An Open-label RCT to Evaluate a New Treatment Regimen for Patients With Multi-drug Resistant Tuberculosis

NCT02454205 | Completed Phase 2 DMC

• 1 other identifier: NExT-5001
• Study Type: interventional
• Target: 154
• Locations: 1 country
• Sites: 1

Brief Summary

This study aims to evaluate the impact of a new injection-free six-to-nine month treatment regimen of linezolid, bedaquiline, levofloxacin, pyrazinamide (PZA) and ethionamide/high dose isoniazid (INH) compared to the conventional empiric injection-based regimen. The secondary aim is to determine if other treatment-related outcomes including adverse events, adherence to treatment, culture conversion, and cure/completion are significantly different in the intervention and conventional arms.

Conditions

Tuberculosis; Multidrug Resistant Tuberculosis; Extensively-drug Resistant Tuberculosis

Outcome Measures

Primary Outcomes (1)

• Treatment success

  In the conventional arm treatment success is defined as the sum of cured or treatment completed cases. In the intervention arm treatment success is defined as the sum of cured and treatment completed cases, without subsequent relapse, re-infection or death during the 15-18 month follow up period.

  24 months after initiation of treatment in either arm.

Secondary Outcomes (9)

• Favourable outcome rate

  At 6-9 months for the intervention arm and 21-24 months for the conventional arm.

• Time specific rate of treatment failure.

  6-36 months

• Time specific culture conversion proportions and rates.

  6-36 months

• Time specific relapse rate.

  6-36 months.

• Rate of re-infection.

  6-36 months.

Study Arms (2)

Conventional treatment 21-24 months

ACTIVE COMPARATOR

Participants will receive a 6-8 month intensive phase of: Kanamycin IM 500-750mg (40-50kg) or 1000mg (51-90kg) daily, Moxifloxacin 400mg od, Pyrazinamide 1000-1750mg (40-50kg) or 1750-2000mg (51-70kg) or 2000-2500mg (71-90kg) daily, Ethionamide 500mg (40-50kg) or 750mg (51-70kg) or 750-1000mg (71-90kg) daily,Terizidone 750mg (40-70kg) or 750-1000mg (71-90kg) daily. The continuation phase will start after 2 consecutive negative sputum cultures and continue for 18 months with Moxifloxacin, PZA, Ethionamide and Terizidone. In 2016 the WHO revised the treatment guidelines for MDR-TB. The South African National Tuberculosis Program adopted these recommendations and it was integrated into the study in September 2016: SA NTP recommended shorter regimen(9-12 months):Intensive phase (4-6 months): kanamycin, levofloxacin, clofazimine, pyrazinamide, high-dose isoniazid/ethionamide, ethambutol. Continuation phase (5 months): levofloxacin, clofazimine, pyrazinamide, ethambutol.

Drug: Pyrazinamide; Drug: Ethionamide; Drug: Terizidone; Drug: Moxifloxacin; Drug: Kanamycin

Interventional treatment 6-9 months

EXPERIMENTAL

Participants will receive six to nine months of oral: Linezolid 600mg daily (reduce to 300mg if toxicity occurs), Bedaquiline 400mg for 2 weeks, followed by 200mg three times per week, Levofloxacin 750mg (\<50kg) or 1000mg (\>50kg) daily, PZA 1000-1750mg (40-50kg) or 1750-2000mg (51-70kg) or 2000-2500mg (71-90kg) daily, Ethionamide 15mg/kg (max 900mg) daily, or high-dose Isoniazid 500mg (40-50kg) or 750mg (51-70kg) or 750-1000mg (71-90kg) daily, or Terizidone 750mg (40-70kg) or 750-1000mg (71-90kg) daily. A gene-directed diagnostic approach will be used in the interventional arm to individualise therapy and to inform on the use of high dose INH versus ethionamide. Treatment will stop after 3 consecutive negative sputum cultures.

Drug: Linezolid; Drug: Bedaquiline; Drug: Levofloxacin; Drug: Pyrazinamide; Drug: Isoniazid; Drug: Ethionamide; Drug: Terizidone

Interventions

Linezolid DRUG

600mg Linezolid po daily, reduced to 300mg po daily if toxicity occurs.

Interventional treatment 6-9 months

Bedaquiline DRUG

400mg po daily for 2 weeks, followed by 200mg three times per week .

Interventional treatment 6-9 months

Levofloxacin DRUG

750mg (\<50kg) 1000mg (\>50kg)

Interventional treatment 6-9 months

Pyrazinamide DRUG

1000-1750mg (40-50kg) 1750-2000mg (51-70kg) 2000-2500mg (71-90kg)

Also known as: PZA

Conventional treatment 21-24 months; Interventional treatment 6-9 months

Isoniazid DRUG

high dose Isoniazid 500mg (40-50kg) 750mg (51-70kg) 750-1000mg (71-90kg)

Also known as: INH

Interventional treatment 6-9 months

Ethionamide DRUG

15mg/kg (max 900mg)

Conventional treatment 21-24 months; Interventional treatment 6-9 months

Terizidone DRUG

750mg (40-70kg) 750-1000mg (71-90kg)

Conventional treatment 21-24 months; Interventional treatment 6-9 months

Moxifloxacin DRUG

400mg po daily.

