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Statin Adjunctive Therapy for TB (StAT-TB)

Primary Purpose

Tuberculosis

Status

Completed

Phase

Phase 2

Locations

South Africa

Study Type

Interventional

Intervention

Pravastatin

About this trial

This is an interventional treatment trial for Tuberculosis

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

18 years of age or older
Clinical signs and symptoms of pulmonary tuberculosis
Abnormal chest radiograph consistent with pulmonary tuberculosis
At least one sputum positive for M. tuberculosis by Xpert Mycobacterium tuberculosis (MTB)/resistance to rifampicin (RIF) with a cycle threshold (Ct) <28.
Documentation of HIV status
Weight ≥45 kg
Karnofsky score of at least 60
Ability to provide informed consent
Ability to adhere to study follow-up visits
Ability to adhere to contraceptive requirements and willing to use two forms of contraception.
Five days or fewer of anti-tuberculosis treatment within the previous 3 months

Exclusion Criteria:

A history of severe adverse reactions to any statin or any other study agent or contraindications to use of statins.
Current use of statins or other lipid-lower agents;
Clinical indication for statin therapy based on cardiovascular risk (Familial hypercholesterolemia, Previous history of myocardial infarction or stroke)
For HIV-positive individuals, a cluster of differentiation 4 (CD4+) T-cell count <100/mm3
Use of antiretroviral drugs
Hemoglobin concentration less than 7 g/dL;
Baseline creatinine kinase elevation more than three times the upper limit of normal
Abnormal baseline laboratory values (Baseline alanine aminotransferase (ALT) concentration more than three times the upper limit of normal, Serum creatinine concentration more than twice the upper limit of normal, Serum total bilirubin level greater than twice the upper limit of normal, Platelet count < 100,000/mm3, White Blood Cell (WBC) < 2500 (mcL))
Pregnant or breastfeeding;
Silico-tuberculosis.
Currently receiving TB treatment
Concomitant disorders or conditions for which isoniazid, rifampin, pyrazinamide, or ethambutol is contraindicated. These include sever hepatic damage, acute liver disease of any cause, acute uncontrolled gouty arthritis and peripheral neuropathy.
Any medical or psychological condition which, in the view of the study investigator, makes study participation inadvisable.
Infection with an isolate known to be resistant to a first -line TB drug; for example rifampin.
More than five days of anti-tuberculosis treatment within the previous 3 months
Planned or current use of cyclosporine, tacrolimus, erythromycin or colchicine
Central nervous system (CNS) TB
Extra-pulmonary TB only, not in combination with pulmonary TB
History of TB

Sites / Locations

Chris Hani Baragwanath Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Other

Arm Label

Pravastatin 80 mg

Pravastatin 120 mg

Pravastatin 160 mg

Pravastatin 40 mg

Arm Description

Pravastatin 80 mg, isoniazid 300 mg, rifampin 450 mg (weight <50 kg) or 600 mg (weight >50 kg), pyrazinamide 20-25 mg/kg, and ethambutol 15-20 mg/kg daily for 14 days Arm 2 will only be recruited if pravastatin 40 mg is well tolerated and safe, yet drug exposures are significantly reduced due to the known interaction with rifampin.

Pravastatin 120 mg, isoniazid 300 mg, rifampin 450 mg (weight <50 kg) or 600 mg (weight >50 kg), pyrazinamide 20-25 mg/kg, and ethambutol 15-20 mg/kg daily for 14 days Arm 3 will only be recruited if pravastatin 80 mg is well tolerated and safe, yet drug exposures are significantly reduced due to the known interaction with rifampin.

Pravastatin 160 mg, isoniazid 300 mg, rifampin 450 mg (weight <50 kg) or 600 mg (weight >50 kg), pyrazinamide 20-25 mg/kg, and ethambutol 15-20 mg/kg daily for 14 days Arm 4 will only be recruited if pravastatin 120 mg is well tolerated and safe, yet drug exposures are significantly reduced due to the known interaction with rifampin.

Pravastatin 40 mg, isoniazid 300 mg, rifampin 450 mg (weight <50 kg) or 600 mg (weight >50 kg), pyrazinamide 20-25 mg/kg, and ethambutol 15-20 mg/kg daily for 14 days

Outcomes

Primary Outcome Measures

Safety of Escalating Doses of Pravastatin as Assessed by Number of Adverse Events

Safety of escalating doses of pravastatin (40 mg - 160 mg) when co-administered with rifampin, as evidenced by number of Grade 3 or higher adverse events.

