A Phase 2 Study of the Activity and Safety of KD025 in Subjects With Idiopathic Pulmonary Fibrosis (IPF)

Sponsor
Kadmon Corporation, LLC (Industry)
Overall Status
Completed
CT.gov ID
NCT02688647
Collaborator
(none)
76
10
2
59
7.6
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Study Details

Study Description

Brief Summary

This Phase 2 study will be conducted to evaluate the safety, tolerability, and activity of 400 mg of KD025 once-daily (QD) compared to Best Supportive Care (BSC) in male and postmenopausal/surgically sterilized female subjects with Idiopathic Pulmonary Fibrosis (IPF). The primary objectives are to evaluate the:

  • Change in forced vital capacity (FVC) from Baseline to 24 weeks after dosing with KD025 400 mg QD in subjects with IPF compared to BSC

  • Safety and tolerability of KD025 400 mg QD when administered for 24 weeks to subjects with IPF compared to BSC

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

This is a Phase 2, randomized, open-label, multicenter study in subjects with IPF who had either received pirfenidone and/or nintedanib or had been offered both treatments.

Approximately 81 eligible subjects with IPF will be randomly enrolled in a 2:1 ratio (KD025 to BSC) to 1 of 2 treatment groups:

  • Treatment Group 1 (Experimental): Receive KD025 400 mg orally QD for 24 weeks

  • Treatment Group 2 (Control): Receive BSC, deemed appropriate by the Investigator, for 24 weeks

Screening Period:

The Screening Period is up to 29 days prior to entry into the study.

Treatment Period:

After the Screening Visit, subjects will visit the site at Baseline (Week 1 Day 1), and the end of Weeks 4, 8, 12, 16, 20, and 24 (± 3 days). Subjects in Treatment Group 1 will receive their first dose of KD025 in the clinic on Week 1 Day 1. KD025 will then be dispensed for home administration.

Subjects in Treatment Group 1 who complete 24 weeks of treatment with KD025 400 mg QD will have the option of continuing therapy with KD025 400 mg QD up to an additional 72 weeks if there are no safety signals and if clinical progress continues. No subject in Treatment Group 1 is permitted to receive therapy with KD025 greater than a total of 96 weeks.

Subjects in Treatment Group 2 who complete 24 weeks of BSC will have the option of crossing over to therapy with KD025 400 mg QD for up to 96 weeks if there are no safety signals and if clinical progress continues. No subject in Treatment Group 2 is permitted to receive KD025 400 mg QD therapy greater than 96 weeks.

All subjects will undergo the same assessments.

Efficacy assessments include:
  • Pulmonary Function Tests (PFTs), which include FVC; residual volume (RV); and diffusing capacity of the lungs for carbon monoxide [DLCO]);

  • Six-minute walking distance (6MWD);

  • Frequency and severity of IPF exacerbation;

  • Time to acute exacerbation of IPF;

  • High-resolution computed tomography (HRCT);

  • St. George's Respiratory Questionnaire (SGRQ)

Safety assessments include:
  • Adverse events (AEs);

  • Serious adverse events (SAEs);

  • Physical examinations (PEs);

  • Vital sign (VS) measurements;

  • Clinical laboratory evaluations (hematology, chemistry, and urinalysis),

  • Electrocardiograms (ECGs);

  • Reasons for treatment discontinuation due to toxicity.

Exploratory assessments include biomarkers:
  • Matrix Metalloproteinase-7 (MMP7);

  • Chemokine Ligand 18 (CCL18);

  • Surfactant Protein-D (SPD).

Follow-up Period:

Follow-up Visits will occur 30 days (± 3 days) after the last dose of KD025. (A Follow-up Visit is not necessary for subjects receiving BSC.) Subjects will undergo the following safety assessments: complete PEs, VS measurements, weight measurements, AE assessments, concomitant medication and procedures assessments, blood sample collection for hematology (including coagulation), chemistry and thyroid function (TSH), pulmonary function tests (PFTs), and urinalysis. If another therapy is started within 30 days after the last dose of study drug, the Follow-up visit will be conducted before the start of the other therapy.

