Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03810755 |
| Other study ID # |
PI17/01172 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
January 10, 2018 |
| Est. completion date |
December 31, 2022 |
Study information
| Verified date |
February 2023 |
| Source |
Basque Health Service |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Clinical objectives: estimate the common effect of the EfiKroniK physical exercise program
for people with a set of Chronic diseases (solid cancers, hematological, schizophrenia and
COPD), expressed in terms of functional capacity, quality of life and others results,
regarding the standardized intervention of healthy habits 'Prescribe Healthy Living 'PVS.
Implementation objectives: describe the adherence, continuity, adequacy and usefulness of
EfiKroniK perceived by patients and professionals, with the purpose of designing
implementation strategies, which will be evaluated in future trials.
Design: clinical trial and implementation, pragmatic and randomized to two groups stratified
by pathology, followed for 12 m.
Participants: 370 patients diagnosed with solid cancers, hematological cancers, schizophrenia
and COPD, in the most advanced stages.
Scope: Hospital de Cruces, Basque Country University, Primary Care Research Unit of Bizkaia.
Intervention: personalized exercise program for patients, supervised during 3 months by
nursing in primary and autonomous care afterwards, with support from community resources.
Reference group: PVS program, of proven effectiveness for the promotion of physical activity,
diet and smoking cessation.
Measurements: main measure of results: functional capacity at 3 months (6-minute test and
submaximal running / running tests at foot to determine the speed of lactate thresholds) and
quality of life at 6 and 12 months (SF-36 and specific questionnaires by pathology).
Secondary variable results: physical and psychic symptomatology, biological markers, physical
form and survival.
Analysis: The common effect of the exercise will be estimated by comparing both groups by
intention to treat, by means of analysis of the covariance of mixed effects for the changes
observed at 3, 6 and 12 months adjusted for the baseline and possible confounders.
Previously, a possible interaction effect between the pathology group and the effect of the
intervention will be ruled out. The cost-effectiveness and cost-utility reasons.
Description:
Study design:
This will be a multicentre pragmatic open-label type I hybrid implementation-effectiveness
trial, in which a total of 370 patients each with one of 4 different chronic conditions,
namely, solid cancer (n=100) and blood cancers (n=70), COPD (n=100) or schizophrenia (n=100),
will be randomised to one of two parallel groups, stratified by illness type: the EfiKroniK
group (EG) (tailored exercise supervised by fitness and health professionals) or the
reference group (PVS group) (36). We deliberately opted to study diverse illnesses seeking to
demonstrate any common effect of physical exercise across all of them, independent of any
additional effects on each condition separately, and for this purpose, this design is much
more efficient than separate clinical trials for each illness. Cardiorespiratory functional
capacity at 3, 6 and 12 months and quality of life at baseline at 6 and 12 months will be
considered the primary outcome variables, and will compare changes over time in both groups.
Additionally, we will explore the perceptions of participants and professionals in terms of
the feasibility of the programme, as well as the barriers and facilitators for adherence and
continuity.
Study population
Inclusion criteria:
Participants are required to be between 18 and 75 years old and diagnosed with: stage IV
solid cancer specifically colon, breast or non-small-cell lung cancer, have an Eastern
Cooperative Oncology Group ECOG Performance Status of ≤1, and be on standard first-line
chemotherapy; malignant blood cancer and have received an autologous transplant or
non-localised lymphoma and be on immune therapy; schizophrenia including first-episode
psychosis or other psychotic disorders; or clinically stable (no exacerbation, antibiotic
treatment, systemic corticosteroid therapy or hospitalization in the previous 30 days) COPD
with a BODE index of 3-7 and a life expectancy >2 years. In addition, the following are
required for patients to be eligible for inclusion: good renal, liver and blood function,
with haemoglobin levels >10 g/dl, a platelet count > 50,000, neutrophil count > 1,000, and
Karnofsky Performance Status score >60, and an Eastern Cooperative Oncology Group Performance
Status score ≥ 1.
