Clinical trial NCT01303783: Study of Nifedipine GITS and Candesartan Combination Compared to Monotherapy in Patients With Essential Hypertension
Official title: A Multicenter, Multifactorial, Randomized, Double-Blind, Placebo-Controlled Dose-Finding Study of Nifedipine GITS and Candesartan in Combination Compared to Monotherapy in Adult Patients With Essential Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hypertension, Essential
Keywords: Nifedipine GITS
Candesartan
mild to moderate Hypertension
Combination therapy
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2011-02-25
Enrollment: 1381
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 purpose of this study is to determine the blood pressure lowering responses of various dose combinations of nifedipine GITS and candesartan as compared to treatment with each component on their own (monotherapy) and placebo (a look-alike tablet without active ingredient). The drugs - nifedipine GITS and candesartan - which are being investigated are currently approved for use in patients with essential hypertension alone or together with other antihypertensive drugs (combination therapy), but the optimal dose of nifedipine GITS and candesartan used together in the treatment of essential hypertension has not been established yet. In this study patients will be treated with various doses of nifedipine GITS and/or candesartan or placebo. These different regimens will be administered once a day and will be assessed based on their blood pressure lowering effects (mean sitting diastolic blood pressure) in subjects with mild to moderate essential hypertension.


Eligibility criteria: Inclusion Criteria:

* Male and female subjects 18 years or older. Female subjects must be either post-menopausal for one year, surgically sterile, or using an effective contraceptive method. Hormonal contraceptive use is disallowed.
* Subjects must have mild to moderate essential hypertension (Grade 1 and 2 WHO classifications) as measured by calibrated standard sphygmomanometer. (MSDBP of ≥90 mmHg and \< 110 mmHg at Visit 1 (placebo run-in), and MSDBP of ≥95 mmHg and \< 110 mmHg at visit 2 (randomization)
* Subjects must have an absolute difference in their MSDBP of less than 10 mmHg between Visit 1 (placebo run- in) and Visit 2 (randomization).

Exclusion Criteria:

* Severe hypertension (Grade 3 WHO classification; MSDBP ≥110 mmHg and/or MSSBP ≥ 180 mmHg)
* Inability to washout of antihypertensive drugs (even if prescribed for another indication) safely for a period of 14 weeks.
* History of hypertensive retinopathy - known Keith-Wagener Grade III or IV
* History of hypertensive encephalopathy
* Cerebrovascular ischemic event (stroke, transient ischemic attack \[TIA\])within the previous 12 months
* History of intracerebral hemorrhage or subarachnoid hemorrhage
* Evidence of secondary hypertension such as coarchation of the aorta, pheochromocytoms, hypersaldosteronism, etc.
* Type I diabetes mellitus (DM) or poorly controlled DM Type II as evidenced by a glycosylated hemoglobin \[HbA1C\] of greater than 9% on visit 1.
* Allergies or known intolerance to one of the investigational drugs/drug class or to one of their ingredients
* Any history of heart failure, New York Heart Association (NYHA) classification III or IV
* Severe coronary heart disease as manifest by a history of myocardial infarction or unstable angina in the last 6 months prior to visit 1.
* Clinically significant cardiac valvular disease
* History of malignancy in the last 5 years, excluding basal or skin cancer
* Uncorrected hypokalemia or hyperkalemia: potassium outside 3.0-5.0 mmol/L
* Surgical or medical conditions that might alter the metabolism, excretion or distribution or absorption of any drug

  1. Gastrointestinal disease or surgery resulting in the potential for malabsorption
  2. Severe gastrointestinal tract narrowing; kock pouch (ileostomy after proctocolectomy)
  3. Cholestasis or biliary obstruction or history of pancreatic injury or clinical significant increase of lipase, amylase, or bilirubin.
  4. Liver disease or AST/ALT levels \>3 x ULN
  5. Renal insufficiency, defined as eGFR of \< 50 mL/min (computed using the Cockroft-Gault formula), or on hemodialysis
* Investigation trial participation with receipt of investigational study drug within the last month
* Previous assignment to treatment in this study
* Female subjects who are pregnant or lactating.
* Subjects who have night employment (night shift).
* Subjects with an aortic aneurysm that, in the opinion of the investigator, will be unsuitable to be enrolled in the study.
* Thought by the investigator for any reason to be unsuitable for participation in a clinical study
* Systemic use of known cytochrome P450-3A4 inhibitors (e.g cimetidine, anti-human immunodeficiency virus \[HIV\] protease inhibitors e.g. ritonavir, azole anti-mycotics eg. ketoconazole,) or inducers (e.g rifampicin, anti-epileptic drugs eg. phenytoin, carbamazepine and phenobarbitone) or some P450-3A4 substrates (e.g quinidine, digoxin, tacrolimus)
* Present severe rhythm or conduction disorder:
* Atrial fibrillation
* Second or third degree heart block without a pacemaker.
* Baseline QTc \>450 msec
* History of non-compliance, alcoholism or drug abuse that in the opinion of the investigator will compromise successful completion of the study.
* If differences greater than 20 mmHg for SBP and 10 mmHg for DBP are present on 3 consecutive BP readings, the subject should be excluded from the study.

