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

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 complete the screening phase will proceed to randomization where they will be randomized 2:1 to either histamine receptor antagonists (cetirizine and famotidine) or matching placebos. 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 treatment phase of 12 weeks starts upon ingestion of the first dose.

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.

• Cetirizine (Drug): Cetirizine will be dispensed as a 10mg capsule with instructions for patients to take one capsule daily by mouth, preferably at bedtime.
• Famotidine (Drug), also known as HRA: 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.
• Cetirizine Placebo (Drug): 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.
• Famotidine Placebo (Drug): 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.

Primary outcomes

• 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 [End of the Treatment Phase at 12 weeks]: 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.
• Number of Participants That Had Trouble Adhering to the Study Drug Schedule [End of the Treatment Phase at 12 weeks]: The number of participants that had trouble adhering to the study drug schedule will be recorded as part of the end-of-study survey.
• Number of Participants That Had Any Difficulty Using the REDCap Interface. [End of the Treatment Phase at 12 weeks]: The number of participants that had any difficulty using the REDCap interface will be recorded as part of the end-of-study survey.
• Number of Participants That Prefer Participating in This Virtual Study [End of the Treatment Phase at 12 weeks]: 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.
• Number of Participants Satisfied With Their Opportunities to Interact With Study Staff [End of the Treatment Phase at 12 weeks]: The number of participants satisfied with their opportunities to interact with study staff will be recorded as part of the end-of-study survey.
• Number of Participants That Felt They Could Reach Study Staff if Needed [End of the Treatment Phase at 12 weeks]: The number of participants that felt they could reach study staff if needed will be recorded as part of the end-of-study survey.
• Number of Participants That Felt That Study Staff Was Available and Easy to Contact to Report Any Adverse Effects [End of the Treatment Phase at 12 weeks]: 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.
• Number of Participants That Felt That the Amount of Information Collected in Each Series of Surveys Was Acceptable [End of the Treatment Phase at 12 weeks]: 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.
• Number of Participants That Felt That the Frequency in Which the Information Was Collected Was Acceptable [End of the Treatment Phase at 12 weeks]: 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.
• Improvement Rating [End of the Treatment Phase at 12 weeks]: 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.
• Quality of Life (QoL) Score Rating [End of the Treatment Phase at 12 weeks]: 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.
• Interest Score [End of the Treatment Phase at 12 weeks]: 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.

Secondary outcomes

• Proportion of Survey Completion [End of the Treatment Phase at 12 weeks]: Percentage of participants who complete 70% of surveys will be assessed
• Proportion of Study Drug Adherence [End of the Treatment Phase at 12 weeks]: Percentage of participants who complete 70% of doses will be assessed
• Proportion of Lost to Follow Up (LFUP) [End of the Treatment Phase at 12 weeks]: Percentage of participants Lost to Follow Up (LFUP) will be assessed
• Proportion of Voluntary Termination [End of the Treatment Phase at 12 weeks]: Percentage of participants that voluntarily terminate participation will be assessed
• Adverse Events (AEs) Incidence [End of the Treatment Phase at 12 weeks]: The mean number of adverse events in the treatment arms will be compared to those in the placebo arm.
• Serious, Unexpected Suspected Adverse Reactions (SUSAR) Incidence [End of the Treatment Phase at 12 weeks]: The number of SUSARs in the treatment arms versus the placebo arm will be recorded.
• Study-wide Serious Adverse Events (SAEs) Incidence [End of the Treatment Phase at 12 weeks]: The total number of SAEs in the treatment arms versus the placebo arm will be recorded.
• Number of Discontinuations or Temporary Suspensions of IP [End of the Treatment Phase at 12 weeks]: The total number of participants who discontinue any of the treatment arms versus the placebo arm will be recorded.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. 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
2. 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.
3. Confirmation of negative urine or serum human chorionic gonadotropin (HCG) (pregnancy) test in women of childbearing potential
4. Willing to use appropriate contraceptives for female and male subjects for the duration of the study
5. Has an address (for mailing of study drug) in the state of Georgia
6. Able to swallow capsules
7. 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
8. Available lab work (CBC and CMP) after the onset of long COVID symptoms
9. Willing and able to comply with scheduled visits, treatment plan, and other study procedures including receiving either intervention or placebo
10. 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:

