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

Individuality Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02294448
• Other study ID #: PopPK profile of Qishe Pill
• Status: Recruiting
• Phase: Phase 1
• First received: September 11, 2014
• Last updated: November 15, 2014
• Start date: November 2014
• Est. completion date: July 2016

Study information

• Verified date: November 2014
• Source: Shanghai University of Traditional Chinese Medicine
• Contact: Xue-Jun Cui, Dr.
• Email: 13917715524[@]139.com
• Is FDA regulated: No
• Health authority: China: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 36
• Est. completion date: July 2016
• Est. primary completion date: December 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 20 Years to 35 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Individuality
• Narrative Medicine

Intervention

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

Locations

Country	Name	City	State
China	Longhua Hospital, Shanghai University of TCM	Shanghai,	Shanghai

Sponsors (1)

Lead Sponsor	Collaborator
Shanghai University of Traditional Chinese Medicine

Country where clinical trial is conducted

China, 

References & Publications (21)

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. — View Citation

Bovim G, Schrader H, Sand T. Neck pain in the general population. Spine (Phila Pa 1976). 1994 Jun 15;19(12):1307-9. — View Citation

Choo V. WHO reassesses appropriate body-mass index for Asian populations. Lancet. 2002 Jul 20;360(9328):235. — View Citation

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;(1):CD006556. doi: 10.1002/14651858.CD006556.pub2. Review. — View Citation

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.

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.

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. — View Citation

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.

Hsu H-Y: 1986 Oriental MateriaMedica. Long Beach, CA: Oriental Healing Arts Institute; 1986.

Johnson CL, Fulwood R, Abraham S, Bryner JD. Basic data on anthropometric measurements and angular measurements of the hip and knee joints for selected age groups 1-74 years of age. Vital Health Stat 11. 1981 Apr;(219):1-68. — View Citation

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.

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.

Mäkelä M, Heliövaara 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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

van der Donk J, Schouten JS, Passchier J, van Romunde LK, Valkenburg HA. The associations of neck pain with radiological abnormalities of the cervical spine and personality traits in a general population. J Rheumatol. 1991 Dec;18(12):1884-9. — View Citation

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

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. — View Citation

Zhang YQ, Liu XH, Zhang N, Liu M. Quality standard research of Qishe Pill. Lishizhen Med Mater Med Res. 2008(19): 977-979.

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* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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	No
Other	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	No
Other	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	No
Primary	Plasma concentration of Qishe Pill	5 ml blood samples for pharmacokinetic analysis	Dosing(0 hour)	No
Primary	Plasma concentration of Qishe Pill	5 ml blood samples for pharmacokinetic analysis	15 min after dosing	No
Primary	Plasma concentration of Qishe Pill	5 ml blood samples for pharmacokinetic analysis	30 min after dosing	No
Primary	Plasma concentration of Qishe Pill	5 ml blood samples for pharmacokinetic analysis	45 min after dosing	No
Primary	Plasma concentration of Qishe Pill	5 ml blood samples for pharmacokinetic analysis	60 min after dosing	No
Primary	Plasma concentration of Qishe Pill	5 ml blood samples for pharmacokinetic analysis	90 min after dosing	No
Primary	Plasma concentration of Qishe Pill	5 ml blood samples for pharmacokinetic analysis	120 min after dosing	No
Primary	Plasma concentration of Qishe Pill	5 ml blood samples for pharmacokinetic analysis	150 min after dosing	No
Primary	Plasma concentration of Qishe Pill	5 ml blood samples for pharmacokinetic analysis	180 min after dosing	No
Primary	Plasma concentration of Qishe Pill	5 ml blood samples for pharmacokinetic analysis	240 min after dosing	No
Primary	Plasma concentration of Qishe Pill	5 ml blood samples for pharmacokinetic analysis	360 min after dosing	No
Primary	Plasma concentration of Qishe Pill	5 ml blood samples for pharmacokinetic analysis	480 min after dosing	No
Primary	Plasma concentration of Qishe Pill	5 ml blood samples for pharmacokinetic analysis	600 min after dosing	No
Primary	Plasma concentration of Qishe Pill	5 ml blood samples for pharmacokinetic analysis	720 min after dosing	No
Primary	Plasma concentrations of Qishe Pill	5 ml blood samples for pharmacokinetic analysis	1440 min after dosing	No
Primary	Plasma concentration of Qishe Pill	5 ml blood samples for pharmacokinetic analysis	2160 min after dosing	No
Primary	Plasma sampling of Qishe Pill for pharmacokinetic analysis	5 ml blood samples for pharmacokinetic analysis	2880 min after dosing	No
Primary	Vital signs	body temperature, heart rate and blood pressure	Dosing(0 hour)	Yes
Primary	Vital signs	body temperature, heart rate and blood pressure	180 min after dosing	Yes
Primary	Vital signs	body temperature, heart rate and blood pressure	720 min after dosing	Yes
Primary	Vital signs	body temperature, heart rate and blood pressure	1440 min after dosing	Yes
Primary	Vital signs	body temperature, heart rate and blood pressure	2160 min after dosing	Yes
Primary	Vital signs	body temperature, heart rate and blood pressure	2880 min after dosing	Yes
Primary	ECG monitoring	Electrocardiograms (ECGs)	Dosing(0 hour)	Yes
Primary	ECG monitoring	Electrocardiograms (ECGs)	180 min after dosing	Yes
Primary	ECG monitoring	Electrocardiograms (ECGs)	720 min after dosing	Yes
Primary	ECG monitoring	Electrocardiograms (ECGs)	1440 min after dosing	Yes
Primary	ECG monitoring	Electrocardiograms (ECGs)	2160 min after dosing	Yes
Primary	ECG monitoring	Electrocardiograms (ECGs)	2880 min after dosing	Yes
Primary	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	Yes
Primary	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	Yes
Primary	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	Yes
Primary	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	Yes
Primary	Peak Plasma Concentration (Cmax) of Qishe Pill in low dosage	The maximum plasma concentration	4 days after drug administration and blood sampling	No
Primary	Peak Plasma Concentration (Cmax) of Qishe Pill in medial dosage	The maximum plasma concentration	4 days after drug administration and blood sampling	No
Primary	Peak Plasma Concentration (Cmax) of Qishe Pill in high dosage	The maximum plasma concentration	4 days after drug administration and blood sampling	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Secondary	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)	No
Secondary	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	No