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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT02589782
Other study ID # 1541
Secondary ID
Status Completed
Phase Phase 2/Phase 3
First received
Last updated
Start date January 2017
Est. completion date August 5, 2022

Study information

Verified date April 2024
Source Medecins Sans Frontieres, Netherlands
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

TB PRACTECAL is a multi-centre, open label, multi-arm, randomised, controlled, phase II-III trial; evaluating short treatment regimens containing bedaquiline and pretomanid in combination with existing and re-purposed anti-TB drugs for the treatment of biologically confirmed pulmonary multi drug-resistant TB (MDR-TB).


Description:

This is a multi-centre, open label, multi-arm, randomised, controlled, phase II-III trial; evaluating short treatment regimens containing bedaquiline and pretomanid in combination with existing and re-purposed anti-TB drugs for the treatment of biologically confirmed pulmonary multidrug-resistant TB (MDR-TB). The study will be divided into two stages, with a seamless transition between the stages, meaning recruitment into an arm will only stop after a decision has been taken following stage 1 primary end point data analysis. All recruited patients will be followed up to 108 weeks post randomisation unless they die or withdraw consent. The local standard of care (SOC) MDR-TB regimen will be used as the internal control for both safety and efficacy. The first stage corresponds to a Phase II trial of safety and preliminary efficacy in patients with MDR-TB. Patients will be recruited into 3 parallel B and Pa containing regimen arms plus a SOC control. The main objective of Stage 1 is to select drug regimens for evaluation in Stage 2 based on 8 week safety and efficacy endpoints. All stage 1 patients will be hospitalised for 8 weeks for intensive cardiological evaluations to establish the QT-specific liability of the regimens. Investigational arms that do not meet predefined safety and efficacy criteria (percentage culture conversion >40%; percentage discontinuation and death <45%) will not be considered for further evaluation. The regimens that do not meet these pre-defined safety and/or efficacy criteria will be eligible to be evaluated for long term safety, tolerability and efficacy in Stage 2. If less than two investigational arms are available for stage two assessment, the SAC will make recommendations on whether new arms should be introduced in the study. If more than two arms are available for the Stage 2 assessment, two regimens will be chosen. The SAC will make recommendations on which arms to take forward to the trial steering committee. The second stage corresponds to a phase III trial. Patients in this stage will be recruited into the arms chosen from stage 1 plus the SOC. The regimens will primarily be evaluated for safety and efficacy in comparison with the SOC arm at 72 weeks post randomisation. The primary efficacy outcome will be a composite endpoint of the percentage of unfavourable outcomes. The secondary outcomes will include safety outcomes and in particular the percentage of Grade 3 or 4 AEs and SAEs in the investigational regimens compared with the SOC.


Recruitment information / eligibility

Status Completed
Enrollment 552
Est. completion date August 5, 2022
Est. primary completion date August 5, 2022
Accepts healthy volunteers No
Gender All
Age group 15 Years and older
Eligibility Inclusion criteria: Patients eligible for inclusion in the trial must fulfil all of the following criteria: - Male or female subjects aged 15 years of age or above, regardless of HIV status; - Microbiological test (molecular or phenotypic) confirming presence of M. tuberculosis; - Resistant to at least rifampicin by either molecular or phenotypic drug susceptibility test; - Completed informed consent form (ICF); Exclusion criteria: Patients will not be eligible for inclusion in the trial if they meet any of the following criteria: - Known allergies, hypersensitivity, or intolerance to any of the study drugs; - Pregnant or breast-feeding; or unwilling to use appropriate contraceptive measures - Liver enzymes >3 times the upper limit of normal (AST or ALT); - Any condition (social or medical) which, in the opinion of the investigator, would make study participation unsafe; - Taking any medications contraindicated with the medicines in the trial; - QTcF > 450ms; - One or more risk factors for QT prolongation (excluding age and gender) or other uncorrected risk factors for TdP; - History of cardiac disease, syncopal episodes, symptomatic or asymptomatic arrhythmias (with the exception of sinus arrhythmia); - Any baseline biochemical laboratory value consistent with Grade 4 toxicity. - Moribund - Known resistance to bedaquiline, pretomanid, delamanid or linezolid. - Prior use of bedaquiline and/or pretomanid and/or linezolid and/or delamanid for one or more months. - Patients not eligible to start a new course of MDR-TB/XDR-TB treatment according to local protocol, including but not limited to: - currently on MDR-TB treatment for more than 2 weeks (and not failing) - unstable address - loss to follow-up in previous treatment with no change in circumstance and motivation. - Tuberculous meningoencephalitis, brain abscesses, osteomyelitis or arthritis. PKPD inclusion/exclusion: - Adult patients (aged 18 years or above) recruited into the investigational arms of the TB-PRACTECAL trial in the approved sites. - Willing to sign the sub-study informed consent form after agreeing to the additional blood draws.

