Participants
200 individuals with schizophrenia will be recruited in 9 centers. Each participating center will include 20 eligible participants in the study; except for the Montpellier center which will include 40 participants. The study protocol has been approved by the Ethical Committee (CNRIPH : 19.11.29.43226) in accordance with the Helsinki Declaration. Written informed consent will be obtained by all participants. The study report will comply with the Consolidated Standards of Reporting Trials (CONSORT) statement and CONSORT-NPT (non-pharmacologic treatments) statement.
Eligibility Criteria
Inclusion criteria:
Patients eligible in participating in this study must comply with the following criteria:
1) Age between 18 and 60 years;
2) Signature of informed consent form. If patients have a tutor, they will have to sign the informed consent form too;
3) Patients with a diagnosis of schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM 5) established and validated by the study center’s investigating psychiatrist;
4) Patients with a score at the “Multidimensional Fatigue Inventory” (MFI) greater or equal to 10;
5) Patients with a follow-up in a day hospital at inclusion;
6) Subjects must be able to attend all scheduled visits and to comply with all trial procedures;
7) Participation of the patient must be noted in their medical files;
8) Subjects must be covered by public health insurance.
Exclusion inclusion criteria are:
Patients will not participate in this study if they meet any of the following criteria:
1) Subject unable to read and/or write French;
2) Planned long-term stay outside of the study region that prevents compliance with the treatment plan;
3) Patients with a history of severe brain trauma;
4) Patients with a history of neurological pathology;
5) Pregnant or breast-feeding patients.
Study Design and Setting
This ENERGY trial is a two-arm study (ENERGY intervention versus TAU), single blind randomized and controlled clinical trial designed to assess the efficacy of an individual cognitive and behavioral therapy in patients with schizophrenia. We adhered to the Consolidated Standards of Reporting Trials (CONSORT) guidelines in the design of the trial.
Patients meeting all of the inclusion criteria and none of the exclusion criteria will be invited to participate in the study. After signing the informed consent form, they will be randomized into one of the two study arms: ENERGY intervention or TAU.
They will be assessed at baseline over a one-week period for fatigue, global functioning, symptomatology, sleep, cognitive functioning and antipsychotic medication. Blood samples will be collected. Patients will be re-assessed 3 months later (corresponding approximately to the end of the ENERGY intervention; if the intervention is delayed, this intermediate assessment will be performed as soon as the intervention is completed and within 15 days of the end of the intervention) and 9 months later (approximately 6 months after the intervention with a delay of 15 days maximum) for fatigue, symptomatology, global functioning, sleep, cognitive functioning and antipsychotic medication. Blood samples will be collected at each of these assessment times.
This study is multi-centered, and will be carried out in 9 of the 10 centers participating in the French national network of schizophrenia expert centers (FondaMental Foundation). Each center will recruit patients to both groups and therefore perform the ENERGY intervention. The following centers will be participating in this study:
- Hôpital la Colombière, Centre Hospitalier Universitaire (CHU) de Montpellier
- CHU de Clermont Ferrand
- Hôpital Albert Chenevier, Créteil
- Hôpitaux Universitaires de Strasbourg
- Hôpital Sainte Marguerite, Marseille
- Hôpital Louis Mourier, Colombes
- Hôpital le Vinatier, Lyon
- Centre Hospitalier Alpes Isère
- Hôpital Charles Perrens Bordeaux
This study protocol has been reported in accordance with the “SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents” (Additional file 1).
Justification of the Study Design
This clinical trial is designed to assess the efficacy of an individual cognitive and behavioral therapy in patients with schizophrenia by comparing results from the ENERGY intervention to TAU.
We chose a single blind study to ensure that the psychologist performing the evaluations will be blinded to the randomization arm. It is not possible for patients following the ENERGY intervention to be in a blinded condition.
For the comparison group, called “treatment as usual” (TAU), no definition of classical usual care for patients with schizophrenia exists; the only consensus is that antipsychotic medication is essential [20,21]. Furthermore, French data show a high rate of care in day hospitals for patients suffering from schizophrenia, with day hospital care accounting for 40% of outpatient care [22]; 84% of French sectors have at least one day hospital [23]. So, the TAU could be defined by antipsychotic medication coupled with day hospital care.
Intervention description
Experimental group:
- Treatment as usual (see below), and
- ENERGY Intervention:
- 14 sessions of 1h CBT intervention
- 1 session per week
- With a psychologist (different to the psychologist who will perform the assessments)
- Individual sessions
ENERGY intervention is a cognitive-behavioral intervention developed by Knoop and Bleijenberg [24] and adapted in French by Cantin and colleagues [25]. The ENERGY intervention will be delivered according to a standardized treatment manual comprising six modules addressing fatigue and sleep over 14 individual therapy sessions (Table 1). The treatment encompasses the core CBT principles of psycho-education, behavioral activation, behavioral experiments, cognitive restructuring, problem-solving and relapse prevention [26]. Sessions will follow the traditional CBT structure of agenda setting, review of homework tasks, and introduction of a new concept/technique with collaborative discussion on how to implement such strategies in the participant’s day-to-day environment [26].
