Adjunctive Acetylsalicylic Acid and Ibuprofen for Tuberculosis (SMA-TB)

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)

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.

Study Overview

• Status: Terminated
• Conditions: Tuberculosis, Pulmonary; Tuberculosis Infection; Tuberculosis, MDR
• Intervention / Treatment: Drug: Control group; Drug: SoC TB; Drug: ASA group; Drug: IBU group

Detailed Description

If eligible and informed consent obtained, patients will be randomized 1:1:1 into one of the following 3 arms, to receive:

1. 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).
2. 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.
3. 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.

• Study Type: Interventional
• Enrollment (Actual): 426
• Phase: Phase 2

Contacts and Locations

Study Locations

• Georgia
  • Tbilisi, Georgia
    • National Center for Tuberculosis and Lung Diseases
• South Africa
  • Johannesburg
    • Soweto, Johannesburg, South Africa, 1864
      • Perinatal HIV Unit (PHRU)- Chris Hani Baragwanath Hospital
  • Matlosana
    • Klerksdorp, Matlosana, South Africa
      • PHRU- Matlosana, Tshepong Hospital MDR Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 56 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adults, 18- 60 years of age
2. Written informed consent in a language they understand. This includes informed consent to be in the trial and informed consent to collect specimens.
3. 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.
4. Women of childbearing potential (including females <2 years post-menopausal) must have a negative pregnancy test at enrolment.
5. 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:

1. Has a comorbid condition where treatment with aspirin, ibuprofen or other NSAID is indicated (e.g. cardiovascular disease, rheumatic fever, chronic pain, etc.)
2. 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.
3. 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.
4. 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.

5. 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

6. 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
7. History or clinical record of sensitivity, asthma or allergy that could be attributed to NSAIDs
8. Weight < 45kg at baseline.

9. 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.

10. 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.
11. 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).
12. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control group; 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; placebo 2 months treatment: 2 tablets during 4 weeks + 1 tablet during 4 weeks; Other Names: placebo; Drug: SoC TB; Standard of Care Tuberculosis treatment; Other Names: Standard of Care Tuberculosis treatment
Experimental: SoC TB + ASA group; 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: SoC TB; Standard of Care Tuberculosis treatment; Other Names: Standard of Care Tuberculosis treatment; Drug: ASA group; Acetylsalicylic acid 2 months treatment: 2 tablets during 4 weeks (600 mg daily) + 1 tablet during 4 weeks (300 mg daily); Other Names: Acetylsalicylic acid (ASA)
Experimental: SoC TB + IBU group; 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: SoC TB; Standard of Care Tuberculosis treatment; Other Names: Standard of Care Tuberculosis treatment; Drug: IBU group; Ibuprofen 2 months treatment: 2 tablets during 4 weeks (800 mg daily) + 1 tablet during 4 weeks (400 mg daily); Other Names: Ibuprofen (IBU)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to ≥ 67% Sustained Reduction in the TB Score	Time taken to reach 67% sustained reduction in the TB score over the course of TB treatment. Minimum value of the score = 0; Maximum value = 13). Higher scores mean a better or worse outcome. Difference between each intervention arm and control group were analysed. The TB Score has been described to be useful to monitor good response to TB treatment, regardless of HIV status.	24 weeks of TB treatment
Time to Stable Culture Conversion (SCC)	Time to SCC is defined as the time until 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
Time to a Stable Culture Conversion (SCC) at Week 8 and Week 16 After Treatment Initiation	Time to SCC is defined as the time until at least 2 consecutive negative cultures for M. tuberculosis at least 4 weeks apart. For this secondary outcome, differences between groups were analyzed at week 8 and week 16	Week 8 and Week 16
Improvement or Resolution of Clinical Signs and Symptoms	Signs and symptoms were assessed using the TB Score (TBS), which ranges from 0 to 13, with higher scores indicating more severe disease. The outcome was defined as the proportion of participants achieving a ≥50% reduction from baseline in TBS at Week 8 and a ≥75% reduction from baseline in TBS at Week 24. Comparisons were performed between each intervention arm and the control group. TBS has been described as a useful tool for monitoring clinical response to tuberculosis treatment.	Baseline, week 8 and week 24
Improvement of Lung Function	Improvement of lung function in the 1-second forced expiratory volume (FEV1)	Baseline, week 8 and week 24
Reduction of the Activity Component of the RTBES	Changes in chest X-ray (CXR) findings were assessed using the Activity component of the RUTI TB Evolution Score (RTBES). The baseline CXR served as the reference for comparison with subsequent CXRs obtained during tuberculosis treatment. The Activity component ranges from 0 to 38, with higher scores indicating more severe radiographic involvement. The outcome was defined as the proportion of participants achieving a ≥50% reduction from baseline in the Activity component at Week 8 and a ≥75% reduction from baseline at Week 24. Comparisons were performed between each intervention arm and the control group.	Baseline, week 8 and week 24
Improvement of Health-related Quality of Life	Number of patients showing improvement in health-related quality of life at weeks 8 and 24 compared to baseline, as measured by the Saint Georges Respiratory Questionnaire (SGRQ). The SGRQ score ranges from 0 (best) to 100 (worst), with scores up to 7 considered to be within the healthy range. Improvement in this study being defined as achieving a score within the healthy range.	Baseline, week 8 and week 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety 1: Serious Adverse Events Participant Proportion	Proportion of participants with at least one Serious Adverse Event by arm until the end of tuberculosis (TB) treatment, between each intervention arm and the control group.	Week 24
Safety 2: Serious Adverse Event Rate Per Person Time	Serious adverse events rate expressed as events per 100-person week, starting the day of the first dose of NSAID or placebo until one month (30 days) after the last placebo or NSAID taken	Up to week 12

