Effect Of The Combination Of Automated Peripheral Mechanical Stimulation And Physical Exercise On Aerobic Functional Capacity And Cardiac Autonomic Control: A Randomized Clinical Trial Protocol.

● Background: Automated peripheral mechanical stimulation (AMPS) has been proposed as a new complementary therapy with potential for improving motor and cardiovascular abnormalities in Parkinson's disease (PD). However, AMPS long-term effects and its combination with physical exercise is unknown. Thus, this study aims to compare the effects of a program of 12 weeks of physical exercise with a 12-week intervention program combining physical exercise and AMPS on the aerobic capacity, cardiac autonomic control and gait parameters in patients with PD. ● Methods: A randomized, controlled clinical trial will be conducted. Volunteers will be randomly assigned to one of the two groups studied: 1) Exercise; or 2) AMPS + Exercise. Both groups will undergo an exercise program of 24 sessions, for 12 weeks, performed twice a week. Before exercise sessions, the group AMPS+Exercise will receive a session of active AMPS, while the group Exercise will receive an AMPS sham intervention. Shapiro-wilk’s and Levene’s tests will be used to check for data normality and homogeneity, respectively. In case parametric assumptions are fullled, per-protocol and intention-to-treat analyses will be performed using a mixed model analysis of variance to check for Group*Time interaction. Signicance level will be set at 5%. ● Discussion: Several non-pharmacological treatment modalities have been proposed for PD, focusing primarily on the reduction of motor and musculoskeletal disorders. Regular exercise and motor training have been shown to be effective in improving quality of life. However, treatment options in general remain limited given the high prevalence and adverse impact of these disorders. So, developing new strategies that can potentiate the improvement of motor disabilities and also improve non-motor symptoms in PD is relevant. It is expected that the participants from both groups will improve their quality of life, gait parameters and their cardiac autonomic control, with greater improvements being observed in the group combining active AMPS and physical exercise. Trial


Background and rationale {6a}
Parkinson's disease (PD) is a degenerative neurological disorder characterized by a loss of dopaminergic neurons at the substantia nigra level, leading to muscle tremor, rigidity, progressive bradykinesia and postural instability, with great impact on the quality of life (1). Based on international data, it can be estimated that there are more than seven million patients with PD worldwide (2). Moreover, about 1 to 2% of the population over 65 years of age suffers from PD, rising to 3 to 5% in those over 85 years of age (3).
Gait disorders are one of the main therapeutic challenges in PD (4), involving a risk of fall, disability and physical decline (5). The progressive deterioration of the physical condition leads to a reduction in aerobic functional capacity and autonomy, thus affecting the ability to perform everyday tasks effectively (6,7). Indeed, it is estimated that between 40-70% of people with PD have falls, in which muscle weakness at lower limbs appears to play a key role, signi cantly reducing their postural stability (8).
These data allow us to consider elderly people with PD in a high degree of frailty, thus with high probability of suffering health problems due to the massive deterioration of physiological systems (9,10).
In terms of intrinsic exercise capacity, studies have shown that the maximum oxygen uptake (VO 2 ) of PD patients was no different from that of controls, but they reached their maximum VO 2 earlier, suggesting a lower mechanical e ciency of movement during exercise, perhaps due to their muscle stiffness (11).
Moreover, some authors have studied the relationship between aerobic functional capacity and gait (12,13). Results showed a positive correlation between VO 2peak and gait speed, meaning that the lower the cardiorespiratory capacity the lower the gait speed.
Besides motor abnormalities, patients with PD present non-motor symptoms such as dysautonomia (14) and sleep disturbances (15). Thus, physical exercise has been highly recommended as nonpharmacological intervention since it has shown to attenuate motor dysfunction, improve cognitive function, effectiveness of medications and sleep patterns, as well as prevent depression and cardiovascular complications (16). In this sense, Amara et al. mention that regular practice of physical exercise has positive effects on the effectiveness of sleep in the long term for patients with PD (17).
Furthermore, according to Fan et al. (18), physical exercise, especially those performed at moderate to vigorous intensities, has a positive impact on PD through multiple mechanisms, including reduction of αsynuclein protein accumulation, decrease in in ammation and oxidative stress, improvement in BDNF activity, nerve regeneration and mitochondrial function. Furthermore, some authors have shown that endurance exercise is safe and well-tolerated for people with PD from a cardiovascular point of view, which supports their recommendation for this population (19).
Although physical exercise has shown to be effective, some authors have proposed other nonpharmacological strategies as complementary therapy. In this sense, Barbic et al (20) proposed an innovative approach aiming at improving walking parameters in PD. The authors evaluated the effect of a single session of peripheral mechanical stimulation therapy. After the stimulus, the authors observed signi cant changes in motor parameters such as improvement in gait length and gait speed. Concomitant to the motor improvement, surprisingly, there was improvement in some cardiovascular parameters, such as decreased resting blood pressure and improved cardiovascular autonomic control in response to orthostatic stimulation. In addition, Zamunér et al (21) studied the effects of ve sessions of automated mechanical peripheral stimulation (AMPS) on cardiovascular parameters in patients with PD. The authors reported that after the AMPS therapy, patients with PD presented a decrease in cardiovascular sympathetic control and an improvement in arterial barore ex sensitivity.
AMPS therapy consists of applying a mechanical pressure with intensity to elicit pain (at pain pressure threshold) at four speci c points on the sole of the both feet of patients with PD. Moreover, the total therapy duration is 96 seconds, and some studies have reported that the effects may last up to 72 hours (22,23). Therefore, due to its promising bene cial results and that it is not a time-consuming therapy, AMPS represents an interesting intervention strategy. So, considering that AMPS therapy promotes bene cial motor and cardiovascular effects for PD patients in the short term, as well as physical exercise, it is important to study whether adding AMPS to an exercise rehabilitation program could potentiate the effects of exercise, since patients are expected to attend the sessions with the potential for improved performance and execution of the exercises during the sessions. Furthermore, no studies have addressed the long-term effects of AMPS (i.e. AMPS intervention program lasting more than 1 month) in patients with PD.

