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

NCT07467252 | Not Yet Recruiting Phase 2

• 1 other identifier: PYZ-HCQ-AIPH-001-Ph2
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Pulmonary Tuberculosis

Keywords

Tuberculosis; Pyrazinamide; Hydroxychloroquine; Artificial Intelligence; Drug-Sensitive TB; AIPH-TB

Outcome Measures

Primary Outcomes (1)

• Sputum Culture Conversion Rate at 2 Months

  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 Outcomes (1)

• Treatment Success Rate at 6 Months (End of Treatment)

  6 months (end of treatment)

Study Arms (2)

AI-Optimised PYZ-HCQ Arm

EXPERIMENTAL

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)

Standard RIPE Regimen Arm

ACTIVE COMPARATOR

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)

Interventions

Pyrazinamide and Hydroxychloroquine (AI-Optimised) DRUG

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.

AI-Optimised PYZ-HCQ Arm

Standard RIPE Regimen (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol) DRUG

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.

Standard RIPE Regimen Arm

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Ministry of Health, Saudi Arabia: lead

Study Sites (1)

Riyadh First Health Cluster, Ministry of Health

Riyadh, Riyadh Region, 11176, Saudi Arabia

Location

Related Publications (3)

• 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 BACKGROUND

• 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 BACKGROUND

• 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. 2021 Jul 20;58(1):2002013. doi: 10.1183/13993003.02013-2020. Print 2021 Jul.

  PMID: 33542052 BACKGROUND

MeSH Terms

Conditions

Tuberculosis, Pulmonary; Tuberculosis

Interventions

Pyrazinamide; Hydroxychloroquine; Rifampin; Isoniazid; Ethambutol

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Pyridines; Ethylenediamines; Diamines; Polyamines; Amines

Central Study Contacts

amr K.K. Ahmed, MD, MSc

CONTACT

00966597310032; drmedahmed@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Public Health Specialist, Principal Investigator

Study Record Dates

• First Submitted: March 9, 2026
• First Posted: March 12, 2026
• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): June 1, 2028
• Last Updated: March 12, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

SA (1)