Study setting {9}
The study will be carried out at the Laboratory of Clinical Research in Kinesiology from the Universidad Católica del Maule, Talca, Maule, Chile and Human Movement Research Laboratory (MOVI-LAB), Bauru, Brazil.
Eligibility criteria {10}
Inclusion criteria
Volunteers must present a clinical diagnosis of PD, made by a board-certified neurologist, according to the UK Brain Bank criteria (24) and be classified 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, benefits 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 fitted 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 specific areas for each foot, at the base of the first 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.mm2), defined 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 first time the VAS is greater than 0) or at the moment when the monosynaptic reflex 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 flat 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 flexors, extensors and abductors; elbow flexors and extenders; trunk extensors and flexors; knee flexors and extenders; and dorsiflexes and plantar flexors.
4) Cool down (5 min): Stretching of the main muscle groups worked during the sessions and relaxation.
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 modification 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) 24-hour 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 specifically 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 defined 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 fifth 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 non-invasive 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 (VCO2), ventilation (VE) and respiratory exchange ratio (RER) will be obtained on a breath-to-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 efficiency 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 specificity 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 specificity 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 flat 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 figure 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% confidence 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.
Assignment of interventions: allocation
Sequence generation {16a}
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 flowchart 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 influences of circadian variations.
Plans to promote participant retention and complete follow-up {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 office 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.
Confidentiality {27}
The confidentiality of the identity will be safeguarded by the following measures:
- Only the responsible researcher and his or her team will have access to the data collected during the evaluations.
- 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
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 significance 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 final evaluations. Missing data will be addressed by a multiple imputation method.
Plans to give access to the full protocol, participant level-data 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 scientific 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 scientific 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 final 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 final results of the trial.