Clinical trial NCT06366659: Unraveling the Pathogenesis of Pruritus in Intrahepatic Cholestasis of Pregnancy
Official title: Unraveling the Pathogenesis of Pruritus in Intrahepatic Cholestasis of Pregnancy
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Intrahepatic Cholestasis of Pregnancy
Keywords: diagnosis
prediction
prognosis
Lead sponsor: Peking University
Sponsor class: OTHER
Collaborators: name: Peking University Third Hospital
First posted: 2024-04-16
Enrollment: 600
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Participants including ICP patients and healthy pregnant women without other complications will be collected form Peking University Third Hospital and Sichuan University West China Second University Hospital.

Brief summary: This study hopes identify the main pruritogens of ICP pruritus and provide new insights for the diagnosis, prediction, and treatment of ICP. Details are as follows: It is planned to include ICP confirmed pregnant women and healthy pregnant women who have given birth in the Peking University Third Hospital and Sichuan University West China Second University Hospital. Then progesterone sulfate levels in plasma samples will be quantified by High Performance Liquid Chromatography-Mass Spectrometry (HPLC-MS) and itch intensity will be quantified by questionnaires. Main study endpoint: To reveal new indicators of ICP diagnosis with high accuracy: single, multiple or combined indicators of progesterone sulfates and other molecules like bile acids; Secondary study endpoint: To determine whether progesterone sulfates can be used as an early screening indicator for ICP for disease prediction, specifically whether elevated levels of progesterone sulfates predate pruritus in pregnant women with ICP.

Detailed description: As the most common liver-related disease in pregnancy, ICP affects an average of 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, the potential itch receptor of ICP pruritus, to mediate ICP pruritus based on a large number of previous cell and animal experiments. Based on clarifying the mechanism of pruritus, this project hopes to provide new biomarkers and new perspectives for the diagnosis and even prediction of the disease combined with the analysis of clinical samples. As such, health monitoring and early intervention may thus be enabled during pregnancy to benefit the treatment outcome of both the patient and child clinically. methods are as follows:

① To characterize the dynamic changes of progesterone sulfates in patients with ICP during the first, second, and third trimesters of pregnancy In cooperation with teams in the Department of Obstetrics and Gynecology of hospitals, blood samples will be collected from pregnant women at three different time points during pregnancy (including healthy pregnant women and pregnant women with ICP). A questionnaire will be completed by the pregnant women in the third trimester or by telephone follow-up after delivery. The degree of pruritus in pregnant women with ICP will be counted. The changes of progesterone sulfate levels and the degree of pruritus are characterized by the progression of pregnancy cycle. For the analysis of metabolite composition in plasma, we developed HPLC-MS based separation and quantification methods, focusing on the progesterone metabolites/derivatives of interest, including the following nine progesterone sulfates: Isopregnanolone sulfate (3β5α) (PM5S), Epipregnanolone sulfate (3β5β) (PM7S), Pregnanolone sulfate (3α5β) (PM6S), Allopregnanolone sulfate (3α5α) (PM4S), Pregnanediol sulfate (3α5β) (PM3S), Isopregnanediol sulfate (3β5α), 5β-pregnan-3α, 20α-diol-3, 20-disulfate (PM3DiS), 5α-pregnan-3α, 20α-diol-3, 20-disulfate (PM2DiS), Pregnenolone sulfate and 17-Hydroxypregnenolone sulfate. A 100 μl plasma sample is mixed with 425 μl methanol and vortexed for 10 min. After centrifugation at 14 000 g for 10 min, the supernatant is transferred to a new tube and stored at -80 ° C before HPLC-MS analysis.

② Develop diagnostic and early prediction models for ICP or pruritus symptoms. After obtaining a sufficient amount of biological samples and the metabolite analysis results, we plan to conduct effective statistical analysis and data mining based on the sample data. Using the data of related metabolites in the blood of ICP patients and healthy pregnant women in the third trimester, Receiver Operating Characteristic (ROC) curves analysis and logistic regression model will be used to find a single characteristic metabolite molecule or a combination of several metabolite molecules, which could effectively distinguish ICP patients from normal pregnant women, and serve as a new indicator with high accuracy to assist the clinical diagnosis of ICP. Furthermore, based on the analysis of blood samples in the first and second trimesters, we expect that characteristic metabolites can be mined, and the dynamic changes in their levels can even predict the probability of ICP before the onset of ICP symptoms, so as to guide the implementation of preventive measures in advance and possibly reduce the probability of adverse events.

Eligibility criteria: Inclusion Criteria:

* Pruritus in pregnancy
* Elevated levels of serum alanine aminotransferase (ALT) activities and total bile acids (TBA)
* Exclusion of other causes of liver dysfunction or itching

Exclusion Criteria:

* Pruritus with skin lesions such as eczema
* Pruritus of other liver-related diseases (PBC, Primary Sclerosing Cholangitis (PSC), etc.)
* Twin pregnancy
* TBA and pruritus did not relieve 4-6 weeks after delivery.

Primary outcomes:
measure: Progesterone metabolites (levels in plasma)
timeFrame: 1 year in total. Plasma samples will be collected every 3 months during the whole pregnancy of every participant. About at the last day of the month 3, month 6, and month 9 of the whole pregnancy, respectively.
measure: Itch intensity
timeFrame: 1 year in total. At the last day of the month 9 of the pregnancy of participants.
Secondary outcomes:
measure: Total bile acids (levels in plasma)
timeFrame: 1 year in total. Plasma samples will be collected every 3 months during the whole pregnancy of every participant. About at the last day of the month 3, month 6, and month 9 of the whole pregnancy, respectively.
Other outcomes:
Locations:
city: Beijing
country: China
facility: Peking University Third Hospital
state: Beijing
city: Chengdu
country: China
facility: Sichuan University West China Second University Hospital
state: Sichuan
Study officials:
affiliation: Peking University
name: Yulong Li
role: PRINCIPAL_INVESTIGATOR
References:
citation: Abu-Hayyeh S, Ovadia C, Lieu T, Jensen DD, Chambers J, Dixon PH, Lovgren-Sandblom A, Bolier R, Tolenaars D, Kremer AE, Syngelaki A, Noori M, Williams D, Marin JJ, Monte MJ, Nicolaides KH, Beuers U, Oude-Elferink R, Seed PT, Chappell L, Marschall HU, Bunnett NW, Williamson C. Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum. Hepatology. 2016 Apr;63(4):1287-98. doi: 10.1002/hep.28265. Epub 2015 Dec 28.
citation: De Borre M, Che H, Yu Q, Lannoo L, De Ridder K, Vancoillie L, Dreesen P, Van Den Ackerveken M, Aerden M, Galle E, Breckpot J, Van Keirsbilck J, Gyselaers W, Devriendt K, Vermeesch JR, Van Calsteren K, Thienpont B. Cell-free DNA methylome analysis for early preeclampsia prediction. Nat Med. 2023 Sep;29(9):2206-2215. doi: 10.1038/s41591-023-02510-5. Epub 2023 Aug 28.