Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT03850171 |
| Other study ID # |
CAPRICE |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
May 1, 2019 |
| Est. completion date |
January 31, 2023 |
Study information
| Verified date |
February 2023 |
| Source |
University Hospital Inselspital, Berne |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Breast cancer is the most common cancer among women worldwide. Similarly, Hodgkin and non-
Hodgkin lymphomas make up two of the most prevalent cancers in men and women. Even though
remarkable improvements in cancer-free survival have been achieved in the last decades, the
development of cardiac toxicity, associated with anthracycline-based chemotherapy (Anth-bC)
counteracts the improvements in survival in these patient groups. One of the first clinical
manifestation of Anth-bC cardiotoxicity is diastolic dysfunction, with further symptoms being
left ventricular dysfunction and heart failure as well as a decline in exercise tolerance.
Besides the direct cardiotoxic effects of anticancer treatment, many drugs also have adverse
effects on the vascular endothelium.
The concept of 'Exercise is Medicine' has become well established in exercise-oncology
research. Exercise therapy is now considered a safe and well-tolerated adjunct therapy
inducing beneficial effects on body composition, aerobic fitness and muscular strength, pain
and fatigue, quality of life (QoL), depressive symptoms, and all cause survival. However,
there is insufficient data on the superiority of performing exercise training therapy before
and during chemotherapy with regard to cardiotoxic and cardiovascular side effects. Further,
there is no data on patient preference for and barriers toward different timings of exercise
training therapy.
Therefore, the aim of the study is to compare left ventricular (LV) function measured by LV
global longitudinal strain (GLS) in breast cancer and lymphoma patients undergoing Anth-bC
randomised to completing an exercise-based rehabilitation programme during chemotherapy to
those randomised to complete the programme after chemotherapy. Further, blood samples will be
drawn to analyse biomarkers of myocardial injury (brain natriuretic peptide and
high-sensitive cardiac troponin).
Additional measurements include aortic distensibility as part of the echocardiographic
examination and exercise capacity through cardiopulmonary exercise testing. QoL and fatigue
will be assessed in a questionnaire, compliance with exercise training through monitoring and
patient preference at 3 and 6 months will be evaluated through an interview. Cardiovascular
risk factors will be assessed through body composition, 24h ambulatory blood pressure
monitoring, 24h electrocardiogram and the analysis of established blood markers.
Women and men aged 18 years and older with histologically confirmed breast cancer or lymphoma
(ECOG grade 0-2) who are Anth-bC naïve and with reasonable life expectancy will be included
in the study.
The exercise programme is part of onco-rehabilitation programmes at the Inselspital Bern, the
Spital AG Thun and the Bürgerspital Solothurn. Programmes last for 12 weeks and offer two
supervised sessions per week (@ 60-90 min). They usually contain an endurance component (e.g.
40 min of cycling) and a strength, agility or relaxation component. Patients are encouraged
to complete a third exercise session per week at home or elsewhere. Home-based training and
general physical activity will be assessed by a questionnaire and an activity monitor.
A total of 120 patients will be recruited. Measurements will be performed at baseline, after
3 months (week 13) and after 6 months (week 26).
Description:
Study Design: A single-center, two-arm, parallel group with standard of care controlled trial
with a balanced 1:1 randomization will be conducted at University Hospital Inselspital,
Berne, Switzerland. A total of 120 women (60 participants per study arm) who are scheduled
for first- line Anthracycline based chemotherapy (Anth-bc) presenting either at the
Inselspital or Lindenhofspital Berne, the Spital AG Thun or the Bürgerspital Solothurn will
be enrolled. After baseline assessments, eligible participants will be randomized to one of
two arms including the exercise rehabilitation programme during chemotherapy or the control
group (exercise training intervention after conclusion of chemotherapy).
Patient Population: Women and men aged 18 years and older with histologically confirmed
breast cancer or lymphoma who are Anth-bC naïve and are scheduled for first-line Anth-bC,
Eastern Cooperative Oncology Group (ECOG) grade 0-2, curative or palliative approach with
reasonable life expectancy and a willingness to attend exercise sessions twice per week for
12 weeks (24 sessions in total).
Procedures: The following measurements will be collected at the beginning (T0), following the
12 week intervention (T1) and after another 12 weeks (T2). Participants will also be expected
to attend two weekly supervised exercise sessions integrated in a multidisciplinary oncology
rehabilitation programme at the Inselspital Bern, Spital AG Thun, and Bürgerspital Solothurn,
and will be expected to complete one additional exercise training session at home or in the
community each week.