Collaborators and Investigators

• Sponsor: Fundació Institut Germans Trias i Pujol
• Collaborators: National Center for Tuberculosis and Lung Disease, Tbilisi, Georgia; Perinatal HIV Research Unit of the University of the Witswatersrand
• Investigators: Study Chair: Cristina Vilaplana, MD, PhD, Fundació Institut Germans Trias i Pujol

Publications and helpful links

General Publications

• Rudolf F, Joaquim LC, Vieira C, Bjerregaard-Andersen M, Andersen A, Erlandsen M, Sodemann M, Andersen PL, Wejse C. The Bandim tuberculosis score: reliability and comparison with the Karnofsky performance score. Scand J Infect Dis. 2013 Apr;45(4):256-64. doi: 10.3109/00365548.2012.731077. Epub 2012 Oct 31.
• Arias L, Otwombe K, Waja Z, Tukvadze N, Korinteli T, Moloantoa T, Fonseca KL, Pillay N, Seiphetlo T, Ouchi-Vernet D, Siles A, Carabias L, Quinones C, Vashakidze S, Martinson N, Vilaplana C. SMA-TB: study protocol for the 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. Trials. 2023 Jun 28;24(1):435. doi: 10.1186/s13063-023-07448-0.
• Wejse C, Gustafson P, Nielsen J, Gomes VF, Aaby P, Andersen PL, Sodemann M. TBscore: Signs and symptoms from tuberculosis patients in a low-resource setting have predictive value and may be used to assess clinical course. Scand J Infect Dis. 2008;40(2):111-20. doi: 10.1080/00365540701558698.
• Cuadras P, Rafart G, Català M, Arias L, Pérez R, Martinson N, Rosenthal A, Gabrielian A, Vashakidze S, Tenesa M, Bechini J, Vilaplana C. RTBES Radiological Index for Quantitative Assessment of Tuberculosis Evolution: Development and Validation. medRxiv 2025.02.14.25322286; doi:10.1101/2025.02.14.25322286.
• Arias L, Waja Z, Tukvadze N, Moloantoa T, Otwombe K, Korinteli T, Farrés J, Sopegno C, Gogichadze N, Fonseca KL, Pillay N, Seiphetlo T, Cardona PJ, Carabias L, Siles A, Llavero N, Quiñones C, McShane H, Hanekom W, Dyrhol-Riise AM, Karakousis PC, Charalambous S, Videla S, Vashakidze S, Martinson N, Vilaplana C. Acetylsalicylic Acid and Ibuprofen as Adjunctive Therapy for Tuberculosis. medRxiv 2025.12.01.25341191; doi:10.64898/2025.12.01.25341191

Helpful Links

• CORDIS -CE database -SMA-TB project description
• SMA-TB repository
• This CT is part of the project which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 847762.

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2021
• Primary Completion (Actual): December 19, 2023
• Study Completion (Actual): March 4, 2024

Study Registration Dates

• First Submitted: August 5, 2020
• First Submitted That Met QC Criteria: September 29, 2020
• First Posted (Actual): October 5, 2020

Study Record Updates

• Last Update Posted (Actual): June 1, 2026
• Last Update Submitted That Met QC Criteria: May 5, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Tuberculosis; Infectious diseases; Drug-resistant tuberculosis; Host-directed therapies; Drug-sensitive tuberculosis
• Additional Relevant MeSH Terms: Latent Infection; Pathologic Processes; Disease Attributes; Respiratory Tract Infections; Infections; Respiratory Tract Diseases; Lung Diseases; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Actinomycetales Infections; Mycobacterium Infections; Pathological Conditions, Signs and Symptoms; Communicable Diseases; Tuberculosis; Latent Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Organic Chemicals; Investigative Techniques; Epidemiologic Research Design; Epidemiologic Methods; Research Design; Methods; Hydrocarbons; Hydrocarbons, Cyclic; Carboxylic Acids; Hydrocarbons, Aromatic; Phenols; Benzene Derivatives; Acids, Carbocyclic; Salicylates; Hydroxybenzoates; Phenylpropionates; Aspirin; Ibuprofen; Control Groups
• Other Study ID Numbers: SMA-TB-001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No