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

This is an interventional treatment trial for Tuberculosis Read More

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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)
  • Platelets grade 3 or worse (<49999 x 109/L)
  • ALT grade 3 or worse (>5 times ULN)
  • Total bilirubin grade 3 or worse (>2.5 times ULN)
• Specific prior or concurrent medication/treatments (see Restrictions section below, Table 3).
• Rifampicin monoresistant TB.
• Fluoroquinolone and/or SLID resistance. Although in South Africa, the standard of care does not single out MDR-TB with fluoroquinolone or aminoglycoside resistance at initiation of MDR-TB treatment, in this study the Hain MTBDRsl LPA will be used on the sputum sample to exclude any pre-XDR and XDR cases from participation in the study (results from the LPA and phenotypic DST testing on the isolate will be available 3-6 weeks later).

All inclusion and no exclusion criteria must be met prior to enrolment and randomisation. Whenever the investigator has reason to suspect that there might be a health problem (other than TB) participation should only be considered after discussing the case with the medical monitor. Note: Participants who are currently on, or have previously been on drug-sensitive TB treatment are not excluded from participation.

Post-randomisation exclusion criteria:

• Fluoroquinolone and/or SLID resistance detected on DST using the isolate. Note: A woman who falls pregnant during the treatment phase of the trial will not be excluded but will be counselled regarding potential termination of pregnancy.