A Study to Evaluate the Efficacy and Safety of CC-90001 in Subjects With Idiopathic Pulmonary Fibrosis

Study Overview
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Brief Summary
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This is a Phase 2, multicenter, multinational, randomized, double-blind, placebo-controlled study evaluating the efficacy, safety, pharmacokinetics (PK), quality of life and exploratory pharmacodynamics (PD) of two treatment doses of CC-90001, 200 mg and 400 mg, compared with placebo, when delivered once daily per os (PO) in subjects with idiopathic pulmonary fibrosis (IPF). This study is designed to assess response to treatment by using measures of lung function, disease progression, fibrosis on radiography, and patient-reported outcomes. It will also assess dose response.

Detailed Description
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Approximately 165 adult male and female subjects with a confirmed diagnosis of Idiopathic pulmonary fibrosis (IPF) (according to the most recent IPF guideline for diagnosis and management) will be randomized 1:1:1 (55 subjects per arm) to treatment with oral CC-90001or matching placebo for an initial 24 weeks. The randomization will be stratified based on the concurrent administration of SOC (Yes/No). Subjects completing the 24-week Double-blind Treatment Phase will continue onto the 80-week Active Treatment Extension Phase. At Week 24, all subjects originally randomized to receive placebo will be re-randomized 1:1 to blinded CC-90001 (200 mg or 400 mg PO QD). During the 80-week Active Treatment Extension Phase, all subjects not on concurrent SOC therapy will have the opportunity, if deemed appropriate by the Investigator, to receive allowed standard of care (SOC). The exploratory Progressive Pulmonary Fibrosis (PPF) sub study will evaluate the efficacy, safety, PK, quality of life and exploratory PD of one PO treatment dose regimen of CC-90001, compared with placebo, for an initial 24 weeks of treatment, in subjects with PPF and long-term safety in the 80-week Active Treatment Extension Phase when all PPF subjects will receive CC-90001. Approximately 45 non-SOC subjects will be randomized in this sub study. All subjects who complete the study treatment phases and those subjects who discontinue investigational product (IP) prior to the completion of the study will participate in the 4-week Post-treatment Observational Follow-up Phase. The study will be conducted in compliance with the International Council Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements. An external DMC, comprised of independent physician experts and a statistician who are not affiliated with the Sponsor and for whom there is no identified conflict of interest will be responsible for safeguarding study participants' interests and for monitoring the overall conduct of the study.

Official Title
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A Phase 2, 24-Week, Randomized, Double-blind, Placebo-controlled, Multicenter Study, With an 80-Week Active Treatment Extension, to Evaluate the Efficacy and Safety of CC-90001 in Subjects With Idiopathic Pulmonary Fibrosis

Conditions
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Idiopathic Pulmonary Fibrosis, Fibrosis, Idiopathic Interstitial Pneumonias, Pathologic Processes, Lung Diseases, Interstitial, Lung Diseases, Respiratory Tract Diseases

