Clinical trial NCT02299414: Chronic Hypertension and Pregnancy (CHAP) Project
Official title: A Pragmatic Multicenter Randomized Clinical Trial (RCT) of Antihypertensive Therapy for Mild Chronic Hypertension During Pregnancy: Chronic Hypertension and Pregnancy (CHAP) Project
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hypertension
Keywords: Pregnancy
Chronic hypertension
Lead sponsor: University of Alabama at Birmingham
Sponsor class: OTHER
Collaborators: name: Columbia University
name: Drexel University College of Medicine
name: Rutgers, The State University of New Jersey
name: Lehigh Valley Hospital
name: Saint Peters University Hospital
name: Christiana Care Health Services
name: Washington University School of Medicine
name: Duke University
name: University of Texas Southwestern Medical Center
name: The University of Texas Health Science Center, Houston
name: Stanford University
name: University of Pennsylvania
name: The University of Texas Medical Branch, Galveston
name: University of Utah
name: Intermountain Health Care, Inc.
name: University of California, San Francisco
name: Johns Hopkins University
name: University of Pittsburgh
name: Ochsner Health System
name: University of North Carolina, Chapel Hill
name: National Heart, Lung, and Blood Institute (NHLBI)
name: WakeMed Health and Hospitals
name: San Francisco General Hospital
name: McKay-Dee Hospital
name: Winthrop University Hospital
name: New York Hospital Queens
name: Latter Day Saints Hospital
name: Lyndon B Johnson General Hospital
name: Virtua Medical Group
name: Duke Regional Hospital
name: Utah Valley Regional Medical Center
name: Northwestern University
name: Women and Infants Hospital of Rhode Island
name: Baylor College of Medicine
name: Case Western/Metro Health
name: Ohio State University
name: University of Iowa
name: University of California, San Diego
name: Indiana University
name: Meriter Foundation
name: Weill Medical College of Cornell University
name: University of Oklahoma
name: Medical University of South Carolina
name: Beaumont Hospital
name: University of Colorado, Denver
name: University of Kansas Medical Center
name: Denver Health and Hospital Authority
name: Gundersen Health System
name: Wake Forest University Health Sciences
name: Oregon Health and Science University
name: Medical College of Wisconsin
name: Temple University
name: New Jersey Medical School
name: University of South Alabama
name: Vanderbilt University
name: University of Arkansas
name: Emory University
name: St. Luke's Hospital and Health Network, Pennsylvania
name: The Cleveland Clinic
name: University of Tennessee
name: TriHealth Inc.
name: Tulane University
name: Yale University
name: Arrowhead Regional Medical Center
name: Geisinger Clinic
name: Miami Valley Hospital
First posted: 2014-11-24
Enrollment: 2408
Sex: FEMALE
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate whether a blood pressure treatment strategy during pregnancy to achieve targets that are recommended for non-pregnant reproductive-age adults (\<140/90 mmHg) compared ACOG- recommended standard during pregnancy (no treatment unless BP is severe) is effective and safe.

Detailed description: During pregnancy, chronic hypertension (CHTN) is the most common major medical disorder encountered, occurring in 2-6%. The substantial negative effect of CHTN on pregnancy includes a consistent 3- to 5-fold increase in superimposed preeclampsia and adverse perinatal outcomes (fetal or neonatal death, preterm birth -PTB, poor fetal growth and placental abruption) and possibly a 5- to10-fold increase in maternal cardiovascular and other complications (death, cerebrovascular accident, pulmonary edema and acute renal failure). Mild CHTN (BP \<160/110) contributes to a large proportion of these adverse outcomes. While antihypertensive treatment of CHTN is standard for the general population, it is uncertain whether treatment during pregnancy reduces maternal or fetal complications, and there are concerns that decreased arterial pressure may reduce fetal blood flow and cause poor fetal growth or small-for-gestational-age (SGA) infants. Some authorities, including the American College of Obstetricians and Gynecologists (ACOG) and American Society of Hypertension (ASH) recommend withholding antihypertensive therapy for mild CHTN, particularly if BP is \<160/105-110 mmHg. The recommendation to withhold antihypertensive treatment in pregnancy conflicts with the broader public health goal to reduce BP in those with CHTN and there is no evidence that discontinuing therapy during the brief period of pregnancy affects maternal outcomes (other than reducing the severe hypertension). For over a decade, authorities have consistently called for well-designed and powered trials to delineate the benefits and risks of pharmacologic therapy for CHTN during pregnancy.

Therefore, our multicenter consortium proposes the Chronic Hypertension and Pregnancy (CHAP) Project, a large pragmatic randomized trial with a primary aim to evaluate the benefits and harms of pharmacologic treatment of mild CHTN in pregnancy.

Eligibility criteria: Inclusion Criteria:

1. Women with chronic hypertension in pregnancy with new or untreated chronic hypertension, blood pressure 140-159 systolic or 90-104 diastolic OR known chronic hypertension on monotherapy and taking any antihypertensive and blood pressure ≤159/104 (including those with blood pressure \<140/90);
2. Singleton; and
3. viable pregnancy \<23 weeks of gestation.

