019
Actual Study Completion Date :
Feb 8, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Part 1, Period 1

Drug: Belumosudil. Subjects will receive belumosudil 200 mg single dose on Day 1

Drug: Belumosudil
Development candidate
Other Names:
  • Rezurock
  • SLx-2119
  • Experimental: Part 1, Period 2

    Drug: Itraconazole. Subjects will receive itraconazole 200 mg QD on Day 1 through Day 7. Drug: Belumosudil. Subjects will receive belumosudil 200 mg + itraconazole 200 mg QD on Day 8 Subjects will receive itraconazole 200 mg QD on Day 9

    Drug: Belumosudil
    Development candidate
    Other Names:
  • Rezurock
  • 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: Belumosudil. Subjects will receive belumosudil 200 mg + rabeprazole 20 mg QD on Day 4.

    Drug: Belumosudil
    Development candidate
    Other Names:
  • Rezurock
  • 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: Belumosudil. Subjects will receive belumosudil 200 mg on Day 10.

    Drug: Belumosudil
    Development candidate
    Other Names:
  • Rezurock
  • SLx-2119
  • Drug: Rifampicin
    Perpetrator drug

    Experimental: Part 2, Period 1

    Drug: Belumosudil. Subjects will receive belumosudil 200 mg BID on Day 1.

    Drug: Belumosudil
    Development candidate
    Other Names:
  • Rezurock
  • SLx-2119
  • Experimental: Part 2, Period 2

    Drug: Omeprazole. Subjects will receive omeprazole 20 mg QD on Day 1 through Day 3. Drug: Belumosudil. Subjects will receive belumosudil 200 mg BID + omeprazole 20 mg QD on Day 4.

    Drug: Belumosudil
    Development candidate
    Other Names:
  • Rezurock
  • SLx-2119
  • Drug: Omeprazole
    Perpetrator drug

    Outcome Measures

    Primary Outcome Measures

    1. Pharmacokinetics: Cmax of KD025 and KD025m2 in Part 1 [Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,24,36, and 48 hours post-dose]

      Maximum concentration (Cmax) of the parent drug, KD025, Metabolite 1 (KD025m1), and Metabolite 2 (KD025m2) for belumosudil alone, belumosudil + itraconazole, belumosudil + rabeprazole, and belumosudil + rifampicin at 0 to 48 hours post-dose

    2. Pharmacokinetics: Cmax of KD025m1 in Part 1 [Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,24,36, and 48 hours post-dose]

      Maximum concentration (Cmax) of Metabolite 1 (KD025m1) for belumosudil alone and for belumosudil + rifampicin up to 48 hours post-dose

    3. Pharmacokinetics: Cmax of KD025, KD025m1, and KD025m2 in Part 2 [Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,12.5,13,13.5,14,15,16,17,18,20,22,24,36, and 48 hours post-dose]

      Maximum concentration (Cmax) of the parent drug (KD025), for Metabolite 1 (KD025m1), and for Metabolite 2 (KD025m2), for belumosudil alone and for belumosudil + omeprazole up to 48 hours post-dose

    4. Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2 [Part 1: Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,24,36, and 48 hours post-dose; Part 2: Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,12.5,13,13.5,14,15,16,17,18,20,22,24,36, and 48 hours post-dose]

      Area under concentration-time curve from zero hours to infinity (AUC[0-inf]) and from zero hours to 24 hours post-dose (AUC[0-24)) for the parent drug KD025, and Metabolite 2, KD025m2, for subjects up to 48 hours each for Part 1 and for Part 2

    5. Pharmacokinetics: AUC(0-24) of KD025m1 for Part 1 and for Part 2 [Part 1: Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12, and 24 hours post-dose; Part 2: Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,12.5,13,13.5,14,15,16,17,18,20,22, and 24 hours post-dose]

      Area under concentration-time curve from zero hours to 24 hours post-dose (AUC[0-24]) for Metabolite 1, KD025m1, for subjects in Part 1 and for subjects in Part 2

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 55 Years
    Sexes Eligible for Study:
    Male
    Accepts Healthy Volunteers:
    Yes
    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), electrocardiogram (ECG) and laboratory investigations (hematology, clinical chemistry, and urinalysis)

    4. Body weight ≥50 kg

    5. Body mass index of 18.0 to 32.0 kg/m^2 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 had previously participated in any other investigational study drug trial in which receipt of an IP occurred within 90 days prior to dosing. (Subjects who had previously received belumosudil in Part 1 at least 90 days prior to dosing in Part 2 were eligible to participate.)

