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

• Sponsor: Spero Therapeutics (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT04553406
• Collaborator: (none)
• Enrollment: 2
• Locations: 9
• Arms: 4
• Actual Duration (Months): 1.8
• Patients Per Site: 0.2
• Patients Per Site Per Month: 0.1

Study Details

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
• 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: Dec 3, 2020
• Actual Primary Completion Date: Jan 28, 2021
• Actual Study Completion Date: Jan 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 [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 [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 [Day 1 and Day 28 pre-dose and 1, 2, 4, 8, 12, and 24 hours post-dose]

4. 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

1. 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.

2. 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.

3. Number of Participants Who Received Any Concomitant Medication During the Study [Day 1 to Day 56]

4. Changes From Baseline in Laboratory Tests [Days 1, 7, 14, 21, 28, and 56]

5. 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.

6. 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]

7. 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.

8. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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 exclusion criteria per protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medical Facility	Altamonte Springs	Florida	United States	32701
2	Medical Facility	Atlantis	Florida	United States	33462
3	Medical Facility	Clearwater	Florida	United States	33765
4	Medical Facility	Kissimmee	Florida	United States	34746
5	Medical Facility	West Palm Beach	Florida	United States	33407
6	Medical Facility	Charlotte	North Carolina	United States	28207
7	Medical Facility	Mooresville	North Carolina	United States	28117
8	Medical Facility	Winston-Salem	North Carolina	United States	27103
9	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)

• Study Protocol and Statistical Analysis Plan - Sep 17, 2020

More Information

Publications

None provided.

• Responsible Party: Spero Therapeutics
• ClinicalTrials.gov Identifier: NCT04553406
• Other Study ID Numbers: SPR720-201
• First Posted: Sep 17, 2020
• Last Update Posted: Feb 28, 2022
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• 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

Study Results

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.

Arm/Group Title	SPR720 500 mg	Placebo
Arm/Group Description	SPR720 500 mg administered orally once daily for 28 days.	Placebo administered orally once daily for 28 days.
Period Title: Overall Study
STARTED	1	1
COMPLETED	1	0
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	SPR720 500 mg	Placebo	Total
Arm/Group Description	SPR720 500 mg administered orally once daily for 28 days.	Placebo administered orally once daily for 28 days.	Total of all reporting groups
Overall Participants	1	1	2
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	0 0%	1 100%	1 50%
>=65 years	1 100%	0 0%	1 50%
Sex: Female, Male (Count of Participants)
Female	1 100%	1 100%	2 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 100%	1 50%
Not Hispanic or Latino	1 100%	0 0%	1 50%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	1 100%	1 100%	2 100%
Region of Enrollment (participants) [Number]
United States	1 100%	1 100%	2 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Plasma Concentration (Cmax) of SPR719
Description	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

Outcome Measure Data

Analysis Population Description

No participants were enrolled at study sites that were conducting intensive PK evaluations.

Arm/Group Title	SPR720 500 mg
Arm/Group Description	SPR720 500 mg administered orally once daily for 28 days.
Measure Participants	0

2. Primary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

No participants were enrolled at study sites that were conducting intensive PK evaluations.

Arm/Group Title	SPR720 500 mg
Arm/Group Description	SPR720 500 mg administered orally once daily for 28 days.
Measure Participants	0

3. Primary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

No participants were enrolled at study sites that were conducting intensive PK evaluations.

Arm/Group Title	SPR720 500 mg
Arm/Group Description	SPR720 500 mg administered orally once daily for 28 days.
Measure Participants	0

4. Primary Outcome

Title	Accumulation Ratio of SPR719
Time Frame	Day 1 and Day 28 pre-dose and 1, 2, 4, 8, 12, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

No participants were enrolled at study sites that were conducting intensive PK evaluations.

