Early Vascular Adjustments During Hypertensive Pregnancy (EVA)

March 23, 2021 updated by: Maastricht University Medical Center

Personalized Hemodynamically Guided Antihypertensive Treatment in Pregnant Women With Mild to Moderate Hypertension: a Randomized Controlled Trial

Paradoxical fetal and maternal results of studies have led to inconsistent use of antihypertensive drugs or no treatment at all in mild to moderate gestational hypertension in the Netherlands. However, none of the studies have taken the individual maternal circulatory state or the contemplated blood pressure response into account. Hypertension may be accompanied by high (hyperdynamic vasodilated profile), normal (normodynamic profile) of low (hypodynamic vasoconstrictive profile) cardiac output, and preeclampsia is not restricted to one circulatory profile. Therefore antihypertensive drugs should be viewed upon as correctors of the hemodynamic state rather than solely reducers of blood pressure. Without taking the maternal hemodynamic profile and condition into account, generic antihypertensive treatment can be expected to result in disappointing, inadequate and paradoxical results. The investigators hypothesize that in mild to moderate hypertension, personalized hemodynamically guided antihypertensive therapy (with target systolic and diastolic blood pressure <130/80mmHg), prevents the progression to severe hypertension and/or preeclampsia compared to no treatment, without the alleged side-effects.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
368

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years to 46 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Patients ages 18years or older
  • Before 37 weeks of gestational age;
  • Diagnosed with mild to moderate gestational hypertension

Exclusion Criteria:

  • Women with severe hypertension: systolic blood pressure ≥ 160mmHg and/or diastolic blood pressure ≥ 110mmHg.
  • Women with chronic hypertension who are already on antihypertensive drugs. If no antihypertensive drugs are used yet, women with pre-existent hypertension are eligible to participate.
  • Women diagnosed with preeclampsia or eclampsia in the current pregnancy.
  • Women who are not able to comprehend the study outline.
  • Women who have already participated in this study cannot be included a second time.
  • Women who have a (relative) contra-indication for one of the possible prescribed medications (for example women who have tested positive for antinuclear antibodies, which is a contraindication for Methyldopa).
  • Women who intend to terminate the pregnancy
  • Women who have a fetus with a major anomaly or chromosomal abnormality

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: randomized, interventiongroup
Women with a hyperdynamic vasodilated profile, characterized by a mean arterial pressure (MAP)/ Heart rate (Hr) ratio ≤ 1.1 are prescribed a beta-blocker. Women with a hypodynamic vasoconstrictive profile (MAP/Hr ratio ≥ 1.4) are prescribed nifedipine. Women with normodynamic profile (MAP/Hr ratio in between 1.1 and 1.4) are prescribed Methyldopa.
Drug: Nifedipine
Other Names:
  • Adalat
Drug: Labetalol
Other Names:
  • Trandate
Drug: Methyldopa
Other Names:
  • Aldomet
No Intervention: randomized, control-group
Women who give informed consent for randomization, and are randomized to the control group will not be medicinally treated for mild to moderate gestational hypertension.
No Intervention: not-randomized, control-group
Women who do not want to be randomized, but who give informed consent for follow-up on their data until discharge after delivery. They will receive standard care, i.e. no medication is prescribed for mild to moderate gestational hypertension.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
number of patients with severe gestational hypertension
Time Frame: from date of randomization until the date of this study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)
Systolic blood pressure ≥ 160mmHg and/or diastolic blood pressure ≥ 110mmHg, measured at every visit
from date of randomization until the date of this study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)
number of patients with preeclampsia
Time Frame: from date of randomization until the date of this study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)

Preeclampsia is defined as the coexistence of de novo hypertension after 20 weeks of gestation and one or more of the following new-onset conditions:

