Prospective Clinical Study of Nintedanib to Inhibit Endometrial Fibrosis to Prevent Recurrence of Uterine Adhesions

In moderate to severe cavity adhesions, the endometrial basal layer is more severely damaged and the regenerative capacity of the endometrium and glands is low. Even though hysteroscopic electrosurgery can roughly restore the cavity morphology, the postoperative recurrence rate is as high as 40%. Abnormal uterine cavity morphology and poor endometrial repair often lead to repeated cancellation of embryo transfer cycles in assisted reproduction treatment, and reduced clinical pregnancy rate, causing mental stress and financial burden to patients, which is one of the current problems in clinically assisted reproduction treatment. Nintedanib is a triple vascular kinase inhibitor that acts primarily on platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR) and has been approved by the FDA for the clinical treatment of idiopathic pulmonary fibrosis and systemic sclerosis. The investigator's preliminary animal study found that endometrial fibrosis was significantly reduced in mice with gastric feeding of nintedanib in uterine adhesion molds. This study aimed to clarify further the role of nintedanib in inhibiting endometrial fibrosis and its clinical application value.

Study Overview

• Status: Not yet recruiting
• Conditions: Uterine Adhesions
• Intervention / Treatment: Drug: Nintedanib 100 MG [Ofev]; Drug: Nintedanib 150 MG [Ofev]

Detailed Description

The experiment will be divided into two groups based on the dose administered. After hysteroscopic surgery, one group will be given Nedanib 100mg bid orally for 15 days and the other group will be given Nedanib 150mg bid orally for 15 days. Hysteroscopic AFS scores and endometrial tissues before and after treatment will be collected for molecular biology experiments.

• Study Type: Interventional
• Enrollment (Anticipated): 90
• Phase: Phase 2; Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 38 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1)Clinical diagnosis of uterine adhesions; 2)Body mass index between 18-27 kg/m2; 3)Have a regular menstrual cycle of 27-35 days for at least six months; 4)Hysteroscopic diagnosis of moderate to severe uterine adhesions (AFS score >5), treated with electrodesiccation; 5)No contraindications to oral estrogen and progestin such as a history of thrombosis/breast tumor/history of abnormal liver function/migraine; 6)≥ 2 oocytes or blastocysts have been frozen.

Exclusion Criteria:

1)Patients with combined ovarian cysts ≥ 20 mm in diameter, submucosal uterine fibroids or intermuscular fibroids > 30 mm in diameter, pituitary tumors, and malignant tumors of various tissues and organs; 2)Patients with clinically significant abnormalities of the uterus (endometrial polyps, uterine malformations, endometriosis) and adnexa (hydrosalpinx); 3)Repeated implantation failures, such as three consecutive transfers with ≥6 failed high-quality embryos; 4)Known malformations of the reproductive organs that are unsuitable for pregnancy; 5)Abnormal cervical cytology (TCT) findings within 1 year before the screening; 6)Severe liver or kidney impairment, heart disease, or hypertension; 7)Known previous or current history of thrombophlebitis or thromboembolic disease; 8)Any known clinically significant systemic disease (e.g., diabetes mellitus, tuberculosis, etc; 9)Known history of recurrent miscarriage; 10)Chromosomal karyotype abnormalities in either spouse; 11)Genetic disorders that make either spouse unsuitable for childbirth as specified in the Maternal and Child Health Law;12)exposure of either spouse to teratogenic amounts of radiation, toxins, and drugs; 13)Participation in another drug or medical device clinical trial within 3 months before enrollment;14)Any medical condition/combined surgery/ medication/other clinically significant abnormal laboratory tests that, in the judgment of the investigator, may affect the outcome of the trial; 15)Known refusal or inability to comply with protocol requirements for any reason (including planned clinical visits and examinations).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nintedanib 100mg; Traditional hormone replacement (HRT) cycle medication (Tegretol 2mg bid for 20 days, followed by Darvon 10mg bid for the last 10 days) + Nintedanib 100mg bid *15 days orally.	Drug: Nintedanib 100 MG [Ofev]; Nintedanib 100mg bid *15 days orally after hysteroscopic surgery; Other Names: Nintedanib 100 MG Oral Capsule
Experimental: Nintedanib 150mg; Traditional hormone replacement (HRT) cycle medication (Tegretol 2mg bid for 20 days, followed by Darvon 10mg bid for the last 10 days) + Nintedanib 150mg bid *15 days orally.	Drug: Nintedanib 150 MG [Ofev]; Nintedanib 150mg bid *15 days orally after hysteroscopic surgery; Other Names: Nintedanib 150 MG Oral Capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
American Fertility Association(AFS) score (mild:1-4，moderate：5-8，severe：9-12）	American Fertility Association(AFS) scoring performed hysteroscopically	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endometrial thickness	Endometrial thickness measured by ultrasonography	3 months

Collaborators and Investigators

• Sponsor: Sixth Affiliated Hospital, Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Anticipated): December 1, 2023
• Primary Completion (Anticipated): July 30, 2024
• Study Completion (Anticipated): December 30, 2024

Study Registration Dates

• First Submitted: November 1, 2022
• First Submitted That Met QC Criteria: November 22, 2022
• First Posted (Actual): December 2, 2022

Study Record Updates

• Last Update Posted (Actual): December 2, 2022
• Last Update Submitted That Met QC Criteria: November 22, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: uterine adhesions; endometrail fibrisis
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Fibrosis; Cicatrix; Recurrence; Tissue Adhesions; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Nintedanib
• Other Study ID Numbers: 2022ZSLYEC-492

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No