Primary outcomes:
measure: The primary efficacy variable is the change from baseline in mean seated diastolic blood pressure (MSDBP) at Week 8
timeFrame: Baseline taken at Visit 1; primary outcome variable assesed at 8 weeks
Secondary outcomes:
measure: Change in mean seated systolic blood pressure (MSSBP) at Week 8
timeFrame: 8 weeks
measure: Control rate at Week 8
timeFrame: 8 weeks
measure: Response rate at Week 8
timeFrame: 8 weeks
measure: Peripheral Edema
timeFrame: 8 weeks
measure: Time to achieve first BP control
timeFrame: 8 weeks
Other outcomes:
Locations:
city: Mobile
country: United States
state: Alabama
city: Los Angeles
country: United States
state: California
city: Coral Gables
country: United States
state: Florida
city: Deerfield Beach
country: United States
state: Florida
city: Deerfield Beach
country: United States
state: Florida
city: Ft. Lauderdale
country: United States
state: Florida
city: Jacksonville
country: United States
state: Florida
city: West Palm Beach
country: United States
state: Florida
city: Atlanta
country: United States
state: Georgia
city: Valparaiso
country: United States
state: Indiana
city: Charlotte
country: United States
state: North Carolina
city: Harrisburg
country: United States
state: North Carolina
city: Raleigh
country: United States
state: North Carolina
city: Salisbury
country: United States
state: North Carolina
city: Cincinnati
country: United States
state: Ohio
city: Philadelphia
country: United States
state: Pennsylvania
city: Greenville
country: United States
state: South Carolina
city: Mt. Pleasant
country: United States
state: South Carolina
city: Dallas
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Salt Lake City
country: United States
state: Utah
city: Salt Lake City
country: United States
state: Utah
city: Kenosha
country: United States
state: Wisconsin
city: Bahía Blanca
country: Argentina
state: Buenos Aires
city: Quilmes
country: Argentina
state: Buenos Aires
city: Zárate
country: Argentina
state: Buenos Aires
city: Buenos Aires
country: Argentina
state: Ciudad Auton. de Buenos Aires
city: Buenos Aires
country: Argentina
state: Ciudad Auton. de Buenos Aires
city: Buenos Aires
country: Argentina
state: Ciudad Auton. de Buenos Aires
city: Buenos Aires
country: Argentina
state: Ciudad Auton. de Buenos Aires
city: Buenos Aires
country: Argentina
state: Ciudad Auton. de Buenos Aires
city: Buenos Aires
country: Argentina
state: Ciudad Auton. de Buenos Aires
city: Rosario
country: Argentina
state: Santa Fe
city: Corrientes
country: Argentina
city: Córdoba
country: Argentina
city: Córdoba
country: Argentina
city: Santa Fe
country: Argentina
city: Wetteren
country: Belgium
state: Oost-Vlaanderen
city: De Pinte
country: Belgium
city: Deurne
country: Belgium
city: HAM
country: Belgium
city: Fortaleza
country: Brazil
state: Ceará
city: Brasília
country: Brazil
state: Distrito Federal
city: Goiania
country: Brazil
state: Goiás
city: Campinas
country: Brazil
state: Sao Paulo
city: Campinas
country: Brazil
state: Sao Paulo
city: São Paulo
country: Brazil
state: Sao Paulo
city: Rio de Janeiro
country: Brazil
city: Sao Paulo
country: Brazil
city: Langley
country: Canada
state: British Columbia
city: St. John's
country: Canada
state: Newfoundland and Labrador
city: St. John's
country: Canada
state: Newfoundland and Labrador
city: Brampton
country: Canada
state: Ontario
city: Corunna
country: Canada
state: Ontario
city: Downsview
country: Canada
state: Ontario
city: Etobicoke
country: Canada
state: Ontario
city: London
country: Canada
state: Ontario
city: London
country: Canada
state: Ontario
city: Newmarket
country: Canada
state: Ontario
city: Sarnia
country: Canada
state: Ontario
city: Strathroy
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Montreal
country: Canada
state: Quebec
city: Chieti
country: Italy
state: Abruzzo
city: Bologna
country: Italy
state: Emilia-Romagna
city: Trieste
country: Italy
state: Friuli-Venezia Giulia
city: Milano
country: Italy
state: Lombardia
city: Pavia
country: Italy
state: Lombardia
city: Sassari
country: Italy
state: Sardegna
city: Pisa
country: Italy
state: Toscana
city: Perugia
country: Italy
state: Umbria
city: Mercato San Severino
country: Italy
city: Daejeon
country: Korea, Republic of
state: Daejeon Gwang''yeogsi
city: Wonju-si
country: Korea, Republic of
