Treating Tuberculosis With the Lipid Lowering Drug Atorvastatin in Nigeria(ATORvastatin in Pulmonary TUBerculosis)
Condition: Tuberculosis, Pulmonary; Tuberculosis
MeSH terms: Tuberculosis; Tuberculosis, Pulmonary
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Tuberculosis (TB) is caused by mycobacterial organism. It is the leading infectious disease
      cause of death globally, with more than 10 million new cases and over 2 million deaths
      annually. Developing countries bear the greatest brunt of the disease. The long duration of
      current treatment is associated with poor compliance, thereby contributing to frequent
      relapses and to the emergence of drug-resistant TB. In addition, individuals who have been
      clinically cured may have lung damage, which could be permanent. Therefore, new and more
      effective therapeutic agents against TB are needed. Emerging evidence has shown that lipid
      lowering drugs like statins can make the TB bacteria more susceptible to current treatments.
      This proof-of-concept clinical trial will add the repurposed drug atorvastatin, commonly used
      to reduce cholesterol levels, to the standard therapies of TB patients in Nigeria.
      Atorvastatin is a well-tolerated and safe drug, and its addition is expected to accelerate
      clearance of the TB-causing bacteria without additional side effects. If this research is
      successful, it could provide evidence for using a common, easily available generic drug to
      improve treatment of one of the most debilitating infectious diseases.
    

Detailed description: 
      INTRODUCTION Tuberculosis is a chronic disease responsible for most deaths from infectious
      disease with an estimated I0 million cases and close to 2million deaths globally. 1 Despite
      the availability of therapy for TB, the scourge of the disease has not abated especially in
      the developing countries. The disease is caused by a bacterium called Mycobacterium
      tuberculosis, a non-spore forming intracellular organism. TB exists in two forms; primary and
      secondary infection. While primary infection most times goes unnoticed and are usually
      associated with non-specific symptoms, secondary infections are usually associated with
      profound symptoms and signs in various organs especially in the lungs. Majority of persons
      overcome primary infection but the tubercule bacilli may lie dormant in the macrophages.2
      Secondary infection occurs as a result of either endogenous reactivation or exogenous
      re-infection. Pulmonary TB is responsible for more than 85% of the cases.

      MTB infect and survive humans by evading the various immune defense systems.3 The organism
      accumulates and utilizes an abundant amount of lipids and cholesterol for its cell wall, and
      as a source of carbon for synthesis of virulence factors. 4 Mycobacterium tuberculosis also
      utilizes cholesterol as a vehicle to enter macrophage, inhibit phagocytosis and inhibit
      growth and development of phagocytes.5 These greatly impairs the hydrolytic and antimicrobial
      properties and activities of phagocytes.5,6 Current therapy is as old as the disease itself;
      is of long duration, hence it is associated with poor compliance. This contributes to
      frequent relapses and emergence of resistant form of the disease. Average interval between
      one episode of TB and another range from 6-18 months after completion of therapy. Despite
      clinical cure, approximately half of patients have permanent lung damage. In Nigeria, TB is a
      major risk factor for Chronic Obstructive Pulmonary Disease, lung fibrosis/scarring and other
      diseases. It is clear that new and innovative therapeutic agents are needed to tackle this
      hydra- headed disease. In order to address these challenges, a lipid lowering agent,
      atorvastatin is being repurposed.

      The use of statins have been demonstrated in infectious diseases and especially in
      tuberculosis than other organisms.7 In vitro studies have demonstrated that statins could
      strengthen the host response against M. tuberculosis and inhibit the activation of T cells
      induced by M. tuberculosis antigens.8,9 In another study, murine bone marrow-derived
      macrophages that were exposed to simvastatin and were infected with M. tuberculosis, showed a
      significant reduction in mycobacterial growth, without adverse effects on cell viability.10
      Treatment of TB in animal model with statins and anti TB drugs showed that treatment with
      anti-TB drugs plus simvastatin reduced the percentage of relapses by 50% compared with
      treatment with only anti-TB drugs.11 Taken together, all these studies in animal model
      indicate that statins has anti-TB effect, reduces bacillary load, shortens the duration of
      therapy and decreases relapse rate when used with first-line anti-TB drugs.