Objectives {7}
The objectives of this study will be to evaluate the effect of 24 sessions of AMPS combined to a physical exercise program performed twice a week for 12 weeks on aerobic functional capacity, gait parameters and cardiac autonomic control in patients with PD. As a hypothesis, the exercise program combined with AMPS therapy is expected to be more effective in improving cardiac autonomic control and aerobic functional capacity in PD patients than exercise alone.

Trial Design {8}
The present study is a double-blind randomized controlled trial. The sample will be selected on a nonprobability basis.

Inclusion criteria
Volunteers must present a clinical diagnosis of PD, made by a board-certi ed neurologist, according to the UK Brain Bank criteria (24) and be classi ed as 1 to 3 at the Hoehn and Yahr scale.

Exclusion criteria
Volunteers who show signs of cognitive impairment, based on the results of the Mini Mental State Examination adjusted for the educational level of the Chilean and Brazilian population (25), who present cardiorespiratory, neuromuscular, and musculoskeletal diseases will be excluded. Volunteers who have peripheral sensory neuropathy, diabetes, or any other condition or disease known to promote autonomic dysfunction will be excluded based on symptoms, physical condition, and routine laboratory tests. In addition, the drug treatment of PD participants must remain unchanged for at least 30 days prior to study inclusion.
Who will take informed consent? {26a} NZA researcher will be in charge to contact potential participants via telephone and invite them to participate in the study. In case we have a positive reply, an appointment will be scheduled and NZA will explain the objectives of the study, the inclusion and exclusion criteria, participant's roles, risks, bene ts and ethical implications. If the participants agree in took part in the study, they will be requested to sign two copies of an informed consent, one for the participants and the other for the researcher.
Additional consent provisions for collection and use of participant data and biological specimens {26b} Not applicable, this trial does not have biological specimens.

Interventions Explanation for the choice of comparators {6b}
In order to comply with the proposed objective, participants will be randomly assigned to one of the two studied groups: 1) Exercise Group (EX-G): participants will undergo 12-week exercise program, held twice a week along with 2 weekly sessions of inactive SHAM during the same period; 2) Group combining AMPS and Exercise (AMPS-G): participants in this group will undergo the same 12-week exercise program of the EX-G, along with 2 weekly sessions of active AMPS during the same period.

