Clinical trial NCT02688647: A 2-Part, Phase 2 Open-label and Crossover Study of Belumosudil for Treatment of Idiopathic Pulmonary Fibrosis
Official title: A Randomized, Phase 2, Open-Label, Multicenter Study to Evaluate the Safety, Tolerability, and Activity of Belumosudil in Subjects With Idiopathic Pulmonary Fibrosis (IPF)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Idiopathic Pulmonary Fibrosis
Keywords: Pulmonary Fibrosis
Fibrosis
Idiopathic Interstitial Pneumonias
Lung Diseases
Lead sponsor: Kadmon Corporation, LLC
Sponsor class: INDUSTRY
First posted: 2016-02-23
Enrollment: 76
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: In Part 1: Subjects are randomized to treatment with either Belumosudil 400 mg PO QD (Belumosudil-R) or to BSC (BSC-R).

In Part 2: Subjects who are randomized and receive Belumosudil 400 mg PO QD during Part 1 have the option to continue treatment with Belumosudil 400 mg PO QD and subjects randomized to BSC have the option to cross over to treatment with Belumosudil 400 mg PO QD.

No subject is permitted \> 96 weeks of treatment with belumosudil
Primary purpose: TREATMENT

Brief summary: This Phase 2 study is to be conducted to evaluate the safety, tolerability, and activity of 400 mg of belumosudil orally (PO) 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 belumosudil 400 mg PO QD in subjects with IPF compared to BSC
* Safety and tolerability of belumosudil 400 mg PO QD when administered for 24 weeks to subjects with IPF compared to BSC

Detailed description: Study KD025-207 is a Phase 2, randomized, 2-part, open-label, crossover study in subjects with IPF.

The purpose of the study is to evaluate the safety, tolerability, and activity of 400 mg of belumosudil administered orally (PO) every day (QD) compared to Best Standard of Care (BSC) in subjects with IPF who have previously been treated with or declined treatment with pirfenidone or nintedanib.

The primary objectives are to evaluate the change in Forced Vital Capacity (FVC), and the safety and tolerability from baseline to 24 weeks in subjects with IPF after dosing with belumosudil 400 mg PO QD compared to BSC.

Part 1: Randomized, Open-label for 24 Weeks

Approximately 81 eligible subjects with IPF are to be enrolled, in 10 to 15 sites, and randomized in a 2:1 ratio (belumosudil:BSC) to 1 of the following 2 groups:

* Belumosudil-R (Investigational Group): Belumosudil 400 mg PO QD for 24 weeks
* BSC-R (Control Group): BSC for 24 weeks

The study plan is for 54 subjects to be entered into the Belumosudil-R Treatment Group and 27 subjects into the BSC-R Treatment Group. This sample size provides over 90% power at the 2-sided 0.05 significance level to detect a 20% difference between treatment groups at 24 weeks in percentage change from baseline in FVC assuming a standard deviation (SD) in percentage change from baseline in FVC of 17%. The sample size of 54 subjects receiving belumosudil provides over 90% probability of ≥ 1 subject in the study experiencing an AE that had an underlying rate of ≥ 5%.

Part 2: Continuation of Belumosudil Therapy or Crossover to Belumosudil Therapy Subjects in the Belumosudil-R group who complete 24 weeks of treatment with belumosudil 400 mg PO QD have the option of continuing therapy with belumosudil 400 mg PO QD up to an additional 72 weeks if there are no safety signals and if clinical progress continues. No subject in the Belumosudil-R group is to be permitted to receive therapy with belumosudil greater than a total of 96 weeks.

Subjects in control group BSC-R who complete 24 weeks of BSC have the option of crossing over to therapy with belumosudil 400 mg PO QD for up to 96 weeks if there are no safety signals and if clinical progress continues. No subject in control group BSC-R is to be permitted to receive belumosudil 400 mg PO QD therapy greater than 96 weeks.

Follow-up Period:

Follow-up Visits are to occur 30 days (± 3 days) after the last dose of belumosudil during which subjects are to undergo safety assessments. (A Follow-up Visit is not necessary for subjects receiving BSC.)

Duration of Study for Individual Subjects:

1. Subjects randomized to belumosudil: total up to 104 weeks (4-week screening, 96-week treatment with belumosudil, and 4-week follow-up)
2. Subject randomized to BSC: total up to 128 weeks (4-week screening; up to 24-week treatment with BSC, 96-week treatment with belumosudil, and 4-week follow-up)

Efficacy Assessments

* FVC
* FVC% Predicted
* 6-minute Walking Distance (6MWD)
* Diffusing Capacity of Carbon Monoxide (DLCO)
* Lung Fibrosis (by HRCT and Radiologist's Visual Assessments)
* Time to Acute Exacerbation
* Time to Progression of IPF
* Time to Respiratory-related Hospitalization
* Time to Respiratory-related Death
* St. Georges Respiratory Questionnaire (SGRQ)

Biomarker Assessments

* Matrix Metalloproteinase-7 (MMP7)
* Chemokine Ligand 18 (CCL18)
* Surfactant Protein-D (SPD)