Exclusion criteria Patients are to be excluded if they have brain metastasis, high risk of
fracture due to bone metastasis, severe emotional instability, cardiorespiratory compromise
or uncontrolled infection; relapse or progression of blood cancer; alterations in
communication or significant cognitive impairment that might hinder data collection;
bronchiectasis or lung disease other than COPD; other comorbidities that might hinder or
prevent them from following the exercise programme; or uncontrolled high blood pressure
(systolic >200 or diastolic >110 mmHg).
Recruitment The Oncology, Haematology and Pulmonology services, primary care doctors and the
Mental Health Network of Bizkaia have established an active surveillance system to identify
patients with the chronic conditions under study. Doctors will inform patients about the
study and invite them to participate. After signing an informed consent form, patients will
be referred by the study coordination group to their primary care doctor who will gather
baseline data. Before each patient's group allocation is known, a fitness and health
professional will measure the study variables at baseline and provide the standardised
healthy lifestyle prescription, encouraging physical activity, a balanced diet and smoking
cessation.
Randomisation Once informed consent has been obtained and baseline measurements taken,
patients will be randomised blindly and centrally to either the EG or PVS group, stratified
by illness type, at the coordinating centre, the Primary care Research Unit of Bizkaia of the
Biocruces Bizkaia Health Research Institute. The randomization will be performed using
computer-generated random numbers in a 1:1 ratio, stratified by illness type, with a block
size of 4 or 6.(Fig.1) Protocol for the PVS group On recruitment, all participants will
receive a standard healthy lifestyle prescription, encouraging physical activity, a balanced
diet and smoking cessation, using the PVS computer tool, which is integrated into the
electronic health record. In addition to other measurements at 3, 6 and 12 months, the
follow-up will include assessment of potential changes in these habits.
Protocol for the EfiKroniK group First phase: the EfiKroniK group are to participate in an
innovative physical exercise programme supervised by fitness and health professionals,
ensuring patient safety and adjusting the intensity of the exercise to each patient. In this
phase, patients are to develop the skills necessary to become an expert regarding the ideal
dose of exercise for them. It consists of 36 sessions of exercise of progressively increasing
intensity and tailored to the physical condition of each patient, assessed based on metabolic
thresholds. Two sessions a week are to be performed in the laboratory, combining aerobic and
strength exercises with stretching, under the supervision of fitness and health professionals
and one session a week independently near the health centre, monitored with a HR monitor
programmed by the fitness and health professionals. In addition to HR measured with the
monitor, exercise is monitored with the modified Borg Rating of Perceived Exertion Scale (37)
and the appearance of any symptoms.
Second phase: In this phase, patients are to work independently following a physical exercise
programme similar to that of the first phase, taking advantage of resources in the community.
To make this feasible, patients are to have been trained during the first phase in the type
of exercise and appropriate intensity (Borg Scale,HR monitor, symptoms), and at the end of
the 3-month training programme, we will contact individuals who can provide support in the
community.
We will calculate the real dose of physical exercise each person has been exposed to:
cumulative metabolic equivalent (MET)*h/week and time spent doing moderate and/or vigorous
intensity of exercise and intensity of exercise under supervision based on the percentage of
heart rate reserve (HRR).
Intensity of aerobic exercise: The American College of Sports Medicine recommends doing at
least 150 minutes/week of moderate or 75 minutes/week of vigorous physical activity or a
combination of both (38). Regarding the definition of relative intensity, 45-59% of the HRR
corresponds to a moderate intensity. Use of this indicator, however, implies carrying out a
maximum stress test, the results of which may be distorted by the high degree of fatigue,
weakened immune system and reduced peripheral muscle strength of patients who are receiving
intensive treatments and have a low level of fitness (28). Furthermore, at the same relative
intensity (59% of HRR), the metabolic response varies greatly between individuals (21). For
these reasons, we will measure MLs in each patient to allow us to: 1) assess patient aerobic
capacity and changes therein, given their strong association with maximum rate of oxygen
consumption (VO2max), and 2) ensure patient safety and provide them with a level of metabolic
stimulus that is similar across patients and effective in improving biochemical parameters
(e.g., reduction in inflammation and improvements in the immune system, blood glucose levels
and lipid profile). In particular, the aerobic threshold (LT) can be used in this way given
the parallel response between the exponential increase in lactate concentrations that occurs
after this LT and the secretion of catecholamines, neurotrophic hormones associated with
improvements in cognitive function (BDNF) and anti-inflammatory interleukins (IL-6) involved
in reductions in tumour size and reproducibility (39).
