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Change in ambulatory systolic blood pressure (A and B) and diastolic blood pressure (C and D) from baseline to week 8 in patient subgroups based on nocturnal blood pressure dipping status (dipper: A and C, nondipper: B and D).
diabetes
DIABETES
Data are least‐squares mean change±standard error (repeated‐measures ANCOVA model). Daytime: 6 Sacubitril/valsartan was significantly more effective than olmesartan at lowering 24‐hour ambulatory SBP in all patient subgroups, except for those with diabetes (Figure All treatments reduced SBP and DBP throughout the 24‐hour dosing interval (Figure 
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Time course of changes in 24‐hour systolic ambulatory blood pressure overall (A) and in patients with a dipper (B) or nondipper (C) profile of nocturnal blood pressure.
ABP indicates ambulatory blood pressure; DBP, diastolic blood pressure; and SBP, systolic blood pressure. *
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Response to Therapy
On average, >30% of all patients treated with sacubitril/valsartan were defined as responders at week 8 (ie, achieving BP control with 24‐hour SBP <130 mm Hg and 24‐hour DBP <80 mm Hg). In addition, BP control rates at week 8 were higher in both sacubitril/valsartan groups than with olmesartan in the nondipper subgroup, whereas differences between sacubitril/valsartan and olmesartan were less marked in the dipper subgroup (Figure 
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Blood pressure control rate at week 8 in patients with a dipper (A) or nondipper (B) profile of nocturnal blood pressure.
SBP control: 24‐hour SBP <130 mm Hg. DBP control: 24‐hour DBP <80 mm Hg. DBP indicates diastolic blood pressure; and SBP, systolic blood pressure. *
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Natriuretic Peptides
NT‐proBNP levels were decreased to a greater extent in the sacubitril/valsartan groups compared with olmesartan, and the difference between sacubitril/valsartan 200 mg/d and olmesartan was statistically significant (Figure 
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Overall change from baseline to week 8 in plasma NT‐proBNP levels (ANCOVA model; covariate: baseline NT‐proBNP). NT‐proBNP indicates N‐terminal pro‐B‐type natriuretic peptide.
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Safety and Tolerability
ADVERSE EVENTS
All treatments were well tolerated, with no significant between‐group differences in reported adverse events (Tables 
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DISCUSSION
DBP reductions, hypertension, Hg reduction
HYPERTENSION
This analysis confirms the 24‐hour BP‐lowering effects of the angiotensin receptor neprilysin inhibitor sacubitril/valsartan in Japanese patients with mild‐to‐moderate hypertension and shows that these effects are greater than those of a midrange dose of the angiotensin receptor blocker olmesartan. Furthermore, we have also demonstrated that sacubitril/valsartan is an effective antihypertensive agent regardless of the nocturnal BP dipping profile and in various patient subgroups. Sacubitril/valsartan had similar antihypertensive effects on all ambulatory BP measures (24‐hour, daytime, and nighttime), although reductions in nighttime BP were slightly greater than the other 2 measures. This indicates consistent BP‐lowering effects throughout 24 hours with good antihypertensive coverage overnight and in the early morning predosing period.In the current analysis, reductions from baseline in 24‐hour, daytime, and nighttime ambulatory SBP over 8 weeks of treatment with sacubitril/valsartan exceeded 12 mm Hg, and DBP reductions were all above 7 mm Hg (Figure Overall, the number of responders to treatment with sacubitril/valsartan was significantly higher than the number of responders to treatment with olmesartan, indicating the superior 24‐hour BP‐lowering efficacy of sacubitril/valsartan. Although a small proportion of patients had a change in 24‐hour BP of <5 mm Hg, most had reductions of ≥5 mm Hg, and some had a substantial response, with a ≥20 mm Hg reduction in 24‐hour BP during treatment (Figure The novel finding of this study is the differences in the BP‐lowering effects of sacubitril/valsartan between patients with a dipper versus nondipper profile of nighttime BP (Figures This study was conducted in Japanese patients, and there is evidence to suggest that angiotensin receptor neprilysin inhibitor drugs may be ideally suited for the treatment of hypertension in Asian populations.Although the data used were generated in a randomized controlled clinical trial, the post hoc analysis was not prespecified. The post hoc nature of this analysis means that potential sources of bias cannot be excluded. Therefore, the findings require confirmation in a prospective clinical study. In addition, only a single midrange dose of olmesartan was used as the comparator, and therefore both agents studied were not investigated across their full dosage range. Another limitation of the study was the single ethnicity population (Japanese), limiting the external generalizability of the findings.
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CONCLUSIONS
ASSOCIATED CONDITIONS, HYPERTENSION
Sacubitril/valsartan has recently been approved in Japan and China for the treatment of hypertension. This analysis provides the first data on the differential effects of treatment with sacubitril/valsartan on ambulatory BP in patient subgroups based on the nocturnal BP dipping status. It also confirms the potent 24‐hour BP‐lowering effects of sacubitril/valsartan in Asian populations with hypertension. Strict reduction in 24‐hour BP and maintaining the dipper pattern of nocturnal BP are critical components of strategies designed to achieve perfect 24‐hour BP control, which is essential to attenuate or prevent hypertension‐mediated target organ damage and associated conditions.
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Sources of Funding
This study was funded by Novartis.
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Disclosures
Dr Kario has received speaker's honoraria and consulting fees from Novartis Pharmaceuticals and Daiichi Sankyo, and a research grant from Daiichi Sankyo. In addition, Dr Rakugi served as the external medical expert for this study and has received consulting fees from Novartis Pharmaceuticals. D. Yarimizu, Dr Morita, S. Eguchi, and Dr Iekushi are employees of Novartis Pharma K.K., Tokyo, Japan.