Table 1. Treatment modules and therapeutic aims
Module Content Summary Aims
|
1
|
Psychoeducation
CBT Framework
|
Shift unhelpful beliefs around symptoms
Encourage understanding of link between activity levels and sleep habits with syndrome maintenance
|
2
|
Reorganize Daily schedules
|
Initiate pacing of tasks, with optimal number of rest breaks
Increase hygiene practices
|
3
|
Energy conservation
|
Integrate meaningful activities depending on goals and available energy
|
4
|
Cognitive restructuring
Sleep interventions
|
Modify rest and sleep appraisals
Stimulus control, bedtime restriction, hypersomnia management
Relaxation
|
5
|
Strategies for physical and mental fatigue
|
Environmental modification, restructuring tasks
Cognitive strategies for information processing, attention and time pressure management
|
6
|
Review techniques
Relapse prevention
|
Consolidate treatment gains
|
The CBT framework for addressing fatigue and sleep disturbance was adapted from previous treatment manuals for Chronic Fatigue Syndrome and insomnia, with further modifications made to its content and delivery [27,28]. To account for possible cognitive impairments frequently encountered in schizophrenia, a specific focus was made on implementing cognitive strategies (e.g., preventing information overload, memory aids, time-pressure management), specific napping schedules and re-organizing activity levels as a means of energy conservation in addition to pacing and graded activity exposure. Deficits in memory and executive functioning are common in individuals with schizophrenia and may be further exacerbated by poor sleep and persisting fatigue. Relative to conventional CBT, greater structure was imposed in sessions with concrete principles as well as more directive guidance from therapists in problem solving and generating alternative helpful thoughts. Simplified hand-outs with pictorial cues were provided after each session to minimize information overload and demands on memory. External aids such as diaries and reminders were used to prompt participants to complete prescribed tasks across the week.
Control group:
Treatment as usual comprises antipsychotic medication, day hospital and ambulatory care during all the study.
Concomitant care: no concomitant care is prohibited during the trial.
Outcome Measures
We will use a majority of French validated scales and cognitive tests, designed for and commonly used in schizophrenia patients.
Primary outcome measures
The primary outcome measure is the score at the Multidimensional Fatigue Inventory (MFI) [29]. The MFI is a self-assessment instrument with 20 items including 5 dimensions: General, Physical, and Mental Fatigue, Reduced Motivation and Reduced Activity. It was validated in 93 patients with schizophrenia spectrum disorders. The test–retest showed a correlation between .66 and .91 for all subscales of MFI. The internal consistency was .92. The analysis of convergent construct validity showed a correlation of .68 (time 1) and .77 (time 2). No item was systematically identified as being difficult to answer [30].
Secondary outcomes measures
Secondary outcome measures will include global functioning, symptomatology, sleep, cognitive functioning and antipsychotic medication, as well as blood samples:
Symptomatology
Positive and Negative Syndrome Scale (PANSS) [31]: The PANSS is a 30 items scale designed to note specific symptomatology of psychotic disorders from 1 to 7. The results include a positive, negative, general psychopathology and total score allowing categorical and dimensional quotation. The 5 dimensions of this scale were validated in French [32].
Clinical Assessment Interview for Negative symptoms (CAINS) [33]: The Clinical Assessment Interview for Negative Symptoms (CAINS) was developed through a multistage scale development process to measure current level of severity of negative symptoms in individuals with schizophrenia and schizoaffective disorder. The time frame for the ratings is the previous week. The scale was designed for use in treatment trials but it can also be used in other types of negative symptom research.
The CAINS comprises two subscales: the nine-item Motivation and Pleasure scale and the four item Expression scale. A composite of the two subscales can be computed.
All ratings are based on a semi-structured interview with prompts and queries. Items are rated on a 5 point (0-4) scale, ranging from 0 (absence of symptom) to 4 (severe symptom level). It should be noted that lower “impaired” scores on several of the items might be within the range of normal variation in the general population. All ratings should be made based solely on descriptors in the anchors without attempting to compare them to clinical or non-clinical reference groups. French validation is in progress by our team with author permission.
Calgary Depression Scale for Schizophrenia (CDSS) [34]: the CDSS is an easy and quick 9 items scale, designed specifically to evaluate depression in schizophrenic patients. The scale was derived from two existing scales by factor analysis and reliability analysis. It has been further tested in two samples. In the first it has been shown to be reliable, congruent with a self-report scale and valid. In the second sample it has been shown that there is no overlap with negative or extrapyramidal symptoms [34]. THE CDSS has been validated in French [35].
