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

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.

• Aspirin 81 mg (Drug), also known as Acetylsalicylic Acid: Aspirin 81 mg po daily in tablet form.
• Low-molecular-weight heparin (Drug), also known as Tinzaparin, Dalteparin, Enoxaparin, LMWH: 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.

Primary outcomes

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

Secondary outcomes

• Essential Documents [18 months]: Proportion of sites requiring >18 months to obtain all required approvals/contracts from time of delivery of all study documents.
• Eligibility [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).
• Consent [24 months]: Proportion of eligible subjects who provide consent.
• Withdrawals/Loss to Follow-up [24 months]: Proportion of withdrawals/loss to follow-up among randomized patients.
• Crossover Rate [52 weeks]: Crossover rate between standard of care and experimental study arms.
• Study Drug Compliance [52 weeks]: Level of compliance with study drug through patient recall and patient medication diary.

Sex: Female, ages: 18 Years to any

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.

Participant flow

Outcome results

• Study Feasibility: Mean Recruitment Rate Per Center Per Month (Primary), Number, participants: Standard of Care Arm ; Experimental Arm 1
• Essential Documents (Secondary), Number, Sites: Approval Timeline 1
• Eligibility (Secondary), Count of participants, Participants: Screened Patients Who Met Eligibility Criteria 4
• Consent (Secondary), Count of participants, Participants: Consented Eligible Patients 1
• Withdrawals/Loss to Follow-up (Secondary), Count of participants, Participants: Withdrawal/Lost to Follow-up 0
• Crossover Rate (Secondary), Count of participants, Participants: Crossover Rate 0
• Study Drug Compliance (Secondary), Count of participants, Participants: Standard of Care Arm 0; Experimental Arm 1

Adverse events

Time frame: The AE reporting period for this trial begun upon randomization, and ended 30 days after receiving the last dose of study drug.

• Results publication: 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. PMID 32358837

• Study Protocol and Statistical Analysis Plan (PDF, 2017-11-07)

• Marc Rodger, MD, Principal investigator, Ottawa Hospital Research Institute
• Leslie Skeith, MD, Principal investigator, Ottawa Hospital Research Institute