Duration of Treatment:
Treatment Group 1:

Subjects will receive KD025 400 mg QD for 24 weeks. After 24 weeks of therapy, subjects will have the option of continuing therapy with KD025 400 mg QD. Subjects who do not continue KD025 400 mg QD after 24 weeks will remain on study up to a total of 32 weeks: 4 weeks for screening, 24 weeks of treatment with KD025 400 mg QD, and 4 weeks of Follow-up.

Subjects who chose to continue therapy with KD025 400 mg QD after 24 weeks will be permitted to remain on-study up to a total of 104 weeks: a 4-week screening, 96-week treatment period with KD025 400 mg QD (an initial 24-week period and an additional 72-week period), and a 4-week Follow-up.

No subject will be permitted to receive more than 96 weeks of treatment with KD025 400 mg QD.

Treatment Group 2:

Subjects will receive BSC for 24 weeks, after which they will have the option to cross over to treatment with KD025 400 mg QD. Subjects who do not cross over will remained on-study up to 32 weeks: 4-week screening, 24-week BSC, and 4-week Follow-up.

Subjects who chose to crossover to KD025 400 mg QD therapy therapy are permitted to remain on-study up to 128 weeks: 4-week screening, 24-week BSC, 96-week treatment with KD025 400 mg QD, and 4-week Follow-up.

No subject will be permitted to receive more than 96 weeks of treatment with KD025 400 mg QD.

Study Design

Study Type:
Interventional
Actual Enrollment :
76 participants
Allocation:
Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Randomized, Phase 2, Open-Label, Multicenter Study to Evaluate the Safety, Tolerability, and Activity of KD025 in Subjects With Idiopathic Pulmonary Fibrosis (IPF)
Actual Study Start Date :
May 1, 2016
Actual Primary Completion Date :
Apr 1, 2021
Actual Study Completion Date :
Apr 1, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: KD025 400 mg Daily

Two 200 mg tablets (400 mg) KD025 QD. Subjects will take 2 tablets with their morning meal or within 5 minutes of completing a meal.

Drug: KD025
Other Names:
  • SLx-2119
  • belumosudil
  • Other: Best Supportive Care (BSC)

    Best supportive care is treatment and/or drug determined by each subject's prescribing physician.

    Other: BSC
    Treatment/drug as determined by each subject's prescribing physician
    Other Names:
  • Best standard of care
  • Outcome Measures

    Primary Outcome Measures

    1. Efficacy: Change in FVC from Baseline to Week 24 [24 weeks]

      Forced Vital Capacity (FVC) from Baseline to Week 24; Group 3 (All KD025-treated) and Group 4 (best supportive care [BSC] without crossover); Group 1 (KD025 as randomized) and Group 4

    2. Efficacy: Change in FVC% Predicted from Baseline to W24 [24 weeks]

      Forced Vital Capacity Predicted (FVC%) from Baseline to Week 24; Group 3 (All KD025-treated) and Group 4; Group 1 (KD025 as randomized) and Group 4

    Secondary Outcome Measures

    1. Efficacy: Change in FVC from Baseline to Week 48 and Week 96 [Up to 96 weeks]

      Forced Vital Capacity (FVC) from Baseline to Week 48 and Week 96 for Group 1 (KD025 as randomized for 24 weeks) and Group 3 (All KD025-treated subjects)

    2. Efficacy: Change in 6-Minute Walking Distance (6MWD) [96 Weeks]

      The distance traveled during 6 minutes will be measured from Baseline to Week 24, Week 48 and Week 96

    3. Efficacy: DLCO (Corrected for Hb) [24 weeks]

      Analyses as described for FVC at Week 24 for hemoglobin- (Hb-) corrected DLCO using the formula: DLCO Predicted Corrected = DLCO Predicted x (1.7 x Hb/[Age-Sex-Factor + Hb) where the age-sex factor was 9.38 for females of any age and children < 15 years old, and the age-sex factor was 10.22 for males >= 15 years old The cutoff criterion for the proportion calculation using a decline of 15% instead of 50 m;

    4. Efficacy: Lung Fibrosis as Measured by Quantitative High Resolution Computer Tomography (HRCT) [Up to 96 weeks]

      Change in severity of lung fibrosis will be measured by HRCT from Baseline to Week 24, Week 48, Week 72 and Week 96

    5. Efficacy: Incidence of Acute Exacerbation of IPF [Up to 96 weeks]

      Incidence of subjects who had an acute exacerbation of idiopathic pulmonary fibrosis (IPF) throughout treatment period by treatment group and compared by means of a Fisher's exact test on Week 24. Kaplan-Meier curves and descriptive statistics also will be used to summarize time to IPF exacerbation.

