A Phase 2/3 interventional study of Atorvastatin 40mg and Placebo oral tablet in Tuberculosis, Pulmonary, sponsored by University of Cape Town. Recruiting at 1 site in South Africa. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2024-08-23.
Sponsored by University of Cape Town · Phase 2/3, Interventional, and Treatment
This is a proof-of-concept phase IIB, double-blind, randomized, placebo-controlled trial to evaluate the safety and efficacy of 40 mg atorvastatin to reduce persistent lung inflammation after successful TB treatment completion in HIV-infected and HIV-uninfected adults measured by PET/CT.
Mycobacterium tuberculosis (Mtb) causes 1.8 million deaths annually. Sub-Saharan Africa carries the highest burden of tuberculosis (TB) with recurrent TB rates between 3-5% after treatment completion accounting for 10-30% of all cases within some TB control programs. Multiple risk factors have been identified to cause recurrent diseases. A recent study has identified persistent lesion activity by 18F-fluoro-D-glucose positron emission tomography (PET/CT) suggesting ongoing inflammation and Mtb mRNA suggesting ongoing infection after cure. The presence of inflammation and mRNA implies that current curative treatment options for pulmonary TB may not eradicate Mtb in most patients and more potent treatment options including host-directed therapy (HDT) to sterilize during or after TB treatment is required.
Mtb accumulates host cholesterol ester in foamy macrophages and utilizes cholesterol for its persistence within macrophages. Statins lower cholesterol in cardiovascular diseases through inhibition of HMG-CoA reductase, the rate-controlling enzyme of the mevalonate pathway. In addition, statins also have broad-range immune-modulatory and anti-inflammatory properties.
As previously reported in pre-clinical models that statins reduced Mtb burden by enhancing autophagy, phagosomal maturation and decreasing pulmonary pathology, suggesting a role for statins as HDT in TB. Others reported that statins as adjunctive therapy reduced the time for TB cure and decreased lung pathology in mice. A recent population-based study consisting of 1 million people reported that statin treatment was associated with a decreased risk of active TB.
This protocol builds upon successful studies suggesting that directly monitoring lung pathology using PET/CT correlates better with treatment outcome than culture and persistent inflammation measured by PET/CT is present after tuberculosis cure in most patients.
The investigators propose a proof-of-concept phase IIB, double-blind, randomized, placebo-controlled trial to evaluate the safety and efficacy of 40 mg atorvastatin per os daily to reduce persistent inflammation after TB treatment completion in HIV-infected and HIV-uninfected adults measured by PET/CT.
If successful, this trial has proven that statins as HDT can be safe and effective adjunctive therapy to TB treatment in general and further efficacy trials can be undertaken to translate the results of this trial into reduced TB relapse rate and reduced post-TB chronic lung disease, thus decreased long-term TB-related morbidity.
The investigators hypothesize that 12 weeks of 40 mg atorvastatin therapy per os initiated at the end of successful TB treatment in HIV infected and HIV-uninfected participants will significantly reduce persistent lung inflammation on PET/CT scan.
Primary objective To compare persistent lung inflammation measured by total lung glycolysis (TLG) on PET/CT after 12 weeks of 40 mg atorvastatin therapy and placebo.
Defined as "cured" by the TB Control Program of South Africa
Laboratory parameters within 30 days before enrolment:
Exclusion criteria
12 weeks of 40 mg atorvastatin therapy per os daily
Drug: Atorvastatin 40mg
Identical placebo tablet is taken per os daily
Drug: Placebo oral tablet
12 weeks of 40 mg atorvastatin therapy per os
Identical placebo
Total lung glycolysis (TLG) on PET/CT imaging
The primary outcome measure is total lung glycolysis (TLG) on PET/CT imaging. Total lung glycolysis (TLG), is the total glycolytic activity (TGA) in regions of interest (both lungs). Primary outcome measurement is semi-automated using nuclear medicine medical imaging software (MIM Software Inc.). Total lung masks are drawn on every participant's PET/CT scans. Glycolytic activity is derived for each lung (SUVbw\*mL), total lung glycolytic activity is the sum of both lungs TGA.
Time frame: 12 weeks
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University of Cape Town