Sleep
Berlin Questionnaire (BQ) [36]: The questionnaire consists of 3 categories related to the risk of having sleep apnea. The BQ incorporates questions about snoring (section 1), daytime somnolence (section 2), hypertension and BMI (section 3). In the first section, the participants are asked to score their snoring. In the second section, daytime fatigue and sleepiness during daily activities are investigated, and in the last section, medical history, demographic, and anthropometric measures such as height and weight, can be evaluated. The first two sections are assumed to be positive, if the total score is 2 or more. If a patient has hypertension or a BMI higher than 30kg/m2, section 3 can be considered positive. In general, if there are two or more sections with positive scores, this subject is categorized as “high risk” for OSA (obstructive sleep apnea).
Idiopathic Hypersomnia Severity Scale (IHSS) [37]. The IHSS is a self-report measure of hypersomnolence symptoms, consequences, and responsiveness to treatment. The IHSS is a 14-item self-administered questionnaire that assesses nighttime sleep symptoms and the related sleep inertia (5 items), daytime sleep symptoms and the related sleep inertia (4 items), and impaired daytime functioning due to hypersomnolence (5 items). All items are scored from 0 to 3 or 4, depending on severity, that provide a score, ranging from 0 to 50, with the highest score reflecting more severe and frequent symptoms.
Sleep Condition Indicator (SCI) [38]: The SCI is a brief 8 items tool to evaluate insomnia based on DSM 5 criteria. The SCI assesses night time and daytime symptoms, and focuses both on the frequency and persistency of these symptoms. The French version of the Sleep Condition Indicator demonstrates satisfactory psychometric properties while being a useful instrument in detecting cases of insomnia disorder, consistent with features of DSM-5 [39].
Physical functioning
International Physical Activity Questionnaire short form (IPAQ)[40]: The IPAQ considers a 7-day recall period, identifying physical activity undertaken in the morning, afternoon and evening. For the purposes of this research the questionnaire was interviewer administered. Data from the IPAQ is summarized according to minutes per week of walking, minutes per week of moderate physical activity (e.g., activities that take moderate physical effort and make you breathe somewhat harder than normal such as carrying light loads, bicycling at a regular pace, or easy swimming), and minutes per week of vigorous physical activity (e.g., activities that take hard physical effort and make you breathe much harder than normal such as heavy lifting, digging, aerobics, or fast bicycling) per week. Previous research demonstrated that the IPAQ is a reliable surveillance tool to assess levels of physical activity in patients with schizophrenia [41].
Quality of life and general functioning
Quality of life (S-QoL) [42]: The S-QoL is a self-administered instrument to assess health-related quality of life (HRQL) among people with schizophrenia. The S-QoL, based on Calman’s approach to the subject’s point of view, is a multidimensional instrument that is sensitive to change. The scale is a 41-item questionnaire with eight subscales (psychological well-being, self-esteem, family relationships, relationships with friends, resilience, physical well-being, autonomy and sentimental life) and a total score. The validation study showed high internal consistency reliability, reproducibility and responsiveness. Construct validity was confirmed using established clinical and HRQL measures. The S-QoL is an efficient instrument for the measurement of the impact of schizophrenia on individuals’ lives.
Functional Remission of General Schizophrenia (FROGS) [43]: The FROGS evaluates patient functioning. It was developed using the expert consensus method following a MEDLINE and standard database search. 19 items were selected as gathering the core aspects of functional remission in schizophrenia detected in the literature. The FROGS was then evaluated in 432 patients with DSM-IV criteria of schizophrenia, all of them meeting the symptomatic remission criteria, total scores were shown to be highly reliable. Exploratory factor analysis after oblique rotation revealed that a three-factor solution was the most meaningful. On the basis of item content these three factors were labelled « Social Functioning », « Daily Life », and « Treatment ». The FROGS total score can be used to measure a general construct for the evaluation of functional remission in schizophrenia.
Intrinsic Motivation Inventory for Schizophrenia Research (IMI-SR) [44]: Intrinsic motivation is an important mediating factor between neurocognition and psychosocial outcome. The IMI-SR is a self-report IM scale that gauges the central motivational structures identified by Self-Determinism Theory as pertinent to cognitive task engagement, skill acquisition, treatment compliance, and remediation outcome. The IMI-SR is a concise instrument, possessing good internal consistency and test-retest reliability. The final form has 21 items questionnaire comprised of 3 domains relevant to motivation for treatments (interest/enjoyment, perceived choice, value/usefulness). The IMI-SR is a viable instrument to measure intrinsic motivation in schizophrenia as part of a cognitive remediation protocol or psychosocial rehabilitation program.
