Combined Antioxidant and Preeclampsia Prediction Studies (CAPPS)

Preeclampsia Clinical Trial

— CAPPS  

Official title:

A Randomized Clinical Trial of Antioxidants to Prevent Preeclampsia and An Observational Cohort Study to Predict Preeclampsia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00135707
• Other study ID #: HD36801-CAPPS
• Secondary ID: U10HD021410U10HD
• Status: Completed
• Phase: Phase 3
• Start date: June 2003
• Est. completion date: January 2009

Study information

• Verified date: February 2019
• Source: The George Washington University Biostatistics Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Preeclampsia is one of the most common complications of pregnancy and is characterized by high blood pressure and protein in the urine. This can cause problems in the second half of pregnancy for both the mother and fetus. This study of preeclampsia consists of two parts: 1) a randomized, placebo controlled, multicenter clinical trial of 10,000 low-risk nulliparous women between 9 and 16 weeks gestation and 2) an observational, cohort study of 4,000 patients between 9 and 12 weeks gestation who are also enrolled in the trial.

Subjects in both parts will receive either 1000 mg of vitamin C and 400 IU of vitamin E or matching placebo daily. The purpose of the randomized, clinical trial is to find out if high doses of vitamin C and E will reduce the risk of preeclampsia and other problems associated with the disease. The study will also evaluate the safety of antioxidant therapy for mother and infant. Patients will be seen monthly to receive their supply of study drug, to have weight and blood pressure recorded, to have urine protein measured, and to assess any side effects. At two visits, blood and urine will be collected.

The observational, cohort study will prospectively measure potential biochemical and biophysical markers that might predict preeclampsia. These patients will have additional procedures including uterine artery Doppler and blood drawn for a complete blood count (CBC).

Description:

A Randomized, Clinical Trial of Antioxidants to Prevent Preeclampsia:

Preeclampsia is the leading cause of maternal morbidity, as well as perinatal morbidity and mortality. Once the diagnosis has been established, therapy other than delivery has not been successful except to prolong pregnancy minimally (at some risk to mother and infant). Prevention efforts to reduce or eliminate preeclampsia are directed at the pathophysiology of the disorder prior to clinically evident preeclampsia and before irreversible changes have occurred.

This double-masked, placebo-controlled trial of 10,000 subjects is designed to evaluate the effects of antioxidant therapy in preventing serious complications associated with pregnancy-related hypertension in low risk, nulliparous women who begin treatment at 9-16 weeks gestation. The hypothesis being tested is that antioxidant therapy initiated prior to 16 weeks gestation will reduce the frequency of serious maternal and infant complications associated with pregnancy-related hypertension.

After randomization, subjects will receive either 1000 mg of vitamin C and 400 IU of vitamin E or matching placebo daily. They will be seen for monthly pill counts and to assess side effects, weight, blood pressure, and urine for protein. Blood and urine are collected at 24 and 32 weeks' gestation.

An Observational Cohort Study to Predict Preeclampsia:

A prospective, cohort study has been designed to complement the randomized, controlled, trial (RCT) and will test various biochemical and biophysical markers for ability to predict preeclampsia in 4,000 of the women who are enrolled in the RCT and are between 9 and 12 weeks gestation. These subjects will have additional procedures including a CBC and uterine artery Doppler.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10154
• Est. completion date: January 2009
• Est. primary completion date: October 2008
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: N/A and older

Eligibility

RCT Inclusion Criteria:

• Gestational age 9 -16 weeks

• Singleton pregnancy

• Nulliparous

Observational Inclusion Criteria:

• Women randomized to the RCT

• Gestational age 9 - 12 wks

Exclusion Criteria RCT and Observational:

• BP >= 135/85

• Proteinuria

• History or current use of anti-hypertensive medication or diuretics

• Use of vitamins C > 150 mg and/or E > 75 IU per day

• Pregestational diabetes

• Current pregnancy is a result of in vitro fertilization

• Regular use of platelet active drugs or non-steroidal anti-inflammatory drugs (NSAIDS)

• Known fetal abnormalities

• Documented uterine bleeding within a week of screening

• Uterine malformations

• History of medical complications

• Illicit drug or alcohol abuse during current pregnancy

• Intent to deliver elsewhere

• Participating in another interventional study

Related Conditions & MeSH terms

• Pre-Eclampsia
• Preeclampsia

Intervention

Drug:
• Dietary Supplement/Vitamins
Vitamin C (1000 mg) and Vitamin E (400 IU) per capsule, two capsules daily between randomization (at 9 - 16 weeks gestation) up to delivery.
• Placebo for Vitamin C and Vitamin E
Placebo two capsules daily between randomization (at 9 - 16 weeks gestation) up to delivery.

