PopPK Profile of Qishe Pill: Study Protocol for a Phase I Clinical Trial

Study Overview
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Brief Summary
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Qishe Pill (Shanghai Sundise Traditional Chinese Medicine Co., Ltd, China), composed of processed Radix Astragali, Muscone, Szechuan Lovage Rhizome, Radix Stephaniae Tetrandrae, Ovientvine, and Calculus Bovis Artifactus, has been developed and spread in use into clinical settings in 2009. As individualization has become the trend of modern medicine, a personalized medicine of Qishe Pill should be documented and practiced with various patients according to the ancient TCM system, a classification of personalized constitution type, which has been established to determine predisposition and prognosis to diseases as well as therapy and life-style administration. Therefore, we describe the population pharmacokinetic profile of Qishe Pill and compare its extent of metabolism in the 3 major Constitution Type (Qi-Deficiency, Yin-Deficiency and Blood-Stasis) to address major challenges of individualized and standardized Traditional Chinese Medicine into clinical practice.

Detailed Description
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With the greatly increased morbidity of neck pain, it brought a large challenge to some optimal therapies for various situations in population at a given time based on their demographic, physiological and pathological characteristics. Chinese proprietary herbal medicines, as a kind of Complementary and Alternative Medicine (CAM), are usually developed from some well-established and long-standing recipes and formulated as tablets or capsules for commerce, convenience or palatability. Although these advantage mentioned, a good quantification and a strict standardization in detail are still need to be improved for individualized implementation in therapeutic strategies. Based on the YQHY decoction (Yi-Qi Hua-Yu Decoction, tonify Qi and promoting circulation and removing stasis), Qishe Pill (Shanghai Sundise Traditional Chinese Medicine Co., Ltd, China) has been developed and spread in use into clinical settings in 2009. As individualization has become the trend of modern medicine, a personalized medicine of Qishe Pill should be documented and practiced with various patients according to the ancient TCM system, a classification of personalized constitution type, which has been established to determine predisposition and prognosis to diseases as well as therapy and life-style administration. Therefore, we describe the population pharmacokinetic profile of Qishe Pill and compare its extent of metabolism in the 3 major Constitution Type (Qi-Deficiency, Yin-Deficiency and Blood-Stasis) to address major challenges of individualized and standardized Traditional Chinese Medicine into clinical practice.

Official Title
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Population Pharmacokinetic Modeling of Qishe Pill in Three Major TCM-defined Constitutional Types of Healthy Chinese Subjects: Study Protocol for a Phase I Clinical Trial

Conditions
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Individuality, Narrative Medicine

Intervention / Treatment
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* Drug: Qishe Pill


Participation Criteria
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Eligibility Criteria
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Inclusion Aged 20-35 18.5 kg/m2 ≤Body mass index (BMI) <23 kg/m2 TCM-constitutionally typed as either the 3 major type Exclusion History of impaired fasting glucose or diabetes mellitus (past history of diabetes or fasting blood glucose at screening ≥100 mg/dl) History of liver disease (hepatitis, hepatic cirrhosis) or hepatic dysfunction (AST or ALT at screening ≥40 U/L) History of renal dysfunction (creatinine at screening ≥1.2 mg/dl) History of heart disease (heart failure, angina pectoris, myocardial infarction, arrhythmia) History of malignant tumor Having digestive disorders that can interfere with normal absorption of standard diet (gastritis, gastric ulcer, duodenitis, duodenal ulcer, etc.) Smoking during the recent 3 months Alcohol consumption 3 or more times a week during the recent 3 months Women who were pregnant, intended to become pregnant, or breast- feeding Medicated during the recent month for therapeutic or prophylactic purposes Participating in another clinical trial

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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All

