To explore the safety and efficacy of daily doses of celecoxib + valacyclovir in thetreatment of patients with prolonged symptoms caused by COVID-19.
This is a randomized, double-blinded, placebo-controlled, single-center, three arm,
12-week study designed to explore the safety and efficacy of daily doses of valacyclovir
+ celecoxib for the treatment of prolonged symptoms caused by COVID-19 infection in adult
female patients. The treatment consists of twice daily doses of valacyclovir and
celecoxib, which is theorized to provide potent suppression of tissue-resident herpes
viruses subsequently activated by an initial infection with the SARS-CoV-2 virus. The
physiological response to tissue-resident herpes virus activation is in turn hypothesized
to be causally related to symptoms associated with the Post-Acute Sequelae of SARS-CoV-2
Infection (PASC). There are three arms and in each arm, patients take four blue capsules
and one white capsule in the morning and again in the evening. The capsules dispensed for
arm 1 will consist of four 375mg valacyclovir capsules and one 200 mg celecoxib capsule.
Arm 2 will be dispensed two blue 375mg valacyclovir capsules, two blue placebo capsules
and one white 200 mg celecoxib capsule. Arm 3 will be dispensed four blue placebo
capsules and one white placebo capsule.
Approximately 60 female patients will be enrolled at Bateman Horne Center for this study.
Candidates will undergo initial pre-screening by telephone or database review, after
which, if they appear to meet initial entry criteria, they will have an in- person
screening visit. They will start recording symptom data, starting at the baseline visit,
and continuing with weekly recordings, for the duration of their study participation.
Each week, the patient will provide information on their average fatigue, sleep quality
and pain intensity.
Patients with underlying medical or psychiatric conditions that could impact their safe
participation in the study or interfere with their ability to complete or comply with the
study's requirements will not be enrolled. In addition, any patient dependent upon
opioids/narcotics (collectively referred to as "opioids") for pain control for any reason
will not be enrolled in the study.
Due to the celecoxib component of the combination therapy, patients using NSAIDs or COX-2
inhibitors will need to discontinue use of NSAIDs at least 7 days before randomization.
NSAIDs including PRN usage should not be utilized for the duration of the study. Instead,
acetaminophen may be utilized as needed throughout the study (but not to exceed 3250 mg
per day). Patients may also continue low-dose aspirin for cardioprotection (< 325
mg/day).
Patients may remain on stable doses of SSRIs and other non-excluded anti- depressants;
however, poorly controlled, or severely depressed patients should not be enrolled. Only
clinically stable and well-controlled patients should be considered, i.e., patients with
mild to moderate depression who in the judgement of the investigator are not at risk of
suicidal ideation or behavior.
For all patients a screening visit will be conducted so the PI or Sub-I can ensure that
all entry criteria have been satisfied. At baseline, the PI/sub-I will ensure all safety
laboratory results are satisfactory, any required washout has been completed and all
entry criteria have been met. Patients should initiate study drug treatment on the day of
the Baseline visit (Day 1), followed by BID dosing for the duration of the study.
Blood and urine will be collected at the Screening visit for safety assessments. Urine
pregnancy tests will be performed at Week 4, 8 and 12 (or early termination) visits for
patients with child-bearing potential. A blood sample for safety labs will be collected
during Week 12/ET. Urine drug screening for drugs of abuse will be conducted at the
Screening visit; patients positive for cocaine, methamphetamine, phencyclidine (PCP),
methadone, non-disclosed amphetamines and non-disclosed opiates will be screen failed.
Patients positive for disclosed, prescribed opioids at the Screening visit, yet deemed
suitable for washout, must be able to remain off all opioids for the duration of the
study and have a negative repeat UDS at the Baseline visit. Additional drug testing may
be conducted at the PI or Sub-I's discretion.
Patients with clinically significant renal insufficiency or a history of renal disease
(as defined in the entry criteria) will be excluded.
Patients will have in-person study visits scheduled for Screening, Baseline, Weeks 4, 8
and 12/ET. If necessary, remote visits may be substituted for the Week 4 and/or Week 8
visits. A follow-up survey or phone call will be scheduled approximately 2 weeks after
completion of study drug treatment at Week 12 or ET.
Drug: Valacyclovir celecoxib dose 1
1500 mg valacyclovir 200 mg celecoxib taken two times a day
Other Name: Arm 1
Drug: Valacyclovir celecoxib dose 2
750 mg valacyclovir 200 celecoxib mg taken two times a day
Other Name: Arm 2
Drug: Placebo
Placebo capsules colored matched to investigational product taken two times a day
Other Name: Arm 3
Inclusion Criteria:
1. Willing and able to read, understand, and sign the informed consent.
2. Female at birth, 18-65 years of age at the time of study entry.
3. Must have smartphone with internet access to complete surveys online.
4. Diagnosis of Long COVID according to any of the following definitions Infected
individuals will have a history of suspected, probable, or confirmed SARS-CoV-2
infection as defined by WHO criteria and at least three months of persistent fatigue
and muscle weakness, functional impairment, and cognitive impairment since the acute
infection.
