The effectiveness, safety, and benefit risk balance of one month of daily rifapentine with isoniazid added to diabetes standard of care, compared to diabetes standard of care alone, to prevent TB in people with diabetes

Plain English Summary

Background and study aims
Diabetes mellitus (diabetes) increases the risk of tuberculosis (TB) 3-fold. However, WHO does not recommend TB preventive treatment (TPT) for people with diabetes except for people living with HIV (PLHIV) or contacts of persons with TB, for whom the benefit of treatment outweighs the harm. There is insufficient evidence to inform the benefit-risk balance for TB prevention using isoniazid for 6 or 9 months; the regimen used in many countries. We and others, however, have shown in mathematical models that TB prevention for people with HIV will only have a modest impact on community-level transmission. Additionally targeting at-risk groups who are HIV-uninfected (HIV-ve), such as people with diabetes, is important to accelerate reductions in TB incidence. There is a need to evaluate the evidence base for TB prevention in people with diabetes, starting with assessing the benefits versus the harms of providing novel ultra-short treatments for prevention.
One month of daily rifapentine with isoniazid (1HP) was shown to be non-inferior to 9 months of isoniazid (9H) to prevent TB in PLHIV. 1HP had a better safety profile as well as superior completion rates when compared to 9H (BRIEF-TB Trial). It is hypothesised that, compared to the WHO standard of care (SoC) for diabetes, 1HP may beneficially alter the risk trade-off due to the potent sterilising mycobactericidal effect of rifamycins, significantly shorter treatment duration, a safer toxicity profile and less burden on the health system, whilst also saving costs. A sufficiently powered trial to evaluate these trade-offs would influence policy.
There is further equipoise in examining this question for Mycobacterium tuberculosis (Mtb)-infected HIV-uninfected persons with diabetes who are on optimal diabetic care and concomitant therapy such as metformin. Metformin, a widely used first-line type 2 diabetes drug, may have potential as a host-directed therapy against Mtb. Its anti-TB effect appears independent of its glucose-lowering ability. A counterhypothesis would be that optimal diabetes care alone may effectively modify TB risk, thus avoiding unnecessary use of anti-TB drugs. Other studies suggest that, regardless of the diabetes drug used, TB risk could be reduced with better glycaemic control (6% increase in risk for TB per 10-mg/dl increase in fasting plasma glucose). 1HP may thus not have a better benefit-risk trade-off than SoC provided the goals of SoC are met. The BALANCE study will test the hypothesis that; compared to standard diabetes care alone, 1HP with standard diabetes care has superior effects and a favourable benefit-risk balance for prevention of TB among HIV-negative people with diabetes who have latent TB infection.
The study will define the best pragmatic strategy for TB prevention in HIV-uninfected individuals with diabetes who are at high risk of developing active TB disease, and establish whether TB preventive treatment should be prescribed to people with diabetes by determining its added value over and above standard diabetes care.

Who can participate?
HIV-negative adults (aged ≥15 years old) with diabetes and reactive tests for TB infection (i. e. positive LTBI test) will be recruited from chronic care outpatient clinics at both private and public healthcare facilities in high-TB burden regions in South Africa and the Philippines.
The study will be conducted in South Africa from the EkhayaVac Clinical Research Site, Khayelitsha, Cape Town and from CareCT, Manilla, Philippines.

What does the study involve?
Participants will be randomised 1:1 across one intervention (1HP + SoC, n ~1,955) and one standard of care (SoC only, n ~1,955) arms. The intervention arm will receive daily 300 milligrams of isoniazid and 600 milligrams of rifapentine for one month (1HP) with the standard of care for diabetes care. The control arm in this study will comprise individuals prescribed standard of care for diabetes alone. There are 12 scheduled study visits over 4 years, which will occur at study sites or affiliated step-down facilities. Visits will involve interviews, clinical examination, phlebotomy, urine test, chest x-ray, and sputum collection at designated time points. Trial participation will be for four years post-randomisation: the primary endpoint will be evaluated at the end of year 2.

What are the possible benefits and risks of participating?
Participants benefit from a thorough medical examination at each study visit. Participants will be screened for TB, HIV and any disease or condition that is identified will be treated early. If any co-morbidities are detected, individuals will be referred to the appropriate clinic in the public health system, helping to fast-track their entry into the system.
There are minor risks related to phlebotomy, including discomfort, hematoma, and rarely an infection. In general, phlebotomy is considered to be a safe procedure.
The safety profiles of 1HP are well known. Clinical staff at sites will be trained on how to recognise the expected side effects of 1HP and how to explain these to participants. Important side effects include (although rare) liver injury. The potential risks of hepatotoxicity induced by 1HP will be monitored through blood ALT testing. Adverse events will be reported to all the necessary authorities as appropriate.
There are no anticipated psychological, social or economic harms following participation in this trial.

Where is the study run from?
Clinical Infectious Diseases Research Institute, University of Cape Town, South Africa

When is the study starting and how long is it expected to run for?
April 2025 to March 2029

Who is funding the study?
1. Wellcome Trust
2. UK Research and Innovation (UKRI)

Who is the main contact?
1. Prof. Molebogeng X. Rangaka (Principal Investigator), l.rangaka@ucl.ac.uk
2. Dr Lauren Barron (CIDRI Africa / UCT Research Medical Officer), lauren.barron@uct.ac.za

Study website

Contact information

Prof Molebogeng X. Rangaka
Public, Scientific, Principal Investigator

School of Public Health & Clinical Infectious Diseases Research Institute - AFRICA
University of Cape Town, Observatory
Cape Town
7925
South Africa

ORCID ID	0000-0001-9594-188X
Phone	+447552526872
Email	l.rangaka@ucl.ac.uk

Study information

Eligibility

Locations

Countries of recruitment

• Philippines
• South Africa

Study participating centres

Sponsor information

University of Cape Town
University/education

Rondebosch, Cape Town
Rondebosch
7700
South Africa

Email	l.rangaka@ucl.ac.uk
Website	https://uct.ac.za
"ROR"	https://ror.org/03p74gp79

Funders

Funder type

Charity

Results and Publications

Editorial Notes

18/03/2025: The following changes were made to the study record:
1. The public title was changed from 'The effectiveness, safety, and benefit-risk balance of one month of daily rifapentine with isoniazid added to diabetes standard of care to prevent tuberculosis in people with diabetes' to 'The effectiveness, safety, and benefit risk balance of one month of daily rifapentine with isoniazid added to diabetes standard of care, compared to diabetes standard of care alone, to prevent TB in people with diabetes'.
2. The interventions, sponsor details and IPD sharing plan were updated.
3. The overall study end date was changed from 01/02/2030 to 01/03/2029.
4. The recruitment start date was changed from 01/02/2025 to 01/04/2025.
5. The recruitment end date was changed from 01/02/2028 to 01/03/2029.
6. The funder was changed from University College London to Wellcome Trust and UK Research and Innovation (UKRI).
22/01/2025: Trial's existence confirmed by the University of Cape Town Human Research Ethics Committee.