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Supporting information
Data S1Tables S1–S3Figures S1–S5Click here for additional data file.
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Acknowledgments
Medical writing support for an initial draft of this article was provided by Nicola Ryan, an independent medical writer, funded by Novartis.
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References
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Background
Cognitive difficulties, infection
INFECTION
Cognitive difficulties are a frequent complaint in long COVID and persist for more than a year post- infection. There is a lack of evidence-based data on effective intervention strategies. Non-pharmacological intervention programs that are used with other neurological populations have not yet been the subject of controlled trials. COVCOG is a multicentric, randomized trial comparing cognitive intervention and a cognitive-behavioural counselling.
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Methods/design
fatigue
Patients with long covid are selected and recruited at least three months post-infection. Patients are randomised in a 1:1 ratio into the cognitive (neuropsychological psychoeducation) and affective (emotion management with cognitive-behavioural counselling) intervention arms. The inclusion of 130 patients is planned. The cognitive intervention includes psycho-educational modules on fatigue and sleep, attention and working memory, executive functions and long-term memory. The affective intervention includes modules on emotion recognition and communication, uncertainty management and behavioral activation. The main objective is to reduce cognitive complaints 2 months after the intervention. A Follow-up is also planned at 8 months.
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Discussion
cognitive impairment
Given the long-term effects of Covid on cognition and the negative effects of cognitive impairment on quality of life and social participation, it is important to determine whether low-dose, non-pharmacological interventions can be effective. The trial will determine which of the usual types of intervention is the most effective.
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Trial registration
Clinicaltrials.gov Number: NCT05167266 (21/12/ 2021).
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Keywords
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Introduction
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Background and rationale
multisystemic syndrome, cognitive difficulties, cognitive deficits
DISEASE CAUSED BY SARS-COV-2, INFECTION
It is now acknowledged that the disease caused by SARS-CoV-2 infection, COVID-19, is a multisystemic syndrome [These difficulties appear to have a multifactorial origin. An association is observed between these cognitive deficits and alterations in olfaction and taste [Regarding the prevalence of persistent cognitive difficulties, a meta-analysis by Ceban et al. [Cognitive remediation therapy has been shown to be effective in reducing long-term cognitive deficits or their impact on daily life in several other neurological conditions [
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Objectives
cognitive difficulties, affective difficulties, cognitive complaints
In this context, our clinical trial aims to explore the potential effectiveness on cognitive complaints of two common low-dose interventions, one targeting cognitive difficulties (cognitive intervention) and the other targeting affective difficulties that may enhance cognitive difficulties, with a CBC approach (affective intervention). This trial will provide information on these interventions and their feasibility. It will allow us to explore the expected superiority of the cognitive intervention over the affective one.
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Trial design
COVCOG is a multicenter, randomized controlled proof-of-concept trial conducted with two parallel groups (ratio 1:1) comparing psychoeducation interventions that focus on cognitive (
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Methods
Reporting and methodology for the proposed study follow the Standard Protocol Items Recommendations for Interventional Trials (SPIRIT). The protocol has been registered on Clinicaltrials.gov: NCT05167266 (21/12/ 2021).
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Study setting
The trial is conducted by the University of Liege in Belgium. The data are collected in Belgium at four centers: the university of Liège (the Psychological Clinic of University of Liege, CPLU and the university hospital, CHU-Liège), the university hospital of the University of Brussel (ERASME hospital), the regional hospital of Liege (CHR-Liège), and the catholic hospital of Liege (CHC-Liège).
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Eligibility criteria
tumor, cognitive impairment, epilepsy, toxicity, stroke, psychiatric illness, intellectual disability, liver or renal failure, substance abuse, cardiac arrest, neurocognitive disorder, encephalopathy, infection, psychiatric, sepsis, cognitive complaints, hearing or vision disorders, head trauma
TUMOR, EPILEPSY, DRUG WITHDRAWAL, NEUROLOGICAL DISORDER, STROKE, MINOR, CARDIAC ARREST, DISORDERS, ENCEPHALOPATHY, INFECTION, SEPSIS
All volunteers will be screened by a psychologist. To be included in the study, participants must meet the following criteria: be able to understand the information and consent forms; aged 18 to 70 years; medically stable and at least 3 months after a positive COVID 19 infection confirmed either by PCR, self-test or medical advice; report sufficiently good physical condition to attend the appointments; report no major hearing or vision disorders; report cognitive complaints (that place the person in the top 20% of dissatisfied functioning on the BRIEF or MMQ questionnaires); poor but not necessarily deficient objective performance (supported by a score below the 20th percentile on one task of the cognitive battery). Participants will be excluded if they have any chronic or remote neurological disorder (i.e. stroke, head trauma, epilepsy, tumor); preexisting cognitive impairment (associated with another minor or major neurocognitive disorder; intellectual disability); acute brain injury or acute encephalopathy from another etiology than covid (e.g., sepsis, liver or renal failure, alcohol or drug withdrawal, drug toxicity); documented preexisting history of psychiatric illness (including substance abuse); open-heart cardiac surgery or cardiac arrest during the last 6 months; current hospitalization; current revalidation care with cognitive treatment. Participants with preexisting neurological, cognitive, or psychiatric disorders (i.e., preceding COVID) are also excluded. Individuals with disorders co-occurring with COVID are not excluded.
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Informed consent
Researchers who take consent from participants are psychologists who are certified in good clinical practice and trained by the principal investigator. The research project is conducted with approval by the relevant Ethic Committees, with the Hospital-Faculty Ethics Committee of CHU Liège serving as the Central Ethic Committee (number: 707).