The two lactate thresholds will be used as a reference for designing exercise intensity zones
for each patient, in terms of speed and HR as well as perceived exertion. The speed at the LT
or aerobic threshold determined during an incremental lactate test and the corresponding HR
will define the lower limit of the moderate intensity zone. On the other hand, the speed at
the threshold, considered the anaerobic threshold, used the measure the maximal lactate
steady state (MLSS) (38) and the corresponding HR will be taken as the upper limit of the
moderate intensity zone.
Based on the individual MLs, we will design five intensity zones. The zone of low-intensity
training (LIT) corresponds to exercise carried out at a HR lower than the LT (~20% of the
HRR) and the zone of moderate intensity zone to exercise carried out between the LT and the
MLSS (~20-85% of HRR or between 1-2.3 Mmol/L), this in turn being divided into three
equally-sized zones: low-moderate (M1), medium-moderate (M2) and high-moderate (M3)
intensity. Finally, the zone of high-intensity training (HIT) (>MLSS, >~85% of the HRR).
During the first month, participants will start carrying out sessions involving endurance
exercise, which will be divided into 3 intervals of 8 minutes each at an M2 intensity,
alternating with 2 minutes at an M1 intensity. In the session in which patients work
independently, they will be monitored with HR monitor and it will be explained that they
should exercise for 30 minutes and for as much of that time as possible at M1.
During the second month, the maximum intensity of the intervals will increase to M3, nearing
the anaerobic threshold HR. Specifically, the fully supervised exercise will be divided into
four intervals of 5 minutes at M3, alternating with 3 minutes at M1, while the indirectly
monitored (semi-supervised) session will be of 30 minutes at M2 (Figure 2).
Three months after the beginning of the project, the assessments are to be repeated and new
intensity zones prescribed, in line with changes in functional capacity as assessed by the
lactate tests. At this point, patients are to be given a report of the results of these
assessments together with guidelines for exercising independently during the following
months. During the same appointment, we will explain to patients how to use the HR zones
prescribed during exercise and we will warn them about any potential risk factors detected
(39,40). Given that a relatively high proportion of people on the same training programme do
not show a good response in various metabolic parameters (41), patients who adapt well to the
training will be recommended to continue exercising at a moderate-high intensity (M3), while
those with a poorer response will be encouraged to continue their training at least at low-
to medium-moderate intensities (M1-M2).
Strength and endurance exercises: Strength training is a key element of the exercise
programme in these conditions which are associated with reduced peripheral muscle strength
and a low level of fitness. The approach taken consists of exercising the largest muscle
groups at high speed and moderate intensity with a moderate load. In each session, 5
exercises are performed involving major muscle groups, namely, the chest, quadriceps, back,
hamstring and gluteal muscles, as well as the shoulder, these being performed in 2-3 series
of 8-12 repetitions of 16-20 possible exercises (~55-65% of the 1 repetition maximum, seeking
to avoid excessive muscle damage and inflammation) and using machines, dumbbells, weight bars
and plates, elastic straps and wearable weights.
This type of strength training has shown to be effective for releasing anabolic myokines
(IL-4, IL-13, IL-15, leukaemia inhibitory factor) and have great therapeutic potential
against osteoporosis and sarcopenia/cachexia (responsible for around 20% of cancer-related
deaths) associated with metastatic cancer and associated treatments (39,42), as well as
resulting in only mild muscle damage and inflammation.
Outcome measures These measurements are made by an interviewer blind to group allocation.
Primary outcome measure (baseline, 3, 6 and 12 months):
- Cardiorespiratory functional capacity, as assessed using a 400-m walk test
- Changes in health-related quality of life, as assessed using the 36-item Short-Form
Health Survey (SF-36) and disease-specific questionnaires: the European Organization for
the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) in
patients with cancer; and the COPD Assessment Test (CAT) and Chronic Respiratory Disease
Questionnaire (CRQ) in patients with COPD.