      Most of the clinical evidence on the role of statins in TB were from retrospective and nested
      case control studies from Asian continent.12,13 In one study in Taiwan, diabetic subjects
      older than 65 treated with statins had a lower risk of developing active tuberculosis, with a
      risk of 0.76 (95% CI, 0.60-0.97). 12 Chronic use of statins (more than 90 days) was
      associated with the lowest risk (RR 0.62; 95% CI 0.53-0.72) as shown in another study.13
      Within the limits of the designs of these studies, the positive and protective role of
      statins in TB in humans were demonstrated and has provided basis for further studies. This
      proposal seeks to provide robust evidence in a well designed study, for repurposing statins
      to treat TB.

      If this is successful, the investigators anticipate a significant improvement in health and
      well being for patients. Patients will have the option of being treated with an effective and
      safe regimen with minimal side effects including patients with HIV/TB co-infection, as
      statins can be co-administered safely with antiretroviral drugs. Additionally, the
      investigators anticipate a reduction in relapse rate, persistence and resistance to
      Mycobacterium tuberculosis. Currently, patients still experience post treatment
      non-infectious complications that limit their functionality. The investigators anticipate
      this treatment will mitigate against this and lead to improvement in the quality of life of
      patients and survivors. Both direct and indirect costs of the disease can be rechanneled to
      revamp the health system and other economic potentials of the developing world. If this prove
      successful, there would be an accelerated and significant progress to achieving the World
      Health Organization and End TB Sustainable Development Goals. Overall the investigators
      anticipate a great turn around in the socio-economic life of people and countries of the
      developing world where TB has caused untoward and unimaginable stagnation.

      1.3 Study Design

      Experimental design/Research Plan The investigators propose a Phase IIA/IIB randomized open
      label trial to evaluate the safety, tolerability, pharmacokinetics(PK), and efficacy of
      atorvastatin in subjects with uncomplicated, smear-positive, drug-susceptible pulmonary
      tuberculosis. See Figure I.

      Consented and eligible patients with active tuberculosis will be recruited and be randomized
      to receive either 30/40mg of atorvastatin with standards anti-TB drugs for 2months or the
      standards anti-TB drugs alone for 2months. Randomization will be based on Zelen rule 14 and
      follow a predefined allocation ratio of 1:1

      Phase IIA will seek to determine the safety and early bactericidal efficacy of atorvastatin
      in combination with standard anti-TB in 40 patients. Phase IIB, will seek to determine
      safety, and sputum culture conversion of atorvastatin in combination with standard anti-TB
      compared with standard anti-TB drugs alone after 2months in a total of 150 patients. Figure
      I.

      Patients will be hospitalized for supervised drug administration and assessed daily for vital
      signs and adverse effects AEs especially at phase IIA. Semi intensive profiling of plasma
      atorvastatin concentrations with a validated high-performance liquid chromatography will be
      conducted after the first dose on day 1 through to the last dose on day 14. Sputum will be
      collected for 16hours overnight for two nights before drug intake, daily from days 1 to 4,
      and every alternate day until day 14 in both cohorts. Samples will be transported and
      refrigerated till colony forming unit is done. Full blood count, coagulation studies, serum
      chemistry, lipid profile, Creatinine phosphokinase, urinalysis, and 12-lead
      electrocardiograms (ECGs) will be performed prior to drug intake and at regular intervals
      during and at 2 weeks. Patients recruited for this phase will continue in the assigned study
      arm and join the phase IIB.

      Interim analysis will be done in the two groups at the end of the 2weeks with particular
      emphasis on safety profile, incidence and number of adverse effects, bactericidal activity
      and a preliminary report of serum levels of atorvastatin in two groups.

      For the phase IIB, patients will be randomized as previously stated into any of the two
      groups and will be monitored closely. Sputum will be collected at 4, 6 and 8 weeks for
      smear/GenXpert. At the end of 8 weeks, sputum will be collected overnight for MTB culture in
      addition. During this period, number and types of AEs in the participants will also be noted.
      At the end, patients will be discharged from the study to continue and complete course of
      standard anti-tuberculosis chemotherapy. To determine the performance of the Sweat TB test,
      patients will be prospectively enrolled and the results from the test compared with
      sputum/GenXpert result.

