Clinical trial NCT00441350: Olmesartan/HCTZ 40/12.5 mg Combination Therapy Versus Olmesartan Medoxomil 40 mg Monotherapy in Essential Hypertension
Official title: Phase III Study Evaluating the Efficacy and Safety of Olmesartan Medoxomil/Hydrochlorothiazide 40/12.5 mg Combination Therapy Versus Olmesartan Medoxomil 40 mg Monotherapy in Patients With Essential Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypertension
Lead sponsor: Menarini Group
Sponsor class: INDUSTRY
Collaborators: name: Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company
First posted: 2007-02-28
Enrollment: 1004
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of this study was to assess the anti-hypertensive effect of OM/HCTZ 40/12.5 mg combination therapy compared to OM 40 mg monotherapy in lowering sitting diastolic BP in hypertensive patients after 8 weeks of double-blind treatment.

The study consisted of two sequential phases of 8 weeks duration each:

During the first phase, OM 40 mg monotherapy was compared with OM/HCTZ 40/12.5 mg in order to evaluate the additional benefit of OM/HCTZ 40/12.5 mg in the treatment of essential moderate to severe hypertension.

During the second phase, patients whose BP proved to be insufficiently controlled by the OM 40 mg monotherapy were to start OM/HCTZ 40/12.5 mg combination therapy while patients whose BP proved to be insufficiently controlled by the OM/HCTZ 40/12.5 mg combination were to be up-titrated to the OM/HCTZ 40/25 mg combination to evaluate the additional benefit of the up-titrated combination.

The study was be conducted by qualified and experienced personnel with adherence to GCP, current guidelines on the design of studies in hypertension, the applicable regulatory requirements and the ethical principles based on the Declaration of Helsinki.

Detailed description: Methodology:

After the signature of the informed consent, patients were screened for eligibility and eligible patients entered into a pre-randomisation period consisting of a taper-off phase of approximately 1-2 weeks (during which patients treated for hypertension were to discontinue their antihypertensive therapy) followed by a 2-week single-blind placebo run-in phase (Visit 1). After conclusion of the placebo run-in phase (Visit 2), eligible patients were randomised to the double-blind active treatment period which consisted of two phases:

First double-blind treatment phase (Phase A, from Randomisation to Week 8):

Eligible patients with mean sitting sBP ≥ 160 and ≤ 200 mmHg and dBP ≥ 100 mmHg and ≤ 120 mmHg were randomised in a 1:2 ratio to receive either OM 40 mg or OM/HCTZ 40/12.5 mg for a total of 8 weeks of treatment (Phase A). Study visits were held after 4 and 8 weeks of double-blind active treatment (Visit 3 and 4, respectively). After 8 weeks (Visit 4), patients reaching the BP goal of \< 140/90 mmHg or \< 130/80 mmHg for diabetics were considered as responders. All patients (responders and non-responders) then entered into the titration phase of the study (Phase B):

Second double-blind treatment phase/titration phase (Phase B, from Week 8 to Week 16):

Treatment assignment in the second part of the study was based on the following criteria:

* Responders to Phase A treatment continued to receive the same double-blind treatment for an additional 8 weeks.
* Non-responders Phase A treatment had their treatment assigned as follows:

  * Non-responders to OM 40 mg were treated with OM/HCTZ 40/12.5 mg for an additional 8 weeks.
  * Non-responders to OM/HCTZ 40/12.5 mg were uptitrated to OM/HCTZ 40/25 mg for an additional 8 weeks. During Phase B of the study, visits were held 12 and 16 weeks after randomisation (Visits 5 and 6, respectively).

The study ended at Visit 6 and a final examination was performed. A safety follow-up (SFU) telephone contact was performed 2 weeks after the end of the treatment. An SFU visit was performed if deemed necessary by the investigator.

Sphygmomanometer was used for BP measurement throughout the trial. BP was measured at all visits as nearly as possible at the same time of the day as trough readings (24 ± 2 h after last drug intake) after a 10 minute rest period. Three separate sitting BP measurements were taken at least 1 minute apart from each other. The 3 results were then averaged and rounded to a whole integer.

Patients with sBP values \> 200 mmHg and/or dBP values \> 120 mmHg at any time during the study were to be discontinued from the study.

