Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202211865409139 Date of Approval: 24/11/2022
Trial Status: Retrospective registration - This trial was registered after enrolment of the first participant
TRIAL DESCRIPTION
Public title StatinTB Trial
Official scientific title Preventing tuberculosis relapse and chronic lung disease: a proof-of-concept, 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
Brief summary describing the background and objectives of the trial 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. We 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. We 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.We 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.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) StatinTB
Disease(s) or condition(s) being studied Infections and Infestations,Respiratory
Sub-Disease(s) or condition(s) being studied Tuberculosis
Purpose of the trial Treatment: Drugs
Anticipated trial start date 01/07/2020
Actual trial start date 14/07/2020
Anticipated date of last follow up 30/04/2024
Actual Last follow-up date 30/06/2024
Anticipated target sample size (number of participants) 342
Actual target sample size (number of participants)
Recruitment status Recruiting
Publication URL statintb.com/publications/
Secondary Ids Issuing authority/Trial register
HREC Ref 675 2019 UCT Human Research Ethics Committee
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Factorial: participants randomly allocated to either no, one, some or all interventions simultaneously Randomised Stratified allocation where factors such as age, gender, center, or previous treatment are used in the stratification Allocation was determined by the holder of the sequence who is situated off site Masking/blinding used Care giver/Provider,Participants
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group Arm C 40mg Atorvastatin daily 12 weeks 40mg Atorvastatin daily for 12 weeks after successful Drug Sensitive Pulmonary TB Treatment completion 57
Control Group Arm B 1 tablet of Placebo daily 12 weeks 1 tablet of Placebo daily for 12 weeks after successful Drug Sensitive Pulmonary TB Treatment completion 57 Placebo
Control Group Arm A No drug or placebo given N.A Observational cohort who does not have extensive persistent lung inflammation as defined by the protocol and are followed up for 12 weeks. 114 Uncontrolled
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
1. Has completed the written informed consent process prior to undergoing any pre-screening or screening evaluations and willing to undergo HIV testing 2. Age 18 to 65 years with body weight from 50 kg to 90 kg 3. Clinical response to TB treatment and sputum culture negative at week 16 4. Completed a course of standard TB treatment Laboratory parameters within 30 days before enrolment: 5. For HIV-infected participants: suppressed HIV viral load within 30 days prior to enrolment 6. AST and ALT <3x upper limit of normal (ULN) 7. Creatinine <2x ULN 8. Hemoglobin >7.0 g/dL 9. Platelet count >50 x109 cells/L 10. Creatinine kinase <2x ULN 11. Able and willing to return to follow-up 12. Willing to have samples, including DNA, stored 13. Willing to consistently practice a highly reliable method of pregnancy prevention 1. Acute illness 2. Fever (temperature >38.0 degrees centigrade) 3. 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. 4. Known allergy or contraindications to the investigational drug or any other statins 5. Any drug with significant drug-drug interaction that increase exposure to atorvastatin and potentially the risk for the participants (E.g. protease inhibitors) 6. Evidence of drug-resistant TB 7. Extrapulmonary TB, including pleural TB and/or large pleural effusion 8. Pregnant or desiring/trying to become pregnant in the next 6 months 9. Unable to take oral medications 10. Diabetes as defined by 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 as a concomitant medicine 11. 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) 12. Use of immunosuppressive medications, such as TNF-alpha inhibitors or systemic or inhaled corticosteroids, within the past 2 weeks 13. Use of any investigational drug in the previous 3 months 14. Alcohol and substance abuse which might interfere with medication adherence during the trial 15. Any person for whom the physician feels this study is not appropriate 16. Positive SARS-CoV-2 PCR or SARS-CoV-2 Rapid Antigen Test in the past 4 weeks 17. Claustrophobia - only for patients opting to undergo cardiac MRI 18. Pacemaker, bullet injury or ferromagnetic device or surgical clip (e.g. brain aneurysm clip, aortic clip, heart valve, insulin pump, IUD, joint replacement, protheses, wire sutures, dentures) - only for patients opting to undergo cardiac MRI 19. Allergy to CMR contrast media - only for patients opting to undergo cardiac MR Adult: 19 Year-44 Year,Middle Aged: 45 Year(s)-64 Year(s) 18 Year(s) 65 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 20/01/2020 UCT Human Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
Room G50-46 Old Main Building, Groote Schuur Hospital, Observatory Cape Town 7925 South Africa
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 19/03/2020 SAHPRA
Ethics Committee Address
Street address City Postal code Country
