Background
Biology of aspirin in pregnancy
Aspirin and preterm birth
Aspirin and preeclampsia
Aspirin and growth restriction (small for gestational Age)
Aspirin safety
Summary
Methods/design
Study hypothesis
Primary hypothesis or question
Secondary hypothesis
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Small for gestational age infants
-
Eclampsia and preeclampsia
-
Perinatal Mortality
Study Population
Inclusion criteria
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Nulliparous women between 18 – 40 years of age (Minors who are ≥ 14 years of age may be enrolled if permitted by the country’s ethical guidelines.);
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No more than two previous first trimester pregnancy losses;
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No medical contraindications to aspirin;
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Single live intrauterine pregnancy (IUP) between 6 0/7 and 13 6/7 weeks GA corroborated by an early dating ultrasound and presence of a heartbeat.
Exclusion criteria
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Women already prescribed daily aspirin for more than 7 days;
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Women with multiple gestations;
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Fetal anomaly by ultrasound (Note: most fetal anomalies are not detectable by ultrasounds done at this early gestation. Subsequent discovery of a fetal anomaly is not an exclusion.);
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Hemoglobin < 7.0 g/dl at screening;
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Systolic blood pressure ≥ 140 and diastolic ≥ 90 at screening;
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Any other medical conditions that may be considered a contraindication per the judgment of the site investigator (e.g., Lupus, Type 1 Diabetes, hypertension, or any other known significant disease).
Study procedures
6 0/7- 13 6/7 weeks GA | Bi-weekly after enrollment | 4 weeks after enrollment | 16-20 weeks GA | 26-30 weeks GA | 28-30 weeks GA | 34 weeks GA | 36 weeks GA until delivery | 6 weeks Post-Partum | As needed | |
---|---|---|---|---|---|---|---|---|---|---|
Screening | ||||||||||
Initial eligibility | ● | |||||||||
Ultrasound | ● | |||||||||
Consent | ● | |||||||||
Randomization/Enrollment | ● | |||||||||
Clinical Assessments | ||||||||||
Physical exam | ● | |||||||||
Medical history | ● | |||||||||
Use of other medicines | ● | ● | ||||||||
Maternal Hb monitoring | ● | ● | ● | |||||||
BP Monitoring | ● | ● | ● | ● | ● | |||||
Medication Activities | ||||||||||
Instructions for medication use | ● | ● | ||||||||
Medication compliancea
| ● | |||||||||
Resupply | ● | |||||||||
Outcome Assessment | ||||||||||
Preterm Birth | ● | |||||||||
SGA | ● | |||||||||
Preeclampsia/Eclampsia | ● | ● | ● | ● | ● | ● | ● | |||
Other maternal outcomes | ● | ● | ● | |||||||
Other fetal outcomes | ● | ● | ||||||||
Unanticipated medical care | ● | ● | ||||||||
Serious Adverse Events | ● | ● | ● |
Initial screening
Ultrasound screening
-
A single intrauterine gestation
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Presence of a fetal heart rate
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Crown rump length (CRL) < 14 weeks gestation
Gestational age by LMP | Difference between LMP and US GA | Basis for assigning projected due date |
---|---|---|
Unknown/Not available | N/A | CRL |
<9 0/7 weeks | >5 days | CRL |
≤5 days | LMP | |
≥9 0/7 and ≤13 6/7 weeks | >7 days | CRL |
≤7 days | LMP |
Clinical assessment
Randomization procedures
Study intervention and comparison
Blinding/masking
Monitoring
-
Between 16 and 20 weeks
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At 28–30 weeks
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At 34 weeks
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Every 2 weeks beyond that until delivery, alternating with pill monitoring visits
Primary outcome
Secondary outcomes
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Preeclampsia and eclampsia
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SGA newborn
-
Perinatal mortality
Other outcomes of interest
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Vaginal bleeding
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Antepartum hemorrhage
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Postpartum hemorrhage
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Maternal mortality
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Late pregnancy termination
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Change in maternal hemoglobin
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Preterm birth <34 0/7 weeks of pregnancy
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Birth weight <2500 g and <1500 g
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Fetal loss
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Spontaneous abortion
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Stillbirth
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Medical termination of pregnancy
Safety monitoring
Compliance monitoring
Site preparation
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Identifying and hiring study staff;
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Developing site-specific procedures for safety monitoring (blood pressure, anemia) and procuring the necessary equipment;
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Exploring locally-acceptable methods to monitor and improve medication compliance;
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Identifying potential implementation challenges and developing culturally-appropriate solutions;
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Identifying local medicines/treatments that contain aspirin or have contraindications for its use;
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Educating health workers and community members on the use of aspirin in pregnancy (including safety of aspirin use).
