Tuberculosis, PulmonaryPhase 2/3StatinTBNCT04147286
Atorvastatin to Reduce Inflammation After Tuberculosis Treatment Completion
A Phase 2/3 study testing Atorvastatin 40mg in people with Tuberculosis, Pulmonary, run by University of Cape Town at 1 site in South Africa.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Tuberculosis, Pulmonary
- What is being tested?
- Atorvastatin 40mg
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 220 participants
- Where
- 1 siteSouth Africa
- Study dates
- 14 Jul 2020to 30 Sep 2027
- Phase
- Phase 2/3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Has completed the written informed consent process prior to undergoing any pre-screening or screening evaluations and willing to undergo HIV testing
- Age 18 to 65 years with body weight from 50 kg to 90 kg
- Clinical response to TB treatment and sputum culture negative at week 16
- Completed a 24-week course of standard TB treatment (4RHZE/2RH)
- Defined as "cured" by the TB Control Program of South Africa
- Laboratory parameters within 30 days before enrolment:
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- For HIV-infected participants: receiving antiretroviral therapy for at least 12 weeks and suppressed HIV viral load within 30 days prior to enrolment
- For HIV-infected participants: CD4 counts above 350 cells/µL within 30 days prior to enrolment
- AST and ALT <3x upper limit of normal (ULN)
- Creatinine <2x ULN
- Hemoglobin >7.0 g/dL
- Platelet count >50 x109 cells/L
- Creatinine kinase <2x ULN
- Able and willing to return to follow-up
- Willing to have samples, including DNA, stored
- Willing to consistently practice a highly reliable method of pregnancy prevention
Who cannot join
- Acute illness
- Fever (temperature >38.0 degrees centigrade)
- Participant receiving any type of lipid lowering agent at the time of screening, within three months prior to screening or likely to require any lipid lowering agent in the near future.
- Known allergy or contraindications to the investigational drug or any other statins
- Evidence of drug-resistant TB
- Extrapulmonary TB, including pleural TB and/or large pleural effusion
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- Pregnant or desiring/trying to become pregnant in the next 6 months
- Unable to take oral medications
- Diabetes as defined by point of care HbA1c≥6.5, random glucose≥200mg/dL (or 11.1mmol/L), fasting plasma glucose≥126mg/dL (or 7.0mmol/L), or the presence of any anti-diabetic agent (including traditional medicines) as a concomitant medicine
- Disease complications or concomitant illnesses that may compromise safety or interpretation of trial endpoints, such as known diagnosis of chronic inflammatory condition (e.g. sarcoidosis, rheumatoid arthritis, connective tissue disorder)
- Use of immunosuppressive medications, such as TNF-alpha inhibitors or systemic or inhaled corticosteroids, within the past 2 weeks
- Use of any investigational drug in the previous 3 months
- Alcohol and substance abuse which might interfere with medication adherence during the trial
- Any person for whom the physician feels this study is not appropriate
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
South Africa1 site, 1 recruiting
- Recruiting
General Medicine & Global Health, Cape Heart Institute, Faculty of Health Sciences, University of Cape Town
Observatory, WC, 7925
Sandra Mukasa, MD, sandra.mukasa@uct.ac.za
Sandra Mukasa, MD
About this study
Official title: Double-blind, Randomized, Placebo-controlled Trial to Evaluate the Safety and Efficacy of Atorvastatin to Reduce Inflammation After Tuberculosis Treatment Completion in HIV-infected and HIV-uninfected Adults Measured by FDG-PET/CT
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.
Read the detailed description
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.