All the previously mentioned measures will be implemented at baseline, 3-month, and 9-month follow-up.
Cognitive assessment
French National Adult Reading Test (fNART) [45]: The test consists of 40 words, graded in difficulty, whose pronunciation cannot be determined from their spelling. The ability to successfully read irregularly spelt words is relatively robust in the face of current cognitive impairment and is a sensitive marker of intellectual attainment. The fNART is a reliable and valid method of assessing premorbid intellectual ability in French speakers.
California Verbal Learning Test (CVLT) [46]: The CVLT was developed to evaluate in a multifactorial way verbal learning and memory. It has the particularity to quantify several cognitive components of verbal memory in only one test. Its duration is around 20 min. A list of 16 words (four from each of four semantic groups) is presented orally to the participants, who are required to recall the words immediately, after short and long delays and also with and without semantic cues. A recognition task is then administered. The test includes the following measures to reflect learning and recall, also called primary variables: Total Trial 1–5, Short Delay Free Recall (SDFR), Short Delay Cued Recall (SDCR), Long Delay Free Recall (LDFR), and Long Delay Cued Recall (LDCR). It also includes other variables that reflect processing of information and other cognitive processes such as Semantic Clustering and Serial Clustering, Region effects, Intrusions, and Perseverations.
Trail Making Test (TMT) [47]: Trail Making Test reflects the control of attention, visual exploration, speed and mental flexibility. The subject is asked to connect, by making pencil lines, encircle numbers randomly arranged on a page in proper order (Part A) and encircle numbers and letters in alternating order (Part B). A French version of the normative data will be used.
Biological measures
The following biological measures will be taken at baseline, 3-month and 9-month follow-up: weight, BMI, abdominal perimeter, hearth rate, and blood pressure.
Pedometer: is an electronic portable device, which counts each step a person takes by detecting the motion of the person’s hands or hips. Distance travelled (by walking or any other means) can be measured directly by a global positioning system (GPS) receiver. Our objective is to measure steps and distance covered by patients. Each patient will wear the pedometer during one week, 3 times during the trial: at inclusion, at 3 months, just after the end of the therapy and at 9 months just before the end of the study.
- Glycaemia, lipids and C-reactive protein (CRP) will be performed with only one tube of 5 ml (dry tube)
- Granulocyte-macrophage colony-stimulating factor (GM-CSF), interferons (IFN)-γ, interleukins (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, tumor necrosis factors (TNF)-α : This kit is comprised of components for the measurement of human GM-CSF, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and TNF-α in serum, plasma, or tissue culture supernatant. They will be tested by Enzyme-linked immunosorbent assays: Commercially available enzyme-linked immunosorbent assay (ELISA) kits will be used according to the manufacturers' recommendations for measuring concentrations of intestinal fatty acid binding protein (I-FABP) (Clinisciences), soluble cluster of differentiation 14 (CD14) (Enzo), lipopolysaccharide binding protein (LBP) (enzo), zonulin (Servbio).
Microbial Translocation:
DNA extraction: Plasma samples will be collected in Ethylenediaminetetraacetic acid (EDTA)-anticoagulated tubes and stored at -80°C. Deoxyribonucleic acid (DNA) will be extracted from 200 µL of plasma using the EZ1 DNA Tissue kit (Qiagen, Courtaboeuf, France) according to the manufacturer’s instructions. DNA will be eluted in a 100 µL final volume.
16S rDNA real-time PCR: Bacterial 16S rDNA levels will be measured by qPolymerase chain reaction (PCR). A 20 µL amplification reaction consisted of 4 µL of LightCycler FastStart DNA MasterPLUS HybProbe (Roche, Meylan, France), 0.5 µmol/L forward and reverse primers, 1 µmol/L TaqMan probe and 10 µL of the template plasma DNA. Degenerate forward (16S-F: 5'-AACAGGATTAGATACCCTGGTAG-3' nucleotide 780 to 802) and reverse (16S-R: 5'-GGTTCTKCGCGTTGCWTC-3' nucleotide 962 to 979) primers will be used to amplify the hypervariable region V5 of the 16S gene. Carboxyfluorescein stained probe (16S-probe: 5’- fluorescein amidites (FAM)-AACAC5TGCTCCACCGCT-BHQ1-3’ nucleotide 937 to 948, where FAM means 6-carboxyfluorescein and BHQ1 means Black Hole Quencher I) will be used as described by Kramski and colleagues [48]. The amplified region is 199bp. The DNA is independently amplified twice in duplicate, and mean values are calculated. A negative control (molecular biology grade water) is systematically used. A standard curve is created from serial dilutions of plasmid DNA containing known copy numbers of the template. The reaction conditions for amplification of DNA are 95°C for 10 min, followed by 45 cycles at 95°C for 15 s, 60°C for 60 s. The assays are performed using a LightCycler 480 II (Roche), with absolute quantification analysis performed with the Lightcycler 480 software (Roche), version 1.5, according to manufacturer’s recommendations.