    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 alanine aminotransaminase (ALT) or aspartate aminotransaminase (AST) > ULN

    • Renal disease and/or serum creatinine > ULN

    • Other condition known to interfere with the absorption, distribution, metabolism or excretion of drugs

    1. Subjects with a history of cholecystectomy or gall stones

    2. Subject has QT interval corrected using Fridericia's formula (QTcF) intervals >450 msec at screening or admission

    3. Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients; including intolerance to itraconazole, rabeprazole, and rifampicin

    4. Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hayfever is allowed unless it is active

    5. Donation or loss of greater than 400 mL of blood within the previous 3 months

    6. 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 IP administration.

    7. Failure to satisfy the investigator of fitness to participate for any other reason

    Subjects Agreed to the Following Restrictions During the Duration of the Study:
    1. No alcohol during the 24-hour period prior to screening and the 24-hour period prior to admission in Period 1, and 24 hours prior to commencing non-IP treatment in Part 1, Periods 2 to 4 and Part 2, Period 2, until discharge for each treatment period.

    2. No food or drinks containing grapefruit or cranberry from 24 hours prior to admission in Period 1, and 24 hours prior to commencing non-IP treatment in Part 1 Periods 2 to 4 and Part 2 Period 2, until discharge for each treatment period.

    3. No food or drinks containing caffeine or other xanthines from 24 hours prior to admission until discharge for each treatment period.

    4. No food containing poppy seeds for 48 hours prior to screening and for 24 hours prior to admission until discharge for each treatment period.

    5. No unaccustomed or strenuous exercise from the 72-hour period before the screening visit and then from 24 hours prior to admission until discharge for each treatment period.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Quotient Sciences Ltd Ruddington Nottingham United Kingdom NG11 6JS

    Sponsors and Collaborators

    • Kadmon Corporation, LLC
    • Quotient Sciences

    Investigators

    None specified.

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    Kadmon Corporation, LLC
    ClinicalTrials.gov Identifier:
    NCT03530995
    Other Study ID Numbers:
    • KD025-107
    • 2018-000316-16
    First Posted:
    May 21, 2018
    Last Update Posted:
    May 25, 2022
    Last Verified:
    May 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    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:

    Study Results

    Participant Flow

    Recruitment Details This was a single centre, non-randomised, open label, two-part study. Part 1 of the study was a 4-period sequential dose study in healthy male subjects. The estimated duration from screening to discharge from the study was approximately 10 weeks. Part 2 of the study was a 2-period sequential dose study in healthy males. The estimated duration from screening to discharge from the study was approximately 7 weeks.
    Pre-assignment Detail
    Arm/Group Title Part 1 Belumosudil (KD025) QD Dosing Part 2 Belumosudil (KD025) BID Dosing
    Arm/Group Description Subjects received a single dose of belumosudil 200 mg on 4 separate occasions, and multiple single doses of itraconazole, rabeprazole and rifampicin, on separate occasions, for 9,4 and 9 consecutive days, respectively. Subjects received a twice daily dose of belumosudil 200 mg on 2 separate occasions, and single doses of omeprazole for 4 consecutive days.
    Period Title: Part 1 Period 1; Part 2 Period 1
    STARTED 35 38
    COMPLETED 35 38
    NOT COMPLETED 0 0
    Period Title: Part 1 Period 1; Part 2 Period 1
    STARTED 35 38
    COMPLETED 35 38
    NOT COMPLETED 0 0
    Period Title: Part 1 Period 1; Part 2 Period 1
    STARTED 35 0
    COMPLETED 32 0
    NOT COMPLETED 3 0
    Period Title: Part 1 Period 1; Part 2 Period 1
    STARTED 32 0
    COMPLETED 30 0
    NOT COMPLETED 2 0

