Treatment of Long CoronaVIrus Disease (COVID) (TLC) Feasibility Trial

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to assess the feasibility and acceptability of methods and procedures to be employed in a larger scale decentralized platform adaptive randomized clinical trial in patients with a history of a Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Polymerase Chain Reaction (PCR) positive test and/or medical records from a healthcare provider that coincides with the diagnosis of long-COVID.

Detailed Description
-----------------
Fully decentralized single-center, double-blind, randomized, placebo-controlled pilot feasibility trial for patients reporting symptoms consistent with at least one of the following PASC symptoms: Brain fog, Fatigue, Headache, Sleep Disturbance, Post-exertional Malaise (PEM), or Dysautonomia. Participants' interactions with study staff and the study visits will occur primarily via REDCap and Zoom. Informed consent will be conducted remotely via Zoom and obtained electronically in REDCap. Subjects will complete protocol-required logs, questionnaires, and surveys in REDCap. Dose tolerability assessments will occur via televisit preferably, or phone if necessary. Following informed consent, subjects will enter a 4-week screening period during which medical records will be obtained and reviewed. At baseline (Day -28) subjects will complete a battery of tests consisting of the World Health Organization Disability Assessment Schedule (WHODAS) 2.0, Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue 7a, Insomnia Severity Scale, PROMIS Cognitive Function 6A, DePaul Symptom Questionnaire - Post-Exertional Malaise (DSQ-PEM) Short Form, Headache Diary, COMPASS 31, and Self-reported persistent symptoms questionnaire. The headache diary requires daily tracking for 7 days (i.e., Day -28- Day -22). Subjects who successfully complete the screening phase will proceed to randomization where they will be randomized 1:1 to either an opioid antagonist arm (low dose naltrexone (LDN)) or a histamine receptor antagonist arm (cetirizine and famotidine). Within arm 2:1 randomization will then occur assigning subjects to either investigational product (IP) or placebo control respectively. Emory University's Investigational Drug Services (IDS) will conduct the randomization and will overnight via national courier the assigned medication to the study subject. The study subject and study team will be unblind to the treatment arm, i.e., LDN or Histamine H2 receptor antagonists (HRA), but blind to within arm treatment, i.e., LDN or placebo or HRA or placebo. The treatment phase of 12 weeks starts upon ingestion of the first dose. LDN will be supplied in 1.5mg capsules. Initial dosing will be 1.5mg daily titrating up biweekly to 3.0 mg and 4.5 mg, as tolerated. Dose tolerability will be assessed biweekly via televisit or phone call. Subjects who tolerate the 4.5 mg dose will remain on it throughout the treatment phase. If the patient does not tolerate the dose, it will be adjusted downward, and tolerance reassessed in two weeks. Subjects who do not tolerate the minimum 1.5mg dose will be removed from the study. Cetirizine and famotidine will be supplied as 10mg capsules and 20mg capsules respectively. Dosing for the entire treatment period is one 10mg capsule cetirizine or placebo once daily, preferably at bedtime, and one 20mg capsule famotidine or placebo twice daily, as near as possible to the same time every day. Dose tolerability will be assessed on Day 14 via televisit or phone call. If the dose of either IP is not tolerated, subjects will be removed from the study. If the doses are tolerated, subjects will be resupplied and tolerability assessed per protocol. Throughout the treatment phase subjects in all arms will complete the symptom questionnaire, adverse event, study drug adherence, and concomitant medication logs weekly. All subjects will complete the full battery of tests on Days 42, 63, and 84 (Weeks 6, 9, and 12). Subjects will have a +/- 3-day window in which to complete the battery. However, the headache diary requires daily tracking for the 7 days preceding Days 43, 63, and 84. On Day 84 all subjects will complete an end-of-study survey assessing their thoughts and feelings about the study methods and procedures.

Official Title
-----------------
A Feasibility Assessment of a Decentralized Platform Adaptive Double-Blind, Randomized Controlled Trial Investigating Repurposed Drugs in the Treatment of Post-Acute Sequelae of Coronavirus-19 (PASC)

Conditions
-----------------
COVID-19

Intervention / Treatment
-----------------
* Drug: Low-dose Naltrexone (LDN)
* Drug: Cetirizine
* Drug: Famotidine
* Drug: LDN Placebo
* Drug: Cetirizine Placebo
* Drug: Famotidine Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adults ≥18 years of age with a history of a SARS-CoV-2 PCR positive test and/or medical records from a healthcare provider that coincides with the diagnosis of long-COVID New or worsened symptoms since the onset of COVID-19 that are persistent at the time of enrollment and have lasted for ≥ 12 weeks (including at least one of the following: fatigue, post-exertional malaise (PEM), headache, brain fog, sleep disturbance, dysautonomia. Confirmation of negative urine or serum human chorionic gonadotropin (HCG) (pregnancy) test in women of childbearing potential Willing to use appropriate contraceptives for female and male subjects for the duration of the study Has an address (for mailing of study drug) in the state of Georgia Able to swallow capsules Has reliable access to a mobile phone, tablet, laptop, or desktop computer capable of connecting to the internet via Wi-Fi or a data plan Available lab work (CBC and CMP) after the onset of long COVID symptoms Willing and able to comply with scheduled visits, treatment plan, and other study procedures including receiving either intervention or placebo Willing to not take any of the study medications while enrolled in the study except for essential needs as prescribed by a healthcare provider Exclusion Criteria: No post-acute COVID-19 symptoms (PASC) symptoms at the time of enrollment or PASC symptoms present <12 weeks at the time of enrollment Inability to provide own informed consent Currently Hospitalized For women of childbearing potential (WOCBP), currently pregnant or plans to become pregnant during the study period; for males with partners of childbearing potential (OCBP), plans to become pregnant during the study period Actively enrolled in another Long COVID/PASC interventional trial or participation in another interventional clinical trial in the last 30 days or planned during the trial period Unstable medical comorbidities (e.g., decompensated cirrhosis, stage III-IV chronic kidney disease, New York Heart Association (NYHA) class III congestive heart failure), per the patient report, telemedicine physical exam, baseline laboratory values (hematology and extended chemistry panels) and/or medical records Other medical conditions occurring after the onset of COVID-19 that can otherwise account for PASC-type symptoms Currently immunocompromised from the following: solid organ transplant, bone marrow transplant (BMT), high dose steroids (>20mg prednisone per day), immune modulators, or chemotherapy Currently taking opioid analgesics, undergoing treatment for opioid addiction, or taking any other prohibited concomitant medication Opioid dependence or withdrawal syndrome Known sensitivity or adverse reaction to naltrexone, H1 or H2 receptor antagonists, or medication components Suspected or confirmed pregnancy or breastfeeding Current users of LDN Participants already on H1 or H2 receptor antagonists within three (3) months of randomization Currently receiving other therapies to treat COVID-19 or Long COVID symptoms, e.g., convalescent plasma, remdesivir, Paxlovid

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LDN Treatment Arm<br>Participants randomized to Treatment Arm will receive Low-dose Naltrexone. | Drug: Low-dose Naltrexone (LDN)<br>* LDN will be administered in an escalating dose beginning at 1.5 mg/day by mouth for 2 weeks and increasing by 1.5mg every two weeks to the maximum dosage of 4.5 mg/day which will continue throughout the treatment phase. Dose escalation or de-escalation will be based on safety and tolerability at the discretion of the Investigator, depending on the patient's response to therapy and experience of adverse events.<br>* Other names: Naltrexone;|
| Experimental: HRA Treatment Arm<br>Participants randomized to Treatment Arm will receive dual histamine receptor antagonists: famotidine and cetirizine daily. | Drug: Cetirizine<br>* Cetirizine will be dispensed as a 10mg capsule with instructions for patients to take one capsule daily by mouth, preferably at bedtime.<br>Drug: Famotidine<br>* Famotidine will be dispensed in 20mg capsules with instructions for patients to take one capsule twice daily, as close to the same times every day as possible.<br>* Other names: HRA;|
| Placebo Comparator: Placebo Arm<br>The compounding study pharmacy will provide placebo capsules to the patients randomized to Placebo. These capsules are manufactured to match each treatment drug for oral administration. | Drug: LDN Placebo<br>* The LDN placebo will be designed as a capsule of an inert substance, that matches the morphology of the LDN treatment capsule. Administration instructions to match that of LDN.<br>Drug: Cetirizine Placebo<br>* The cetirizine placebo will be designed as a capsule of an inert substance and will match the morphology of the cetirizine treatment capsule. Administration instructions to match that of cetirizine.<br>Drug: Famotidine Placebo<br>* The famotidine placebo will be designed as a capsule of an inert substance and will match the morphology of the famotidine treatment capsule. Administration instructions to match that of famotidine.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants that had any confusion over how to take the study drug, including which pill to take, when to take it, or how many to take | The number of participants that had any confusion over how to take the study drug, including which pill to take, when to take it, or how many to take will be recorded as part of the end-of-study survey. | 12 weeks post-intervention | 
| Number of participants that had trouble adhering to the study drug schedule | The number of participants that had trouble adhering to the study drug schedule will be recorded as part of the end-of-study survey. | 12 weeks post-intervention | 
| Number of participants that had any difficulty using the REDCap interface. | The number of participants that had any difficulty using the REDCap interface will be recorded as part of the end-of-study survey. | 12 weeks post-intervention | 
| Number of participants that prefer participating in this virtual study | The number of participants that prefer participating in this virtual study compared to participating in an in-person study hosted at a medical center will be recorded as part of the end-of-study survey. | 12 weeks post-intervention | 
| Number of participants satisfied with their opportunities to interact with study staff | The number of participants satisfied with their opportunities to interact with study staff will be recorded as part of the end-of-study survey. | 12 weeks post-intervention | 
| Number of participants that felt they could reach study staff if needed | The number of participants that felt they could reach study staff if needed will be recorded as part of the end-of-study survey. | 12 weeks post-intervention | 
| Number of participants that felt that study staff was available and easy to contact to report any adverse effects | The number of participants that felt that study staff was available and easy to contact to report any adverse effects that they experienced from the medication will be recorded as part of the end-of-study survey. | 12 weeks post-intervention | 
| Number of participants that felt that the amount of information collected in each series of surveys was acceptable | The number of participants that felt that the amount of information collected in each series of surveys was acceptable will be recorded as part of the end-of-study survey. | 12 weeks post-intervention | 
| Number of participants that felt that the frequency in which the information was collected was acceptable | The number of participants that felt that the frequency in which the information was collected was acceptable will be recorded as part of the end-of-study survey. | 12 weeks post-intervention | 
| Improvement rating | Participants will be asked how much they feel they improved from this treatment over the last 12 week using a scale from 1 to 5, with 5 being complete improvement (better outcome) and 1 being no improvement. | 12 weeks post-intervention | 
| Quality of life (QoL) score rating | Participants will be asked how much their quality of life was impacted by changes to their health during the study. On a scale of 1 to 5 with 5 being the most impacted (better outcome) and 1 being not at all impacted by changes to their health. | 12 weeks post-intervention | 
| Interest score | Participants will be asked how interested they are in continuing treatment with the study medication after the study. On a scale of 1 to 5, with 5 being completely interested (better outcome) and 1 being completely uninterested. | 12 weeks post-intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of survey completion | Percentage of participants who complete 70% of surveys will be assessed | 12 weeks post-intervention | 
| Proportion of study drug adherence | Percentage of participants who complete 70% of doses will be assessed | 12 weeks post-intervention | 
| Proportion of Lost to Follow Up (LFUP) | Percentage of participants Lost to Follow Up (LFUP) will be assessed | 12 weeks post-intervention | 
| Proportion of voluntary termination | Percentage of participants that voluntarily terminate participation will be assessed | 12 weeks post-intervention | 
| Adverse events (AEs) incidence | The total number of adverse events in the treatment arms versus the placebo arm will be recorded. | 12 weeks post-intervention | 
| Serious, unexpected suspected adverse reactions (SUSAR) incidence | The number of SUSARs in the treatment arms versus the placebo arm will be recorded. | 12 weeks post-intervention | 
| Study-wide serious adverse events (SAEs) incidence | The total number of SAEs in the treatment arms versus the placebo arm will be recorded. | 12 weeks post-intervention | 
| Number of discontinuations or temporary suspensions of IP | The total number of participants who discontinue any of the treatment arms versus the placebo arm will be recorded. | 12 weeks post-intervention | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Long COVID-19