Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202403493915530 Date of Approval: 05/03/2024
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Platform Assessing Regimens And Durations In a Global Multisite Consortium for TB [PARADIGM4TB (UNITE4TB – 01)]
Official scientific title A Seamless Phase 2B/2C Platform Trial to Evaluate Multiple Regimens and Durations of Treatment in Pulmonary Tuberculosis
Brief summary describing the background and objectives of the trial To gain marketing approval for anti-TB drugs, large, prolonged and expensive phase 3 clinical trials are required to provide the necessary robust evidence for efficacy and safety. The sequential use of phase 2 and 3 trials minimises the risk of failure and yet this de-risking approach has been shown to be limited (Refer to REMoxTB, RIFAQUIN and OFLOTUB) Additionally, technical consultation meetings co-organized by WHO/GTB in 2018(9) and 2020(10) concluded that the traditional endpoint used in phase 2 trials (culture conversion by 2 months) does not predict relapse-free cure, the usual primary endpoint in phase 3 trials, with sufficient accuracy. New and innovative phase 2 designs and biomarker-driven endpoints are required to overcome the substantial barriers to new anti-TB drug development and to accelerate the rate of progression of novel drugs and regimens through to definitive phase 3 trials and registration. The PARADIGM4TB (UNITE4TB-01) trial addresses these concerns with a seamless phase 2B/2C trial design that is intended to overcome many of the limitations of the conventional approach. In this protocol, the phase 2B component will select regimens that show sufficient evidence of efficacy The main trial 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 that could be used to treat both rifampicin-susceptible and resistant TB. Specifically two phases will be employed each with an objective: Phase 2B: To identify 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 Phase 2C: Amongst regimens selected for progression from phase 2B, to further evaluate the safety profile and to identify the optimal treatment duration (between 8 and 16 we
Type of trial RCT
Acronym (If the trial has an acronym then please provide) PARADIGM4TB
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied Tuberculosis
Purpose of the trial Treatment: Drugs
Anticipated trial start date 15/04/2024
Actual trial start date
Anticipated date of last follow up 15/06/2028
Actual Last follow-up date
Anticipated target sample size (number of participants) 2500
Actual target sample size (number of participants)
Recruitment status Not yet recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Randomised Simple randomization using a randomization table created by a computer software program Central randomisation by phone/fax Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group Arm B Bedaquiline 400mg once a day for two weeks then 100mg daily with Delamanid 300mg and Moxifloxacin 400mg once a day 16 weeks Treatment will be taken once daily with food 58
Control Group Arm A Rifampicin Weight Dose Frequency 30-<35kg 450mg once daily 35-<65kg 600mg once daily ≥65kg 750mg once daily Isoniazid Weight Dose Frequency 30-<35kg 225mg once daily 35-<65kg 300mg once daily ≥65kg 375mg once daily Pyrazinamide Weight Dose Frequency 30-<35kg 1200mg once daily 35-<65kg 1600mg once daily ≥65kg 2000mg once daily Ethambutol Weight Dose Frequency 30-<35kg 825mg once daily 35-<65kg 1100mg once daily ≥65kg 1375mg once daily for 8 weeks followed by isoniazid + rifampicin for 16 weeks This will be dosed through fixed dose combination of all the four drugs in the intensive phase-8weeks and then two drugs in the continuation phase (16weeks). 222 Active-Treatment of Control Group
Experimental Group Arm C Bedaquiline 400mg once a day for two weeks then 100mg daily with Delamanid 300mg, Moxifloxacin 400mg once a day and GSK3036656 20mg once daily 16 weeks in phase 2B and 8-16weeks in phase 2C Treatment will be taken daily with food 222
