Safety, Tolerability, Pharmacokinetics and Efficacy of SPR720 for the Treatment of Patients With Mycobacterium Avium Complex (MAC) Pulmonary Disease

Study Overview
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Brief Summary
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To evaluate the pharmacokinetics (PK) of SPR719, the active moiety, generated from the orally (po) administered SPR720 prodrug in a patient population with nontuberculous mycobacteria pulmonary disease (NTM-PD)

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

Conditions
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Mycobacterium Avium Complex, Non-tuberculous Mycobacterium Pulmonary Disease

Intervention / Treatment
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* Drug: SPR720
* Drug: Placebo
* Drug: Open-label Standard of Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a diagnosis of NTM-PD due to MAC Had at least 1 prior positive culture (sputum or bronchoalveolar lavage) positive for MAC in the previous 6 months Has an induced sputum culture at screening positive for MAC by at least one of the following methods performed by the microbiology laboratory: quantitative culture on solid agar or growth on liquid media (MGIT) Is either treatment naïve and has not received any prior treatment for MAC, OR if previously treated for MAC, has culture evidence of persistent, recurrent, or relapsed disease and has been off therapy for at least 6 months In the opinion of the Investigator, is ready to initiate treatment (treatment naïve) or reinitiate treatment (previously treated) within the next 3 months, and for whom a delay, in order to participate in a placebo-controlled clinical trial, is considered reasonable and clinically acceptable Had clinical signs and symptoms within the 6 weeks before the date of consent that are consistent with NTM-PD with at least two of the following: chronic cough fatigue frequent throat clearing shortness of breath (dyspnea) coughing up of blood (hemoptysis) excessive mucus (sputum) production fever night sweats loss of appetite unintended weight loss wheezing chest pain Has a measured forced expiratory volume in 1 second (% predicted FEV1) ≥30% on pulmonary function test within 3 months prior to consent Has a chest radiograph (CXR) or computed tomography (CT) scan within 6 months prior to consent with findings consistent with NTM-PD. If no CXR or CT scan is available, a CXR or CT scan should be performed at screening to confirm eligibility. Other inclusion criteria per protocol Exclusion Criteria: Has disseminated or extrapulmonary NTM Has end-stage NTM-PD or treatment-refractory NTM-PD and is unlikely to respond to protocol-specified SOC treatment Had isolation on sputum cultures of any species of Mycobacterium other than a species included in MAC within the past 6 months Had prior isolation of MAC with macrolide resistance Has received any systemic (oral or IV) or inhaled antibiotic with activity against MAC between consent and randomization Has a potentially confounding underlying pulmonary disease, including but not limited to cystic fibrosis, active pulmonary malignancy (primary or metastatic), NTM-hypersensitivity disease pneumoconiosis, or another advanced lung disease with a % predicted FEV1<30% Other exclusion criteria per protocol

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 |
| --- | --- |
| Experimental: SPR720 low dose<br>SPR720 500 mg administered orally once daily for 28 days. | Drug: SPR720<br>* Capsules for oral administration<br>|
| Experimental: SPR720 high dose<br>SPR720 1000 mg administered orally once daily for 28 days. | Drug: SPR720<br>* Capsules for oral administration<br>|
| Placebo Comparator: Placebo<br>Placebo administered orally once daily for 28 days | Drug: Placebo<br>* Capsules for oral administration<br>|
| Active Comparator: Standard of Care (SOC)<br>Standard of Care regimen per the Investigator's discretion. | Drug: Open-label Standard of Care<br>* Standard of Care regimen is at the Investigator's discretion; recommended 2-drug or 3-drug SOC, consisting of either: Clarithromycin 500-1000 mg, plus ethambutol hydrochloride (HCl) 15 mg/kg orally once daily or Azithromycin 250-500 mg plus ethambutol HCl 15 mg/kg orally once daily. Optional rifampin 600 mg or rifabutin 300 mg orally once daily may be added to the SOC regimen for up to 28 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) of SPR719 | SPR719 is the active moiety of the prodrug SPR720. Blood samples were planned to be taken at a subset of study sites in order to conduct intensive pharmacokinetic (PK) evaluation. | Day 1 and Day 28 pre-dose and 1, 2, 4, 8, 12, and 24 hours post-dose | 
| Time to Reach Maximum Plasma Concentration (Tmax) of SPR719 |  | Day 1 and Day 28 pre-dose and 1, 2, 4, 8, 12, and 24 hours post-dose | 
| Area Under the Concentration-time Curve From Zero to Tau, Where Tau is the Dosing Interval (AUC0-tau) for SPR719 |  | Day 1 and Day 28 pre-dose and 1, 2, 4, 8, 12, and 24 hours post-dose | 
| Accumulation Ratio of SPR719 |  | Day 1 and Day 28 pre-dose and 1, 2, 4, 8, 12, and 24 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation patient 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. This includes any newly occurring event or previous condition that has increased in severity or frequency since starting active or randomized treatment. The Investigator assessed the intensity for each AE reported during the study using the latest version of the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, as Mild, Moderate, Severe, Life-threatening, or Death. | From first dose of study drug (Day 1) up to 28 days after last dose (56 days) | 
| Number of Participants With Clinically Meaningful Change in Physical Examination Findings | Full physical examination were conducted on Day 1 and 28 days after last dose (Day 56) and included, at a minimum, assessment of the following systems: skin, head, ears, eyes, nose and throat, respiratory system, cardiovascular system, gastrointestinal system, neurological condition, blood and lymphatic systems, and the musculoskeletal system. Symptom-directed physical examinations were conducted at study visits on Days 7, 14, 21, and 28. | Days 1, 7, 14, 21, 28, and 56 | 
| Number of Participants Who Received Any Concomitant Medication During the Study |  | Day 1 to Day 56 | 
| Changes From Baseline in Laboratory Tests |  | Days 1, 7, 14, 21, 28, and 56 | 
| Number of Participants With Clinically Significant Out-of-normal Range Laboratory Tests | Clinical laboratory tests included serum chemistry, hematology, coagulation tests, and urinalysis. The investigator determined whether any changes in laboratory values were clinically significant based on the condition of the participant and the extent and duration of the deviation from the reference range. | Days 1, 7, 14, 21, 28, and 56 | 
| Shifts From Baseline in Selected Laboratory Tests Using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Shift Categories |  | Days 1, 7, 14, 21, 28, and 56 | 
| Changes From Baseline in Vital Sign Measurements | Vital signs measurements included systolic and diastolic blood pressure, pulse, temperature, and respiratory rate. | Days 1, 7, 14, 21, 28, and 56 | 
| Number of Participants With Clinically Significant Abnormal Electrocardiogram Findings | Standard 12-lead electrocardiogram (ECG) assessments included heart rate, cardiac rhythm, PR interval, RR interval, QRS interval, QT interval and QTC interval. Clinical significance was determined by the investigator. | Days 1, 14, 28, and 56 |