Ground Truth
Inclusion Criteria:Adult male and postmenopausal/surgically sterilized female subjects at least 18 years of age (if female, is surgically sterilized [ie, 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 be consistent with usual interstitial pneumonitis.Resting state 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 (IUD) plus 1 barrier method; (b) stable doses of hormonal contraception for at least 3 months (eg, oral, injectable, implant, transdermal) plus 1 barrier method; (c) 2 barrier methods.
Effective barrier methods 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:ANC > 1500/mm3Hemoglobin > 9.0 g/LPlatelets > 100,000/mm3Willing to complete all study measurements and assessments in compliance with the protocolHas either received pirfenidone and/or nintedanib or has been 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 has not been given, then documentation that the patient was offered both treatments must be documented.Exclusion Criteria:Interstitial lung disease caused by conditions other than IPFSevere concomitant illness limiting life expectancy (< 1 year)Diffusing capacity of the lung for carbon monoxide (DLCO) < 30% predictedResidual volume ≥ 120% predictedObstructive lung disease: FEV1/ FVC ratio < 0.70Documented sustained improvement of the subject's IPF condition up to 12 months before study entry with or without IPF-specific therapyPulmonary or upper respiratory tract infection within 4 weeks before study entryAcute or chronic impairment (other than dyspnea) limiting the ability to comply with study requirements (eg, 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 (ie, Child-Pugh Class B or C)Estimated creatinine clearance < 30 mL/minAspartate aminotransferase (AST) and/or ALT > 2.0 × upper limit of normal (ULN)Hemoglobin < 75% of the lower limit of normalSystolic blood pressure < 100 mmHgMen whose partner is pregnant or breastfeedingCurrent drug or alcohol dependenceChronic treatment with the following drugs (within 4 weeks of study entry and during the study)Immunosuppressive or cytotoxic drugs including cyclophosphamide and azathioprineAntifibrotic drugs including pirfenidone, nintedanib, D penicillamine, colchicine, tumor necrosis factor α blockers, imatinib and interferon-γChronic use of N-acetylcysteine prescribed for IPF (> 600 mg/day)Oral anticoagulants prescribed for IPFTreatment with endothelin receptor antagonists within 4 weeks before study entrySystemic 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 ROCK2 inhibitorPlanned treatment, or treatment with another investigational drug within 4 weeks before study entrySubject is taking a medication that has the potential for QTc prolongation (see Appendix A)Subject is taking a drug that is a sensitive substrate of CYP enzymesSubject is taking an inhibitor or inducer of CYP3A4Subject has consumed an herbal medication (eg, St.
John's Wort) or grapefruit/grapefruit juice within 14 days prior to the Week 1, Day 1 visit
Prediction
Amended Eligibility Criteria (version 10):
Inclusion Criteria:
- Adult male and postmenopausal or surgically sterilized female subjects at least 18 years of age (if female, is surgically sterilized [ie, 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 be consistent with usual interstitial pneumonitis.
- Resting state 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 (IUD) plus 1 barrier method; (b) stable doses of hormonal contraception for at least 3 months (eg, oral, injectable, implant, transdermal) plus 1 barrier method; (c) 2 barrier methods.
Effective barrier methods 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: ANC > 1500/mm³, Hemoglobin > 9.0 g/L, Platelets > 100,000/mm³
- Willing to complete all study measurements and assessments in compliance with the protocol
- Has either received pirfenidone and/or nintedanib or has been 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 has not been given, then documentation that the patient was offered both treatments must be documented.
Exclusion Criteria:
- Interstitial lung disease caused by conditions other than IPF
- Severe concomitant illness limiting life expectancy (≥ 2 × upper limit of normal (ULN))
- Diffusing capacity of the lung for carbon monoxide (DLCO) < 30% predicted
- Residual volume ≥ 120% predicted
- Obstructive lung disease: 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
- Acute or chronic impairment (other than dyspnea) limiting the ability to comply with study requirements (eg, pulmonary function tests)
- Pulmonary or upper respiratory tract infection within 4 weeks before study entry
- Moderate to severe hepatic impairment (ie, Child-Pugh Class B or C)
- Estimated creatinine clearance < 30 mL/min
- Aspartate aminotransferase (AST) and/or ALT > 2.0 × upper limit of normal (ULN)
- Hemoglobin < 75% of the lower limit of normal
- Systolic blood pressure < 100 mmHg
- 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 α 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 KD025 or known allergy/sensitivity to KD025 or any other ROCK2 inhibitor
- Planned treatment, or treatment with another investigational drug within 4 weeks before study entry
- Subject is taking a medication that has the potential for QTc prolongation (see Appendix H)
- Subject is taking a drug that is a sensitive substrate of CYP enzymes
- Subject is taking a strong inducer of CYP3A4 (see Appendix F)
- Subject has consumed an herbal medication (eg, St.
John’s Wort) or grapefruit/grapefruit juice within 14 days prior to the Week 1, Day 1 visit
Test Drug: Oral KD025.
KD025 will be provided as 200-mg tablets.
Dosage and Administration: KD025 400 mg (two 200-mg tablets) will be administered orally QD.
Subjects should take KD025 within 5 minutes of completing a meal.