Potential risks and benefits to participants
Analytical plan
Statistical analysis plan
Primary analysis—risk of preterm (<37 weeks) birth
Secondary and exploratory analysis
Sample size and power estimates
PTB rate in Placebo Arm | PTB rate in ASA | % Red. | Sample size per group | PTB rate in ASA | % Red. | Sample size per group | PTB rate in ASA | % Red. | Sample size per group |
---|---|---|---|---|---|---|---|---|---|
Power = 80% (α = 0.05; β = 0.2) | |||||||||
8% | 4.8% | 40% | 918 | 6.0% | 25% | 2554 | 6.40% | 20% | 4096 |
10% | 6.0% | 40% | 721 | 7.5% | 25% | 2005 | 8.00% | 20% | 3213 |
12% | 7.2% | 40% | 591 | 9.0% | 25% | 1638 | 9.60% | 20% | 2625 |
14% | 8.4% | 40% | 497 | 10.0% | 25% | 1377 | 11.20% | 20% | 2204 |
Power = 90% (α = 0.05; β = 0.1) | |||||||||
8% | 4.8% | 40% | 1228 | 6.0% | 25% | 3419 | 6.40% | 20% |
5483
|
10% | 6.0% | 40% | 965 | 7.5% | 25% | 2683 | 8.00% | 20% | 4301 |
12% | 7.2% | 40% | 790 | 9.0% | 25% | 2193 | 9.60% | 20% | 3513 |
14% | 8.4% | 40% | 665 | 10.5% | 25% | 1842 | 11.20% | 20% | 2950 |
Sample size—secondary outcomes
Available population
Projected recruitment time
YR 1 | YR 2 | YR 3 | YR 4 | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Q1 | Q2 | Q3 | Q4 | Q1 | Q2 | Q3 | Q4 | Q1 | Q2 | Q3 | Q4 | Q1 | Q2 | |
Preparatory Activities | ||||||||||||||
Document Development (Protocol, forms, etc.) | ● | ● | ● | ● | ||||||||||
Procurement of medication and other materials | ● | ● | ● | ● | ||||||||||
Approvals (IRB, ERC, Drug Authorities, etc.) | ● | ● | ● | ● | ||||||||||
Site Preparation | ● | ● | ● | ● | ||||||||||
Training | ● | ● | ● | |||||||||||
Recruitment (24 months) | ● | ● | ● | ● | ● | ● | ● | ● | ||||||
Data Cleaning and Analysis (6 months) | ● | ● |
Study monitoring plan
Serious adverse events
-
Results in death;
-
Is life-threatening;
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Requires hospitalization or prolongs existing hospitalization;
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Results in persistent or significant disability or incapacity;
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Any other serious or unexpected adverse event that the study investigator(s) feels should be reported.
Data monitoring plan and stopping rules
Central Study Team: Global Network |
Site 08 (Belgaum, India) |
Richard Derman, MD, MPH Principal Investigator, Thomas Jefferson University, Philadelphia, PA USA
|
Bhalchandra Kodkany, MD, MBBS Senior Foreign Investigator, KLE University’s JN Medical College, Belagavi, India |
Shivaprasad S. Goudar MD, MHPE Co-Investigator, KLE University’s JN Medical College, Belagavi, India |
Matthew K. Hoffman, MD, MPH Lead Investigator for ASPIRIN Protocol, Christiana Care, Newark, DE USA |
Mrityunjay C. Metgud, MD ASPIRIN Country Coordinator, KLE University’s JN Medical College, Belagavi, India |
Frances Jaeger, MA, DrPhCo-Investigator, Thomas Jefferson University, Philadelphia, PA USA |
Amit Revankar Data Manager, KLE University’s JN Medical College, Belagavi, India |
Data Coordinating Center - RTI International Elizabeth McClure, PhD Principal Investigator Data Coordinating Center, RTI International, Research Triangle Park, NC USA |
Dennis Wallace, PhD Senior Statistician, RTI International, Research Triangle Park, NC USA |
Norman Goco, MHS Protocol Manager, RTI International, Research Triangle Park, NC USA |
Jay Hemingway-Foday, MPH, MSW Protocol Manager for ASPIRIN Protocol, RTI International, Research Triangle Park, NC USA |
Steve Litavecz, MBA Data Manager, RTI International, Research Triangle Park, NC USA |
Janet Moore, MS Statistician, RTI International, Research Triangle Park, NC USA |
Emily MacGuire, MPH Study Coordinator, RTI International, Research Triangle Park, NC USA |
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) |
Marion Koso-Thomas, MD MPH, Medical Officer, Global Network for Women's and Children's Health Research, NICHD, Washington, DC USA
