Evaluating the Effect of Candesartan vs Placebo in Prevention of Trastuzumab-associated Cardiotoxicity
NCT ID: NCT00459771
Last Updated: 2014-12-02
Study Results
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Basic Information
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COMPLETED
PHASE3
210 participants
INTERVENTIONAL
2007-06-30
2014-12-31
Brief Summary
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Detailed Description
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Primary objectives:
\- to determine whether concurrent ATII-antagonist treatment can prevent trastuzumab-related cardiotoxicity, defined as a decline in LVEF of more than 15% or a decrease to an absolute value \<45%
Secondary objectives:
* To determine if 'Brain Natriuretic Peptide' (NT-proBNP) and troponin T can be used as surrogate marker in the monitoring of trastuzumab-associated cardiotoxicity
* To determine genetic variability in relevant genes such as the HER2 gene (by assessing single nucleotide polymorphisms \[SNPs\] in the kinase domain) and explore any correlations with trastuzumab induced cardiotoxicity 3) To determine the reversibility of a decrease in left ventricular ejection fraction (LVEF) associated with trastuzumab treatment
Arm I : placebo Arm II : AT1 blocker candesartan (32 mg/day; run in 16 mg during week 1)
Randomization: before chemotherapy treatment period. Study period: chemotherapy period, trastuzumab treatment period 26 weeks follow up after discontinuation of trastuzumab treatment and thereafter 1 month follow-up after end of placebo or AT1 blocker.
Candesartan treatment will start the same day as the first infusion of trastuzumab and will continue up to 26 weeks after the end of treatment with trastuzumab.
Women with primary HER2 positive breast cancer who are considered for adjuvant systemic treatment with anthracycline containing chemotherapy and trastuzumab.
Before start of anthracycline treatment:
* Medical history, physical examination
* New York Heart Association (NYHA) score
* Cardiac questionnaire
* Electrocardiogram
* MUGA scan
* Laboratory assessments; hemoglobin, hematocrit, white blood cell count, platelet count, serum creatinine, sodium, potassium, calcium, thyroid stimulating hormone, glucose, cholesterol, bilirubin, alkaline phosphatase, ASAT/ALAT, LDH, albumin, NT-proBNP, troponin T analysis
* Pregnancy test
* Genotype analysis
Every chemotherapy cycle
\- Laboratory assessments; hemoglobin, hematocrit, white blood cell count, platelet count, serum creatinine, sodium, potassium, calcium, glucose, bilirubin, alkaline phosphatase, ASAT/ALAT, LDH, albumin, (NT-proBNP, troponin T analysis)
Before start of trastuzumab treatment:
* Physical examination
* New York Heart Association (NYHA) score
* Cardiac questionnaire
* Electrocardiogram
* MUGA scan
* Laboratory assessments; hemoglobin, hematocrit, white blood cell count, platelet count, serum creatinine, sodium, potassium, calcium, glucose, bilirubin, alkaline phosphatase, ASAT/ALAT, LDH, albumin, NT-proBNP, troponin T analysis
After 3, 6 and 9 months trastuzumab:
* Physical examination
* New York Heart Association (NYHA) score
* Cardiac questionnaire
* MUGA scan
* Laboratory assessments; hemoglobin, hematocrit, white blood cell count, platelet count, serum creatinine, sodium, potassium, calcium, glucose, bilirubin, alkaline phosphatase, ASAT/ALAT, LDH, albumin, NT-proBNP, troponin T analysis
After 1 year trastuzumab, 26 weeks after the last trastuzumab administration:
* Physical examination
* New York Heart Association (NYHA) score
* Cardiac questionnaire
* Electrocardiogram
* MUGA scan
* Laboratory assessments; hemoglobin, hematocrit, white blood cell count, platelet count, serum creatinine, sodium, potassium, calcium, glucose, bilirubin, alkaline phosphatase, ASAT/ALAT, LDH, albumin, NT-proBNP, troponin T analysis
The primary endpoint of the study is the deterioration of the cardiac function defined as a decline in LVEF of 15% or more to an absolute value below 45% during the year with trastuzumab.
From previous studies it is estimated that about 30% of the patients treated with trastuzumab will show deterioration of LVEF.
