Pharmacometabolomics of Andrographis Paniculata And Metformin In Healthy Volunteers Under Fasting Condition

Study Overview
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Brief Summary
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This study is a phase 1, open label, randomized, three-way crossover, single dose, oral- administration of Andrographis paniculata and Metformin in healthy volunteers under fasting condition. The study will demonstrate the pharmacokinetics profile and pharmacodynamic through metabolic pathway analysis for Andrographis paniculata and Metformin.

Detailed Description
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This is a phase 1, open label, randomized, three period, crossover, single dose oral administration of Andrographis Paniculata 1000mg, 2000mg and Metformin 1000mg clinical trial in healthy volunteers under fasting condition. Approximately 18 healthy volunteers will be enrolled into this study. The healthy volunteers will be screened for inclusion and exclusion criteria. Eligible subjects will be enrolled into either Metformin 1000mg tablet, Andrographis Paniculata 1000mg or 2000mg capsule in a ratio of 1:1:1 in period 1 for single dose oral administration. Subjects will then undergo a washout period of at least 7 days. After the washout period, subjects will crossover over to another investigational product according to the randomization sequence. Subjects will fast overnight prior to dosing. The volunteers will be admitted to Clinical Investigation Center ward at 7 am in the morning and will confine in air-conditioning environment with beds and chairs. The means during the stay at CIC ward will be provided to the subjects. The dosing will be performed at 8am. A series of plasma will be collected at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12 and 24 hours post-dose. Urine samples will be collected at 0, 0-4 hours, 4-8 hours and 8-12 hours. A safety follow-up call will be made to subjects to record any adverse events that occurred post-dosing within 1 week.

Official Title
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A Phase 1, Open Label, Randomized, Three-Period, Crossover, Single Dose Oral Administration Of Andrographis Paniculata And Metformin Clinical Trial In Healthy Volunteers Under Fasting Condition

Conditions
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Pharmacokinetics, Molecular Mechanisms of Pharmacological Action