Experimental Group Arm D Bedaquiline 400mg once a day for two weeks then 100mg daily, Delamanid 300mg once a daily, Pyrazinamide 1200mg for participants 30-<35kg,1600mg for participants 35-<65kg, 2000mg for participants ≥65kg once a daily and GSK3036656 20mg once daily 16 weeks in phase 2B and 8-16weeks in phase 2C Treatment will be taken daily with food 222
Experimental Group Arm E Bedaquiline 400mg once a day for two weeks then 100mg daily, Delamanid 300mg once a daily, Linezolid 600mg once daily, GSK3036656 20mg once daily 8 weeks followed by 8 weeks Bedaquiline, Delamanid and GSK3036656 in Phase 2B and 8 weeks followed by 0-8 weeks Bedaquiline, Delamanid and GSK3036656 in Phase 2C Treatment will be taken daily with food 222
Experimental Group Arm F Bedaquiline 400mg once a day for two weeks then 100mg daily, Pretomanid 200mg once daily, Moxifloxacin 400mg once daily and GSK3036656 20mg once daily 16 weeks in Phase 2B and 8-16 weeks in Phase 2C Treatment will be taken daily with food 222
Experimental Group Arm G Bedaquiline 400mg once a day for two weeks then 100mg daily with Delamanid 300mg once daily, Moxifloxacin 400mg once a day and BTZ-043 1000mg once daily 16 weeks in Phase 2B and 8-16 weeks in phase 2C Treatment will be taken daily after completion of a meal 222
Experimental Group Arm H Bedaquiline 400mg once a day for two weeks then 100mg daily, Delamanid 300mg once a daily, Pyrazinamide 1200mg for participants 30-<35kg, 1600mg for participants 35-<65kg, 2000mg for participants ≥65kg once a daily and BTZ-043 1000mg once daily 16 weeks in Phase 2B and 8-16 weeks in phase 2C Treatment will be taken daily after completion of a meal 222
Experimental Group Arm I Bedaquiline 400mg once a day for two weeks then 100mg daily, Delamanid 300mg once a daily, Linezolid 600mg once daily and BTZ-043 1000mg once daily 8 weeks followed by 8 weeks Bedaquiline, Delamanid and BTZ-043 in Phase 2B and 8 weeks followed by 0-8 weeks Bedaquiline, Delamanid and BTZ-043 in Phase 2C Treatment will be taken daily after completion of a meal 222
Experimental Group Arm J Bedaquiline 400mg once a day for two weeks then 100mg daily, Pretomanid 200mg once daily, Moxifloxacin 400mg once daily and BTZ-043 1000mg once daily 16 weeks in Phase 2B and 8-16 weeks in Phase 2C Treatment will be taken daily with food 222
Experimental Group Arm K Bedaquiline 400mg once a day for two weeks then 100mg daily, Moxifloxacin 400mg once daily, Pyrazinamide 1200mg for participants 30-<35kg, 1600mg for participants 35-<65kg, 2000mg for participants ≥65kg once a daily and BTZ-043 1000mg once daily 16 weeks in Phase 2B and 8-16 weeks in phase 2C Treatment will be taken daily after completion of a meal. 222
Experimental Group Arm L Bedaquiline 400mg once a day for two weeks then 100mg daily, Delamanid 300mg once a daily, GSK3036656 20mg once daily and BTZ-043 1000mg once daily 16 weeks in Phase 2B and 8-16 weeks in phase 2C Treatment will be taken daily after completion of a meal 222
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
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 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)* 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 e Adult: 19 Year-44 Year 18 Year(s) 100 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 14/07/2023 Joint Clinical Research Centre REC
Ethics Committee Address
Street address City Postal code Country
Plot 101 Lubowa, off Entebbe Road Kampala 10005 Uganda
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 03/10/2023 Mbeya Medical Research and Ethics Review Committee
Ethics Committee Address
Street address City Postal code Country
Hospital Hill Raoad Mbeya 419 Tanzania
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 31/05/2023 Pharma Ethics
Ethics Committee Address
Street address City Postal code Country
123 Amkor Road Gauteng 786 South Africa
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome 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 2B: Over 0 to 12 weeks and 2C: At 48 weeks from randomisation