Adults with suspected SARS-CoV-2 infection. An adult qualifies as having suspected
SARS-CoV-2 infection if meeting at least one of the following criteria (a-e) below:
a. Clinical criteria: Acute onset of fever and cough OR acute onset of any three or more
of the following signs or symptoms: fever, cough, general weakness /fatigue, headache,
myalgia, sore throat, coryza, dyspnea, anorexia/nausea/vomiting, diarrhea, altered mental
status. These patients should also meet one of the following epidemiological criteria: i.
Epidemiological criteria:
1. Residing or working in an area with a high risk of transmission of virus: closed
residential settings, humanitarian settings such as camp and camp-like settings for
displaced persons; anytime within the 14 days before symptom onset; or
2. Residing or travel to an area with community transmission anytime within the 14 days
before symptom onset; or
3. Working in any health care setting, including within health facilities or the
community, anytime within the 14 days before symptom onset.
b. A patient with severe acute respiratory illness: (acute respiratory infection
with history of fever or measured fever of ≥38C°; and cough; with onset within the
last ten days; and requires hospitalization).
c. An asymptomatic patient not meeting any of the epidemiologic criteria above but
with a previously positive SARS-CoV-2 Antigen- RDT.
d. Adults with probable SARS-CoV-2 infection. An adult qualifies as having probable
SARS-CoV-2 infection if meeting any one of 1-3 below: i. A patient who meets
clinical criteria for suspected SARS- CoV-2 AND is a contact of a probable or
confirmed case or linked to a COVID-19 cluster; ii. A suspect case with chest
imaging showing findings suggestive of COVID-19 disease; iii. A person with recent
onset of anosmia (loss of smell) or ageusia (loss of taste) in the absence of any
other identified cause; e. Adults with confirmed SARS-CoV-2 infection. An adult
qualifies as having confirmed SARS-CoV-2 infection if meeting any one of 1-4 below:
i. Any person with a positive Nucleic Acid Amplification Test (NAAT); ii. Any person
with of a positive SARS-CoV-2 Antigen-RDT AND meeting either the probable case
definition or suspect criteria A OR B; iii. An asymptomatic person with a positive
SARS-CoV-2 Antigen-RDT who is a contact of a probable or confirmed case; iv. Any
person with a positive SARS-CoV-2 nucleocapsid protein antibody test OR a positive
SARS-CoV-2 spike protein antibody test IF not vaccinated
5. Women of child-bearing potential must have a negative serum pregnancy test at
screening and agree to on-site urine pregnancy testing at all subsequent study visits.
Women confirmed to be of non-childbearing potential do not require pregnancy testing.
Pregnancy tests will not be required for remote visits. To be considered of
non-child-bearing potential, the patient must be:
a. Post-menopausal (defined as no menses for at least one year); or b. Surgically sterile
(s/p hysterectomy, bilateral oophorectomy, or bilateral tubal ligation at least six
months prior to beginning treatment with study drug); or c. At least three months s/p a
non-surgical permanent sterilization procedure 6. A urine drug screen performed at the
Screening Visit must be negative for drugs of abuse such as methamphetamine, cocaine,
phencyclidine (PCP), and non-disclosed amphetamines and opioids/opiates. The following
stipulations also apply:
1. Patients with a positive screening UDS due to prescribed amphetamines for allowed
conditions do not require further UDS testing. They may proceed with study
treatment, assuming no evidence of abuse or dependency.
2. Patients positive for prescribed opioids at the Screening Visit yet deemed
appropriate for washout and study participants must have a negative repeat UDS at
the Baseline Visit.
7. Patients must be willing and able to withdraw and refrain from chronic use of
antivirals (as defined in Exclusion Criterion, below). In the judgement of the
investigator, it must be medically advisable for these therapies to be withdrawn.
8. Qualified patients with mild to moderate depression who in the judgment of the
investigator are not at risk of suicidal ideation or behavior. The dose of allowed
antidepressants should have been stable for at least 30 days prior to Baseline
Visit..
9. In the opinion of the Investigator, the patient is willing and able to comply
with all protocol-specified requirements.
10. Women of child-bearing potential must be willing to utilize an effective birth
control method for the duration of the study. Allowable contraceptive methods
include:
a. Oral, implantable, injectable, or transdermal hormonal contraceptives (should have
been used for a minimum of one full cycle prior to administration of study drug) b.
Intrauterine devices (IUD) c. Double barrier method (male or female condom, sponge,
diaphragm, or vaginal ring with simultaneous use of spermicidal jelly or cream) 11.
