Study design and objectives
PEPSY V@Si is designed as an interventional, multicenter, randomized controlled open-label trial. The main objective is to demonstrate an increase in overall hippocampal volumes (right and left) in SZ receiving a 16-week, web-based e-APA program compared to SZ receiving a 16-week, web-based e-HE program (Figure 1). SZ are randomized to either the active group (e-APA) or the non-active control group (e-HE). Subsequently, HV are matched to SZ on age, gender, and baseline level of PA. Both HV receive the same interventions as the corresponding SZ. The present protocol followed the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines and fulfilled the SPIRIT checklist (Additional file 1).
All participants (SZ and HV) are assessed for the primary endpoint at the start (baseline assessment, V1) and at the end of the intervention (the 16-week follow-up assessment, V6). Other visits are conducted between V1 and V6 to assess secondary endpoints.
Ethics and regulatory considerations
Written informed consent is obtained from all participants before their inclusion. The protocol was approved by Health Authorities (ANSM; Agence Nationale de Sécurité du Médicament et des produits de santé) on 19 July 2016 (ID-RCB number 2016-A00930-51) and by the ethical committee (Comité de Protection des Personnes, CPP Nord-Ouest IV, France) on 10 January 2017 (CCP16/39) in compliance with French regulations. Trial registration was carried out at ClinicalTrial.gov on 25 August 2017 (NCT03261817).
Recruitment and randomization
Forty-two SZ are recruited from Caen and Rouen University Hospitals (France). SZ are diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR, 4th edition, text revision) criteria with the structured Mini-International Neuropsychiatric Interview (MINI, French version 5.0.0). All patients are stabilized outpatients with no change in their treatment over the last two months prior to their inclusion.
Forty-two HV are recruited from the general community in Caen via an announcement broadcast by press, posting or mailing. Matching criteria are checked by phone and supplementary interviews.
For both groups, the clinicians assess the subject’s eligibility and provide to each subject and to the patient’s legal representative, comprehensive, verbal and written information regarding the objectives and procedures of the study as well as the possible risks.
A signed informed consent is obtained from each participant and/or legal representative for SZ prior to undertaking any study-related procedure. SZ patient who does not wish to take part in the study continues to have treatment as usual.
Inclusion and exclusion criteria are presented in Table 1 for SZ and in Table 2 for HV.
Randomization is established only for eligible patients and is performed in a 1:1 ratio by a central computer-assisted procedure centralized at the PEPSY V@Si data center (Ennov Clinical Software®). SZ are assigned either to the active group (e-APA) or to the control group (e-HE). HV are recruited and matched to SZ on age, gender and physical activity level according to the Ricci and Gagnon self-questionnaire [60]. Each participant who enters into the study receives a unique identification number.
Intervention / study protocol
In this study, each intervention delivered, carried out or received electronically is called an “e-intervention”. Both interventional activities, e-APA and e-HE, are delivered via videoconferencing using a secure web-based platform named SAPATIC® (Santé Activités Physiques Adaptées utilisant les Technologies de l’Information et de la Communication). All participants’ data are hosted on a HADS server (Hébergeur Agrée de Données de Santé). All participants are able to connect to the platform at home or in a connected room in ambulatory care services. The time spent with the intervention staff are the same in both groups, and a specific time schedule are followed to ensure that each session lasts 60 minutes. Participants receive 2 sessions per week for 16 weeks, which is a total of 32 sessions.
The intervention in both groups begins with a motivational interview for increasing e-APA or e-HE participation. In the e-APA group, the motivational interview allows the professional to better understand the expectations of participants in terms of PA.
SZ assigned to the active or to the control group receive their usual medications during the 16-week program.
Active group
For all participants (SZ and HV) assigned to the active group, e-APA sessions is implemented in addition to daily life activities.