Other data collected
Socio-demographic data:
At inclusion we will record: age, gender, education level, marital status, occupation, living status, income level.
Medical History:
At inclusion we will record: age at first episode, duration of untreated psychosis, comorbid disorder including addictions, and other somatic diseases.
Current drug therapy and psychosocial interventions will be recorded at each visit.
Biological sampling collection
We will collect blood samples:
- 5ml on dry tube for glycemia, CRP and lipids on dry tube
- 1,5 ml for microbial translocation on dry tube
- 5 ml for Interleukins and Cytokins on dry tube
Glycemia, CRP and lipids will be dosed in each of the 10 centers and results noted in the eCRF.
Microbial translocation analysis will be centralized in Nîmes, U1047 Inserm Unit and Interleukins and Cytokins analysis will be centralized in CHU Montpellier.
Samples will be stored in each center in a -80°C fridge until the end of the study and sent to the analysis centers with dry-ice.
The blood samples for Cytokins need to be centrifuged before freezing within 24 hours from time of collection. Samples will be stored in Montpellier and preserved for 15 years.
Participant Timeline
Participants will be assessed at the beginning of the study, then re-assessed 3 months later (corresponding approximately to the end of the ENERGY intervention; if the intervention is delayed, this intermediate assessment will be performed as soon as the intervention is completed and within 15 days of the end of the intervention) and 9 months later (approximately 6 months after the intervention with a delay of 15 days maximum) for fatigue, symptomatology, global functioning, sleep, cognitive functioning and antipsychotic medication. Blood samples will be collected at each of these assessment times (see Figure below).
Planned Trial Calendar
Planned regulatory period: 6 months
Planned duration of recruitment: 36 months
Duration of participation of each subject: 9 months
Planned statistical analysis/valorization period: 6 months
Planned total trial period: 57 months
Visits Schedule
Item
|
Screening
|
Baseline
|
|
Final Visit
|
|
V0
|
V1
|
V2
|
V3
|
Date
|
|
Day 0 +7 days
|
3 months
±15days
|
9 months
±15days
|
Informed consent
|
X
|
|
|
|
Medical history
|
X
|
|
|
|
Treatment
|
|
X
|
X
|
X
|
Socio-demographic data
|
|
X
|
|
|
Clinical evaluation
|
|
|
|
|
PANSS
|
|
X
|
X
|
X
|
CAINS
|
|
X*
|
X*
|
X*
|
CDSS
|
|
X
|
X
|
X
|
IHSS
|
|
X*
|
X*
|
X*
|
BQ
|
|
X*
|
X*
|
X*
|
SCI
|
|
X*
|
X*
|
X*
|
Fatigue
|
|
|
|
|
MFI
|
X
|
X
|
X
|
X
|
Physical functioning
|
|
|
|
|
IPAQ
|
|
X*
|
X*
|
X*
|
Quality of life and functioning
|
|
|
|
|
S-QoL
|
|
X
|
X
|
X
|
FROGS
|
|
X
|
X
|
X
|
IMI-SR
|
|
X*
|
X*
|
X*
|
Cognitive assessment
|
|
|
|
|
fNART
|
|
X
|
|
X*
|
CVLT
|
|
X
|
|
X*
|
TMT
|
|
X
|
|
X*
|
Biological measures
|
|
|
|
|
Pedometer1
|
|
X
|
X
|
X
|
Physical examination and Vital signs2
|
|
X
|
X
|
X
|
Blood sample
|
|
X*
|
X*
|
X*
|
Microbial translocation
|
|
X*
|
X*
|
X*
|
* specific to the project
- The pedometer will be used one week before each evaluation
- Physical examination includes: weight, BMI, abdominal perimeter, Vital signs include: heart rate, and arterial blood pressure
Determination of sample size and power calculation
The main objective is to evaluate the efficacy of a therapeutic protocol for the management of fatigue in schizophrenia patients. The change in fatigue level will be compared 6-month after the intervention (9-month follow-up) between two groups of patients: one following the 3-month individual program for the management of fatigue, and one receiving care as usual. The sample size calculation is based on the change in the general fatigue score, one of the five sub-scales of the Multidimensional Fatigue Inventory (MFI) [29], measured at inclusion and 9 months later.
A study exploring the psychometric properties of the MFI in 93 out-patients with schizophrenia spectrum disorders reported a mean score on the general fatigue subscale of 13.4 (standard deviation (SD): 3.9) [30]. An earlier study reported a mean score of 16 (SD 3.2) for this sub-scale in 166 patients with fibromyalgia and chronic widespread pain [49].