Patients should not require routine treatment with warfarin, heparin, lithium, digoxin,
amiodarone, isoniazid, phenytoin, fluconazole, methotrexate, probenecid, or raloxifene.
Patients on these medications should not be screened. PRN usage of fluconazole for short
time periods is permitted.
12. Patients must have successfully completed at least two PROMIS Fatigue and two PROMIS
Sleep Disturbance surveys a minimum of 7 days apart during the interval leading up to the
baseline visit.
Exclusion Criteria:
1. Breastfeeding, pregnant, or planning to become pregnant during the next six months.
2. In the opinion of the Investigator, any clinically significant, uncontrolled, or
unstable medical or surgical condition that could affect the patient's ability to
participate in the study or potentially compromise her well-being while enrolled in
the study.
3. In the opinion of the Investigator or based on results of the HADS, evidence of a
clinically significant psychiatric disorder; e.g., severe, unstable or poorly
controlled depression, anxiety or obsessive-compulsive disorder; moderate or severe
alcohol use disorder; substance use disorder other than mild cannabis use disorder;
or any history of bipolar disorder, schizophrenia, schizoaffective disorder or other
psychotic disorder.
4. A score of >15 on the Patient Health Questionnaire-9 (PHQ-9) determined by survey at
screening.
5. A positive response to thoughts of suicide or self-harm on the PHQ-9 determined by
survey at screening.
6. A diagnosis of ME/CFS prior to January 2020.
7. Any anticipated need for surgery that in the opinion of the Principal Investigator
or Sub-I might confound results or interfere with the patient's ability to comply
with the protocol.
8. Symptomatic and/or otherwise clinically significant cardiac disease, including but
not limited to myocardial infarction during the preceding two years; uncontrolled
hypertension; symptomatic heart failure (e.g., New York Heart Association Class II
or higher); angina or other evidence of significant coronary artery disease;
clinically significant cardiac rhythm or conduction abnormality or anticipation of
bypass or other cardiac surgery within the next 12 months.
9. Acute non-COVID systemic infection (e.g., HIV, hepatitis) or other active viral or
bacterial infection during the screening/washout period or at the Baseline visit.
(Patient may remain in screening until the active infection has resolved, or
re-screen after recuperation.)
10. Currently receiving chronic systemic corticosteroids (>5 mg prednisone daily, or
equivalent).
11. Uncontrolled sleep apnea. Patients successfully treated with CPAP or other devices
are eligible.
12. Use of chronic nucleoside analog antiviral suppression therapy within one month of
the Screening Visit or requiring on average more than one acute treatment course
every two months.
13. Current use of celecoxib either alone or in combination with valacyclovir or
famciclovir
14. In the opinion of the Investigator, evidence of current drug or alcohol abuse or
dependency, or history of abuse or dependence during the preceding 12 months.
15. The patient has undergone a malabsorptive weight loss procedure (e.g., Roux-en-Y or
other bypass procedure).
16. Severe IBS-C or colonic inertia as evidenced by seven or more days between bowel
movements.
17. History of significant adverse reaction or allergy to sulfonamides, celecoxib,
famciclovir, acyclovir, valacyclovir or penciclovir cream (Denavir®).
18. History of aspirin-sensitive asthma, or any other history of other allergic- type
reactions after taking aspirin or other NSAID such as asthma or urticaria.
19. History of Sulfa Allergy.
20. History of peptic ulcer disease or upper gastrointestinal bleeding that is thought
to pose a significant risk of GI bleeding with the daily use of celecoxib.
21. Clinically significant elevations of AST, ALT, or bilirubin at the screening
assessment (or at the last assessment prior to baseline, if repeated) in the opinion
of the Investigator.
22. Presence of active kidney disease, as evidenced by an estimated glomerular
filtration rate (eGFR) of less than 60 mL/min/1.73m2.
23. History of acute kidney injury within the past year, any history of chronic kidney
disease stage 3 or higher.
24. In the opinion of the Investigator, evidence of other clinically significant
laboratory abnormality(ies) based on the screening laboratory assessments and/or
medical history.
25. Untreated, symptomatic gall bladder disease (i.e., symptoms within preceding six
months).
26. Plans to undergo vaccination against Herpes varicella/ zoster (i.e., shingles or
chickenpox) during the study. Instead, vaccination should be completed at least 14
days prior to the Baseline Visit or delayed until at least two weeks after the last
dose of study medication.
27. Patients known or suspected to be slow CYP2C9 metabolizers based on genotype or
previous history/experience with other CYP2C9 substrates (such as warfarin,
phenytoin, glimepiride, tolbutamide, celecoxib, meloxicam, piroxicam, or ibuprofen).
28. Investigational drug usage within 30 days of Screening.
Bateman Horne Center
Salt Lake City 5780993, Utah 5549030, United States
Lucinda Bateman, MD, Principal Investigator
Bateman Horne Center