Conventional treatment 21-24 months

Kanamycin DRUG

500-750mg (40-50kg) 1000mg (51-90kg) intramuscular daily during 6-8 month intensive phase.

Conventional treatment 21-24 months

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Newly diagnosed culture and/or GeneXpert positive pulmonary TB.
• Rifampicin resistance detected using at least two susceptibility testing assays (GeneXpert, HainMTBDRplus or phenotypic) using a sputum sample during screening.
• Provide written informed consent prior to all trial-related procedures including HIV testing.
• Male or female aged 18 years and older.
• Body weight between 40 and 90 kg, inclusive.
• Women of non-childbearing potential or participants of either sex who are using or willing to use effective methods of birth control

You may not qualify if:

• A participant who in the opinion of the investigator is unlikely to cope with regular visits to the trial site either because of travel constraints, or because of drug or alcohol abuse, or other reason.
• Known at screening to have XDR-TB or pre-XDR-TB (i.e. fluoroquinolone or second-line injectable drug (SLID) resistance i.e. to capreomycin, amikacin and kanamycin).
• Previous history of treatment for MDR-TB or XDR-TB or previous treatment with bedaquiline.
• Currently on MDR-TB treatment for more than 2 weeks.
• Any participant with a Karnofsky score \< 50.
• Known allergy to any of the trial drugs or related substances.
• Having participated in other clinical studies within 8 weeks prior to trial start where investigational agents were used that may potentially impact current trial outcome.
• Presence (or evidence) of symptomatic neuropathy grade 3 or higher.
• Epilepsy where drugs prolonging QT interval are used.
• Participant who is pregnant, breast-feeding (and not willing to stop), or planning to conceive a child within 6 months of cessation of treatment.
• Incompatibility between microbiological and clinical/ radiological findings (i.e. where the clinical and/or radiological findings are discordant with microbiological testing suggesting laboratory contamination).
• Participants with ECG abnormalities, in particular QT prolongation.
• Any pre-existing laboratory abnormality which in the opinion of the investigator will place the participant at risk. Patients with any of the following baseline laboratory abnormalities will be excluded from the study:
• Creatinine grade 2 or worse (\>1.4 times ULN)
• Hemoglobin level grade 4 (HB \<6.5g/dL)

Sponsors & Collaborators

• University of Cape Town: lead
• University of Limpopo: collaborator
• Walter Sisulu University: collaborator
• University of Stellenbosch: collaborator
• University of Cape Town Lung Institute: collaborator

Study Sites (1)

Brooklyn Chest Hospital

Cape Town, Western Cape, 7441, South Africa

Location

Related Publications (2)

• Esmail A, Oelofse S, Lombard C, Perumal R, Mbuthini L, Goolam Mahomed A, Variava E, Black J, Oluboyo P, Gwentshu N, Ngam E, Ackerman T, Marais L, Mottay L, Meier S, Pooran A, Tomasicchio M, Te Riele J, Derendinger B, Ndjeka N, Maartens G, Warren R, Martinson N, Dheda K. An All-Oral 6-Month Regimen for Multidrug-Resistant Tuberculosis: A Multicenter, Randomized Controlled Clinical Trial (the NExT Study). Am J Respir Crit Care Med. 2022 May 15;205(10):1214-1227. doi: 10.1164/rccm.202107-1779OC.

  PMID: 35175905 DERIVED

• Wasserman S, Huo S, Ky K, Malig YN, Esmail A, Dheda K, Bacchetti P, Gerona R, Maartens G, Gandhi M, Metcalfe J. Correlation of Linezolid Hair Concentrations with Plasma Exposure in Patients with Drug-Resistant Tuberculosis. Antimicrob Agents Chemother. 2020 Feb 21;64(3):e02145-19. doi: 10.1128/AAC.02145-19. Print 2020 Feb 21. No abstract available.

  PMID: 31932382 DERIVED

Related Links

• Home page of the Lung Institute

MeSH Terms

Conditions

Tuberculosis; Tuberculosis, Multidrug-Resistant; Extensively Drug-Resistant Tuberculosis

Interventions

Linezolid; bedaquiline; Levofloxacin; Pyrazinamide; Isoniazid; Ethionamide; terizidone; Moxifloxacin; Kanamycin

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Oxazolidinones; Oxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Ofloxacin; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pyrazines; Hydrazines; Isonicotinic Acids; Acids, Heterocyclic; Pyridines; Aminoglycosides; Glycosides; Carbohydrates

Study Officials

• Keertan Dheda, MBChB

  UCT Lung Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principle Investigator

Study Record Dates

• First Submitted: May 22, 2015
• First Posted: May 27, 2015
• Study Start: November 12, 2015
• Primary Completion: December 31, 2020
• Study Completion: August 30, 2021
• Last Updated: September 29, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will not share

Locations

ZA (1)