AIPH-TB: AI-Optimised Pyrazinamide-Hydroxychloroquine vs Standard RIPE for Drug-Sensitive Pulmonary Tuberculosis - A Phase II RCT (AIPH-TB-RCT-P2)

March 9, 2026 updated by: Amr kamel khalil Ahmed, Ministry of Health, Saudi Arabia

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

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

200

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Saudi Arabia
    • Riyadh Region
      • Riyadh, Riyadh Region, Saudi Arabia, 11176
        • Riyadh First Health Cluster, Ministry of Health
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 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.
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.
Active Comparator: 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.
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Sputum Culture Conversion Rate at 2 Months
Time Frame: 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.
2 months after treatment initiation

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Treatment Success Rate at 6 Months (End of Treatment)
Time Frame: 6 months (end of treatment)
Proportion of participants achieving treatment success (cure or treatment completion) as defined by WHO criteria at 6 months (end of treatment).
6 months (end of treatment)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Ministry of Health, Saudi Arabia

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

September 1, 2026

Primary Completion (Estimated)

December 1, 2027

Study Completion (Estimated)

June 1, 2028

Study Registration Dates

First Submitted

March 9, 2026

First Submitted That Met QC Criteria

March 9, 2026

First Posted (Actual)

March 12, 2026

Study Record Updates

Last Update Posted (Actual)

March 12, 2026

Last Update Submitted That Met QC Criteria

March 9, 2026

Last Verified

March 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PYZ-HCQ-AIPH-001-Ph2

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Individual participant data will not be shared due to patient privacy and data protection regulations. Aggregate results will be published in peer-reviewed journals.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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