Study of Epetraborole in Patients With Treatment-refractory MAC Lung Disease

Study Overview
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Brief Summary
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This is a pivotal Phase 2/3, double-blind, placebo-controlled study of epetraborole + OBR (Optimized Background Regimen) versus placebo + OBR in patients with treatment-refractory MAC lung disease. This study will enroll adult patients with treatment-refractory MAC lung disease who meet all eligibility criteria (including clinical, radiographic, and microbiological criteria).

Detailed Description
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In the Phase 2 part of the study, approximately 80 patients will be randomized in a 1:1 ratio (40 patients receiving active epetraborole tablets and 40 patients receiving matching placebo tablets). The Phase 2 part of the study includes a blinded psychometric analysis plan to assess the psychometric properties of a novel PRO instrument. In addition, symptom-based clinical responses will be assessed using blinded data, to inform the measurement of clinical response in the Phase 3 part of the study. The Phase 3 part of the study will test the superiority of epetraborole + OBR compared to placebo + OBR. In this part of the study, approximately 234 patients are planned to be randomized in a 2:1 ratio (156 patients receiving active epetraborole tablets and 78 patients receiving matching placebo tablets). The current symptom-based clinical response definition (using the novel PRO) in Phase 3 is a placeholder to be verified after Phase 2 analyses based on data through Month 6. In addition, the Sponsor will determine if the sample size for Phase 3 should be adjusted and will verify the Phase 3 epetraborole dosage regimen based on the observed plasma epetraborole exposure. Phase 3 data analyses will include a review of patient-reported outcomes, microbiological, safety, and PK data collected at multiple time points through Month 6. Patients in Phase 3 will continue double-blinded study drug for 12 months after the first negative MAC culture that defines sputum culture conversion; study drug will be discontinued in patients who remain MAC culture positive despite 6 months of therapy with study drug.

Official Title
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A Phase 2/3, Randomized, Double-blind, Placebo-controlled, Multicenter, Prospective Study to Assess the Efficacy, Safety, and Pharmacokinetics of Orally Administered Epetraborole in Patients With Treatment-refractory Mycobacterium Avium Complex Lung Disease

Conditions
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MAC Lung Disease, Treatment Refractory MAC Lung Disease

Intervention / Treatment
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* Drug: Epetraborole
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients who are 18 years of age or older. Willing and able to provide written informed consent. Patients with a diagnosis of treatment-refractory MAC lung disease consisting of all of the following (a) Microbiological, (b) Clinical, and (c) Radiographic criteria: Microbiological criteria: One Pre-Study MAC-positive respiratory specimen. Documentation of a MAC positive specimen collected per standard of care within 6 months prior to signing the informed consent form (ICF). One Screening MAC-positive expectorated or induced sputum sample. Clinical criteria: At least 2 of the following patient-reported clinical symptoms: Cough with sputum production Cough without sputum Chest congestion Hemoptysis Dyspnea Fatigue Night sweats or unusual sweating Radiographic criteria: Non contrast Chest CT scan within 6 months prior to signing the ICF with abnormalities consistent with MAC lung disease. OBR criteria: An OBR is a combination regimen that consists of ≥2 antimycobacterial agents. The patient-specific OBR must be administered for a minimum duration of 6 consecutive months that is either ongoing at the time of Screening or was stopped or paused no more than 12 months before screening. The OBR regimen administered during Screening must be continued after randomization. Patients who are willing to comply with all the study activities and procedures throughout the duration of the study and comply with all planned study visits and study procedures from Screening through the LFU Visit. All patients must agree to use an effective method of birth control. Patients expected to survive with continued antimycobacterial therapy and appropriate supportive care from Screening through the LFU Visit, in the judgment of the Investigator. Exclusion Criteria: Patients with a presence of any suspected or confirmed disease or condition at Screening or the time of randomization that, in the opinion of the Investigator, may confound the assessment of symptom-based clinical response. Patients with active pulmonary malignancy or any malignancy that required or would require chemotherapy or radiation therapy within 1 year prior to randomization through the LFU Visit. Patients with creatinine clearance (CrCl) of ≤30 mL/min, as estimated by the Cockcroft Gault formula, at Screening. Patients with hemoglobin <10.0 g/dL or <6.2 mmol/L at Screening; donation of blood or plasma within 28 days prior to randomization; or symptomatic loss of blood or hemorrhage within 28 days prior to randomization. Patients with severe hemoptysis within 28 days prior to randomization, defined as >100 mL over any 24-hour period or severe or extremely severe hemoptysis. Patients with severe hepatic impairment, as evidenced by alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × upper limit of normal (ULN) or total bilirubin >2 × ULN, or clinical signs of cirrhosis or end-stage hepatic disease. Patients who are pregnant or breastfeeding. Patients with a mean QT interval corrected using Fridericia's formula (QTcF) >480 msec based on triplicate 12-lead ECGs at Screening. Patients with an immunodeficiency or an immunocompromised condition and risk for an opportunistic pulmonary infection. Patients with an anticipated start of new non-study antimycobacterial therapy to be administered at any time between Screening and Month 6. Patients who have received any investigational medication during the 30 days or 5 half-lives, whichever is longer, prior to randomization. Patients with any prior exposure to epetraborole. Patients with any condition that, in the opinion of the Investigator, interferes with the ability to safely complete the study or adhere to study requirements, including the patient's inability or unwillingness to comply with all study assessments and visits.

