Rosuvastatin Evaluation as a Tuberculosis Treatment Adjunct

NCT ID: NCT04504851

Last Updated: 2020-08-07

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 154 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-08-12
• Study Completion Date: 2021-03-31

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.

Conditions

Pulmonary Tuberculosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A (Standard of Care)

Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol, then 16 weeks rifampicin, isoniazid

Group Type: ACTIVE_COMPARATOR

Rifampicin

Intervention Type: DRUG

Rifampicin 10mg/kg

Isoniazid

Intervention Type: DRUG

Isoniazid 5mg/kg

Pyrazinamide

Intervention Type: DRUG

Pyrazinamide 25mg/kg

Ethambutol

Intervention Type: DRUG

Ethambutol 15mg/kg

Arm B (Standard of Care plus Rosuvastatin)

Standard combination treatment for pulmonary TB of 8 weeks rifampicin, isoniazid, pyrazinamide, ethambutol PLUS rosuvastatin, then 16 weeks rifampicin, isoniazid

Group Type: EXPERIMENTAL

Rosuvastatin 10mg

Intervention Type: DRUG

10mg of Rosuvastatin in the Intensive Phase of Therapy (8 weeks)

Rifampicin

Intervention Type: DRUG

Rifampicin 10mg/kg

Isoniazid

Intervention Type: DRUG

Isoniazid 5mg/kg

Pyrazinamide

Intervention Type: DRUG

Pyrazinamide 25mg/kg

Ethambutol

Intervention Type: DRUG

Ethambutol 15mg/kg

Interventions

Rosuvastatin 10mg

10mg of Rosuvastatin in the Intensive Phase of Therapy (8 weeks)

Intervention Type: DRUG

Rifampicin

Rifampicin 10mg/kg

Intervention Type: DRUG

Isoniazid

Isoniazid 5mg/kg

Intervention Type: DRUG

Pyrazinamide

Pyrazinamide 25mg/kg

Intervention Type: DRUG

Ethambutol

Ethambutol 15mg/kg

Intervention Type: DRUG

Other Intervention Names

Crestor

Eligibility Criteria

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

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).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National University Hospital, Singapore

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nicholas Paton

Role: PRINCIPAL_INVESTIGATOR

National University Hospital, Singapore

Locations

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

Joint Clinical Research Centre

Kampala, , Uganda

Vietnam Military Medical University

Hanoi, , Vietnam

Countries

Philippines; Singapore; Uganda; Vietnam

Central Contacts

Gail Cross

Role: CONTACT

mdcgbc@nus.edu.sg

+65 83280377

Nicholas Paton

Role: CONTACT

mdcnijp@nus.edu.sg

+65 6601 5371

References

Cross GB, Sari IP, Burkill SM, Yap CW, Nguyen H, Quyet D, Dalay VB, Gutierrez E, Balanag VM, Castillo RJ, Chang CC, Kelleher AD, O'Doherty J, Paton NI. PET-CT outcomes from a randomised controlled trial of rosuvastatin as an adjunct to standard tuberculosis treatment. Nat Commun. 2024 Dec 2;15(1):10475. doi: 10.1038/s41467-024-54419-3.

Reference Type: DERIVED

PMID: 39622823 (View on PubMed)

Cross GB, Sari IP, Kityo C, Lu Q, Pokharkar Y, Moorakonda RB, Thi HN, Do Q, Dalay VB, Gutierrez E, Balanag VM, Castillo RJ, Mugerwa H, Fanusi F, Kwan P, Chew KL, Paton NI; ROSETTA trial team. Rosuvastatin adjunctive therapy for rifampicin-susceptible pulmonary tuberculosis: a phase 2b, randomised, open-label, multicentre trial. Lancet Infect Dis. 2023 Jul;23(7):847-855. doi: 10.1016/S1473-3099(23)00067-1. Epub 2023 Mar 23.

Reference Type: DERIVED

PMID: 36966799 (View on PubMed)

Other Identifiers

ROSETTA

Identifier Type: -

Identifier Source: org_study_id