Locations

Country	Name	City	State
United States	University of Alabama - Birmingham	Birmingham	Alabama
United States	University of North Carolina - Chapel Hill	Chapel Hill	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	Case Western University	Cleveland	Ohio
United States	Ohio State University	Columbus	Ohio
United States	University of Texas - Southwest	Dallas	Texas
United States	Wayne State University	Detroit	Michigan
United States	University of Texas Medical Branch	Galveston	Texas
United States	University of Texas - Houston	Houston	Texas
United States	Columbia University	New York	New York
United States	Drexel University	Philadelphia	Pennsylvania
United States	University of Pittsburgh Magee Womens Hospital	Pittsburgh	Pennsylvania
United States	Oregon Health and Sciences University	Portland	Oregon
United States	Brown University	Providence	Rhode Island
United States	University of Utah Medical Center	Salt Lake City	Utah
United States	Wake Forest University School of Medicine	Winston-Salem	North Carolina

Sponsors (3)

Lead Sponsor	Collaborator
The George Washington University Biostatistics Center	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (18)

Abramovici A, Gandley RE, Clifton RG, Leveno KJ, Myatt L, Wapner RJ, Thorp JM Jr, Mercer BM, Peaceman AM, Samuels P, Sciscione A, Harper M, Saade G, Sorokin Y; Eunice Kennedy Shriver National Institute of Child Health Human Development Maternal-Fetal Medicine Units Network. Prenatal vitamin C and E supplementation in smokers is associated with reduced placental abruption and preterm birth: a secondary analysis. BJOG. 2015 Dec;122(13):1740-7. doi: 10.1111/1471-0528.13201. Epub 2014 Dec 17. — View Citation

Basraon SK, Mele L, Myatt L, Roberts JM, Hauth JC, Leveno KJ, Varner MW, Wapner RJ, Thorp JM Jr, Peaceman AM, Ramin SM, Sciscione A, Tolosa JE, Sorokin Y; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. Relationship of Early Pregnancy Waist-to-Hip Ratio versus Body Mass Index with Gestational Diabetes Mellitus and Insulin Resistance. Am J Perinatol. 2016 Jan;33(1):114-21. doi: 10.1055/s-0035-1562928. Epub 2015 Sep 9. — View Citation

Cantu J, Clifton RG, Roberts JM, Leveno KJ, Myatt L, Reddy UM, Varner MW, Wapner RJ, Thorp JM Jr, Mercer BM, Peaceman AM, Ramin SM, Samuels P, Sciscione A, Saade G, Sorokin Y; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network. Laboratory abnormalities in pregnancy-associated hypertension: frequency and association with pregnancy outcomes. Obstet Gynecol. 2014 Nov;124(5):933-40. doi: 10.1097/AOG.0000000000000509. — View Citation

Carreno CA, Clifton RG, Hauth JC, Myatt L, Roberts JM, Spong CY, Varner MW, Thorp JM Jr, Mercer BM, Peaceman AM, Ramin SM, Carpenter MW, Sciscione A, Tolosa JE, Saade GR, Sorokin Y; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network. Excessive early gestational weight gain and risk of gestational diabetes mellitus in nulliparous women. Obstet Gynecol. 2012 Jun;119(6):1227-33. doi: 10.1097/AOG.0b013e318256cf1a. Erratum in: Obstet Gynecol. 2012 Sep;120(3):710. Saade, George R [added]. — View Citation

