Platform Assessing Regimens and Durations In a Global Multisite Consortium for TB — PARADIGM4TB  

Pulmonary Tuberculosis Clinical Trial

Official title: A Seamless Phase 2B/C Platform Trial to Evaluate Multiple Regimens and Durations of Treatment in Pulmonary Tuberculosis

Status Recruiting

Clinical Trial Summary

The UNITE4TB consortium is a group of universities and pharmaceutical companies funded by the European Union. This consortium are carrying out a trial to find better and faster ways to treat tuberculosis (TB). The standard treatment for TB takes 24 weeks and uses four drugs. The consortium want to find new treatments that are faster but just as safe and effective.

In the trial, two new drugs will be used, BTZ-043 and GSK3036656, along with the drugs that are already used to treat TB in a variety of combinations (11 different combinations initially). These new drugs have worked well in tests with animals and have reduced the amount of TB bacteria in people's sputum/phlegm when used alone for two weeks. These new drugs will be used in combination with other TB drugs for a longer time (up to 16 weeks) in people with TB. The UNITE4TB consortium want to see if they work well and are safe.

This trial will take place at sites across the world and will involve people with TB of the lungs that would usually respond well to the standard treatment. But the new treatments being tested might also work for people with drug resistant TB, that's harder to treat.

The trial has two parts. In the first part, different combinations of drugs will be tried on up to 700 people for 16 weeks. These combinations will be compared to the standard 24-week treatment to see which ones work the best and are safe.

In the second part, the best combinations from the first part will be taken to try to find out what the best length of time is to give the treatment for. These combinations will be tried on up to 1800 people giving them either 8, 10, 12, 14 or 16 weeks treatment. The investigators will follow these people for a total of 72 weeks to make sure the treatment is working.

The UNITE4TB consortium hope that this trial will find new treatments that are fast, safe, and effective for both regular TB and resistant TB. If it works, it can then be tested again in a bigger trial to be sure.

Clinical Trial Description

Study Design:

This will be a randomised, open-label, multicentre, seamless phase 2B (regimen selection) and 2C (duration randomisation), multi-arm multi-stage, platform clinical trial

Overall objective:

The overall objective is to identify novel drug regimen(s) with acceptable safety profile, non-inferior efficacy, and shortened treatment duration compared to the standard-of-care 24-week HRZE/HR regimen (isoniazid + rifampicin + pyrazinamide + ethambutol for 8 weeks then isoniazid + rifampicin for 16 weeks) that could be used to treat both rifampicin-susceptible and resistant TB.

Specific sub-objectives:

The objective of the Phase 2B stage is to identify novel regimens of 16 weeks' duration with acceptable safety profile and the greatest potential, based on assessment of quantitative sputum liquid culture and treatment failure/relapse, to progress to investigation of optimal treatment duration

Amongst the regimens selected for progression from phase 2B to phase 2C stage, the objective is then to further evaluate the safety profile of these regimens and to identify the optimal treatment duration (between 8 and 16 weeks) based on unfavourable outcome to support advancement to future Phase 3 trials.

Setting:

Specialist TB clinics and research centres in sites across Europe, Asia, Africa and South America

Population:

Adults with newly diagnosed, rifampicin-susceptible pulmonary TB

Duration:

Individual participant participation will be for 72 weeks. The total duration of trial is 5 years.

Interventions:

Phase 2B: Participants will be randomised (1:1:1..1) to the following 12 arms (A-L) initially. Additional arms maybe added through protocol amendment.

Control, standard-of-care regimen, given for 24 weeks

A. Isoniazid + rifampicin + pyrazinamide + ethambutol for 8 weeks then isoniazid + rifampicin for 16 weeks

Novel treatment regimens each given for 16 weeks

B. Bedaquiline + delamanid + moxifloxacin

C. Bedaquiline + delamanid + moxifloxacin + GSK306656

D. Bedaquiline + delamanid + pyrazinamide + GSK306656

E. Bedaquiline + delamanid + linezolid (for first 8 weeks) + GSK306656

F. Bedaquiline + pretomanid + moxifloxacin + GSK306656

G. Bedaquiline + delamanid + moxifloxacin + BTZ-043

H. Bedaquiline + delamanid + pyrazinamide + BTZ-043

I. Bedaquiline + delamanid + linezolid (for first 8 weeks) + BTZ-043

J. Bedaquiline + pretomanid + moxifloxacin + BTZ-043

K. Bedaquiline + moxifloxacin + pyrazinamide + BTZ-043

L. Bedaquiline + delamanid + GSK306656 + BTZ-043

There are two planned interim analyses of safety and efficacy data by an Independent Data Monitoring Committee in Phase 2B. The first interim analysis will occur when the last participant for arms to be included in the analysis, completes 16 weeks of treatment and all necessary data are available. The second interim analysis will occur when the last participant for arms to be included in the analysis completes to week 48 (from randomisation) and all necessary data are available. The IDMC will make recommendation to the Trial Steering Committee (TSC) and Asset Holders on the progression of regimens to Phase 2C. The TSC will make the final decision. Arm B (bedaquiline + delamanid + moxifloxacin) will not be considered for progression to 2C.

Phase 2C:

For regimens selected for progression (following interim phase 2B evaluation). Participants will be randomised to treatment durations of either 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks or to the 24-week standard-of-care regimen (as described above).

Primary Efficacy Outcome Measure(s) -

Phase 2B: rate of change in log10(TTP) over 0 to 12 weeks, where TTP is time to positivity measured in days from MGIT culture

Phase 2C: Favourable/unfavourable status (binary) at week 48 from randomisation

Safety Outcome Measures (Phase 2B and 2C) -

The following outcomes will be reported up to week 26 from randomisation (unless otherwise stated):

• Grade 3/4/5 adverse events (DAIDS grading scale)

• Serious Adverse Events

• Adverse Events of Special Interest

• Regimen-related adverse events leading to withdrawal from the study

• Adverse events leading to discontinuation of the regimen

Number of Participants to be Studied:

Up to 2500 overall - 700 in phase 2B and 1800 in phase 2C (distribution between phases depends on progression according to specified decision-making steps) ;

Related Conditions & MeSH terms

• Pulmonary Tuberculosis
• Tuberculosis
• Tuberculosis, Pulmonary

• NCT number: NCT06114628
• Study type: Interventional
• Source: University College, London
• Contact: Robyn Henry-Cockles
• Phone: 2076704760
• Email: PARADIGM4TB@ucl.ac.uk
• Status: Recruiting
• Phase: Phase 2
• Start date: January 9, 2024
• Completion date: August 11, 2027