Fixed-Dose Combinations (FDCs) of anti-tubercular drugs have been recommended as a step towards ensuring better treatment and compliance of patients receiving Anti-Tubercular Therapy (ATT). However, a major concern with FDCs has been low bioavailability of rifampicin due to interaction with isoniazid in the stomach. A novel FDC of gastro-retentive rifampicin and delayed release isoniazid was developed to overcome this interaction. Methods: The study was a parallel-group, open-label, randomized controlled trial conducted at a tertiary referral centre in northern India. Patients were randomized to receive daily treatment with the conventional FDC dosage formulation or the novel FDC formulation of rifampicin and isoniazid as a part of 4 drug ATT regimen. The outcome measures were sputum conversion rates, radiological response and clinical response. Drug levels of rifampicin and isoniazid were also measured and compared at various time points.