A Study on Molecular Genetics of Drug Responsiveness in Essential Hypertension

NCT03276598 | Completed Phase 4

• 1 other identifier: GENRES
• Study Type: interventional
• Target: 233
• Locations: 1 country
• Sites: 1

Brief Summary

Blood pressure variation and the risk of essential hypertension have an important genetic component. In most cases susceptibility to essential hypertension is likely determined by the action of more than one gene. The identification of genes causing susceptibility to hypertension is important, since it would give new tools for the diagnosis and enable better etiological classification and specific treatment of the disease. The innovation of this study is to use the response to antihypertensive therapy as an intermediate phenotype. In the study, each subject uses one of four antihypertensive drugs, each as a monotherapy in a rotational fashion, for 28 days in a randomized order. The antihypertensive drugs to be tested include a thiazide diuretic, a beta-adrenergic antagonist, an angiotensin-II receptor antagonist and a calcium channel blocker. The drugs that are selected for the study are "typical" representatives of their groups and long-acting, and the dosages are sufficient but well tolerable.

Conditions

Hypertension; Pharmacogenetics

Outcome Measures

Primary Outcomes (1)

• Blood pressure

  Change in blood pressure

  4 weeks

Study Arms (5)

Amlodipine

ACTIVE COMPARATOR

One of the four monotherapy treatment periods.

Drug: Amlodipine

Bisoprolol

ACTIVE COMPARATOR

One of the four monotherapy treatment periods.

Drug: Bisoprolol

Hydrochlorothiazide

ACTIVE COMPARATOR

One of the four monotherapy treatment periods.

Drug: Hydrochlorothiazide

Losartan

ACTIVE COMPARATOR

One of the four monotherapy treatment periods.

Drug: Losartan

Placebo

PLACEBO COMPARATOR

Placebo treatment period.

Drug: Placebo

Interventions

Amlodipine DRUG

Treatment for four weeks. Dose: 5 mg o.d.

Amlodipine

Bisoprolol DRUG

Treatment for four weeks. Dose: 5 mg o.d.

Bisoprolol

Hydrochlorothiazide DRUG

Treatment for four weeks. Dose: 25 mg o.d.

Hydrochlorothiazide

Losartan DRUG

Treatment for four weeks. Dose: 50 mg o.d.

Losartan

Placebo DRUG

Treatment for four weeks. Dose: 1 tablet per day.

Placebo

Eligibility Criteria

• Age: 35 Years - 59 Years
• Gender Eligibility Details: Based on self-representation of gender identity
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• essential hypertension diagnosed on an earlier occasion or during the present study (three diastolic blood pressure readings \>=95 mmHg on separate occasions are required).

You may not qualify if:

• usage of three or more antihypertensive drugs
• secondary hypertension
• left ventricular hypertrophy
• drug-treated diabetes mellitus
• coronary heart disease
• stroke and other disorders of cerebral circulation
• renal disease
• obstructive pulmonary disease
• a disease treated with corticosteroids
• a disease with drug treatment potentially influencing blood pressure levels
• significant obesity (BMI \>=32 kg/m2)
• allergic reaction towards any of the study drugs
• The patient is excluded from the study if his blood pressure level rises to 200/120 mmHg or above during the study.

Sponsors & Collaborators

• Helsinki University Central Hospital: lead

Study Sites (1)

Helsinki University Central Hospital

Helsinki, Finland

Location

Related Publications (5)

• Hiltunen TP, Suonsyrja T, Hannila-Handelberg T, Paavonen KJ, Miettinen HE, Strandberg T, Tikkanen I, Tilvis R, Pentikainen PJ, Virolainen J, Kontula K. Predictors of antihypertensive drug responses: initial data from a placebo-controlled, randomized, cross-over study with four antihypertensive drugs (The GENRES Study). Am J Hypertens. 2007 Mar;20(3):311-8. doi: 10.1016/j.amjhyper.2006.09.006.

  PMID: 17324745 RESULT

• Suonsyrja T, Hannila-Handelberg T, Paavonen KJ, Miettinen HE, Donner K, Strandberg T, Tikkanen I, Tilvis R, Pentikainen PJ, Kontula K, Hiltunen TP. Laboratory tests as predictors of the antihypertensive effects of amlodipine, bisoprolol, hydrochlorothiazide and losartan in men: results from the randomized, double-blind, crossover GENRES Study. J Hypertens. 2008 Jun;26(6):1250-6. doi: 10.1097/HJH.0b013e3282fcc37f.

  PMID: 18475165 RESULT

• Hiltunen TP, Donner KM, Sarin AP, Saarela J, Ripatti S, Chapman AB, Gums JG, Gong Y, Cooper-DeHoff RM, Frau F, Glorioso V, Zaninello R, Salvi E, Glorioso N, Boerwinkle E, Turner ST, Johnson JA, Kontula KK. Pharmacogenomics of hypertension: a genome-wide, placebo-controlled cross-over study, using four classes of antihypertensive drugs. J Am Heart Assoc. 2015 Jan 26;4(1):e001521. doi: 10.1161/JAHA.115.001778.

  PMID: 25622599 RESULT

• Nuotio ML, Sanez Tahtisalo H, Lahtinen A, Donner K, Fyhrquist F, Perola M, Kontula KK, Hiltunen TP. Pharmacoepigenetics of hypertension: genome-wide methylation analysis of responsiveness to four classes of antihypertensive drugs using a double-blind crossover study design. Epigenetics. 2022 Nov;17(11):1432-1445. doi: 10.1080/15592294.2022.2038418. Epub 2022 Feb 25.

  PMID: 35213289 DERIVED

• Ala-Mutka EM, Rimpela JM, Fyhrquist F, Kontula KK, Hiltunen TP. Effect of hydrochlorothiazide on serum uric acid concentration: a genome-wide association study. Pharmacogenomics. 2018 Apr;19(6):517-527. doi: 10.2217/pgs-2017-0184. Epub 2018 Mar 27.

  PMID: 29580174 DERIVED

MeSH Terms

Conditions

Hypertension

Interventions

Amlodipine; Bisoprolol; Hydrochlorothiazide; Losartan

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Dihydropyridines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Chlorothiazide; Benzothiadiazines; Sulfonamides; Sulfones; Sulfur Compounds; Thiazides; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Imidazoles; Azoles; Tetrazoles

Study Officials

• Kimmo K Kontula, Professor

  Helsinki University Central Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The placebo tablets and drugs are packed in similar gelatin capsules.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: The design of the study is a randomized placebo-controlled cross-over study. The study starts with a run-in placebo period lasting for four weeks. The four monotherapy treatment periods last for four weeks and they are separated by placebo periods lasting also for four weeks. Randomization occurs after the first placebo period in blocks of 24 (all possible drug sequences).

Study Record Dates

• First Submitted: September 6, 2017
• First Posted: September 8, 2017
• Study Start: November 25, 1999
• Primary Completion: April 1, 2004
• Study Completion: April 1, 2004
• Last Updated: September 11, 2017

Record last verified: 2017-09

Data Sharing

• IPD Sharing: Will not share

Locations

FI (1)