    6. Efficacy: Time to IPF Progression [Up to 96 weeks]

      Kaplan-Meier curves and descriptive statistics summarizing the time of idiopathic pulmonary fibrosis (IPF) progression. Log-rank testing for comparing treatment differences.

    7. Efficacy: Time to First Respiratory-related Hospitalization [Up to 96 weeks]

      Kaplan-Meier curves and descriptive statistics for summarizing the time to first respiratory-related hospitalization. Long-rank testing for comparing treatment differences.

    8. Efficacy: Time to Respiratory-related Death [Up to 96 weeks]

      Kaplan-Meier curves and descriptive statistics for summarizing the time to first respiratory-related death. Long-rank testing for comparing treatment differences.

    9. Efficacy: St. George Respiratory Questionnaire [Up to 96 weeks]

      The St. George Respiratory Questionnaire (SGRQ) is a standardized self-completed questionnaire for measuring impaired health and perceived well-being in airway diseases. The questionnaire contains multiple sections with differing scales associated with each question to assess how breathing is affecting the subject's life. SGRQ is measured at Baseline, Week 12, Week 24, Week 48, and Week 96.

    10. Exploratory: Measurement of Biomarker MMP7 [Up to 96 weeks]

      Descriptive statistics (n, mean, SD, median, minimum, maximum) by treatment and study visit for modified metalloproteinase-7 (MMP7)

    11. Exploratory: Measurement of Biomarker CCL 18 [Up to 96 weeks]

      Descriptive statistics (n, mean, SD, median, minimum, maximum) by treatment and study visit for chemokine ligand 18 (CCL 18)

    12. Exploratory: Measurement of Biomarker SPD [Up to 96 weeks]

      Descriptive statistics (n, mean, SD, median, minimum, maximum) by treatment and study visit for surfactant protein-D (SPD)

    13. Safety: Incidence of AEs Overall, by Intensity, and by Relation to Study Drug [Up to 104 weeks (96 weeks treatment + 30 day follow-up)]

      Incidence of adverse events (AEs), as measured by Common Terminology Criteria for Adverse Events (CTCAE) version 22.1, overall, by intensity, and by relationship to study drug.

    14. Safety: Incidence of SAE Overall and by Relation to Study Drug [Up to 104 weeks (96 weeks treatment + 30-day follow-up)]

      Incidence of serious adverse events (SAEs), as measured by CTCAE version 22.1, overall and relationship to study drug

    15. Safety: Measurement of ECG Parameters [Up to 104 weeks (96 weeks treatment + 30-day follow-up)]

      Measurement of digital 12-lead electrocardiogram (ECG) parameters during the study which include PR interval, QRS interval, and QTcF (QTc interval using Fridericia's correction)

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Adult male and postmenopausal/surgically sterilized female subjects at least 18 years of age (if female, was surgically sterilized [i.e., total hysterectomy, or bilateral salpingo-oophorectomy]).

    • Able to provide written informed consent before the performance of any study specific procedures.

    • IPF diagnosis within 5 years before study entry, proven according to the American Thoracic Society/European Respiratory Society consensus conference criteria, with surgical lung biopsy. In the absence of a surgical lung biopsy, HRCT must have been consistent with usual interstitial pneumonitis.

    • Resting state pulse oximeter oxygen saturation (SpO2) ≥ 88% with or without supplemental oxygen, FVC% ≥ 50% normal predicted value, and DLCO ≥ 30% normal predicted value at baseline.

    • Men with partners of childbearing potential must be willing to use 2 medically acceptable methods of contraception during the trial and for 3 months after the last dose of study drug. Effective birth control includes (a) intrauterine device plus 1 barrier method; (b) stable doses of hormonal contraception for at least 3 months (e.g., oral, injectible, implant, transdermal) plus 1 barrier method; (c) 2 barrier methods considered effective are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm); or (d) vasectomy.