Intervention description {11a}
Automated Mechanical Peripheral Stimulation AMPS therapy will be applied through a therapeutic device (Gondola, Ecker Technologies, Lugano, Switzerland), which will be tted to each patient's feet. The device consists of a foot stand for each foot with two electric motors that activate two 2 mm diameter metal bars. The mechanical pressure stimulus occurs when the motors are activated. Before application, the device is adjusted so that the stimulus is applied to two speci c areas for each foot, at the base of the rst metatarsal joint and at the head of the hallux of the right and left feet. The intensity of the pressure is adjusted to reach the participant's pain threshold (which normally occurs around 0. 3-0. 9 N.mm 2 ), de ned as the moment when the participant reports that they began to feel pain (the moment of transition between the strong pressure and the painful pressure and the rst time the VAS is greater than 0) or at the moment when the monosynaptic re ex appears in the anterior tibial muscle. After these preparatory procedures, treatment begins. The therapy will be carried out in 4 cycles. A cycle is completed when the four target areas are stimulated, which requires 24 s (6 s per area) so the complete therapy lasts 96 s (26).
The SHAM intervention will replicate the same procedure described for active AMPS. However, a rubber adapter will be positioned at the tip of the metal bars to increase the contact surface area and the pressure will be set to the sensorial threshold (i.e. when the patient report that they feel a touch at the point). AMPS sessions will be performed 24 hours before all the exercise sessions (27).

Physical Exercise Program
Physical exercise sessions will be composed of: 1) Warm-up (5 min): patients perform stretching of the main muscle groups of the upper limbs, lower limbs and trunk.
2) Aerobic exercise (30 min): Patients will perform continuous aerobic exercise consisting of walking on at ground and ramps, with intensity between 40 and 60% of the heart rate reserve.
3) Strengthening exercises (20 min): volunteers will perform resistance exercises (2 series x 15 repetitions) for the upper and lower limbs, and the trunk working the following muscle groups: shoulder exors, extensors and abductors; elbow exors and extenders; trunk extensors and exors; knee exors and extenders; and dorsi exes and plantar exors. Criteria for discontinuing or modifying allocated interventions {11b} Participants who attend less than 70% of the training sessions, participants who have been absent on evaluation days and participants who start performing other regular physical exercises after baseline assessments will be excluded from the study.

Strategies to improve adherence to interventions {11c}
In order to improve adherence to interventions, researchers will continuously request feedback from the participants throughout the sessions to check for possible discomfort and adjust the exercises execution if it is needed. Moreover, every session will be supervised by at least two researchers with experience in exercise rehabilitation, in order to ensure the patients are executing the exercises properly.
Relevant concomitant care permitted or prohibited during the trial {11d} Participants will be allowed to keep their pharmacological treatment during the entire study. However, participants will be excluded in case of any dose modi cation during the trial. Participants who report to attend physical therapy sessions or any other non-pharmacological regular intervention for at least 3 months prior the study will be also allowed. However, they will be excluded in case of suspension of any intervention or start of a new regular intervention. For the outcome assessments performed at baseline and after the intervention program, participants will be instructed not to drink alcohol and/or stimulants (coffee, teas and energy drinks), avoiding heavy meals, having a light meal at least two hours before the test and not doing strenuous exercise 48 hours before the evaluations.

Provisions for post-trial care {30}
At the end of the study, if AMPS is effective in promoting higher improvement than exercise alone, the same treatment will be offered at no cost to EX-G participants.

Outcomes {12}
The results will be evaluated at 2 time points: 1) Baseline (before starting the intervention program); 2) after 12 weeks of intervention (after 48 hours to 1 week from the last intervention). The primary outcomes will be: 1) quality of life; 2) heart rate variability indices; 3) VO2peak. Secondary outcomes include: 1) 24hour blood pressure, 2) sleep quality, 3) VO2 at the anaerobic threshold, 4) dynamic balance and 5) gait velocity.