    Baseline Characteristics

    Arm/Group Title All Subjects Part 1: KD025 QD Dosing All Subjects in Part 2: KD025 BID Dosing Total
    Arm/Group Description Period 1: 200 mg KD025 QD alone; Period 2: 200 mg KD025 QD with Itraconazole; Period 3: 200 mg KD025 QD with Rabeprazole; Period 4: 200 mg KD025 QD with Rifampicin Period 1: 200 mg KD025 BID alone; Period 2: 200 mg KD025 BID with Omeprazole Total of all reporting groups
    Overall Participants 35 38 73
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    37.0
    (11.8)
    32.6
    (10.6)
    34.7
    (11.4)
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    0
    0%
    0
    0%
    Male
    35
    100%
    38
    100%
    73
    100%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    2
    5.7%
    1
    2.6%
    3
    4.1%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    4
    11.4%
    1
    2.6%
    5
    6.8%
    White
    28
    80%
    35
    92.1%
    63
    86.3%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    1
    2.9%
    1
    2.6%
    2
    2.7%
    BMI (body mass index) (kg/m^2) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kg/m^2]
    26.81
    (3.00)
    25.94
    (3.36)
    26.36
    (3.20)

    Outcome Measures

    1. Primary Outcome
    Title Pharmacokinetics: Cmax of KD025 and KD025m2 in Part 1
    Description Maximum concentration (Cmax) of the parent drug, KD025, Metabolite 1 (KD025m1), and Metabolite 2 (KD025m2) for belumosudil alone, belumosudil + itraconazole, belumosudil + rabeprazole, and belumosudil + rifampicin at 0 to 48 hours post-dose
    Time Frame Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,24,36, and 48 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Subject in Part 1 who received belumosudil alone, belumosudil with itraconazole, belumosudil with rabeprazole, and belumosudil with rifampicin. The number of subjects who participated in the study may differ from the number of subjects with an observation due to missing samples at critical timepoints or protocol deviations.
    Arm/Group Title Part 1, Period 1: Belumosudil Alone Part 1, Period 2: Belumosudil + Itraconazole Part 1, Period 3: Belumosudil + Rabeprazole Part 1, Period 4: Belumosudil + Rifampicin
    Arm/Group Description Belumosudil 200 mg single dose on Day 1 Itraconazole 200 mg QD on Day 1 through Day 7; Belumosudil 200 mg + Itraconazole 200 mg QD on Day 8; Itraconazole 200 mg QD on Day 9 Rabeprazole 20 mg BID on Day 1 through Day 3; Belumosudil 200 mg + Rabeprazole 20 mg QD on Day 4 Rifampicin 600 mg QD on Day 1-9; Belumosudil 200 mg on Day 10.
    Measure Participants 35 35 32 29
    Parent Drug KD025
    1770
    (31.3)
    2130
    (31.0)
    227
    (58.4)
    712
    (35)
    KD025m2
    337
    (54.7)
    221
    (60.8)
    23.5
    (70.7)
    148
    (57.3)
    2. Primary Outcome
    Title Pharmacokinetics: Cmax of KD025m1 in Part 1
    Description Maximum concentration (Cmax) of Metabolite 1 (KD025m1) for belumosudil alone and for belumosudil + rifampicin up to 48 hours post-dose
