ATORvastatin in Pulmonary TUBerculosis: a POPulation PharmacoKinetics -PharmacoDynamics Sub-study (ATORTUB popPK-PD)

Obafemi Awolowo University Teaching Hospital

Status and phase: Enrolling; Phase 2

Conditions: Pulmonary Tuberculosis (TB)

Treatments: Drug: Fixed dose combination of Rifampicin (R) Isoniazid (H) Pyrazinamid (Z) Ethambutol (E); Drug: Atorvastatin 40 mg; Drug: Atorvastatin 60 mg; Drug: Atorvastatin 20 mg

Study type: Interventional

Funder types: Other

Identifiers

NCT07303699

ERC/2023/11/15/B

IRB/IEC/0004553 (Other Identifier)

Details and patient eligibility

About

The purpose of this study is to assess pharmacokinetic parameters of atorvastatin at different doses when combined with the standard first line tuberculosis (TB) treatment regimen in adults with drug sensitive pulmonary TB. The pharmacokinetics parameters will be correlated with Pharmcodynamic measures and a PK/PD model that will identify an optimal dosing regimen of atorvastatin that is appropriate for the treatment of pulmonary tuberculosis will be developed.

Full description

This is a pharmacokinetics-pharmacodynamics sub-study of ATORTUB trial (NCT06199921) and a dose finding study of atorvastatin in adults with pulmonary TB.

It is a parallel dose comparison trial in which participants will be randomised into four treatment arms. Participants in the experimental arms of the study will receive standard anti-TB therapy for 24 weeks plus oral atorvastatin daily in the first 16 weeks. Study participants will be followed up for another 6 months post treatment. Total study duration for participants will be 52 weeks post randomization, during which participants will attend several study visits. Sputum specimen collection, chest Xray, lung function test, and sparse pharmacokinetic sampling will be done at each visit.

The pharmacokinetic/ Pharmacodynamic data for atorvastatin will be used to identify a dose to be studied as adjunctive TB treatment in subsequent trials.

Enrollment: 80 estimated patients

Sex: All

Ages: 12+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Sputum specimen positive for tubercle bacilli on Gene Xpert or direct smear microscopy

• Either no previous anti-TB chemotherapy, or less than 2 weeks of previous chemotherapy

• Aged 12years and above

• A firm home address that is readily accessible for visiting

• Agreement to participate in the study and to give a sample of blood for HIV testing

• Normal baseline laboratory values at or within 14 days prior to screening:

  • Serum or plasma alanine aminotransferase (ALT) less than or equal to 3 times the upper limit of normal
  • Serum or plasma total bilirubin less than or equal to 2.5 times the upper limit of normal
  • Serum or plasma creatinine level less than or equal to 2 times the upper limit of normal
  • Serum or plasma potassium level greater than or equal to 3.5 meq/L
  • Hemoglobin level of 7.0 g/dL or greater
  • Platelet count of 100,000/mm3 or greater

• Informed consent to participate in the study and to give a sample of blood for HIV testing

Exclusion criteria

• Participants known or suspected of having any form of drug resistance TB.
• Patients co infected with HIV
• Those with poor general condition where no delay in treatment can be tolerated
• Evidence of clinically significant metabolic or co morbid medical conditions ; malignancy; or other diseases like history of or current cardiovascular disorder such as heart failure, coronary heart disease, arrhythmia.
• Known or family history of bleeding disorders.
• Any renal impairment characterized by serum creatinine clearance of 1.5 x upper limit of normal of the clinical laboratory reference range at screening.
• Myositis and or Creatinine phosphokinase three times upper limit of normal
• Patient in a moribund state
• Has TB meningitis
• Presence of any of the pre-existing non-TB diseases outlined in the protocol
• Diabetes mellitus
• Hypertension
• Currently on anti TB medication
• Any other chronic illness/ co morbidities that warrants being on daily routine medications
• Presence of a psychiatric illness
• pregnant, or breast feeding mothers
• Current Tobacco Smokers/ tobacco use in any form
• Alcoholism
• alcoholic beverages, food or drinks containing methyl- xanthine (i.e. energy drinks, tea leaves, coffee beans, cocoa, kola nuts, medications e.g. theophylline). Ingestion of grapefruit/ products containing grapefruit juice, bitter oranges, garlic supplements, St John's Wort or other herbal supplements, within 7 days prior to the first treatment and throughout the study will not be allowed.
• Individuals that are enrolled in other therapeutic clinical trials

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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80 participants in 4 patient groups

20mg atorvastatin with standard of care (SOC) for TB

Experimental group

Description:

Trial of 20mg atorvastatin with standard of care (SOC) for TB \[2RHZE/4RH + 4AT(20)\]

Treatment:

Drug: Atorvastatin 20 mg

Drug: Fixed dose combination of Rifampicin (R) Isoniazid (H) Pyrazinamid (Z) Ethambutol (E)

40mg atorvastatin with standard of care (SOC) for TB

Experimental group

Description:

Trial of 40mg atorvastatin with standard of care (SOC) for TB \[2RHZE/4RH + 4AT(40)\]

Treatment:

Drug: Fixed dose combination of Rifampicin (R) Isoniazid (H) Pyrazinamid (Z) Ethambutol (E)

Drug: Atorvastatin 40 mg

60mg atorvastatin with standard of care (SOC) for TB

Experimental group

Description:

Trial of 60mg atorvastatin with standard of care (SOC) for TB \[2RHZE/4RH + 4AT(60)\]

Treatment:

Drug: Atorvastatin 60 mg

Drug: Fixed dose combination of Rifampicin (R) Isoniazid (H) Pyrazinamid (Z) Ethambutol (E)

standard of care (SOC) for TB

Active Comparator group

Description:

Standard of Care (SOC) for TB \[2RHZE/4RH\]

Treatment:

Drug: Fixed dose combination of Rifampicin (R) Isoniazid (H) Pyrazinamid (Z) Ethambutol (E)