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Interventions
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Explanation for the choice of comparator
affective difficulties
Given that it would have been unethical not to propose an intervention, a pragmatic clinical trial logic was adopted by comparing the effect of cognitive psychoeducation program with another psychoeducation program targeting affective difficulties, two common approaches in current practice. We based our reasoning for choosing the second intervention on two elements. Psychological difficulties are also observed in Long-COVID patients [
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Interventions description
cognitive and affective
The cognitive and affective interventions are a 4-session, psycho-educative interventions designed to prevent post-acute cognitive symptoms. Each individual session will last 90 min. One month after the last session, a reactivation session of 30 min is organized (remotely or in person) to reactivate or help the patient to apply one or the other strategy in his daily life.
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Cognitive intervention
The structure of the four sessions is similar: 1) explanation of cognitive (dys)functioning; 2) identification of significant problems in the daily life of each participant; 3) explanation and application of (meta)cognitive strategies. Throughout the presentation, the risks of causal over-attribution (i.e., misattributing common difficulties in daily life to COVID) and the anticipation of long-term negative outcomes will be addressed. The patient will also be made aware of the coping style that can aggravate difficulties (passivity, activity avoidance, focus on difficulties).Each of the four modules concerns a specific cognitive domain. A module can be delivered in one session but may take less or more than one session depending on the patient's difficulties. The content of the modules is also accessible outside the sessions via a video support. The patient is invited to explore these contents between sessions.
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Module 1—Cognition in COVID; sleep and fatigue
fatigue, cognitive deficits
The first step is to provide feedback on the results of cognitive assessment from the baseline visit and to relate it to the cognitive deficits observed in the long covid. Validating and normalizing symptomatology while simultaneously highlighting appropriate strategies to alleviate problems is an important step in psychoeducational programs [Regarding sleep and fatigue, the mechanisms underlying sleep–wake regulation are explained to the patient. For fatigue management, recommendations include the use of a fatigue diary to identify triggers and patterns of fatigue, reorganization of patient’s schedule of the week to avoid exhaustion, practice of physical activity as well as relaxation techniques.
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Module 2—Working memory and attentional functions
Psychoeducation focuses on 1) how to optimize the environment to minimize difficulties (how to reduce interference and dual-task situations, etc.); 2) how to optimize task design to minimize difficulties. If necessary, Time Pressure Management (TPM) is also used to improve adaptation to slowed information processing [
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Module 3 – Executive control
cognitive impairment
Regarding executive functions, the literature on mild cognitive impairment supports the use of instructional procedures for training patients to regulate their behavior and thinking (see DCoE and DVBIC consensus conference) [
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Module 4 – Long-term memory
memory impairments
AIDS
Practice-standards for mild memory impairments suggest the use of internalized strategies (e.g., mental imagery) and external memory compensations (e.g., notebook, diary) to enhance retrieval of information. Training the use of these types of memory compensations and aids within activities of daily living continues to be efficacious and consistently supported by empirical evidence [
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Affective intervention
The structure of the four sessions will be similar: 1) analysis of a fictitious vignette illustrating the thoughts and affect that can be provoked by the long COVID; 2) in connection with the explanations, identification of significant problems in the daily life of each participant; 3) explanation of psychological functioning; 4) discovery and application of strategies. Each time, the strategies will have to be practiced at home and will be discussed again at the next session.
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Module 1—Recognizing emotions and affective states
SECONDARY
Psychoeducation on emotions will be proposed (e.g., triggers of emotions, category of primary and secondary emotions, meaning of emotions). The patient will be asked to reflect on his or her emotions associated with long-covid and their manifestations (internal and external physical and physiological manifestations; cognitive effects of emotions and thought patterns; subjective feeling; action tendencies). The effects of negative emotions will also be discussed. The Stimulus-Organismic-Response-Consequence model (SORC) [
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Module 2—Accepting and communicating about difficulties
cognitive difficulties
After a review of the patient's diary, the patient will be asked to share his or her observations on the emotion self-observation. Afterwards, the interest of being able to communicate calmly about one's cognitive difficulties and one's feelings in relation to the COVID will be discussed with the patient. The principles of assertive communication will be addressed by following Fanget and Rouchouse's principles [
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Module 3—Accepting the uncertainty associated with difficulties
Following Ladouceur's model of uncertainty management [
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Module 4—Behavioral activation
fatigue
EVENTS
Patients will be invited to identify their values to better calibrate the choice of activities according to their fatigue but also according to what is important to them. If the patient has difficulties with ruminations, the impact of these on activation will be discussed. A behavioral activation plan will also be constructed with the patient. Different techniques will be taught (e.g., increasing rewarding activities, recalling positive moments of the day, mental imagery of positive events).
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Criteria for discontinuing or modifying allocated interventions
Reasons for discontinuing protocol treatment may include, but are not limited to, the patient's desire not to continue or a change in health status requiring alternative treatment. There are no reasons envisaged for a change of allocation.
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Strategies to improve adherence to interventions
Clinicians are trained in psychoeducation interventions; manuals list each module ingredient in detail (with examples of instructions and exercises to be provided to patients). A roadmap summarizes the sequence of steps in each module. An adherence checklist with the essential topics to be covered is to be completed by the clinician. Each deviation will be noted in the eCRF.
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Relevant concomitant care permitted or prohibited during the trial
Treatment similar to that of one of the two arms is not accepted.
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Provisions for post-trial care
Not applicable.
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Baseline and endline assessment
A psychological evaluation is administered before and 2 months and 8 months after treatment. This evaluation involves 2 sessions of 90 min.
