Efficacy of HUEXC030 in Subjects With Pulmonary Tuberculosis

Overview

Assess the Efficacy of HUEXC030 as Add-on Excipient to Eradicate Anti-Tuberculosis Drugs Induced Hepatic Injury ( ATDH ) in Subjects with Pulmonary Tuberculosis

Full Title of Study: “A Randomized, Double-Blind, Active Drug Controlled Study to Assess the Efficacy of HUEXC030 as Add-on Excipient to Eradicate Anti-Tuberculosis Drugs Induced Liver Injury in Subjects With Pulmonary Tuberculosis”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Triple (Participant, Care Provider, Investigator)
  • Study Primary Completion Date: December 2019

Detailed Description

The study drug is Isoniazid formulated with HUEXC030 as excipient for eradicating ATDH, whereas the reference control is Isoniazid formulated with inactive excipient. Subjects who fulfill all the entry criteria and have written informed consent will be enrolled to the study. Eligible subjects will be randomized in a 1:1 ratio to receive study drug or reference control drug. Subjects will be genotyped according to a selected panel of single nucleotide polymorphisms (SNPs) and categorized into high risk or low risk groups for occurring ATDH via a specific haplotype consists of CYP2E1 and NAT2 SNPs. Based on an extensive study result during 2007 to 2011,the estimated frequency for patients bearing high risk genotypes in Taiwanese population is around 25%. Approximately 352 subjects will be enrolled for genotype screening in order to recruit 88 high risk subjects for each of 44 subjects in the intervention and control arms. Subjects who are stratified as high risk groups will be administered the test drug or reference control drugs oral daily for 6 months or until treatment completion, i.e. bacteriologically confirmed negative of active M. tuberculosis. Subjects who are of low risk genotype will be removed from study after 8 weeks of study treatment, then return to conventional TB medication under the care of their investigator for at least one follow-up visit at 4 weeks after the End of Study.

Interventions

  • Drug: Isoniazid with HUEXC030 and RZE
    • Subjects will receive oral study drug daily in accordance with the following regimen, that is, INH, RMP, PZA, and EMB for the first 2 months followed by INH, RMP and EMB (if medically indicated) daily for 4 additional months
  • Drug: HRZE
    • the same as experimental group,without the excipient of HUEXC030 only

Arms, Groups and Cohorts

  • Experimental: Isoniazid with HUEXC030 and RZE
    • Subjects who are genotyped as high risk group will be receiving 2 months of intensive treatment comprised of 4 drugs (Isoniazid with HUEXC030 [H], rifampin [R], pyrazinamide [Z] and ethambutol [E]), followed by 4 months of continual chemotherapy consist of Isoniazid, Rifampin (2HRZE/4HR regimen). Subjects who are of low risk genotype will be removed from study after 8 weeks of study treatment, then return to conventional TB medication at least one follow-up visit at 4 weeks after the end of study treatment visit. Dosage is as below: Isoniazid with Isoniazid(H):300mg/600mg daily, rifampin [R]: 450~600mg daily, pyrazinamide [Z]; 1000~2000mg daily and ethambutol [E]: 800-1600mg daily)
  • Other: Isoniazid
    • Subjects who are genotyped as high risk group will be receiving 2 months of intensive treatment comprised of 4 drugs (Isoniazid [H], rifampin [R], pyrazinamide [Z] and ethambutol [E]), followed by 4 months of continual chemotherapy consist of Isoniazid, Rifampin (2HRZE/4HR regimen). Subjects who are of low risk genotype will be removed from study after 8 weeks of study treatment, then return to conventional TB medication at least one follow-up visit at 4 weeks after the end of study treatment visit. Dosage is as below: Isoniazid (H):300mg daily, rifampin [R]: 450~600mg daily, pyrazinamide [Z]; 1000~2000mg daily and ethambutol [E]: 800-1600mg daily)

Clinical Trial Outcome Measures

Primary Measures

  • ALT change from baseline to the 8 weeks of study treatment
    • Time Frame: 8 weeks
    • The primary efficacy endpoint is the time-interval weighted area under the curve (AUC) of change from baseline in serum ALT, primarily in patients with high risk genotypes. The area under ALT change curve was estimated using the linear trapezoidal rule. The AUC was a measure of cumulative ALT differences from baseline to the 8 weeks of double-blind treatment period.

Secondary Measures

  • Incidence of ATDH in high risk genotype subjects treated with investigational drugs
    • Time Frame: 8 weeks
    • Primarily in patients with high risk genotypes, the lowering incidence of ATDH in subjects treated with anti-TB drugs in combination with HUEXC030 for 8 weeks.
  • Incidence of ATDH in high risk genotype subjects treated with investigational drugs
    • Time Frame: 26 weeks
    • Primarily in patients with high risk genotypes, the lowering incidence of ATDH in subjects treated with anti-TB drugs in combination with HUEXC030 for 26 weeks or at treatment completion.
  • Percentage of patients cured by the end of treatment
    • Time Frame: 8 weeks
    • At 8 weeks, the investigational product is not inferior in effectiveness of TB treatment to the control drug, primarily in patients with high risk genotypes.
  • Percentage of patients cured by the end of treatment
    • Time Frame: 26 weeks
    • At 26 weeks or at treatment completion, the investigational product is not inferior in effectiveness of TB treatment to the control drug, primarily in patients with high risk genotypes.
  • The overall reduced incidence of ATDH in subjects treated with investigational drugs
    • Time Frame: 26 weeks
    • Compared to control drugs, the overall reduced incidence of ATDH in all enrolled subjects treated with investigational drugs at study ends.
  • The lowering average level of liver function tests
    • Time Frame: 26 weeks
    • Compared to control drugs, the lowering average level of liver function tests in all enrolled subjects treated with investigational drugs at study ends.

Participating in This Clinical Trial

Main inclusion criteria:

1. A definite case of pulmonary TB 2. Patient who is exposed to 3 or less doses of first-line anti-TB drug treatment for current disease. 3. Age ≥ 20 years 4. Have well documented baseline liver function tests that indicates patient's adequate liver function for enrollment to study. i. AST and ALT < 3x ULN ii. total serum bilirubin < 2.0 mg/dL Main Exclusion Criteria:

1. Have alcoholic liver disease or habitual alcohol consumption > 30 g/day for more than one year 2. Previously diagnosed of: i. extra-pulmonary TB without concomitant lung invasion ii. HIV iii. liver malignancy iv. liver cirrhosis v. any other systemic diseases that may cause liver dysfunction 3. Documented history of serious allergic reaction or resistance to isoniazid, rifampicin, ethambutol, pyrazinamide, sugar alcohols or any structurally related compounds 4. Subjects who will be using the following therapies after TB treatment starts: i. antiretroviral agents ii. oral corticosteroids 5. Subjects are pregnant or lactating 6. Subjects with child-bearing potential who are not committed to take reliable contraception during the participation of the study and at least 4 weeks after the end of the study treatment 7. Subjects with any other serious disease considered by the investigator not in the condition to enter into the trial

Gender Eligibility: All

Minimum Age: 20 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Orient Pharma Co., Ltd.
  • Collaborator
    • National Defense Medical Center, Taiwan
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Yu-Pu Hu, PhD, Study Chair, National Defense Medical Center, Taiwan

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