    Time Frame Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,24,36, and 48 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Subjects in Part 1 who received belumosudil alone and belumosudil with rifampicin. The number of subjects who participated in the study may differ from the number of subjects with an observation due to missing samples at critical timepoints or protocol deviations.
    Arm/Group Title Part 1, Period 1: Belumosudil Alone Part 1, Period 4: Belumosudil + Rifampicin
    Arm/Group Description Belumosudil 200 mg single dose on Day 1 Rifampicin 600 mg QD on Day 1-9; Belumosudil 200 mg on Day 10.
    Measure Participants 35 29
    Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
    23.2
    (40.0)
    52.5
    (34.0)
    3. Primary Outcome
    Title Pharmacokinetics: Cmax of KD025, KD025m1, and KD025m2 in Part 2
    Description Maximum concentration (Cmax) of the parent drug (KD025), for Metabolite 1 (KD025m1), and for Metabolite 2 (KD025m2), for belumosudil alone and for belumosudil + omeprazole up to 48 hours post-dose
    Time Frame Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,12.5,13,13.5,14,15,16,17,18,20,22,24,36, and 48 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Subjects in Part 2 who received belumosudil alone and belumosudil with omeprazole. The number of subjects who participated in the study may differ from the number of subjects with an observation due to missing samples at critical timepoints or protocol deviations.
    Arm/Group Title Part 2, Period 1: Belumosudil Alone Part 2, Period 2: Belumosudil + Omeprazole
    Arm/Group Description Belumosudil 200 mg BID (Q12h) on Day 1 Omeprazole 20 mg QD fasted for 3 days (Period 2 Days -3 to -1), Omeprazole 20 mg QD fasted + Belumosudil 200 mg BID (Q12h) fed on 4th day (Period 2 Day 1)
    Measure Participants 38 38
    Cmax--1st dose: KD025
    1790
    (34.5)
    575
    (145.7)
    Cmax--2nd dose: KD025
    1760
    (37.0)
    903
    (63.8)
    Cmax--1st Dose: KD025m1
    23.8
    (39.6)
    18.0
    (54.6)
    Cmax--2nd Dose: KD025m1
    23.6
    (46.4)
    18.9
    (48.7)
    Cmax--1st Dose: KD025m2
    282
    (75.6)
    72.3
    (166.8)
    Cmax--2nd Dose: KD025m2
    257
    (83.9)
    115
    (121.8)
    4. Primary Outcome
    Title Pharmacokinetics: AUC(0-inf) and AUC(0-24) of KD025 and KD025 m2 for Subject in Part 1 and Part 2
    Description Area under concentration-time curve from zero hours to infinity (AUC[0-inf]) and from zero hours to 24 hours post-dose (AUC[0-24)) for the parent drug KD025, and Metabolite 2, KD025m2, for subjects up to 48 hours each for Part 1 and for Part 2
    Time Frame Part 1: Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,24,36, and 48 hours post-dose; Part 2: Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,12.5,13,13.5,14,15,16,17,18,20,22,24,36, and 48 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Subjects in Part 1 who received belumosudil alone, belumosudil with itraconazole, belumosudil with rabeprazole, and belumosudil with rifampicin; Subjects in Part 2 who received belumosudil alone and belumosudil with omeprazole. The number of subjects who participated in the study may differ from the number of subjects with an observation due to missing samples at critical timepoints or protocol deviations.
