THYME: Treatment of HYpertension: Morning Versus Evening

Sponsor

Erasmus Medical Center (Other)

Overall Status

Unknown status

CT.gov ID

NCT02214498

Collaborator

ZonMw: The Netherlands Organisation for Health Research and Development (Other)

120

Enrollment

Location

Arms

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Essential Hypertension	Drug: Enalapril/hydrochlorothiazide Drug: Placebo	Phase 4

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Treatment of HYpertension: Morning Versus Evening

Study Start Date :

May 1, 2015

Anticipated Primary Completion Date :

May 1, 2017

Anticipated Study Completion Date :

May 1, 2017

Arms and Interventions

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: Enalapril/hydrochlorothiazide The intervention implies that morning and evening administration of enalapril/hydrochlorothiazide will be compared Other Names: To be determined Drug: Placebo
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: Enalapril/hydrochlorothiazide The intervention implies that morning and evening administration of enalapril/hydrochlorothiazide will be compared Other Names: To be determined Drug: Placebo

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: Enalapril/hydrochlorothiazide

The intervention implies that morning and evening administration of enalapril/hydrochlorothiazide will be compared

Other Names:

To be determined

Drug: Placebo

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: Enalapril/hydrochlorothiazide

The intervention implies that morning and evening administration of enalapril/hydrochlorothiazide will be compared

Other Names:

To be determined

Drug: Placebo

Outcome Measures

Primary Outcome Measures

Average nocturnal blood pressure, percentage dipping and nadir of nocturnal blood pressure [24 hours]
At the end of each treatment period of six weeks, a 24 hour ambulatory blood pressure measurement will be performed

Secondary Outcome Measures

Percentage of nocturnal diastolic blood pressure measurements below 65 mm hg [24 hours]
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.
Urine: Sodium, potassium, protein, melatonin, creatinin [Two times within 24 hours at the end of six weeks of treatment according to one of the two regimes]
Excretion of sodium, potassium, protein and melatonin depend on the circadian clock. Therefore, differences between morning and evening administration of antihypertensive medication are tested
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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 85 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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