Hauth JC, Clifton RG, Roberts JM, Myatt L, Spong CY, Leveno KJ, Varner MW, Wapner RJ, Thorp JM Jr, Mercer BM, Peaceman AM, Ramin SM, Carpenter MW, Samuels P, Sciscione A, Tolosa JE, Saade G, Sorokin Y, Anderson GD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Maternal insulin resistance and preeclampsia. Am J Obstet Gynecol. 2011 Apr;204(4):327.e1-6. doi: 10.1016/j.ajog.2011.02.024. — View Citation

Hauth JC, Clifton RG, Roberts JM, Spong CY, Myatt L, Leveno KJ, Pearson GD, Varner MW, Thorp JM Jr, Mercer BM, Peaceman AM, Ramin SM, Sciscione A, Harper M, Tolosa JE, Saade G, Sorokin Y, Anderson GB; Eunice Kennedy Shriver National Institute of Child Hea — View Citation

Hughes BL, Clifton RG, Hauth JC, Leveno KJ, Myatt L, Reddy UM, Varner MW, Wapner RJ, Mercer BM, Peaceman AM, Ramin SM, Tolosa JE, Saade G, Sorokin Y; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Is Mid-trimester Insulin Resistance Predictive of Subsequent Puerperal Infection? A Secondary Analysis of Randomized Trial Data. Am J Perinatol. 2016 Aug;33(10):983-90. doi: 10.1055/s-0036-1583188. Epub 2016 Apr 27. — View Citation

Johnson J, Clifton RG, Roberts JM, Myatt L, Hauth JC, Spong CY, Varner MW, Wapner RJ, Thorp JM Jr, Mercer BM, Peaceman AM, Ramin SM, Samuels P, Sciscione A, Harper M, Tolosa JE, Saade G, Sorokin Y; Eunice Kennedy Shriver National Institute of Child Health; Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network. Pregnancy outcomes with weight gain above or below the 2009 Institute of Medicine guidelines. Obstet Gynecol. 2013 May;121(5):969-75. doi: 10.1097/AOG.0b013e31828aea03. — View Citation

Makhlouf MA, Clifton RG, Roberts JM, Myatt L, Hauth JC, Leveno KJ, Varner MW, Thorp JM Jr, Mercer BM, Peaceman AM, Ramin SM, Iams JD, Sciscione A, Tolosa JE, Sorokin Y; Eunice Kennedy Shriver National Institute of Child Health Human Development Maternal-Fetal Medicine Units Network. Adverse pregnancy outcomes among women with prior spontaneous or induced abortions. Am J Perinatol. 2014 Oct;31(9):765-72. doi: 10.1055/s-0033-1358771. Epub 2013 Dec 17. — View Citation

McDonnold M, Mele LM, Myatt L, Hauth JC, Leveno KJ, Reddy UM, Mercer BM; Eunice Kennedy Shriver National Institute of Child Health Human Development Maternal-Fetal Medicine Units (MFMU) Network. Waist-to-Hip Ratio versus Body Mass Index as Predictor of Obesity-Related Pregnancy Outcomes. Am J Perinatol. 2016 May;33(6):618-24. doi: 10.1055/s-0035-1569986. Epub 2016 Jan 20. — View Citation

Myatt L, Clifton RG, Roberts JM, Spong CY, Hauth JC, Varner MW, Thorp JM Jr, Mercer BM, Peaceman AM, Ramin SM, Carpenter MW, Iams JD, Sciscione A, Harper M, Tolosa JE, Saade G, Sorokin Y, Anderson GD; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network. First-trimester prediction of preeclampsia in nulliparous women at low risk. Obstet Gynecol. 2012 Jun;119(6):1234-42. doi: 10.1097/AOG.0b013e3182571669. — View Citation

Myatt L, Clifton RG, Roberts JM, Spong CY, Hauth JC, Varner MW, Wapner RJ, Thorp JM Jr, Mercer BM, Grobman WA, Ramin SM, Carpenter MW, Samuels P, Sciscione A, Harper M, Tolosa JE, Saade G, Sorokin Y, Anderson GD; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units Network (MFMU). The utility of uterine artery Doppler velocimetry in prediction of preeclampsia in a low-risk population. Obstet Gynecol. 2012 Oct;120(4):815-22. — View Citation