The e-APA program, designed according to the American College of Sports Medicine (ACSM) guidelines [61], is individually supervised by qualified APA professional trainers from the V@Si company selected from a list of certified professionals chosen for the study. Physical exercises are individualized and adapted for each participant according to standardized guidelines and to his/her sporting past, treatment, preferences and fitness level (estimated by the Global Physical Activity Questionnaire - GPAQ) [62], baseline maximal exercise test and maximal strength test. Exercises are conducted at a moderate to vigorous intensity (60 to 75% of maximal heart rate based on participant’s baseline maximal exercise test), assessed through real-time heart rate monitoring using cardiac sensors (Zephyr BioHarness® or OnRythm 500®). Exercises are performed with an intensity that allows the participant to speak with moderate breathlessness.
Three alternative types of exercises are proposed to participants: 1) aerobic exercises, 2) resistance exercises to maintain or increase arm and leg muscle strength, and 3) balance exercises combining flexibility and coordination. The number of repetitions and the difficulty of the exercise are gradually increased during the sessions and are modulated according to the participant’s capacities at the time of the exercises. Difficulties of activities are increased in duration, then in frequency, and ultimately in intensity only if the participant tolerates previous increases. The heart rate, the perceived exertion as assessed by the Borg Rating of Perceived Exertion Scale [63], and the perceived dyspnea (visual analogue scale) evaluated at each session are the three indicators that allow the professional to ensure that work is done at the targeted intensity while respecting the participant’s tolerance.
Each 60-minute APA session is composed of a verbal contact sequence, warm-up exercises (5 to 10 minutes), aerobic, resistance or balance exercises (40 minutes), a cool-down period (5 to 10 minutes) and finally a verbal feedback sequence. The warm-up and recuperation periods and verbal sequences are account for at least 30% of the session duration. During the e-APA program, participants are asked to report and estimate, in a dedicated activity digital booklet on the SAPATIC platform, their dyspnea (on a visual analogue scale) as well as their perception of the effort and muscle pain in the pre- and post-session periods. This booklet can be used to help participants recall exercises performed and difficulties encountered. Real-time videoconferencing plus heart rate monitoring allow the professional to assess the participant’s tolerance and difficulties in completing the targeted PA level during aerobic training, resistance exercises, and balance exercises.
Control group
The participants (SZ and HV) assigned to the control group receive an e-HE program including web-delivered information on the main mental illnesses, the benefits of physical activity, healthy lifestyles (dietary balance, sleep cycle, stress management), alcohol, drug, tobacco and cardiovascular risk factors and are conducted with the same conditions (duration and frequency) as the active group. Individual training of participants in the e-HE group is carried out by researchers (EL, LB, MT, SG).
The 50-minute training is followed by a 10-minute quiz aiming to assess their involvement in the course.
Specific aims
The main objective of this study is to demonstrate that e-APA compared to e-HE can improve cerebral plasticity reflected by an increase in the overall hippocampal volumes in both the SZ and HV groups.
The secondary objective is to assess the impact of the active intervention (e-APA) compared to the non-active intervention (e-HE) on the following other variables in both SZ and HV:
- Cerebral variables (volumetric changes in the different subregions of the hippocampus (cornu ammonis (CA: CA1, CA2-3-4), subiculum and dentate gyrus); cerebral cortical thickness; N-acetyl aspartate (NAA) reflecting neuronal integrity in the hippocampus; integrity of white matter in whole brain and in the frontomedio-hippocampal fibres; and cerebral blood irrigation)
- Physiological variables (i.e., neuromuscular, cardiovascular (heart rate variability) and aerobic)
- Cognitive variables (i.e., working memory, episodic memory, attentional and executive functions)
- Circadian rhythms (i.e., temperature, motor activity (actimetry) and wake-sleep cycle)
- Clinical status of participants (i.e., severity of symptoms only for SZ, quality of life, level of activity and physical abilities)
- Biological variables (i.e., fasting glucose and lipidic dysregulation)
Assessments
All participants are assessed at 2 time points for the primary endpoint (V1 and V6) and at 6 time points for the secondary endpoints (from V1 to V6). The first assessment occurs at baseline (V1) prior to randomization. The final assessment takes place after completion of the intervention (V6). Other visits occur during the intervention (V2, V3, V4, V5). The content of all assessments (V1, V2, V3, V4, V5 and V6) is outlined in Table 3.