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Primary outcome
forgetfulness, memory difficulties
The primary outcome is a subjective report of difficulties experienced by patients in daily life at two months post-intervention measured via two questionnaires.The Behavioral Rating Inventory of Executive Function (BRIEF) is a validated questionnaire assessing the main cognitive complaints of the patients (e.g., attention, concentration, disorganization,). It measures the impact of difficulties in daily life and has two indexes (Behavioral Regulation, BRI; Metacognition, MI) and an overall score (Global Executive Composite, GEC). The BRIEF’s reliability is high; Cronbach’s alphas for the BRI and MI have been found to be 0.94 and 0.96, respectively [The Multifactorial Memory Questionnaire (MMQ) is a validated questionnaire measuring affects related to memory abilities, frequency of forgetfulness in different situations, and strategies used in everyday life to cope with memory difficulties. The scores proved to be reliable (Cronbach's α for the subscales ranged from 0.79 to 0.88) [
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Secondary outcome
cognitive difficulties, fatigue
SECONDARY
BRIEF and MMQ will also be administered 8 months after intervention. Other secondary outcomes at 2- and 8-months post-intervention are [1] quality of life; [2] the presence of objective cognitive difficulties, assessed by neuropsychological tasks; [3] fatigue level and sleep quality; [4] psychological distress; [5] work productivity and activity impairment.
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Quality of life (QOL)
The status of Quality of life is self-assessed through the Quality of Life Systemic Inventory [Participants also complete the EQ-5D [
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Neuropsychological tasks
cognitive difficulties
A cognitive assessment is carried out by a neuropsychologist before the intervention as well as 2 months and 8 months after the intervention. The battery takes about 150 min to complete and is administered in two sessions. It includes several psychometric tests with normative data for french-speaking population.The tasks chosen to detect the presence of objective cognitive difficulties in the attentional and executive domains are the following: selective auditory and visual attention, divided attention, updating and flexibility tasks from the Attentional Performance Battery (TAP, v2.3.1) [Global cognitive performance is assessed with the screening tool Montréal Cognitive Assessment (MOCA) which is widely used in clinical settings and research [
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Fatigue and sleep
Fatigue
MULTIPLE SCLEROSIS
A 19-item self-report inventory (Pittsburgh Sleep Quality Inventory, PSQI [Fatigue level was also examined through the Modified Fatigue Impact Scale (M-FIS). The M-FIS is a 21-item self-report questionnaire developed by the US NMSS (National Multiple Sclerosis Society) and derived from the original 40-item Fatigue Scale [
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Psychological distress
The Outcome Questionnaire 45 (OQ-45) [
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Work and activity
The Work Productivity and Activity Impairment (WPAI) [
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Participant timeline
After a telephone screening, the patients corresponding to the eligibility criteria are invited to participate in the study with a first appointment for the baseline. The full assessment protocol is then administered. Individuals completing the inclusion criteria are randomized within one week of baseline and intervention can start the following week. The intervention sessions are proposed with a week interval followed by a reactivation session 1 month after the 4th session. Immediate and long-term follow-up will be administered 2 and 8 months after the end of intervention. This timeline is summarized in Fig. Participant timeline
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Sample size
RECRUITMENT
The uniqueness of our research does not make it possible to determine the exact expected effect size. Thus, we decided to follow a proof-of-concept study logic with a pragmatic approach to setting our sample size. A feasibility analysis led us to the conclusion that we could reach a sample of 130 participants in 10 months. We next measured the sensitivity of our experimental design on this expected recruitment rate with Gpower [
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Recruitment
word of mouth
An initial set of patients will be identified by the usual physicians/clinical teams of the centers participating in the study. Patients will be informed and will contact the study team. Participants will also be recruited by word of mouth ("flyer", Covid long facebook group, primary care physicians). Finally, if needed, patients who had a post-Covid follow-up consultation in one of the centers will be contacted again.
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Assignment of interventions: allocation
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Sequence generation
milder difficulties, cognitive impairments, cognitive complaints, cognitive deficits
SECONDARY
Given our small sample size, and because individuals with more severe cognitive impairments might respond differently to the intervention than those with milder difficulties, we will use randomization by minimization. Although severity and interval since COVID episode are probably important prognostic factors in outcomes, we decided to achieve trial arm balance only on age, education level, gender, Centre, and severity of cognitive deficits and complaints. For cognitive deficits, scores will first be Z-scored based on normative data, and next a global Z-score calculated on all variables will be considered (sum of Z-scores divided by number of measures). A Z-score will also be calculated for both tools assessing cognitive complaints. For both these objective and subjective indices, balance will be done by Z-score range of 0.5 (e.g., Z-score from 0 to -0.50; -0.51 to -1, etc.). For age we will use 18–29; 30–39; 40–49; 50–59; 60–70. For education, we will use 4 levels: 1. primary or professional education; 2. secondary education; 3. bachelor; 4. master. In the calculation of the imbalance each arm and each prognostic factor will have the same weight. The imbalance score is calculated based on all previous allocations as well as the current participant's hypothetical allocation to each treatment. The distance measure used to calculate the imbalance score is the marginal balance. If there is no imbalance, the allocation will be completely random. If there is an imbalance, the treatment with the lowest imbalance score is chosen with a 75% probability.
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Concealment mechanism and Implementation
After the baseline session, an attribution request is then emailed, including the ID, to a researcher responsible for the attribution process with the QMinim software. This researcher does not participate in the follow-up assessment. This researcher then sets up the appointment with the clinician of the assigned arm.
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Assignment of interventions: Blinding
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Who will be blinded
cognitive difficulties
BLIND
The statistician will be blind to the content of the intervention arm that will be called “A” and “B”. The neuropsychologists who perform the baseline assessment do not know about the randomisation (which is only carried out after the visits). The neuropsychologists that will be in charge of follow-up will also be blinded to the arm of the intervention. Patients will be warned to not mention their intervention arm or provide information that could cue the clinician (this will be reminded before each assessment session). If the clinician becomes unblinded during the testing session, this will be reported in the eCRF.The person administering the intervention cannot be blinded, as the content is different. The participants cannot be blinded. However, the trial will be presented as “assessing the positive effect of two interventions on post-covid cognitive difficulties” Our prediction (superiority of the cognitive intervention) will not be communicated to the participants until the end of the trial (last follow-up for the last participant included).
