BACKGROUND: Rifampicin resistant tuberculosis (RR-TB) causes disease in 410,000 people annually. Treatment of RR-TB used to be lengthy, complex, ineffective, poorly tolerated and expensive. We aimed to identify short, effective and safe all oral regimen(s) for the treatment of pulmonary RR-TB. In addition, we aimed to investigate the relationship between the patients’ exposure to anti-TB drugs and treatment outcomes. METHODS: An open label, randomised, controlled, multi-arm, multicentre, non-inferiority trial was conducted in Uzbekistan, Belarus, and South Africa. Participants were randomised in a 1:1:1:1 ratio to receive standard of care (SoC); 24-week oral bedaquiline, pretomanid, and linezolid (BPaL); BPaL plus clofazimine (BPaLC); or BPaL plus moxifloxacin (BPaLM) in stage one of the trial and in a 1:1 ratio to receive SoC or BPaLM in stage two of the trial. The primary outcome was the percentage of participants with a composite unfavourable outcome (death, treatment failure, treatment discontinuation, recurrence or loss to follow-up) at 72 weeks post randomisation. A non-inferiority margin of 12% and a power of 85% were assumed. In the pharmacokinetic study, blood samples were collected on Day 1 (0, 2 and 23 hours), Weeks 8 (predose, 6.5 and 23 hours), 12, 16, 20, 24, 32 and 72 post randomisation visits from a subset of participants randomised to the interventional arms only. Drug concentrations were quantified in a Good Clinical Practice (GCP) laboratory using a high performance liquid chromatography-tandem mass spectrometry. nlmixr2, an opensource R package was used for population pharmacokinetic (PK) modelling. Probability of target attainment for concentration dependent and time dependent indices were area under the concentration-time curve from zero to twenty four hours over minimum inhibitory concentration (AUC0-24 /MIC) and percentage of the dosing interval during which the plasma concentration exceeds the MIC (%T>MIC). RESULTS: 552 participants were enrolled in the randomised controlled trial (RCT), 41% were female, with a median age of 35 years. 28% were living with HIV, 65% had smear positive, 61% had cavities on chest x-ray and 89% were culture positive. In stage 1, BPaLM was chosen due to higher culture-conversion rates at 8 weeks (BPaLM 77%, BPaLC 67%, and BPaL 46%). The trial was discontinued early for benefit. The primary unfavourable outcomes proportions at 72 weeks post randomisation were 41%, 12%, 23% and 14% for SoC, BPaLM, BPaLC and BPaL arms respectively. 23%, 30% and 24% of participants receiving BPaLM, BPaLC and BPaL respectively, had adverse events of grade 3 or higher or serious adverse events, compared with 48% of participants receiving standard care. A one-compartment, first order absorption and elimination disposition model with fat free mass allometric scaling and Caucasian race covariate on clearance best described the linezolid pharmacokinetics. The 600mg dose probability of free drug area under the concentration-time curve from zero to twenty four hours of free drug (fAUC0-24) divided by the minimum inhibitory concentration (MIC) target of 119 was reached for MIC of 0.25 mg/L. A one-compartment first order absorption and elimination model with allometric scaling of fat-free mass on both clearance and volume of distribution best characterised pretomanid pharmacokinetics. Virtually all patients on a 200mg daily had drug exposures above 77% of the dosing interval during which the unbound drug plasma concentration exceeds the MIC (fT>MIC) target and at least 96% would have been above the 167 fAUC0-24 /MIC target. A two-compartment first order absorption and elimination body weight allometric scaling model with a lag time absorption parameter best described the pharmacokinetics of clofazimine. Using 100mg daily, the probability %T>MIC target could be achieved at MIC of 0.5mg/L. Bedaquiline population pharmacokinetics was best described by a three-compartment model with fixed transit compartments with BMI allometry. When dosed at 400mg daily for two weeks followed by 200mg three times a week, probability of target attainment above 90% was only achieved for MICs below 0.063mg/L. CONCLUSION: BPaLM was both safer and more efficacious than the then SoC. An optimal design-led sparse sampling schedule allowed for satisfactory population pharmacokinetic modelling for linezolid, pretomanid, clofazimine and bedaquiline. Further pharmacodynamic analyses are recommended to elucidate the contribution of each drug to the trial outcomes.