Breast CancerPhase 3NCT00459771
Evaluating the Effect of Candesartan vs Placebo in Prevention of Trastuzumab-associated Cardiotoxicity
A Phase 3 study testing AT1 blocker candesartan in people with Breast Cancer, run by The Netherlands Cancer Institute at 19 sites in Netherlands.
Trial summary
Evaluating the effect of the angiotensin II-receptor (AT1) blocker candesartan vs placebo in prevention of trastuzumab-associated cardiotoxicity in patients with primary breast cancer treated with trastuzumab. Read more about this study
- Who is it for?
- Ages 18 to 79 years, women only
- Conditions the study is for
- Breast Cancer
- What is being tested?
- AT1 blocker candesartan
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 210 participants
- Where
- 19 sitesNetherlands
- Study dates
- Jun 2007to Dec 2014
- Phase
- Phase 3
- 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 18 to 79 years
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Women aged ≥18 years
- 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)
Show all 10Show fewer
- 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
Who cannot join
- Prior anthracycline chemotherapy regimen or anti-HER2 therapy, or other prior biologic or immunotherapy for breast cancer treatment or any malignancy
- 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
Trial locations and contacts
19 sites in 1 country.
19 sites in 1 country
Netherlands19 sites
Jeroen Bosch Hospital
's-Hertogenbosch
Medisch Centrum Alkmaar
Alkmaar
Flevoziekenhuis
Almere Stad
The Netherlands Cancer Institute
Amsterdam, 1066 CX
Onze Lieve Vrouwe Gasthuis
Amsterdam
Slotervaart Hospital
Amsterdam
Wilhelmina Ziekenhuis
Assen
Deventer Ziekenhuis
Deventer
Medisch Spectrum Twente
Enschede
Martini Ziekenhuis
Groningen
University Medical Center Groningen
Groningen
Ziekenhuis de Tjongerschans
Heerenveen
Medisch Centrum Leeuwarden
Leeuwarden
Antonius Ziekenhuis
Nieuwegein
Canisius-Wilhelmina Hospital
Nijmegen
UMC St. Radboud
Nijmegen
VieCuri Medisch Centrum voor Noord-Limburg
Venlo
Streekziekenhuis Koningin Beatrix
Winterswijk
Isala Klinieken
Zwolle
About this study
Official title: Prospective, Randomized, Pharmacological Intervention Study; Evaluating Effect of the Angiotensin II-receptor (AT1) Blocker Candesartan vs Placebo in Prevention of Trastuzumab-associated Cardiotoxicity in Patients Treated With Trastuzumab
Evaluating the effect of the angiotensin II-receptor (AT1) blocker candesartan vs placebo in prevention of trastuzumab-associated cardiotoxicity in patients with primary breast cancer treated with trastuzumab.
Read the detailed description
Prospective, randomized pharmacological intervention study
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
- Breast Cancer
- Being tested
- AT1 blocker candesartan, Placebo
- Keywords
- angiotensin II-receptor (AT1) blocker, prevention, trastuzumab, cardiotoxicity
- Medical subject headings
- Breast Neoplasms, Cardiotoxicity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AT1 blocker candesartanDrug
AT1 blocker candesartan, 32 mg oral QD
PlaceboDrug
Placebo, 32 mg, oral QD
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | Placebo Receives: Drug: Placebo |
| Candesartan | Active comparator | Candasartan Receives: Drug: AT1 blocker candesartan |
What is being measured
The primary outcome is the main question the study is designed to answer.
The occurrence of cardiotoxicity, defined as a decline in LVEF (MUGA) of more than 15% or a decrease of less than 15% to an absolute value below 45%.
Measured: during 1 year trastuzumab therapy and during 26 weeks after discontinuation of trastuzumab
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Apr 2007 (estimated)
- Study startJun 2007
- Primary completionDec 2013
- Study completionDec 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- More trials run by The Netherlands Cancer InstituteThe 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 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 210 participants (actual)
Sponsor and investigators
- Lead sponsor
- The Netherlands Cancer Institute
- Sponsor type
- University, hospital or other
- Collaborators
- AstraZeneca, Roche Pharma AG
- Responsible party
- Sponsor
- Investigators
- J.H.M. Schellens, MD PhD, Principal investigator, The Netherlands Cancer Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00459771
- Sponsor's protocol ID
- M06HER
- Other IDs
- 2006-001707-11
- Status last verified
- Dec 2014
- First submitted
- 11 Apr 2007
- Last updated
- 2 Dec 2014
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 27348762
Study at a glance
From the registry record, last updated by the sponsor on 2 Dec 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prospective, Randomized, Pharmacological Intervention Study; Evaluating Effect of the Angiotensin II-receptor (AT1) Blocker Candesartan vs Placebo in Prevention of Trastuzumab-associated Cardiotoxicity in Patients Treated With Trastuzumab
- ClinicalTrials.gov ID
- NCT00459771
- Acronym / sponsor ID
- M06HER
- Conditions
- Breast Cancer
- Keywords
- angiotensin II-receptor (AT1) blocker, prevention, trastuzumab, cardiotoxicity
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 210 participants (actual)
- Lead sponsor
- The Netherlands Cancer InstituteUniversity, hospital or other
- Collaborators
- AstraZeneca, Roche Pharma AG
- Study start
- Jun 2007
- Primary completion
- Dec 2013 (actual)
- Study completion
- Dec 2014 (actual)
- First posted
- 12 Apr 2007 (estimated)
- 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.
Evaluating the effect of the angiotensin II-receptor (AT1) blocker candesartan vs placebo in prevention of trastuzumab-associated cardiotoxicity in patients with primary breast cancer treated with trastuzumab.
Detailed description
Prospective, randomized pharmacological intervention study
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: PlaceboPlacebo |
| Candesartan | Active comparator | Drug: AT1 blocker candesartanCandasartan |
Who may qualify
- Ages
- 18 to 79 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Women aged ≥18 years
- 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
Key exclusion criteria (8 listed)
- Prior anthracycline chemotherapy regimen or anti-HER2 therapy, or other prior biologic or immunotherapy for breast cancer treatment or any malignancy
- 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
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 |
|---|---|---|
| AT1 blocker candesartanAT1 blocker candesartan, 32 mg oral QD | Drug | Candesartan |
| PlaceboPlacebo, 32 mg, oral QD | Drug | Placebo |
Primary outcome
The occurrence of cardiotoxicity, defined as a decline in LVEF (MUGA) of more than 15% or a decrease of less than 15% to an absolute value below 45%.
Time frame: during 1 year trastuzumab therapy and during 26 weeks after discontinuation of trastuzumab
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 2 Dec 2014.
- Derived from this study: PubMed 27348762Boekhout 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.
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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.
J.H.M. Schellens, MD PhD principal investigator
The Netherlands Cancer Institute
19 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing AT1 blocker candesartan in people with Breast Cancer, run by The Netherlands Cancer Institute at 19 sites in Netherlands.
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 10 inclusion and 8 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 2 Dec 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 19 sites in Netherlands. 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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
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?
The occurrence of cardiotoxicity, defined as a decline in LVEF (MUGA) of more than 15% or a decrease of less than 15% to an absolute value below 45%. (time frame: during 1 year trastuzumab therapy and during 26 weeks after discontinuation of trastuzumab). 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 NCT00459771, which also lists 1 linked publication.
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 2 Dec 2014.