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

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.

Inclusion criteria

• Confirmed diagnosis of drug-sensitive pulmonary tuberculosis (bacteriologically confirmed by positive sputum smear microscopy or GeneXpert MTB/RIF)
• Age 18 to 65 years
• Naive to anti-tuberculosis treatment (no previous TB treatment or less than 1 month of TB treatment in the past)
• Willing to provide written informed consent
• Able to comply with study visits and procedures
• HIV-negative or HIV-positive with CD4 count ≥200 cells/mm³ on stable antiretroviral therapy

Exclusion criteria

• Drug-resistant tuberculosis (confirmed resistance to Rifampicin or Isoniazid)
• Severe hepatic impairment (Child-Pugh Class C) or ALT/AST >3 times upper limit of normal
• Severe renal impairment (eGFR <30 mL/min/1.73m²)
• Known hypersensitivity to Pyrazinamide, Hydroxychloroquine, or any RIPE drugs
• Pregnancy or breastfeeding
• Retinal disease or known contraindications to Hydroxychloroquine
• Concomitant use of medications with significant interactions with study drugs
• Extrapulmonary tuberculosis as the primary site
• Currently enrolled in another clinical trial