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CompletedNCT03276598GENRESUpdated Sep 11, 2017

A Study on Molecular Genetics of Drug Responsiveness in Essential Hypertension

A Phase 4 interventional study of Amlodipine and Bisoprolol in Hypertension and Pharmacogenetics, sponsored by Helsinki University Central Hospital. Completed at 1 site in Finland. Open to male participants aged 35 Years to 59 Years. Per ClinicalTrials.gov, last updated 2017-09-11.

Sponsored by Helsinki University Central Hospital · Phase 4, Interventional, and Treatment

Phase
Phase 4
Study type
Interventional
Enrollment
233
Allocation
Randomized
Ages
35 Years to 59 Years
Sex
Male
01

Study 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.

Read the detailed description

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. Finland is an ideal place for a study like this because of the genetic homogeneity of the population, the relatively high prevalence of the disease and the established protocols for the treatment and follow-up of hypertension in public health care.

The molecular genetic studies on hypertension performed so far (by 1999) have primarily been association studies, which are based on case-control classification and may produce erroneous results. Particularly, a reliable phenotyping of cases and controls has been difficult. Consequently, more attention should be paid to the phenotyping of patients, and novel intermediate phenotypes characteristic of certain subtypes of hypertension should be used to facilitate the search for hypertension genes. 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. The study design does not necessitate the use of equipotent doses of the various agents, since the study is not designed to compare the antihypertensive effectiveness of the study drugs or, due to the short treatment periods, their effects on clinical endpoints.

02

Conditions studied

  • Hypertension
  • Pharmacogenetics
03

Who can participate

Ages eligible
35 Years to 59 Years
Sexes eligible
Male
Accepts healthy volunteers
No

Inclusion criteria

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

Exclusion criteria

Exclusion Criteria (before and during the study):

  • 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.
04

Study design

Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Crossover assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
233 participants (actual)

Study arms

  • Active comparator
    Amlodipine

    One of the four monotherapy treatment periods.

    Drug: Amlodipine

  • Active comparator
    Bisoprolol

    One of the four monotherapy treatment periods.

    Drug: Bisoprolol

  • Active comparator
    Hydrochlorothiazide

    One of the four monotherapy treatment periods.

    Drug: Hydrochlorothiazide

  • Active comparator
    Losartan

    One of the four monotherapy treatment periods.

    Drug: Losartan

  • Placebo comparator
    Placebo

    Placebo treatment period.

    Drug: Placebo

Interventions

  • DrugAmlodipine

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

  • DrugBisoprolol

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

  • DrugHydrochlorothiazide

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

  • DrugLosartan

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

  • DrugPlacebo

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

05

What researchers measure

Primary outcomes

  1. Blood pressure

    Change in blood pressure

    Time frame: 4 weeks

06

Study locations

1 site
  • Helsinki University Central Hospital
    Helsinki, Finland
07

References and documents

Publications

  • 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. Erratum In: Am J Hypertens. 2018 Nov 13;31(12):1333. doi: 10.1093/ajh/hpy099. PubMed 17324745 ↗
  • 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. PubMed 18475165 ↗
  • 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. PubMed 25622599 ↗
  • 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. PubMed 35213289 ↗
  • 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. PubMed 29580174 ↗

Individual participant data

Plan to share: No

08

Registry details

Key details

Study ID
NCT03276598
Lead sponsor
Helsinki University Central Hospital
Responsible party
Kimmo Kontula (Professor, Helsinki University Central Hospital) — Principal investigator
First posted
Sep 8, 2017
Start date
Nov 25, 1999
Primary completion
Apr 1, 2004
Completion
Apr 1, 2004
Last update
Sep 11, 2017

Study contacts

Kimmo K Kontula, Professor
principal investigator · Helsinki University Central Hospital

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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