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Efficacy of HUEXC030 in Subjects With Pulmonary Tuberculosis

Primary Purpose

Pulmonary Tuberculosis

Status
Completed
Phase
Phase 2
Locations
Taiwan
Study Type
Interventional
Intervention
Isoniazid with HUEXC030 and RZE
HRZE
Sponsored by
Orient Pharma Co., Ltd.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pulmonary Tuberculosis focused on measuring HUEXC030, Pulmonary Tuberculosis

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Changhua Christian Hospital
  • Changhua Hosiptal Ministry of Health And Welfare
  • Chang Gung Memorial Hospital, ChiaYi
  • Chang Gung Memorial Hospital, Kaohsiung
  • E-DA Hospital, I-Shou University
  • Kaohsiung Medical University Hospital
  • Kaohsiung Veterans General Hospital
  • Chang Gung Memorial Hospital ,Linkou
  • Taichung Veterans General Hospital
  • Taipei Veterans General Hospital
  • Tri-Service General Hospital
  • Buddhist Tzu Chi General Hospital
  • Cheng Hsin General Hospital
  • National Taiwan University Hospital
  • Taipei City Hospital
  • Taipei Medical University Hospital
  • Taipei Medical University-Shuang Ho Hospital
  • Taipei Wanfang Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Other

Arm Label

Isoniazid with HUEXC030 and RZE

Isoniazid

Arm Description

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)

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)

Outcomes

Primary Outcome Measures

ALT change from baseline to the 8 weeks of study treatment
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 Outcome Measures

Incidence of ATDH in high risk genotype subjects treated with investigational drugs
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
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
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
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
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
Compared to control drugs, the lowering average level of liver function tests in all enrolled subjects treated with investigational drugs at study ends.

Full Information

First Posted
May 31, 2015
Last Updated
June 14, 2022
Sponsor
Orient Pharma Co., Ltd.
Collaborators
National Defense Medical Center, Taiwan, National Research Program for Biopharmaceuticals, Taiwan
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1. Study Identification

Unique Protocol Identification Number
NCT02467608
Brief Title
Efficacy of HUEXC030 in Subjects With Pulmonary Tuberculosis
Official Title
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
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Completed
Study Start Date
December 6, 2012 (Actual)
Primary Completion Date
January 9, 2019 (Actual)
Study Completion Date
January 9, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Orient Pharma Co., Ltd.
Collaborators
National Defense Medical Center, Taiwan, National Research Program for Biopharmaceuticals, Taiwan

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Tuberculosis
Keywords
HUEXC030, Pulmonary Tuberculosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
557 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Isoniazid with HUEXC030 and RZE
Arm Type
Experimental
Arm Description
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)
Arm Title
Isoniazid
Arm Type
Other
Arm Description
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)
Intervention Type
Drug
Intervention Name(s)
Isoniazid with HUEXC030 and RZE
Other Intervention Name(s)
INH with HUEXC030, RMP, PZA and EMB
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
HRZE
Other Intervention Name(s)
INH, RMP, PZA and EMB
Intervention Description
the same as experimental group,without the excipient of HUEXC030 only
Primary Outcome Measure Information:
Title
ALT change from baseline to the 8 weeks of study treatment
Description
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.
Time Frame
8 weeks
Secondary Outcome Measure Information:
Title
Incidence of ATDH in high risk genotype subjects treated with investigational drugs
Description
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.
Time Frame
8 weeks
Title
Incidence of ATDH in high risk genotype subjects treated with investigational drugs
Description
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.
Time Frame
26 weeks
Title
Percentage of patients cured by the end of treatment
Description
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.
Time Frame
8 weeks
Title
Percentage of patients cured by the end of treatment
Description
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.
Time Frame
26 weeks
Title
The overall reduced incidence of ATDH in subjects treated with investigational drugs
Description
Compared to control drugs, the overall reduced incidence of ATDH in all enrolled subjects treated with investigational drugs at study ends.
Time Frame
26 weeks
Title
The lowering average level of liver function tests
Description
Compared to control drugs, the lowering average level of liver function tests in all enrolled subjects treated with investigational drugs at study ends.
Time Frame
26 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Main inclusion criteria: A definite case of pulmonary TB Patient who is exposed to 3 or less doses of first-line anti-TB drug treatment for current disease. Age ≥ 20 years 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: Have alcoholic liver disease or habitual alcohol consumption > 30 g/day for more than one year 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 Documented history of serious allergic reaction or resistance to isoniazid, rifampicin, ethambutol, pyrazinamide, sugar alcohols or any structurally related compounds Subjects who will be using the following therapies after TB treatment starts: i. antiretroviral agents ii. oral corticosteroids Subjects are pregnant or lactating 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 Subjects with any other serious disease considered by the investigator not in the condition to enter into the trial
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yu-Pu Hu, PhD
Organizational Affiliation
National Defense Medical Center, Taiwan
Official's Role
Study Chair
Facility Information:
Facility Name
Changhua Christian Hospital
City
Changhua
Country
Taiwan
Facility Name
Changhua Hosiptal Ministry of Health And Welfare
City
Changhua
Country
Taiwan
Facility Name
Chang Gung Memorial Hospital, ChiaYi
City
Chiayi City
Country
Taiwan
Facility Name
Chang Gung Memorial Hospital, Kaohsiung
City
Kaohsiung
Country
Taiwan
Facility Name
E-DA Hospital, I-Shou University
City
Kaohsiung
Country
Taiwan
Facility Name
Kaohsiung Medical University Hospital
City
Kaohsiung
Country
Taiwan
Facility Name
Kaohsiung Veterans General Hospital
City
Kaohsiung
Country
Taiwan
Facility Name
Chang Gung Memorial Hospital ,Linkou
City
Linkou
Country
Taiwan
Facility Name
Taichung Veterans General Hospital
City
Taichung
Country
Taiwan
Facility Name
Taipei Veterans General Hospital
City
Taipei
ZIP/Postal Code
112
Country
Taiwan
Facility Name
Tri-Service General Hospital
City
Taipei
ZIP/Postal Code
11490
Country
Taiwan
Facility Name
Buddhist Tzu Chi General Hospital
City
Taipei
Country
Taiwan
Facility Name
Cheng Hsin General Hospital
City
Taipei
Country
Taiwan
Facility Name
National Taiwan University Hospital
City
Taipei
Country
Taiwan
Facility Name
Taipei City Hospital
City
Taipei
Country
Taiwan
Facility Name
Taipei Medical University Hospital
City
Taipei
Country
Taiwan
Facility Name
Taipei Medical University-Shuang Ho Hospital
City
Taipei
Country
Taiwan
Facility Name
Taipei Wanfang Hospital
City
Taipei
Country
Taiwan

12. IPD Sharing Statement

Learn more about this trial

Efficacy of HUEXC030 in Subjects With Pulmonary Tuberculosis

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