1. No post-acute COVID-19 symptoms (PASC) symptoms at the time of enrollment or PASC symptoms present <12 weeks at the time of enrollment
2. Inability to provide own informed consent
3. Currently Hospitalized
4. 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
5. 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
6. 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
7. Other medical conditions occurring after the onset of COVID-19 that can otherwise account for PASC-type symptoms
8. Currently immunocompromised from the following: solid organ transplant, bone marrow transplant (BMT), high dose steroids (>20mg prednisone per day), immune modulators, or chemotherapy
9. Currently taking opioid analgesics, undergoing treatment for opioid addiction, or taking any other prohibited concomitant medication
10. Opioid dependence or withdrawal syndrome
11. Known sensitivity or adverse reaction to H1 or H2 receptor antagonists, or medication components
12. Suspected or confirmed pregnancy or breastfeeding
13. Participants already on H1 or H2 receptor antagonists within three (3) months of randomization
14. Currently receiving other therapies to treat COVID-19 or Long COVID symptoms, e.g., convalescent plasma, remdesivir, Paxlovid

Participant flow

Outcome results

• 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 (Primary), Count of participants, Participants: HRA Treatment Arm 0; Placebo Arm 0
• Number of Participants That Had Trouble Adhering to the Study Drug Schedule (Primary), Count of participants, Participants: HRA Treatment Arm 0; Placebo Arm 0
• Number of Participants That Had Any Difficulty Using the REDCap Interface. (Primary), Count of participants, Participants: HRA Treatment Arm 0; Placebo Arm 0
• Number of Participants That Prefer Participating in This Virtual Study (Primary), Count of participants, Participants: HRA Treatment Arm 3; Placebo Arm 2
• Number of Participants Satisfied With Their Opportunities to Interact With Study Staff (Primary), Count of participants, Participants: HRA Treatment Arm 3; Placebo Arm 2
• Number of Participants That Felt They Could Reach Study Staff if Needed (Primary), Count of participants, Participants: HRA Treatment Arm 3; Placebo Arm 2
• Number of Participants That Felt That Study Staff Was Available and Easy to Contact to Report Any Adverse Effects (Primary), Count of participants, Participants: HRA Treatment Arm 3; Placebo Arm 2
• Number of Participants That Felt That the Amount of Information Collected in Each Series of Surveys Was Acceptable (Primary), Count of participants, Participants: HRA Treatment Arm 3; Placebo Arm 2
• Number of Participants That Felt That the Frequency in Which the Information Was Collected Was Acceptable (Primary), Count of participants, Participants: HRA Treatment Arm 3; Placebo Arm 2
• Improvement Rating (Primary), Mean, Score on a scale: HRA Treatment Arm 2.3 +/- 0.94; Placebo Arm 2 +/- 0
• Quality of Life (QoL) Score Rating (Primary), Mean, Score on a scale: HRA Treatment Arm 2 +/- 1.4; Placebo Arm 1.5 +/- 0.5
• Interest Score (Primary), Mean, score on a scale: HRA Treatment Arm 4.3 +/- 0.94; Placebo Arm 3 +/- 2
• Proportion of Survey Completion (Secondary), Count of participants, Participants: HRA Treatment Arm 3; Placebo Arm 2
• Proportion of Study Drug Adherence (Secondary), Count of participants, Participants: HRA Treatment Arm 3; Placebo Arm 2
• Proportion of Lost to Follow Up (LFUP) (Secondary), Count of participants, Participants: HRA Treatment Arm 0; Placebo Arm 0
• Proportion of Voluntary Termination (Secondary), Count of participants, Participants: HRA Treatment Arm 0; Placebo Arm 0
• Adverse Events (AEs) Incidence (Secondary), Mean, number of adverse events: HRA Treatment Arm 3.7 +/- 1.2; Placebo Arm 2 +/- 1
• Serious, Unexpected Suspected Adverse Reactions (SUSAR) Incidence (Secondary), Number, Number of SUSARs: HRA Treatment Arm 0; Placebo Arm 0
• Study-wide Serious Adverse Events (SAEs) Incidence (Secondary), Number, Number of SAEs: HRA Treatment Arm 0; Placebo Arm 0
• Number of Discontinuations or Temporary Suspensions of IP (Secondary), Count of participants, Participants: HRA Treatment Arm 0; Placebo Arm 0

Adverse events

Time frame: Information on adverse events, Serious Adverse Effects were assessed after randomization until completion of the study (12 weeks post-intervention).

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2023-11-20)

• Tiffany Walker, MD, Principal investigator, Emory University