RHB-204 for the Treatment of Pulmonary Mycobacterium Avium Complex Disease (CleaR-MAC)

Study of RHB-204 for the Treatment of Pulmonary Mycobacterium Avium Complex (MAC) Disease in Adults With Nodular Bronchiectasis (CleaR-MAC Trial)

A 2-part multi-center, Phase 3, randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of RHB-204 in adult subjects with underlying nodular bronchiectasis and documented MAC lung infection.

A 2-part multi-center, Phase 3, randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of RHB-204 in adult subjects with underlying nodular bronchiectasis and documented MAC lung infection. The co-primary efficacy endpoints at the end of Part 1 evaluate the proportion of patients with sputum culture conversion after 6 months of treatment defined as three consecutive monthly negative sputum cultures at Months 4, 5, and 6 for RHB-204 compared to placebo and the mean change in the Quality of Life Questionnaire - Bronchiectasis (QoL-B) Respiratory Symptoms domain score from baseline to Month 6 for RHB-204 compared to placebo. At the Month 6 visit (end of Part 1), after all assessments including questionnaires and sputum samples have been collected, subjects will enter Part 2 of the study and receive open-label RHB-204. In order to comply with current treatment duration guidelines (Nontuberculous Mycobacterial Pulmonary Disease Caused by Mycobacterium avium Complex: Developing Drugs for Treatment - FDA Draft Guidance September 2021) in this protocol subjects will receive active treatment for 12 months after sputum culture conversion. As such, each subject's first negative culture that defines conversion will determine the total duration of their active study drug treatment. The longest duration of active study drug treatment will be 16 months. At the end of study treatment, all subjects will enter a 3-month post-treatment follow-up period (see study design section below for additional details). To maintain the blind and integrity of the data, an independent team (Sputum Culture Monitors) will inform sites on each subject's treatment duration based on sputum culture conversion. Sputum Culture Monitors will also have access to randomized treatment allocation. All other study related personnel will remain blinded to sputum culture results and treatment allocation (Sponsor, CRO, medical monitors, safety, ECG and sputum laboratories, site personnel as well as participating subjects). During Part 1, subjects who have completed at least the first 3 months of treatment with study drug, and at the Investigator's discretion, require rescue therapy (alternative anti-NTM treatment) will discontinue study drug (performing an EOT visit) and remain in the study to complete all scheduled study visits and assessments/procedures to Month 6 (performing an EOS visit). Subjects who complete treatment based on the timeline provided by the Sputum Culture Monitors (EOT visit) and have an ongoing negative sputum culture will be reconsented to enter a follow-up Extension Study, to evaluate sputum culture results at two (2) further time points: 6 months and 12 months following end of treatment (EOT) for each subject in protocol RHB-204-01.

Matching placebo will contain riboflavin, a type of B vitamin, which may discolor urine in a similar fashion as RHB-204.

Quality of Life Questionnaire - Bronchiectasis (QoL B) Respiratory Symptoms domain score from baseline to Month 6 for RHB-204 compared to placebo

The mean change in the Quality of Life Questionnaire - Bronchiectasis (QoL B) Respiratory Symptoms domain score from baseline to Month 6 for RHB-204 compared to placebo

The proportion of subjects who achieve SCC by Month 6, defined by 3 consecutive monthly negative sputum cultures, without reversion, at Months 4, 5 & 6 for THB-204 compared to placebo.

The mean change in the PROMIS Fatigue SF 8a score from baseline to Month 6 for RHB-204 compared to placebo. The PROMIS Fatigue SF 8a score from baseline to Month 6 for RHB-204 compared to placebo.

The mean change in the Short Form 36 Physical Functioning domain score from baseline to Month 6 for RHB-204 compared to placebo.

The proportion of subjects with SCC by Month 6 who sustain negative sputum cultures at Month 16 and negative sputum culture at Month 19 (3 months off treatment) for RHB-204 compared to placebo (durable responders).

Measure the proportion of subjects with SCC by Month 6 who sustain negative sputum cultures at Month 16 for RHB-204 compared to placebo.

The mean change in Quality of Life Questionnaire - Bronchiectasis (QoL-B) Respiratory Symptoms domain scores from baseline to Month 16 for ex-RHB-204 compared to ex-placebo

The mean change in the PROMIS Fatigue SF 8a score from baseline to Month 16 for ex-RHB-204 compared to ex-placebo

The mean change in the PROMIS Fatigue SF 8a score from baseline to Month 19 for ex-RHB-204 compared to ex-placebo

The mean change in the Short Form 36 Physical Functioning domain score from baseline to Month 16 for ex-RHB-204 compared to ex-placebo

The mean change in the Short Form 36 Physical Functioning domain score from baseline to Month 19 for ex-RHB-204 compared to ex-placebo

The mean change in Quality of Life Questionnaire - Bronchiectasis (QoL-B) Respiratory Symptoms domain scores from baseline to Month 19 for ex-RHB-204 compared to ex-placebo

Key Inclusion Criteria Males and females aged ≥18 years to ≤85 years of age, inclusively Have a MAC lung infection documented by one MAC positive culture within 18 months prior to screening and a MAC positive culture at screening (cultures need to be at least 1 month apart). Prior sputum for culture may be obtained from sputum or bronchial washings however, sputum collected during screening must be either spontaneously expectorated by the patient or after sputum induction. Have MAC lung infection with evidence of underlying nodular infiltrates and/or bronchiectasis on a chest computed tomography (Chest CT) within 6 months of screening. Have symptoms of MAC lung infection that include one of the following: respiratory symptoms such as chronic cough, excessive mucous production, fatigue, dyspnea, hemoptysis or systemic symptoms such as fever, night sweats or loss of appetite. Be treatment naïve, or if previously treated for MAC, have not received treatment within the 6 months prior to screening Subject's weight is above 41 Kilograms or 90 pounds. Key Exclusion Criteria Cavitary lung disease as observed on a chest CT scan (cavitary lesions exceeding 2 cm in diameter). Currently taking or treated in the 6 months prior to screening with any of the following: bedaquiline, clofazimine or any component of American Thoracic Society(ATS)/Infectious Diseases Society of America (IDSA) multi-drug recommended therapy (macrolides, ethambutol, rifabutins/rifampins) for MAC or other multi-drug regime for NTM lung disease Clarithromycin minimum inhibitory concentration (MIC) ≥32μg/mL on MAC isolates in screening sputum Known hypersensitivity or suspected history of hypersensitivity reactions to clarithromycin, rifabutin, or clofazimine or other drugs in each class Subjects requiring chronic supplemental oxygen use (including intermittent or continuous use) Planned lung resection surgery for MAC lung disease Subjects with Cystic Fibrosis, prior solid organ or hematologic transplant Current usage of inhaled products containing amikacin, tobramycin or gentamicin History of ventricular arrhythmias or family history of Long QT syndrome, including torsades de pointes Corrected QT (QTc) interval on electrocardiogram (ECG) >460 ms for females or >450 ms for males, calculated using Fridericia's formula (QTcF)