Treatment of HYpertension: Morning Versus Evening (THYME)

Rationale:

The nocturnal blood pressure mean is an independent and stronger predictor of cardiovascular disease (CVD) risk than either daytime office, awake or 24hour mean blood pressure. In general, when nocturnal blood pressure does not decline CVD risk is higher, usually referred to as "dippers" versus "non-dippers". Evening administration of treatment might lower nocturnal blood pressure more effectively than morning administration, which is most commonly advised.

The main hypothesis of this study is that evening administration of antihypertensive medication might resume the dipping pattern in non-dippers and as a consequence might reduce CVD risk more than morning administration.

Primary objective (in short):

-to prove that evening administration of enalapril/hydrochlorothiazide in non-dippers can resume a dipping blood pressure pattern in non-dippers

Study design: A double-blind placebo-controlled cross-over study Each person will use for one period of six weeks enalapril/hydrochlorothiazide in the morning and placebo in the evening, and one period of six weeks the other way around

Study Overview

• Status: Unknown
• Conditions: Essential Hypertension
• Intervention / Treatment: Drug: Placebo; Drug: Enalapril/hydrochlorothiazide

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jorie Versmissen, MD, PhD; Email: j.versmissen@erasmusmc.nl

Study Locations

• Netherlands
  • Rotterdam, Netherlands
    • Erasmus MC
    • Contact: Jorie Versmissen, MD, PhD; Email: j.versmissen@erasmusmc.nl
    • Principal Investigator: Jorie Versmissen, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Essential hypertension
• Stable blood pressure on treatment with Angiotensin Converting Enzyme Inhibitor (ACEI) or Angiotensin II Receptor Blocker (ARB) and hydrochlorothiazide
• Age between 18 and 85 years
• WHO performance status 0-1
• Available for a time period of 15 weeks
• Written informed consent
• Dippers: Nocturnal blood pressure fall of 10-20% of daytime values.20
• Non-dippers: -Nocturnal blood pressure fall of <10% of daytime values

Exclusion Criteria:

• secondary cause of hypertension
• use of ARB because of intolerability (e.g. dry cough) of ACEI
• nocturnal blood pressure fall of >20% or rise
• renal insufficiency (GFR<60 ml/min)
• shift work
• pregnancy or wish to get pregnant
• use of other antihypertensive medication than ACEI, ARB, hydrochlorothiazide or a calcium channel blocker
• use of sleeping medication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Enalapril/hydrochlorothiazide; This arm will start with six weeks of administration of enalapril/hydrochlorothiazide in the evening and placebo in the morning, followed by six weeks of active treatment in the morning and placebo in the evening	Drug: Placebo; Drug: Enalapril/hydrochlorothiazide; The intervention implies that morning and evening administration of enalapril/hydrochlorothiazide will be compared; Other Names: To be determined
Placebo Comparator: Placebo; This arm will start with six weeks of morning administration of enalapril/hydrochlorothiazide in the morning and placebo in the evening, followed by six weeks of placebo in the morning and active treatment in the evening	Drug: Placebo; Drug: Enalapril/hydrochlorothiazide; The intervention implies that morning and evening administration of enalapril/hydrochlorothiazide will be compared; Other Names: To be determined

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average nocturnal blood pressure, percentage dipping and nadir of nocturnal blood pressure	At the end of each treatment period of six weeks, a 24 hour ambulatory blood pressure measurement will be performed	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of nocturnal diastolic blood pressure measurements below 65 mm hg	One safety issue on evening administration of antihypertensive treatment is that blood pressure might get too low. We will assess this especially in the dippers.	24 hours
Urine: Sodium, potassium, protein, melatonin, creatinin	Excretion of sodium, potassium, protein and melatonin depend on the circadian clock. Therefore, differences between morning and evening administration of antihypertensive medication are tested	Two times within 24 hours at the end of six weeks of treatment according to one of the two regimes
Plasma: enalapril, cortisol, melatonin, aldosterone, ACE activity, gene expression of clock genes		Moring of 24 hour blood pressure measurement after six weeks of treatment according to a certain regime

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development
• Investigators: Principal Investigator: Jorie Versmissen, MD, PhD, Erasmus Medical Center; Study Director: Teun Van Gelder, Prof, Erasmus Medical Center; Study Chair: Eric Sijbrands, Prof, Erasmus Medical Center

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Anticipated): May 1, 2017
• Study Completion (Anticipated): May 1, 2017

Study Registration Dates

• First Submitted: August 8, 2014
• First Submitted That Met QC Criteria: August 8, 2014
• First Posted (Estimate): August 12, 2014

Study Record Updates

• Last Update Posted (Estimate): August 15, 2014
• Last Update Submitted That Met QC Criteria: August 13, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: Non-dipper; Dipper; Chronopharmacology
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Essential Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Angiotensin-Converting Enzyme Inhibitors; Sodium Chloride Symporter Inhibitors; Enalapril; Hydrochlorothiazide
• Other Study ID Numbers: 2014_THYME