Primary endpoint
The primary outcome is the change in left and right hippocampal volumes between V1 and V6. Neuroimaging data is acquired on a 3 Tesla scanner (Intera Achieva 3T Quasar Dual, Philips Medical System, Netherlands) at V1 and V6. A proton density-weighted T2 image focalized on the hippocampus is acquired using anatomical MRI (aMRI).
Secondary endpoints
The secondary outcomes consist in assessing neuroimaging data, neurocognitive, clinical, biological, cardiorespiratory function, body composition and muscle strength, motor activity and circadian rhythms, psychoactive substance use, and psychosocial functioning between different visits (V1 to V6) (see Table 3).
Neuroimaging
Volumetric changes in the different subregions of the hippocampus are assessed from proton density-weighted T2 images; cerebral cortical thickness will be assessed from T1-weighted images using aMRI; NAA in the hippocampi is assessed using the magnetic resonance spectroscopy; integrity of white matter is assessed through diffusion parameters (fractional anisotropy, radial diffusivity and mean diffusivity reflecting the number of axons and the degree of myelination of fibres) using diffusion tensor imaging; the functional resting state is assessed with functional MRI; and cerebral blood irrigation is assessed through arterial spin labelling imaging.
Neurocognitive tests
Episodic and/or working memories are assessed using the Wechsler Adult Intelligence Scale (WAIS) Memory subtest [64, 65], the Rey Auditory Verbal Learning Test (RAVLT) [66] and the Corsi test [65]; attentional functions are assessed using the Stroop test [67] and the WAIS Coding subtest; executive functions are assessed using the Trail Making Test (TMT) [68], the d2 test [69] and the verbal fluency [70].
Clinical symptoms
Psychotic and affective symptoms are assessed using the Positive and Negative Syndrome Scale (PANSS) [71], Self-Assessment of Negative Symptoms (SNS) [72], Brief Negative Syndrome Scale (BNSS) [73], and Hospital Anxiety and Depression Scale (HADS) [74]. General symptoms are appraised using the Clinical Global Impression scale (CGI) [75]. Insight of illness is evaluated with the Insight Scale (IS) [76].
Biological data
Fasting blood exams are performed in order to measure the level of glucose, triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDLc), and low-density lipoprotein cholesterol (LDLc).
Cardiorespiratory fitness
Maximal oxygen uptake (V02max) are measured at V1 and V6 during a maximal exercise test on an electromagnetic bicycle ergometer (Ergoline er900®). The exercise test is triangular by direct measurement. Participants have to pedal as long as possible while the load is increasing by 20 watts every 2 minutes. Developed power, 02 and CO2 flow rates are recorded before the beginning of the test (resting values), at each level (relative values), until the end of the test (maximal values) and during the following 3 minutes of passive recovery (recovery values). Heart rate and electrocardiogram are also recorded continuously, and blood pressure is recorded at the end of each level. The ventilatory regime and gas exchange are measured cycle to cycle continuously with a pneumotachograph. Parameters such as ventilation, oxygen consumption and respiratory quotient are recorded.
Body composition and muscle strength
Body composition assessment is performed using the BIA101® impedance analyser, which measures body impedance using four electrodes (two on the right wrist and two on the right ankle). The patient is lying down to avoid any pressure variation that would affect the accuracy and reproducibility of the measurements.
Evaluation of maximal muscle strength is recorded with a hand dynamometer (model TK-200®). The force developed in isometry by the upper limbs (the gripping force of the hand) is analysed. Three successive measurements are collected in a standardized position for each arm, consisting of an orthostatic position with their arm at the side and the instrument held in the extension of the forearm. A recovery of one minute is granted between each repetition. Participants need to maintain their effort for 6 seconds to record maximal muscle tension.
Motor activity and circadian rhythms
Actimetry recording is performed continuously for 7 days at baseline (V1) and after the intervention (V6) using a lightweight, autonomous and waterproof actimeter (e-tact actimeterâ, BodyCap, France). The following parameters are analysed with ACTISOMM® software [77]: duration of the total night rest period; duration of the total period of daytime activity; average night activity; average daytime activity; magnitude, mesor and acrophase of circadian rhythms of motor activity; and night inactivity index (%) (corresponding to the number of minutes where the amount of movement is zero, divided by the number of minutes of the night). Coupled with the sleep schedule, the data allow us to analyse the sleep/wake cycle.
