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

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

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.

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)

Inclusion Criteria:

1. Age 18 years or above at screening (or above age of legal consent at screening, if this is higher than 18 years in the jurisdiction in which the study is taking place)

2. Clinical evidence of active TB disease, meeting either or both of the following criteria:

   • Symptoms consistent with pulmonary TB at screening AND/OR
   • Imaging findings consistent with active pulmonary TB on chest X-ray performed at screening or within 7 days prior to screening

3. At least one sputum specimen produced at screening tested on Xpert MTB/RIF Ultra that has:

   • a semi-quantitative result of 'medium' or 'high' AND
   • does not show rifampicin resistance

4. Body weight within the range of 30 to 100kg and body mass index within the range of 15 to 40kg/m2

5. Willing to comply with study visits, all study procedures and treatment observation

6. Resident at a fixed address that is readily accessible for visiting, within feasible travelling distance to the site and likely to remain resident there for the duration of trial follow-up

7. Has provided written informed consent

Exclusion Criteria:

1. Taken more than 1 daily dose of medication with anti-tuberculous activity during the 14 days prior to randomisation (isoniazid, rifampicin, pyrazinamide, ethambutol; linezolid, moxifloxacin, levofloxacin or amikacin) (for Phase 2b and Phase 2c)

2. Known isoniazid resistance (at sites where national isoniazid monoresistance is greater than 10% rapid testing at screening is mandated; at other sites rapid testing at screening is optional)

3. Known or suspected extra-thoracic TB, miliary TB or disseminated TB (in the judgement of the investigator; note uncomplicated pleural effusion occupying <50% of hemithorax or concomitant intra- or extra-thoracic lymphadenopathy are not exclusions)

4. Severe clinical pulmonary TB e.g. respiratory failure or complications likely to require hospital admission in the opinion of the investigator

5. Poor general condition (Karnofsky score ≤50) OR where any delay in treatment cannot be tolerated in the opinion of the investigator

6. Active malignancy requiring systemic therapy, radiotherapy or palliative therapy

7. History of myocardial infarction, coronary heart disease or congestive cardiac failure; long QT syndrome or clinically significant arrhythmias; pulmonary hypertension; any known congenital cardiac problems; family history of long QT syndrome or sudden death from unknown or cardiac related cause; uncontrolled arterial hypertension (not excluded if this is corrected prior to randomisation)

8. Vitiligo

9. History of seizure(s)

10. Current tendinitis (any cause) or history of tendinopathy associated with fluoroquinolone use

11. History of vascular aneurysm

12. Symptomatic peripheral neuropathy causing greater than minimal interference with usual social and functional activities

13. Current alcohol or illicit drug use sufficient to compromise the safety of the participant or research staff or compromise adherence to study procedures, in the opinion of the investigator

14. Any current or recent use of amphetamines or methamphetamines, either reported or evident on toxicity screen, if performed

15. Any other medically or socially significant condition (e.g. psychiatric illness, chronic diarrhoeal disease, metabolic condition, other cardiovascular disease not listed under criterion 7), that would, in the opinion of the investigator, compromise the participant's safety or outcome in the trial; or lead to poor compliance with study visits and protocol requirements; or compromise the interpretation of trial safety and efficacy endpoints

16. Women who are currently pregnant or breast-feeding

17. Women of childbearing potential unwilling or unable to use appropriate effective contraception during the study intervention period and for at least 14 days after the last dose of study intervention; and unwilling to commit to refrain from donating eggs (ova, oocytes) for the purpose of reproduction during this period; definitions of childbearing potential and appropriate effective contraception given below**

18. Men who are unwilling to use a condom during the study period and for at least 90 days after the last dose of study drug during any activity that allows for the passage of ejaculate to another person; and are unwilling to commit to refrain from donating fresh unwashed semen

19. Known allergy to one or more of the study drugs

20. Taking a concomitant medication that has a known or predicted interaction with any of the study drugs to which the participant might be randomised. The participant need not be excluded if:

    1. the concomitant medication can be stopped or replaced with an alternative non-interacting medication, if needed AND
    2. the investigator judges there to be no residual clinical risk to the participant after stopping the concomitant medication (taking into account the washout period of 5x the half-life of the concomitant medication and the duration of the effect of the interaction on levels of study medication)

21. Taking a concomitant medication that is known to prolong the QTc interval. The participant need not be excluded if the concomitant medication can be stopped or replaced with an alternative medication, if needed, and the duration of the QTc prolongation is expected to resolve prior to dosing of study medication (taking into account the washout period of 5x the half-life of the concomitant medication)

22. Treatment with any immunosuppressive drugs within the 2 weeks prior to screening (taking systemic corticosteroids for less than 5 consecutive days and stopped at or prior to screening are not an exclusion; topical or inhaled steroids that are taken at a dose below the threshold considered to have systemic immunosuppressive effects are not excluded)

23. Participation in other clinical intervention trial with an investigational agent within 8 weeks prior to the first dosing day in this trial

24. 12-lead ECGs at screening or at baseline shows QTcF >450ms (men) or >460ms (women) calculated by Fridericia's formula; and/or any other clinically significant abnormality such as arrhythmia or ischaemia

25. Any of the following laboratory parameters at screening:

    1. Haemoglobin < 9g/dl
    2. Platelet count < 50 x 109 cells/L
    3. Absolute neutrophil count <1000 cells/μL
    4. Creatinine clearance of <75ml/min, calculated using Cockcroft-Gault equation*
    5. ALT or AST > 3 times the upper limit of normal
    6. Total bilirubin > 1.5 times upper limit of normal
    7. Serum potassium <3.5 mmol/L (not excluded if corrected to above this level)
    8. Serum magnesium < 0.70mmol/L (not excluded if corrected to above this level)
    9. Serum calcium (corrected for albumin level) < 2.10 mmol/L (not excluded if corrected to above this level)

26. Hepatitis B surface antigen positive (known, or on a test performed at screening)

27. HIV antibody positive (known, or on test performed at screening)*

28. Known Hepatitis C virus infection (unless also known to have negative PCR test)*