Intervention / Treatment
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* Drug: Brand name: Andrographis paniculata (Shine Hempedu Bumi) 1000mg capsules
* Drug: Brand name: Andrographis paniculata (Shine Hempedu Bumi) 2000mg
* Drug: Metformin (Glucophage) 1000mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Sex: male 18 to 45 years of age (inclusive both) BMI 18.5 - 29.5 kg/m2 (inclusive both) with minimum weight of 50kg Non-smokers Legible and willing to provide written informed consent. Exclusion Criteria: Volunteers suffering from any chronic illness such as arthritis, asthma, etc. History of pre-existing bleeding disorder. Clinically relevant abnormalities in the results of the laboratory screening evaluation. Clinically significant abnormal electrocardiogram (ECG). Positive HIV or positive hepatitis B or C in screening test or no known other hepatitis infection. History of significant blood loss due to any reason, including blood donation in the past 3 months. Participation in any study within past 3 months History of alcohol or drug abuse History of consumption of prescribed medication since last 14 days or Over-the-counter medication/ herbal remedies since last 7 days before beginning of the study. Systolic blood pressure less than 100 mmHg or more than 139 mmHg and diastolic blood pressure less than 60 mmHg or more than 89 mmHg. Pulse rate less than 60/minutes or more than 100/minute unless deem not clinically significant by investigator. Oral temperature more than 37.5 degree Celsius. History of allergy to the investigational product or any drug chemically similar to the drug under investigation. Recent history of kidney or liver dysfunction. Volunteers suffering from any psychiatric (acute or chronic) disorder. Existence of any surgical or medical condition, which, in the judgment of the chief investigator and/or clinical investigator/physician, might interfere with the absorption, distribution, metabolism or excretion of the drug or likely to compromise the safety of volunteers. Inability to communicate or co-operate.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Open label, block-randomized, three-period, crossover, single dose oral administration of investigational products. Subjects will undergo at least 7 days washout period.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Period 1<br>Subjects will randomized to either of the intervention drug in a ratio of 1:1:1 following three period, cross-over study design. | Drug: Brand name: Andrographis paniculata (Shine Hempedu Bumi) 1000mg capsules<br>* Andrographis paniculata or hempedu bumi capsule is a traditional medicinal product registered under Ministry of Health Malaysia for general wealth being. It is traditionally used for anti-diabetic, anti-bacterial, anti-pyretic, anti-malarial, anti-inflammatory, antidiarrhoeal and other effects.<br>* Other names: Product name: Shine Hempedu Bumi;Drug: Brand name: Andrographis paniculata (Shine Hempedu Bumi) 2000mg<br>* Andrographis paniculata or hempedu bumi capsule is a traditional medicinal product registered under Ministry of Health Malaysia for general wealth being. It is traditionally used for anti-diabetic, anti-bacterial, anti-pyretic, anti-malarial, anti-inflammatory, antidiarrhoeal and other effects.<br>* Other names: Product name: Shine Hempedu Bumi;Drug: Metformin (Glucophage) 1000mg<br>* Metformin is an oral glucose-lowering drug of the biguanides class. Drug: Period 1 Subjects<br>* Other names: Brand name: Glucophage;|
| Experimental: Period 2<br>Subjects will randomized to either of the intervention drug in a ratio of 1:1:1 following three period, cross-over study design. | Drug: Brand name: Andrographis paniculata (Shine Hempedu Bumi) 1000mg capsules<br>* Andrographis paniculata or hempedu bumi capsule is a traditional medicinal product registered under Ministry of Health Malaysia for general wealth being. It is traditionally used for anti-diabetic, anti-bacterial, anti-pyretic, anti-malarial, anti-inflammatory, antidiarrhoeal and other effects.<br>* Other names: Product name: Shine Hempedu Bumi;Drug: Brand name: Andrographis paniculata (Shine Hempedu Bumi) 2000mg<br>* Andrographis paniculata or hempedu bumi capsule is a traditional medicinal product registered under Ministry of Health Malaysia for general wealth being. It is traditionally used for anti-diabetic, anti-bacterial, anti-pyretic, anti-malarial, anti-inflammatory, antidiarrhoeal and other effects.<br>* Other names: Product name: Shine Hempedu Bumi;Drug: Metformin (Glucophage) 1000mg<br>* Metformin is an oral glucose-lowering drug of the biguanides class. Drug: Period 1 Subjects<br>* Other names: Brand name: Glucophage;|
| Experimental: Period 3<br>Subjects will randomized to either of the intervention drug in a ratio of 1:1:1 following three period, cross-over study design. | Drug: Brand name: Andrographis paniculata (Shine Hempedu Bumi) 1000mg capsules<br>* Andrographis paniculata or hempedu bumi capsule is a traditional medicinal product registered under Ministry of Health Malaysia for general wealth being. It is traditionally used for anti-diabetic, anti-bacterial, anti-pyretic, anti-malarial, anti-inflammatory, antidiarrhoeal and other effects.<br>* Other names: Product name: Shine Hempedu Bumi;Drug: Brand name: Andrographis paniculata (Shine Hempedu Bumi) 2000mg<br>* Andrographis paniculata or hempedu bumi capsule is a traditional medicinal product registered under Ministry of Health Malaysia for general wealth being. It is traditionally used for anti-diabetic, anti-bacterial, anti-pyretic, anti-malarial, anti-inflammatory, antidiarrhoeal and other effects.<br>* Other names: Product name: Shine Hempedu Bumi;Drug: Metformin (Glucophage) 1000mg<br>* Metformin is an oral glucose-lowering drug of the biguanides class. Drug: Period 1 Subjects<br>* Other names: Brand name: Glucophage;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration-time curve (AUC) of Andrographis paniculata | Area under the plasma concentration curve of Andrographis paniculata from administration to 24 hours | 0-24 hours | 
| Cmax of Andrographis paniculata | Maximum plasma concentration of Andrographis paniculata after single dose oral administration. | 0-24 hours | 
| Tmax of Andrographis paniculata | Time until Cmax of Andrographis paniculata is reached after single dose oral administration. | 0-24 hours | 
| Area under the plasma concentration-time curve (AUC) of Metformin | Area under the plasma concentration curve of Metformin from administration to 24 hours | 0-24 hours | 
| Cmax of Metformin | Maximum plasma concentration of Metformin after single dose oral administration. | 0-24 hours | 
| Tmax of Metformin | Time until Cmax of Metformin is reached after single dose oral administration. | 0-24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolic pathway of Andrographis paniculata | Pre-dose and post-dose samples will be analysed using LCMSMS. Normalization, log-transformation and center scaling will then apply to batches of chromatograms. Global metabolomics analyses will be performed to identify significant endogenous metabolites between post-dose and pre-dose samples using T-Test, Principal Component Analysis, Partial Least Square Discriminant Analysis. Annotations of significant compounds will be perform using METLIN database. The significant compounds will lead to prediction of relevant metabolomic pathway from Human Metabolome Database/ Kyoto Encyclopedia of Gene and Genome pathway for Andrographis paniculata. | 24 hours | 
| Metabolic pathway of Metformin | Pre-dose and post-dose samples will be analysed using LCMSMS. Normalization, log-transformation and center scaling will then apply to batches of chromatograms. Global metabolomics analyses will be performed to identify significant endogenous metabolites between post-dose and pre-dose samples using T-Test, Principal Component Analysis, Partial Least Square Discriminant Analysis. Annotations of significant compounds will be perform using METLIN database. The significant compounds will lead to prediction of relevant metabolomic pathway from Human Metabolome Database/ Kyoto Encyclopedia of Gene and Genome pathway for Metformin. | 24 hours | 
| Adverse drug reaction | Number of subjects with adverse drug reaction | 3 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacometabolomic, Metformin, Andrographis paniculata, Metabolomics, Phase 1, Healthy volunteers, Herbal Medicine