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

• ClinicalTrials.gov Identifier: NCT04553406
• Recruitment Status: Terminated
• First Posted: September 17, 2020
• Results First Posted: February 28, 2022
• Last Update Posted: February 28, 2022
• Sponsor: Spero Therapeutics
• Information provided by (Responsible Party): Spero Therapeutics

Study Description

Brief Summary:

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)

Condition or disease	Intervention/treatment	Phase
Mycobacterium Avium Complex; Non-tuberculous Mycobacterium Pulmonary Disease	Drug: SPR720; Drug: Placebo; Drug: Open-label Standard of Care	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 2 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Treatment Arms 1 to 3 are masked while Treatment Arm 4 is open-label
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: December 3, 2020
• Actual Primary Completion Date: January 28, 2021
• Actual Study Completion Date: January 28, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: SPR720 low dose; SPR720 500 mg administered orally once daily for 28 days.	Drug: SPR720; Capsules for oral administration
Experimental: SPR720 high dose; SPR720 1000 mg administered orally once daily for 28 days.	Drug: SPR720; Capsules for oral administration
Placebo Comparator: Placebo; Placebo administered orally once daily for 28 days	Drug: Placebo; Capsules for oral administration
Active Comparator: Standard of Care (SOC); Standard of Care regimen per the Investigator's discretion.	Drug: Open-label Standard of Care; 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.

Outcome Measures

Primary Outcome Measures :

1. Maximum Plasma Concentration (Cmax) of SPR719 [ Time Frame: Day 1 and Day 28 pre-dose and 1, 2, 4, 8, 12, and 24 hours post-dose ]
   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.
2. Time to Reach Maximum Plasma Concentration (Tmax) of SPR719 [ Time Frame: Day 1 and Day 28 pre-dose and 1, 2, 4, 8, 12, and 24 hours post-dose ]
3. Area Under the Concentration-time Curve From Zero to Tau, Where Tau is the Dosing Interval (AUC0-tau) for SPR719 [ Time Frame: Day 1 and Day 28 pre-dose and 1, 2, 4, 8, 12, and 24 hours post-dose ]
4. Accumulation Ratio of SPR719 [ Time Frame: Day 1 and Day 28 pre-dose and 1, 2, 4, 8, 12, and 24 hours post-dose ]

Secondary Outcome Measures :

1. Number of Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: From first dose of study drug (Day 1) up to 28 days after last dose (56 days) ]

   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.

2. Number of Participants With Clinically Meaningful Change in Physical Examination Findings [ Time Frame: Days 1, 7, 14, 21, 28, and 56 ]
   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.
3. Number of Participants Who Received Any Concomitant Medication During the Study [ Time Frame: Day 1 to Day 56 ]
4. Changes From Baseline in Laboratory Tests [ Time Frame: Days 1, 7, 14, 21, 28, and 56 ]
5. Number of Participants With Clinically Significant Out-of-normal Range Laboratory Tests [ Time Frame: Days 1, 7, 14, 21, 28, and 56 ]
   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.
6. Shifts From Baseline in Selected Laboratory Tests Using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Shift Categories [ Time Frame: Days 1, 7, 14, 21, 28, and 56 ]
7. Changes From Baseline in Vital Sign Measurements [ Time Frame: Days 1, 7, 14, 21, 28, and 56 ]
   Vital signs measurements included systolic and diastolic blood pressure, pulse, temperature, and respiratory rate.
8. Number of Participants With Clinically Significant Abnormal Electrocardiogram Findings [ Time Frame: Days 1, 14, 28, and 56 ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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:

  1. chronic cough
  2. fatigue
  3. frequent throat clearing
  4. shortness of breath (dyspnea)
  5. coughing up of blood (hemoptysis)
  6. excessive mucus (sputum) production
  7. fever
  8. night sweats
  9. loss of appetite
  10. unintended weight loss
  11. wheezing
  12. 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

Contacts and Locations

Locations

United States, Florida

Medical Facility

Altamonte Springs, Florida, United States, 32701

Medical Facility

Atlantis, Florida, United States, 33462

Medical Facility

Clearwater, Florida, United States, 33765

Medical Facility

Kissimmee, Florida, United States, 34746

Medical Facility

West Palm Beach, Florida, United States, 33407

United States, North Carolina

Medical Facility

Charlotte, North Carolina, United States, 28207

Medical Facility

Mooresville, North Carolina, United States, 28117

Medical Facility

Winston-Salem, North Carolina, United States, 27103

United States, Pennsylvania

Medical Facility

Pittsburgh, Pennsylvania, United States, 15213

Sponsors and Collaborators

Spero Therapeutics

Investigators

• Study Director: David Melnick, MD; Spero Therapeutics Inc

  Study Documents (Full-Text)

Documents provided by Spero Therapeutics:

Study Protocol and Statistical Analysis Plan  [PDF] September 17, 2020

More Information

• Responsible Party: Spero Therapeutics
• ClinicalTrials.gov Identifier: NCT04553406
• Other Study ID Numbers: SPR720-201
• First Posted: September 17, 2020
• Results First Posted: February 28, 2022
• Last Update Posted: February 28, 2022
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Mycobacterium Infections; Mycobacterium avium-intracellulare Infection; Lung Diseases; Respiratory Tract Diseases; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Mycobacterium Infections, Nontuberculous