Myatt L, Clifton RG, Roberts JM, Spong CY, Wapner RJ, Thorp JM Jr, Mercer BM, Peaceman AM, Ramin SM, Carpenter MW, Sciscione A, Tolosa JE, Saade G, Sorokin Y, Anderson GD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Can changes in angiogenic biomarkers between the first and second trimesters of pregnancy predict development of pre-eclampsia in a low-risk nulliparous patient population? BJOG. 2013 Sep;120(10):1183-91. doi: 10.1111/1471-0528.12128. Epub 2013 Jan 18. — View Citation

Roberts JM, Myatt L, Spong CY, Thom EA, Hauth JC, Leveno KJ, Pearson GD, Wapner RJ, Varner MW, Thorp JM Jr, Mercer BM, Peaceman AM, Ramin SM, Carpenter MW, Samuels P, Sciscione A, Harper M, Smith WJ, Saade G, Sorokin Y, Anderson GB; Eunice Kennedy Shriver — View Citation

Silver RM, Myatt L, Hauth JC, Leveno KJ, Peaceman AM, Ramin SM, Samuels P, Saade G, Sorokin Y, Clifton RG, Reddy UM. Cell-Free Total and Fetal DNA in First Trimester Maternal Serum and Subsequent Development of Preeclampsia. Am J Perinatol. 2017 Jan;34(2):191-198. doi: 10.1055/s-0035-1570383. Epub 2016 Jul 11. — View Citation

Tita AT, Doherty L, Roberts JM, Myatt L, Leveno KJ, Varner MW, Wapner RJ, Thorp JM Jr, Mercer BM, Peaceman A, Ramin SM, Carpenter MW, Iams J, Sciscione A, Harper M, Tolosa JE, Saade GR, Sorokin Y; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Adverse Maternal and Neonatal Outcomes in Indicated Compared with Spontaneous Preterm Birth in Healthy Nulliparas: A Secondary Analysis of a Randomized Trial. Am J Perinatol. 2018 Jun;35(7):624-631. doi: 10.1055/s-0037-1608787. Epub 2017 Nov 30. — View Citation

Weissgerber TL, Gandley RE, McGee PL, Spong CY, Myatt L, Leveno KJ, Thorp JM Jr, Mercer BM, Peaceman AM, Ramin SM, Carpenter MW, Samuels P, Sciscione A, Harper M, Tolosa JE, Saade G, Sorokin Y; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Haptoglobin phenotype, preeclampsia risk and the efficacy of vitamin C and E supplementation to prevent preeclampsia in a racially diverse population. PLoS One. 2013;8(4):e60479. doi: 10.1371/journal.pone.0060479. Epub 2013 Apr 3. — View Citation

