Study of Epetraborole in Patients With Treatment-refractory MAC Lung Disease
Study Details
Study Description
Brief Summary
This 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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2/Phase 3 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: epetraborole + OBR epetraborole + Optimized Background Regimen |
Drug: Epetraborole
500 mg taken orally QD
Other Names:
|
| Placebo Comparator: placebo + OBR Placebo + Optimized Background Regimen |
Drug: Placebo
Placebo taken orally QD
|
Outcome Measures
Primary Outcome Measures
- Phase 2: Change from baseline to month 6 of novel Patient Reported Outcome instrument [Baseline to Month 6]
Detection of within-patient changes in symptoms reported in a novel Patient-Reported Outcome (PRO) instrument bewteen baseline and month 6.
- Phase 3: Change from baseline to month 6 of novel Patient Reported Outcome instrument [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.
- Phase 2: Adverse Event Profile of 500 mg Once Daily Dose of epetraborole [Up to Month 16]
Number of Participants with indicated Adverse Events in subjects receiving 500 mg Once Daily Dose of epetraborole
Secondary Outcome Measures
- Phase 2: Percentage of Participants Achieving Culture Conversion at Month 6 [Up to Month 6]
By-subject sputum conversion monthly through Month 6 in the Micro-ITT Population. Sputum conversion will be assessed using culture conversion based on 3 consecutive monthly negative sputum cultures for MAC.
- Phase 2: Microbiological changes [Baseline to Month 6]
By-subject microbiological changes monthly through Month 6 in the Micro-ITT Population. Microbiological changes will be assessed using decrease in MAC colony counts of ≥1 category
- Phase 3: Microbiological changes [Baseline to Month 6]
By-subject microbiological changes monthly through Month 6 in the Micro-ITT Population. Microbiological changes will be assessed using decrease in MAC colony counts of ≥1 category
- Phase 2: PK analysis of volume of distribution [Vd] [One month]
To evaluate the volume of distribution [Vd] in epetraborole recipients in the PK Population
- Phase 2: PK analysis of maximum plasma drug concentration [Cmax] [One month]
To evaluate the maximum plasma drug concentration [Cmax], in epetraborole recipients in the PK Population
- Phase 2: PK analysis of the area under the concentration-time curve [AUC] [One month]
To evaluate the area under the concentration-time curve [AUC]) in epetraborole recipients in the PK Population
- Phase 3: Percentage of Participants Achieving Culture Conversion at Month 6 [Up to Month 6]
Microbiological response will be evaluated using decrease in semiquantitative culture MAC colony counts of ≥1 grade to determine if epetraborole + OBR is superior to placebo + OBR in reduction of colony counts
- Phase 3: PK analysis of volume of distribution [Vd] [One month]
To evaluate the volume of distribution [Vd] in epetraborole recipients in the PK Population
- Phase 3: PK analysis of maximum plasma drug concentration [Cmax] [One month]
To evaluate the maximum plasma drug concentration [Cmax], in epetraborole recipients in the PK Population
- Phase 3: PK analysis of the area under the concentration-time curve [AUC] [One month]
To evaluate the area under the concentration-time curve [AUC]) in epetraborole recipients in the PK Population
- Phase 3: Adverse Event Profile of 500 mg Once Daily Dose of epetraborole [Up to Month 16]
Number of Participants with indicated Adverse Events in subjects receiving 500 mg Once Daily Dose of epetraborole
Eligibility Criteria
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 of screening.
-
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: Chest CT scan within 8 weeks prior to randomization with abnormalities consistent with MAC lung disease.
-
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 ≤50 mL/min, as estimated by the Cockcroft Gault formula, at Screening or at the time of randomization.
-
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Havana Research Institute | Pasadena | California | United States | 91105 |
| 2 | Midland Florida Clinical Research Center, LLC | DeLand | Florida | United States | 32720 |
| 3 | MB & V Medical Research | Doral | Florida | United States | 33172 |
| 4 | L&A Morales Healthcare, Inc | Hialeah | Florida | United States | 33012 |
| 5 | Infectious Diseases Consultants of the Treasure Coast | Vero Beach | Florida | United States | 32960 |
| 6 | Southern Lung Specialists, PC | Macon | Georgia | United States | 31201 |
| 7 | Washington University School of Medicine | Saint Louis | Missouri | United States | 63110 |
| 8 | University of Nebraska | Omaha | Nebraska | United States | 68198 |
| 9 | Northwell Health | Manhasset | New York | United States | 11030 |
| 10 | New York University Langone Medical Center | New York | New York | United States | 10017 |
| 11 | Mount Sinai Roosevelt Hospital | New York | New York | United States | 10029 |
| 12 | Clinical Research of Rock Hill | Rock Hill | South Carolina | United States | 28207 |
| 13 | The University of Texas Health Science Center at Tyler | Tyler | Texas | United States | 75708 |
Sponsors and Collaborators
- AN2 Therapeutics, Inc
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- EBO-301