NCT07467252

AIPH-TB: AI-Optimised Pyrazinamide-Hydroxychloroquine vs Standard RIPE for Drug-Sensitive Pulmonary Tuberculosis - A Phase II RCT

A Phase II, Open-Label, Randomised, Parallel-Group, Active-Controlled Trial Evaluating the Efficacy, Safety, and Tolerability of AI-Optimised Pyrazinamide 1,500 mg / Hydroxychloroquine 200 mg Twice Daily (AIPH-TB Protocol) Versus Standard Four-Drug RIPE Regimen in Adults With Newly Diagnosed Drug-Sensitive Pulmonary Tuberculosis

• Status: Not Yet Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 200 (estimated)
• Sponsor: Ministry of Health, Saudi Arabia · Other Government
• Sex: All
• Age: 18 Years – 65 Years
• Healthy volunteers: Not accepted

Summary

Tuberculosis (TB) kills 1.3 million people annually and remains the world's deadliest bacterial disease. The standard four-drug RIPE regimen achieves only 85% cure rates and causes drug-induced hepatotoxicity in 25-37% of patients. Hydroxychloroquine (HCQ), an FDA-approved antimalarial, has been shown to synergise with pyrazinamide (PZA) by inhibiting the BCRP-1 efflux pump and raising phagolysosomal pH, increasing intracellular PZA concentrations (FICI 0.38 in vitro). The AIPH-TB computational framework (Artificial Intelligence Physicochemical Harmonisation for Tuberculosis) uses multi-objective reinforcement learning, Gaussian process regression, and a digital twin macrophage simulator to identify an AI-optimised dosing schedule that maximises this synergy (PZA 1,500 mg + HCQ 200 mg at 0800 and HCQ 200 mg at 2000), maintaining phagolysosomal pH within 5.2-5.8 for 18 of 24 hours. The computational model predicts FICI 0.28 (strongly synergistic), 9.4-fold increase in intracellular PZA concentration, 99.5% cure rate, and \<1.5% hepatotoxicity. This Phase II randomised controlled trial will test whether the AI-optimised PYZ-HCQ protocol is superior to standard RIPE in 200 newly-diagnosed drug-sensitive pulmonary TB patients over 6 months of treatment with 6 months of follow-up.

Detailed description

BACKGROUND AND RATIONALE: Pyrazinamide (PZA) is the only first-line agent active against dormant intracellular MTB, making it irreplaceable for sterilising activity. Its clinical utility is limited by BCRP-1-mediated efflux - after entering the phagolysosome, PZA is rapidly expelled before it can be protonated to its active form, pyrazinoic acid (POA). Hydroxychloroquine (HCQ) inhibits BCRP-1 and raises phagolysosomal pH. The AIPH-TB AI framework identified that an oscillating HCQ schedule (0800/2000) maintains optimal pH 5.2-5.8 for 18 h/day - a 125% improvement over unoptimised dosing - and predicts a novel second mechanism: reduction of mycobacterial cell wall zeta potential from -18 mV to -8 mV, increasing membrane permeability to POA by 340%. STUDY DESIGN OVERVIEW: This is a Phase II, open-label, randomised, parallel-group, active-controlled superiority trial conducted at two tertiary TB treatment centres in Riyadh, Saudi Arabia. Participants will be randomised 1:1 to receive either the AIPH-TB protocol (Arm A) or standard RIPE therapy (Arm B) for 6 months, with 6 months post-treatment follow-up (total study duration per participant: 12 months). RANDOMISATION: Block randomisation (block size 4 and 6, randomly varied), stratified by site and HIV status. Centralised web-based randomisation via REDCap (MOH Research Directorate Biostatistics Unit). BLINDING: Open-label study. Laboratory personnel processing sputum cultures and liver enzyme results are blinded to treatment arm (assessor-blind for primary outcomes). The DSMB will conduct unblinded interim analyses. SAMPLE SIZE: Total 200 participants (100 per arm). Based on 80% sputum culture conversion at Week 8 for standard RIPE vs 95% for AIPH-TB (15 percentage point difference), alpha=0.05, power=80%, with 25% dropout inflation.

Conditions

• Pulmonary Tuberculosis

Interventions

Type	Name	Description
DRUG	Pyrazinamide and Hydroxychloroquine (AI-Optimised)	AI-optimised combination drug regimen consisting of Pyrazinamide (PYZ) and Hydroxychloroquine (HCQ) for treating drug-sensitive pulmonary tuberculosis. Dosing is personalised using AI algorithms that analyse patient pharmacokinetic parameters, pharmacogenomic data, and real-time treatment response. The AI system adjusts doses to optimise bactericidal activity while minimising adverse effects. PYZ dose: 15-30 mg/kg/day; HCQ dose: 200-400 mg/day, duration adjusted per AI protocol over 6 months.
DRUG	Standard RIPE Regimen (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol)	Standard WHO first-line anti-tuberculosis treatment regimen: 2 months of Rifampicin (R) 10 mg/kg/day, Isoniazid (I) 5 mg/kg/day, Pyrazinamide (Z) 25 mg/kg/day, and Ethambutol (E) 15 mg/kg/day (intensive phase), followed by 4 months of Rifampicin and Isoniazid (continuation phase). Total treatment duration: 6 months.

Timeline

• Start date: 2026-09-01
• Primary completion: 2027-12-01
• Completion: 2028-06-01
• First posted: 2026-03-12
• Last updated: 2026-03-12

Locations

1 site across 1 country: Saudi Arabia