In our study of SZ patients attending a day hospital, with a general fatigue subscale score greater or equal to 10 at study entry, we can expect an average score of approximately 16 (SD 4) on this subscale.
We can also hypothesize a 2-point reduction in the mean score on this sub-scale between the start of the trial and the 9-month follow-up in the group receiving the intervention. No change in the severity of fatigue is expected in the group receiving treatment as usual. Under this effect-size hypothesis, with scores in both groups set at 16 (SD 4) at inclusion, the mean score in the group receiving the intervention is expected to drop to 14. Under the hypothesis of a stable standard deviation of 4 in both groups and at both time points, power set at .085 and alpha at p=0.05, 73 patients per group are necessary.
In order to allow for loses at follow-up (estimated for SZ patients at 15-20% over a 9-month period), it will be necessary to recruit 100 subjects per group.
The 9 centers participating in this study are part of the French network of expert centers in schizophrenia of the FondaMental foundation. Participants will be recruited directly from the day hospitals in each of the centers.
Methods: Assignment of Interventions
Randomization and Matching
After checking for all inclusion and non-inclusion criteria by the study investigator, patients will be randomized to either of the study arms (intervention or TAU). Allocation concealment will be guaranteed as the randomization will not be released until the participant has been recruited into the trial, taking place after all baseline measurements have been done.
Randomization will be performed by the Clinical Research Unit of the Department of Medical Information of the Montpellier University Hospital. Randomization will be stratified by study center. It will be centralized, accessible online, and programmed using the data Capture Software System (EnnovClinical randomization module) according to a minimization algorithm with a 1:1 ratio. The trial manager will be responsible for setting up and testing the randomization process, incorporating stratification by study center using random blocks 1:1, assuring that study groups of approximately the same size will be produced.
The patient number will be automatically generated by EnnovClinical software.
Blinding
The psychologists performing inclusion, 3 month, and 9 month assessments, will be blind to the allocations of the patients to either study arms of the randomized controlled study (RCT). Patients and psychologists performing the ENERGY therapy will be asked to avoid telling the assessor to which group they/the patient belongs to. A psychologist, blind to the randomization process, will perform the assessments, and another psychologist will perform the therapy interventions. Participants will be asked to not reveal their group allocation to the assessors. The data analysts that will be performing the analyses at the conclusion of the trial will also be blinded as to what group the data corresponds to. Unblinding should occur only in exceptional circumstances in case of any adverse events (AE) which will reported immediately to the investigator.
Methods: Data collection, management, and analysis
Data collection
Several scales and tests used in this study are comprised within the standardized evaluations performed in the schizophrenia expert centers and are therefore already used on a daily basis in the centers implicated in the study. Each year, all the members of the centers attend quotation sessions in order to ensure inter-rater validity.
For the scales specific to this study (MFI, CAINS, IMI-SR, IHSS, BQ, SCI, IPAQ), we will organize training sessions before the beginning of the protocol in the French expert schizophrenia Network. In addition, all schizophrenia expert centers meet monthly in Créteil, in a meeting organized by the FondaMental Foundation and have specific expertise in clinical, neuropsychological and biological evaluation in schizophrenia. All teams will be trained in the intervention the year before the beginning of the study to guarantee the homogeneity and quality of treatment across the centers.
Data will be collected or reported in an electronic Case Report Form (e-CRF) developed using the software Capture System EnnovClinical to control for data quality at entry. The connection is via a username and password unique to each specific user and giving access only to the data of the centers’ user. An audit trail function is included allowing a supervision and traceability of all actions from all users.
Concerning biological evaluations, we will have access to specialized platforms for Microbial translocation and inflammatory and immunologic dosing, localized in Nîmes and Montpellier allowing great communication with the study coordinator based in Montpellier.
Once a participant has been enrolled and randomized into their study arm, the study site will put in place every effort to follow the participant throughout the course of the study. In order to improve adherence and prevent loss to follow-up, we will organize, phone calls and/or emails that will be sent before the intervention to recall patients of their appointments. Patients will be already following day hospital care, which we believe will also increase adherence the study. Furthermore, each evaluation will be planned in accordance with each patients’ schedule and all patients will be phoned 24h before their evaluation to remind them of their appointment.
If a patient misses their appointment, the psychologist will call him/her. All attempts will be documented in the patient's medical records. In case of discontinuation, the investigator will perform all examinations scheduled for the final study visit, which includes recording of AEs. In any case, the patient will be treated in accordance with standard care in the center.
Investigators should make every effort to minimize the number of patients lost to follow-up and to obtain a maximum of information on patients lost to follow-up, particularly in the search for any AEs.