    Arm/Group Title Part 1, Period 1: Belumosudil Alone Part 1, Period 2: Belumosudil + Itraconazole Part 1, Period 3: Belumosudil + Rabeprazole Part 1, Period 4: Belumosudil + Rifampicin Part 2, Period 1: Belumosudil Only Part 2, Period 2: Belumosudil + Omeprazole
    Arm/Group Description Belumosudil 200 mg single dose on Day 1 Itraconazole 200 mg QD on Day 1-7; Belumosudil 200 mg + Itraconazole 200 mg QD on Day 8; Itraconazole 200 mg QD on Day 9 Rabeprazole 20 mg BID on Day 1-3; Belumosudil 200 mg + Rabeprazole 20 mg QD on Day 4. Rifampicin 600 mg QD on Day 1-9; Belumosudil 200 mg on Day 10 Belumosudil 200 mg BID (Q12h) fed on a single day, Period 1 Day 1 Omeprazole 20 mg QD fasted for 3 days (Period 2, Days -3 to -1); Omeprazole 20 mg QD fasted + Belumosudil 200 mg BID (Q12h) fed on 4th day (Period 2 Day 1)
    Measure Participants 35 35 32 29 38 38
    AUC(0-inf): KD025
    9080
    (33.3)
    11200
    (38.1)
    1680
    (65.8)
    2500
    (34.5)
    18800
    (37.1)
    9880
    (59.2)
    AUC(0-inf): KD025m2
    1230
    (69.5)
    843
    (73.7)
    174
    (11.1)
    396
    (50.2)
    1900
    (90.4)
    1110
    (30.3)
    AUC(0-24): KD025
    8430
    (30.5)
    10400
    (35.8)
    1510
    (60.7)
    2490
    (34.1)
    16800
    (36.4)
    7970
    (58.9)
    AUC(0-24): KD025m2
    1100
    (63.7)
    745
    (70.7)
    110
    (84.0)
    376
    (56.7)
    1950
    (82.3)
    767
    (115.3)
    5. Primary Outcome
    Title Pharmacokinetics: AUC(0-24) of KD025m1 for Part 1 and for Part 2
    Description Area under concentration-time curve from zero hours to 24 hours post-dose (AUC[0-24]) for Metabolite 1, KD025m1, for subjects in Part 1 and for subjects in Part 2
    Time Frame Part 1: Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12, and 24 hours post-dose; Part 2: Pre-dose and 0.5,1,1.5,2,3,4,5,6,8,10,12,12.5,13,13.5,14,15,16,17,18,20,22, and 24 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Subjects in Part 1 who received belumosudil alone and belumosudil with rifampicin; Subjects in Part 2 who received belumosudil alone and belumosudil with omeprazole. The number of subjects who participated in the study may differ from the number of subjects with an observation due to missing samples at critical timepoints or protocol deviations.
    Arm/Group Title Part 1, Period 1: Belumosudil Alone Part 1, Period 4: Belumosudil + Rifampicin Part 2, Period 1: Belumosudil Alone Part 2, Period 2: Belumosudil + Omeprazole
    Arm/Group Description Belumosudil 200 mg single dose on Day 1 Rifampicin 600 mg QD on Day 1-9; Belumosudil 200 mg on Day 10. Belumosudil 200 mg BID (Q12h) fed on a single day, Period 1 Day 1 Omeprazole 20 mg QD fasted for 3 days (Period 2, Days -3 to -1); Omeprazole 20 mg QD fasted + Belumosudil 200 mg BID (Q12h) fed on 4th day (Period 2 Day 1)
    Measure Participants 27 29 35 15
    Geometric Mean (Geometric Coefficient of Variation) [(ng*h)/mL]
    75.6
    (42.1)
    148
    (41.9)
    138
    (91.3)
    91.5
    (76.3)