- Conditions
- Tuberculosis, Pulmonary
- Being tested
- Atorvastatin 40mg, Placebo oral tablet
- Keywords
- tuberculosis, HIV, COPD, inflammation
- Medical subject headings
- Tuberculosis, Pulmonary, Tuberculosis, Pulmonary Disease, Chronic Obstructive, Inflammation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Atorvastatin 40mgDrug
12 weeks of 40 mg atorvastatin therapy per os
Placebo oral tabletDrug
Identical placebo
| Study group | Role | What they receive |
|---|---|---|
| Atorvastatin (Arm B) | Active comparator | 12 weeks of 40 mg atorvastatin therapy per os daily Receives: Drug: Atorvastatin 40mg |
| Placebo (Arm C) | Placebo comparator | Identical placebo tablet is taken per os daily Receives: Drug: Placebo oral tablet |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Nov 2019
- Study start14 Jul 2020
- Primary completion30 Sep 2025 (estimated)
- Study completion30 Sep 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Tuberculosis, PulmonaryStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 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.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 220 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Cape Town
- Sponsor type
- University, hospital or other
- Collaborators
- University of Zurich, University of Namibia, University of Bern, University of Stellenbosch
- Responsible party
- Principal investigator, Prof Friedrich Thienemann, University of Cape Town
- Investigators
- Friedrich Thienemann, MD, Principal investigator, University of Cape TownReto Guler, PhD, Study chair, University of Cape Town
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04147286
- Sponsor's protocol ID
- HREC 675/2019
- Other IDs
- RIA2017T-2004, HREC 675/2019
- Acronym
- StatinTB
- Status last verified
- Aug 2024
- First submitted
- 23 Oct 2019
- Last updated
- 23 Aug 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 23 Aug 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Double-blind, Randomized, Placebo-controlled Trial to Evaluate the Safety and Efficacy of Atorvastatin to Reduce Inflammation After Tuberculosis Treatment Completion in HIV-infected and HIV-uninfected Adults Measured by FDG-PET/CT
- ClinicalTrials.gov ID
- NCT04147286
- Acronym / sponsor ID
- StatinTB / HREC 675/2019
- Conditions
- Tuberculosis, Pulmonary
- Keywords
- tuberculosis, HIV, COPD, inflammation
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 220 participants (estimated)
- Lead sponsor
- University of Cape TownUniversity, hospital or other
- Collaborators
- University of Zurich, University of Namibia, University of Bern, University of Stellenbosch
- Study start
- 14 Jul 2020 (actual)
- Primary completion
- 30 Sep 2025 (estimated)
- Study completion
- 30 Sep 2027 (estimated)
- First posted
- 1 Nov 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Atorvastatin (Arm B) | Active comparator | Drug: Atorvastatin 40mg12 weeks of 40 mg atorvastatin therapy per os daily |
| Placebo (Arm C) | Placebo comparator | Drug: Placebo oral tabletIdentical placebo tablet is taken per os daily |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- Has completed the written informed consent process prior to undergoing any pre-screening or screening evaluations and willing to undergo HIV testing
- Age 18 to 65 years with body weight from 50 kg to 90 kg
- Clinical response to TB treatment and sputum culture negative at week 16
- Completed a 24-week course of standard TB treatment (4RHZE/2RH)
- Defined as "cured" by the TB Control Program of South Africa
Key exclusion criteria (14 listed)
- Acute illness
- Fever (temperature >38.0 degrees centigrade)
- Participant receiving any type of lipid lowering agent at the time of screening, within three months prior to screening or likely to require any lipid lowering agent in the near future.
- Known allergy or contraindications to the investigational drug or any other statins
- Evidence of drug-resistant TB
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Atorvastatin 40mg12 weeks of 40 mg atorvastatin therapy per os | Drug | Atorvastatin (Arm B) |
| Placebo oral tabletIdentical placebo | Drug | Placebo (Arm C) |
Primary outcome
Total lung glycolysis (TLG) on PET/CT imaging
Time frame: 12 weeks
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.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Aug 2024.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Friedrich Thienemann, MD principal investigator
University of Cape Town
Reto Guler, PhD study chair
University of Cape Town
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Atorvastatin 40mg in people with Tuberculosis, Pulmonary, run by University of Cape Town at 1 site in South Africa.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 23 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Friedrich Thienemann, MD (+27 21 406 6358, friedrich.thienemann@uct.ac.za), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Total lung glycolysis (TLG) on PET/CT imaging (time frame: 12 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Aug 2024.