MAC Lung Disease, Treatment Refractory MAC Lung Disease
Conditions
Keywords
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, 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, Treatment refractory NTM pulmonary disease
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.
Interventions
DRUGEpetraborole
500 mg taken orally QD
DRUGPlacebo
Placebo taken orally QD
Sponsors
AN2 Therapeutics, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Double-Blind
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female patients who are 18 years of age or older. 2. Willing and able to provide written informed consent. 3. Patients with a diagnosis of treatment-refractory MAC lung disease consisting of all of the following (a) Microbiological, (b) Clinical, and (c) Radiographic criteria: 1. 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. 2. 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 3. Radiographic criteria: Non contrast Chest CT scan within 6 months prior to signing the ICF with abnormalities consistent with MAC lung disease. 4. 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. 4. 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. 5. All patients must agree to use an effective method of birth control. 6. 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
1. 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. 2. 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. 3. Patients with creatinine clearance (CrCl) of ≤30 mL/min, as estimated by the Cockcroft Gault formula, at Screening. 4. 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. 5. 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. 6. 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. 7. Patients who are pregnant or breastfeeding. 8. Patients with a mean QT interval corrected using Fridericia's formula (QTcF) \>480 msec based on triplicate 12-lead ECGs at Screening. 9. Patients with an immunodeficiency or an immunocompromised condition and risk for an opportunistic pulmonary infection. 10. Patients with an anticipated start of new non-study antimycobacterial therapy to be administered at any time between Screening and Month 6. 11. Patients who have received any investigational medication during the 30 days or 5 half-lives, whichever is longer, prior to randomization. 12. Patients with any prior exposure to epetraborole. 13. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Adverse Event Profile of 500 mg Once Daily Dose of Epetraborole | Baseline to Month 16 | Percentage of Participants reporting treatment emergent adverse events |
| Phase 2: Percentage of Participants Achieving Clinical Response | Baseline to Month 6 | Detection of within-patient changes in symptoms reported in a novel Patient-Reported Outcome (PRO) instrument at Month 6 (Clinical Response measured as improvement in at least one symptom and no worsening in any others from baseline) |
| Phase 3: Percentage of Participants Achieving Clinical Response | Baseline to Month 6 | Detection of within-patient changes in symptoms reported in a novel Patient-Reported Outcome (PRO) instrument at Month 6 (Clinical Response measured as improvement in at least one symptom and no worsening in any others from baseline) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Percentage of Participants Achieving Culture Conversion | Baseline to Month 6 | Sputum conversion will be assessed using culture conversion based on 3 consecutive monthly negative sputum cultures for MAC by Month 6. |
| Phase 2: Percentage of Participants Achieving Microbiological Improvement | Baseline to Month 6 | Microbiological improvement will be assessed at Month 3 and Month 6 using decrease in MAC colony counts of ≥1 category. |
| Phase 2: Change From Baseline in QOL-B Respiratory Domain PRO | Measured at Baseline and months 1, 2, 3, 4, 5, and 6; Change from Baseline to Month 6 Reported | Mean change from baseline in Quality of Life - Bronchiectasis (QOL-B) respiratory domain score measured monthly through Month 6 (Change from Baseline to Month 6 Reported). QOL-B respiratory domain score is measured on a scale from 0 to 100 (with higher scores indicating better health-related quality of life). |
| Phase 2: Change From Baseline in NTM Symptoms Module PRO | Measured at Baseline and months 1, 2, 3, 4, 5, and 6; Change from Baseline to Month 6 Reported | Mean change from baseline in NTM Symptoms Module PRO measured monthly through Month 6 (Change from Baseline to Month 6 Reported). NTM Symptoms Module score is measured on a scale from 0 to 100 (with higher scores indicating better function). |