The GPAQ [62] is completed by participants. It collects information on the practice of PA in the following three situations (i.e., activities at work, moving from place to place, and recreational activities) and on sedentary behaviours. This questionnaire is used as part of the program start interview, because it provides a diagnostic evaluation of the participant's habits, allowing the APA program to be individualized.
Moreover, central temperature recording is performed via the gastrointestinal tract using the e-Celsius® performance telemetry system (BodyCap, France) before and after the intervention program. The temperature is recording from ingestion until faecal elimination of the capsule. This device consists of a portable monitor that allows the continuous collection and recording internal temperature data. This electronic capsule, made in a biocompatible PVC (polycarbonate) envelope, consists of a temperature sensor that measures the gastrointestinal temperature every 30 seconds. The temperature data are then transmitted by telemetry to the monitor which records them in real time.
Psychoactive substance use
The severity of alcohol use is appraised with the Alcohol Use Disorders Identification Test (AUDIT) [78]. This tool is a 10-item screening questionnaire with 3 subscales: the first scale includes 3 questions on the amount and frequency of drinking; the second scale includes 3 questions on alcohol dependence; and the third scale includes 4 questions on problems caused by alcohol. Low-risk consumption is defined by an AUDIT score below 6 for women or 7 for men; a score between 6 for women or 7 for men and 12 determines excessive alcohol consumption, whereas a score greater than or equal to 13 in either gender suggests alcohol dependence.
Participants are also asked about current or past tobacco consumption, their desire to quit tobacco and their degree of dependence according to the Fagerström test for Nicotine Dependence [79]. Little or no dependence was defined by a score of 0 or 1, moderate dependence by a score of 2 or 3, and severe dependence by a score above 3.
The use of cannabis is assessed by the Cannabis Abuse Screening Test (CAST) [80]. It is a 6-item scale designed for adolescents and young adults to identify problematic forms of cannabis use that might lead to negative social and health consequences. Scores can vary from 0 to 24, and users are defined without risk when they have a score below 3, with a low risk for a score equal to 3 and below 7 or with a high risk of dependence for a score greater than or equal to 7.
Psychosocial functioning
The Social Adjustment Scale Self-Report (SAS-SR) [81] provides an understanding of an individual’s level of satisfaction with his or her social situation.
Ryff’s Psychological Well-Being Scale (PWB) [82] evaluates the participant’s psychological well-being through six dimensions (autonomy, environmental mastery, personal growth, positive relations with others, purpose in life, and self-acceptance).
Sample size calculations
The number of participants to be included takes into account the risk of participants being lost to follow-up. Based on preliminary and comparable studies (12-week PA program in SZ), one could estimate that 20% of participants would discontinue the protocol prematurely [83].
Given the literature regarding the impact of PA on hippocampal volume in SZ [84], a difference of 6% between mean volume changes (as a percentage of total brain volume) between groups with and without PA for a standard deviation of hippocampal volume(s) of 8% is quite conceivable and clinically relevant based on Pajonk’s study [84]. The standard deviation (Sv) of the change in hippocampal volume(s) is estimated at 5% based on a correlation coefficient (r) between baseline assessments (V1) and at the end of PA program at least equal to 0.8.
For an alpha risk of 5% and a power of 80%, the number of participants to be included per group is 12. Given the small number of participants and a distribution of changes in relative hippocampal volumes possibly not being normal, a Mann-Whitney test can be used. In this case, a correction must be made using the ARE (asymptotic relative efficiency) of the Mann-Whitney test in relation to the Student's test, which amounts to the following ratio: 12 / 0.864 = 14, i.e., the number of participants to be included per group. While it is customary to consider a 20% increase for those lost to follow-up, this brings the number of participants to 17 per group. Our inclusion capacity is higher, and to meet the tests that will be carried out for the secondary objectives, 84 participants are included (21 for each of the 4 groups).