Arm/Group Title	SPR720 500 mg
Arm/Group Description	SPR720 500 mg administered orally once daily for 28 days.
Measure Participants	0

5. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Description	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)

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	SPR720 500 mg	Placebo
Arm/Group Description	SPR720 500 mg administered orally once daily for 28 days.	Placebo administered orally once daily for 28 days.
Measure Participants	1	1
All TEAEs	1 100%	1 100%
Mild TEAEs	1 100%	1 100%
Moderate TEAEs	0 0%	0 0%
Severe TEAEs	0 0%	0 0%
TEAEs leading to discontinuation of study drug	0 0%	0 0%
TEAEs leading to discontinuation from study	0 0%	0 0%

6. Secondary Outcome

Title	Number of Participants With Clinically Meaningful Change in Physical Examination Findings
Description	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

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	SPR720 500 mg	Placebo
Arm/Group Description	SPR720 500 mg administered orally once daily for 28 days.	Placebo administered orally once daily for 28 days.
Measure Participants	1	1
Count of Participants [Participants]	0 0%	0 0%

7. Secondary Outcome

Title	Number of Participants Who Received Any Concomitant Medication During the Study
Time Frame	Day 1 to Day 56

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	SPR720 500 mg	Placebo
Arm/Group Description	SPR720 500 mg administered orally once daily for 28 days.	Placebo administered orally once daily for 28 days.
Measure Participants	1	1
Count of Participants [Participants]	1 100%	1 100%

8. Secondary Outcome

Title	Changes From Baseline in Laboratory Tests
Time Frame	Days 1, 7, 14, 21, 28, and 56

Outcome Measure Data

Analysis Population Description

Individual laboratory test results are not reported in order to protect patient confidentiality.

Arm/Group Title	SPR720 500 mg	Placebo
Arm/Group Description	SPR720 500 mg administered orally once daily for 28 days.	Placebo administered orally once daily for 28 days.
Measure Participants	0	0

9. Secondary Outcome

Title	Number of Participants With Clinically Significant Out-of-normal Range Laboratory Tests
Description	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

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	SPR720 500 mg	Placebo
Arm/Group Description	SPR720 500 mg administered orally once daily for 28 days.	Placebo administered orally once daily for 28 days.
Measure Participants	1	1
Clinical chemistry	0 0%	0 0%
Hematology	0 0%	0 0%
Coagulation tests	0 0%	0 0%
Urinalysis	0 0%	0 0%

10. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

No participants had out-of-range laboratory test results hence shift tables could not be created.

Arm/Group Title	SPR720 500 mg	Placebo
Arm/Group Description	SPR720 500 mg administered orally once daily for 28 days.	Placebo administered orally once daily for 28 days.
Measure Participants	0	0

11. Secondary Outcome

Title	Changes From Baseline in Vital Sign Measurements
Description	Vital signs measurements included systolic and diastolic blood pressure, pulse, temperature, and respiratory rate.
Time Frame	Days 1, 7, 14, 21, 28, and 56

Outcome Measure Data

Analysis Population Description

Individual vital sign measurement results are not reported in order to protect patient confidentiality.

Arm/Group Title	SPR720 500 mg	Placebo
Arm/Group Description	SPR720 500 mg administered orally once daily for 28 days.	Placebo administered orally once daily for 28 days.
Measure Participants	0	0

12. Secondary Outcome

Title	Number of Participants With Clinically Significant Abnormal Electrocardiogram Findings
Description	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

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	SPR720 500 mg	Placebo
Arm/Group Description	SPR720 500 mg administered orally once daily for 28 days.	Placebo administered orally once daily for 28 days.
Measure Participants	1	1
Count of Participants [Participants]	0 0%	0 0%

Adverse Events

Time Frame	From first dose of study up to 28 days after last dose (56 days).
Arm/Group Title	SPR720 500 mg		Placebo
Arm/Group Description	SPR720 500 mg administered orally once daily for 28 days.		Placebo administered orally once daily for 28 days.
All Cause Mortality
	SPR720 500 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/1 (0%)
Serious Adverse Events
	SPR720 500 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/1 (0%)
Other (Not Including Serious) Adverse Events
	SPR720 500 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		1/1 (100%)
Gastrointestinal disorders
Diarrhea	1/1 (100%)		0/1 (0%)
Vomiting	1/1 (100%)		0/1 (0%)
Nausea	1/1 (100%)		1/1 (100%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The PI may not publish the results prior to the first multi-site publication. If there is no multi-site publication within 18 months after Trial completion the PI may publish results from the trial, subject to the following. PI will submit proposed Publication to Sponsor 60 days prior to submission of the Publication. PI will, at Sponsor's request, delay such Publication for up to 90 days for Sponsor to obtain appropriate intellectual property protection.