    Adverse Events

    Time Frame Part 1, Period 1: 1 day Part 1, Period 2: 9 days Part 1, Period 3: 4 days Part 1, Period 4: 10 days Part 2, Period 1: 1 day Part 2, Period 2: 4 days
    Adverse Event Reporting Description
    Arm/Group Title Part 1, Period 1: Belumosudil Only Part 1, Period 2: Belumosudil + Itraconazole Part 1, Period 3: Belumosudil +Rabeprazole Part 1, Period 4: Belumosudil + Rifampicin Part 2, Period 1: Belumosudil Only Part 2, Period 2: Belumosudil + Omeprazole
    Arm/Group Description Belumosudil 200 mg single dose on Day 1 Itraconazole 200 mg QD Day 1-7, Belumosudil 200 mg QD with itraconazole on Day 8, Itraconazole 200 mg QD on Day 9 Rabeprazole 20 mg BID on Day 1-3, Belumosudil 200 mg + rabeprazole 20 mg QD on Day 4 Rifampicin 600 mg QD on Day 1-9, Belumosudil 200 mg on Day 10 Belumosudil 200 mg BID (Q12h) fed on a single day, Period 1 Day 1: KD025 200 mg BID Omeprazole 20 mg QD fasted for 3 days (Period 2 Days -3 to -10, Omeprazole 20 mg QD fasted + Belumosudil 200 mg BID (Q12h) fed on 4th day (Period 2 Day 1)
    All Cause Mortality
    Part 1, Period 1: Belumosudil Only Part 1, Period 2: Belumosudil + Itraconazole Part 1, Period 3: Belumosudil +Rabeprazole Part 1, Period 4: Belumosudil + Rifampicin Part 2, Period 1: Belumosudil Only Part 2, Period 2: Belumosudil + Omeprazole
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/35 (0%) 0/35 (0%) 0/33 (0%) 0/32 (0%) 0/38 (0%) 0/38 (0%)
    Serious Adverse Events
    Part 1, Period 1: Belumosudil Only Part 1, Period 2: Belumosudil + Itraconazole Part 1, Period 3: Belumosudil +Rabeprazole Part 1, Period 4: Belumosudil + Rifampicin Part 2, Period 1: Belumosudil Only Part 2, Period 2: Belumosudil + Omeprazole
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/35 (0%) 1/35 (2.9%) 0/33 (0%) 0/32 (0%) 0/38 (0%) 0/38 (0%)
    Injury, poisoning and procedural complications
    Ankle fracture 0/35 (0%) 0 1/35 (2.9%) 1 0/33 (0%) 0 0/32 (0%) 0 0/38 (0%) 0 0/38 (0%) 0
    Other (Not Including Serious) Adverse Events
    Part 1, Period 1: Belumosudil Only Part 1, Period 2: Belumosudil + Itraconazole Part 1, Period 3: Belumosudil +Rabeprazole Part 1, Period 4: Belumosudil + Rifampicin Part 2, Period 1: Belumosudil Only Part 2, Period 2: Belumosudil + Omeprazole
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 6/35 (17.1%) 9/35 (25.7%) 6/33 (18.2%) 8/32 (25%) 9/38 (23.7%) 5/38 (13.2%)
    Blood and lymphatic system disorders
    Neutropenia 0/35 (0%) 0 0/35 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 0/38 (0%) 0 0/38 (0%) 0
    Eye disorders
    Ocular hyperaemia 0/35 (0%) 0 0/35 (0%) 0 1/33 (3%) 1 0/32 (0%) 0 0/38 (0%) 0 0/38 (0%) 0
    Gastrointestinal disorders
    Abdominal distension 3/35 (8.6%) 3 0/35 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/38 (0%) 0 0/38 (0%) 0
    Diarrhoea 0/35 (0%) 0 1/35 (2.9%) 1 1/33 (3%) 1 0/32 (0%) 0 1/38 (2.6%) 1 0/38 (0%) 0
    Constipation 0/35 (0%) 0 1/35 (2.9%) 1 0/33 (0%) 0 0/32 (0%) 0 0/38 (0%) 0 0/38 (0%) 0
    Dyspepsia 0/35 (0%) 0 1/35 (2.9%) 1 0/33 (0%) 0 0/32 (0%) 0 0/38 (0%) 0 0/38 (0%) 0
    Nausea 0/35 (0%) 0 1/35 (2.9%) 1 0/33 (0%) 0 0/32 (0%) 0 0/38 (0%) 0 0/38 (0%) 0
    Toothache 0/35 (0%) 0 1/35 (2.9%) 1 0/33 (0%) 0 0/32 (0%) 0 0/38 (0%) 0 0/38 (0%) 0
    Abdominal pain lower 0/35 (0%) 0 0/35 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/38 (2.6%) 1 0/38 (0%) 0
    Vomiting 0/35 (0%) 0 0/35 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/38 (2.6%) 1 0/38 (0%) 0