  1. Proteinuria (spot urine protein/creatinine ≥ 30g/mol or ≥ 300mg/day or at least 1 g/L [2+] on dipstick testing).

  2. Other maternal organ dysfunction:

    • Renal insufficiency (creatinine levels ≥ 90μmol/L);
    • Liver involvement (elevated transaminases: ASAT ≥31 U/L and/or ALAT ≥34U/L);
    • Neurological complications (hyperreflexia when accompanied by clonus and/or severe headaches, persistent visual scotomata, altered mental status, eclampsia);
    • Haematological complications (thrombocytopenia, platelet count below 150.000/dL, disseminated intravascular coagulation, haemolysis).
from date of randomization until the date of this study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
the pattern of change of the hemodynamic profile, measured by the ratio of mean arterial pressure and heart rate.
Time Frame: at baseline and each study visit/follow up measurement (at 1 week, 2 weeks, etc. up to 23 weeks after inclusion. The expected average is 8 weeks
hemodynamic profiles will be classified as hyperdynamic, hypodynamic vasocontricted or mixed profile.
at baseline and each study visit/follow up measurement (at 1 week, 2 weeks, etc. up to 23 weeks after inclusion. The expected average is 8 weeks
hemodynamic profile by mean arterial pressure/heart rate ratio
Time Frame: from date of randomization until the date of study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)
hemodynamic profiles will be classified as hyperdynamic, hypodynamic vasocontricted or mixed profile.
from date of randomization until the date of study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)
diameter aortic outflow tract and left ventricular outflow tract measured by transthoracic echocardiography
Time Frame: from baseline, and every 4 weeks (maximum 6 times, because in max. 23 weeks end of study is reached)
cardiac output can be derived from these values + heart rate
from baseline, and every 4 weeks (maximum 6 times, because in max. 23 weeks end of study is reached)
left ventricular volume after diastole and systole measured by transthoracic echocardiography
Time Frame: from baseline, and every 4 weeks (maximum 6 times, because in max. 23 weeks end of study is reached)
ejection fraction can be derived from these values
from baseline, and every 4 weeks (maximum 6 times, because in max. 23 weeks end of study is reached)
diameter aortic outflow tract and left ventricular outflow tract measured by transthoracic echocardiography
Time Frame: from date of randomization until the date of study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)
cardiac output can be derived from these values + heart rate
from date of randomization until the date of study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)
left ventricular volume after diastole and systole measured by transthoracic echocardiography
Time Frame: from date of randomization until the date of study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)
ejection fraction can be derived from these values
from date of randomization until the date of study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)
cardiac remodeling during pregnancy: number of patients with concentric left ventricular remodeling or concentric hypertrophy.
Time Frame: from baseline, and every 4 weeks (maximum 6 times, because in max. 23 weeks end of study is reached)
Echocardiographic concentric left ventricular (LV) remodelling and hypertrophy. Concentric remodeling is defined as a relative wall thickness (RWT) <=0.43 with a Left Ventricular Mass index (LVMi) of <95 gram/m2. Concentric hypertrophy is defined as a RWT <0.43 with a LVMi of ≥95 gram/m2.
from baseline, and every 4 weeks (maximum 6 times, because in max. 23 weeks end of study is reached)
cardiac remodeling during pregnancy: number of patients with concentric left ventricular remodeling or concentric hypertrophy.
Time Frame: from date of randomization until the date of study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)
Echocardiographic concentric left ventricular (LV) remodelling and hypertrophy. Concentric remodeling is defined as a relative wall thickness (RWT) <=0.43 with a Left Ventricular Mass index (LVMi) of <95 gram/m2. Concentric hypertrophy is defined as a RWT <0.43 with a LVMi of ≥95 gram/m2.
from date of randomization until the date of study event, assessed up to 1 week post partum (maximum 23weeks after inclusion)
health status of the newborn by Apgar score
Time Frame: assessed immediately after delivery
scored by gynecologist or paediatrician on a scale of 1 to 10
assessed immediately after delivery
prevalence of small for gestational age infancy
Time Frame: assessed at delivery date
birth weight and percentile combined with gestational age at delivery
assessed at delivery date
prevalence of premature neonates
Time Frame: assessed at delivery date
gestational age at delivery
assessed at delivery date
number of a composite of adverse neonatal outcomes
Time Frame: from delivery up neonates will be followed for the duration of the hospital stay, an expected average of 6 weeks
Stillbirth, perinatal mortality, morbidity: chronic lung disease, neonatal sepsis, severe intra-ventricular haemorrhage (IVH) > grade II, periventricular leucomalacia > grade I, and necrotizing enterocolitis. Days on ventilation support, length of admission in neonatal intensive care, and total days in hospital until 3 months corrected age.
from delivery up neonates will be followed for the duration of the hospital stay, an expected average of 6 weeks
maternal well-being questionnaire,
Time Frame: at baseline and each study visit/follow up measurement (at 1 week, 2 weeks, etc. up to 23 weeks after inclusion. The expected average is 8 weeks
Reported medication side effects, and maternal well-being by signs and symptoms during pregnancy
at baseline and each study visit/follow up measurement (at 1 week, 2 weeks, etc. up to 23 weeks after inclusion. The expected average is 8 weeks
number of assessed maternal complications
Time Frame: from a study event participants will be followed for the duration of hospital stay, an expected average of 1 week
Composite of maternal complications including: mortality, stroke, eclampsia, blindness, uncontrolled hypertension, respiratory failure, birth related variables, needed level of care
from a study event participants will be followed for the duration of hospital stay, an expected average of 1 week
gestational age at the moment of progression to primary outcome.
Time Frame: from baseline/inclusion until a study event is reached (up to 18 weeks after inclusion), with an expected average of 4 weeks.
from baseline/inclusion until a study event is reached (up to 18 weeks after inclusion), with an expected average of 4 weeks.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Maastricht University Medical Center

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Marc Spaanderman, professor, Maastricht University Medical Centre

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 1, 2015

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
February 1, 2023

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
April 1, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 5, 2015

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 21, 2015

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 24, 2015

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 24, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 23, 2021

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • METC152017

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