Ages Eligible for Study
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Minimum Age: 18 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: epetraborole + OBR<br>epetraborole + Optimized Background Regimen | Drug: Epetraborole<br>* 500 mg taken orally QD<br>* Other names: AN2-501971;|
| Placebo Comparator: placebo + OBR<br>Placebo + Optimized Background Regimen | Drug: Placebo<br>* Placebo taken orally QD<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Assessment of novel Patient Reported Outcome instrument psychometric properties | Assessment of novel Patient Report outcomes | Screening (Day -14 to Day -7) to Month 6 + 1 week | 
| Phase 2: Percentage of Participants Achieving Clinical Response | Detection of within-patient changes in symptoms reported in a novel Patient-Reported Outcome (PRO) instrument at Month 3 and Month 6. | Baseline to Month 6 | 
| Phase 2: Adverse Event Profile of 500 mg Once Daily Dose of Epetraborole | Percentage of Participants reporting treatment emergent adverse events | Baseline to Month 16 | 
| Phase 3: Percentage of Participants Achieving Clinical Response | Detection of within-patient changes in symptoms reported in a novel Patient-Reported Outcome (PRO) instrument at Month 6 | Baseline to Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Percentage of Participants Achieving Culture Conversion | Sputum conversion will be assessed using culture conversion based on 3 consecutive monthly negative sputum cultures for MAC by Month 6. | Baseline to Month 6 | 
| Phase 2: Percentage of Participants Achieving Microbiological Improvement | Microbiological improvement will be assessed at Month 3 and Month 6 using decrease in MAC colony counts of ≥1 category. | Baseline to Month 6 | 
| Phase 2: Change from Baseline in QOL-B Respiratory Domain PRO | Mean change from baseline in Quality of Life - Bronchiectasis (QOL-B) respiratory domain score measured monthly through Month 6. | Baseline to Month 6 | 
| Phase 2: Change from Baseline in NTM Symptoms Module PRO | Mean change from baseline in NTM Symptoms Module score measured monthly through Month 6. | Baseline to Month 6 | 
| Phase 2: Change from Baseline in SGRQ-C PRO | Mean change from baseline in total Saint George's Respiratory Questionnaire for COPD Patients (SGRQ-C) score measured monthly through Month 6 | Baseline to Month 6 | 
| Phase 2: Concordance Analysis of PRO-based Clinical Response and Microbiological Response | Concordance between clinical response in a novel Patient-Reported Outcome (PRO) instrument and microbiological response will be assessed at Months 3 and 6. Microbiological response will be assessed using both sputum culture conversion and microbiological improvement. | Baseline to Month 6 | 
| Phase 2: Percentage of Participants with Reinfection | By-subject reinfection will be assessed at Month 6, End of Therapy, and Late Follow-up. Reinfection is defined as a new pulmonary MAC infection caused by pathogen[s] different from the baseline MAC isolate. | Baseline to Month 16 | 
| Phase 2: Percentage of Participants with Relapse | By-subject relapse will be assessed at Month 6, End of Therapy, and Late Follow-up. Relapse is defined as a pulmonary MAC infection caused by the same baseline MAC isolate after initial culture conversion. | Baseline to Month 16 | 
| Phase 2: Maximum plasma concentration (Cmax) of epetraborole | Cmax is the maximum plasma concentration of epetraborole estimated by population PK model. | Day 1 and Day 29 | 
| 14. Phase 2: Area Under the Plasma Concentration-Time Curve from Time Point 0 Hours Until 24 hours [AUC(0-24)] post dose | AUC(0-24) is defined as area under the plasma concentration-time curve of epetraborole from timepoint 0 hours until 24 hours post dose estimated by population PK model. | Day 29 | 
| Phase 2: Volume of distribution (Vd) of epetraborole | Vd is the apparent volume of distribution of epetraborole estimated by population PK model. | Day 29 | 