Building A, Lotus Park, 402 Kirkness Street, Arcadia Pretoria 0083 South Africa
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome To compare persistent lung inflammation measured by total lung glycolysis (TLG) on PET/CT after 12 weeks of 40 mg atorvastatin therapy and placebo. At the start of the trial and then after 12 weeks of treatment/ placebo
Secondary Outcome 1. To compare safety profile including laboratory findings, HIV viral load and CD4 count after 12 weeks of atorvastatin therapy and placebo. 2. To compare persistent lung damage measured by hard volume and cavity air volume on PET/CT after 12 weeks of atorvastatin therapy and placebo. 3. To compare pulmonary functions by spirometry, lung volumes, oxygen desaturation, and 6-minute walk test (6MWT) after 12 weeks of atorvastatin therapy and placebo. 4. To evaluate whether atorvastatin therapy reduces the proportion of participants with TB relapse by sputum reversion at 12- and 24-weeks post treatment by allocation. 5. To compare sputum culture reversion rates to Xpert® MTB/RIF Ultra and PET/CT at 12 weeks post treatment by allocation. 6. To compare changes on PET/CT after 12 weeks of atorvastatin therapy and placebo to baseline PET/CT. 7. To evaluate the effect of atorvastatin therapy on serum low-density lipoprotein (LDL) cholesterol levels by lipid profiling at 2, 4, 8, 12- and 24-weeks post treatment by allocation. 8. To compare the immunological and blood biomarkers, blood transcriptional and proteomic profiling by ELISA/Luminex, RNAseq, mass spectrometry and macrophage assays (phagosomal, autophagy and ex vivo Mtb growth) after 2, 4, 8 and 12 weeks of atorvastatin therapy and placebo, and at week 24. 9. To compare the immunological and blood biomarkers, blood transcriptional and proteomic profiling by ELISA/Luminex, RNAseq, mass spectrometry and macrophage assays (phagosomal, autophagy and ex vivo Mtb growth) of participants with no or minimal persistent inflammation on baseline PET/CT (TLG<50SUV*mL) to participants with extensive persistent inflammation on baseline PET/CT (TLG≥50SUV*mL) and week 12 and 24 after enrolment. 10. To compare week 24 sputum culture reversion rates, Xpert® MTB/RIF Ultra of participants with no or minimal persistent inflammation on baseline PET/CT (TLG<50SUV*mL) to participants with extensive persistent inflammation on baseline PET/CT Depending on the test, at baseline, 2 weeks, 4 weeks, 8 weeks,12 weeks and 24 weeks respectively
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
General Medicine and Global Health Research Site 157 12th Avenue Kensington Cape Town 7405 South Africa
FUNDING SOURCES
Name of source Street address City Postal code Country
European and Developing Countries Clinical Trials Partnership Francie van Zijl Drive, Parrow valley Cape Town 7505 South Africa
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor University of Cape Town The UCT Faculty of Health Sciences, Anzio Road, Observatory Cape Town 7925 South Africa University
COLLABORATORS
Name Street address City Postal code Country
University of Cape Town The UCT Faculty of Health Sciences, Anzio Road, Observatory Cape Town 7925 South Africa
University of Zurich Ramistrasse 71 CH-8006 Zurich Switzerland
University of Namibia 340 Pioneers Park, Mandume Ndemufayo Windhoek Namibia
Imperial College London Exhibition Road London United Kingdom
LINQ Management GMBH 14 A Trendelenburg Street Berlin Germany
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Sandra Mukasa sandra.mukasa@uct.ac.za +27214066088 157 12th Avenue Kensington
City Postal code Country Position/Affiliation
Cape Town 7405 South Africa University of Cape Town
Role Name Email Phone Street address
Public Enquiries Nosie Mkuzangwe nosie.mkuzangwe@uct.ac.za +27730551794 157 12th Avenue Kensington
City Postal code Country Position/Affiliation
Cape Town 7405 South Africa University of Cape Town
Role Name Email Phone Street address
Scientific Enquiries Friedrich Thienemann friedrich.thienemann@uct.ac.za +27214066358 Cape Heart Institute, 4th floor, Chris Barnard Building, UCT Faculty of Health Sciences, Anzio Road, Observatory
City Postal code Country Position/Affiliation
Cape Town 7925 South Africa University of Cape Town and University of Zurich
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Data to be shared include information collected from participants of the StatinTB study in the clinical research forms and metadata. All shared data will be de-identified and presented using the assigned participant identifier (PID) Clinical Study Report Requests may be made on completion of data collecting, which is likely to be December 2023. A decision on the request will be provided to the requesting party shortly after the request. A data request can only be submitted by an experienced data manager and analyst or if the requesting team has an experienced data manager or analyst. Data may only be shared in the context of non-commercial studies which are relevant to the advancement of TB or related research. Seeking direct financial benefits for the samples and/or data that have been shared is not permitted.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
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Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
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