Data Management and monitoring
The patients will be identified by the patient code:
- Number of the center (1 digit)
- Number of the patient in the center, by chronological order of selection (2 digits)
- First letter of first name
- First letter of family name
Source documents
Source documents are original documents and patient records from which patient data are reported in the e-CRF. The investigator must commit to allow direct access to data sources in the study during inspections or audits.
The source documents that may be used to complete the e-CRF are the patient records. The investigator for each study center commits to allow direct access to the patient records during inspections or audits.
The encrypted data is transmitted to the data-management center via a secure internet connection.
The eCRF will be designed to capture all relevant medical information from patients included in the project. The study methodologist will have a restricted reader-only access to all data in order to monitor the progress and the quality of the data.
The purpose of an audit is to confirm that the study is conducted as per protocol, International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) and applicable regulatory requirements, that the well-being and the rights of the subjects enrolled have been protected, and that the data relevant for the evaluation of the investigational product have been recorded, processed, and reported in compliance with the planned arrangements. The investigators will permit a direct access to all study documents, drug accountability records, medical records and source data.
Data processing
Individual data needed for the study analysis must:
- be entered in the e-CRF as they are obtained, for both clinical and paraclinical data
- be anonymized by the investigator
- be authentified by an electronic signature of the investigator
- all be entered, and missing data must be justified
Site training and monitoring procedures
The monitor must present the protocol and all procedures related to the study during an initiation visit performed before the first patient is included. A case report form of completion guidelines will be provided to the Investigator.
The monitor will be allowed to have access to all source documents needed to verify the entries on the eCRF and other protocol-related documents.
To ensure accurate, complete, and reliable data, the sponsor or its representatives will do the following:
- Provide instructional material to the study sites, as appropriate
- Provide a start-up training session to instruct the investigator(s) and study coordinator(s). This session will give instruction on the protocol, the prompt and full completion of the clinical report forms, study procedures, and the transmission of data in a timely manner to the clinical database for statistical analyses
- Make periodic visits to the study site
- Be available for consultation and stay in contact with the study site personnel by mail, telephone, and/or fax
- Review and evaluate Case Report Form data and use
- Conduct quality review of database
Routine monitoring visits will be made by the monitors, designated by the sponsor to check compliance with the protocol, the completeness, accuracy and consistency of the data, and adherence to good clinical practice (GCP).
The principal investigator must ensure that eCRFs are completed in a timely manner and must allow periodical access to eCRFs, patient records, drug logs and all other study-related documents and materials.
The investigator will agree to provide the monitor direct access to the subjects’ source data, which may exist in the form of hospital records, patient files and notes, and laboratory assessment reports and results.
Considering the low risks in this study, there will be no formal Data Safety and Monitoring Board for this study.
Trial governance and monitoring
The sponsor is responsible for the administrative and financial management of the study, for its quality, and for the choice of the investigators and sites. The sponsor is also responsible in the assessment of sAE, in reporting any suspected unexpected serious adverse reaction (SUSAR) and new events according to the legislation and good clinical practices, to the competent authorities. In addition to the expedited reporting, the sponsor shall submit, once a year, throughout the clinical trial or on request, a safety report to the competent authorities and the Ethics Committee (EC) of the concerned Member States taking into account all new available safety information received during the reporting period. The aim of the annual safety report is to assess the safety conditions of subjects included in the concerned trial(s). It should be the same for the competent authorities (CA) concerned and the Ethics Committee concerned. The sponsor is responsible for the ongoing safety evaluation of the Investigational Product. The sponsor should promptly notify all concerned investigators and the regulatory authorities of findings that could affect adversely the safety of subjects, impact the conduct of the trial, or alter the CA approval/EC's favorable opinion to continue the trial.
The investigator is responsible for the study quality, the respect of the GCP and protocol during the conduct of the study. The investigator will ensure information on the study is given to participants and will check that they have given their informed consent. The study coordinator (psychologist in the department of the CHU Adult Psychiatry of Montpellier) will be in charge of coordinating the 9 centers: general organization (follow-up of inclusions of all centers), discussing progress, and study logistics. Each site will have a co-investigator responsible in contacting an appropriate pool of potential subjects and inviting them to participate in the study as well as ensuring the participants’ eligibility. A core project management team consisting of the principal investigator, all co-investigators, and study coordinator will meet monthly to oversee the general running of the trial.
Psychologists in each center will be in charge of assisting the investigators on site for the following:
- Management of study on site
- Reporting of data in the eCRF
- Verification of respect of study procedures
- Recruitments
Another psychologist, from each center, will deliver the ENERGY therapy.
The physicians will be responsible in presenting the study (information, consent, inclusion) and following the patients during the entire study. Study nurses will be responsible in the management of blood sample, freezing, and shipment.
The methodologist will be in charge of the quality of the data and the statistics
The laboratories implicated in the study will be in charge of the reception, storage and analysis of blood samples.