| Phase 3: Percentage of Participants Achieving Culture Conversion | Sputum conversion will be assessed using culture conversion based on 3 consecutive monthly negative sputum cultures for MAC by Month 6. | Baseline to Month 6 | 
| Phase 3: Percentage of Participants Achieving Microbiological Improvement | Microbiological improvement will be assessed at Month 3 and Month 6 using decrease in MAC colony counts of ≥1 category. | Baseline to Month 6 | 
| Phase 3: Change from Baseline in QOL-B Respiratory Domain PRO | Mean change from baseline in Quality of Life - Bronchiectasis (QOL-B) respiratory domain score measured monthly through Month 6. | Baseline to Month 6 | 
| Phase 3: Change from Baseline in NTM Symptoms Module PRO | Mean change from baseline in NTM Symptoms Module score measured monthly through Month 6. | Baseline to Month 6 | 
| Phase 3: Change from Baseline in SGRQ-C PRO | Mean change from baseline in total Saint George's Respiratory Questionnaire for COPD Patients (SGRQ-C) score measured monthly through Month 6. | Baseline to Month 6 | 
| Phase 3: Concordance Analysis of PRO-based Clinical Response and Microbiological Response | Concordance between clinical response in a novel Patient-Reported Outcome (PRO) instrument and microbiological response will be assessed at Months 3 and 6. Microbiological response will be assessed using both sputum culture conversion and microbiological improvement | Baseline to Month 6 | 
| Phase 3: Percentage of Participants with Reinfection | By-subject reinfection will be assessed at Month 6, End of Therapy, and Late Follow-up. Reinfection is defined as a new pulmonary MAC infection caused by pathogen[s] different from the baseline MAC isolate. | Baseline to Month 16 | 
| Phase 3: Percentage of Participants with Relapse | By-subject relapse will be assessed at Month 6, End of Therapy, and Late Follow-up. Relapse is defined as a pulmonary MAC infection caused by the same baseline MAC isolate after initial culture conversion. | Month 6, End of Therapy and Late Follow-up | 
| Phase 3: Adverse Event Profile of 500 mg Once Daily Dose of Epetraborole | Percentage of Participants reporting treatment emergent adverse events. | Baseline to Month 16 | 
| Phase 3: Maximum plasma concentration (Cmax) of epetraborole | Cmax is the maximum plasma concentration of epetraborole estimated by population PK model. | Day 1 and Day 29 | 
| Phase 3: Area Under the Plasma Concentration-Time Curve from Time Point 0 Hours Until 24 hours [AUC(0-24)] post dose | AUC(0-24) is defined as area under the plasma concentration-time curve of epetraborole from timepoint 0 hours until 24 hours post dose estimated by population PK model. | Day 29 | 
| Phase 3: Volume of distribution (Vd) of epetraborole | Vd is the apparent volume of distribution of epetraborole estimated by population PK model. | Day 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mycobacterium Avium Complex, Treatment refractory NTM pulmonary disease, NTM, Respiratory Infection, antimycobacterial activity, antimycobacterial agent, antimycobacterial therapy, MAC infections, MAC lung disease, MAC lung infection, MAC pulmonary infection, Mycobacteria, mycobacterial disease, mycobacterium, Mycobacterium Avium Complex Infections, Mycobacterium avium complex lung disease, Mycobacterium Infections, Nontuberculous, Nontuberculous mycobacteria / mycobacterial / mycobacterium, Non-tuberculous mycobacteria disease, Non-tuberculous mycobacterial (NTM) infections, Nontuberculous mycobacterial lung disease, Non-tuberculous mycobacterial lung disease, Nontuberculous mycobacterial pulmonary disease, NTM infection, NTM lung disease, NTM Pulmonary Disease, NTM lung infection, Pulmonary MAC disease, Pulmonary MAC lung disease, Pulmonary Mycobacterium Avium Complex disease, Treatment refractory MAC lung disease, Treatment refractory mycobacterial lung disease, Treatment refractory NTM lung disease, Treatment refractory NTM lung infection