Secondary Outcome Measures

Full Information

NCT ID

NCT03456102

First Posted

February 19, 2018

Last Updated

June 7, 2023

Sponsor

Johns Hopkins University

1. Study Identification

Unique Protocol Identification Number

NCT03456102

Brief Title

Statin Adjunctive Therapy for TB

Acronym

StAT-TB

Official Title

Statin Adjunctive Therapy for TB (StAT- TB)

Study Type

Interventional

2. Study Status

Record Verification Date

June 2023

Overall Recruitment Status

Completed

Study Start Date

March 9, 2020 (Actual)

Primary Completion Date

August 31, 2022 (Actual)

Study Completion Date

August 31, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Johns Hopkins University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

There is an urgent need for novel therapies to shorten TB treatment and improve long-term lung function outcomes. Host-directed therapies (HDT) have received significant attention recently given the ability of M. tuberculosis to subvert host immune responses and cause destructive lung pathology. Statins are among the most promising HDT agents for TB. In addition to having a highly favorable safety profile, statins have been shown to have anti-TB activity in macrophages, to synergize with anti-TB drugs, and to shorten the duration of TB treatment in the standard mouse model. The StAT-TB trial will comprise two different stages. In the 14-day Stage 1 study, investigators will test the safety and tolerability, as well as Pharmacokinetics (PK), of two different doses of pravastatin co-administered with standard anti-TB treatment. In Stage 2, investigators will test the ability of pravastatin adjunctive therapy (dose to be determined in Stage 1) to shorten the mean time to sputum culture conversion (primary endpoint) and improve lung function outcomes (secondary endpoints) relative to the standard regimen. In addition, investigators will continue to investigate the anti-TB mechanism of action of pravastatin in order to further improve HDT options for TB in the future.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Tuberculosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

16 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Pravastatin 80 mg

Arm Type

Other

Arm Description

Arm Title

Pravastatin 120 mg

Arm Type

Other

Arm Description

Arm Title

Pravastatin 160 mg

Arm Type

Other

Arm Description

Arm Title

Pravastatin 40 mg

Arm Type

Other

Arm Description

Pravastatin 40 mg, isoniazid 300 mg, rifampin 450 mg (weight <50 kg) or 600 mg (weight >50 kg), pyrazinamide 20-25 mg/kg, and ethambutol 15-20 mg/kg daily for 14 days

Intervention Type

Drug

Intervention Name(s)

Pravastatin

Intervention Description

Phase IIB clinical trial: A two-week safety/PK study to determine pravastatin exposures over 24 hours when given together with first-line treatment (HRZE) and ensure the combination is safe and well-tolerated. A two-week safety/PK study to determine pravastatin exposures over 24 hours when given together with first-line treatment (HRZE) and ensure the combination is safe and well-tolerated.

Primary Outcome Measure Information:

Title

Safety of Escalating Doses of Pravastatin as Assessed by Number of Adverse Events

Description

Safety of escalating doses of pravastatin (40 mg - 160 mg) when co-administered with rifampin, as evidenced by number of Grade 3 or higher adverse events.

Time Frame

Up to 30 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 18 years of age or older Clinical signs and symptoms of pulmonary tuberculosis Abnormal chest radiograph consistent with pulmonary tuberculosis At least one sputum positive for M. tuberculosis by Xpert Mycobacterium tuberculosis (MTB)/resistance to rifampicin (RIF) with a cycle threshold (Ct) <28. Documentation of HIV status Weight ≥45 kg Karnofsky score of at least 60 Ability to provide informed consent Ability to adhere to study follow-up visits Ability to adhere to contraceptive requirements and willing to use two forms of contraception. Five days or fewer of anti-tuberculosis treatment within the previous 3 months Exclusion Criteria: A history of severe adverse reactions to any statin or any other study agent or contraindications to use of statins. Current use of statins or other lipid-lower agents; Clinical indication for statin therapy based on cardiovascular risk (Familial hypercholesterolemia, Previous history of myocardial infarction or stroke) For HIV-positive individuals, a cluster of differentiation 4 (CD4+) T-cell count <100/mm3 Use of antiretroviral drugs Hemoglobin concentration less than 7 g/dL; Baseline creatinine kinase elevation more than three times the upper limit of normal Abnormal baseline laboratory values (Baseline alanine aminotransferase (ALT) concentration more than three times the upper limit of normal, Serum creatinine concentration more than twice the upper limit of normal, Serum total bilirubin level greater than twice the upper limit of normal, Platelet count < 100,000/mm3, White Blood Cell (WBC) < 2500 (mcL)) Pregnant or breastfeeding; Silico-tuberculosis. Currently receiving TB treatment Concomitant disorders or conditions for which isoniazid, rifampin, pyrazinamide, or ethambutol is contraindicated. These include sever hepatic damage, acute liver disease of any cause, acute uncontrolled gouty arthritis and peripheral neuropathy. Any medical or psychological condition which, in the view of the study investigator, makes study participation inadvisable. Infection with an isolate known to be resistant to a first -line TB drug; for example rifampin. More than five days of anti-tuberculosis treatment within the previous 3 months Planned or current use of cyclosporine, tacrolimus, erythromycin or colchicine Central nervous system (CNS) TB Extra-pulmonary TB only, not in combination with pulmonary TB History of TB

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Richard Chaisson

Organizational Affiliation

Johns Hopkins University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Chris Hani Baragwanath Hospital

City

Johannesburg

Country

South Africa

12. IPD Sharing Statement

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Statin Adjunctive Therapy for TB

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