Clinical trial NCT05327803: Study of Epetraborole in Patients With Treatment-refractory MAC Lung Disease
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: MAC Lung Disease
Treatment Refractory MAC Lung Disease
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
Lead sponsor: AN2 Therapeutics, Inc
Sponsor class: INDUSTRY
First posted: 2022-04-14
Enrollment: 177
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Phase 2: Assessment of novel Patient Reported Outcome instrument psychometric properties
timeFrame: Screening (Day -14 to Day -7) to Month 6 + 1 week
measure: Phase 2: Percentage of Participants Achieving Clinical Response
timeFrame: Baseline to Month 6
measure: Phase 2: Adverse Event Profile of 500 mg Once Daily Dose of Epetraborole
timeFrame: Baseline to Month 16
measure: Phase 3: Percentage of Participants Achieving Clinical Response
timeFrame: Baseline to Month 6
Secondary outcomes:
measure: Phase 2: Percentage of Participants Achieving Culture Conversion
timeFrame: Baseline to Month 6
measure: Phase 2: Percentage of Participants Achieving Microbiological Improvement
timeFrame: Baseline to Month 6
measure: Phase 2: Change from Baseline in QOL-B Respiratory Domain PRO
timeFrame: Baseline to Month 6
measure: Phase 2: Change from Baseline in NTM Symptoms Module PRO
timeFrame: Baseline to Month 6
measure: Phase 2: Change from Baseline in SGRQ-C PRO
timeFrame: Baseline to Month 6
measure: Phase 2: Concordance Analysis of PRO-based Clinical Response and Microbiological Response
timeFrame: Baseline to Month 6
measure: Phase 2: Percentage of Participants with Reinfection
timeFrame: Baseline to Month 16
measure: Phase 2: Percentage of Participants with Relapse
timeFrame: Baseline to Month 16
measure: Phase 2: Maximum plasma concentration (Cmax) of epetraborole
timeFrame: Day 1 and Day 29
measure: 14. Phase 2: Area Under the Plasma Concentration-Time Curve from Time Point 0 Hours Until 24 hours [AUC(0-24)] post dose
timeFrame: Day 29
measure: Phase 2: Volume of distribution (Vd) of epetraborole
timeFrame: Day 29
measure: Phase 3: Percentage of Participants Achieving Culture Conversion
timeFrame: Baseline to Month 6
measure: Phase 3: Percentage of Participants Achieving Microbiological Improvement
timeFrame: Baseline to Month 6
measure: Phase 3: Change from Baseline in QOL-B Respiratory Domain PRO
timeFrame: Baseline to Month 6
measure: Phase 3: Change from Baseline in NTM Symptoms Module PRO
timeFrame: Baseline to Month 6
measure: Phase 3: Change from Baseline in SGRQ-C PRO
timeFrame: Baseline to Month 6
measure: Phase 3: Concordance Analysis of PRO-based Clinical Response and Microbiological Response
timeFrame: Baseline to Month 6
measure: Phase 3: Percentage of Participants with Reinfection
timeFrame: Baseline to Month 16
measure: Phase 3: Percentage of Participants with Relapse
timeFrame: Month 6, End of Therapy and Late Follow-up
measure: Phase 3: Adverse Event Profile of 500 mg Once Daily Dose of Epetraborole
timeFrame: Baseline to Month 16
measure: Phase 3: Maximum plasma concentration (Cmax) of epetraborole
timeFrame: Day 1 and Day 29
measure: Phase 3: Area Under the Plasma Concentration-Time Curve from Time Point 0 Hours Until 24 hours [AUC(0-24)] post dose
timeFrame: Day 29
measure: Phase 3: Volume of distribution (Vd) of epetraborole
timeFrame: Day 29
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: 423032
state: Alabama
city: Tucson
country: United States
facility: 423037
state: Arizona
city: Sacramento
country: United States
facility: 423070
state: California
city: San Francisco
country: United States
facility: 423069
state: California
city: Stanford
country: United States
facility: 423006
state: California
city: Washington
country: United States
facility: 423068
state: District of Columbia
city: Bay Pines
country: United States
facility: 423075
state: Florida
city: DeLand
country: United States
facility: 423018
state: Florida
city: Kissimmee
country: United States
facility: 423034
state: Florida
city: Tampa
country: United States
facility: 423033
state: Florida
city: Tampa
country: United States
facility: 423054
state: Florida
city: Tampa
country: United States
facility: 423047
state: Florida
city: Vero Beach
country: United States
facility: 423038
state: Florida
city: Atlanta
country: United States
facility: 423027
state: Georgia
city: Indianapolis
country: United States
facility: 423076
state: Indiana
city: Iowa City
country: United States
facility: 423029
state: Iowa
city: Kansas City
country: United States
facility: 423015