T0: All participants will undergo baseline assessments at the University Hospital
Inselspital, Berne. This includes cardiac assessment by a skilled clinical cardiac
sonographer to obtain left ventricular (LV) global longitudinal strain (GLS) and aortic
distensibility. Further, cardiopulmonary exercise testing (CPET) will be completed on a cycle
ergometer to obtain VO2peak and to calculate corresponding training zones. Standard measures
conducted during the intake process including height, weight, body composition (assessed by
bio-impedance- measurement) and waist circumference will also be collected. Blood samples
will be obtained from each participant and analyzed for biomarkers of myocardial injury as
well as lipid profile and HbA1C. Following each visit, twenty-four-hour ambulatory blood
pressure monitoring and 24h Holter ECG will be performed. The questionnaires for physical
activity patterns (GPAQ) and fatigue (FACIT-F), a health history questionnaire and the
activity tracking devices will also be administered by the research coordinator upon their
initial visit.
T1: All measurements from T0 will be repeated. Additionally, patients from the ExEarly
(experimental) group will be interviewed by the study coordinator to assess barriers for
missed exercise sessions. Simultaneously, patients from the ExStandard group will be asked to
anticipate barriers which may impede their participation in regular exercise training during
the next 12 weeks. It will further be assessed whether it would have been feasible for them
to complete the exercise programme concurrently to chemotherapy.
T2: All measurements from T0 will be repeated. Additionally, patients from the ExStandard
(active comparator) group will be interviewed by the study coordinator to assess barriers for
missed exercise sessions. Simultaneously, patients from the ExEarly group will be asked to
indicate their preferred time point for the completion of the exercise programme.
Throughout the programme: Information regarding adherence to the exercise programme will also
be collected by the research coordinator each month via the exercise training diaries and
activity tracking devices from each participant. The study coordinator will also assess
reasons for missed exercise sessions. Lastly, chemotherapy adherence will be assessed by dose
adjustments in percent of the intended dose and reason for adjustment.
Intervention (ExEarly): The 12-week exercise training programme will be integrated in a
multidisciplinary oncology rehabilitation programme at the Inselspital Bern, Spital AG Thun,
and Bürgerspital Solothurn. The exercise programme will comprise 2 weekly exercise sessions
lasting 90 min, supervised by experienced exercise therapists. The sessions start with
approximately 40 min cycling on an ergometer at moderate intensity, increasing on a weekly
basis if possible. After the cycling training, patients continue the exercise session with 40
min of strength training, stretching, relaxation, coordination and balance training. In
addition, patients will be instructed to perform at least one additional endurance-related
activity per week in their own time with a duration of 30-60 min at moderate intensity levels
(e.g. walking, bicycling). In the ExEarly group, patients start in the week preceding the
first dose of Anth-bC. They perform exercise training therapy for 12 weeks during which they
will normally have 4 cycles of Anth-bC.
Control Group (ExStandard): Participants who are randomized to the control group will undergo
baseline and follow up assessments at 13 and 26 weeks. They will be encouraged to continue
with their regular physical activity routine and will be medically managed as per standard of
care by their Cardiologist and Oncologists. All participants will also complete the GPAQ
Questionnaire to determine if there are potential increases in physical activity in the
exercise and control group, which may account for changes in all outcome measures. 1-4 weeks
after completion of their last dose of Anth-bc the participants will commence exercise
training. All participants in both groups will also be asked to wear an activity-tracking
device, namely a step counter (Fitbit Zip) during the intervention and control period (25
weeks) to objectively quantify their daily physical activity.
Randomization: Randomization will occur at the central site, the University Hospital,
Inselspital Berne, using minimisation based on strata recruiting center, age, therapy
(adjuvant/ neoadjuvant), Global Longitudinal Strain (GLS), HER2 status and metastases, with
an allocation ratio of 1:1.
Blinding: The participants will not be blinded to their intervention arm. Assessors of
outcome data and analysis will be blinded to the study arm.
Analytical Plan: The primary outcome, change in global longitudinal strain (GLS) from before
Anth-bC to immediately after Anth-bC (T1 vs T0), will be compared between the two groups
(ExEarly and ExStandard) by independent one-sided t-test (or Wilcoxon two-sample test as
appropriate) with alpha set at 0.05. Values from baseline (before Anth-bC, T0), completion of
Anth-bC (week 13, T1), and follow-up (T2) will be compared between groups using ANCOVA with
repeated measures (or mixed models in case of missing data) including baseline values as
covariate and post-hoc testing for different time points. Intention-to-treat (ITT) analysis
will be performed with group allocation according to randomization to assess the
effectiveness of ExEarly in the clinical setting. Per-protocol analysis will be performed
with patients allocated with regard to time period they completed more supervised sessions
in, with a minimum requirement of 15 of the 24 (60%) scheduled training sessions within one
or the other time period to assess the potential effects of an optimal training. Linear
models will be performed to find independent baseline parameters to predict negative outcome
of cardiac function (LV GLS, NT-proBNP, hsTnT). Secondary endpoints will be analysed
accordingly. Statistical analyses will be performed using the software R (Version 3.3.1, R
Core Team, 2016).
Significance: Outcomes from this project will improve long term care of patients with early
breast cancer and lymphoma as well as other cancers, such that patients can be offered the
possibility of active involvement towards mitigating undesirable side effects of a very
effective cancer treatment. The assessment of barriers to training therapy may help to adapt
the offered physical training programmes to reduce these barriers.