Exclusion Criteria:

1. Blood pressures prior to randomization ≥160 systolic or ≥105 diastolic (with or without treatment);
2. Severe hypertension including patients currently treated with \>1 antihypertensive medication (more likely to have severe chronic hypertension);
3. Multi-fetal pregnancy;
4. Known secondary cause of chronic hypertension;
5. High-risk co-morbidities for which treatment may be indicated:

   * Diabetes mellitus diagnosed at age ≤10 years or duration of diagnosis ≥20 years
   * Diabetes mellitus complicated by end organ damage (retinopathy, nephropathy, heart disease, transplant)
   * Chronic kidney disease - including baseline proteinuria (\>300mg/24-hr, protein/creatinine ratio ≥0.3, or persistent 1+ proteinuria\*) or creatinine \>1.2.

     \*If a dipstick value at screening is more than trace, a clean catch or catheter urine should be obtained and re-tested by dipstick. If this shows trace or absence of protein, the patient is included. If it again shows 1+ protein, the patient is excluded until a 24-hr urine \<300mg/24hr or p/c ratio is \<0.3. If a p/c ratio is \>0.3, the patient may be included if a 24-hour urine is \< 300 mg.
   * Cardiac disorders: cardiomyopathy, angina, CAD
   * Prior stroke
   * Retinopathy
   * Sickle cell disease
6. Known major fetal anomaly;
7. Known fetal demise;
8. Suspected IUGR;
9. Membrane rupture or planned termination prior to randomization;
10. Plan to deliver outside the consortium centers (unless approved by the Clinical Coordinating Center) or unlikely to follow-up in the opinion of study staff or previous participation in this trial;
11. Contraindication to labetalol and nifedipine (e.g. know hypersensitivity);
12. Current substance abuse or addiction (cocaine, methamphetamine)
13. Participation in another trial without prior approval (CHAP participants will not be enrolled in other trials without prior approval by protocol committee)
14. Physician or provider refusal
15. Patient refusal \*The minimum age varies by center

