Treatment of HYpertension: Morning Versus Evening

Study Overview
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Brief Summary
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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

Official Title
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Treatment of HYpertension: Morning Versus Evening

Conditions
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Essential Hypertension

Intervention / Treatment
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* Drug: Enalapril/hydrochlorothiazide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Enalapril/hydrochlorothiazide<br>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<br>* The intervention implies that morning and evening administration of enalapril/hydrochlorothiazide will be compared<br>* Other names: To be determined;Drug: Placebo<br> <br> |
| Placebo Comparator: Placebo<br>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<br>* The intervention implies that morning and evening administration of enalapril/hydrochlorothiazide will be compared<br>* Other names: To be determined;Drug: Placebo<br> <br> |

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dipper, Non-dipper, Chronopharmacology