A Randomized, Phase 2, Open-Label, Multicenter Study to Evaluate the Safety, Tolerability, and Activity of Belumosudil in Subjects With Idiopathic Pulmonary Fibrosis (IPF)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 76
- 试验地点
- 10
- 主要终点
- Efficacy: Mean Changes in FVC From Baseline to Week 24
研究概览
简要总结
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
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •A subject had to meet all of the following criteria to be eligible for the study:
- •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, high-resolution computerized tomography (HRCT) consistent with usual interstitial pneumonitis.
- •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.
- •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:
- •Intrauterine device plus 1 barrier method
- •Stable doses of hormonal contraception for ≥ 3 months (e.g., oral, injectible, implant, transdermal) plus 1 barrier method
- •2 barrier methods. Effective barrier methods were male or female condoms, diaphragms, and spermicides (creams or gels containing a chemical to kill sperm)
- •Have adequate bone marrow function:
- •Absolute neutrophil count > 1500/mm^3
- •Hemoglobin (Hb) > 9.0 g/L
- •Platelets > 100,000/mm^3
- •Willing to complete all study measurements and assessments in compliance with 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.
排除标准
- •A subject who met any of the following criteria was ineligible for the study:
- •Interstitial lung disease caused by conditions other than IPF
- •Severe concomitant illness limiting life expectancy (< 1 year)
- •DLCO < 30% predicted
- •Residual volume (RV) ≥ 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 infection or upper respiratory tract infection (URTI) 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 [PFTs])
- •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 (AST) and/or alanine aminotransferase (ALT) > 2.0 * upper limit of normal (ULN)
- •Hb < 75% of the lower limit of normal
- •Systolic blood pressure < 100 mmHg
- •Pregnant or breastfeeding female subject
- •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:
- •Immunosuppressive or cytotoxic drugs including cyclophosphamide and azathioprine
- •Antifibrotic drugs including pirfenidone, nintedanib, D-penicillamine, colchicine, tumor necrosis factor-alpha blockers, imatinib, and interferon-γ
- •Chronic use of N-acetylcysteine prescribed for IPF (> 600 mg/day)
- •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 belumosudil or known allergy/sensitivity to belumosudil 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 (e.g., St. John's Wort) or grapefruit/grapefruit juice within 14 days prior to the Week 1 Day 1 visit
研究组 & 干预措施
Belumosudil-R
Subjects receive two 200 mg tablets of belumosudil (400 mg) PO QD for 24 weeks. Subjects may also continue treatment with belumosudil 400 mg PO QD after 24 weeks.
No subject may receive more than 96 weeks of treatment with belumosudil
干预措施: Belumosudil (Drug)
BSC-R
Subjects receive best supportive care as determined by the physician. Subjects may later crossover to treatment with belumosudil 400 mg PO QD. No subject may receive more than 96 weeks of treatment with belumosudil.
干预措施: BSC (Other)
结局指标
主要结局
Efficacy: Mean Changes in FVC From Baseline to Week 24
时间窗: 24 weeks
Changes in the mean Forced Vital Capacity (FVC) from baseline at Week 24. Normal FVC-- Healthy males 20 to 60 years: 4.75 to 5.5 L; healthy females 20 to 60 years: 3.25 to 3.75 L
Safety: Percentages of Subjects With TEAEs Leading to Discontinuation of Treatment With Belumosudil
时间窗: Up to 96 weeks (Weeks 24, 48, and 96) of treatment with belumosudil
Percentage of subjects with treatment-emergent adverse events (TEAEs) leading to subjects discontinuing from treatment. Investigators assessed whether TEAEs leading to discontinuation were related to study drug (possibly, probably, or definitely), belumosudil 400 mg PO QD.
Efficacy: Mean Changes in FVC% Predicted From Baseline at Week 24
时间窗: 24 weeks
Changes in the mean Forced Vital Capacity (FVC)% Predicted from baseline at Week 24. Normal FVC%: 80% to 120%
Safety: Percentages of Subjects With Non-serious TEAEs and Relationship to Study Treatment
时间窗: 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.
