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: Recruiting
• 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 (Estimated): 354
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Cristina Vilaplana, MD, PhD; Phone Number: +34930330527; Email: cvilaplana@igtp.cat
• Study Contact Backup: Name: Lilibeth Arias de la Cruz; Phone Number: +34934978681; Email: larias@igtp.cat

Study Locations

• Georgia
  • Tbilisi, Georgia
    • Recruiting
    • National Center for Tuberculosis and Lung Diseases
    • Contact: Sergo Vashakidze, MD, PhD; Phone Number: +995599236553; Email: sergovashakidze@yahoo.com
    • Sub-Investigator: Nestani Tukvadze, MD
    • Sub-Investigator: Lali Kupreishvili, MD
    • Sub-Investigator: Ketevan Barbakadze, MD
• South Africa
  • Johannesburg
    • Soweto, Johannesburg, South Africa, 1864
      • Recruiting
      • Perinatal HIV Unit (PHRU)- Chris Hani Baragwanath Hospital
      • Contact: Neil Martinson, MBBCh MPH; Phone Number: +27 11 989 9700
      • Principal Investigator: Ziyaad Waja, MD, PhD
  • Matlosana
    • Klerksdorp, Matlosana, South Africa
      • Recruiting
      • PHRU- Matlosana, Tshepong Hospital MDR Unit
      • Contact: Neil Martinson, MBBCh MPH; Phone Number: +27 11 989 9700; Email: martinson@phru.co.za
      • Contact: Tumelo Moloantoa; Email: moloantoat@phru.co.za
      • Principal Investigator: Tumelo Moloantoa

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 58 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 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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety 1: SAEs participant proportion.	Proportion of participants with at least one serious adverse events (SAEs) by arm until the end of TB treatment, between each intervention arm and the control group.	Up to month 6 in DS TB patients and up to month 20 in MDR TB patients
Safety 2: SAEs in person time.	Serious adverse event (SAEs) rate expressed in person time, starting the day of the first dose of NSAID or placebo until one month (30 days) after the last placebo or NSAID taken, including all adverse events recorded in each arm.	Up to week 12
Tolerability 1: permanent discontinuity proportion.	The proportion of patients in each arm who either permanently discontinued either placebo, acetylsalicylic acid or ibuprofen.	Up to week 8
Tolerability 2: treatment interruption proportion	The proportion of patients in each arm who had TB treatment interruption for longer than seven days/doses, prescribed either by a listed investigator, or a non-study physician up to two weeks after scheduled or unscheduled permanent discontinuation of placebo/NSAID	Up to week 10

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

Helpful Links

• 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.
• CORDIS -CE database -SMA-TB project description
• SMA-TB repository

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2021
• Primary Completion (Estimated): October 1, 2024
• Study Completion (Estimated): June 1, 2025

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): March 25, 2024
• Last Update Submitted That Met QC Criteria: March 22, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Tuberculosis; Infectious diseases; Drug-resistant tuberculosis; Host-directed therapies; Drug-sensitive tuberculosis
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Latent Infection; Tuberculosis; Latent Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Aspirin; Ibuprofen
• 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