Eligibility criteria: Inclusion Criteria:

* Patients with a diagnosis of essential hypertension, either treatment-naive or including currently on anti-hypertensive medication (in Italy only treatment naive patients) in whom it is medically justifiable to withdraw treatment , and who are likely to meet the required BP inclusion criteria at randomisation:

  * Mean sitting dBP ≥ 100 mmHg and ≤ 120 mmHg.
  * Mean sitting sBP ≥ 160 mmHg and ≤ 200 mmHg.

Main Exclusion Criteria:

* Mean sitting sBP values \> 200 mmHg and/or dBP \> 120 mmHg.
* Pregnant or nursing women.
* Patients with serious disorders which may limit the ability to evaluate the efficacy or safety of the tested medication, including cerebrovascular, cardiovascular, renal, respiratory, hepatic, gastrointestinal, endocrine or metabolic, haematological, oncological, neurological, and psychiatric diseases. The same applies for immunocompromised and/or neutropenic patients.
* Patients with secondary hypertension of any aetiology such as renal disease, pheochromocytoma, or Cushing's syndrome.

Primary outcomes:
measure: dBP Change After 8 Weeks Phase A
timeFrame: Eight weeks
measure: sBP Change After 8 Weeks Phase A
timeFrame: Eight weeks
Secondary outcomes:
measure: dBP Change After 8 Weeks Phase B
timeFrame: Eight weeks
measure: sBP Change After 8 Weeks Phase B
timeFrame: Eight weeks
Other outcomes:
Locations:
city: Rijeka
country: Croatia
city: Slavonski Brod
country: Croatia
city: Split
country: Croatia
city: Varaždin
country: Croatia
city: Zadar
country: Croatia
city: Zagreb
country: Croatia
city: Benatky nad Jizerou
country: Czechia
city: Bilovec
country: Czechia
city: Brodce
country: Czechia
city: Jablonec nad Nisou
country: Czechia
city: Mlada Boleslav
country: Czechia
city: Praha
country: Czechia
city: Rokycany
country: Czechia
city: Tabor
country: Czechia
city: Teplice
country: Czechia
city: Unicov
country: Czechia
city: Aalborg
country: Denmark
city: Ballerup
country: Denmark
city: Vejle
country: Denmark
city: Berlin
country: Germany
city: Dresden
country: Germany
city: Einbeck
country: Germany
city: Essen
country: Germany
city: Giengen an der Brenz
country: Germany
city: Großheirath
country: Germany
city: Hamburg
country: Germany
city: Hanau
country: Germany
city: Heidelberg
country: Germany
city: Köln
country: Germany
city: Künzing
country: Germany
city: Leipzig
country: Germany
city: Lollar
country: Germany
city: Mannheim
country: Germany
city: München
country: Germany
city: Nürnberg
country: Germany
city: Ashkelon
country: Israel
city: Beer Sheva
country: Israel
city: Haifa
country: Israel
city: Jerusalem
country: Israel
city: Kfar Saba
country: Israel
city: Nahariya
country: Israel
city: Petach Tikva
country: Israel
city: Tel-Aviv
country: Israel
city: Tel-Hashomer
country: Israel
city: Busto Arsizio
country: Italy
city: Ferrara
country: Italy
city: Pavia
country: Italy
city: Pisa
country: Italy
city: San Daniele del Friuli
country: Italy
city: Sassari
country: Italy
city: Somma Lombardo
country: Italy
city: Venezia
country: Italy
city: Białystok
country: Poland
city: Gdańsk
country: Poland
city: Gdynia
country: Poland
city: Lublin
country: Poland
city: Płock
country: Poland
city: Warszawa
country: Poland
city: Wąbrzeżno
country: Poland
city: Baia-Mare
country: Romania
city: Braila
country: Romania
city: Bucharest
country: Romania
city: Cluj
country: Romania
city: Oradea
country: Romania
city: Suceava
country: Romania
Study officials:
affiliation: Medical Clinic Policlinico San Matteo University of Pavia Italy
name: Roberto Fogari, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Fogari R, Taddei S, Holm-Bentzen M, Baszak J, Melani L, Schumacher K. Efficacy and safety of olmesartan medoxomil 40 mg/hydrochlorothiazide 12.5 mg combination therapy versus olmesartan medoxomil 40 mg monotherapy in patients with moderate to severe hypertension: a randomized, double-blind, parallel-group, multicentre, multinational, phase III study. Clin Drug Investig. 2010;30(9):581-97. doi: 10.2165/11536710-000000000-00000.