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
Overview
- Phase
- Phase 2
- Intervention
- Epetraborole
- Conditions
- MAC Lung Disease
- Sponsor
- AN2 Therapeutics, Inc
- Enrollment
- 177
- Locations
- 91
- Primary Endpoint
- Phase 3: Percentage of Participants Achieving Clinical Response
- Status
- Terminated
- Last Updated
- 11 months ago
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
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
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
Arms & Interventions
epetraborole + OBR
epetraborole + Optimized Background Regimen
Intervention: Epetraborole
placebo + OBR
Placebo + Optimized Background Regimen
Intervention: Placebo
Outcomes
Primary Outcomes
Phase 3: Percentage of Participants Achieving Clinical Response
Time Frame: Baseline to Month 6
Detection of within-patient changes in symptoms reported in a novel Patient-Reported Outcome (PRO) instrument at Month 6
Phase 2: Adverse Event Profile of 500 mg Once Daily Dose of Epetraborole
Time Frame: Baseline to Month 16
Percentage of Participants reporting treatment emergent adverse events
Phase 2: Assessment of novel Patient Reported Outcome instrument psychometric properties
Time Frame: Screening (Day -14 to Day -7) to Month 6 + 1 week
Assessment of novel Patient Report outcomes
Phase 2: Percentage of Participants Achieving Clinical Response
Time Frame: Baseline to Month 6
Detection of within-patient changes in symptoms reported in a novel Patient-Reported Outcome (PRO) instrument at Month 3 and Month 6.
Secondary Outcomes
- Phase 3: Maximum plasma concentration (Cmax) of epetraborole(Day 1 and Day 29)
- Phase 2: Percentage of Participants Achieving Culture Conversion(Baseline to Month 6)
- Phase 2: Change from Baseline in QOL-B Respiratory Domain PRO(Baseline to Month 6)
- Phase 2: Volume of distribution (Vd) of epetraborole(Day 29)
- Phase 3: Percentage of Participants Achieving Culture Conversion(Baseline to Month 6)
- Phase 3: Percentage of Participants Achieving Microbiological Improvement(Baseline to Month 6)
- Phase 3: Change from Baseline in NTM Symptoms Module PRO(Baseline to Month 6)
- Phase 3: Percentage of Participants with Relapse(Month 6, End of Therapy and Late Follow-up)
- Phase 2: Percentage of Participants with Reinfection(Baseline to Month 16)
- Phase 3: Change from Baseline in QOL-B Respiratory Domain PRO(Baseline to Month 6)
- Phase 3: Adverse Event Profile of 500 mg Once Daily Dose of Epetraborole(Baseline to Month 16)
- Phase 2: Percentage of Participants Achieving Microbiological Improvement(Baseline to Month 6)
- Phase 2: Change from Baseline in NTM Symptoms Module PRO(Baseline to Month 6)
- Phase 2: Change from Baseline in SGRQ-C PRO(Baseline to Month 6)
- Phase 2: Concordance Analysis of PRO-based Clinical Response and Microbiological Response(Baseline to Month 6)
- Phase 2: Percentage of Participants with Relapse(Baseline to Month 16)
- Phase 2: Maximum plasma concentration (Cmax) of epetraborole(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(Day 29)
- Phase 3: Concordance Analysis of PRO-based Clinical Response and Microbiological Response(Baseline to Month 6)
- Phase 3: Area Under the Plasma Concentration-Time Curve from Time Point 0 Hours Until 24 hours [AUC(0-24)] post dose(Day 29)
- Phase 3: Volume of distribution (Vd) of epetraborole(Day 29)
- Phase 3: Change from Baseline in SGRQ-C PRO(Baseline to Month 6)
- Phase 3: Percentage of Participants with Reinfection(Baseline to Month 16)