Potential Efficacy and Safety of Using Adjunctive Ibuprofen for XDR-TB Tuberculosis

Study Overview
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Brief Summary
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Novel approaches to improve TB treatment outcomes (to reduce morbidity, mortality, and the duration of TB treatment) and to treat XDR-TB cases are urgently required. Host-Directed therapies (especially repurposed drugs such as Non-Steroid AntiInflammatory Drugs NSAIDS) could be useful in this context, and therefore the appropriateness and potential effect of this approach needs to be evaluated in humans. Investigators do propose a prospective, randomized, pilot study to estimate the potential efficacy and safety of using adjunctive ibuprofen for the treatment of XDR tuberculosis.

Detailed Description
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There are a need for novel approaches to improve TB treatment outcomes (to reduce morbidity, mortality, and the duration of TB treatment) and to treat XDR-TB cases. Host-Directed therapies (especially repurposed drugs such as Non-Steroid AntiInflammatory Drugs NSAIDS) could be useful in this context, and therefore the appropriateness and potential effect of this approach needs to be evaluated in humans. Investigators do propose a prospective, randomized, pilot clinical trial to evaluate the potential efficacy and safety of using adjunctive ibuprofen during two months for the treatment of XDR tuberculosis.

Official Title
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Pilot Study to Estimate the Potential Efficacy and Safety of Using Adjunctive Ibuprofen for the Treatment of XDR Tuberculosis

Conditions
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Tuberculosis

Intervention / Treatment
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* Drug: Ibuprofen
* Drug: Standard of Care TB treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females and males aged ≥ 16 The patient must provide written informed consent Females of childbearing potential (including females less than 2 years post- menopausal) must have a negative pregnancy test at enrolment and must agree to use highly effective methods of birth control M.tuberculosis (Mtb) detected by culture with available drug susceptibility results for current isolate XDR- TB confirmed by drug susceptibility testing (DST) Exclusion Criteria: A potential subject who meets any of the following criteria will be excluded from participation in this study: Inability to provide written informed consent First line drug treatment susceptible Mtb strain Prior Treatment of either >3 days of TB treatment prior to randomization Pregnancy/Breastfeeding at inclusion Any of the following laboratory parameters: Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 x upper limit of normal (ULN); total bilirubin > 2 x ULN; estimated glomerular filtration rate (eGFR) <60ml/hr; Neutrophil count ≤ 500 neutrophils / mm3; Platelet count < 50,000 cells / mm3 Receiving or anticipated to receive a daily dose of ≥ 10 mg of systemic prednisone or equivalent within the period starting 14 days prior to enrolment, or > 5 doses per week of any NSAID for ≥2 weeks in the month prior to randomization. History of sensitivity or allergy to ibuprofen.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control: Standard of Care TB treatment<br>Individuals with confirmed pulmonary XDR-TB and receiving Standard of Care TB treatment according to national and WHO guidelines; n=12 | Drug: Standard of Care TB treatment<br>* Standard of Care (SoC) TB Treatment will be optimized and drugs selected according to the National and WHO Guidelines, sensitivity profile and as per routine.<br>* Other names: anti-TB treatment;|
| Experimental: Ibuprofen-treated<br>Individuals with confirmed pulmonary XDR-TB and receiving Standard of Care TB treatment according to national and WHO guidelines plus ibuprofen (400mg/day/2 months); n=12 | Drug: Ibuprofen<br>* Non-Steroid Anti-Inflammatory drug to be administered as adjunctive therapy<br>* Other names: NSAID;Drug: Standard of Care TB treatment<br>* Standard of Care (SoC) TB Treatment will be optimized and drugs selected according to the National and WHO Guidelines, sensitivity profile and as per routine.<br>* Other names: anti-TB treatment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of pilot study participants with microbiological efficacy-related events that are related to treatment. | Number of pilot study participants with negative sputum culture at M2 and M6 following inclusion | 6 months | 
| Number of pilot study participants with radiological efficacy-related events that are related to treatment. | Changes detected by X-ray during follow-up up to month 6 | 6 months: at baseline, at month 3 and month 6 | 
| Number of pilot study participants with clinical efficacy-related events that are related to treatment. | Final treatment outcomes according to the WHO definitions including all time in follow-up to M6 on TB treatment | 6 months | 
| Microbiological efficacy-related events: Time to stable culture conversion up to M6 | Time to stable culture conversion up to M6: (≥ two consecutive cultures negative for M. tuberculosis) including all time in follow-up to month six on TB treatment. Differences between the two groups | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of pilot study participants with Safety-related events. | Outcome measurements: incidence of safety-related events during the whole study period: clinical worsening of the disease, no sputum conversion (if AFS-), any worsening concerning vital parameters and routine blood work. | 6 months | 
| Proportion of pilot study participants showing differences in Health Quality of Life (HQoL). | Outcome measurements: HQoL measures at M2 and M6 relative to baseline. | 2 and 6 months | 
| Proportion of pilot study participants showing differences in Immune Responses at M2 and M6 relative to baseline. | Outcome measurements: changes detected in immune responses at M2 and M6. | 2 and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSAIDS, tuberculosis treatment, anti-inflammatories, Host-directed therapies, TB