      All investigations will be done at laboratories at OAU/OUATHC, Ile Ife. Microbiological
      assessment including CFU/ culture conversion will be done at the Mycobacterial Laboratory,
      OAU/OAUTHC, Ile Ife. Drug assays will be done at the collaborating center; Birmingham
      Heartlands Hospital/University of Birmingham, UK

      Patients will not be coerced to enroll in the study but they will be allowed to enroll after
      full written and informed consent. However they will be encouraged to attend all clinic and
      research appointment. However in order to ensure adherence to research protocol especially
      the period they need to be assessed, they will be provided with transport fare for the period
      of evaluation. For the initial 2 weeks of hospilisation, all fee including feeding will be
      borne by the research.

      .

      2.0 STUDY OBJECTIVES B. SPECIFIC AIMS, EXPECTED MEASURABLE OUTCOMES AND DELIVERABLES.

      1.1.Specific aims:

        1. To determine the safety profile of atorvastatin in combination with anti-TB drugs

        2. Determine the efficacy of atorvastatin in treating patients with tuberculosis, i.e if
           atorvastatin has early bactericidal activity and effect on sputum culture conversion

        3. To determine the pharmacodynamics and pharmacokinetics of atorvastatin in combination
           with anti-TB drugs in patients with active TB

      1.2. Primary outcome measures:

        1. Efficacy of atorvastatin treatment in combination with standard anti-TB chemotherapy as
           measured by:

             1. Sputum conversion at 2 month as measured by the number of patients with a negative
                culture at 2 months

             2. Time to sputum conversion as measured by the time interval to the first sputum
                negative result with sputum smear microscopy/GenXpert [ Time Frame: up to 2 months

             3. Early Bactericidal Activity /Overall response rate associated with atorvastatin
                treatment in combination with standard anti-TB chemotherapy. [ Time Frame: up to
                2weeks ) Measured as the Daily Rate of Change in log10 Colony Forming Units of M.
                Tuberculosis in Sputum on Solid Media [ Time Frame: up to 2weeks )

        2. Incidence of treatment-emergent adverse events associated with atorvastatin treatment in
           combination with standard anti TB chemotherapy. [ Time Frame: up to 2 months ] The
           incidence of AEs will measured by the incidence of abnormalities in clinical laboratory
           tests (serum chemistry, hematology, urinalysis, and coagulation), physical examinations,
           vital signs, and electrocardiograms.

      1.3. Secondary Outcome Measure :

        1. Plasma level of atorvastatin in combination with standard anti TB chemotherapy [ Time
           Frame: up to 2 months ] Measured by Pharmacokinetics: Maximum Plasma Concentration
           (Cmax) of atorvastatin

        2. Early bactericidal activity as measured by change in CFU for days 0-2 and 7-14

      1.4. Exploratory Outcome measure:

      1. Diagnostic utility of Sweat TB test in detecting tuberculosis. This is as measured by
      sensitivity, specificity, PPV and degree of agreement.
    

Intervention name(s): Atorvastatin with standard anti tuberculosis drugs; Standard anti tuberculosis drugs only
Intervention type(s): Drug; Drug
Intervention description(s): Participants will receive oral 30/40mg of atorvastatin daily for 2 months together with oral doses of standard antituberculosis drugs consisting of Rifampicin, INH, Ethambuthol and pyrazinamide for 2months. At the end of 2months, participants will continue with only standard anti tuberculosis drugs, Rifampicin and INH for 4months.Doseage of antituberculosis drugs are dependent on weight; Participants will receive oral doses of standard antituberculosis drugs consisting of Rifampicin, INH, Ethambuthol and pyrazinamide for 2months. At the end of 2months, participants will continue with only standard anti tuberculosis drugs, Rifampicin and INH for 4months.Doseage of antituberculosis drugs are dependent on weight
Other intervention name(s): Atorvastatin, Statins; Rifampicin, INH, Ethambuthol and Pyrazinamide
Intervention MeSH terms: Pyrazinamide; Antitubercular Agents; Atorvastatin
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomised
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: lipids drugs; atorvastatin; outcome