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

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)

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.

Study Overview

• Status: Recruiting
• Conditions: Pulmonary Tuberculosis (TB)
• Intervention / Treatment: Drug: Atorvastatin 20 mg; Drug: Fixed dose combination of Rifampicin (R) Isoniazid (H) Pyrazinamid (Z) Ethambutol (E); Drug: Atorvastatin 40 mg; Drug: Atorvastatin 60 mg

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.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Olanisun O Adewole, MD; Phone Number: +2348034074930; Email: adewolef@yahoo.co.uk , ola.adewole@oauife.edu.ng

Study Locations

• Nigeria
  • Kaduna State
    • Zaria, Kaduna State, Nigeria
      • Recruiting
      • National Tuberculosis and Leprosy Training Centre, Saye
      • Sub-Investigator: Eunice Jiya, MD
      • Contact: Eunice N Jiya - Chitumu, MD; Phone Number: +2348033714310
  • Katsina State
    • Katsina, Katsina State, Nigeria
      • Recruiting
      • Federal Teaching Hospital
      • Contact: Taofeek Oloyede, MD; Phone Number: +2348029423132
      • Sub-Investigator: Taofeek Oloyede, MD
  • Osun State
    • Ile-Ife, Osun State, Nigeria, 2345
      • Recruiting
      • Obafemi Awolowo University Teaching Hospitals Complex, Ile Ife, Osun state, Nigeria
      • Contact: Olanisun O Adewole, MD; Phone Number: +2348034074930; Email: adewolef@yahoo.co.uk , ola.adewole@oauife.edu.ng
      • Sub-Investigator: Bolanle A Omotoso, MD
      • Sub-Investigator: Olugbenga Ayoola, MD
      • Contact: Bolanle A Omotoso, MD; Phone Number: +2347037350229; Email: bolamotee@yahoo.co.uk
      • Principal Investigator: Olanisun O Adewole, MD
      • Sub-Investigator: Olayemi F Awopeju, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 20mg atorvastatin with standard of care (SOC) for TB; Trial of 20mg atorvastatin with standard of care (SOC) for TB [2RHZE/4RH + 4AT(20)]	Drug: Atorvastatin 20 mg; Participants will receive 16weeks of daily oral treatment with 20mg atorvastatin 4AT(20)]; Other Names: Astin; 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]; Other Names: Stop TB Kit
Experimental: 40mg atorvastatin with standard of care (SOC) for TB; Trial of 40mg atorvastatin with standard of care (SOC) for TB [2RHZE/4RH + 4AT(40)]	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]; Other Names: Stop TB Kit; Drug: Atorvastatin 40 mg; Participants will receive 16 weeks of daily oral treatment with 40mg atorvastatin 4AT(40)]; Other Names: Astin
Experimental: 60mg atorvastatin with standard of care (SOC) for TB; Trial of 60mg atorvastatin with standard of care (SOC) for TB [2RHZE/4RH + 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]; Other Names: Stop TB Kit; Drug: Atorvastatin 60 mg; Participants will receive 16weeks of daily oral treatment with 60mg atorvastatin 4AT(60); Other Names: Astin
Active Comparator: standard of care (SOC) for TB; Standard of Care (SOC) for TB [2RHZE/4RH]	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]; Other Names: Stop TB Kit