state: Gang''weondo
city: Anyang-si
country: Korea, Republic of
state: Gyeonggido
city: Goyang-Si
country: Korea, Republic of
state: Gyeonggido
city: Goyang-si
country: Korea, Republic of
state: Gyeonggido
city: Goyang-si
country: Korea, Republic of
state: Gyeonggido
city: Goyang-si
country: Korea, Republic of
state: Gyeonggido
city: Uijeongbu
country: Korea, Republic of
state: Gyeonggido
city: Seoul
country: Korea, Republic of
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
state: Seoul Teugbyeolsi
city: Busan
country: Korea, Republic of
city: Chungchungbuk-do
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Alytus
country: Lithuania
city: Kaunas
country: Lithuania
city: Kaunas
country: Lithuania
city: Vilnius
country: Lithuania
city: Moscow
country: Russian Federation
city: Moscow
country: Russian Federation
city: Moscow
country: Russian Federation
city: Moscow
country: Russian Federation
city: Moscow
country: Russian Federation
city: Smolensk
country: Russian Federation
city: St Petersburg
country: Russian Federation
city: St. Petersburg
country: Russian Federation
city: St. Petersburg
country: Russian Federation
city: St. Petersburg
country: Russian Federation
city: St. Petersburg
country: Russian Federation
city: St. Petersburg
country: Russian Federation
city: St. Petersburg
country: Russian Federation
city: St. Petersburg
country: Russian Federation
city: Port Elizabeth
country: South Africa
state: Eastern Cape
city: Johannesburg
country: South Africa
state: Gauteng
city: Petoria
country: South Africa
state: Gauteng
city: Roodepoort
country: South Africa
state: Gauteng
city: Durban
country: South Africa
state: KwaZulu Natal
city: Witbank
country: South Africa
state: Mpumalanga
city: Somerset West
country: South Africa
state: Western Cape
city: Stellenbosch
country: South Africa
state: Western Cape
city: Santiago de Compostela
country: Spain
state: A Coruña
city: Benidorm
country: Spain
state: Alicante
city: Petrer
country: Spain
state: Alicante
city: Oviedo
country: Spain
state: Asturias
city: Hostalets de Balenyà
country: Spain
state: Barcelona
city: Peralada
country: Spain
state: Girona
city: Barcelona
country: Spain
city: Granada
country: Spain
city: Huelva
country: Spain
city: Valencia
country: Spain
city: Dnipropetrovsk
country: Ukraine
city: Kharkiv
country: Ukraine
city: Kiev
country: Ukraine
city: Kiev
country: Ukraine
city: Kiev
country: Ukraine
city: Kiev
country: Ukraine
city: Kiev
country: Ukraine
city: Vinnitsa
country: Ukraine
city: Zaporizhzhya
country: Ukraine
city: Zhytomyr
country: Ukraine
city: Bath
country: United Kingdom
state: Avon
city: Fowey
country: United Kingdom
state: Cornwall
city: Penzance
country: United Kingdom
state: Cornwall
city: Penzance
country: United Kingdom
state: Cornwall
city: St Austell
country: United Kingdom
state: Cornwall
city: Chesterfield
country: United Kingdom
state: Derbyshire
city: Glasgow
country: United Kingdom
state: Glasgow City
city: Glasgow
country: United Kingdom
state: Glasgow City
city: Blackpool
country: United Kingdom
state: Lancashire
city: Bath
country: United Kingdom
state: Somerset
city: Addlestone
country: United Kingdom
state: Surrey
city: Coventry
country: United Kingdom
state: Warwickshire
city: Leamington Spa
country: United Kingdom
state: Warwickshire
city: Chippenham
country: United Kingdom
state: Wiltshire
city: Trowbridge
country: United Kingdom
state: Wiltshire
city: Westbury
country: United Kingdom
state: Wiltshire
city: Bath
country: United Kingdom
city: Bath
country: United Kingdom
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References:
citation: Kjeldsen SE, Cha G, Villa G, Mancia G; DISTINCT Investigators. Nifedipine GITS/Candesartan Combination Therapy Lowers Blood Pressure Across Different Baseline Systolic and Diastolic Blood Pressure Categories: DISTINCT Study Subanalyses. J Clin Pharmacol. 2016 Sep;56(9):1120-9. doi: 10.1002/jcph.712. Epub 2016 Mar 7.
citation: Kjeldsen SE, Sica D, Haller H, Cha G, Gil-Extremera B, Harvey P, Heyvaert F, Lewin AJ, Villa G, Mancia G; DISTINCT Investigators. Nifedipine plus candesartan combination increases blood pressure control regardless of race and improves the side effect profile: DISTINCT randomized trial results. J Hypertens. 2014 Dec;32(12):2488-98; discussion 2498. doi: 10.1097/HJH.0000000000000331.