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
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 200
- 试验地点
- 1
- 主要终点
- Sputum Culture Conversion Rate at 2 Months
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
AI-Optimised PYZ-HCQ Arm
Participants receive AI-optimised combination of Pyrazinamide (PYZ) and Hydroxychloroquine (HCQ) for drug-sensitive pulmonary tuberculosis. AI algorithms determine optimal dosing and duration based on patient pharmacokinetic and pharmacogenomic parameters over a 4-month intensive phase followed by 2-month continuation phase.
干预措施: Pyrazinamide and Hydroxychloroquine (AI-Optimised) (Drug)
Standard RIPE Regimen Arm
Participants receive standard WHO-recommended RIPE regimen (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol) for drug-sensitive pulmonary tuberculosis. Standard 2-month intensive phase followed by 4-month continuation phase with Rifampicin and Isoniazid.
干预措施: Standard RIPE Regimen (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol) (Drug)
结局指标
主要结局
Sputum Culture Conversion Rate at 2 Months
时间窗: 2 months after treatment initiation
Proportion of participants achieving sputum culture negativity (conversion from positive to negative culture on Löwenstein-Jensen medium) at 2 months after treatment initiation, compared between AI-optimised PYZ-HCQ arm and standard RIPE arm.
次要结局
- Treatment Success Rate at 6 Months (End of Treatment)(6 months (end of treatment))
研究者
Amr kamel khalil Ahmed
Public Health Specialist, Principal Investigator
Ministry of Health, Saudi Arabia