Rosuvastatin Evaluation as a Tuberculosis Treatment Adjunct

Phase 2

• Conditions: Pulmonary Tuberculosis
• Interventions: Drug: Rifampicin; Drug: Rosuvastatin 10mg; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Ethambutol

• Registration Number: NCT04504851
• Lead Sponsor: National University Hospital, Singapore

Brief Summary

This trial aims to determine whether the addition of rosuvastatin to standard TB therapy in pulmonary tuberculosis results in accelerated of sputum culture conversion. The trial will also investigate potential new biomarkers of sterilising activity and immune-modulatory activity.

Detailed Description

Rosuvastatin is an HMG Co-A reductase inhibitor which may be of value as possible adjunctive agents to standard TB therapy. Cell culture assays and animal models demonstrate that statins are bactericidal against Mtb with effects that are additive to that of anti-tuberculous therapy.

This is a Phase IIb randomised, controlled, open-label, early bactericidal activity trial. We will recruit patients between the ages of 18 and 75 with newly-diagnosed smear or Xpert positive pulmonary TB, who have had no more than 7 days of TB therapy.

Patients will be randomised to take either standard TB therapy or standard TB therapy plus rosuvastatin for the first 8 weeks of their therapy. After the first 8 weeks, patients will continue standard combination TB therapy and remain in trial follow-up until week 24. The trial will collect sputum for culture on a weekly basis for the first 8 weeks of the trial, and less frequently leading up to week 24.

Study Timeline

• Status Verified: 2020-08
• Study First Submitted: 2020-08-05
• Study First Submitted QC: 2020-08-05
• Last Update Submitted: 2020-08-05
• Study First Posted: 2020-08-07
• Last Update Posted: 2020-08-07
• Study Start: 2020-08-12
• Primary Completion: 2021-03-31
• Study Completion: 2021-03-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 154

Inclusion Criteria

1. Aged 18 - 75 years of age

2. Abnormalities on CXR compatible with pulmonary TB

3. At least one sputum specimen, produced at or prior to screening during the current illness episode, that is:

   (i) positive for acid-fast bacilli on smear microscopy (with at least 1+ on the IUATLD/WHO scale) and/or (ii) positive on testing by Xpert MTB/RIF or Xpert Ultra (with semi-quantitative cycle threshold (CT) result of 'medium' or 'high')

4. Able to produce at least 5ml of sputum per day at the time of screening

5. Current or planned treatment with a regimen containing rifampicin, isoniazid and pyrazinamide (with or without ethambutol) only

6. Resident at a fixed address within feasible travelling distance to the site and likely to remain a local resident for the duration of trial follow-up

7. Willing to have directly observed therapy (DOT)

8. Willing to comply with the study visits and procedures

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Exclusion Criteria

1. More than 7 days of standard TB treatment by the time of the baseline visit

2. Known rifampicin resistance or isoniazid resistance at the time of randomization (results by conventional DST or molecular tests are not required to be available prior to randomization)

3. Previous treatment for active TB disease, unless rifampicin susceptibility has been demonstrated on a molecular test performed during this episode.

4. Extrapulmonary TB that, in the opinion of the treating clinician, is likely to require concurrent use of steroids, or require surgical management.

5. Known hypersensitivity to rosuvastatin

6. History of myopathy or family history of hereditary muscular disorders

7. Acute liver failure or decompensated chronic liver disease

8. Current alcohol abuse

9. Known hypothyroidism

10. Any of the following laboratory parameters at screening:

    1. ALT >3 times upper limit of normal (ULN)
    2. Estimated glomerular filtration rate (eGFR) < 60ml/min/1.73m2 (calculated using the CKD-EPI equation) (81)
    3. Creatine Kinase >5 times ULN
    4. Potassium <2.5 mmol/L

11. Active malignancy on chemotherapy or radiotherapy

12. Current use of immunosuppressive medication (≤ 5mg/ day of prednisolone or equivalent is acceptable).

13. HIV infection (unless patient has been stable on continuous antiretroviral therapy for at least 6 months, with CD4 count >/= 250 cells/mm3 and viral load </= 200 copies/ml, on a test performed at screening or during the last 12 months prior to screening, in which case they may be enrolled)