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Bedaquiline

Pretomanid

Moxifloxacin

Linezolid

Clofazimine

Locally accepted standard of care which is consistent with the WHO recommendations for the treatment of M/XDR-TB.


Locations

Country Name City State
Belarus Republican Scientific and Practical Centre for Pulmonology and Tuberculosis hospital Minsk
South Africa King DinuZulu Hospital Durban KwaZulu-Natal
South Africa THINK Clinical Trial Unit, Hillcrest Durban KwaZulu-Natal
South Africa Helen Jospeh Hospital Johannesburg Gauteng
South Africa Doris Goodwin Hospital Pietermaritzburg KwaZulu Natal
Uzbekistan Republican TB Hospital No. 2 Nukus Karakalpakstan
Uzbekistan Sh Alimov Republican Specialised Scientific-Practical Medical Centre for Phthysiology and Pulmonology Hospital Tashkent

Sponsors (15)

Lead Sponsor Collaborator
Medecins Sans Frontieres, Netherlands Drugs for Neglected Diseases, eResearch Technology, Inc., Global Alliance for TB Drug Development, London School of Hygiene and Tropical Medicine, Ministry of Health, Republic of Uzbekistan, Ministry of Public Health, Republic of Belarus, Rutgers, The State University of New Jersey, Swiss Tropical & Public Health Institute, THINK TB & HIV Investigative Network, University College, London, University of California, San Francisco, University of Liverpool, Wits Health Consortium (Pty) Ltd, World Health Organization

Countries where clinical trial is conducted

Belarus,  South Africa,  Uzbekistan, 

Outcome

Type Measure Description Time frame Safety issue
Primary Stage 1:Percentage of patients with culture conversion in liquid media at 8 weeks post randomisation. 8 weeks post randomisation
Primary Stage 1: Percentage of patients who discontinue treatment for any reason or die 8 weeks post randomisation
Primary Stage 2: Percentage of patients with an unfavourable outcome (failure, death, recurrence, loss to follow-up) 72 weeks post-randomisation
Secondary Stage 1: Percentage of patients with grade 3 or higher QT prolongation within 8 weeks post randomisation
Secondary Stage 1: Percentage of patients experiencing at least one Serious Adverse Event (SAE) within 8 weeks post randomisation
Secondary Stage 1:Percentage of patients experiencing at least one new grade 3 or higher Adverse Event within 8 weeks post randomisation
Secondary Stage 2: Percentage of patients with culture conversion 12 weeks post randomisation
Secondary Stage 2: Percentage of patients with an unfavourable outcome (i.e. failure, treatment discontinuation, death, loss to follow up) 24 weeks post randomisation
Secondary Stage 2: Percentage of patients with an unfavourable outcome (i.e. failure, treatment discontinuation, death, loss to follow up, still on treatment at censure and recurrence) 108 weeks post randomisation
Secondary Stage 2: Median time to culture conversion 108 weeks
Secondary Stage 2: Percentage of patients with an SAE or new grade 3 or higher AE 72 weeks post randomisation
Secondary Stage 2: Percentage of patients with an SAE or new grade 3 or higher AE 108 weeks post randomisation
Secondary Stage 2: Percentage of patients with an SAE or new grade 3 or higher AE at the end of treatment The percentage of patients with an SAE or new grade 3 or higher AE at the end of treatment in the investigational arms (maximum of 24 weeks) and the SOC arm which varies in length (maximum 108 weeks). 24 weeks in investigational arms and 108 weeks in SOC arm
Secondary Stage 2: Mean single ?QTcF 24 weeks post randomisation
Secondary Stage 2: Percentage of patients experiencing recurrence week 48 in investigational arms
Secondary Stage 2: Plasma drug concentrations In relation to dose intake and start of treatment over a 72 week period
Secondary Stage 2: TB drug hair levels In relation to dose intake and start of treatment over a 72 week period
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