    • Have adequate bone marrow function:

    1. Absolute neutrophil count > 1500/mm^3

    2. Hemoglobin > 9.0 g/L

    3. Platelets > 100,000/mm^3

    • Willing to complete all study measurements and assessments in compliance with the protocol

    • Had either received pirfenidone and/or nintedanib or offered both treatments (with last dose administered at least 1 month before the expected start of study drug dosing). If either or both pirfenidone and nintedanib treatment had not been given, then documentation that the subject was offered both treatments must have been documented.

    Exclusion Criteria:
    • Interstitial lung disease caused by conditions other than IPF

    • Severe concomitant illness limiting life expectancy (< 1 year)

    • DLCO < 30% predicted

    • Residual volume ≥ 120% predicted

    • Obstructive lung disease: Forced Expiratory Volume in 1 Second (FEV1_/ FVC ratio < 0.70

    • Documented sustained improvement of the subject's IPF condition up to 12 months before study entry with or without IPF-specific therapy

    • Pulmonary or upper respiratory tract infection within 4 weeks before study entry

    • Acute or chronic impairment (other than dyspnea) limiting the ability to comply with study requirements (e.g., pulmonary function tests)

    • Chronic heart failure with New York Heart Association Class III/IV or known left ventricular ejection fraction < 25%

    • Moderate to severe hepatic impairment (i.e., Child-Pugh Class B or C)

    • Estimated creatinine clearance < 30 mL/min

    • Aspartate aminotransferase and/or alanine aminotransferase > 2.0 × upper limit of normal

    • Hemoglobin < 75% of the lower limit of normal

    • Systolic blood pressure < 100 mmHg

    • Female subject who is pregnant or breastfeeding

    • Men whose partner is pregnant or breastfeeding

    • Current drug or alcohol dependence

    • Chronic treatment with the following drugs within 4 weeks of study entry and during the study:

    1. Immunosuppressive or cytotoxic drugs including cyclophosphamide and azathioprine

    2. Antifibrotic drugs including pirfenidone, nintedanib, D-penicillamine, colchicine, tumor necrosis factor-alpha blockers, imatinib, and interferon-γ

    3. Chronic use of N-acetylcysteine prescribed for IPF (> 600 mg/day)

    4. Oral anticoagulants prescribed for IPF

    • Treatment with endothelin receptor antagonists within 4 weeks before study entry

    • Systemic treatment within 4 weeks before study entry with cyclosporine A or tacrolimus, everolimus, or sirolimus (calcineurin or mammalian target of rapamycin inhibitors)

    • Previous exposure to KD025 or known allergy/sensitivity to KD025 or any other Rho-associated protein kinase 2 (ROCK2) inhibitor

    • Planned treatment or treatment with another investigational drug within 4 weeks before study entry

    • Taking a medication with the potential for QTc prolongation

    • Taking a drug sensitive substrate of CYP enzymes

    • Taking a strong inducer of CYP3A4

    • Had consumed an herbal medication (eg, St. John's Wort) or grapefruit/grapefruit juice within 14 days prior to the Week 1 Day 1 visit

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Pulmonary Associates, PA Phoenix Arizona United States 85006
    2 University of Arizona Tucson Arizona United States 85724
    3 UC Davis Medical Center, Division of Pulmonary/CC/SM Sacramento California United States 95817
    4 St. Francis Medical Institute Clearwater Florida United States 33765
    5 Pulmonary Disease Specialists, PA, d/b/a PDS Research Kissimmee Florida United States 34741
    6 Central Florida Pulmonary Group, PA Orlando Florida United States 32803
    7 Piedmont Healthcare Pulmonary and Critical Care Research Austell Georgia United States 30106
    8 Pulmonix, LLC Greensboro North Carolina United States 27403
    9 University of Pittsburgh Medical Center Pittsburgh Pennsylvania United States 15213
    10 Medical University of South Carolina Charleston South Carolina United States 29425

    Sponsors and Collaborators

    • Kadmon Corporation, LLC

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Kadmon Corporation, LLC
    ClinicalTrials.gov Identifier:
    NCT02688647
    Other Study ID Numbers:
    • KD025-207
    First Posted:
    Feb 23, 2016
    Last Update Posted:
    Jul 29, 2021
    Last Verified:
    Jul 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Kadmon Corporation, LLC
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Jul 29, 2021