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

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: NCT02688647
Recruitment Status : Active, not recruiting
First Posted : February 23, 2016
Last Update Posted : March 9, 2021
Sponsor:
Information provided by (Responsible Party):
Kadmon Corporation, LLC

Tracking Information
First Submitted Date  ICMJE February 18, 2016
First Posted Date  ICMJE February 23, 2016
Last Update Posted Date March 9, 2021
Actual Study Start Date  ICMJE May 2016
Estimated Primary Completion Date August 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 4, 2021)
  • Efficacy: Change in FVC from Baseline to Week 24 [ Time Frame: 24 weeks ]
    1. Forced Vital Capacity (FVC) from Baseline to Week 24;
    2. Group 3 (All KD025-treated) and Group 4 (best supportive care [BSC] without crossover);
    3. Group 1 (KD025 as randomized) and Group 4
  • Efficacy: Change in FVC% Predicted from Baseline to W24 [ Time Frame: 24 weeks ]
    1. Forced Vital Capacity Predicted (FVC%) from Baseline to Week 24;
    2. Group 3 (All KD025-treated) and Group 4;
    3. Group 1 (KD025 as randomized) and Group 4
Original Primary Outcome Measures  ICMJE
 (submitted: February 22, 2016)
  • Change in Forced Vital Capacity (FVC) in baseline to 24 weeks [ Time Frame: 24 weeks ]
    To evaluate the change in FVC from baseline to 24 weeks after dosing with KD025 400 mg QD in subjects with IPF compared with SOC. The change in FVC from baseline to 24 weeks will be evaluated through the pulmonary function test being conducted at baseline, end of week 12, end of week 24, end of week 36 and end of week 48. with SOC
  • Number of Subjects Experiencing Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 24 weeks ]
    To evaluate the safety and tolerability of KD025 400 mg QD when administered for 24 weeks to subjects with IPF compared to SOC
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 4, 2021)
  • Efficacy: Change in FVC from Baseline to Week 48 and Week 96 [ Time Frame: 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)
  • Efficacy: Change in 6-Minute Walking Distance (6MWD) [ Time Frame: 96 Weeks ]
    The distance traveled during 6 minutes will be measured from Baseline to Week 24, Week 48 and Week 96
  • Efficacy: DLCO (Corrected for Hb) [ Time Frame: 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;
  • Efficacy: Lung Fibrosis as Measured by Quantitative High Resolution Computer Tomography (HRCT) [ Time Frame: 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
  • Efficacy: Incidence of Acute Exacerbation of IPF [ Time Frame: 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.
  • Efficacy: Time to IPF Progression [ Time Frame: 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.
  • Efficacy: Time to First Respiratory-related Hospitalization [ Time Frame: 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.
  • Efficacy: Time to Respiratory-related Death [ Time Frame: 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.
  • Efficacy: St. George Respiratory Questionnaire [ Time Frame: 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.
  • Exploratory: Measurement of Biomarker MMP7 [ Time Frame: Up to 96 weeks ]
    Descriptive statistics (n, mean, SD, median, minimum, maximum) by treatment and study visit for modified metalloproteinase-7 (MMP7)
  • Exploratory: Measurement of Biomarker CCL 18 [ Time Frame: Up to 96 weeks ]
    Descriptive statistics (n, mean, SD, median, minimum, maximum) by treatment and study visit for chemokine ligand 18 (CCL 18)
  • Exploratory: Measurement of Biomarker SPD [ Time Frame: Up to 96 weeks ]
    Descriptive statistics (n, mean, SD, median, minimum, maximum) by treatment and study visit for surfactant protein-D (SPD)
  • Safety: Incidence of AEs Overall, by Intensity, and by Relation to Study Drug [ Time Frame: 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.
  • Safety: Incidence of SAE Overall and by Relation to Study Drug [ Time Frame: 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
  • Safety: Measurement of ECG Parameters [ Time Frame: 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)
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase 2 Study of the Activity and Safety of KD025 in Subjects With Idiopathic Pulmonary Fibrosis (IPF)
Official Title  ICMJE A Randomized, Phase 2, Open-Label, Multicenter Study to Evaluate the Safety, Tolerability, and Activity of KD025 in Subjects With Idiopathic Pulmonary Fibrosis (IPF)
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
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Idiopathic Pulmonary Fibrosis
Intervention  ICMJE
  • Drug: KD025
    Other Name: SLx-2119
  • Other: BSC
    Treatment/drug as determined by each subject's prescribing physician
    Other Name: Best standard of care
Study Arms  ICMJE
  • 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.
    Intervention: Drug: KD025
  • Best Supportive Care (BSC)
    Best supportive care is treatment and/or drug determined by each subject's prescribing physician.
    Intervention: Other: BSC
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: August 13, 2019)
76
Original Estimated Enrollment  ICMJE
 (submitted: February 22, 2016)
36
Estimated Study Completion Date  ICMJE August 2021
Estimated Primary Completion Date August 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02688647
Other Study ID Numbers  ICMJE KD025-207
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Kadmon Corporation, LLC
Study Sponsor  ICMJE Kadmon Corporation, LLC
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Kadmon Corporation, LLC
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP