A Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of SPR720 as Compared With Placebo for the Treatment of Participants With Mycobacterium Avium Complex (MAC) Pulmonary Disease

Study Overview
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Brief Summary
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The purpose of the study is to evaluate The microbiological response and clinical efficacy of SPR720 compared with placebo in participants with nontuberculous mycobacteria pulmonary disease (NTM-PD). The safety and tolerability of SPR720 in a participants population with NTM- PD The pharmacokinetic (PK) of SPR719, active moiety, following orally (po) administered prodrug SPR720 in a participant population with NTM-PD.

Official Title
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A Randomized, Double-Blinded, Placebo-Controlled, Multicenter, Phase 2, Dose-Ranging Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of SPR720 as Compared With Placebo for the Treatment of Patients With Mycobacterium Avium Complex (MAC) Pulmonary Disease

Conditions
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Nontuberculous Mycobacterial Pulmonary Disease (NTM-PD)

Intervention / Treatment
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* Drug: Placebo
* Drug: SPR720 500 mg
* Drug: SPR720 1000 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a prior diagnosis of NTM-PD due to MAC Has at least one prior lower respiratory culture (sputum or bronchoalveolar lavage [BAL]) positive for MAC in the 12 months prior to consent Has an induced sputum culture at Screening positive for MAC by quantitative culture on solid agar Is either treatment naïve and has not received any prior treatment for MAC, OR if previously treated for MAC and meets all of the following criteria: Has a history of successful treatment with sputum culture conversion to negative Has recent sputum or BAL culture evidence of recurrent or relapsed disease and Has been off therapy for at least 3 months prior to consent Has clinical signs and symptoms within the 6 weeks prior to consent that are consistent with NTM-PD ≥2 of the following: chronic cough fatigue frequent throat clearing shortness of breath (dyspnea) coughing up of blood (hemoptysis) excessive mucus (sputum) production fever (temperature >38ºC or >100.4ºF) night sweats loss of appetite unintended weight loss wheezing chest pain Has a measured forced expiratory volume in the first second following maximal inhalation (FEV1) % predicted ≥30% within 3 months prior to consent. If prior FEV1% predicted test result is not available, obtain FEV1% predicted at Screening to confirm eligibility Exclusion Criteria: In the opinion of the Investigator, is not a candidate for a 4-month delay in initiation of standard multidrug therapy to participate in a placebo-controlled clinical trial (e.g., participant has severe symptoms or, extensive disease burden) Has disseminated or extrapulmonary NTM disease Has end-stage NTM-PD or treatment-refractory NTM-PD Has isolation on lower respiratory (sputum or BAL) cultures of any Mycobacterium species other than those included in MAC within the 6 months prior to consent Has any other condition or prior therapy, which, in the opinion of the Investigator, would make the participant unsuitable for this study, including compliance with all study assessments and adherence to the protocol schedule of assessment Prior exposure to SPR720. Participants who are unable to comply with the requirements of the study or who in the opinion of the Investigator should not participate in the study are not eligible Other inclusion and exclusion criteria as per protocol may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Double Blind: Placebo<br>Participants will receive matching placebo 4 capsules, orally once daily (QD) for 56 days. | Drug: Placebo<br>* Placebo-matching capsules will be administered orally.<br>|
| Experimental: Double Blind: SPR720 Low Dose<br>Participants will receive SPR720 500 milligrams (mg) [250 mg × 2 capsules and 2 matching placebo capsules, orally QD for 56 days. | Drug: Placebo<br>* Placebo-matching capsules will be administered orally.<br>Drug: SPR720 500 mg<br>* SPR720 500 mg (250 mg × 2 capsules) will be administered orally.<br>|
| Experimental: Double Blind: SPR720 High Dose<br>Participants will receive SPR720 1000 mg [250 mg × 4 capsules], orally QD for 56 days. | Drug: SPR720 1000 mg<br>* SPR720 500 mg (250 mg × 4 capsules) will be administered orally.<br>|