Intervention / Treatment
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* Drug: CC-90001
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject understands and has voluntarily signed and dated an informed consent form Subject is male or female ≥ 40 years of age Diagnosis of IPF is supported by HRCT and historical lung biopsy (surgical lung biopsy [SLB] or cryobiopsy) if available according to guidelines. No features supporting an alternative diagnosis on transbronchial biopsy, bronchoalveolar lavage (BAL), or SLB, if performed. Percent predicted forced vital capacity (% FVC) ≥ 45% and ≤ 95% at Screening Percent predicted diffusion capacity of the lung for carbon monoxide (DLCO) ≥ 25% and ≤ 90% predicted at Screening. Able to walk ≥ 150 meters during the 6-minute walk test (6MWT) at Screening Females of childbearing potential (FCBP) must commit to true abstinence or agree to use two effective birth control methods. Male subjects must practice true abstinence or use a barrier method of contraception. Additional inclusion criteria apply. Progressive Pulmonary Fibrosis (PPF) Sub-Study: Met all inclusion criteria described for IPF subjects other than Inclusion Criterion 5. Features of diffuse fibrosing lung disease of > 10% on HRCT by central reading. Investigator-documented ≥ 5% annualized relative decline in FVC in past 24 months from Screening Visit 1 Exclusion Criteria: The presence of any of the following will exclude a subject from enrollment: Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study. Subject with a QTcF > 450 msec. Evidence of clinically relevant airways obstruction at Screening. Subjects using therapy targeted to treat IPF. History of latent or active TB, unless there is medical record documentation of successful completion of a standard course of treatment History of hepatitis B and/or hepatitis C, including those considered successfully treated/cured Pregnancy or lactation. Additional exclusion criteria apply.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CC-90001 400 mg PO QD<br>55 subjects will be randomized to CC-90001 400mg | Drug: CC-90001<br>* CC-90001 is a potent, selective inhibitor of JNK.<br>|
| Experimental: CC-90001 200 mg PO QD<br>55 subjects will be randomized to CC-90001 200mg | Drug: CC-90001<br>* CC-90001 is a potent, selective inhibitor of JNK.<br>|
| Placebo Comparator: Placebo PO QD<br>55 subjects will be randomized to placebo | Other: Placebo<br>* Placebo<br>|
| Experimental: CC-90001 400 mg PO QD- Sub-Study<br>30 subjects will be randomized to CC-90001 400mg | Drug: CC-90001<br>* CC-90001 is a potent, selective inhibitor of JNK.<br>|
| Placebo Comparator: Placebo PO QD- Sub-Study<br>15 subjects will be randomized to placebo | Other: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Point Difference in % Predicted Forced Vital Capacity (FVC). | Mean change from baseline in percentage point difference in % predicted forced vital capacity (FVC) FAS population is defined as all randomized participants who received at least one dose of the investigational product. Baseline is defined as day 1 of treatment. | from baseline to week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Absolute Forced Vital Capacity (FVC). | Mean change from baseline in absolute FVC in the full analysis set (FAS) population. FAS population is defined as all randomized participants who received at least one dose of the investigational product. Baseline is defined as day 1 of treatment. | from baseline to week 24 | 
| Mean Change in Distance Walked in the 6-minute Walk Test (6MWT) | Mean change in distance walked in the 6-minute Walk Test (6MWT) The 6MWT measures the distance a participant is able to walk on a hard, flat surface, over a total of six minutes. The time points which will be measured are from baseline to Week 24, Extension Week 52, Extension Week 76, Extension Week 104, Week 24 to extension (Ext) Week 52 and Week 24 to Ext Week 104 FAS population is defined as all randomized participants who received at least one dose of the investigational product. Baseline is defined as day 1 of treatment. Week 24 is the start of baseline of the active treatment extension period. | From baseline up to week 104 | 
| Mean Change From Baseline in Dyspnea Rating on Borg Scale | Mean change from baseline in dyspnea rating on Borg Scale after the 6MWT. The Borg scale ranges from 0 to 10. Where 0 is no dyspnea and a 10 is extremely strong dyspnea. The lower the number the better. The time points which will be measured are from baseline to Week 24, Extension Week 52, Extension Week 76, Extension Week 104, Week 24 to extension (Ext) Week 52 and Week 24 to Ext Week 104 FAS population is defined as all randomized participants who received at least one dose of the investigational product. Baseline is defined as day 1 of treatment. Week 24 is the start of baseline of the active treatment extension period. | From baseline up to week 104 | 
| Percentage of Participants Who Had Disease Progression | Disease progression is defined as one or more of the following: Death from respiratory failure, Absolute decrease of ≥ 10% from baseline in % predicted FVC at two consecutive evaluations at a minimum of 4 weeks between evaluations Decrease from baseline of ≥ 50 meters in 6MWT distance (in the absence of a readily explainable cause, such as injury or trauma). Unexplained worsening hypoxemia (an absolute decrease from baseline of 4% or more in arterial oxygen saturation by pulse oximetry [SpO2]). FAS population is defined as all randomized participants who received at least one dose of the investigational product. Baseline is defined as day 1 of treatment. | From Baseline up to week 24 | 