Quality of Life
Quality of life will be assessed by the Parkinson's Disease Questionnaire 39 (PDQ-39), which is a questionnaire developed speci cally for people with PD and consists of 39 items, and assesses 8 dimensions of daily life, including relationships, social situations and communication (28) Heart rate variability HRV is de ned as the variation that occurs in the time interval between consecutive heartbeats and it has been proposed that its behavior depends on autonomic modulation, as well as its implications on cardiovascular mortality (29). This time it will be done by continuous recording of RR intervals with 1000 Hz sampling frequency (Polar V800, Finland). R-R intervals will be recorded with a Polar V800 heart rate monitor (Polar, Oi, Finland); a sensor will be placed on the chest at the fth intercostal space. Prior the beginning of data collection, volunteers will remain at rest for approximately 20 min for baseline heart rate and BP stabilization. Recording will occur under the following conditions: 1) Resting in supine position for 15 minutes; and 2) resting in orthostatic posture for 15 min. The volunteers will be instructed to maintain spontaneous breathing throughout the collection period in the supine and orthostatic postures. The participants' respiratory rate will be recorded throughout the test. Heart rate variability will be analysed through spectral analysis in an autoregressive model. The spectral components will be obtained at low frequency (LF, 0.04-0.15 Hz) and high frequency (HF, 0.15-0.4 Hz). The LF band is modulated by the sympathetic and parasympathetic autonomic nervous system (with sympathetic predominance), the HF band is associated with cardiac vagal control, and the LF/HF ratio is calculated to assess sympathovagal balance.
Peak oxygen uptake All participants will undergo a cardiopulmonary exercise testing (CPET) studies in a global and noninvasive way the integral response of the organism to exercise, through a rational analysis of the respiratory, cardiovascular, hematopoietic, neuropsychological and skeletal muscle systems (30) CPET will be performed with an ergometric bike (Ergoselect 5M, Ergoline, Germany). An incremental ramp-type protocol will be used to determine the workload imposed on aerobic training and possible comorbidities that impede the performance of the proposed physical training protocol (31). The outcomes VO2, carbon dioxide output (VCO 2 ), ventilation (VE) and respiratory exchange ratio (RER) will be obtained on a breathto-breath basis during the entire CPET using an expired gas measurement system (metalyzer 3b -Cortex Medical, Germany) duly calibrated before each test (this equipment is available for common use in our university). During CPET, electrocardiogram and heart rate (HR) will be continuously recorded in real-time via a 12-lead integrated ECG (Quark T12, Cosmed, Italy). Blood pressure and the ratings of perceived exertion using the Borg CR10 scale will be monitored throughout the test.

24-hour Blood Pressure
The electrocardiogram and blood pressure will be recorded for 24 hours concomitantly through the 3 channel Cardio Map digital equipment, before and after the application of the protocol (Cardio Sistemas Comércio e Industria Ltda, Sao Paulo, SP, Brazil).

Sleep quality
Sleep quality will be assessed using an actigraph monitor (ActTrust, Condor Instruments Ltda) (32). Sleep quality will be assessed by quantifying the sleep onset, sleep latency, sleep duration, sleep e ciency and sleep disturbances. This device has been used in people with sleep disorders, obtaining very good results and demonstrating that it is a low-cost protocol, more durable assessment and simple in its interpretation, also has good sensitivity and accuracy (33).

Timed Up and Go
It was designed to measure mobility in older people and has been recommended as a useful tool to quantify locomotor performance in people with PD (34). It is also validated for adults with Parkinson's with a sensitivity of 76%, a speci city of 66%, a positive predictive value of 39% and a negative predictive value of 91% (35). An instrumented TUG (iTUG) will be used to complement the results obtained from the TUG and to characterize the motor impairment resulting from the disease (36).

Tinetti Scale
Evaluates the mobility of the elderly, the scale has two domains: gait and balance; its main objective is to detect those elderly people at risk of falling, it has greater predictive value than the muscle test (Tinetti, 1986). It is also validated for adults with PD with a sensitivity of 76%, a speci city of 66%, a positive predictive value of 39% and a negative predictive value of 91% (37).

10-m Walk Test
It is a performance measure used to evaluate walking speed in meters per second over a short distance. It can be used to determine functional mobility, gait and vestibular function. (38) The assessment measures the time in seconds it takes the patient to travel 10 meters in a straight line. It will be applied in a corridor with a distance of more than 10 meters and a at surface. This test will be done 3 times conserving the best time that will be registered by 2 evaluators simultaneously.
Participant timeline {13} Fig. 1 show the recommended SPIRIT gure with the participant timeline.