| Phase 2: Change From Baseline in SGRQ-C PRO | Measured at Baseline and months 1, 2, 3, 4, 5, and 6; Change from Baseline to Month 6 Reported | Mean change from baseline in Saint George's Respiratory Questionnaire for COPD Patients (SGRQ-C) total score measured monthly through Month 6 (Change from Baseline to Month 6 Reported). SGRQ-C total score is measured on a scale from 0 to 100 (with lower scores representing better quality of life). |
| Phase 2: Concordance Analysis of PRO-based Clinical Response and Microbiological Response | Baseline to Month 6 | 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. |
| Phase 2: Maximum Plasma Concentration (Cmax) of Epetraborole | Day 1 (2-3 hours post-dose) and Day 29 (within 1 hour pre-dose and 2-3 hours post-dose); Day 29 Result Reported | Cmax is the maximum plasma concentration of epetraborole estimated by population PK model. |
| Phase 2: Area Under the Plasma Concentration-Time Curve From Time Point 0 Hours Until 24 Hours [AUC(0-24)] Post Dose | Day 1 (2-3 hours post-dose) and Day 29 (within 1 hour pre-dose and 2-3 hours post-dose); Day 1 Result Reported | 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. |
| Phase 2: Volume of Distribution (Vd) of Epetraborole | Day 1 (2-3 hours post-dose) and Day 29 (within 1 hour pre-dose and 2-3 hours post-dose); Day 29 Result Reported | Vd is the apparent volume of distribution of epetraborole estimated by population PK model. |
| Phase 3: Percentage of Participants Achieving Culture Conversion | Baseline to Month 6 | Sputum conversion will be assessed using culture conversion based on 3 consecutive monthly negative sputum cultures for MAC by Month 6. |
| Phase 3: Percentage of Participants Achieving Microbiological Improvement | Baseline to Month 6 | Microbiological improvement will be assessed at Month 3 and Month 6 using decrease in MAC colony counts of ≥1 category. |
| Phase 3: Change From Baseline in QOL-B Respiratory Domain PRO | Measured at Baseline and months 1, 2, 3, 4, 5, and 6; Change from Baseline to Month 6 Reported | Mean change from baseline in Quality of Life - Bronchiectasis (QOL-B) respiratory domain score measured monthly through Month 6 (Change from Baseline to Month 6 Reported). QOL-B respiratory domain score is measured on a scale from 0 to 100 (with higher scores indicating better health-related quality of life). |
| Phase 3: Change From Baseline in NTM Symptoms Module PRO | Measured at Baseline and months 1, 2, 3, 4, 5, and 6; Change from Baseline to Month 6 Reported | Mean change from baseline in NTM Symptoms Module PRO measured monthly through Month 6 (Change from Baseline to Month 6 Reported). NTM Symptoms Module score is measured on a scale from 0 to 100 (with higher scores indicating better function). |
| Phase 3: Change From Baseline in SGRQ-C PRO | Measured at Baseline and months 1, 2, 3, 4, 5, and 6; Change from Baseline to Month 6 Reported | Mean change from baseline in Saint George's Respiratory Questionnaire for COPD Patients (SGRQ-C) total score measured monthly through Month 6 (Change from Baseline to Month 6 Reported). SGRQ-C total score is measured on a scale from 0 to 100 (with lower scores representing better quality of life). |
| Phase 3: Concordance Analysis of PRO-based Clinical Response and Microbiological Response | Baseline to Month 6 | 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 |
| Phase 3: Adverse Event Profile of 500 mg Once Daily Dose of Epetraborole | Baseline to Month 16 | Percentage of Participants reporting treatment emergent adverse events. |
Countries
Australia, Japan, South Korea, United States
Participant flow
Recruitment details
This study included 2 phases of enrollment. 80 participants in Phase 2 were randomized 1:1 to Epetraborole or Placebo arms, both including Optimized Background Regimen (OBR) 97 participants in Phase 3 were randomized 2:1 to Epetraborole or Placebo arms, both including Optimized Background Regimen (OBR)
Pre-assignment details
Phase 2 : 39 participants were randomized to Epetraborole + OBR arm and 41 participants were randomized to placebo + OBR arm. Phase 3 : 66 participants were randomized to Epetraborole + OBR arm and 31 participants were randomized to placebo + OBR arm.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 18 Participants |
| Age, Categorical Between 18 and 65 years | 70 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 38 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 23 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 13 Participants |
| Region of Enrollment Australia | 1 Participants |
| Region of Enrollment Japan | 14 Participants |
| Region of Enrollment South Korea | 6 Participants |
| Region of Enrollment United States | 59 Participants |
| Sex: Female, Male Female | 22 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 105 | 0 / 72 |
| other Total, other adverse events | 67 / 105 | 31 / 72 |
| serious Total, serious adverse events | 15 / 105 | 13 / 72 |
Outcome results
None listed