A total of 200 patients will receive trastuzumab and candesartan or trastuzumab and placebo in this double blind placebo-controlled study. The number of patients randomized (= before chemotherapy period) for this trial shall be more than 200 as a small number of patients might drop out before start of therapy with trastuzumab. This number cannot exactly be determined beforehand.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Placebo
Placebo
Placebo
Placebo, 32 mg, oral QD
Candesartan
Candasartan
AT1 blocker candesartan
AT1 blocker candesartan, 32 mg oral QD
Interventions
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AT1 blocker candesartan
AT1 blocker candesartan, 32 mg oral QD
Placebo
Placebo, 32 mg, oral QD
Eligibility Criteria
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Inclusion Criteria
* WHO: ≤ 2
* Strongly HER2-positive breast cancer, defined as an immunohistochemistry score of 3+ using the HercepTestTM, or gene amplification by fluorescence in situ hybridization, or chromogenic in situ hybridization (CISH).
* Serum creatinine \<140 umol/l or creatinine clearance \> 50 ml/min (by Cockcroft-Gault formula)
* Thyroid stimulating hormone between 0.5-3.9 MU/l
* Blood pressure systolic ≥ 140 mmHg and diastolic ≥ 90 mmHg is acceptable at randomization. However prior to the first administration of trastuzumab blood pressure should be regulated and should be systolic ≥ 100 mmHg and ≤ 180 mmHg and diastolic ≥ 60 mmHg and ≤ 100 mmHg. (blood pressure should be regulated according to the guidelines of appendix 5)
* LVEF ³ 50% assessed by multigated angiography (MUGA) or cardiac ultrasound
* Adjuvant regimen: trastuzumab start ≥ 3 weeks after day 1 of the last anthracycline chemotherapy cycle
* Trastuzumab treatment according to standard medical care
* Written informed consent to participate in the study
Exclusion Criteria
* Previous malignancy requiring chemotherapy or radiotherapy
* Uncontrolled serious concurrent illness
* Patients with New York Heart Association (NYHA) class II/III/IV congestive heart failure
* Myocardial infarction \< 6 months before randomization
* Treatment with ACE inhibitor, ATII blocker, or lithium. Patients treated with ACE inhibitor, or ATII blocker can switch (after randomization and during the chemotherapy period) to alternative antihypertensive therapy; see appendix 5.
* History of hypersensitivity to the study medication
* Pregnancy or breast feeding
18 Years
79 Years
FEMALE
No
Sponsors
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AstraZeneca
INDUSTRY
Roche Pharma AG
INDUSTRY
The Netherlands Cancer Institute
OTHER
Responsible Party
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Principal Investigators
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J.H.M. Schellens, MD PhD
Role: PRINCIPAL_INVESTIGATOR
The Netherlands Cancer Institute
Locations
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Jeroen Bosch Hospital
's-Hertogenbosch, , Netherlands
Medisch Centrum Alkmaar
Alkmaar, , Netherlands
Flevoziekenhuis
Almere Stad, , Netherlands
The Netherlands Cancer Institute
Amsterdam, , Netherlands
Onze Lieve Vrouwe Gasthuis
Amsterdam, , Netherlands
Slotervaart Hospital
Amsterdam, , Netherlands
Wilhelmina Ziekenhuis
Assen, , Netherlands
Deventer Ziekenhuis
Deventer, , Netherlands
Medisch Spectrum Twente
Enschede, , Netherlands
Martini Ziekenhuis
Groningen, , Netherlands
University Medical Center Groningen
Groningen, , Netherlands
Ziekenhuis de Tjongerschans
Heerenveen, , Netherlands
Medisch Centrum Leeuwarden
Leeuwarden, , Netherlands
Antonius Ziekenhuis
Nieuwegein, , Netherlands
Canisius-Wilhelmina Hospital
Nijmegen, , Netherlands
UMC St. Radboud
Nijmegen, , Netherlands
VieCuri Medisch Centrum voor Noord-Limburg
Venlo, , Netherlands
Streekziekenhuis Koningin Beatrix
Winterswijk, , Netherlands
Isala Klinieken
Zwolle, , Netherlands
Countries
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References
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Boekhout AH, Gietema JA, Milojkovic Kerklaan B, van Werkhoven ED, Altena R, Honkoop A, Los M, Smit WM, Nieboer P, Smorenburg CH, Mandigers CM, van der Wouw AJ, Kessels L, van der Velden AW, Ottevanger PB, Smilde T, de Boer J, van Veldhuisen DJ, Kema IP, de Vries EG, Schellens JH. Angiotensin II-Receptor Inhibition With Candesartan to Prevent Trastuzumab-Related Cardiotoxic Effects in Patients With Early Breast Cancer: A Randomized Clinical Trial. JAMA Oncol. 2016 Aug 1;2(8):1030-7. doi: 10.1001/jamaoncol.2016.1726.
Other Identifiers
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2006-001707-11
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
M06HER
Identifier Type: -
Identifier Source: org_study_id