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Procedure for unblinding if needed
Not applicable: the patients and the clinicians know the intervention as the content of the sessions is different in the two arms.
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Data collection and management
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Plans for assessment and collection of outcomes
All tests and questionnaires are administered by a trained psychologist specialized in neuropsychology. The primary outcome is administered via a computerized questionnaire system in the eCRF (Castor). MMQ and BRIEF (primary outcome) will be remotely administered again after a 2-week interval to take account of fluctuating difficulties.
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Plans to promote participant retention and complete follow-up
Patients will be reminded by the researcher to log in and complete assessments.
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Data management
SECONDARY
The data are entered into the eCRF by the clinician researchers in charge of the evaluation. A manual was written to guide the encoding. Double entries were made on the first patients. 100% of the primary and 10% of the secondary outcomes are verified by independent monitor of Antwerpen University Hospital Clinical Trial Centre (UZA CTC). Last checks for data values will be done by the statistician and the data manager of UZA CTC.
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Confidentiality
Confidentiality and data protection will comply with European and Belgian directives on the protection of individuals with regard to the processing of personal data and on the free movement of such data (GDPR). Standard operating procedure (SOP) for data protection are detailed on the website of the Faculty of Psychology EC (Personal information and linking code will be saved in a location separate from the one where data were collected, in encrypted, password-protected folders. Access to these data will be limited to only those who need it for the purposes of trial management, quality control, audit, and analysis. These data will be destroyed 5 years after the end of the trial.Data entered into the eCRF will be coded and pseudo-anonymized. Computers used for storage of personal and research data are professional (not personal) laptops, protected by password. The folders where information will be stored will be also protected by password, and temporarily backuped on an encrypted external device stored in the researcher office.
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Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use
Not applicable for this study.
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Statistical methods
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Statistical methods for primary and secondary outcomes
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Summary of baseline data and flow of patients
Preliminary analyses will be conducted to ensure comparability of both groups on demographic (sex, age, education years) and clinical characteristics at baseline. Two-sided independent sample t tests will be conducted for continuous variables and categorical variables will be analyzed with Fisher exact tests. A consort flow diagram will be produced to get an overview of the number of patients available at each stage: eligibility, allocation, discontinuation, short and long-term follow-up.
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Primary outcome analysis
Primary outcome will be first analyzed on an intention-to-treat (ITT) basis, including all patients as originally allocated after randomisation. For missing information due to patient drop-out, we will rely on the linear mixed model and consider the baseline data as part of the outcome matrix. We will also perform a per-protocol (PP) sensitivity analysis including only those patients who completed the treatment originally allocated.Analyses should be considered as hypotheses generating. To explore the effects of the intervention type on the two primary outcome measures, the results will be compared using linear mixed models. More precisely, the moment of the measure (baseline and immediate follow-up), the intervention (nested within the centers), the centers and the interaction of these factors will be considered as fixed factors. A nested random intercepts and slopes for each participant within the centers will be implemented. Age groups, educational level, objective Z-score (Z-score from 0 to -0.50; -0.51 to -1, etc.) and gender will also be included in the model as stratification factors. Following the linear mixed model, linear contrast will be performed between the two levels of the intervention variable on the first follow-up measure (T1) to explicitly compare the potential benefit of the intervention. Bonferroni adjustment will be performed to correct for multiple testing, more precisely 2 tests (the number of primary measures), and p-value < 0.025 will be considered as statistically significant. 95% CI and standardized effect sizes (SES) from the null model will be calculated. The following convention will be used to interpret effect size: small 0.2–0.49, moderate 0.5–0.79, large ≥ 0.8. As a Proof-of-Concept (POC) study, estimation will be focused on ES but will include p-values as help in interpreting the data.
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Secondary outcome analysis
SECONDARY
Mixed linear models will also be used to assess the maintenance of effect across time (baseline, immediate and long-term follow-up). We will re-run the same analysis as for primary outcome, this time by including scores at long-term follow-up. Intervention effect size will be estimated using the same mixed models for each secondary and exploratory outcome measurement (Scores of ISQV and EQ-5D, the 5 overall Z-score per cognitive domain, Outcome-Questionnaire 45, PSQI, M-FIS) at both short-term follow-up (T1) and long-term follow-up (T2). As a rule, stratification factors will be included in the analyses.
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Interim analyses
infection
INFECTION
The objective of interim analyses will be to determine if there exist profiles of patients with specific characteristics, to assess if the interventions act differently according to subgroup. We hypothesize a subdivision of patients according to the presence of a more cognitive or psychological profile. For this Latent Profile Analysis (LPA), the z-standardized mean scale scores of the following variables will be entered in the model: composite scores for memory, attention and executive performance, global score at OCQ and M-FIS. All this continuous variables will be used If the presence of these two sub-groups is confirmed, we will next assess if they differ on primary outcomes (complaints at BRIEF and MMQ scales), quality of life (ISQV), medical variables (length of potential hospitalization; presence and duration of ventilation; presence of neurological symptoms at acute phase time since infection), presence/absence of antecedent psychological difficulties, age and sex.
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Methods for additional analyses (e.g. subgroup analyses)
cognitive sequelae
Analyses will be conducted to identify trajectories of participants according to their baseline characteristics (i.e., subgroup identified with the cluster analysis) and the allocated intervention. To explore the effects of the intervention on the two primary outcome measures according to the baseline participant characteristics (profile corresponding to cognitive or psychological difficulties), the same analysis will be performed as for primary outcomes (linear mixed models, see (Analyses will be conducted to identify individual trajectories, in the different cognitive domains and for primary outcome, to identify which variable predict long-term cognitive sequelae. Our analyses will include latent growth curve modelling techniques that use repeated measures to estimate trajectories.
