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

• ClinicalTrials.gov Identifier: NCT03100123
• Recruitment Status: Terminated
• First Posted: April 4, 2017
• Results First Posted: April 8, 2020
• Last Update Posted: April 8, 2020
• Sponsor: Ottawa Hospital Research Institute
• Information provided by (Responsible Party): Ottawa Hospital Research Institute

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Antiphospholipid Syndrome in Pregnancy; Pregnancy Loss	Drug: Aspirin 81 mg; Drug: Low-molecular-weight heparin	Early Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Eligible and consenting subjects will be assigned to one of two study arms. Randomization is stratified by 'high-risk' or 'non-high risk' laboratory criteria and the timing of pregnancy loss (late loss or no late loss).
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: November 6, 2017
• Actual Primary Completion Date: October 7, 2019
• Actual Study Completion Date: October 7, 2019

Arms and Interventions

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: Tinzaparin; Dalteparin; Enoxaparin; 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 Name: Acetylsalicylic Acid

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

Canada, Ontario

Ottawa Hospital Research Institute

Ottawa, Ontario, Canada

Sponsors and Collaborators

Ottawa Hospital Research Institute

Investigators

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

  Study Documents (Full-Text)

Documents provided by Ottawa Hospital Research Institute:

Study Protocol and Statistical Analysis Plan  [PDF] November 7, 2017

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Hamulyák 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:CD012852. doi: 10.1002/14651858.CD012852.pub2.

• Responsible Party: Ottawa Hospital Research Institute
• ClinicalTrials.gov Identifier: NCT03100123
• Other Study ID Numbers: CTO 0807
• First Posted: April 4, 2017
• Results First Posted: April 8, 2020
• Last Update Posted: April 8, 2020
• Last Verified: March 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Abortion, Spontaneous; Fetal Death; Antiphospholipid Syndrome; Syndrome; Disease; Pathologic Processes; Pregnancy Complications; Death; Autoimmune Diseases; Immune System Diseases; Aspirin; Heparin; Enoxaparin; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Enzyme Inhibitors