| Mean Change From Baseline in Total Score and Domains on the Saint George's Respiratory Questionnaire (SGRQ) | The SGRQ is a quality of life health questionnaire that has been validated in IPF. It consists of 76 items in three domains: Symptoms Activity Impact of disease on daily life A total score is calculated from 0 (no health impairment) to 100 (maximum health impairment). In addition to the total score, there is also a score for each domain: symptoms, activity, and impact which are scored 0-100. Each component score is derived by dividing the summed weights, unique for all questions, by the maximum possible weight. | From Baseline up to week 24 | 
| Mean Change From Baseline in The University of California San Diego Shortness of Breath Questionnaire (UCSD-SOBQ) | The UCSD-SOBQ is a 24-item dyspnea questionnaire that asks participants to rate themselves from 0 (Not at all) to 5 (Maximally or unable to do because of breathlessness) in two areas: 1) how short of breath they are while performing various activities (21 items); and 2) how much shortness of breath, fear of hurting themselves by overexerting, and fear of shortness of breath limit them in their daily lives (3 items). If the subject does not routinely perform the activity, they are asked to estimate the degree of shortness of breath anticipated. The UCSD-SOBQ is scored by summing responses across all 24 items to form a total score. Scores range from 0 to 120. The lower the score the better. | From Baseline up to week 24 | 
| Number of Participants With Adverse Events at the End of the Active Treatment Phase | Number of participants with Adverse events at the end of the active treatment phase | From re-randomization to end of treatment (approximately 84 weeks) | 
| Number of Participants With Adverse Events in the Placebo Controlled Period | Number of participants with Adverse events | from baseline to re-randomization (approximately 56 weeks for the IPF cohort and 28 weeks for the PPF cohort) | 
| Number of Participants With Worst Changes in Hematology Laboratory Parameters During the Active Treatment Extension Period | Number of participants with worst changes in hematology laboratory parameters including: basophils, hemoglobin, lymphocytes, neutrophils and platelets. | From re-randomization to end of treatment (approximately 84 weeks) | 
| Number of Participants With Worst Changes in Hematology Laboratory Parameters During the in the Placebo Controlled Period | Number of participants with worst changes in hematology laboratory parameters including: basophils, hemoglobin, lymphocytes, neutrophils and platelets. | from baseline to re-randomization (approximately 56 weeks for the IPF cohort and 28 weeks for the PPF cohort) | 
| Number of Participants With a Change From Worst Post-baseline in Urinalysis Laboratory Analysis in the Active Treatment Extension Period | Number of participants who had a change from worst post- baseline in urinalysis laboratory analysis for the following measures: Erythrocytes, Leukocytes, Tubular Epithelial Cells | From re-randomization to end of treatment (approximately 84 weeks) | 
| Number of Participants With a Change From Worst Post-baseline in Urinalysis Laboratory Analysis in the Placebo Controlled Period | Number of participants who had a change from worst post- baseline in urinalysis laboratory analysis for the following measures: Erythrocytes, Leukocytes, Tubular Epithelial Cells | from baseline to re-randomization (approximately 56 weeks for the IPF cohort and 28 weeks for the PPF cohort) | 
| Mean Change From Baseline in Electrocardiogram Measurements in the Active Treatment Extension Period | Mean change from baseline in Electrocardiogram readings for the following measures: QT interval, QTcF interval, QTcB interval, PR interval, QRS duration and RR interval | From re-randomization to 4 week follow up after end of treatment (approximately 84 weeks) | 
| Mean Change From Baseline in Electrocardiogram Measurements in the Placebo Controlled Period | Mean change from baseline in Electrocardiogram readings for the following measures: QT interval, QTcF interval, QTcB interval, PR interval, QRS duration and RR interval | from baseline to week 24 | 
| Number of Participants With Worst Increase From Baseline in Blood Pressure in the Active Extension Period | Number of participants with worst increase from baseline in systolic and diastolic blood pressure. | From re-randomization to 4 week follow up after end of treatment (approximately 84 weeks) | 
| Number of Participants With Worst Increase From Baseline in Blood Pressure in the Placebo-controlled Period | Number of participants with worst increase from baseline in systolic and diastolic blood pressure. | from baseline to re-randomization (approximately 56 weeks for the IPF cohort and 28 weeks for the PPF cohort) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Idiopathic Pulmonary Fibrosis (IPF), Pulmonary Fibrosis, CC-90001, Efficacy, IPF, idiopathic pulmonary fibrosis, Safety