| Experimental: Open Label: SPR720 High Dose<br>Participants will receive SPR720 1000 mg [250 mg × 4 capsules], orally QD for 56 days. | Drug: SPR720 1000 mg<br>* SPR720 500 mg (250 mg × 4 capsules) will be administered orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Slope of the Weekly Sputum Log10 Colony Forming Units Per Millilitre (CFU/mL) Change From Day 1 Through 56 in micro-Intent to Treat (m-ITT) Population |  | Days 1 through 56 (end of the treatment [EOT]) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Slope of the Weekly Sputum Log10 CFU/mL Change From Days 1 Through 28 in micro-ITT Population |  | Days 1 through 28 | 
| Slope of the Time to Positivity (TTP) using MGIT on Samples of Induced Sputum From Days 1 Through 56 (EOT) in micro-ITT Population |  | Days 1 through 56 (EOT) | 
| Change from Baseline in the Sputum Log10 CFU/mL in the micro-ITT Population |  | Days 1 through 56 (EOT) | 
| Change from Baseline in the Sputum TTP Using MGIT in micro-ITT Population |  | Days 1 through 56 (EOT) | 
| Time to Negative Sputum Culture in micro-ITT Population |  | Days 1 through 56 (EOT) | 
| Percent with Negative Sputum Culture in micro-ITT Population |  | Days 14 through Day 84 (FU) | 
| Changes in Susceptibility in SPR719 From Days 1 through 56 (EOT) in the micro-ITT Population | Susceptibility is ≥4-fold increase in minimum inhibitory concentration for same pathogen identified at Baseline. | Days 1 through 56 (EOT) | 
| Clinical Response in the micro-ITT Population | Investigator indicated their assessment of participants overall clinical response as resolved, improved, unchanged, or worsened. | Baseline up to Day 84 (FU) | 
| Clinical Response in the Clinically Evaluable (CE) Populations | Investigator indicated their assessment of participants overall clinical response as resolved, improved, unchanged, or worsened. | Baseline up to Day 84 (FU) | 
| Change From Baseline in 11-point Nontuberculous Mycobacteria Pulmonary Disease (NTM-PD) Symptoms and Impact Scale for Quality of Life (QOL) Assessments | The 11-point NTM-PD Symptoms and Impact Scale will evaluate specific clinical signs and symptoms and QOL improvements and will include symptoms of chronic cough, fatigue, frequent throat clearing, dyspnea, hemoptysis, excessive mucus (sputum) production, chills, night sweats, loss of appetite, unintended weight loss, wheezing, and chest pain. | Baseline up to FU Day 84 | 
| Change From Baseline in 6-point Patient Global Impression of Severity (PGI-S) Scale for Quality of Life (QOL) Assessments | The PGI-S scale is comprised of a 6-point verbal descriptor scale to determine meaningful change reported for the other symptom ratings in participants with NTM-PD. | Baseline up to FU Day 84 | 
| Change From Baseline in 7-point Patient Global Impression of Change (PGI-C) scale for Quality of Life (QOL) Assessments | The PGI-C scale is a patient-reported rating of improvement on a 7-point verbal descriptor scale. | Baseline up to FU Day 84 | 
| Change From Baseline in Flu, COVID-19, or Other Illness Questionnaire (2 questions) for Quality of Life (QOL) Assessments | This 2-question form will assess the participants flu, COVID-19 or other illness status and how these illnesses have affected the participants NTM-PD disease over the past 7 days. | Baseline up to FU Day 84 | 
| Change from Baseline in PROMIS® V1.0 Fatique Shortform 7a scale for Quality of Life (QOL) Assessments | The PROMIS® scale will assess the participants experience of fatigue (frequency, duration, and intensity) and the impact of fatigue on physical, mental, and social activities using a validated 5-point Likert scale. | Baseline up to FU Day 84 | 
| Number of Participants with Treatment Emergent Adverse Events (TEAEs) | An adverse event is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product, which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational/experimental) product, whether related to this product or not. | From first dose of study drug (Day 1) up to follow up Day 84 | 
| Maximum Plasma Concentration (Cmax) (Intensive PK group only) |  | Pre-dose and post-dose on Days 1 and 14 | 
| Time to reach Cmax (Tmax) (Intensive PK group only) |  | Pre-dose and post-dose on Days 1 and 14 | 
| Area Under the Concentration-time Curve (AUC0-τ) (Intensive PK group only) |  | Pre-dose and post-dose on Days 1 and 14 | 
| Accumulation Ratio of SPR719 Cmax on Day 14 Compared to Day 1 (Intensive PK group only) |  | Pre-dose and post-dose on Days 1 and 14 | 
| Accumulation Ratio of SPR719 AUC0-τ on Day 14 Compared to Day 1 (Intensive PK group only) |  | Pre-dose and post-dose on Days 1 and 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MAC, Mycobacterium avium Complex, Pulmonary disease