Investigation of the Pruritogens of Liver-related Diseases

This study hopes investigate the itch-inducing ability of different potential pruritogen candidates of cholestasis pruritus, especially the intrahepatic cholestasis of pregnancy (ICP). In this study, a combination of skin application and needle-free subcutaneous injection was used to investigate whether human endogenous molecules can cause itching. And a questionnaire is used to quantify the intensity of different candidates-induced itch.

Study Overview

• Status: Not yet recruiting
• Conditions: Cholestasis; Intrahepatic Cholestasis of Pregnancy

Detailed Description

Liver-related diseases are a large group of diseases that seriously affect people's healthy life. For example, ICP, the most common liver-related disease in pregnancy, affects on average about 4% of pregnant women worldwide. In a cohort study of 12200 eligible Chinese pregnant women, the reported incidence of ICP was 6.06%. ICP is harmful to the health of both pregnant women and fetuses. For the fetus, ICP directly affects the healthy growth and smooth delivery of the fetus. Disease-related adverse events have been reported, including preterm birth, meconium contamination of amniotic fluid, fetal hypoxia, prolonged length of stay in neonatal unit, and even stillbirth. ICP has a serious impact on the physical and mental health of pregnant women, typically severe pruritus. This itching occurs mainly in the second and third trimesters of pregnancy (usually the third trimester) and tends to become progressively worse as the pregnancy progresses. It is most commonly present on the palms and soles of the feet, and some patients have generalized itching. Moreover, the itching was aggravated at night, leading to severe insomnia. Under the background of advocating multiple births in our country, the effective prevention and treatment of such diseases is particularly important.

At present, there are no effective drugs for the treatment of ICP, especially pruritus symptoms, because the molecular mechanism of ICP and its pruritus is still unclear. In this study, we have identified several endogenous potential pruritogens that can activate human MRGPRX4 (hX4), the potential itch receptor of ICP pruritus, to mediate ICP pruritus based on a large number of previous cell and animal experiments. On this basis, the present study aims to evaluate the direct pruritic ability of different endogenous metabolites through human psychophysical experiments and subcutaneous administration of drugs to human subjects through a needle-free injection system.

In detail, this study includes two parts.

1. Test whether the molecule causes itching i) Skin application: a certain amount of human endogenous metabolites (progesterone sulfates) are dissolved in Cold cream (Avene, France). Firstly, disposable medical disinfection cotton (Lu Qing Food and Drug Supervision and Equipment (Zhun) word 2013 No. 1640069) is used to disinfect the forearm flexor skin of healthy adult subjects. The cream is then applied to the surface of the forearm (double-blind requirements were followed). During the experiment, the subjects complete the itch and pain perception questionnaire. At the end of the experiment, the changes in the administration area are observed and recorded by the chief test, including whether erythema and wheals occur.

   ii) Needle-free subcutaneous injection: a certain amount of human endogenous metabolites or FDA-approved drugs is dissolved in normal saline. Firstly, disposable medical disinfection cotton (Lu Qing Food and Drug Supervision and Equipment (Zhun) word 2013 No. 1640069) is used to disinfect the forearm skin of healthy adult subjects. Then, the drug solution is injected into the forearm surface of healthy adults using the clinical insulin injection needle-free injection system (INJEX30 needle-free injection system) (China Food and Drug Supervision Instrument (Jin) Word 2013 No. 3151260). The system mainly includes a disposable syringe, a pressurizer, a disposable ampoule and a disposable shock cushion. During the experiment, the subjects complete the itch and pain perception questionnaire. At the end of the experiment, the changes in the administration area are observed and recorded by the chief test, including whether erythema and wheals occur.

2. Molecular mechanisms of pruritus About 2g antihistamine cream (doxepin hydrochloride cream, H20041591) and placebo (Cold cream, Avene, France) are applied to the flexor muscles of the forearm (about 4cm2). After 2 hours, the drug is administered as a skin application or needle-free subcutaneous injection as described above: 2.5ug of histamine (positive control) and the indicated doses of the aforementioned potentially itch-causing molecule (double-blind requirements were followed). The changes of the skin administration area (whether there is erythema and wheals) are observed during the experiment, and the subjects complete the itch and pain perception questionnaires.
3. Psychophysical experiments The general Labeled Magnitude Scale (gLMS) is used to estimate the level of itch (or pain) at the current moment, relative to the level of itch (or pain) experienced by the subjects in previous situations. Subjects chose from the following adjectives to describe the degree of itching (or pain) : ① barely felt, ② faint, ③ mild, ④ intense, ⑤ very intense, or ⑥ most intense.

• Study Type: Observational
• Enrollment (Estimated): 200

Contacts and Locations

• Study Contact: Name: Guangyi Lan; Phone Number: 8613176881226; Email: guangyi_lan@stu.pku.edu.cn

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100000
      • Peking University
      • Contact: Guangyi Lan; Phone Number: 13176881226; Email: Guangyi_lan@stu.pku.edu.cn
      • Principal Investigator: Yulong Li

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

Both male and female Healthy adult volunteers (aged 18-35 years)

Description

Inclusion Criteria:

• Healthy adult volunteers

Exclusion Criteria:

• People with mental disorders, bone or skeletal muscle disorders, psychological disorders, various skin diseases, allergic symptoms, and similar medical histories
• People with itching or pain symptoms
• People who were on medication

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Healthy subjects; Healthy adult volunteers (aged 18-35 years)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Itch intensity	by questionnaire	Half an hour after receiving the injection

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Flare areas	Measuring by the ruler	Half an hour after receiving the injection

Collaborators and Investigators

• Sponsor: Peking University
• Investigators: Principal Investigator: Yulong Li, Peking University

Publications and helpful links

General Publications

• Yu H, Zhao T, Liu S, Wu Q, Johnson O, Wu Z, Zhuang Z, Shi Y, Peng L, He R, Yang Y, Sun J, Wang X, Xu H, Zeng Z, Zou P, Lei X, Luo W, Li Y. MRGPRX4 is a bile acid receptor for human cholestatic itch. Elife. 2019 Sep 10;8:e48431. doi: 10.7554/eLife.48431.

Study record dates

Study Major Dates

• Study Start (Estimated): April 20, 2024
• Primary Completion (Estimated): August 1, 2025
• Study Completion (Estimated): August 1, 2025

Study Registration Dates

• First Submitted: April 10, 2024
• First Submitted That Met QC Criteria: April 10, 2024
• First Posted (Actual): April 15, 2024

Study Record Updates

• Last Update Posted (Actual): April 16, 2024
• Last Update Submitted That Met QC Criteria: April 14, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: pruritus; cholestasis
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Biliary Tract Diseases; Bile Duct Diseases; Cholestasis; Cholestasis, Intrahepatic
• Other Study ID Numbers: 2021-06-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Privacy and competition

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No