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Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data
SECONDARY
In the ITT analysis, we will measure our primary and key secondary outcomes by patient report in the last assessment. For the PP analysis, the proposed linear mixed model allows missing values at certain time points. The missing value assumption of the model is Missing At Random which means that missing values can only be dependent on the observed responses which seems a reasonable assumption in this case. Missing data should be kept at minimum by applying the following rules: We will check completion of questionnaires at the end of the testing session and ask the participant to try to complete missing information.
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Plans to give access to the full protocol, participant level-data and statistical code
The complete protocol is available on the KCE website. (
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Oversight and monitoring
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Composition of the coordinating centre and trial steering committee
In summary, ULiège is the study Sponsor. Willems S. and Collette F. are the Chief Investigator (CI) and responsible for clinical elements of the trial. ULiège and UZA CTC are both responsible for project management. ULiège and UZA CTC will hold joint data controller responsibilities.
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Trial Steering Committee (TSC)
A TSC meets three times in the first year and twice in the second. The committee will provide overall supervision of the trial and ensure that the study is conducted according to the protocol and within the overarching ethical framework. It is composed of chief investigators, trial project manager, statistician, clinical experts (Chief of Internal Medicine and Chief of post intensive care Unit) of the coordinating centre; principal investigators of each participating centre, independent clinical expert (psychologist from University of Montreal); representative of UZA CTC; representative of the funder (KCE); two representatives of patients.
PMC10436391
Trial Management Group (TMG)
The TMG is the executive decision-making body and is responsible for the day-to-day running and management of the trial. It is led by the CIs and consists of representative of UZA CTC, representative of the funder, project manager and principal investigator from coordinating centre. The team meets each trimester (or more frequently if needed) via a teleconference to discuss clinical challenges and risks.
PMC10436391
Composition of the data monitoring committee, its role and reporting structure
ICH
Charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed.Data monitoring is under the responsibility of CTC UZA, that is independent from the sponsor and funder. A Clinical Monitoring Plan (CMP) was conjointly written by the CTC UZA, in collaboration with the chief investigators. The CMP establishes the guidelines for conducting monitoring visits and related tasks for monitoring protocol Long Covid. The CTC UZA will perform monitoring tasks in accordance with the protocol specific requirements. This plan aims to support the UZA monitor(s) to ensure that the investigational sites follow the International Conference on Harmonisation (ICH) Good Clinical Practice Guidelines (GCP), the local regulatory requirements and he study protocol.
PMC10436391
Adverse event reporting and harms
cognitive difficulties, anxio-depressive
ADVERSE EVENTS, ADVERSE EVENT
The project does involve interventions, but they are considered ‘low risk’ with no anticipated serious adverse events. Here, we should observe only mild adverse events related to the interventions, such as increased anxio-depressive affects in some patients when faced with cognitive difficulties. Such adverse events will be discussed with clinician and a trial safety group (composed of one principal investigator of the center, chief investigator, Trial Project Manager, one representative of patients) to determine the most appropriate response (e.g. mail to the general practitioner, psychological counselling outside of the intervention protocol). The date, description of the related adverse event, solution proposed will be recorded in the eCRF and in the source documentation (patient medical record). This information will be also transmitted to TSC.
PMC10436391
Frequency and plans for auditing trial conduct
Trial conduct will be closely monitored by independent subgroup (as previously described). An independent audit will be ordered by the funder.
PMC10436391
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees)
Any proposed amendments to the protocol will first be discussed within the Trial Management Group and the Trial Steering Committee. Approval will be required from all parties before implementation (Funder and Ethics Committee). The chief investigators will take responsibility for communicating protocol amendments to all trial members and participating centers.
PMC10436391
Dissemination plans
cognitive difficulties
Scientific results of the project will be disseminated via publications in peer-reviewed journals and in abstracts of national and international conferences. Open access will be guaranteed by filling all publications related to the project in the ULiège institutional repository—ORBI. Decisions about the scientific content and the publisher will be decided conjointly by researchers involved in the publication.We will rely on patient representatives to ensure that information emanating from the project can be utilized to support information towards that population.Neurologists, physical therapists, intensive care physician, neuropsychologists, and psychologists, all involved with the medical and social care of patients with cognitive difficulties are targets for dissemination of information about the objectives and results of COV-COG.
