Temelimab as a Disease Modifying Therapy in Patients With Neuropsychiatric Symptoms in Post-COVID 19 or PASC Syndrome

Study Overview
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Brief Summary
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This study is a Phase 2, 24-week, randomized, prospective, double-blind, multicenter study in patients experiencing neuropsychiatric symptoms and functional impairment in the course of PASC. The purpose of the study is to evaluate the efficacy and safety of Temelimab as a treatment for PASC neuropsychiatric symptoms in patients who had severe acute respiratory syndrome coronavirus - type 2 (SARS-CoV-2) infection but did not undergo intensive care treatment during the acute period. Patients meeting eligibility criteria will be randomized to Temelimab or placebo in a 1:1 ratio via interactive voice/web response system to obtain 182 protocol completers. The randomization will be stratified by age (≤65 years versus >65 years).

Official Title
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Temelimab as a Disease Modifying Therapy in Patients With Neurological, Neuropsychological, and Psychiatric (=Neuropsychiatric) Symptoms in Post-COVID 19 or Postacute Sequelae of COVID-19 (PASC) Syndrome

Conditions
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Post-COVID-19 Syndrome

Intervention / Treatment
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* Drug: Temelimab 54mg/kg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: PASC Syndrome in accordance with NICE criteria with with neuropsychiatric symptoms still occurring >12 to 96 weeks after their first appearance. Has had a SARS-CoV-2-positive diagnostic test (using a validated SARS-CoV-2 antigen, reverse transcription polymerase chain reaction [RT-PCR], or other molecular diagnostic assay, and an appropriate sample such as nasopharyngeal [NP], nasal, oropharyngeal [OP], or saliva). In case that the local standard of care did not foresee the previously mentioned tests, a confirmed SARS-CoV-2 nucleocapsid or membrane antibody test associated to a medical report documenting the date of COVID-19 clinical diagnostic, will be accepted. PROMIS Fatigue SF 7a total raw score ≥21 with onset of fatigue post coronavirus disease 2019 (COVID-19) infection. Patients affected with at least one of the following measures of objective impairment of cognitive function or of quality of life as defined by: i. Token Motor Test ≥1 z-score below the age/sex-adjusted mean ii. EQ5D-5L: Presence of at least 1 score ≥3 in any of the 5 variables of EQ5D-5L questionnaire (mobility; self-care; usual activities; pain/discomfort; anxiety/depression) iii. PQD-20 ≥27 HERV-W ENV positive as defined by automated capillary western system, specific signal level over background noise (S/N) >1. Main Exclusion Criteria: Intubation and mechanical ventilation in the course of COVID19 or reception of convalescent COVID19 plasma treatment at any time prior to study entry Major psychiatric conditions including but not restricted to (attention deficit/hyperactivity disorder, substance use disorder, schizophrenia documented in patient history or diagnosed using M.I.N.I), at the discretion of the site investigator, these do not refer to patients with typical mild to moderate symptoms of depression and anxiety associated with PASC Neurological signs and symptoms including change in level of consciousness, seizures, movement disorders or focal neurological deficits, disorders of the central nervous system with tissue damage or a pre-COVID-19 diagnosis of Chronic Fatigue Syndrome documented in the patient history or diagnosed during the neurological examination Current immunosuppressive//immunomodulating medication (e.g., azathioprine, tacrolimus, cyclosporine, methotrexate, hydroxychloroquine, cytotoxic chemotherapy, or neutralizing antibodies against SARS-CoV-2 epitopes) or therapy with HIV protease inhibitors

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Temelimab 54mg/kg<br>Monthly IV repeated dose in addition to standard of care | Drug: Temelimab 54mg/kg<br>* Temelimab 54mg/kg will be given as monthly (every 4 weeks) intravenous (IV) infusion over 24 weeks (6 infusions in total)<br>|
| Placebo Comparator: Placebo<br>Monthly IV repeated dose in addition to standard of care | Drug: Placebo<br>* Placebo will be given as monthly (every 4 weeks) intravenous (IV) infusion over 24 weeks (6 infusions in total)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite endpoint: improvement in cognitive impairment or fatigue in PASC patients | Occurrence of an improvement in cognitive impairment, measured by an increase of ≥0.5 z-scores in the Token Motor Test, or in fatigue, measured by a decrease of ≥3 points in the Patient-Reported Outcomes Measurement Information System Fatigue Short Form 7a (PROMIS Fatigue SF 7a) score, at Week 24 as compared to baseline. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fatigue | Change from baseline to Week 24 in the Severity of fatigue as measured by the PROMIS Fatigue SF 7a score | 24 weeks | 
| Cognitive function | Change from baseline to Week 24 in 5 domain scores (verbal memory test, digit sequencing test, Token Motor Test, verbal semantic and letter fluency, and Tower of London) as measured by BAC tests | 24 weeks | 
| Cognitive function | Change from baseline to Week 24 in Symbol Digit Modalities Test (SDMT) score | 24 weeks | 
| Cognitive function | Change from baseline to Week 24 in Cognitive function as measured by the composite score of the BAC excluding symbol coding test | 24 weeks | 
| Cognitive function | Change from baseline to Week 24 in Cognitive function as measured by the Perceived Deficits Questionnaire, 20 items (PDQ-20) | 24 weeks | 
| Anxiety | Change from baseline to Week 24 in Severity of anxiety as measured by the Generalized Anxiety Disorder, 7 Items (GAD 7) | 24 weeks | 
| Depression | Change from baseline to Week 24 in Severity of depression as measured by the Patient Health Questionnaire, 9 Items (PHQ-9) | 24 weeks | 
| Quality of Life | Change from baseline to Week 24 in Overall quality of life as measured by the European Quality of Life 5 Dimensions, 5 Levels (EQ5D-5L) | 24 weeks | 
| Functional impairment | Change from baseline to Week 24 in Level of functional impairment as measured by the Sheehan Disability Scale (SDS) | 24 weeks | 
| Post-COVID-19 Functional Status | Change from baseline to Week 24 in Post-COVID-19 Functional Status Scale (PCFS) | 24 weeks | 
| Safety and tolerability of Temelimab in PASC patients | Incidence of serious AEs [SAEs], AEs and analysis of physical examination findings, clinical laboratory values results | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GNbAC1, Human Endogenous Retrovirus Type W, HERV-W, Temelimab, Post-COVID-19, PASC syndrome, Neuropsychiatric sequelae