Percentage of subjects with non-serious TEAEs by relationship to treatment with belumosudil, BSC, or belumosudil and BSC. Severity of TEAEs were measured using the Common Terminology Criteria for Adverse Events (CTCAE) version 22.1 (Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = fatal).
Safety: Percentages of Subjects With SAEs Related to Study Treatment
时间窗: 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.
Percentage of subjects with serious TEAEs by relationship to treatment with belumosudil and/or BSC. Investigators assessed whether events were related to treatment as possibly, probably, or definitely related.
Safety: Percentages of Subjects With Deaths Related to Study Treatment
时间窗: 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.
Percentage of subjects with deaths by relationship to treatment with belumosudil, BSC, or belumosudil and BSC. Investigators assessed whether events were related to treatment as possibly, probably, or definitely related.
次要结局
- Efficacy: Mean Change in Mean FEV1/FVC Ratio From Baseline at Weeks 24, 48, and 96 and EOT(Up to 96 weeks (Weeks 24, 48, and 96))
- Efficacy: Mean Change in 6MWD at Weeks 24, 48, and 96(Up to 96 weeks (Weeks 24, 48, and 96))
- Efficacy: Event-free Probability of First Respiratory-related Hospitalization(Up to 96 weeks (Weeks 24, 48, and 96))
- Efficacy: Mean Changes in FVC From Baseline at Week 48, Week 96, and EOT(Up to 96 weeks (Weeks 24, 48, and 96))
- Efficacy: Mean Changes in FVC% Predicted at Week 24 by GAP Stage and by Use of Pirfenidone or Nintedanib--(24 weeks)
- Efficacy: Percentage of Subjects With Decrease ≥ 10% in FVC% Predicted at Weeks 24, 48, and 96(Up to 96 weeks (Weeks 24, 48, and 96))
- Efficacy: Percentages of Subjects With ≥ 50 Meter Improvement in 6MWD at Weeks 24, 48, and 96(Up to 96 weeks (Weeks 24, 48, and 96))
- Efficacy: Mean Changes in DLCO (%) at Weeks 24, 48, and 96(Up to 96 weeks (Weeks 24, 48, and 96))
- Efficacy: Mean Changes in Total Lung Fibrosis Score, by HRCT, From Baseline at Weeks 24, 48, and 96(Up to 96 weeks (Weeks 24, 48, and 96))
- Efficacy: Categorical Changes in Lung Fibrosis as Observed by Sequential Scans of Radiologist Visual Assessment, From Baseline at Weeks 24, 48, and 96(Up to 96 weeks (Weeks 24, 48, and 96))
- Efficacy: Event-free Probability of Acute Exacerbation of IPF(Up to 96 weeks (Weeks 24, 48, and 96))
- Efficacy: Percentages of Subjects With Change From Baseline in DLCO (%) ≤ -15% at Weeks 24, 48, and 96(Up to 96 weeks (Weeks 24, 48, and 96))
- Efficacy: Changes in Mean DTA Lung Fibrosis Score, by Radiologist Visual Assessment, From Baseline at Weeks 24, 48, and 96(Up to 96 Weeks (Weeks 24, 48, and 96))
- Efficacy: Event-free Probability of Progression of IPF(Up to 96 weeks (Weeks 24, 48, and 96))
- Efficacy: Mean Changes in FVC From Baseline at Week 24 by GAP Stage and by Use of Pirfenidone or Nintedanib--(24 weeks)
- Efficacy: Percentages of Subjects With Decrease ≥ 5% in FVC% Predicted From Baseline at Weeks 24, 48, and 96(Up to 96 weeks (Weeks 24, 48, and 96))
- Efficacy: Event-free Probability of Respiratory-related Death(Up to 96 weeks (Weeks 24, 48, and 96))
- Efficacy: Mean Changes in SGRQ From Baseline at Weeks 24, 48 and 96(Up to 96 weeks (Weeks 24, 48, and 96))