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the plasma concentration versus time curve (AUC 0-24) for atorvastatin acid, rifampicin, isoniazid and their metabolites at steady state	Sparse pharmacokinetic sampling will be employed during participants treatment follow up visits for the determination of plasma concentrations of atorvastatin acid, rifampicin, isoniazid. and their active metabolites (2-hydroxyl atorvastatin 4- hydroxyl atorvastatin, acetyl - isoniazid, desacetyl - rifampicin). AUC will be estimated using Population Pharmacokinetics analysis	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	Sparse pharmacokinetic sampling will be employed during participants treatment follow up visits for the determination of plasma concentrations of atorvastatin acid, rifampicin, isoniazid. and their active metabolites (2-hydroxyl atorvastatin 4- hydroxyl atorvastatin, acetyl - isoniazid, desacetyl - rifampicin). Cmax will be estimated using Population Pharmacokinetics analysis	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	Sparse pharmacokinetic sampling will be employed during participants treatment follow up visits for the determination of plasma concentrations of atorvastatin acid, rifampicin, isoniazid. and their active metabolites (2-hydroxyl atorvastatin 4- hydroxyl atorvastatin, acetyl - isoniazid, desacetyl - rifampicin). Plasma clearance of aforementioned drugs and metabolites will be estimated using Population Pharmacokinetics analysis	Sampling will be on day 14 & week 8, 16 and 24 post randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 to achieve culture negative sputum result as measured by growth on solid mycobacteria culture medium	2 - 24 weeks post randomization
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	steady state AUC 0-24 of atorvastatin acid, 2-hydroxyl atorvastatin and 4- hydroxyl atorvastatin will be correlated with early bactericidal activity on day 14. Early bactericidal activity will be measured as the daily rate of change in log10 Colony Forming Units of M. Tuberculosis in Sputum on Solid Media	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	Cmax of atorvastatin acid, 2-hydroxyl atorvastatin and 4- hydroxyl atorvastatin will be correlated with early bactericidal activity on day 14. Early bactericidal activity will be measured as the daily rate of change in log10 Colony Forming Units of M. Tuberculosis in Sputum on Solid Media	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 to achieve culture negative sputum result as measured by growth on solid mycobacteria culture medium	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	Change in baseline chest Xray severity score as measured by Timika Chest X ray scoring system. At least 30% reduction in Chest x-ray severity score is desirable	16 -52weeks post randomisation
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	Change in baseline chest Xray severity score as measured by Timika Chest X ray scoring system. At least 30% reduction in Chest x-ray severity score is desirable	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	Change in baseline lung function (FEV1 and FVC) test will be assessed using a spirometer at 4, 6 and 12 months. At least 15% improvement in FEV1 and FVC is desirable.	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	Change in baseline lung function (FEV1 and FVC) test will be assessed using a spirometer at 4, 6 and 12 months. At least 15% improvement in FEV1 and FVC is desirable.	16 - 52 weeks post randomization
The optimal dose of atorvastatin that will be safe and effective as an adjunctive pulmonary TB treatment	A pharmackinetic - Pharmacodynamic (PK/ PD) model will be developed for each drug (using PK -PD data generated from other secodary outcomes described above) and the the optimal dose of atorvastatin that will be appropriate as adjunctive TB treatment will be investigated using Monte-Carlo simulations.	week 52 post randomization

Collaborators and Investigators

• Sponsor: Obafemi Awolowo University Teaching Hospital
• Collaborators: Obafemi Awolowo University; Open Philanthropy
• Investigators: Principal Investigator: Olanisun O Adewole, MD, Obafemi Awolowo University / Teaching Hospital, Ile Ife, Nigeria; Study Director: Bolanle A Omotoso, MD, Obafemi Awolowo University /Teaching Hospital, Ile- Ife, Osun State, Nigeria; Study Chair: Olanisun O Adewole, MD, Obafemi Awolowo University /Teaching Hospital, Ile- Ife, Osun State, Nigeria

Study record dates

Study Major Dates

• Study Start (Estimated): January 3, 2026
• Primary Completion (Estimated): March 30, 2027
• Study Completion (Estimated): March 30, 2028

Study Registration Dates

• First Submitted: September 21, 2025
• First Submitted That Met QC Criteria: December 18, 2025
• First Posted (Actual): December 26, 2025

Study Record Updates

• Last Update Posted (Actual): January 23, 2026
• Last Update Submitted That Met QC Criteria: January 21, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Tuberculosis; Atorvastatin; Mycobacterium tuberculosis; Ethambutol; Pulmonary Tuberculosis; Isoniazid; Rifampin; statins; Pulmonary TB; Rifampicin; pyrazinamide; Continuation Phase; Koch's disease; Intensive Phase; Antitubercular therapy (ATT)
• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; Respiratory Tract Diseases; Lung Diseases; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fatty Acids; Lipids; Azoles; Physical Phenomena; Amines; Inorganic Chemicals; Elements; Pyrroles; Heptanoic Acids; Ions; Electrolytes; Pyrazines; Gases; Elementary Particles; Hydrazines; Isonicotinic Acids; Acids, Heterocyclic; Ethylenediamines; Diamines; Polyamines; Cations, Monovalent; Cations; Hydrogen; Nucleons; Atorvastatin; Ethambutol; Isoniazid; Pyrazinamide; Protons
• Other Study ID Numbers: ERC/2023/11/15/B; IRB/IEC/0004553 (Other Identifier: International)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No