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
Trial ID: NCT07467252
Status: NOT_YET_RECRUITING
Study type: INTERVENTIONAL
Phase: PHASE2
Start date: 2026-09
Completion date: 2028-06
Sponsor: Ministry of Health, Saudi Arabia
Conditions: Pulmonary Tuberculosis
Interventions: Pyrazinamide and Hydroxychloroquine (AI-Optimised); Standard RIPE Regimen (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol)
Locations: Riyadh First Health Cluster, Ministry of Health
Countries: Saudi Arabia
Enrollment: 200
Age range: 18 Years - 65 Years
Sex: ALL

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.

Eligibility criteria:
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

Outcomes:
Sputum Culture Conversion Rate at 2 Months