|
Menachem Miodovnik, MD Medical Officer, Global Network for Women’s and Children’s Health
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) |
Site Investigators
|
Global Network Site 02 (Democratic Republic of Congo) |
Carl L. Bose, M.D. Principal Investigator, University of North Carolina School of Medicine |
Antoinette Tshefu, M.D, Ph.D., M.P.H Senior Foreign Investigator, Kinshasa School of Public Health, Kinshasa, Democratic Republic of Congo |
Adrien Lokangaka, M.D., M.P.H. Country Coordinator, Kinshasa School of Public Health, Kinshasa, Democratic Republic of Congo |
Daniel Ishoso, MD ASPIRIN Coordinator, Kinshasa School of Public Health, Kinshasa, Democratic Republic of Congo |
Global Network Site 06 (Guatemala) |
Nancy Krebs, MD Principal Investigator, University of Colorado Health Care System (UCHCS) |
K. Michael Hambidge, MD Co-Investigator, University of Colorado Health Care System (UCHCS) |
Ana Garces, MD, MPH Senior Foreign Investigator, Instituto de Nutrición de Centroamérica y Panamá (INCAP), Guatemala City, Guatemala |
Lester Figueroa, MD Country Coordinator, Instituto de Nutrición de Centroamérica y Panamá (INCAP), Guatemala City, Guatemala |
Maynor Manrique, Data Manager, INCAP, Instituto de Nutrición de Centroamérica y Panamá (INCAP), Guatemala City, Guatemala |
Global Network Site 09 (Pakistan) |
Robert L. Goldenberg, MD Principal Investigator, Columbia University |
Sarah Saleem, MD Senior Foreign Investigator, Aga Khan University, Karachi, Pakistan |
Saleem Jessani ASPIRIN Coordinator, Aga Khan University Karachi, Pakistan |
Zaheer Habib Data Manager, Aga Khan University, Karachi, Pakistan |
Global Network Site 11 (Nagpur, India) |
Patricia L. Hibberd, MD, PhD Boston University School of Public Health |
Archana Patel, MD, DNB, MSCE Senior Foreign Investigator, Lata Medical Research Foundation (LMRF), Nagpur, India |
Prabir B. Das, MD ASPIRIN Country Coordinator, Lata Medical Research Foundation (LMRF), Nagpur, India |
Amber Prakash, Data Manager, Lata Medical Research Foundation (LMRF), Nagpur, India |
Global Network Site 03 (Zambia) |
Wally Carlo, MDPrincipal Investigator, University of Alabama at Birmingham |
Elwyn Chomba, MBChB, DCH, MRCPSenior Foreign Investigator, University Teaching Hospital, Lusaka, Zambia |
Musaku Mwenechanya, MD Country Coordinator, University Teaching Hospital, Lusaka, Zambia |
Cindy Chirwa ASPIRIN Coordinator, University Teaching Hospital, Lusaka, Zambia |
Ernest Banda Data Manager, University Teaching Hospital, Lusaka, Zambia |
Global Network Site 12 (Kenya) |
Edward A. Liechty, MDPrincipal Investigator, Indiana University School of Medicine |
Fabian Esamai, MBChB, MMed, PhDSenior Foreign Investigator, Moi University School of Medicine, Eldoret, Kenya |
Emmah Achieng ASPIRIN Coordinator, Moi University, Eldoret, Kenya |
Kevin Otieno Data Manager, Moi University, Eldoret, Kenya |
Technical Advisory Group |
Robert M. Silver, MD University of Utah Health Sciences Center |
Enrique Schisterman, Ph.D Chief and Senior Investigator Epidemiology Branch, DIPHR
Eunice Kennedy Shriver National Institute of Child Health and Human Development |
Rob Nathan, MD Ultrasound Quality Control Advisory, Department of Radiology, University of Washington, Seattle, WA |
Data management procedures
Quality control
Training
Study monitoring
Drug quality assurance and monitoring
Ultrasound gestational age dating
Discussion
Acknowledgements
Funding
University of North Carolina at Chapel Hill – C. Bose | U10 HD076465 |
University of Alabama at Birmingham – W. Carlo | U10 HD078437 |
University of Colorado – N. Krebs | U10 HD076474 |
Thomas Jefferson University – R. Derman | U10 HD076457 |
Columbia University – R. Goldenberg | U10 HD078438 |
Boston University – P. Hibberd | U10 HD078439 |
Indiana University - Liechty | U10 HD076461 |
RTI International – E. McClure | U01 HD040636 |