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.: PACTR201409000848428 Date of Approval: 02/07/2014
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Evaluating a new treatment regimen for patients with multidrug-resistant TB (MDR-TB)
Official scientific title Evaluating a new treatment regimen for patients with multidrug-resistant TB (MDR-TB) - a randomised controlled Phase 3 trial.
Brief summary describing the background and objectives of the trial Objectives 1-To evaluate the impact of a new injection-free 6-month treatment regimen of linezolid, bedaquiline, levofloxacin, pyrazinamide (PZA) and ethionamide/high dose isoniazid (INH) compared to the conventional empiric injection-based regimen of kanamycin, moxifloxacin, PZA, ethionamide, terizidone, and potentially other group 5 drugs (21-24 months as DoH 2012 policy is to continue for 18 months after sputum conversion). A gene-directed diagnostic approach (mutational analysis using the Hain platform) will be used in the interventional arm to individualise therapy and to inform on the use of high dose INH versus ethionamide. 2-To evaluate the impact of ART on bedaquiline concentrations in HIV-infected participants in the interventional arm. This information is critically needed to minimise the development of resistance to bedaquiline. An additional sub-aim will be to evaluate the PK/PD relationships of linezolid.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) NExT
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied HIV/AIDS,Tuberculosis
Purpose of the trial Treatment: Drugs
Anticipated trial start date 01/10/2014
Actual trial start date
Anticipated date of last follow up 01/10/2018
Actual Last follow-up date
Anticipated target sample size (number of participants) 256
Actual target sample size (number of participants)
Recruitment status Not yet recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
3810 NHREC
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 1:1 randomization (open label) Open Label Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group Linezolid, Bedaquiline and Levofloxacin Linezolid 600mg daily, Bedaquiline 400mg for 2 weeks, followed by 200mg three times per week, Levofloxacin750mg (<50kg), 1000mg (>50kg) 6 months medicinal product 128
Control Group Conventional MDR-TB treatment As per South African National MDR-TB Program 21-24 months 128 Active-Treatment of Control Group
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
¿ Provide written, informed consent prior to all trial-related procedures including HIV testing. ¿ Male or female, aged 18 years and older. ¿ Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive. ¿ Newly diagnosed culture and/or GeneXpert positive pulmonary TB. ¿ GeneXpert rifampicin resistance confirmed on an alternative method of susceptibility testing (line probe assay (LPA) or phenotypic DST using a culture isolate or sputum sample. ¿ Ability to produce an adequate volume of sputum as estimated from a spot assessment (estimated 10 ml or more overnight production). ¿ Women of non-childbearing potential or using effective methods of birth control. ¿ Previous history of treatment for MDR-TB. ¿ Having received any drug active against MDR-TB within 3 months or less prior to enrolment. ¿ Having been on treatment for drug sensitive TB treatment within 3 months or less prior to enrolment. ¿ Currently on MDR-TB treatment for more than 2 weeks. ¿ Fluoroquinolone-resistant and/or aminoglycoside-resistant TB detected (pre-XDR and XDR-TB). ¿ Rifampicin mono-resistance. ¿ Incompatibility between microbiological and clinic-radiological findings (i.e. where the clinico-radiological findings do not confirm the positive microbiological testing) ¿ Primarily extra-thoracic TB as judged by the investigator. ¿ History of allergy to any of the trial IMP/s or related substances. ¿ Known or suspected, current alcohol or drug abuse, that is, in the opinion of the Investigator, sufficient to compromise the safety or cooperation of the participant. ¿ Significant cardiac arrhythmia requiring medication. ¿ Having participated in other clinical studies with investigational agents within 8 weeks prior to trial start. ¿ Participants with specific ECG abnormalities at screening (see full protocol for details) ¿ Participant who is pregnant, breast-feeding, or planning to conceive a child within 6 months of cessation of treatment. ¿ Diabetes Mellitus requiring insulin. ¿ History and/or presence (or evidence) of neuropathy or epilepsy. ¿ History and/or presence (or evidence) of any haematogical disorder. ¿ Specific concurrent treatments: - Any diseases or conditions in which the use of the standard TB drugs or any of their components is contra-indicated, including but not limited to allergy to any TB drug, their component or to the IMP. - Concomitant use of any drug (other than the study drugs) known to prolong QTc interval (see full protocol for details). - Use of any drugs or substances within 30 days prior to dosing known to be strong inhibitors or inducers of cytochrome P450 enzymes (see full protocol for details). Exceptions may be made for participants that have received 3 days or less of one of these drugs or substances, if there has been a wash-out period before administration of IMP equivalent to at least 5 half-lives of that drug or substance. - Use of any therapeutic agents known to alter any major organ function (see full protocol for details). ¿ Laboratory abnormalities: Participants with specific toxicities at screening as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November 2007) (see full protocol for details). 18 Year(s) 999 Year(s) Male
