HypertensionPhase 4GENRESNCT03276598
A Study on Molecular Genetics of Drug Responsiveness in Essential Hypertension
A Phase 4 study testing Amlodipine, Bisoprolol and Hydrochlorothiazide in people with Hypertension and Pharmacogenetics, run by Helsinki University Central Hospital at 1 site in Finland.
Trial 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. Read more about this study
- Who is it for?
- Ages 35 to 59 years, men only
- Conditions the study is for
- Hypertension, Pharmacogenetics
- What is being tested?
- Amlodipine, Bisoprolol and Hydrochlorothiazide
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 233 participants
- Where
- 1 siteFinland
- Study dates
- 25 Nov 1999to 1 Apr 2004
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 35 to 59 years
- Men only
- No healthy volunteers
- Adult
Who may be able to join
- essential hypertension diagnosed on an earlier occasion or during the present study (three diastolic blood pressure readings >=95 mmHg on separate occasions are required).
Who cannot join
- 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
Show all 13Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Randomised Double-blind Cross-over Single-centre Study on Molecular Genetics of Drug Responsiveness in Essential Hypertension
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.
Read more
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.
- Conditions
- Hypertension, Pharmacogenetics
- Being tested
- Amlodipine, Bisoprolol, Hydrochlorothiazide, Losartan, Placebo
- Medical subject headings
- Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AmlodipineDrug
Treatment for four weeks. Dose: 5 mg o.d.
BisoprololDrug
Treatment for four weeks. Dose: 5 mg o.d.
HydrochlorothiazideDrug
Treatment for four weeks. Dose: 25 mg o.d.
LosartanDrug
Treatment for four weeks. Dose: 50 mg o.d.
PlaceboDrug
Treatment for four weeks. Dose: 1 tablet per day.
| Study group | Role | What they receive |
|---|---|---|
| Amlodipine | Active comparator | One of the four monotherapy treatment periods. Receives: Drug: Amlodipine |
| Bisoprolol | Active comparator | One of the four monotherapy treatment periods. Receives: Drug: Bisoprolol |
| Hydrochlorothiazide | Active comparator | One of the four monotherapy treatment periods. Receives: Drug: Hydrochlorothiazide |
| Losartan | Active comparator | One of the four monotherapy treatment periods. Receives: Drug: Losartan |
| Placebo | Placebo comparator | Placebo treatment period. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Blood pressure
Change in blood pressure
Measured: 4 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Sep 2017
- Study start25 Nov 1999
- Primary completion1 Apr 2004
- Study completion1 Apr 2004
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for HypertensionStudies of the same condition, open and under way.
- More trials run by Helsinki University Central HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- 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).
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 233 participants (actual)
Sponsor and investigators
- Lead sponsor
- Helsinki University Central Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Kimmo Kontula, Helsinki University Central Hospital
- Investigators
- Kimmo K Kontula, Professor, Principal investigator, Helsinki University Central Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03276598
- Sponsor's protocol ID
- GENRES
- Acronym
- GENRES
- Status last verified
- Sep 2017
- First submitted
- 6 Sep 2017
- Last updated
- 11 Sep 2017
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
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.
PubMed 17324745Suonsyrja 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 18475165Hiltunen 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 25622599Nuotio 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 35213289Ala-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
Study at a glance
From the registry record, last updated by the sponsor on 11 Sep 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomised Double-blind Cross-over Single-centre Study on Molecular Genetics of Drug Responsiveness in Essential Hypertension
- ClinicalTrials.gov ID
- NCT03276598
- Acronym / sponsor ID
- GENRES / GENRES
- Conditions
- Hypertension, Pharmacogenetics
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 233 participants (actual)
- Lead sponsor
- Helsinki University Central HospitalUniversity, hospital or other
- Study start
- 25 Nov 1999 (actual)
- Primary completion
- 1 Apr 2004 (actual)
- Study completion
- 1 Apr 2004 (actual)
- First posted
- 8 Sep 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 5
- Model description
- 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).
| Arm | Type | Receives |
|---|---|---|
| Amlodipine | Active comparator | Drug: AmlodipineOne of the four monotherapy treatment periods. |
| Bisoprolol | Active comparator | Drug: BisoprololOne of the four monotherapy treatment periods. |
| Hydrochlorothiazide | Active comparator | Drug: HydrochlorothiazideOne of the four monotherapy treatment periods. |
| Losartan | Active comparator | Drug: LosartanOne of the four monotherapy treatment periods. |
| Placebo | Placebo comparator | Drug: PlaceboPlacebo treatment period. |
Who may qualify
- Ages
- 35 to 59 years
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (1 listed)
- essential hypertension diagnosed on an earlier occasion or during the present study (three diastolic blood pressure readings >=95 mmHg on separate occasions are required).
Key exclusion criteria (13 listed)
- usage of three or more antihypertensive drugs
- secondary hypertension
- left ventricular hypertrophy
- drug-treated diabetes mellitus
- coronary heart disease
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AmlodipineTreatment for four weeks. Dose: 5 mg o.d. | Drug | Amlodipine |
| BisoprololTreatment for four weeks. Dose: 5 mg o.d. | Drug | Bisoprolol |
| HydrochlorothiazideTreatment for four weeks. Dose: 25 mg o.d. | Drug | Hydrochlorothiazide |
| LosartanTreatment for four weeks. Dose: 50 mg o.d. | Drug | Losartan |
| PlaceboTreatment for four weeks. Dose: 1 tablet per day. | Drug | Placebo |
Primary outcome
Blood pressure
Time frame: 4 weeks
Change in blood pressure
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Sep 2017.
- Results publication: PubMed 17324745Hiltunen 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.
- Results publication: PubMed 18475165Suonsyrja 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.
- Results publication: PubMed 25622599Hiltunen 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.
- Derived from this study: PubMed 35213289Nuotio 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.
- Derived from this study: PubMed 29580174Ala-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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Kimmo K Kontula, Professor principal investigator
Helsinki University Central Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Amlodipine, Bisoprolol and Hydrochlorothiazide in people with Hypertension and Pharmacogenetics, run by Helsinki University Central Hospital at 1 site in Finland.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Sep 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Finland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Blood pressure (time frame: 4 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03276598, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Sep 2017.