PMC10436391
Discussion
fatigue, traumatic brain injury, cognitive disorders, anxiety, depression, cognitive difficulties, post-traumatic symptoms, cognitive deficits, cognitive impairments, cognitive complaints, neurological complaints, disability
This randomized controlled trial with minimization aims to test the effectiveness of two approaches commonly proposed to people with cognitive complaints on patients with long covid. Because of the impact of cognitive disorders on functional disability and long-term quality of life, such clinical trials seem essential to target the type of intervention that can be proposed to reduce post-COVID cognitive disorders and their impact on daily life (subjective perception of difficulties and quality of life). This is especially true given the unknown outcome of long-term cognitive deficits in that population.The cognitive approach aims at a better understanding of cognitive impairments and the adoption of adequate strategies to manage them. The approach targets difficulties frequently reported in patients with COVID (sleep and fatigue, attention and concentration, memory, and organization) with several modules whose dosage is adapted to the person's difficulties. The intervention is based on a biopsychosocial model (i.e., an integrative approach taking into account cognitive, contextual and psychological factors) and therefore also aims to reassure, reduce some misconceptions and negative interpretation bias of difficulties. This psychoeducational approach is different from restorative cognitive intervention which aims to improve cognitive performance itself. This type of high-dose intervention requires several dozen sessions with specific exercises to train deficient cognitive process [In the context of mild traumatic brain injury (mTBI), persistent cognitive difficulties can be addressed through this type of cognitive psychoeducation. However, some psychoeducational programs focus less on cognitive difficulties per se and more on managing the negative emotions associated with cognitive difficulties and other post-traumatic symptoms [In this context of a potential dissociation between the evolution of complaints and objective difficulties, a CBT type approach also seems appropriate. Therefore, the cognitive intervention is here compared to another potentially effective intervention focused on the management of emotions. It will aim at helping patient to better recognize their emotions, to determine how to react to them, by giving them the tools to better manage their post-COVID anxiety and stress. Patients will also be brought to become aware of their values and to develop his/her motivation to change. Finally, patients will also be made aware of interpretation biases and negative adaptive behavior (e.g., avoidance of problem situations).It is reasonable to think that the effect on cognitive functioning of an intervention targeting affective dimensions (anxiety, depression, motivation, etc.) will be lower than an intervention more specifically targeting cognitive dimensions. However, this prediction has to be taken with caution. No study at this time assessed which of the two interventions has the larger effect in long covid patients or in other neurological population. Furthermore, studies testing the effectiveness of a CBT approach used very general scales measuring the set of persistent post-concussion symptoms after mTBI. They do not specifically include measures of cognitive complaints. There is evidence in studies that this type of intervention results in moderate changes in quality of life, with small effects on functioning in daily life and neurological complaints [To the best of our knowledge, there is no clinical trial dealing with these cognitive difficulties in long COVID. Therefore, there is no data to suggest which strategy would help these patients.
PMC10436391
Acknowledgements
Gilles, Alexia, Charonitis
We would like to thank all the who participated in the construction of the material for the two interventions, as well as in the numerous meetings to prepare the trial : Maud Billet (ULiège, PsyNCog) ; Christina Léonard (ULiège, PsyNCog) ; Guillemin, Camille (ULiège, PsyNCog) ; Mathilde Reyt (ULiège, GIGA) ; Florence Requier (ULiège, PsyNCog) ; Maëlle Charonitis (ULiège, GIGA) ; Valentine Demoulin (University Hospital of Liege) ; Fréderique Leens (Catholic Hospital Center of Liege) ; Marianne Rotsaert (Erasme, University of ULB) ; Fanny Kreusch (ULiège, CPLU) ; Marie Dethier (ULiège, CPLU). We thank Nelle Stocquart from the KCE funder and the UZA CTC team for their close monitoring.We would also like to acknowledge the input of our colleague Alexia Lesoinne for the management of this trial and her administrative support. We would like to thank all the participating psychologist who have been so enthusiastic about this trial. The support of our expert advisors, Michel Moutschen (Chief of infectiology Unit of University Hospital of Liege), Anne-Françoise Rousseau (Chief of post intensive care Unit of University Hospital of Liege), Gilles Dupuis, (University of Montreal) is also greatly valued. The role of the Trial Steering Committee is also recognised. We thank, for their participation in the TSC, Maude Evrard (Regional Hospital of Liege); Anne-Sophie Spiette, Audrey Pregaldien (representative of patients). Michel Moutschen6. Department of infectiology, Liège University Hospital, Liège, Belgium.7. Department of Intensive Care and Burn Center, Liège University Hospital, Liège, Belgium.8. Regional hospital of Liege (CHR-Liège), Liège, Belgium.9. Psychological Unit, Brussel University Hospital, Erasme, Brussel, Belgium.
PMC10436391
Public and patient involvement
EVENT
A partnership with patients has been set up from the design of the study, to validate the question, draw up the study plan, assess the acceptability of the protocol (assessment and intervention) and check all the study documents (information and consent letter, intervention manuals). Two patients are included in the steering committee.  Patients will remain involved throughout the study and will be consulted in the event of any significant changes. They will participate in the review of publications (reading and commenting) and will take part in a discussion group on feedback to participants.
PMC10436391
Authors’ contributions
SW is chief investigator; she conceived the study and led the development of the proposal and protocol; she contributed to the development of the statistical design; led the construction of the clinical material; she has drafted the work; she contributes to the acquisition of data. FC is chief investigator; she conceived the study and led the development of the proposal and protocol; she contributed to the development of the statistical design; she led all trial plans; she has drafted the work. CC is investigator; she contributed to the construction of the clinical material; she substantively revised draft; she contributes to the acquisition of data. VD is statistician; he contributed to the development of the statistical design; he participated in the review of the draft; GD is investigator; he contributed to the conception of the study; he contributed to the construction of the clinical material; he participated in the review of the draft; HS is investigator; he contributed to the conception of the study; he contributed to the construction of the clinical material; he participated in the review of the draft; PF is investigator; he contributed to the conception of the study; he contributed to the construction of the clinical material; he participated in the review of the draft; JG is investigator; he contributed to the construction of the clinical material; he contributed to the construction of the clinical material; he participated in the review of the draft; CD is investigator; she contributed to the construction of the clinical material ; she contributed to the construction of the clinical material; she participated in the review of the draft. All authors read and approved the final manuscript. COVCOG group contributed to the conception of the study.
PMC10436391
Funding
This study is funded by the KCE Trials program of the Belgian Federal Center of Expertise for Health Care (KCE) (KCE ref: LCOV21-1303). The funder itself is not involved in the reporting of the study. It will however take a key monitoring role, to ensure that the study progresses satisfactorily according to expected timeline. The content is solely the responsibility of the authors and does not necessarily represent the view of KCE.
PMC10436391
Availability of data and materials
The dataset generated during the trial will be available upon reasonable request from the CI. The data will be available following publication of the trial results.
PMC10436391
Declarations
PMC10436391
Ethics approval and consent to participate
This study complies with the Declaration of Helsinki. The protocol and all materials have been reviewed and approved by the CHULiege Ethical Review Committee (B7072021000098) and all Centres Committees (REF:2021/432). Written informed consent will be obtained from all participants.