Secondary Outcome • Incident cases of failure/relapse and favorable/unfavorable status week 48 and week 72 respectively
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Joint Clinical Research Centre Plot 101Lubowa, off Entebbe Road Kampala 10005 Uganda
Makerere University Lung Institute Upper Mulago Hill Road Kampala 7749 Uganda
Cape Town TASK Smith Street Cape Town 7500 South Africa
University of Cape Town Lung Institute Roundebosch Cape Town 7700 South Africa
George TASK 4 Victoria Street Western Cape 6529 South Africa
JHB Clinical HIV Research Unit Perth Road Johannesburg 2092 South Africa
JHB Esizayo Tennessee Avenue Cosmo 2188 South Africa
Gqeberha Jose Pearson TB Hospital Bethelsdorp Bethelsdorp 6003 South Africa
NIMR Mbeya Medical Research Centre Hospital Hill Road Mbeya 2410 Tanzania
Moshi Kilimanjaro Christian Medical Centre Moshi Moshi 2236 Tanzania
Mwanza Intervention Trials Unit Isamilo Street Mwanza 11936 Tanzania
Hanoi National Lung Hospital Hoang Hoa Tham Hanoi 463D Viet Nam
The Lung Centre of the Philippines Metro Manila Quezon Philippines
Evadro chagas National Institute of Infectious Diseases Avenida Brasil 4 365 Rio de Janeiro 21040-900 Brazil
Hospital Universitario Clementino Fraga Filho Rua Prof. Rodolpho Paulo Rocco 255. Cidade Universitaria Rio De Janeiro CEP 21941 Brazil
Manaus Av. Pedro Teixeira Manaus 69040-000 Brazil
Hospital nacional sergio E Bernale Avenida Tupac Amaru Comas Peru
Hospital Nacional Hipolito Unanue El Agustino El Agustino 15007 Peru
IMSP Chisinau Chisinau Republic of Moldova
National Centre of Tuberculosis and Lung Disease 8 Adjara St Tbilisi Georgia
Vilnius University Hospital Santaros Klinikos Santariskiu st. 2 Vilnius 08661 Lithuania
La Molina Av. Los Constructores La Molina 1230 Peru
Oswalo Cruz Foundation Av. Brasil Rio de Janeiro CEP:21040 Brazil
FUNDING SOURCES
Name of source Street address City Postal code Country
Innovative Medicines Initiative 1060 Brussels Brussels 1060 Belgium
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor University College London 2nd Floor, 90 High Holborn London WC1V 6LJ United Kingdom University
COLLABORATORS
Name Street address City Postal code Country
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Cissy Kityo ckityo@jcrc.org.ug +256417723008 Plot 101 Lubowa Estates, off Entebbe road
City Postal code Country Position/Affiliation
Kampala 1005 Uganda Executive Director
Role Name Email Phone Street address
Scientific Enquiries Henry Mugerwa hmugerwa@jcrc.org.ug +256704621379 Plot 101 Lubowa Estates, off Entebbe road
City Postal code Country Position/Affiliation
Kampala 10005 Uganda Director Research Directorate
Role Name Email Phone Street address
Public Enquiries Esether Nambi enambi@jcrc.org.ug +256759326002 Plot 101 Lubowa Estates, off Entebbe road
City Postal code Country Position/Affiliation
Kampala 10005 Uganda Trial Coordinator
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Any information that could identify the participant will be held securely. Only authorised people will be able to access it. All samples and medical information will be stored under a participant unique code. This will help prevent confusion and make sure you are not recognizable. The code will also ensure that other researchers or people they work with do not have access to your personal data, such as your name and address. The people who analyse the information will not be able to identify you. If any qualified researcher asks to use the information, samples and/or X-Rays from this study for other new TB studies, the request will be considered very carefully and will be reviewed by a scientific and ethics committee. Informed Consent Form,Study Protocol This will be completed in a timely manner following completion of the data collection phase and full primary analysis. The CAG and local CAB will work to advise sites on when to conduct dissemination events at the end of the trial. The participating sites will have the contact details/methods preferred by the participant in order to communicate/access results.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information