14. Use of any statin drug at screening or during the 3 months prior to screening

15. History of Atherosclerotic Cardiovascular Disease (ASCVD; defined as myocardial infarction, stable or unstable angina, coronary artery disease or coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral artery disease including aortic aneurysm, all of atherosclerotic origin)

16. Known Familial Hypercholesterolaemia

17. Other reasons, in the opinion of the investigator (and taking into consideration current local and international guidelines for primary prevention of cardiovascular disease), why the patient should commence statin treatment during the 6-month period following randomization

18. Current use of drugs contraindicated for use with rosuvastatin or standard TB drugs including fusidic acid, gemfibrozil, feno-fibrate, nicotinic acid (>1 gram/day), cyclosporine, directly acting antivirals for chronic Hepatitis C, protease inhibitors for HIV and praziquantel.

19. Women who are pregnant or breastfeeding

20. Women of childbearing potential unwilling or unable to use appropriate effective contraception for the first 12 weeks of the trial.

21. Any serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (such as extensive surgery, significant trauma, uncontrolled seizures)

22. Any other severe underlying condition that would, in the opinion of the investigator, compromise the patient's safety or outcome in the trial.

23. Participation in other clinical intervention trial or research protocol (participation in other studies that do not involve an intervention may be allowed, but this must be discussed and approved by the Chief Investigator).

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A (Standard of Care)	Isoniazid	Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol, then 16 weeks rifampicin, isoniazid
Arm A (Standard of Care)	Rifampicin	Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol, then 16 weeks rifampicin, isoniazid
Arm A (Standard of Care)	Pyrazinamide	Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol, then 16 weeks rifampicin, isoniazid
Arm A (Standard of Care)	Ethambutol	Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol, then 16 weeks rifampicin, isoniazid
Arm B (Standard of Care plus Rosuvastatin)	Rosuvastatin 10mg	Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol PLUS rosuvastatin, then 16 weeks rifampicin, isoniazid
Arm B (Standard of Care plus Rosuvastatin)	Ethambutol	Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol PLUS rosuvastatin, then 16 weeks rifampicin, isoniazid
Arm B (Standard of Care plus Rosuvastatin)	Pyrazinamide	Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol PLUS rosuvastatin, then 16 weeks rifampicin, isoniazid
Arm B (Standard of Care plus Rosuvastatin)	Rifampicin	Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol PLUS rosuvastatin, then 16 weeks rifampicin, isoniazid
Arm B (Standard of Care plus Rosuvastatin)	Isoniazid	Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol PLUS rosuvastatin, then 16 weeks rifampicin, isoniazid

Primary Outcome Measures

Name	Time	Method
Time to culture conversion in Liquid Media	within 8 weeks after randomisation	Time to culture conversion is defined is time from randomisation to the first of two consecutive negative sputum cultures

Secondary Outcome Measures

Name	Time	Method
Time to culture conversion in Solid media	within 8 weeks after randomisation	Time to culture conversion is defined is time from randomisation to the first of two consecutive negative sputum cultures
Sputum culture negative in Solid media	at 8 weeks from randomisation
Change in the aggregate cavity size on CXR	from baseline to week 8
One or more Grade 3 or Grade 4 adverse events	by week 24
Change in time to positivity (TTP)	from baseline to week 8
Change in FEV1/FVC	from baseline to week 8
Change in proportion of lung affected on CXR	from baseline to week 8
Change in score on St George's Respiratory Questionnaire (SGRQ)	from baseline to week 8
Time to culture conversion in Liquid media	within 12 weeks after randomisation	Time to culture conversion is defined is time from randomisation to the first of two consecutive negative sputum cultures
Sputum culture negative in Liquid media	at 8 weeks from randomisation
One of more Serious Adverse Events (SAEs)	by week 24

Trial Locations

Locations (6)

Joint Clinical Research Centre; 🇺🇬 Kampala, Uganda

Vietnam Military Medical University; 🇻🇳 Hanoi, Vietnam

Tropical Disease Foundation; 🇵🇭 Makati City, Philippines

De La Salle Health Sciences Institute; 🇵🇭 Manila, Philippines

Lung Center Philippines; 🇵🇭 Quezon City, Philippines

National University Hospital, Singapore; 🇸🇬 Singapore, Singapore