Clinical trial NCT04575519: Adjunctive Acetylsalicylic Acid and Ibuprofen for Tuberculosis
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Tuberculosis, Pulmonary
Tuberculosis, MDR
Tuberculosis Infection
Keywords: Tuberculosis
Host-directed therapies
Infectious diseases
Drug-sensitive tuberculosis
Drug-resistant tuberculosis
Lead sponsor: Fundació Institut Germans Trias i Pujol
Sponsor class: OTHER
Collaborators: name: National Center for Tuberculosis and Lung Disease, Tbilisi, Georgia
name: Perinatal HIV Research Unit of the University of the Witswatersrand
First posted: 2020-10-05
Enrollment: 354
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicentre, phase IIB, placebo controlled, randomized, 3-arm trial in DS and MDR TB patient
Primary purpose: TREATMENT

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:

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Time to ≥ 67% sustained reduction in the TB score
timeFrame: Week 8 of follow-up
measure: Hazard ratio for time to stable culture conversion (SCC)
timeFrame: 24 weeks of TB treatment
Secondary outcomes:
measure: Hazard ratio for stable culture conversion (SCC) at week 8 and week 16 after treatment start.
timeFrame: At week 8 and week 16
measure: Proportion of patients with improvement or resolution of clinical signs and symptoms at end of treatment (TB score).
timeFrame: At week 24
measure: 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.
timeFrame: At baseline, week 8 and week 24
measure: Changes in the BCN-SA Radiological Score Value.
timeFrame: At baseline, week 8, week 24 (and month 12 if MDR)
measure: Number of patients with improvement of Health-related Quality of Life comparing baseline measure with that over the course of therapy.
timeFrame: At week 8, week 24 and for MDR TB patients at the end of treatment
Other outcomes:
measure: Safety 1: SAEs participant proportion.
timeFrame: Up to month 6 in DS TB patients and up to month 20 in MDR TB patients
measure: Safety 2: SAEs in person time.
timeFrame: Up to week 12
measure: Tolerability 1: permanent discontinuity proportion.
timeFrame: Up to week 8
measure: Tolerability 2: treatment interruption proportion
timeFrame: Up to week 10
Locations:
city: Tbilisi
country: Georgia
facility: National Center for Tuberculosis and Lung Diseases
city: Soweto
country: South Africa
facility: Perinatal HIV Unit (PHRU)- Chris Hani Baragwanath Hospital
state: Johannesburg
city: Klerksdorp
country: South Africa
facility: PHRU- Matlosana, Tshepong Hospital MDR Unit
state: Matlosana
Study officials:
affiliation: Fundació Institut Germans Trias i Pujol
name: Cristina Vilaplana, MD, PhD
role: STUDY_CHAIR
References: