AntiPhospholipid Syndrome Low-molecular-weight Heparin Pregnancy Loss Evaluation: The Pilot Study (APPLE)

A Pilot Study Assessing the Feasibility of a Randomized Controlled Trial Evaluating Aspirin Versus Low-molecular-weight Heparin (LMWH) and Aspirin in Women With Antiphospholipid Syndrome and Pregnancy Loss

The APPLE pilot trial is a feasibility study that is a multicentre, open-label, randomized controlled trial. Pregnant women with antiphospholipid syndrome (APS) and a history of late (≥10 weeks gestation) or recurrent early (2 <10 weeks) pregnancy loss will be recruited.

Eligible and consenting subjects will be assigned to one of two study arms: open-label low-molecular-weight heparin (LMWH) prophylaxis until 37 weeks gestation AND low-dose aspirin (ASA) daily until delivery, or open-label low-dose aspirin daily from randomization until delivery.

Study Overview

• Status: Terminated
• Conditions: Pregnancy Loss; Antiphospholipid Syndrome in Pregnancy
• Intervention / Treatment: Drug: Low-molecular-weight heparin; Drug: Aspirin 81 mg

Detailed Description

The purpose of this pilot trial is to determine the feasibility of conducting a multicenter randomized full trial evaluating antepartum prophylaxis with ASA versus LMWH/ASA in women with confirmed APS and a history of late or recurrent early pregnancy loss.

Given the large sample size needed to adequately power a large multicenter trial that assesses the efficacy of ASA alone versus LMWH/ASA, the investigators first need to determine if it is possible to meet minimum recruitment rates needed for a full multicenter trial. If the pilot feasibility trial is successful, then the secondary outcomes collected will be used in the analysis of the full multicenter trial.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada
      • Ottawa Hospital Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Confirmed pregnancy;
• 18 years or older;
• Two or more unexplained pregnancy loss before the 10th week of gestation, AND/OR one or more unexplained pregnancy loss at or beyond the 10th week of gestation;
• One or more APS laboratory criteria present, according to the revised Sapporo criteria;

Exclusion Criteria:

• Greater than 11 weeks +6 days gestational age at time of randomization;
• Indication(s) for prophylactic or therapeutic-dose anticoagulation;
• Contraindication to heparin or aspirin;
• Received 7 or more doses of LMWH;
• Previous participation in the trial;
• Geographic inaccessibility;
• Refused consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Standard of Care Arm; Open-label low-molecular-weight heparin (LMWH) prophylaxis until 37 weeks gestation AND low-dose aspirin daily until delivery.	Drug: Low-molecular-weight heparin; The LMWH regime will be at the discretion of the treating physician, with a suggested regime as follows: tinzaparin 4,500 IU sc daily until 20 weeks gestation, and then 4,500 IU sc twice daily until 37 weeks gestation.; Other Names: Enoxaparin; Dalteparin; Tinzaparin; LMWH
EXPERIMENTAL: Experimental Arm; Open-label low-dose Aspirin 81 mg daily from randomization until delivery.	Drug: Aspirin 81 mg; Aspirin 81 mg po daily in tablet form.; Other Names: Acetylsalicylic Acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Study Feasibility: Mean Recruitment Rate Per Center Per Month	The primary feasibility outcome of the pilot trial is the mean recruitment rate per center per month.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Essential Documents	Proportion of sites requiring >18 months to obtain all required approvals/contracts from time of delivery of all study documents.	18 months
Eligibility	Proportion of screened patients who meet eligibility criteria (i.e. patients who meet inclusion criteria and are also eligible based on exclusion criteria).	24 months
Consent	Proportion of eligible subjects who provide consent.	24 months
Withdrawals/Loss to Follow-up	Proportion of withdrawals/loss to follow-up among randomized patients.	24 months
Crossover Rate	Crossover rate between standard of care and experimental study arms.	52 weeks
Study Drug Compliance	Level of compliance with study drug through patient recall and patient medication diary.	52 weeks

Collaborators and Investigators

• Sponsor: Ottawa Hospital Research Institute
• Investigators: Principal Investigator: Marc Rodger, MD, Ottawa Hospital Research Institute; Principal Investigator: Leslie Skeith, MD, Ottawa Hospital Research Institute

Publications and helpful links

General Publications

• Hamulyak EN, Scheres LJ, Marijnen MC, Goddijn M, Middeldorp S. Aspirin or heparin or both for improving pregnancy outcomes in women with persistent antiphospholipid antibodies and recurrent pregnancy loss. Cochrane Database Syst Rev. 2020 May 2;5(5):CD012852. doi: 10.1002/14651858.CD012852.pub2.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 6, 2017
• Primary Completion (ACTUAL): October 7, 2019
• Study Completion (ACTUAL): October 7, 2019

Study Registration Dates

• First Submitted: February 21, 2017
• First Submitted That Met QC Criteria: March 28, 2017
• First Posted (ACTUAL): April 4, 2017

Study Record Updates

• Last Update Posted (ACTUAL): April 8, 2020
• Last Update Submitted That Met QC Criteria: March 25, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Autoimmune Diseases; Disease; Pregnancy Complications; Death; Syndrome; Abortion, Spontaneous; Antiphospholipid Syndrome; Fetal Death; 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; Heparin; Enoxaparin; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin
• Other Study ID Numbers: CTO 0807

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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