Safety Assessments

* Adverse event (AE)
* Serious adverse event (SAE)
* Physical examination (PE)
* Vital signs (VS)
* Clinical laboratory evaluations (hematology, chemistry, and urinalysis)
* Electrocardiogram (ECG)
* Reason for treatment discontinuation due to toxicity

Analyses

Efficacy and safety are to be analyzed at the end of Part 1 (Week 24) and for the Entire Treatment Period (Parts 1 and 2). Analyses of study subjects are to be grouped and defined as follows:

* Belumosudil-R: subjects randomized to belumosudil
* BSC-R: subjects randomized to BSC
* Belumosudil-WC: subjects randomized to belumosudil plus subjects randomized to BSC and who cross over to treatment with belumosudil
* BSC-NC: subjects randomized to BSC and who cross over to treatment with belumosudil but have data censored by the date of crossover

Eligibility criteria: Inclusion Criteria:

A subject had to meet all of the following criteria to be eligible for the study:

1. Adult male and postmenopausal/surgically sterilized female subjects at least 18 years of age (if female, was surgically sterilized \[i.e., total hysterectomy, or bilateral salpingo-oophorectomy\]).
2. Able to provide written informed consent before the performance of any study specific procedures.
3. 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, high-resolution computerized tomography (HRCT) consistent with usual interstitial pneumonitis.
4. Resting state pulse oximeter oxygen saturation (SpO2) ≥ 88% with or without supplemental oxygen, Forced Vital Capacity % (FVC%) ≥ 50% normal predicted value, and diffusing capcity (in the lung) of carbon monoxide (DLCO) ≥ 30% normal predicted value at baseline.
5. Men with partners of childbearing potential 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:

   1. Intrauterine device plus 1 barrier method
   2. Stable doses of hormonal contraception for ≥ 3 months (e.g., oral, injectible, implant, transdermal) plus 1 barrier method
   3. 2 barrier methods. Effective barrier methods were male or female condoms, diaphragms, and spermicides (creams or gels containing a chemical to kill sperm)
   4. Vasectomy.
6. Have adequate bone marrow function:

   1. Absolute neutrophil count \> 1500/mm\^3
   2. Hemoglobin (Hb) \> 9.0 g/L
   3. Platelets \> 100,000/mm\^3
7. Willing to complete all study measurements and assessments in compliance with protocol
8. 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:

A subject who met any of the following criteria was ineligible for the study:

1. Interstitial lung disease caused by conditions other than IPF
2. Severe concomitant illness limiting life expectancy (\< 1 year)
3. DLCO \< 30% predicted
4. Residual volume (RV) ≥ 120% predicted
5. Obstructive lung disease: Forced Expiratory Volume in 1 Second (FEV1/FVC ratio \< 0.70)
6. Documented sustained improvement of the subject's IPF condition up to 12 months before study entry with or without IPF-specific therapy
7. Pulmonary infection or upper respiratory tract infection (URTI) within 4 weeks before study entry
8. Acute or chronic impairment (other than dyspnea) limiting the ability to comply with study requirements (e.g., pulmonary function tests \[PFTs\])
9. Chronic heart failure with New York Heart Association Class III/IV or known left ventricular ejection fraction \< 25%
10. Moderate to severe hepatic impairment (i.e., Child-Pugh Class B or C)
11. Estimated creatinine clearance \< 30 mL/min
12. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \> 2.0 \* upper limit of normal (ULN)
13. Hb \< 75% of the lower limit of normal
14. Systolic blood pressure \< 100 mmHg
15. Pregnant or breastfeeding female subject
16. Men whose partner is pregnant or breastfeeding
17. Current drug or alcohol dependence
18. 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
19. Treatment with endothelin receptor antagonists within 4 weeks before study entry
20. Systemic treatment within 4 weeks before study entry with cyclosporine A or tacrolimus, everolimus, or sirolimus (calcineurin or mammalian target of rapamycin inhibitors)
21. Previous exposure to belumosudil or known allergy/sensitivity to belumosudil or any other Rho-associated protein kinase 2 (ROCK2) inhibitor
22. Planned treatment or treatment with another investigational drug within 4 weeks before study entry
23. Taking a medication with the potential for QTc prolongation
24. Taking a drug sensitive substrate of CYP enzymes
25. Taking a strong inducer of CYP3A4
26. Had consumed an herbal medication (e.g., St. John's Wort) or grapefruit/grapefruit juice within 14 days prior to the Week 1 Day 1 visit

