Mycobacterium Avium Complex, Non-tuberculous Mycobacterium Pulmonary Disease
Conditions
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)
Interventions
DRUGSPR720
Capsules for oral administration
DRUGPlacebo
Capsules for oral administration
DRUGOpen-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.
Sponsors
Spero Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Treatment Arms 1 to 3 are masked while Treatment Arm 4 is open-label
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of SPR719 | 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinically Significant Out-of-normal Range Laboratory Tests | 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. |
| 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 | — |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 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. |
| Number of Participants With Clinically Significant Abnormal Electrocardiogram Findings | 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. |
| Changes From Baseline in Vital Sign Measurements | Days 1, 7, 14, 21, 28, and 56 | Vital signs measurements included systolic and diastolic blood pressure, pulse, temperature, and respiratory rate. |
| Number of Participants With Clinically Meaningful Change in Physical Examination Findings | 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. |
| 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 | — |
Countries
United States
Participant flow
Recruitment details
A total of 90 participants were planned to be enrolled across 4 treatment groups. As a result of early discontinuation of the study, only 2 treatment groups were initiated, with 1 participant enrolled in each group.
Participants by arm
| Arm | Count |
|---|---|
| SPR720 500 mg SPR720 500 mg administered orally once daily for 28 days. | 1 |
| Placebo Placebo administered orally once daily for 28 days. | 1 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Study Discontinuation | 0 | 1 |
Baseline characteristics
| Characteristic | SPR720 500 mg | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment United States | 1 participants | 1 participants | 2 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 1 |
| other Total, other adverse events | 1 / 1 | 1 / 1 |
| serious Total, serious adverse events | 0 / 1 | 0 / 1 |
Outcome results
Primary
Accumulation Ratio of SPR719
Time frame: Day 1 and Day 28 pre-dose and 1, 2, 4, 8, 12, and 24 hours post-dose
Population: No participants were enrolled at study sites that were conducting intensive PK evaluations.
Primary
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
Population: No participants were enrolled at study sites that were conducting intensive PK evaluations.
Primary
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.
Time frame: Day 1 and Day 28 pre-dose and 1, 2, 4, 8, 12, and 24 hours post-dose
Population: No participants were enrolled at study sites that were conducting intensive PK evaluations.
Primary
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
Population: No participants were enrolled at study sites that were conducting intensive PK evaluations.
Secondary
Changes From Baseline in Laboratory Tests
Time frame: Days 1, 7, 14, 21, 28, and 56
Population: Individual laboratory test results are not reported in order to protect patient confidentiality.
Secondary
Changes From Baseline in Vital Sign Measurements
Vital signs measurements included systolic and diastolic blood pressure, pulse, temperature, and respiratory rate.
Time frame: Days 1, 7, 14, 21, 28, and 56
Population: Individual vital sign measurement results are not reported in order to protect patient confidentiality.
Secondary
Number of Participants Who Received Any Concomitant Medication During the Study
Time frame: Day 1 to Day 56
Population: All treated participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SPR720 500 mg | Number of Participants Who Received Any Concomitant Medication During the Study | 1 Participants |
| Placebo | Number of Participants Who Received Any Concomitant Medication During the Study | 1 Participants |
Secondary
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.
Time frame: Days 1, 7, 14, 21, 28, and 56
Population: All treated participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SPR720 500 mg | Number of Participants With Clinically Meaningful Change in Physical Examination Findings | 0 Participants |
| Placebo | Number of Participants With Clinically Meaningful Change in Physical Examination Findings | 0 Participants |
Secondary
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.
Time frame: Days 1, 14, 28, and 56
Population: All treated participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SPR720 500 mg | Number of Participants With Clinically Significant Abnormal Electrocardiogram Findings | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Abnormal Electrocardiogram Findings | 0 Participants |
Secondary
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.
Time frame: Days 1, 7, 14, 21, 28, and 56
Population: All treated participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| SPR720 500 mg | Number of Participants With Clinically Significant Out-of-normal Range Laboratory Tests | Clinical chemistry | 0 Participants |
| SPR720 500 mg | Number of Participants With Clinically Significant Out-of-normal Range Laboratory Tests | Hematology | 0 Participants |
| SPR720 500 mg | Number of Participants With Clinically Significant Out-of-normal Range Laboratory Tests | Coagulation tests | 0 Participants |
| SPR720 500 mg | Number of Participants With Clinically Significant Out-of-normal Range Laboratory Tests | Urinalysis | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Out-of-normal Range Laboratory Tests | Urinalysis | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Out-of-normal Range Laboratory Tests | Clinical chemistry | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Out-of-normal Range Laboratory Tests | Coagulation tests | 0 Participants |
| Placebo | Number of Participants With Clinically Significant Out-of-normal Range Laboratory Tests | Hematology | 0 Participants |
Secondary
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.
Time frame: From first dose of study drug (Day 1) up to 28 days after last dose (56 days)
Population: All treated participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| SPR720 500 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | All TEAEs | 1 Participants |
| SPR720 500 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Mild TEAEs | 1 Participants |
| SPR720 500 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Moderate TEAEs | 0 Participants |
| SPR720 500 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Severe TEAEs | 0 Participants |
| SPR720 500 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAEs leading to discontinuation of study drug | 0 Participants |
| SPR720 500 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAEs leading to discontinuation from study | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAEs leading to discontinuation of study drug | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | All TEAEs | 1 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Severe TEAEs | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Mild TEAEs | 1 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAEs leading to discontinuation from study | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Moderate TEAEs | 0 Participants |
Secondary
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
Population: No participants had out-of-range laboratory test results hence shift tables could not be created.