Rosuvastatin Evaluation as a Tuberculosis Treatment Adjunct

Pulmonary Tuberculosis Clinical Trial

— ROSETTA  

Official title:

Rosuvastatin Evaluation as a Tuberculosis Treatment Adjunct

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04504851
• Other study ID #: ROSETTA
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: August 12, 2020
• Est. completion date: March 31, 2021

Study information

• Verified date: August 2020
• Source: National University Hospital, Singapore
• Contact: Gail Cross
• Phone: +65 83280377
• Email: mdcgbc[@]nus.edu.sg
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 154
• Est. completion date: March 31, 2021
• Est. primary completion date: March 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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).

Related Conditions & MeSH terms

• Pulmonary Tuberculosis
• Tuberculosis
• Tuberculosis, Pulmonary

Intervention

Drug:
• Rosuvastatin 10mg
10mg of Rosuvastatin in the Intensive Phase of Therapy (8 weeks)
• Rifampicin
Rifampicin 10mg/kg
• Isoniazid
Isoniazid 5mg/kg
• Pyrazinamide
Pyrazinamide 25mg/kg
• Ethambutol
Ethambutol 15mg/kg

Locations

Country	Name	City	State
Philippines	Tropical Disease Foundation	Makati City
Philippines	De La Salle Health Sciences Institute	Manila
Philippines	Lung Center Philippines	Quezon City
Singapore	National University Hospital, Singapore	Singapore
Uganda	Joint Clinical Research Centre	Kampala
Vietnam	Vietnam Military Medical University	Hanoi

Sponsors (1)

Lead Sponsor	Collaborator
National University Hospital, Singapore

Countries where clinical trial is conducted

Philippines,  Singapore,  Uganda,  Vietnam, 

Outcome

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