Tuberculosis Infection, Tuberculosis, MDR, Tuberculosis, Pulmonary
Conditions
Keywords
Tuberculosis, Host-directed therapies, Infectious diseases, Drug-sensitive tuberculosis, Drug-resistant tuberculosis
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.
Interventions
DRUGControl group
placebo 2 months treatment: 2 tablets during 4 weeks + 1 tablet during 4 weeks
DRUGASA group
Acetylsalicylic acid 2 months treatment: 2 tablets during 4 weeks (600 mg daily) + 1 tablet during 4 weeks (300 mg daily)
DRUGIBU group
Ibuprofen 2 months treatment: 2 tablets during 4 weeks (800 mg daily) + 1 tablet during 4 weeks (400 mg daily)
DRUGSoC TB
Standard of Care Tuberculosis treatment
Sponsors
Fundació Institut Germans Trias i Pujol
National Center for Tuberculosis and Lung Disease, Tbilisi, Georgia
Perinatal HIV Research Unit of the University of the Witswatersrand
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Multicentre, phase IIB, placebo controlled, randomized, 3-arm trial in DS and MDR TB patient
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to ≥ 67% Sustained Reduction in the TB Score | 24 weeks of TB treatment | 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. |
| Time to Stable Culture Conversion (SCC) | 24 weeks of TB treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to a Stable Culture Conversion (SCC) at Week 8 and Week 16 After Treatment Initiation | Week 8 and Week 16 | 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 |
| Improvement or Resolution of Clinical Signs and Symptoms | Baseline, week 8 and week 24 | 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. |
| Improvement of Lung Function | Baseline, week 8 and week 24 | Improvement of lung function in the 1-second forced expiratory volume (FEV1) |
| Reduction of the Activity Component of the RTBES | Baseline, week 8 and week 24 | 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. |
| Improvement of Health-related Quality of Life | Baseline, week 8 and week 24 | 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. |
Countries
Georgia, South Africa
Contacts
STUDY_CHAIRCristina Vilaplana, MD, PhD
Fundació Institut Germans Trias i Pujol
Participant flow
Pre-assignment details
205 were excluded mainly due to: lack of microbiological TB confirmation; HIV-related exclusion criteria; major comorbid conditions or investigator's decision; prior TB treatment; ALT/AST above threshold; body weight, haemoglobin or neutrophil below threshold; alcohol use; age outside the range; allergy to NSAIDs; use of antacids; proton pump inhibitors or immune-modulating therapy; multiple exclusion criteria.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 221 Participants |
| Drug susceptibility Drug-susceptible TB | 64 Participants |
| Drug susceptibility Multidrug-resistant TB | 8 Participants |
| Race and Ethnicity Not Collected | 0 Participants |
| Region of Enrollment Georgia | 24 participants |
| Region of Enrollment South Africa | 48 participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 159 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 73 | 0 / 74 | 2 / 74 |
| other Total, other adverse events | 17 / 73 | 19 / 74 | 12 / 74 |
| serious Total, serious adverse events | 10 / 73 | 8 / 74 | 4 / 74 |
Outcome results
None listed