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

Official title

Population Pharmacokinetics and Pharmacodynamics of Standard First Line Anti-TB Versus Atorvastatin-Containing Regimens in the Treatment of Pulmonary Tuberculosis: A Sub-study of the ATORTUB Phase 2C Randomized Controlled Trial (ATORTUB popPK-PD Study)

Overview

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.

Detailed 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.

Interventions

• Drug Atorvastatin 20 mg
  Participants will receive 16weeks of daily oral treatment with 20mg atorvastatin 4AT(20)\]
• Drug Atorvastatin 40 mg
  Participants will receive 16 weeks of daily oral treatment with 40mg atorvastatin 4AT(40)\]
• Drug Atorvastatin 60 mg
  Participants will receive 16weeks of daily oral treatment with 60mg atorvastatin 4AT(60)
• Drug Fixed dose combination of Rifampicin (R) Isoniazid (H) Pyrazinamid (Z) Ethambutol (E)
  Participants will receive 8 weeks of daily oral treatment with rifampin, isoniazid, pyrazinamide, ethambutol, followed by 16 weeks of daily treatment with rifampin, isoniazid \[2RHZE/4RH\]

Primary outcome measures

• Area under the plasma concentration versus time curve (AUC 0-24) for atorvastatin acid, rifampicin, isoniazid and their metabolites at steady state [Time frame: Sampling will be on day 14 & week 8, 16 and 24 post randomization]
• Peak Plasma Concentration (Cmax) for atorvastatin acid, rifampicin, isoniazid and their metabolites at steady state [Time frame: Sampling will be on day 14 & week 8, 16 and 24 post randomization]
• Plasma Clearance (Cl/F) in mL/min of atorvastatin acid, rifampicin, isoniazid and their metabolites at steady state [Time frame: Sampling will be on day 14 & week 8, 16 and 24 post randomization]

Secondary outcome measures (9)

• Correlation between AUC 0-24 of atorvastatin acid, 2-hydroxyl atorvastatin and 4- hydroxyl atorvastatin at steady state and days 0-14 early bactericidal activity in participants on atorvastatin-based regimens [Time frame: day 14 post randomization]
• Correlation between Cmax of atorvastatin acid, 2-hydroxyl atorvastatin and 4- hydroxyl atorvastatin at steady state and days 0-14 early bactericidal activity in participants on atorvastatin-based regimens [Time frame: day 14 post randomization]
• Correlation between Cmax of atorvastatin acid, 2-hydroxyl atorvastatin and 4- hydroxyl atorvastatin at steady state and time to stable sputum culture conversion [Time frame: 2 - 24 weeks post randomization]
• Correlation between AUC 0-24 of atorvastatin, atorvastatin acid, 2-hydroxyl atorvastatin and 4- hydroxyl atorvastatin) at steady state and change in baseline chest Xray severity score at 4, 6 and 12 months [Time frame: 16 -52weeks post randomisation]
• Correlation between AUC 0-24 of atorvastatin acid, 2-hydroxyl atorvastatin and 4- hydroxyl atorvastatin at steady state and time to stable sputum culture conversion [Time frame: 2 - 24 weeks post randomization]
• Correlation between Cmax of atorvastatin, atorvastatin acid, 2-hydroxyl atorvastatin and 4- hydroxyl atorvastatin) at steady state and change in baseline chest Xray severity score at 4, 6 and 12 months [Time frame: 16 - 52 weeks post randomization]
• Correlation between AUC 0-24 of atorvastatin acid, 2-hydroxyl atorvastatin and 4- hydroxyl atorvastatin) at steady state and change in baseline lung function at 4, 6 and 12 months [Time frame: 16 -52 weeks post randomization]
• Correlation between Cmax of atorvastatin acid, 2-hydroxyl atorvastatin and 4- hydroxyl atorvastatin) at steady state and change in baseline lung function at 4, 6 and 12 months [Time frame: 16 - 52 weeks post randomization]
• The optimal dose of atorvastatin that will be safe and effective as an adjunctive pulmonary TB treatment [Time frame: week 52 post randomization]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Nigeria · 3 centers

• National Tuberculosis and Leprosy Training Centre, Saye — Zaria
• Federal Teaching Hospital — Katsina
• Obafemi Awolowo University Teaching Hospitals Complex, Ile Ife, Osun state, Nigeria — Ile-Ife

Identifiers

NCT: NCT07303699 · ERC/2023/11/15/B · IRB/IEC/0004553

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