Primary outcomes:
measure: Efficacy: Mean Changes in FVC From Baseline to Week 24
timeFrame: 24 weeks
measure: Efficacy: Mean Changes in FVC% Predicted From Baseline at Week 24
timeFrame: 24 weeks
measure: Safety: Percentages of Subjects With Non-serious TEAEs and Relationship to Study Treatment
timeFrame: Up to 96 weeks (Weeks 24, 48, and 96) of treatment with belumosudil. Subjects randomized to BSC had the option of crossing over at 24 weeks.
measure: Safety: Percentages of Subjects With SAEs Related to Study Treatment
timeFrame: Up to 96 weeks (Weeks 24, 48, and 96) of treatment with belumosudil. Subjects randomized to BSC and crossing over also up to 24 weeks of BSC.
measure: Safety: Percentages of Subjects With TEAEs Leading to Discontinuation of Treatment With Belumosudil
timeFrame: Up to 96 weeks (Weeks 24, 48, and 96) of treatment with belumosudil
measure: Safety: Percentages of Subjects With Deaths Related to Study Treatment
timeFrame: Up to 96 weeks (Weeks 24, 8, and 96) of treatment with belumosudil. Subjects randomized to BSC also had the option of crossing over to treatment with belumosudil at 24 weeks.
Secondary outcomes:
measure: Efficacy: Mean Changes in FVC From Baseline at Week 24 by GAP Stage and by Use of Pirfenidone or Nintedanib--
timeFrame: 24 weeks
measure: Efficacy: Mean Changes in FVC From Baseline at Week 48, Week 96, and EOT
timeFrame: Up to 96 weeks (Weeks 24, 48, and 96)
measure: Efficacy: Mean Change in Mean FEV1/FVC Ratio From Baseline at Weeks 24, 48, and 96 and EOT
timeFrame: Up to 96 weeks (Weeks 24, 48, and 96)
measure: Efficacy: Mean Changes in FVC% Predicted at Week 24 by GAP Stage and by Use of Pirfenidone or Nintedanib--
timeFrame: 24 weeks
measure: Efficacy: Percentages of Subjects With Decrease ≥ 5% in FVC% Predicted From Baseline at Weeks 24, 48, and 96
timeFrame: Up to 96 weeks (Weeks 24, 48, and 96)
measure: Efficacy: Percentage of Subjects With Decrease ≥ 10% in FVC% Predicted at Weeks 24, 48, and 96
timeFrame: Up to 96 weeks (Weeks 24, 48, and 96)
measure: Efficacy: Mean Change in 6MWD at Weeks 24, 48, and 96
timeFrame: Up to 96 weeks (Weeks 24, 48, and 96)
measure: Efficacy: Percentages of Subjects With ≥ 50 Meter Improvement in 6MWD at Weeks 24, 48, and 96
timeFrame: Up to 96 weeks (Weeks 24, 48, and 96)
measure: Efficacy: Mean Changes in DLCO (%) at Weeks 24, 48, and 96
timeFrame: Up to 96 weeks (Weeks 24, 48, and 96)
measure: Efficacy: Percentages of Subjects With Change From Baseline in DLCO (%) ≤ -15% at Weeks 24, 48, and 96
timeFrame: Up to 96 weeks (Weeks 24, 48, and 96)
measure: Efficacy: Mean Changes in Total Lung Fibrosis Score, by HRCT, From Baseline at Weeks 24, 48, and 96
timeFrame: Up to 96 weeks (Weeks 24, 48, and 96)
measure: Efficacy: Categorical Changes in Lung Fibrosis as Observed by Sequential Scans of Radiologist Visual Assessment, From Baseline at Weeks 24, 48, and 96
timeFrame: Up to 96 weeks (Weeks 24, 48, and 96)
measure: Efficacy: Changes in Mean DTA Lung Fibrosis Score, by Radiologist Visual Assessment, From Baseline at Weeks 24, 48, and 96
timeFrame: Up to 96 Weeks (Weeks 24, 48, and 96)
measure: Efficacy: Event-free Probability of Acute Exacerbation of IPF
timeFrame: Up to 96 weeks (Weeks 24, 48, and 96)
measure: Efficacy: Event-free Probability of Progression of IPF
timeFrame: Up to 96 weeks (Weeks 24, 48, and 96)
measure: Efficacy: Event-free Probability of First Respiratory-related Hospitalization
timeFrame: Up to 96 weeks (Weeks 24, 48, and 96)
measure: Efficacy: Event-free Probability of Respiratory-related Death
timeFrame: Up to 96 weeks (Weeks 24, 48, and 96)
measure: Efficacy: Mean Changes in SGRQ From Baseline at Weeks 24, 48 and 96
timeFrame: Up to 96 weeks (Weeks 24, 48, and 96)
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Pulmonary Associates, PA
state: Arizona
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Sacramento
country: United States
facility: UC Davis Medical Center, Division of Pulmonary/CC/SM
state: California
city: Clearwater
country: United States
facility: St. Francis Medical Institute
state: Florida
city: Kissimmee
country: United States
facility: Pulmonary Disease Specialists, PA, d/b/a PDS Research
state: Florida
city: Orlando
country: United States
facility: Central Florida Pulmonary Group, PA
state: Florida
city: Austell
country: United States
facility: Piedmont Healthcare Pulmonary and Critical Care Research
state: Georgia
city: Greensboro
country: United States
facility: Pulmonix, LLC
state: North Carolina
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
Study officials:
References: