Evaluating the Effect of Candesartan vs Placebo in Prevention of Trastuzumab-associated Cardiotoxicity
Condition: Breast Cancer
MeSH terms: Cardiotoxicity
Study type: Interventional
Phase: Phase 3

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.
    

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.
    

Intervention name(s): AT1 blocker candesartan; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): AT1 blocker candesartan, 32 mg oral QD; Placebo, 32 mg, oral QD
Intervention MeSH terms: Candesartan; Candesartan cilexetil
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: angiotensin II-receptor (AT1) blocker; prevention; trastuzumab; cardiotoxicity