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

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

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.

Study Overview

• Status: Unknown
• Conditions: Individuality; Narrative Medicine
• Intervention / Treatment: Drug: Qishe Pill

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai,, Shanghai, China, 200032
      • Recruiting
      • Longhua Hospital, Shanghai university of TCM
      • Contact: Yue-li Sun, Dr; Email: edisonlike2008@gmail.com
      • Contact: Ting Hou, Miss; Email: Houting003@gmail.com
      • Principal Investigator: Yong-jun Wang, Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 35 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: cohort 1; Qishe Pill（Shanghai Sundise Traditional Chinese Medicine Co., Ltd, China） in low dosage(3.75mg)	Drug: Qishe Pill; 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
Experimental: cohort 2; Qishe Pill（Shanghai Sundise Traditional Chinese Medicine Co., Ltd, China) in medial dosage(7.5mg)	Drug: Qishe Pill; 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
Experimental: cohort 3; Qishe Pill（Shanghai Sundise Traditional Chinese Medicine Co., Ltd, China）in high dosage(15mg)	Drug: Qishe Pill; 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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Constitution in Chinese Medicine Questionnaire (CCMQ)	Two qualified traditional Chinese medical doctors licensed by the Chinese government determine the constitution according to CCMQ	During screening in the recuitment
The Constitution in Chinese Medicine Questionnaire (CCMQ)	Two qualified traditional Chinese medical doctors licensed by the Chinese government determine the constitution according to CCMQ	2880 min after dosing
Laboratory measures and clinical assessment	These parameters including blood count, electrolytes, renal and liver function parameters, blood lipids, age, gender, history of smoking, blood pressure, weight (kg), and height (meters) will be obtained for all subjects.	During screening in the recuitment

Collaborators and Investigators

• Sponsor: Shanghai University of Traditional Chinese Medicine

Publications and helpful links

General Publications

• Bovim G, Schrader H, Sand T. Neck pain in the general population. Spine (Phila Pa 1976). 1994 Jun 15;19(12):1307-9. doi: 10.1097/00007632-199406000-00001.
• Aker PD, Gross AR, Goldsmith CH, Peloso P. Conservative management of mechanical neck pain: systematic overview and meta-analysis. BMJ. 1996 Nov 23;313(7068):1291-6.
• Makela M, Heliovaara M, Sievers K, Impivaara O, Knekt P, Aromaa A. Prevalence, determinants, and consequences of chronic neck pain in Finland. Am J Epidemiol. 1991 Dec 1;134(11):1356-67. doi: 10.1093/oxfordjournals.aje.a116038.
• Cui X, Trinh K, Wang YJ. Chinese herbal medicine for chronic neck pain due to cervical degenerative disc disease. Cochrane Database Syst Rev. 2010 Jan 20;2010(1):CD006556. doi: 10.1002/14651858.CD006556.pub2.
• Wang Q. Classification of the nine basic TCM constitutional type and based expression and diagnosis. Journal of Beijing University of Traditional Chinese medicine. 2005.1-8
• Liu Mei, Zhang N, Wang YJ, Shi Q. Purification process research of major compound in Qishe Pill as Astragalus. Acta Chinese Medicine and Pharmacology. 2006(34):14-16.
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• Liu M, Zhang N, Wang YJ, Zhang YQ, Zhou CJ. Technology research of Qishe Pill, a new medicine for cervical spondylosis. Lishizhen Med Mater Med Res. 2010(21):176-179.
• Ge JR, Wang HM, Meng CX, Tong PJ. Effects of Qishe Pill, a compound traditional Chinese herbal medicine, on cervical radiculopathy: a randomized controlled trial for Phase III. Chinese Journal of New Drugs and Clinical. 2014(7):56-58.
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• FDA/CDER. Guidance for industry estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers; 2005, http://www.fda.gov/downloads/drugs/guidance-complianceregulatoryinformation/guidances/ucm078932.pdf.
• EMEA. Strategies to identify and mitigate risks for first-in-human clinical trialswith investigational medicinal products; 2009, http:// www.ema.europa.eu/docs/en_GB/document_library/Scientific_ guideline/2009/09/WC500002988.pdf.
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• Sheiner LB, Beal SL. Evaluation of methods for estimating population pharmacokinetics parameters. I. Michaelis-Menten model: routine clinical pharmacokinetic data. J Pharmacokinet Biopharm. 1980 Dec;8(6):553-71. doi: 10.1007/BF01060053.
• Sheiner LB, Beal SL. Evaluation of methods for estimating population pharmacokinetic parameters. II. Biexponential model and experimental pharmacokinetic data. J Pharmacokinet Biopharm. 1981 Oct;9(5):635-51. doi: 10.1007/BF01061030.
• Sheiner LB, Beal SL. Evaluation of methods for estimating population pharmacokinetic parameters. III. Monoexponential model: routine clinical pharmacokinetic data. J Pharmacokinet Biopharm. 1983 Jun;11(3):303-19. doi: 10.1007/BF01061870.
• Feng Y, Pollock BG, Coley K, Marder S, Miller D, Kirshner M, Aravagiri M, Schneider L, Bies RR. Population pharmacokinetic analysis for risperidone using highly sparse sampling measurements from the CATIE study. Br J Clin Pharmacol. 2008 Nov;66(5):629-39. doi: 10.1111/j.1365-2125.2008.03276.x. Epub 2008 Jul 31.
• Zhang WJ, Hufnagl P, Binder BR, Wojta J. Antiinflammatory activity of astragaloside IV is mediated by inhibition of NF-kappaB activation and adhesion molecule expression. Thromb Haemost. 2003 Nov;90(5):904-14. doi: 10.1160/TH03-03-0136.
• Sun YL, Hou T, Liu SF, Zhang ZL, Zhang N, Yao M, Yang L, Shi Q, Cui XJ, Wang YJ. Population pharmacokinetic modeling of the Qishe pill in three major traditional Chinese medicine-defined constitutional types of healthy Chinese subjects: study protocol for a randomized controlled trial. Trials. 2015 Feb 26;16:64. doi: 10.1186/s13063-015-0568-6.

Study record dates

Study Major Dates

• Study Start: November 1, 2014
• Primary Completion (Anticipated): December 1, 2015
• Study Completion (Anticipated): July 1, 2016

Study Registration Dates

• First Submitted: September 11, 2014
• First Submitted That Met QC Criteria: November 15, 2014
• First Posted (Estimate): November 19, 2014

Study Record Updates

• Last Update Posted (Estimate): November 19, 2014
• Last Update Submitted That Met QC Criteria: November 15, 2014
• Last Verified: November 1, 2014

More Information

Terms related to this study

• Keywords: Population Pharmacokinetics; Personalized Medicine; Neck pain; Cervical radiculopathy; Individualized Medicine; Qishe pill; raditional Chinese medicine; healthy Chinese subject
• Other Study ID Numbers: PopPK profile of Qishe Pill