Statin Adjunctive Therapy for TB

NCT03456102 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: IRB00145353
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

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.

Conditions

Tuberculosis

Outcome Measures

Primary Outcomes (1)

• 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.

  Up to 30 days

Study Arms (4)

Pravastatin 80 mg

OTHER

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.

Drug: Pravastatin

Pravastatin 120 mg

OTHER

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.

Drug: Pravastatin

Pravastatin 160 mg

OTHER

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.

Drug: Pravastatin

Pravastatin 40 mg

OTHER

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

Drug: Pravastatin

Interventions

Pravastatin DRUG

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.

Pravastatin 120 mg; Pravastatin 160 mg; Pravastatin 40 mg; Pravastatin 80 mg

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Johns Hopkins University: lead

Study Sites (1)

Chris Hani Baragwanath Hospital

Johannesburg, South Africa

Location

MeSH Terms

Conditions

Tuberculosis

Interventions

Pravastatin

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Results Point of Contact

• Title: Petros C. Karakousis, MD
• Organization: Johns Hopkins University School of Medicine

petros@jhmi.edu

410-502-8233

Study Officials

• Richard Chaisson

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 19, 2018
• First Posted: March 7, 2018
• Study Start: March 9, 2020
• Primary Completion: August 31, 2022
• Study Completion: August 31, 2022
• Last Updated: June 28, 2023
• Results First Posted: June 28, 2023

Record last verified: 2023-06

Locations

ZA (1)