GCP requires that the clinical protocol, any protocol amendments, the informed consent and all other forms of patient information related to the study (e.g., advertisements used to recruit patients) and any other necessary documents be reviewed by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB). IEC/IRB approval of the protocol, informed consent and patient information and/or advertising, as relevant, will be obtained prior to the authorization of enrolling patients in the study. The study shall be conducted as described in this approved protocol. Any revisions/amendments to the protocol will not be permitted without prior approval by the study steering committee. Any amendments to the protocol will require IEC/IRB approval prior to implementation of any changes made to the study design.
Statistical Analysis
The statistical analysis plan (SAP), covering all the analyses to be performed on all data, will be written before database lock for final extraction.
For all collected variables, descriptive statistics will be shown for both study arms in order to verify the initial comparability of the groups. For metric variables, a check as to whether the data can be assumed to be normally distributed will be first conducted. For normally distributed variables, means and standard deviations will be calculated, whereas for skewed variables, medians and ranges will be given. For categorical variables group proportions and contingency tables will be prepared.
All tests of efficacy will be conducted on an intentions to treat (ITT) basis using, in case of missing data, the Last Observation Carried Forward method, and/or multiple or mean imputation [50]. A per protocol sensitivity analysis will also be performed taking into account only patients who completed the whole study without any major protocol deviations. This will enable us to reinforce the stability of results obtained by ITT approach.
Significance level will be set at p<0.05. All statistical analyses will be performed using SAS software (SAS Institute, Cary, NC, USA).
Main endpoint analysis
The efficacy of the ENERGY intervention will be studied firstly by comparing the change in fatigue score (using the scores on the MFI) between inclusion/randomization and the 9-month follow-up (primary outcome) in the intervention group compared to the TAU group.
For each subject, the relative difference (delta) between the inclusion and 9-month fatigue score will be calculated. The normality of the delta score will be tested using the Shapiro Wilk’s test. If the distribution is skewed a transformation will be performed to normalize it.
Study arms will be compared between inclusion scores and the 9-month scores using mean differences. These comparisons will be done using Student’s T-test and general linear regression models adjusting for covariates. Socio-demographic and clinical variables will be tested as potential confounders using general linear regression models, with the p-value set at 0.10.
A second analysis will be carried out with the general fatigue score as the outcome variable, adjusting for general fatigue score at inclusion.
Secondary endpoint analysis
The secondary outcome analyses will be assessed similarly to the main endpoint analyses. Specifically, for normally distributed variables, means and standard deviations will be used to conduct the analyses, whereas for skewed variables, medians and ranges will be used.
- A secondary outcome variable will be constructed, measuring the change in fatigue score (based on MFI scores) between inclusion scores and the 3-month follow-up, representing the end of the ENERGY intervention (for the intervention study arm). Change in fatigue score over the three time points using mean differences in scores between the intervention and TAU study arms will be compared using a mixed-effects model, taking into account the repeated and reversible time-dependent outcome measures.
- Assessment of the effect of the intervention on a range of exploratory outcomes (clinical and cognitive factors, biological markers) measured at the 9-month follow-up will be carried out using either linear regression models or logistic regression models, depending on the type of variable (continuous or binary). These scores will be compared to the initial scores obtained at inclusion. For each outcome variable, the model will be adjusted for the baseline value. These secondary analyses will include measures of:
- general symptomatology - scores of the PANSS
- severity in negative symptoms - scores of the CAINS
- depression - scores of the CDSS
- risk of sleep apnea – scores on BQ
- hypersomnolence – scores on IHSS
- insomnia – scores on SCI
- level of physical activity – scores on IPAQ
- quality of life – scores on S-QoL
- functional remission – scores on FROGS
- level of intrinsic motivation – scores on IMI-SR
- intellectual ability – scores on fNART
- learning and recall – scores on CVLT
- attention – scores on TMT
- weight, BMI, abdominal perimeter, hearth rate, blood pressure
- number of steps and distance covered over a week using the pedometer
- A sub-group analysis will be performed on the intervention arm of the RCT, to identify potential factors that are linked to efficacy of the intervention. This main outcome variable will be the change in fatigue score between inclusion and the 9-month follow-up. Linear regression models will be constructed to study the effect of each dependent variable, individually and altogether in a multi-adjusted model, on the outcome.
- Additionally, a cross-sectional analysis of baseline data will be performed to study the biological (inflammatory markers, microbiota) and psychological factors associated with fatigue severity, overall and on each of the five MFI sub-scales, using general linear regression models.
Modifications to the initial SAP will require an amendment to the protocol. Exploratory statistical analyses not documented in the initial SAP will be discussed by the co-investigators and statisticians, in order to establish their importance and acceptability with respect to the study’s main and secondary objectives.