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

Official title

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

Overview

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.

Interventions

• 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.

Primary outcome measures

• Sputum Culture Conversion Rate at 2 Months [Time frame: 2 months after treatment initiation]

Secondary outcome measures (1)

• Treatment Success Rate at 6 Months (End of Treatment) [Time frame: 6 months (end of treatment)]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Saudi Arabia · 1 center

• Riyadh First Health Cluster, Ministry of Health — Riyadh

Publications

• Crowle AJ, May MH. Inhibition of tubercle bacilli in cultured human macrophages by chloroquine used alone and in combination with streptomycin, isoniazid, pyrazinamide, and two metabolites of vitamin D3. Antimicrob Agents Chemother. 1990 Nov;34(11):2217-22. doi: 10.1128/AAC.34.11.2217. PMID 2127346
• Zhang Y, Shi W, Zhang W, Mitchison D. Mechanisms of Pyrazinamide Action and Resistance. Microbiol Spectr. 2014 Aug;2(4):MGM2-0023-2013. doi: 10.1128/microbiolspec.MGM2-0023-2013. PMID 26104205
• Zhang N, Savic RM, Boeree MJ, Peloquin CA, Weiner M, Heinrich N, Bliven-Sizemore E, Phillips PPJ, Hoelscher M, Whitworth W, Morlock G, Posey J, Stout JE, Mac Kenzie W, Aarnoutse R, Dooley KE; Tuberculosis Trials Consortium (TBTC) and Pan African Consortium for the Evaluation of Antituberculosis Antibiotics (PanACEA) Networks. Optimising pyrazinamide for the treatment of tuberculosis. Eur Respir J. PMID 33542052

Identifiers

NCT: NCT07467252 · PYZ-HCQ-AIPH-001-Ph2

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