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

• Sponsor: Ottawa Hospital Research Institute (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03100123
• Collaborator: (none)
• Enrollment: 1
• Location: 1
• Arms: 2
• Actual Duration (Months): 23
• Patients Per Site Per Month: 0

Study Details

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
• 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).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: Nov 6, 2017
• Actual Primary Completion Date: Oct 7, 2019
• Actual Study Completion Date: Oct 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 Names: Acetylsalicylic Acid

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Essential Documents [18 months]

   Proportion of sites requiring >18 months to obtain all required approvals/contracts from time of delivery of all study documents.

2. 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).

3. Consent [24 months]

   Proportion of eligible subjects who provide consent.

4. Withdrawals/Loss to Follow-up [24 months]

   Proportion of withdrawals/loss to follow-up among randomized patients.

5. Crossover Rate [52 weeks]

   Crossover rate between standard of care and experimental study arms.

6. Study Drug Compliance [52 weeks]

   Level of compliance with study drug through patient recall and patient medication diary.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	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)

• Study Protocol and Statistical Analysis Plan - Nov 7, 2017

More Information

Publications

None provided.

• Responsible Party: Ottawa Hospital Research Institute
• ClinicalTrials.gov Identifier: NCT03100123
• Other Study ID Numbers: CTO 0807
• First Posted: Apr 4, 2017
• Last Update Posted: Apr 8, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• 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; Aspirin; Heparin; Enoxaparin; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin

Study Results

Participant Flow

Arm/Group Title	Standard of Care Arm	Experimental Arm
Arm/Group Description	Open-label low-molecular-weight heparin (LMWH) prophylaxis until 37 weeks gestation AND low-dose aspirin daily until delivery. 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.	Open-label low-dose Aspirin 81 mg daily from randomization until delivery. Aspirin 81 mg: Aspirin 81 mg po daily in tablet form.
Period Title: Overall Study
STARTED	0	1
COMPLETED	0	1
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Standard of Care Arm	Experimental Arm	Total
Arm/Group Description	Open-label low-molecular-weight heparin (LMWH) prophylaxis until 37 weeks gestation AND low-dose aspirin daily until delivery. 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.	Open-label low-dose Aspirin 81 mg daily from randomization until delivery. Aspirin 81 mg: Aspirin 81 mg po daily in tablet form.	Total of all reporting groups
Overall Participants	0	1	1
Age (Count of Participants)
<=18 years	0 NaN	0 0%	0 0%
Between 18 and 65 years	0 NaN	1 100%	1 100%
>=65 years	0 NaN	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	0 NaN	1 100%	1 100%
Male	0 NaN	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 NaN	0 0%	0 0%
Asian	0 NaN	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 NaN	0 0%	0 0%
Black or African American	0 NaN	0 0%	0 0%
White	0 NaN	1 100%	1 100%
More than one race	0 NaN	0 0%	0 0%
Unknown or Not Reported	0 NaN	0 0%	0 0%
Region of Enrollment (participants) [Number]
Canada	1 Infinity	1 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

1 participant was recruited (ASA alone arm) and the pilot trial was stopped early due to feasibility.

Arm/Group Title	Standard of Care Arm	Experimental Arm
Arm/Group Description	Open-label low-molecular-weight heparin (LMWH) prophylaxis until 37 weeks gestation AND low-dose aspirin daily until delivery. 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.	Open-label low-dose Aspirin 81 mg daily from randomization until delivery. Aspirin 81 mg: Aspirin 81 mg po daily in tablet form.
Measure Participants	0	1
Number [participants]	1 Infinity

2. Secondary Outcome

Title	Essential Documents
Description	Proportion of sites requiring >18 months to obtain all required approvals/contracts from time of delivery of all study documents.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

Site #1 was able to obtain all applicable approvals and begin recruitment in 12 months. Not applicable applicable for site #2 as study was closed early due to low recruitment.

Arm/Group Title	Approval Timeline
Arm/Group Description	Sites requiring >18 months for all approvals
Measure Participants	1
Number [Sites]	1

3. Secondary Outcome

Title	Eligibility
Description	Proportion of screened patients who meet eligibility criteria (i.e. patients who meet inclusion criteria and are also eligible based on exclusion criteria).
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Screened Patients Who Met Eligibility Criteria
Arm/Group Description	Screened patients who meet eligibility criteria
Measure Participants	25
Count of Participants [Participants]	4 Infinity

4. Secondary Outcome

Title	Consent
Description	Proportion of eligible subjects who provide consent.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Consented Eligible Patients
Arm/Group Description	Eligible patients who provided consent
Measure Participants	4
Count of Participants [Participants]	1 Infinity

5. Secondary Outcome

Title	Withdrawals/Loss to Follow-up
Description	Proportion of withdrawals/loss to follow-up among randomized patients.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Withdrawal/Lost to Follow-up
Arm/Group Description	Withdrawal/Lost to follow-up among randomized patients
Measure Participants	1
Count of Participants [Participants]	0 NaN

6. Secondary Outcome

Title	Crossover Rate
Description	Crossover rate between standard of care and experimental study arms.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Crossover Rate
Arm/Group Description	Crossover rate between standard of care and experimental study arms.
Measure Participants	1
Count of Participants [Participants]	0 NaN

7. Secondary Outcome

Title	Study Drug Compliance
Description	Level of compliance with study drug through patient recall and patient medication diary.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

No participants in standard of care arm

Arm/Group Title	Standard of Care Arm	Experimental Arm
Arm/Group Description	Open-label low-molecular-weight heparin (LMWH) prophylaxis until 37 weeks gestation AND low-dose aspirin daily until delivery. 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.	Open-label low-dose Aspirin 81 mg daily from randomization until delivery. Aspirin 81 mg: Aspirin 81 mg po daily in tablet form.
Measure Participants	0	1
Count of Participants [Participants]	0 NaN	1 100%

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.
Adverse Event Reporting Description	AEs were elicited, monitored and recorded throughout the study. For each participant, AEs were submitted to the trial office after each follow-up visit. The investigator is to report all directly observed AEs and all AEs spontaneously reported by the participant. In addition, each participant will be questioned about AEs at each clinic visit following initiation of treatment.
Arm/Group Title	Standard of Care Arm		Experimental Arm
Arm/Group Description	Open-label low-molecular-weight heparin (LMWH) prophylaxis until 37 weeks gestation AND low-dose aspirin daily until delivery. 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.		Open-label low-dose Aspirin 81 mg daily from randomization until delivery. Aspirin 81 mg: Aspirin 81 mg po daily in tablet form.
All Cause Mortality
	Standard of Care Arm		Experimental Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/1 (0%)
Serious Adverse Events
	Standard of Care Arm		Experimental Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/1 (0%)
Other (Not Including Serious) Adverse Events
	Standard of Care Arm		Experimental Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/1 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.