Adjunctive Acetylsalicylic Acid and Ibuprofen for Tuberculosis

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the efficacy and safety of 2 repurposed drugs (acetylsalicylic acid and ibuprofen), for use as adjunct therapy added to, and compared with, the standard of care (SoC) WHO-recommended TB regimen in drug-sensitive (DS) and multi-drug resistant (MDR) TB patients.

Detailed Description
-----------------
If eligible and informed consent obtained, patients will be randomized 1:1:1 into one of the following 3 arms, to receive: Standard of Care (SoC) TB treatment + placebo twice daily during the first 4 weeks of TB treatment followed by placebo once daily for an additional 4 weeks. (control group). SoC TB treatment + acetylsalicylic acid 300mg twice daily during the first 4 weeks of TB treatment followed by acetylsalicylic acid 300mg once daily for an additional 4 weeks. SoC TB treatment + ibuprofen 400mg twice daily during the first 4 weeks of TB treatment followed by ibuprofen 400mg once daily for an additional 4 weeks.

Official Title
-----------------
Phase 2b Randomized Double-blind, Placebo-controlled Trial to Estimate the Potential Efficacy and Safety of Two Repurposed Drugs, Acetylsalicylic Acid and Ibuprofen, for Use as Adjunct Therapy Added to, and Compared With, the Standard WHO-recommended TB Regimen (SMA-TB)

Conditions
-----------------
Tuberculosis, Pulmonary, Tuberculosis, MDR, Tuberculosis Infection

Intervention / Treatment
-----------------
* Drug: Control group
* Drug: ASA group
* Drug: IBU group
* Drug: SoC TB