Weissgerber TL, McGee PL, Myatt L, Hauth JC, Varner MW, Wapner RJ, Thorp JM Jr, Mercer BM, Peaceman AM, Ramin SM, Samuels P, Sciscione AC, Harper M, Saade G, Sorokin Y; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Haptoglobin phenotype and abnormal uterine artery Doppler in a racially diverse cohort. J Matern Fetal Neonatal Med. 2014 Nov;27(17):1728-33. doi: 10.3109/14767058.2013.876622. Epub 2014 Jan 13. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite of Pregnancy-associated Hypertension and Serious Adverse Outcomes in the Mother or Fetus or Neonate	Severe hypertension (blood pressure [BP]>= 160/110) or mild hypertension (BP>= 140/90) >= 20 weeks gestation in conjunction with one of the following: elevated liver enzymes, thrombocytopenia, elevated serum creatinine levels, eclamptic seizure, an indicated preterm birth before 32 weeks of gestation owing to hypertension-related disorders, a fetus that was small for gestational age (below 3rd percentile) adjusted for sex and race or ethnic group, fetal death after 20 weeks of gestation, or neonatal death	20 weeks through discharge following delivery
Primary	Severe Hypertension	Included here are women who had severe hypertension only and those who had severe hypertension with elevated liver enzyme levels, thrombocytopenia, elevated serum creatinine levels, eclamptic seizure, medically indicated preterm birth, fetal-growth restriction, or fetal death after 20 weeks of gestation, or neonatal death.	20 weeks through discharge following delivery
Primary	Severe or Mild Pregnancy-associated Hypertension With Elevated Liver Enzyme Levels	Elevated liver enzyme levels are specified as an aspartate aminotransferase level of >= 100 U per liter. Women who met more than one component of the primary outcome were counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome.	20 weeks through discharge following delivery
Primary	Severe or Mild Pregnancy-associated Hypertension With Thrombocytopenia	Thrombocytopenia defined as a platelet count of <100,000 per cubic millimeter. Women who met more than one component of the primary outcome were counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome.	20 weeks through discharge following delivery
Primary	Severe or Mild Pregnancy-associated Hypertension With an Elevated Serum Creatinine Level	Elevated serum creatinine defined as =1.5 mg per deciliter or 132.6 µmol per liter. Women who met more than one component of the primary outcome were counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome.	20 weeks through discharge following delivery
Primary	Severe or Mild Pregnancy-associated Hypertension With an Eclamptic Seizure	Women who met more than one component of the primary outcome were counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome.	20 weeks through discharge following delivery
Primary	Severe or Mild Pregnancy-associated Hypertension With an Indicated Preterm Birth Before 32 Weeks of Gestation Owing to Hypertension-related Disorders	Women who met more than one component of the primary outcome were counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome.	20 weeks through discharge following delivery
Primary	Severe or Mild Pregnancy-associated Hypertension With a Fetus That Was Small for Gestational Age (Below the 3rd Percentile) Adjusted for Sex and Race or Ethnic Group	Women who met more than one component of the primary outcome were counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome.	20 weeks through discharge following delivery
Primary	Severe or Mild Pregnancy-associated Hypertension With a Fetal Death After 20 Weeks of Gestation or Neonatal Death	Women who met more than one component of the primary outcome were counted for each component. Therefore, the number of women for all individual components combined is greater than the number of women with the primary outcome.	20 weeks through discharge or prior to discharge following delivery admission
Secondary	Preeclampsia (Mild, Severe, HELLP Syndrome, Eclampsia)	HELLP denotes hemolytic anemia, elevated liver enzymes, and low platelet count.	20 weeks through discharge following delivery
Secondary	Pregnancy Associated Hypertension		20 weeks through discharge following delivery
Secondary	Medically Indicated Delivery Because of Hypertension		20 weeks through discharge following delivery
Secondary	Aspartate Aminotransferase =100 U/Liter		20 weeks through discharge
Secondary	Creatinine =1.5 mg/dl (133 µmol/Liter)		20 weeks through discharge
Secondary	Antepartum Bleeding		During pregnancy
Secondary	Premature Rupture of Membranes		During pregnancy
Secondary	Placental Abruption		During pregnancy
Secondary	Cesarean Delivery		Delivery
Secondary	Maternal Death		Delivery through hospital discharge
Secondary	Postpartum Pulmonary Edema		After delivery through discharge
Secondary	Hematocrit =24% With Transfusion		Delivery admission to discharge
Secondary	Maternal Hospital Stay		Delivery through discharge
Secondary	Gestational Age at Delivery		Delivery
Secondary	Preterm Birth		Delivery
Secondary	Fetal or Neonatal Death		During pregnancy or thorugh discharge
Secondary	Birth Weight		At birth
Secondary	Small for Gestational Age	A baby whose birth weight is less than the 3rd percentile is considered to be small for gestational age (adjusted for sex and race or ethnic group)	At birth
Secondary	Birth Weight <2500 Grams		At birth
Secondary	Admission to NICU	NICU denotes neonatal intensive care unit.	Delivery through discharge
Secondary	Respiratory Distress Syndrome		Delivery through discharge
Secondary	Intraventricular Hemorrhage, Grade III or IV		Delivery through discharge
Secondary	Sepsis		Delivery through discharge
Secondary	Necrotizing Enterocolitis		Delivery through discharge
Secondary	Retinopathy of Prematurity		Within 1 month of birth
Secondary	Apgar Score <=3 at 5 Minutes		At birth
Secondary	Neonatal Hospital Stay		Birth through discharge from hospital

External Links

•   The public website of the NICHD Maternal-Fetal Medicine Units (MFMU) Network