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
No 10/07/2014 University of Cape Town Human Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
Faculty Of health Sciences, University of Cape Town Human Research Ethics Committee, Old Main Building, Groote Schuur Drive Cape Town 7295 South Africa
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome The proportion of patients with favourable outcome i.e. achieving treatment success (cure/completion) in either arm. 24 months
Secondary Outcome Favourable outcome rate (time-specific and at the end of treatment) 6 months in interventional arm and 24 months in conventional arm
Secondary Outcome Rate of treatment failure (time-specific and at the end of treatment) 6 months and 24 months
Secondary Outcome time-specific culture conversion rates Time specific
Secondary Outcome Adherence (monitored using a combination of self-report and/ or diary cards and/or DOTs) Any
Secondary Outcome Adverse events Any
Secondary Outcome Adverse drug reactions Any
Secondary Outcome Death Any
Secondary Outcome Default rate Any
Secondary Outcome Rate of loss to follow-up Any
Secondary Outcome Interaction between bedaquiline and ART. time specific during the first 6 months
Secondary Outcome Relapse rate time-specific and during the 12 and 30 months of follow-up in the interventional and conventional arms respectively
Secondary Outcome Rate of re-infection Any
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Brooklyn Chest Hospital Stanberry Road, Ysterplaat Cape Town 7405 South Africa
Gordonia Hospital Schroeder Street, Northern Cape Upington 8801 South Africa
City of Cape Town Clinics Cape Town South Africa
Jose Pearson TB Hospital Mission Road, Bethelsdorp, Eastern Cape Port Elizabeth, 7236 South Africa
TB Clinics and TB Hospitals at various sites Multiple Multiple Multiple South Africa
FUNDING SOURCES
Name of source Street address City Postal code Country
Medical Research Council Medical Research Council Private Bag 19070 Tygerberg Cape Town 7505 South Africa
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor university of Cape Town Lung Institute 1 George street, Mowbray Cape Town 7700 South Africa Charities/Societies/Foundation
COLLABORATORS
Name Street address City Postal code Country
Prof Gary Maartens University of Cape Town and Groote Schuur Hospital, Deparment of Medicine, Old Main Building, Groote Schuur Drive Cape Town 7925 South Africa
Prof Patrick Oluboyo Jose Pearson TB HospitalMission Road, Bethelsdorp, Port Elizabeth, Eastern Cape, South Africa Port Elizabeth 6605 South Africa
Prof Nesri Padayatchi university of Kwazulu Natal Kwazulu Natal South Africa
Prof Rob Warren Stellenbosch University Private Bag X1 Matieland Cape Town 7602 South Africa
Dr Barbara Mastrapa Schroeder Street, Northern Cape Upington 8801 South Africa
Dr Aliasgar Esmail university Of Cape Town Lung Institute, Lung Infection and immunity unit, H46, Old main Building, Groote Schuur Hospital, Groote Schuur drive Cape Town 7925 South Africa
Dr Gregory Calligaro university Of Cape Town Lung Institute, Lung Infection and immunity unit, H46, Old main Building, Groote Schuur Hospital, Groote Schuur drive Cape Town 7925 South Africa
Dr John Black Jose Pearson TB HospitalMission Road, Bethelsdorp, Port Elizabeth, Eastern Cape, South Africa Port Elizabeth 6055 South Africa
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Keertan Dheda keertan.dheda@uct.ac.za +27214047654 University of Cape Town Lung Infection and Immunity Unit, H 46.41 Old Main Building, Groote Schuur Hospital, Groote Schuur Drive
City Postal code Country Position/Affiliation
Cape Town 7925 South Africa Head:Department of Pulmonology Groote schuur Hospital and UCT Lung Infection and Immunity Unit
Role Name Email Phone Street address
Principal Investigator Akhter Goolam-Mahomed akhtergm@telkomsa.net +2712521 4542 / 5706 Medunsa Campus Library PO Box 156 MEDUNSA 0204
City Postal code Country Position/Affiliation
Limpopo 0204 South Africa Head : Critical Care Unit
Role Name Email Phone Street address
Public Enquiries Dr Aliasgar Esmail aliasgaresmail@gmail.com +27214047654 University of Cape Town Lung Infection and Immunity Unit, H 46.41 Old Main Building, Groote Schuur Hospital, Groote Schuur Drive
City Postal code Country Position/Affiliation
Cape Town 7925 South Africa Trial Cordinator
Role Name Email Phone Street address
Scientific Enquiries Keertan Dheda keertan.dheda@uct.ac.za +27214047654 University of Cape Town Lung Infection and Immunity Unit, H 46.41 Old Main Building, Groote Schuur Hospital, Groote Schuur Drive
City Postal code Country Position/Affiliation
Cape Town 7925 South Africa Head:Department of Pulmonology Groote schuur Hospital and UCT Lung Infection and Immunity Unit
Role Name Email Phone Street address
Scientific Enquiries Keertan Dheda keertan.dheda@uct.ac.za +27214047654 University of Cape Town Lung Infection and Immunity Unit, H 46.41 Old Main Building, Groote Schuur Hospital, Groote Schuur Drive
City Postal code Country Position/Affiliation
Cape Town 7925 South Africa Head:Department of Pulmonology Groote schuur Hospital and UCT Lung Infection and Immunity Unit
REPORTING
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