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adults, 18- 60 years of age Written informed consent in a language they understand. This includes informed consent to be in the trial and informed consent to collect specimens. Laboratory confirmed pulmonary TB (with or without extrapulmonary involvement) defined as a hard copy of a sputum laboratory result that reports M. tuberculosis (Mtb) detection by a WHO-recommended assay -both rapid molecular assays or mycobacterial culture with subsequent speciation are acceptable as inclusion criteria. Women of childbearing potential (including females <2 years post-menopausal) must have a negative pregnancy test at enrolment. Participants must be willing to have an HIV test done unless there is compelling evidence that the patient is HIV-infected at the time of randomization. Exclusion Criteria: Has a comorbid condition where treatment with aspirin, ibuprofen or other NSAID is indicated (e.g. cardiovascular disease, rheumatic fever, chronic pain, etc.) People institutionalized (incarceration in jail or prison, or due to chronic mental illness). If incarcerated during the study, participants may be terminated, those incarcerated in the first 8 weeks of follow up will be late exclusions and replaced*. Patients either who are planned to be hospitalized or currently hospitalized whilst treated for MDR TB in a TB hospital or ward may be enrolled. Receipt of multi-drug TB treatment (including rifamycin plus isoniazid preventive treatment regimens) for ≥3 days in the 6 months prior to randomization. Participants who have received ≥3 days of TB preventive treatment in the month prior to TB treatment initiation will also be excluded. Currently Pregnancy/breastfeeding. Women who conceive and are found to be pregnant in the first 4 weeks of the trial will be terminated from the trial and excluded from the analysis. Any of the following laboratory parameters taken prior to randomization: Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x upper limit of normal (ULN); Total bilirubin > 2 x ULN; Neutrophil count ≤ 700 neutrophils /mm3; Platelet count < 50,000 cells / mm3 Haemoglobin concentration less than 8 g/dL Serum creatinine concentration more than twice the upper limit of normal Co-treatment in the three months prior to randomization, or planned treatment over the course of the trial follow up with any one of the following agents: anticoagulant therapy immune modulating therapy (cancer treatments, any oral or daily use of inhaled steroids; Antacids or proton pump inhibitors - including self-treatment and prescription History or clinical record of sensitivity, asthma or allergy that could be attributed to NSAIDs Weight < 45kg at baseline. History or clinical record suggestive of any of the following in the past two years: peptic ulcer disease or gastro-intestinal bleeding, coagulopathy or other bleeding disorder, renal disease requiring hospitalization - in addition, any prior record at any time of acute kidney injury will be an exclusion criterion. liver disease requiring further investigation or hospitalization, underlying cardiovascular disease or risk factors for cardiovascular disease. Patients with HIV infection (irrespective of ART status) if: CD4 <350 cells/mm3 if on ART, unsuppressed (>200 copies/ml) viral load if not on ART, either in the opinion of the attending doctor or according to local ART guidelines, the patient should initiate ART during the 8-week initial placebo or NSAID treatment phase. Alcohol use: potential participant either self-reports or in the investigator's opinion that the patient drinks more than an average of four units/day over a usual week or is a binge drinker (men: 5 or more drinks; women: consume 4 or more drinks, in about 2 hours). Major co-morbid conditions or any other finding which in the opinion of the investigator would compromise the protocol compliance or significantly influence the interpretation of results.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicentre, phase IIB, placebo controlled, randomized, 3-arm trial in DS and MDR TB patient
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control group<br>Standard of Care (SoC) TB treatment + placebo twice daily during first 4 weeks of TB treatment followed by placebo once daily for an additional 4 weeks. | Drug: Control group<br>* placebo 2 months treatment: 2 tablets during 4 weeks + 1 tablet during 4 weeks<br>* Other names: placebo;Drug: SoC TB<br>* Standard of Care Tuberculosis treatment<br>* Other names: Standard of Care Tuberculosis treatment;|
| Experimental: SoC TB + ASA group<br>Standard of Care (SoC) TB treatment + acetylsalicylic acid 300mg twice daily during first 4 weeks of TB treatment followed by aspirin 300mg once daily for an additional 4 weeks. | Drug: ASA group<br>* Acetylsalicylic acid 2 months treatment: 2 tablets during 4 weeks (600 mg daily) + 1 tablet during 4 weeks (300 mg daily)<br>* Other names: Acetylsalicylic acid (ASA);Drug: SoC TB<br>* Standard of Care Tuberculosis treatment<br>* Other names: Standard of Care Tuberculosis treatment;|
| Experimental: SoC TB + IBU group<br>Standard of Care (SoC) TB treatment + ibuprofen 400mg twice daily during first 4 weeks of TB treatment followed by ibuprofen 400mg once daily for an additional 4 weeks | Drug: IBU group<br>* Ibuprofen 2 months treatment: 2 tablets during 4 weeks (800 mg daily) + 1 tablet during 4 weeks (400 mg daily)<br>* Other names: Ibuprofen (IBU);Drug: SoC TB<br>* Standard of Care Tuberculosis treatment<br>* Other names: Standard of Care Tuberculosis treatment;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to ≥ 67% sustained reduction in the TB score | Time to ≥ 67% sustained reduction in the TB score over the course of TB treatment | Week 8 of follow-up | 
| Hazard ratio for time to stable culture conversion (SCC) | Hazard ratio for time to stable culture conversion (SCC), at least 2 consecutive negative cultures for M. tuberculosis at least 4 weeks apart during the first 24 weeks of TB treatment. | 24 weeks of TB treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hazard ratio for stable culture conversion (SCC) at week 8 and week 16 after treatment start. | Difference between each intervention arm and control group | At week 8 and week 16 | 
| Proportion of patients with improvement or resolution of clinical signs and symptoms at end of treatment (TB score). | Difference between each intervention arm and control group | At week 24 | 
| Proportion of patients with improvement of lung function impairment as change from baseline at week 8, 24 and end of treatment in the 1-second forced expiratory volume (FEV1) expressed as FEV1. | Difference between each intervention arm and control group | At baseline, week 8 and week 24 | 
| Changes in the BCN-SA Radiological Score Value. | Change in chest-X ray (measured with the BCN-SA score) using the x-ray taken at baseline as the comparator compared with subsequent x-rays over the course of TB therapy. Difference between each intervention arm and control group. The BCN-SA Radiological Score Value assesses the sum of acute and chronic findings in the chest X-ray. Per each finding, a minimum score of 0 and a maximum score of 8 is recorded. The total score value is calculated by adding all the individual findings score values. Higher values of total score represent a worse outcome. | At baseline, week 8, week 24 (and month 12 if MDR) | 
| Number of patients with improvement of Health-related Quality of Life comparing baseline measure with that over the course of therapy. | Difference between each intervention arm and control group | At week 8, week 24 and for MDR TB patients at the end of treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Tuberculosis, Host-directed therapies, Infectious diseases, Drug-sensitive tuberculosis, Drug-resistant tuberculosis