state: Kansas
city: Wichita
country: United States
facility: 423063
state: Kansas
city: Jefferson
country: United States
facility: 423065
state: Louisiana
city: New Orleans
country: United States
facility: 423042
state: Louisiana
city: Baltimore
country: United States
facility: 423060
state: Maryland
city: Baltimore
country: United States
facility: 423003
state: Maryland
city: Boston
country: United States
facility: 423074
state: Massachusetts
city: Boston
country: United States
facility: 423061
state: Massachusetts
city: Ann Arbor
country: United States
facility: 423078
state: Michigan
city: Rochester
country: United States
facility: 423031
state: Minnesota
city: Saint Louis
country: United States
facility: 423008
state: Missouri
city: Omaha
country: United States
facility: 423004
state: Nebraska
city: Lebanon
country: United States
facility: 423009
state: New Hampshire
city: Manhasset
country: United States
facility: 423024
state: New York
city: New York
country: United States
facility: 423014
state: New York
city: New York
country: United States
facility: 423013
state: New York
city: Chapel Hill
country: United States
facility: 423071
state: North Carolina
city: Charlotte
country: United States
facility: 423072
state: North Carolina
city: Durham
country: United States
facility: 423017
state: North Carolina
city: Winston-Salem
country: United States
facility: 423039
state: North Carolina
city: Cleveland
country: United States
facility: 423079
state: Ohio
city: Oklahoma City
country: United States
facility: 423082
state: Oklahoma
city: Portland
country: United States
facility: 423007
state: Oregon
city: Philadelphia
country: United States
facility: 423002
state: Pennsylvania
city: Philadelphia
country: United States
facility: 423058
state: Pennsylvania
city: Charleston
country: United States
facility: 423045
state: South Carolina
city: Charleston
country: United States
facility: 423001
state: South Carolina
city: Nashville
country: United States
facility: 423067
state: Tennessee
city: Fort Worth
country: United States
facility: 423081
state: Texas
city: Tyler
country: United States
facility: 423005
state: Texas
city: Charlottesville
country: United States
facility: 423012
state: Virginia
city: Edmonds
country: United States
facility: 423080
state: Washington
city: Milwaukee
country: United States
facility: 423011
state: Wisconsin
city: Concord
country: Australia
facility: 501005
state: New South Wales
city: Birtinya
country: Australia
facility: 501007
state: Queensland
city: Chermside West
country: Australia
facility: 501003
state: Queensland
city: Greenslopes
country: Australia
facility: 501001
state: Queensland
city: Perth
country: Australia
facility: 501008
state: Western Australia
city: Clayton
country: Australia
facility: 501004
city: South Brisbane
country: Australia
facility: 501002
city: Aichi
country: Japan
facility: 215019
city: Aomori
country: Japan
facility: 215026
city: Fukuoka
country: Japan
facility: 215004
city: Fukuoka
country: Japan
facility: 215025
city: Fukuoka
country: Japan
facility: 215016
city: Gifu
country: Japan
facility: 215006
city: Hiroshima
country: Japan
facility: 215030
city: Hokkaido
country: Japan
facility: 215014
city: Ibaraki
country: Japan
facility: 215028
city: Ishikawa
country: Japan
facility: 215018
city: Ishikawa
country: Japan
facility: 215020
city: Kanagawa
country: Japan
facility: 215017
city: Kitakyushu
country: Japan
facility: 215021
city: Kyoto
country: Japan
facility: 215009
city: Kyoto
country: Japan
facility: 215013
city: Mie
country: Japan
facility: 215022
city: Nagano
country: Japan
facility: 215023
city: Niigata
country: Japan
facility: 215002
city: Osaka
country: Japan
facility: 215029
city: Osaka
country: Japan
facility: 215008
city: Osaka
country: Japan
facility: 215012
city: Tokyo
country: Japan
facility: 215001
city: Tokyo
country: Japan
facility: 215005
city: Tokyo
country: Japan
facility: 215024
city: Tokyo
country: Japan
facility: 215003
city: Tokyo
country: Japan
facility: 215027
city: Wakayama
country: Japan
facility: 215010
city: Yamaguchi
country: Japan
facility: 215007
city: Yokohama
country: Japan
facility: 215011
city: Gwangju
country: Korea, Republic of
facility: 219003
city: Incheon
country: Korea, Republic of
facility: 219005
city: Seongnam-si
country: Korea, Republic of
facility: 219001
city: Seoul
country: Korea, Republic of
facility: 219002
city: Seoul
country: Korea, Republic of
facility: 219007
city: Seoul
country: Korea, Republic of
facility: 219008
Study officials:
References: