Study of LAU-7b for the Treatment of Long COVID in Adults

Study Overview
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Brief Summary
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ESSOR is a double-blind, placebo-controlled study of the orally-administered antiviral and inflammation-controlling LAU-7b for the treatment of adults with Long COVID and moderate to severe symptoms.

Detailed Description
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ESSOR is a multicenter, randomized, double-blind, placebo-controlled Phase 2/3 study of LAU-7b for the treatment of Long COVID in non-hospitalized adults with moderate to severe Long COVID symptoms. The goal of the study is to evaluate the efficacy of LAU-7b therapy + stable symptomatic standard-of-care relative to placebo + stable symptomatic standard-of-care at reducing the overall Long COVID burden by improving multiple dimensions of quality-of-life and alleviating the symptoms. This study is a logical extension of investigating LAU-7b as a potential therapeutic against various phases of COVID-19. LAU-7b is therefore being proposed as a potential disease-modifying medication for the treatment of Long COVID.

Official Title
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A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, ADAPTIVE PHASE 2/3 STUDY OF THE EFFICACY OF LAU-7b IN THE TREATMENT OF ADULTS WITH LONG COVID AND MODERATE TO SEVERE SYMPTOMS

Conditions
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Long COVID

Intervention / Treatment
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* Drug: LAU-7b for 3 cycles
* Drug: LAU-7b for 1 cycle, then placebo
* Other: Placebo for 3 cycles


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must be 18 years and older, of either gender, and able to give informed consent; Subjects diagnosed with Long COVID and exhibiting persisting, relapsing or new Long COVID symptom(s) at least 12 weeks beyond the start (test positivity or symptom onset) of the causative COVID-19 infection; At least one of the Long COVID symptoms must be from the core list of Long COVID symptoms, and be present for a minimum of 2 weeks prior to screening and of moderate or severe intensity as per the 4-level Likert severity scale (0 to 3; 0 = no symptoms; 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms); If female, must be either post-menopausal (one year or greater without menses), surgically sterile, or, for female subjects of child-bearing potential who are capable of conception, must be: practicing a highly effective method of birth control (acceptable methods include intrauterine device, complete abstinence, spermicide + barrier, male partner surgical sterilization, or hormonal contraception) during the study treatment intake and through 30 days after the last dose of the study medication. Periodical abstinence is not classified as an effective method of birth control. A pregnancy test for female subjects of child-bearing potential must be negative at the Screening Visit; Subjects deemed capable of adequate compliance including attending scheduled follow-up calls/visits for the duration of the study, have internet access and able to read and answer questionnaires on electronic Patient Reported Outcomes platform (ePRO) or paper; Screening laboratory test and vital signs results within ranges compatible with the subject's health condition, as per investigator's judgement. See also the last exclusion for certain liver function tests; Subjects deemed capable of swallowing the study treatment capsules Exclusion Criteria: Subject is currently hospitalized (any reason); Pregnancy or breastfeeding; Any COVID vaccination within 4 weeks of screening or planned during study participation; Presence of any health condition judged by the investigator to be directly causing one or more of the most common Long COVID symptoms; Health condition deemed to possibly interfere with the study endpoints and/or the safety of the subjects. For example, the following conditions should be considered contraindicated for participation in the study. In case of doubt, the Investigator should consult with the Sponsor's medical representative: Febrile neutropenia; Fibromyalgia deemed to interfere with generalized pain measurements; Presence of end-stage cancer (palliative care). Presence or suspicion of drug or alcohol abuse, as judged by the Investigator; Known history of a severe allergy or sensitivity to retinoids, or with known allergies to excipients in the oral capsule formulation proposed to be used in the study; Participation in another interventional drug, alimentary supplement, psychological or device...etc. clinical trial within 30 days (or a minimum of 5 elimination half-lives for drugs) prior to screening, except ongoing participation in non-interventional studies; Presence of total bilirubin >1.5 x Upper Limit of Normal (in the absence of demonstrated Gilbert's syndrome), alanine aminotransferase and/or aspartate aminotransferase > 2.5 x Upper Limit of Normal (unless there are clinical evidences of hepatic steatosis).

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
Interventional Model Description: Parallel, regimen-finding, adaptive design well-controlled randomized clinical trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LAU-7b for 3 cycles<br>Each study arm will consist of three (3) cycles of 14 days of treatment intake each spaced by a treatment holiday of 14 days. | Drug: LAU-7b for 3 cycles<br>* Three cycles of 14 days of once-a-day intake of LAU-7b, each followed by a treatment intake pause of14 days.<br>* Other names: fenretinide;|
| Experimental: LAU-7b for 1 cycle, then placebo<br>Each study arm will consist of three (3) cycles of 14 days of treatment intake each spaced by a treatment holiday of 14 days. | Drug: LAU-7b for 1 cycle, then placebo<br>* One cycle of 14 days of once-a-day intake of LAU-7b followed by two cycles of 14 days of placebo administered similarly, each followed by a treatment intake pause of14 days.<br>* Other names: fenretinide;|
| Placebo Comparator: Placebo for 3 cycles<br>Each study arm will consist of three (3) cycles of 14 days of treatment intake each spaced by a treatment holiday of 14 days. | Other: Placebo for 3 cycles<br>* Three cycles of 14 days of once-a-day intake of placebo, each followed by a treatment intake pause of14 days<br>* Other names: sugar pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Physical Functioning Score (PCS) of the Medical Outcomes Study Short-Form-36 (SF-36) at Week 12 | The SF-36 questionnaire consists of eight sections: (1) vitality, (2) physical functioning, (3) bodily pain, (4) general health perceptions, (5) physical role functioning, (6) emotional role functioning, (7) social role functioning, and (8) mental health. All are completed at each visit and the PCS constitutes the primary outcome variable. | Week 0 and 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of LAU-7b | The safety will be assessed through the monitoring of treatment emergent adverse events, compared to placebo | From Week 0 to Week 12 | 
| Patient Global Impression of Change | The PGI-C is a single item questionnaire that asks: Overall, how would you rate the change in your ability to perform usual daily activities since you started the study?. These are the 7-point scale options: 1) very much better, 2) much better, 3) minimally better, 4) no change, 5) minimally worse, 6) much worse, or 7) very much worse. Higher scores indicate a change for the worse and lower scores indicate a change for the better. | Weeks 4, 8 and 12 | 
| Change from baseline in the FACIT-Fatigue scale | This instrument was developed to characterize fatigue, in cancer and used in other conditions with a phenotype of fatigue. It is a 13-item measure that assesses self-reported fatigue and its impact upon daily activities and function. The recall period is 7 days and the response scale employs a 5-point Likert-type scale. | Weeks 0, 4, 8 and 12 | 
| Change from baseline in the DePaul Post-Exertional Malaise Questionnaire (DPEMQ) | This instrument was developed to characterize and evaluate the debilitation caused by a physical exertion, whether a usual daily activity or a leisure activity. It is a 10-item questionnaire that assess both the nature of post-exertional malaise and duration of symptom. | Weeks 0 and 12 | 
| Change from baseline in Physical Functioning Score (PCS) of the Medical Outcomes Study Short-Form-36 (SF-36) at Weeks 4 and 8 | The SF-36 questionnaire is completed in entirety at each visit and the PCS is extracted. The analysis is performed jointly with the primary outcome measure (Week 12). | Weeks 0, 4 and 8 | 
| Change from baseline in the other aspects than the PCS of the Medical Outcomes Study Short-Form-36 (SF-36) | The SF-36 questionnaire consists of eight sections: (1) vitality, (2) physical functioning, (3) bodily pain, (4) general health perceptions, (5) physical role functioning, (6) emotional role functioning, (7) social role functioning, and (8) mental health. All are completed at each visit. | Weeks 0, 4, 8 and 12 | 
| Proportion of subjects who judge to have regained their daily usual activity level of pre-causative-infection. | This will be assessed by a single question with either yes or no as answer: Do you judge that you have regained the daily usual activity level you had prior to being infected by COVID-19 back in Month xxxx? By daily usual activity we mean work, leisure, physical exercise...etc. | From Week 0 through Weeks 4, 8 and 12 | 
| Proportion of subjects achieving >=25%, >=50% or >=75% improvement in the sum of individual Core Long COVID symptom severity as evaluated by a standard 4-level Likert scale. | The Core (most common) Long COVID symptoms are: fatigue, trouble sleeping, shortness of breath, general pain and discomfort, cognitive problems (most commonly known as brain fog or memory fog) and mental health symptoms. Each symptom is rated as: 0=No symptom, 1=Mild symptom (no interference with daily activities), 2=Moderate symptom (interfere and may limit daily activities), and 3=Severe symptom (strong interference preventing daily activities. 0 and 1 are deemed not burdensome, 2 and 3 are burdensome A sum of the burdensome category is calculated for each visit. | Weeks 4, 8 and 12 | 
| Change from baseline in the EQ-5D-5L score | EQ-5D-5L is a validated Quality-of-Life short questionnaire by EuroQol Research Foundation. The EQ-5D-5L is a descriptive system in which subjects are asked to report their current state in 5 dimensions through a 5-level response scale, plus a visual analogue scale (VAS). In total there are 6 items. The higher the score is, the better the quality of life. | Weeks 0, 4, 8 and 12 | 
| Proportion of subjects with relief of at least one core Long COVID symptom for a minimum of 2 weeks. | The core Long COVID symptoms are: fatigue, trouble sleeping, shortness of breath, general pain and discomfort, cognitive problems (most commonly known as brain fog or memory fog) and mental health symptoms. Relief means a reduction of severity from moderate to none, or severe to mild/none (≥2-point Likert score change from outcome #9) | From Week 0 to Week 12 | 
| Time to relief of the first core Long COVID symptom for a minimum of 2 weeks, among those symptoms present at baseline. | The core Long COVID symptoms are: fatigue, trouble sleeping, shortness of breath, general pain and discomfort, cognitive problems (most commonly known as brain fog or memory fog) and mental health symptoms. This will be assessed through periodic inventory of the core Long COVID symptoms, performed at each visit. A longer time is worse than a short time to resolution. | From Week 0 to Week 12 | 
| Proportion of subjects with a sustained clinical recovery, meaning a relief (as defined in outcome #11) of all core Long COVID symptoms. | The core Long COVID symptoms are: fatigue, trouble sleeping, shortness of breath, general pain and discomfort, cognitive problems (most commonly known as brain fog or memory fog) and mental health symptoms. This will be assessed through periodic inventory of the core Long COVID symptoms, performed at each visit. A higher proportion is better than a lower proportion. | Weeks 4, 8 and 12 | 
| Change from baseline in the total number of Long COVID symptoms (core and non-core). | This will be assessed through periodic inventory of all the Long COVID symptoms, performed at each visit, relative to the baseline inventory. A lower total number is better than a higher total number. | Weeks 0, 4, 8 and 12 | 
| Proportion of subjects with Long COVID-related unplanned medical visits | This will be assessed by probing the subjects at each visit. Long COVID-related unplanned medical visits includes visits to practitioner's office, urgent care visits, emergency room <24h, or hospitalization >24 hours. A higher proportion is worse than a lower proportion | From Week 0 to Week 12 | 
| Proportion of subjects deceased from any cause through Week 12. | This will be assessed by probing the subjects at each visit, including caretakers or relatives if the subjects cannot be reached at a given visit. A higher proportion is worse than a lower proportion | From Week 0 to Week 12 | 
| Proportion of subjects with significant cardiovascular events | A significant cardiovascular event is one that results in at least an acute care visit, a hospitalization or an event-related death. A higher proportion is worse than a lower proportion | From Week 0 to Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Long COVID, COVID-19, Antiviral, Inflammation control