Ignite Creation Date:
2024-05-06 @ 3:42 PM
Last Modification Date:
2024-10-26 @ 1:54 PM
Study NCT ID:
NCT04721795
Status:
COMPLETED
Last Update Posted:
2023-12-08
First Post:
2021-01-19
Brief Title:
Treating Tuberculosis With the Lipid Lowering Drug Atorvastatin in NigeriaATORvastatin in Pulmonary TUBerculosis
Sponsor:
Obafemi Awolowo University Teaching Hospital
Organization:
Obafemi Awolowo University Teaching Hospital
Study Overview
Official Title:
Repurposing a Lipid Lowering Drug to Treat Tuberculosis Effectiveness of Statins as Adjuvant to Treatment of Pulmonary Tuberculosis in Nigeria
Status:
COMPLETED
Status Verified Date:
2023-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ATORTUB
Brief 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 macrophages2 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 systems3 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 phagocytes5 These greatly impairs the hydrolytic and antimicrobial properties and activities of phagocytes56 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 fibrosisscarring 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 organisms7 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 antigens89 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 viability10 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 drugs11 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 continent1213 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 076 95 CI 060-097 12 Chronic use of statins more than 90 days was associated with the lowest risk RR 062 95 CI 053-072 as shown in another study13 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 HIVTB 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
13 Study Design
Experimental designResearch Plan The investigators propose a Phase IIAIIB randomized open label trial to evaluate the safety tolerability pharmacokineticsPK 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 3040mg 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 11
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 smearGenXpert 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 sputumGenXpert result
All investigations will be done at laboratories at OAUOUATHC Ile Ife Microbiological assessment including CFU culture conversion will be done at the Mycobacterial Laboratory OAUOAUTHC Ile Ife Drug assays will be done at the collaborating center Birmingham Heartlands HospitalUniversity 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
20 STUDY OBJECTIVES B SPECIFIC AIMS EXPECTED MEASURABLE OUTCOMES AND DELIVERABLES
11Specific 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 ie 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
12 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 microscopyGenXpert 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
13 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
14 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
MTB infect and survive humans by evading the various immune defense systems3 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 phagocytes5 These greatly impairs the hydrolytic and antimicrobial properties and activities of phagocytes56 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 fibrosisscarring 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 organisms7 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 antigens89 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 viability10 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 drugs11 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 continent1213 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 076 95 CI 060-097 12 Chronic use of statins more than 90 days was associated with the lowest risk RR 062 95 CI 053-072 as shown in another study13 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 HIVTB 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
13 Study Design
Experimental designResearch Plan The investigators propose a Phase IIAIIB randomized open label trial to evaluate the safety tolerability pharmacokineticsPK 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 3040mg 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 11
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 smearGenXpert 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 sputumGenXpert result
All investigations will be done at laboratories at OAUOUATHC Ile Ife Microbiological assessment including CFU culture conversion will be done at the Mycobacterial Laboratory OAUOAUTHC Ile Ife Drug assays will be done at the collaborating center Birmingham Heartlands HospitalUniversity 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
20 STUDY OBJECTIVES B SPECIFIC AIMS EXPECTED MEASURABLE OUTCOMES AND DELIVERABLES
11Specific 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 ie 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
12 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 microscopyGenXpert 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
13 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
14 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| NHREC27022009a | OTHER | NHREC | None |