Statistical analysis
In order to meet the main objective, Student’s t-test will be used to determine if the averages of two samples are significantly different (SZ_e-APA vs SZ_e-HE). In a first step, to analyze primary and secondary outcomes, analyses of covariance (ANCOVAs) will be computed between the four groups of participant (SZ_e-APA vs. SZ_e-HE vs. HV_e-APA vs. HV_e-HE). Primary or secondary outcomes will be considered as the dependent variable and the group as the independent variable. In a second step, gender and age will be included as covariates in the analyses. Post-hoc analyses will be conducted when a significant main effect is observed using a Tukey’s HSD test to correct for multiple comparisons. We will also conduct intra-group Pearson correlation analyses in the SZ groups to evaluate the relationships between neuroimaging, physiological data with clinical, neurocognitive data and medication. The same correlations will be tested in the HV group except with medication. The correlations will be considered statistically significant after the adjustment for multiple comparisons. All statistical analyses will be performed with JMP v12.0 Software (SAS Institute, Inc., Cary, NC) or IBM®-SPSS® 25.0 (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp). The significance level is set at P ˂ 0.05.
Study outings before the start or the beginning of interventions (e-APA or e-HE) before the 10th session will be systematically replaced. Study outings after the 10th session will be not replaced. Any participant who leaves prematurely program after the 10th session and before the end of the study will benefit for all the examinations planned at the end of the study. Causes of nonobservances will be analyzed and listed. Rates and reasons for premature study outing will be analyzed in relation to their impact on the obtained results. In case of premature outing, data will be collected in the CRF at the time of the event and will be taken into account in the analysis of the primary outcome (hippocampal volumes) if the number of planned sessions exceeds 75% (24 sessions or more). Analysis will be conducted in intention to treat and will concern all of the variables. Non-compliant participants will be defined as the absence to 4 consecutive sessions.
Data management and monitoring
Data are initially collected and anonymously registered using paper forms (CRF), which are then securely stored and extracted into protected electronic files (e-CRF) in Ennov Clinical Software®.
The medical procedures used in this trial comply with the most recent recommendations of the Declaration of Helsinki and French Public Health Law 2004-806 of 9 August 2004 on participant protection and safety in accordance with good clinical practice. A data manager mandated by the trial sponsor (CHU de Caen, Avenue de la Côte de Nacre, CS30001, Caen, France) ensures monitoring of this trial to guarantee that accurate, full, and reliable data are collected.
At the end of the study, the data review committee, comprising the data manager and the biostatistician will review all deviations from the protocol. The committee will qualify deviations as major or minor and shall clarify the relevance of the data with respect to these deviations: conservation of the data (for minor deviation) or exclusion of the data (for major deviation).
Safety and emergency procedures
All adverse events (AEs) reported by the participants or observed by the clinicians and the APA professionals are recorded. All serious AEs are reported to the ANSM.
The clinical investigator is responsible for the record of all the relevant information regarding any event occurring during the e-APA or e-HE program. The investigator is requested to assess the relationship between the intervention and occurrence of each AE using clinical criteria. Alternative causes, such as natural history of the underlying diseases, concomitant therapy, other risk factors, and temporal relationship of an event to the intervention, are considered and investigated.
The investigators and all other appropriate persons are informed of events that could adversely affect the safety of participants in a timely manner during the study duration.
Participants are able to interrupt their participation in the study if they wish, at any time and for whatever reason, or according to the decision of the investigator. Reasons for premature study exit can include a relapse requiring hospitalization or a significant increase in medications, a refusal by the participant to continue, a withdrawal of consent, a protocol violation requiring a study exit, a serious AE, a decision of the investigator, and a decision of the funding agency or French Health authorities.
Dissemination policy and data sharing
The University Hospital of Caen will keep participants informed of the overall results at the end of the study. All publications must comply with the rules set out in the Consortium Agreement and the International Committee of Medical Journal Editors (ICMJE). In case of additional studies, the results can only be published with the agreement of the principal investigator and the statistician, and only after publication of the main study to be quoted. Analysis of the results will be the object of communications in congresses and publications. The text of publications and papers will be discussed with all investigators participating in the trial.