Primary outcomes:
measure: Composite Adverse Perinatal Outcome
timeFrame: Up to 2 weeks postpartum for preeclampsia or 90 days for neonatal death
measure: Small for Gestational Age (Safety)
timeFrame: Until delivery
Secondary outcomes:
measure: Composite of Maternal Death or Severe Cardiovascular Morbidity
timeFrame: Up to 6 weeks (4-12 weeks) after delivery
measure: Severe Maternal Hypertension + Components of the Primary Composite Endpoint
timeFrame: Up to 2 weeks postpartum or 90 days for neonatal death
measure: Preterm Birth and Indicated Preterm Birth (<37 Weeks)
timeFrame: Until delivery
measure: Composite of Severe Neonatal Morbidities
timeFrame: Up to 90 days post delivery
measure: Adherence to Treatment After Delivery
timeFrame: 6 weeks (4-12 weeks) after delivery
Other outcomes:
measure: Superimposed Preeclampsia
timeFrame: Up to 2 weeks after delivery
measure: Superimposed Gestational Hypertension
timeFrame: Enrollment (between 6 and 18 weeks gestation) to delivery
measure: Severe Hypertension
timeFrame: Up to 6 weeks (4-12 weeks) after delivery
measure: Cesarean Delivery
timeFrame: Until delivery
measure: Blood Transfusion
timeFrame: Up to 6 weeks
measure: NICU Admission
timeFrame: Up to 6 weeks (4-12 weeks) after delivery
measure: Low Birth Weight
timeFrame: At birth
measure: Ponderal Index
timeFrame: At birth
measure: Head Circumference
timeFrame: At birth
measure: Placental Weight
timeFrame: At delivery
measure: Hypoglycemia
timeFrame: From delivery to hospital discharge (2 - 3 days after delivery)
measure: Bradycardia
timeFrame: From delivery to hospital discharge (2 - 3 days after delivery)
measure: Hypotension
timeFrame: From delivery to hospital discharge (2 - 3 days after delivery)
measure: Respiratory Distress Syndrome (RDS)
timeFrame: From delivery to hospital discharge (2 - 3 days after delivery)
measure: Bronchopulmonary Dysplasia (BPD)
timeFrame: Up to 3 months after delivery
measure: Intubation/Ventilation
timeFrame: From delivery to hospital discharge (2 - 3 days after delivery)
measure: Intraventricular Hemorrhage (IVH)
timeFrame: From delivery to hospital discharge (2 - 3 days after delivery)
measure: Necrotizing Enterocolitis (NEC)
timeFrame: Up to 3 months after delivery
measure: Hyperbilirubinemia
timeFrame: From delivery to hospital discharge (2 - 3 days after delivery)
measure: 5-min Apgar Score
timeFrame: At delivery
measure: Sepsis
timeFrame: From delivery to hospital discharge (2 - 3 days after delivery)
measure: Unscheduled Prenatal Clinic or ER Visits
timeFrame: Up to 3 months after delivery
measure: Hospitalizations
timeFrame: Up to 3 months postpartum
measure: Postpartum Unscheduled or ER Visits
timeFrame: Up to 3 months after delivery
measure: Postpartum Hospitalizations
timeFrame: Up to 3 months after delivery
measure: Neonatal Hospital Stay of 3 or More Days
timeFrame: after delivery
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham, Clinical Coordinating Center
state: Alabama
city: Birmingham
country: United States
facility: University of Alabama at Birmingham, Data Coordinating Center
state: Alabama
city: Mobile
country: United States
facility: University of South Alabama
state: Alabama
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Colton
country: United States
facility: Arrowhead Regional Medical Center
state: California
city: San Diego
country: United States
facility: University of California, San Diego
state: California
city: San Francisco
country: United States
facility: General Hospital of San Francisco
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Boulder
country: United States
facility: University of Colorado
state: Colorado
city: Denver
country: United States
facility: Denver Health
state: Colorado
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Newark
country: United States
facility: Christiana Care Health Services
state: Delaware
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Evanston
country: United States
facility: Northwestern
state: Illinois
city: Bloomington
country: United States
facility: Indiana University
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Lawrence
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: New Orleans
country: United States
facility: Tulane
state: Louisiana
city: New Orleans
country: United States
facility: Ochsner Health System/Medical Center
state: Louisiana
city: Royal Oak
country: United States
facility: Beaumont Hospital
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical College
state: Mississippi
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: New Brunswick
country: United States
facility: Robert Wood Johnson Medical School
state: New Jersey
city: New Brunswick
country: United States
facility: St. Peters University Hospital
state: New Jersey
city: Newark
country: United States
facility: New Jersey Medical School
state: New Jersey
city: Sewell
country: United States
facility: Virtua Medical Group
state: New Jersey
city: Flushing
country: United States
facility: New York Presbyterian Queens
state: New York
city: Mineola
country: United States
facility: Winthrop University Hospital
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: New York
country: United States
facility: Weill Cornell
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Durham
country: United States
facility: Duke Regional Medical Center
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Raleigh
country: United States
facility: WakeMed
state: North Carolina
city: Cincinnati
country: United States
facility: TriHealth, Inc
state: Ohio
city: Cleveland
country: United States
facility: Case Western/Metro Health
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Fairview
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Dayton
country: United States
facility: Miami Valley Hospital
state: Ohio
city: Mayfield Heights
country: United States
facility: Cleveland Clinic-Hillcrest Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Allentown
country: United States
facility: Lehigh Valley Hospital/Health Network
state: Pennsylvania
city: Bethlehem
country: United States
facility: St. Luke's University Health Network
state: Pennsylvania
city: Danville
country: United States
facility: Geisinger Clinic
state: Pennsylvania
city: Philadelphia
country: United States
facility: Drexel University College of Medicine
state: Pennsylvania
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Pennsylvania Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburg/Magee Women's Center
state: Pennsylvania
city: Providence
country: United States
facility: Brown (WIHRI)
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Memphis
country: United States
facility: University of Tennessee Health Science Center
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern
state: Texas
city: Galveston
country: United States
facility: UT Medical Branch
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: UT Houston
state: Texas
city: Ogden
country: United States
facility: McKay Dee Hospital
state: Utah
city: Provo
country: United States
facility: Utah Valley Regional Medical Center
state: Utah
city: Salt Lake City
country: United States
facility: Intermountain Healthcare
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Salt Lake City
country: United States
facility: LDS Hospital
state: Utah
city: La Crosse
country: United States
facility: Gundersen Health System
state: Wisconsin
city: Madison
country: United States
facility: Unity Point Health-Meriter Hospital
state: Wisconsin
city: Marshfield
country: United States
facility: Marshfield Clinic
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Milwaukee
country: United States
facility: Aurora Research Institute
state: Wisconsin
Study officials:
affiliation: University of Alabama at Birmingham - Clinical Coordinating Center
name: Alan Tita, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alabama at Birmingham-Data Coordinating Center
name: Gary Cutter, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alabama at Birmingham-Data Coordinating Center
name: Jeff Szychowski, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tita AT, Szychowski JM, Boggess K, Dugoff L, Sibai B, Lawrence K, Hughes BL, Bell J, Aagaard K, Edwards RK, Gibson K, Haas DM, Plante L, Metz T, Casey B, Esplin S, Longo S, Hoffman M, Saade GR, Hoppe KK, Foroutan J, Tuuli M, Owens MY, Simhan HN, Frey H, Rosen T, Palatnik A, Baker S, August P, Reddy UM, Kinzler W, Su E, Krishna I, Nguyen N, Norton ME, Skupski D, El-Sayed YY, Ogunyemi D, Galis ZS, Harper L, Ambalavanan N, Geller NL, Oparil S, Cutter GR, Andrews WW; Chronic Hypertension and Pregnancy (CHAP) Trial Consortium. Treatment for Mild Chronic Hypertension during Pregnancy. N Engl J Med. 2022 May 12;386(19):1781-1792. doi: 10.1056/NEJMoa2201295. Epub 2022 Apr 2.