Secondary outcome measures (baseline, 3, 6 and 12 months):
- Muscle strength test measured by the handgrip strength and sit-and-stand tests
- Thresholds for lactate (LT) and anaerobic threshold or maximal lactate steady state
(MLSS), HR, and accelerometer activity counts for tailoring the exercises, determined in
submaximal walking or running tests. For detecting the LT, a test will be carried out on
a 20-metre track. This will be an incremental test combining 2-minute active period and
1-minute rest period. To help the participant adjust their speed in each 2-minute
period, red markers will be placed every 5 metres on the floor and on the wall on both
sides and two large cones on the floor at each end of the track. Participants will be
asked to reach the next red markers each time they hear a beep, continually adjusting
their speed but without stopping; that is, they should go faster or more slowly seeking
to pass each set of markers at the time of the corresponding beep. The speed will start
at 2.4 km/h in the first stage; and will increase by 0.61 km/h each stage (42). At the
end of each stage, the following will be recorded: HR, Rating of Perceived Exertion and
lactate concentration, by taking a blood sample from each earlobe to find the minimum
lactate equivalent (LEmin) above which the lactate concentration starts to increase
exponentially. Hence, the aerobic threshold is defined as the intensity of exercise
(speed) at which the lowest recorded lactate level is followed by changes ≥ 0.1 mmol/L
in the next stage and >0.2 mmol/L the one after (25). The test will be stopped if the
participant becomes exhausted or lactate levels exceed 3 mmol/L.
To identify MLSS, another test will be performed a week after the incremental lactate test to
identify the corresponding LT. Based on certain parameters from this progressive test,
detailed below, it has been shown to be possible to estimate the speed at which an individual
reaches the MLSS accurately (estimates accounting for 86% of the variance in MLSS with
standard error of the estimate of 0.385 km/h and the difference between the estimated value
of MLSS and the true value lying between -0.77 and 0.81 km/h 95% of the time) (25).
For assessing the MLSS, the patient should return to the health centre where the measurements
are taken 1 week later. The infrastructure required is the same as for the incremental
lactate test; all that changes is the protocol. An audio recording will be made with two
blocks of 10 minutes separated by a 2-minute recovery period, at an MLSS speed estimated
using the results obtained in the incremental lactate test and the following equation: MLSS =
3.408 + (1.094·LEmin+1 mM) - (0.036·age - (0.013· LEmin HR)) (25)
- Physical activity performed. For this, each participant will be fitted with an Actigraph
wGT3X-BT accelerometer on their right hip at the level of the iliac crest and a HR
monitor band (Polar OH1). They should wear these monitors for a week and complete a
daily record of their activity, to monitor activity counts during different intensities
of activity. To analyse these data, we will assess the activity counts which correlated
with the LT during the incremental test and thereby be able to assess their weekly
physical activity based on personal activity count thresholds.
- Body composition (OMROM body fat percentage), body mass index and abdominal
circumference, estimated cardiovascular risk and the onset of any cardiovascular events
- Psychological changes assessed using Goldberg's 12-item General Health Questionnaire
(GHQ-12) and Duke Social Support Index
- In addition, in the case of schizophrenia, changes in mental state assessed using the
Positive and Negative Syndrome Scale (PANSS), and the severity of the patient's
condition and changes therein during the course of the programme assessed using the
Clinical Global Impression (CGI) and the Global Assessment of Functioning (GAF) scale
- Lipid profile, as well as levels of C-reactive protein, glucose, insulin and specific
exercise-related parameters: adiponectin, BDNF in participants with schizophrenia, TNF-α
in those with cancer and Il-1 and Il-6 in those who have COPD or are transplant
recipients (at baseline and 3 months).
- Potential predictive, modifying and confounding factors: sex, age, comorbidities
(Adjusted Clinical Groups Case-Mix System), risk factors, socioeconomic status, drug
treatments and characteristics of each chronic condition.