Sample size {14}
To determine the number of volunteers, the sample size was calculated using GPower version 3 software. 1, for a 95% con dence level and 80% study power. The calculation was based on a pilot study that considered the LF/HF index of HRV, SRB and systolic blood pressure. The largest suggested sample size was 19 volunteers per group to detect a decrease in systolic blood pressure with an effect size of 0.80. Therefore, considering possible dropouts, 25 participants will be enrolled for each group.

Recruitment {15}
Participants will be recruited from the community by radio and online advertisements and notices, advertisements posted in strategic places such as neurological clinics. Also, researchers will contact the director of all Public Family Health Center (CESFAM) in the region of Maule to present the project and to check for potential participants.

Concealment mechanism {16b}
Implementation {16c} Randomization will be carried out by a member of the group of investigators, blinded to the study protocol, by means of opaque sealed envelopes containing the letters "A"; corresponding to the EX-G, and the letter "B", corresponding to the AMPS-G. Figure 2 shows the study design owchart describing all the steps of the study (Fig. 2).

Assignment of interventions: Blinding
Who will be blinded {17a} This will be a double-blinded study. Participants will be assigned to Exercise plus AMPS group or Exercise plus SHAM. Thus, participants will be not aware if they are assigned to active AMPS or sham. Also, the outcomes assessor will be in charge only of the evaluations with no information about the group participants belong to.

Procedure for unblinding if needed {17b}
Not applicable, unblinding is not permissible in this trial.

Data collection and management
Plans for assessment and collection of outcomes {18a} Both interventions (AMPS and exercise) will be carried out within the facilities of the Catholic University of Maule, located at Avenida San Miguel 3605, in the city of Talca, inparallelwith Human Movement Research Laboratory of the São Paulo State University, Brazil. In addition, evaluations should be conducted in a room with temperature maintained between 22 and 24ºC and relative humidity between 40 and 60% at the same time of day (2:00 p. m. to 6:00 p. m.) to minimize the in uences of circadian variations.

Plans to promote participant retention and complete followup {18b}
A weekly phone call will be made to participants in both groups, asking about their health status and reinforcing the pre-session recommendations for physical exercise. Moreover, the participants who wish and agree, will be added to a telephone messenger group app with the objective of solving doubts and share information and experiences about PD.

Data management {19}
All the information gathered from this investigation will always be safeguarded and under the care of the Investigator in charge (ARZ), who will allocate a locker in his o ce under lock and key where all documents of this research will be kept.
Evaluations and data collection will only be carried out by the Responsible Researcher or thesis students from undergraduate and graduate programs authorized and supervised by him.
All electronic material will be properly stored and backed up on the researcher's computer equipment with a password. Both this consent and the printed documents generated and necessary to use will be stored for ten years from the end of the study, after which time they will be disposed of in a reserved manner.

Con dentiality {27}
The con dentiality of the identity will be safeguarded by the following measures: 1. Only the responsible researcher and his or her team will have access to the data collected during the evaluations.
2. The interviews and data will be given a code for each participant, which will only be known by the researcher responsible for this study and will be carried out in an environment that encourages communication and anonymity chosen by the participant.
The data collected will be used only in academic research and research dissemination.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} Not applicable, this trial does not have biological specimens.

Statistical methods for primary and secondary outcomes {20a}
The Shapiro-Wilk and Levene's tests will be applied to check for data normality and the homogeneity of the variance, respectively. To check the interaction between the Groups (EX-G and AMPS-G) and time (baseline and post-intervention) a mixed ANOVA model with Bonferroni adjustment will be applied for the variables that meet the ANOVA assumptions. Otherwise, the data will be analyzed by the Wilcoxon (intragroup) and Mann-Whitney (intergroup) tests with a priori Bonferroni correction. For all tests, the signi cance level will be set at 5%.

Interim analyses {21b}
Not Applicable. Interim analyses will not be performed in the present study.

Methods for additional analyses (e.g. subgroup analyses) {20b}
Not Applicable. Additional analyses are not planned in the present study.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} Per-protocol and intention-to-treat analysis will be performed. Per-protocol analysis will include only participants who attended at least 70% of the sessions and underwent baseline and nal evaluations.
Missing data will be addressed by a multiple imputation method.
Plans to give access to the full protocol, participant leveldata and statistical code {31c} Participants may consult the information generated at any time during the execution of the project upon request to the investigator responsible for the study, who undertakes to provide cooperation and to propose ways to access it.
Likewise, the Responsible Researcher agrees with each participant to send the research report generated at the end of the study to the respective emails, as well as copies of the scienti c articles that may result from the study.

Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d} Not applicable. This trial was approved by the scienti c ethics committee of the Catholic University of Maule and does not require the supervision of a steering committee.
Composition of the data monitoring committee, its role and reporting structure {21a} Not applicable.

Adverse event reporting and harms {22}
In the end of each training session and therapy participants will be asked to report any complains and symptoms produced by the proposed activity. Outcome assessor and the lead researcher will be in charge to collect and record this information throughout the study. All complications and dropouts will be reported in the nal manuscript.
Frequency and plans for auditing trial conduct {23} Not Applicable. Auditing trial conduct are not planned for this study.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25} In case of any change to the current protocol, the lead research will be responsible to inform and send the new version the ethical committee for their approval. After the approval the clinical register will be updated and all the amendments will be informed.

Dissemination plans {31a}
Each participant will receive a full report with the results of their assessments. By the end of the study, the lead research will be contact all the participants to provide the nal results of the trial.

Discussion
Several non-pharmacological treatment modalities have been proposed in the treatment of PD, focusing primarily on the treatment of motor and musculoskeletal disorders (39). In this context, regular exercise and motor training have been shown to be effective in improving people's quality of life, balance, physical functioning and activities of daily living, and are therefore strongly recommended for patients with PD (40).
An analysis of the potential bene ts of exercise in people with PD concluded that exercise could improve physical functioning, health-related quality of life, leg strength, balance, posture, walking and tness (41).
Therefore, the authors statement that exercise improves functional motor performance in PD patients appears robust; however, the question remains as to which exercise protocol is most appropriate for individual patients (41). In summary, the evidence base for treating a variety of non-motor symptoms in PD has grown substantially in recent years. However, treatment options in general remain limited given the high prevalence and adverse impact of these disorders, so the development and testing of new treatments for non-motor symptoms in PD remains a priority (42).
In this sense, some authors have proposed the use of AMPS as complementary therapy. This therapy has shown to provide promising effects such as better performance in the gait pattern (43) and decrease the treating freezing of gait (44). Also, a single session of AMPS treatment is able to modify the resting state in regions of the brain and cerebellum (45), changes the shu ing steps pattern (that is typical of PD subjects), increases the shu ing steps pattern of hip, knee and ankle joints during the gait cycle (46). In additions, AMPS treatment induces an increased activation of brain areas involved in the visual-space and in the sensory-motor integration (47), which could explain the positive effects on bradykinesia and several gait parameters (48).
Another point that must be mentioned is that patients with PD present disautonomia (49) and high prevalence of cardiovascular diseases (50). It is well established that exercise is effective in improving cardiac autonomic control, usually quanti ed by heart rate variability indices, which is considered a prognosis marker for cardiovascular mortality (51; 52). In the same line, some studies have shown that AMPS may improve the cardiovascular autonomic control (53;54). However, despite the positive effects of exercise and AMPS for patients with PD, no studies have addressed its long-term effects combined with an exercise program, since it is a relatively new intervention. Therefore, this study may help to elucidate the potential bene cial effects of adding AMPS to a rehabilitation program. If AMPS provides positive results, it may represent a new therapy strategy for patients with PD complementary to the physical exercise.
Our hypothesis is that the exercise program combined with AMPS therapy would be more effective in improving cardiac autonomic control and aerobic functional capacity in PD patients than exercise alone. This can be explained by two aspects. First, the combination of interventions can change brain functioning strongly than only exercise. While AMPS presents potential to change sensory-motor integration (55), exercise promotes consistent bene ts on brain functioning and body system, but without consistent effects on sensory-motor integration. Second, the application of AMPS before the exercise can improve the performance of patients with PD during exercise. The positive effects of AMPS on walking and balance (56) can increase the exercise intensity and quality of movements during the exercise session. Increasing exercise intensity is an important component to improve the bene ts of exercise in PD (57). Thus, in case our hypothesis is con rmed, patients with PD submitted to physical exercise program combined to AMPS could have a greater improvement in their functionality, quality of life and cardiac autonomic control. Participant recruitment started on March 2, 2020.
Recruitment is expected to be completed on October 31, 2021.