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: cohort 1<br>Qishe Pill（Shanghai Sundise Traditional Chinese Medicine Co., Ltd, China） in low dosage(3.75mg) | Drug: Qishe Pill<br>* Qishe Pill is a thin 0.15 g film-coated pill, composed of processed Radix Astragali, Muscone, Szechuan Lovage Rhizome, Radix Stephaniae Tetrandrae, Ovientvine, and Calculus Bovis Artifactus, which should be taken orally with water (240mL) after a minimum 10-hour fast<br>|
| Experimental: cohort 2<br>Qishe Pill（Shanghai Sundise Traditional Chinese Medicine Co., Ltd, China) in medial dosage(7.5mg) | Drug: Qishe Pill<br>* Qishe Pill is a thin 0.15 g film-coated pill, composed of processed Radix Astragali, Muscone, Szechuan Lovage Rhizome, Radix Stephaniae Tetrandrae, Ovientvine, and Calculus Bovis Artifactus, which should be taken orally with water (240mL) after a minimum 10-hour fast<br>|
| Experimental: cohort 3<br>Qishe Pill（Shanghai Sundise Traditional Chinese Medicine Co., Ltd, China）in high dosage(15mg) | Drug: Qishe Pill<br>* Qishe Pill is a thin 0.15 g film-coated pill, composed of processed Radix Astragali, Muscone, Szechuan Lovage Rhizome, Radix Stephaniae Tetrandrae, Ovientvine, and Calculus Bovis Artifactus, which should be taken orally with water (240mL) after a minimum 10-hour fast<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | Dosing(0 hour) | 
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 15 min after dosing | 
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 30 min after dosing | 
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 45 min after dosing | 
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 60 min after dosing | 
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 90 min after dosing | 
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 120 min after dosing | 
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 150 min after dosing | 
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 180 min after dosing | 
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 240 min after dosing | 
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 360 min after dosing | 
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 480 min after dosing | 
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 600 min after dosing | 
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 720 min after dosing | 
| Plasma concentrations of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 1440 min after dosing | 
| Plasma concentration of Qishe Pill | 5 ml blood samples for pharmacokinetic analysis | 2160 min after dosing | 
| Plasma sampling of Qishe Pill for pharmacokinetic analysis | 5 ml blood samples for pharmacokinetic analysis | 2880 min after dosing | 
| Vital signs | body temperature, heart rate and blood pressure | Dosing(0 hour) | 
| Vital signs | body temperature, heart rate and blood pressure | 180 min after dosing | 
| Vital signs | body temperature, heart rate and blood pressure | 720 min after dosing | 
| Vital signs | body temperature, heart rate and blood pressure | 1440 min after dosing | 
| Vital signs | body temperature, heart rate and blood pressure | 2160 min after dosing | 
| Vital signs | body temperature, heart rate and blood pressure | 2880 min after dosing | 
| ECG monitoring | Electrocardiograms (ECGs) | Dosing(0 hour) | 
| ECG monitoring | Electrocardiograms (ECGs) | 180 min after dosing | 
| ECG monitoring | Electrocardiograms (ECGs) | 720 min after dosing | 
| ECG monitoring | Electrocardiograms (ECGs) | 1440 min after dosing | 
| ECG monitoring | Electrocardiograms (ECGs) | 2160 min after dosing | 
| ECG monitoring | Electrocardiograms (ECGs) | 2880 min after dosing | 
| Number of Participants with Adverse Events | The investigators will assess all clinical AEs according to the Medical Dictionary for Regular Activities criteria, in terms of intensity (mild, moderate, or severe), duration, outcome and relationship to the study drug. | Day 1 of drug administration and blood sampling | 
| Number of Participants with Adverse Events | The investigators will assess all clinical AEs according to the Medical Dictionary for Regular Activities criteria, in terms of intensity (mild, moderate, or severe), duration, outcome and relationship to the study drug. | Day 2 of drug administration and blood sampling | 
| Number of Participants with Adverse Events | The investigators will assess all clinical AEs according to the Medical Dictionary for Regular Activities criteria, in terms of intensity (mild, moderate, or severe), duration, outcome and relationship to the study drug. | Day 3 of drug administration and blood sampling | 
| Number of Participants with Adverse Events | Subjects will be requested to return to the study unit 4 d after drug administration and blood sampling for a follow-up visit. | 4 days after drug administration and blood sampling | 
| Peak Plasma Concentration (Cmax) of Qishe Pill in low dosage | The maximum plasma concentration | 4 days after drug administration and blood sampling | 
| Peak Plasma Concentration (Cmax) of Qishe Pill in medial dosage | The maximum plasma concentration | 4 days after drug administration and blood sampling | 
| Peak Plasma Concentration (Cmax) of Qishe Pill in high dosage | The maximum plasma concentration | 4 days after drug administration and blood sampling | 
| The Time to Peak Plasma Concentration (Tmax) of Qishe Pill in low dosage | The time to maximum concentration | 4 days after drug administration and blood sampling | 
| The Time to Peak Plasma Concentration (Tmax) of Qishe Pill in medial dosage | The time to maximum concentration | 4 days after drug administration and blood sampling | 
| The Time to Peak Plasma Concentration (Tmax) of Qishe Pill in high dosage | The time to maximum concentration | 4 days after drug administration and blood sampling | 
| Area under the Plasma Concentration versus Time Curve (AUC) of Qishe Pill in low dosage | The area under the plasma concentration-time curve (AUC) will be calculated using the linear trapezoidal rule. | 4 days after drug administration and blood sampling | 
| Area under the Plasma Concentration versus Time Curve (AUC) of Qishe Pill in medial dosage | The area under the plasma concentration-time curve (AUC) will be calculated using the linear trapezoidal rule. | 4 days after drug administration and blood sampling | 
| Area under the Plasma Concentration versus Time Curve (AUC) of Qishe Pill in high dosage | The area under the plasma concentration-time curve (AUC) will be calculated using the linear trapezoidal rule. | 4 days after drug administration and blood sampling | 
| The distribution volume (DF) of Qishe Pill in low dosage | The distribution volume (DF) will be calculated by Dose/AUC/ke. ke is the elimination rate constant. | 4 days after drug administration and blood sampling | 
| The distribution volume (DF) of Qishe Pill in medial dosage | The distribution volume (DF) will be calculated by Dose/AUC/ke. ke is the elimination rate constant. | 4 days after drug administration and blood sampling | 
| The distribution volume (DF) of Qishe Pill in high dosage | The distribution volume (DF) will be calculated by Dose/AUC/ke. ke is the elimination rate constant. | 4 days after drug administration and blood sampling | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Deep phenotyping with genomics and functional genomics approaches | 3 ml blood samples for genomic variants analysis. The cytochrome P450 gene family, such as CYP1A1, CYP1A2, CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP3A4 and CYP3A5 , etc, will be chosen as the target objective. | Dosing(0 hour) | 
| Deep phenotyping with genomics and functional genomics approaches | 3 ml blood samples for genomic variants analysis. The cytochrome P450 gene family, such as CYP1A1, CYP1A2, CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP3A4 and CYP3A5 , etc, will be chosen as the target objective. | 2880 min after dosing | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Personalized Medicine, Cervical radiculopathy, Neck pain, Qishe pill, raditional Chinese medicine, healthy Chinese subject, Population Pharmacokinetics, Individualized Medicine