    General disorders
    Fatigue 0/35 (0%) 0 0/35 (0%) 0 1/33 (3%) 1 1/32 (3.1%) 1 0/38 (0%) 0 0/38 (0%) 0
    Medical device site rash 1/35 (2.9%) 1 0/35 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/38 (0%) 0 0/38 (0%) 0
    Vessel puncture site bruise 0/35 (0%) 0 0/35 (0%) 0 1/33 (3%) 1 0/32 (0%) 0 0/38 (0%) 0 0/38 (0%) 0
    Catheter site related reaction 0/35 (0%) 0 0/35 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/38 (2.6%) 1 0/38 (0%) 0
    Feeling hot 0/35 (0%) 0 0/35 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/38 (2.6%) 1 0/38 (0%) 0
    Immune system disorders
    Seasonal allergy 0/35 (0%) 0 1/35 (2.9%) 1 0/33 (0%) 0 1/32 (3.1%) 1 0/38 (0%) 0 0/38 (0%) 0
    Infections and infestations
    Hordeolum 1/35 (2.9%) 1 0/35 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/38 (0%) 0 0/38 (0%) 0
    Paronychia 0/35 (0%) 0 0/35 (0%) 0 1/33 (3%) 1 0/32 (0%) 0 0/38 (0%) 0 0/38 (0%) 0
    Upper respiratory tract infection 1/35 (2.9%) 1 0/35 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/38 (0%) 0 0/38 (0%) 0
    Nasopharyngitis 0/35 (0%) 0 0/35 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/38 (0%) 0 3/38 (7.9%) 3
    Viral upper respiratory tract infection 0/35 (0%) 0 0/35 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 0/38 (0%) 0 1/38 (2.6%) 1
    Injury, poisoning and procedural complications
    Ankle fracture 0/35 (0%) 0 1/35 (2.9%) 1 0/33 (0%) 0 0/32 (0%) 0 0/38 (0%) 0 0/38 (0%) 0
    Back injury 0/35 (0%) 0 0/35 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 0/38 (0%) 0 0/38 (0%) 0
    Laceration 0/35 (0%) 0 0/35 (0%) 0 0/33 (0%) 0 1/32 (3.1%) 1 0/38 (0%) 0 0/38 (0%) 0
    Musculoskeletal and connective tissue disorders
    Back pain 0/35 (0%) 0 2/35 (5.7%) 2 0/33 (0%) 0 0/32 (0%) 0 0/38 (0%) 0 0/38 (0%) 0
    Myalgia 0/35 (0%) 0 1/35 (2.9%) 1 0/33 (0%) 0 0/32 (0%) 0 0/38 (0%) 0 0/38 (0%) 0
    Nervous system disorders
    Headache 1/35 (2.9%) 1 1/35 (2.9%) 1 1/33 (3%) 1 3/32 (9.4%) 3 6/38 (15.8%) 6 1/38 (2.6%) 1
    Somnolence 0/35 (0%) 0 2/35 (5.7%) 2 0/33 (0%) 0 1/32 (3.1%) 1 0/38 (0%) 0 0/38 (0%) 0
    Presyncope 0/35 (0%) 0 0/35 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/38 (2.6%) 1 0/38 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis 1/35 (2.9%) 1 1/35 (2.9%) 1 0/33 (0%) 0 0/32 (0%) 0 0/38 (0%) 0 0/38 (0%) 0
    Rhinorrhoea 0/35 (0%) 0 0/35 (0%) 0 0/33 (0%) 0 0/32 (0%) 0 1/38 (2.6%) 1 0/38 (0%) 0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis 0/35 (0%) 0 1/35 (2.9%) 1 0/33 (0%) 0 0/32 (0%) 0 0/38 (0%) 0 0/38 (0%) 0
    Miliaria 0/35 (0%) 0 0/35 (0%) 0 1/33 (3%) 1 0/32 (0%) 0 0/38 (0%) 0 0/38 (0%) 0
    Vascular disorders
    Hot flush 0/35 (0%) 0 1/35 (2.9%) 1 0/33 (0%) 0 0/32 (0%) 0 0/38 (0%) 0 0/38 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding results. The sponsor cannot require changes to the study results in the communication except to remove sponsor's confidential information. Sponsor cannot unilaterally extend the embargo.

    Results Point of Contact

    Name/Title Olivier Schueller, Senior Vice President, CMC & Clinical Pharmacology
    Organization Kadmon Corporation
    Phone 833-900-5366
    Email olivier.schueller@kadmon.com
    Responsible Party:
    Kadmon Corporation, LLC
    ClinicalTrials.gov Identifier:
    NCT03530995
    Other Study ID Numbers:
    • KD025-107
    • 2018-000316-16
    First Posted:
    May 21, 2018
    Last Update Posted:
    May 25, 2022
    Last Verified:
    May 1, 2022