Effect of Low Molecular Heparin on Pregnancy Outcome With Protein S Deficiency

A Multicenter, Open-label, Randomized, Controlled, Phase 2 Trial Evaluating Whether Low Molecular Heparin Could Improve Pregnancy Outcomes With Protein S Deficiency

To evaluate whether low molecular heparin could improve pregnancy outcomes in pregnancies with protein S deficiency.

Study Overview

• Status: Not yet recruiting
• Conditions: Pregnancy Related; Protein S Deficiency
• Intervention / Treatment: Drug: Enoxaparin; Drug: Aspirin; Drug: Enoxaparin

Detailed Description

This is a parallel-group, multicenter, randomized controlled trial of 48 pregnancies with protein S deficiency in China. Patients are randomized into three groups to receive enoxaparin combined with aspirin, aspirin alone and no intervention. The primary outcome measure is livebirth rate.

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Xiao-Hui Zhang, Professor; Phone Number: +8613522338836; Email: zhangxh100@sina.com
• Study Contact Backup: Name: Meng-Tong Zang, MD; Phone Number: 18744579871; Email: zangztong@163.com

Study Locations

• China
  • Beijing/Beijing
    • Beijing, Beijing/Beijing, China, 100010
      • Peking University Insititute of Hematology, Peking University People's Hospital
      • Contact: Meng-Tong Zang, MD; Phone Number: 18744579871; Email: zangztong@163.com
      • Contact: Xiao-Hui Zhang, Professor; Phone Number: +8613522338836; Email: zhangxh@bjmu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Plasma activity levels of PS when not pregnant are below the lower limits of the adult reference values (generally about 60-70% for PS) without the use of warfarin. Or, free protein S antigen levels in the second and third trimesters are less than 30% and less than 24%, respectively
2. Pregnant women who delivered from Aug 1st, 2024 to Oct 15th, 2027
3. One or more family members exhibiting the same symptoms as the patient
4. Past history of early onset thrombosis (age 50 or below)
5. Repeated recurrence of thrombosis
6. Thromboses in unusual sites
7. New onset of thrombosis during current pregnancy or after delivery
8. Patients with diagnosis confirmed by gene analysis Inclusion criteria 1 and 2 must always be met regardless of items of 3-8.
9. Written informed consent

Exclusion Criteria:

1. Thrombophilia other than Protein S deficiency
2. Antiphospholipid syndrome, systemic lupus erythematosus, platelet abnormalities, vascular disorders, blood flow obstruction, paroxysmal nocturnal hemoglobinuria, malignant tumor and other conditions that tend to cause thrombosis
3. Allergy/hypersensitivity to enoxaparin or aspirin
4. Heparin-associated thrombocytopenia or thrombocytopenia (platelet count<75 × 10^9/L)
5. Organ lesions at risk for bleeding such as acute stomach/bowel ulcers, cerebral hemorrhage, cerebral aneurysm
6. uncontrolled hypertension or Severe hypertension (Systolic Blood Pressure >200mmhg and/or Diastolic Blood Pressure >120mmHg)
7. Severe hepatic failure (INR >1.8)
8. Serum creatinine greater than 80 umol/L (1.3mg/dl) and an abnormal 24 hour urine creatine clearance (<30ml/min)
9. Abnormal uterine cavity on hysterosalpingogram/hysteroscopy

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: No intervention
Experimental: The combination group; Subjects randomized to the combination group will receive daily injections of enoxaparin at a dose of 4000 IU and aspirin 75mg per day orally until delivery.	Drug: Enoxaparin; Enoxaparin 4000 IU/day by subcutaneous injection at the time of randomization and continued until delivery. Dose adjustments were made throughout the study based on symptoms such as bleeding and thrombosis.; Other Names: clexane; lovenox; Drug: Aspirin; Aspirin 75mg, orally, once daily at the time of randomization and continued until delivery. Dose adjustments were made throughout the study based on symptoms such as bleeding and thrombosis.; Other Names: ASA; Drug: Enoxaparin; Participants in all groups will receive daily injections of enoxaparin at a dose of 4000 IU within 6 weeks at postpartum.; Other Names: clexane; lovenox
Active Comparator: The Aspirin group; Aspirin will be given at a dose of 75mg, orally, each day until delivery.	Drug: Aspirin; Aspirin 75mg, orally, once daily at the time of randomization and continued until delivery. Dose adjustments were made throughout the study based on symptoms such as bleeding and thrombosis.; Other Names: ASA
Other: All groups; Participants in all groups will receive daily injections of enoxaparin at a dose of 4000 IU within 6 weeks at postpartum.	Drug: Enoxaparin; Enoxaparin 4000 IU/day by subcutaneous injection at the time of randomization and continued until delivery. Dose adjustments were made throughout the study based on symptoms such as bleeding and thrombosis.; Other Names: clexane; lovenox; Drug: Enoxaparin; Participants in all groups will receive daily injections of enoxaparin at a dose of 4000 IU within 6 weeks at postpartum.; Other Names: clexane; lovenox

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of livebirth	Incidents of livebirth	From date of randomization until delivery, assessed up to 42 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Parameters of maternal coagulation-related indicators	D-Dimer in ng/ml, Protein S activity in %	From the start of study treatment to 6 weeks post-partum
Parameters to assess the safety of low molecular heparin	Maternal platelet count in 10^9/L, Number of haemorrhagic events, Number of cases of skin reactions at injection site	From the start of study treatment to 6 weeks post-partum
Other incidents of adverse pregnancy outcomes	early miscarriage (until 12 weeks of gestation), late miscarriage (12-28 weeks of gestation), premature livebirths (28-37 weeks of gestation)	up to 37 weeks
Neonatal Data	Neonatal weight in grams, Neonatal length in centimetres, Apgar 1-minute, 5-minute, 10-minute scores in scores, Number of neonatal complications	after the delivery (an expected average of one month)
Incidents of placental insufficiency	Incidents of pre-eclampsia, intrauterine growth retardation, placental abruption, and intrauterine foetal death, etc.	up to 6 weeks post-partum
Incidents of thrombosis/thromboembolism	thrombosis/thromboembolism	From the start of study treatment to 6 weeks post-partum

Collaborators and Investigators

• Sponsor: Peking University People's Hospital
• Collaborators: Xiangya Hospital of Central South University; Beijing Friendship Hospital; Peking Union Medical College Hospital; Chinese PLA General Hospital; Beijing Hospital; China-Japan Friendship Hospital; Sichuan Academy of Medical Sciences; Beijing Obstetrics and Gynecology Hospital; Beijing Chuiyangliu Hospital
• Investigators: Principal Investigator: Xiao-Hui Zhang, Professor, Peking University Insititute of Hematology, Peking University People's Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: July 22, 2024
• First Submitted That Met QC Criteria: July 29, 2024
• First Posted (Actual): August 1, 2024

Study Record Updates

• Last Update Posted (Actual): August 1, 2024
• Last Update Submitted That Met QC Criteria: July 29, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: pregnancy; therapy; Protein S Deficiency
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Protein Disorders; Blood Coagulation Disorders; Thrombophilia; Protein S Deficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Anticoagulants; Aspirin; Enoxaparin; Enoxaparin sodium
• Other Study ID Numbers: PKU-PS-01

Drug and device information, study documents

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