PMC10436391
Consent for publication
Not applicable.
PMC10436391
Competing interests
The authors declare that they have no competing interests.
PMC10436391
References
PMC10436391
Simple Summary
ASD, impaired language and communication skills, Autism spectrum disorder, impaired social–emotional interactions, aggressive behavior, neurodevelopmental disorder, autism
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that can cause impaired social–emotional interactions, impaired language and communication skills, repetitive or restrictive behaviors, and sometimes aggressive behavior. An emerging topic in research is the imbalance between bodily oxidative systems and anti-oxidative stress in autism spectrum cases. Glutathione (an antioxidant agent) is involved in many anti-oxidative stress systems, but our research target is to study the role of glutathione as a neuro-protective agent. Our pilot study demonstrates general glutathione tolerability and some efficacy in decreasing problematic behaviors observed in children with ASD.
PMC10660524
Abstract
neurodevelopmental disorder, ASD, Autism spectrum disorder, autism spectrum disorder
OXIDATIVE STRESS
Autism spectrum disorder (ASD) is a type of neurodevelopmental disorder that has been diagnosed in an increasing number of children around the world. The existing data suggest that early diagnosis and intervention can improve ASD outcomes. The causes of ASD remain complex and unclear, and there are currently no clinical biomarkers for autism spectrum disorder. There is an increasing recognition that ASD might be associated with oxidative stress through several mechanisms including abnormal metabolism (lipid peroxidation) and the toxic buildup of reactive oxygen species (ROS). Glutathione acts as an antioxidant, a free radical scavenger and a detoxifying agent. This open-label pilot study investigates the tolerability and effectiveness of oral supplementation with Opitac
PMC10660524
1. Introduction
impaired neurotransmission, ASD, metabolic abnormalities, behavioral deficits, traumatic brain injuries, Autism spectrum disorder, fibrogenesis, neurodevelopmental disorder, psychotic disorders, mitochondrial dysfunction, DSM-5
DISORDER, DISORDERS, PROLIFERATION, NEURODEGENERATIVE DISEASES, DISORDERS, MULTIPLE SCLEROSIS, LACTIC ACIDOSIS, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, CORTEX
Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined by the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) as observable behavioral deficits in social communication and social interaction across multiple contexts. Oftentimes, patients with ASD present with difficulties relating to others in the form of repetitive patterns of behaviors and limited interests. Although ASD can present at any age, the disorder usually manifests early in childhood and can be reliably diagnosed by age 2 [The cause of ASD is currently unknown and involves a mix of genetics and environmental factors. Based on the current literature, ASD involves many complex biological processes that manifest as physiologic and metabolic abnormalities. Namely, ASD has been reported to be in association with impaired neurotransmission, immune dysregulation in the brain, mitochondrial dysfunction, and increased oxidative stress [The neurodevelopmental nature of ASD is partially explained by the pathophysiologic imbalance of neurochemical signaling in the central nervous system. ASD has been observed to be associated with changes to neurotransmission involving gamma aminobutyric acid (GABA), glutamate, serotonin, dopamine, acetylcholine, N-acetyl aspartate, and endogenous opioids, amongst others [There is growing evidence that supports a role for immune dysregulation in the brain in ASD. Neurobiological studies on children with ASD have demonstrated an excess in neuronal synapses in the cerebral cortex. An impairment in synaptic pruning is observed to lead to social and behavioral dysregulation, as is seen in ASD. On an immunologic level, brain microglia are crucial in the synaptic refinement process [Synaptic transmission is an energy intensive process that requires large amounts of ATP produced by mitochondria. The synthesis of proteins and dendrites for synaptic plasticity is also another energy intensive process. As such, functional mitochondria are crucial to neurodevelopment. An early study in 1985 cited lactic acidosis in a subset of children with ASD, which further paved the way to explore the association between mitochondrial dysfunction in ASD [Lastly, an imbalance in oxidation–reduction (redox) reactions in cells favor pro-oxidant agents, such as free radicals, which promote oxidative stress. More specifically, the generation of ROS outweighs the body’s ability to remove them. In low concentrations, reactive oxygen species act as signaling molecules that induce apoptosis and dysregulates cell proliferation via changes to gene expression [In order to protect itself, the body utilizes an antioxidant defense mechanism that includes both enzymatic and non-enzymatic ways to remove ROS. Enzymatic defense includes the biological action of superoxide dismutase, catalase, peroxiredoxins, glutathione peroxidase, and several enzymes in the ascorbate-glutathione pathway [One of the most studied antioxidants is glutathione due to its ubiquitous nature and its role as the most abundant non-protein thiol antioxidant in mammalian tissue. Glutathione is a naturally occurring cysteine-glutamate-glycine tripeptide that is synthesized primarily in the liver with significant antioxidative action. In addition to its key role in redox signaling, crucial in the detoxification of xenobiotics, glutathione is an important factor in regulating cell proliferation, apoptosis, immune function, and fibrogenesis [NAC has been a target of interest primarily for its antioxidative role in a variety of disorders including neural cell survival, cell signaling, neurodegenerative diseases, multiple sclerosis, traumatic brain injuries, and other psychotic disorders [Further research into anti-oxidative agents for ASD begs the question of whether direct supplementation with glutathione is equally or more efficacious than NAC supplementation due to bypassing the rate-limiting transsulfuration step (cysteine) in glutathione synthesis. Despite its proposed benefits, oral glutathione supplementation failed to show changes to the observed biomarkers of oxidative stress and glutathione status, due to the enzymatic degradation of supplemental glutathione in the intestine [
PMC10660524
2. Methods and Materials
PMC10660524