Intervention: Naltrexone
Trial phase: Phase 2
ATC code: A08AA62 | N02AA56 | N07BB04
SMILES: [H][C@@]12Oc3c(O)ccc4c3[C@@]13CCN(CC1CC1)[C@]([H])(C4)[C@]3(O)CCC2=O
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 35
Group description: Patients randomized to an LDN-containing treatment arm (including the "combined arm") will receive naltrexone 4.5 mg once daily. The first dose can be given at any time during the day of enrollment/randomization, and will be timed at 08:00 daily thereafter (with AM colchicine dose, if in combined colchicine/LDN arm) for up to 28 days (unless new contraindication or exclusion criteria met).

Patients in this arm will also receive the investigating institution's current standard of care (described in detail in the "standard of care" arm) for patients with COVID-19.

Naltrexone: Most well known as an opioid antagonist, or a treatment for alcohol dependence, naltrexone also possesses immunomodulatory effects. Seen exclusively at low doses, this attribute is being employed in the pain community as a novel anti-inflammatory agent that has been shown to reduce symptom severity in fibromyalgia, Crohn's disease, multiple sclerosis, and complex regional pain syndrome.

For this study, patients enrolled in a naltrexone-containing arm will take their daily dose of the medication (4.5mg) by oral suspension.
Eligibility criteria:
Inclusion Criteria:

Male and (non-pregnant, non-breastfeeding) females aged 18 years or older
Requiring admission to Methodist or Regions Hospital due to laboratory-confirmed COVID-19

Meets criteria of only up to moderate COVID-19 disease as defined by a clinical score of 2 or 3 at the time of enrollment, and one or more of the following:

Dyspnea limiting usual activities on baseline O2 needs
Respiratory rate >/= 30/min on O2 or room air
Blood oxygen saturations <94% on room air (or on baseline O2 needs if on supplemental oxygen prior to presentation at the hospital for a condition unrelated to COVID-19).
Requiring supplemental 02 above baseline needs (i.e. prior to presentation at hospital)
COVID-19 contributed to the current hospital admission, per attending provider's clinical assessment of the patient.
Ability to provide written informed consent, or has identifiable LAR that is able to do so on the patient's behalf as defined by study protocol, prior to performing study procedures.

Exclusion Criteria:

Patients meeting criteria for severe/critical COVID-19 as defined by study protocol or requiring O2 supplementation ≥10L nasal cannula at screening
Patients currently in shock as defined by hemodynamic instability requiring vasopressors
Patients with a current hospitalization for COVID-19 that is >/=7 days at the time of screening.
Clinical estimation of attending physician that the patient will require mechanical respiratory support within 48 hours of enrollment
Patients in which EITHER symptom onset OR a positive COVID-19 laboratory test occurred >14 days prior to enrollment.
Patients with concomitant influenza A or B at time of hospitalization if tested as part of ED/hospital admission.
Female patients who are pregnant or breastfeeding at time of hospital admission
Diagnosis of Chronic Kidney Disease stage ≥4 as documented in the patient's problem list (not based on CrCI calculations alone)
CrCl < 30 mL/min or requiring renal replacement therapy (e.g. intermittent hemodialysis, continuous renal replacement therapy, peritoneal dialysis) at screening
History of cirrhosis or advanced liver disease, or active hepatic viral infection
Transplant of kidney, lung, heart, or liver in the past 2 years
Uncontrolled severe gastrointestinal disorders, Crohn's disease, ulcerative colitis, chronic diarrhea, diarrhea predominant irritable bowel syndrome, active stomach or intestinal ulcer, or one that was treated within the last 6 months
Patients currently receiving agents that are p-glycoprotein AND strong CYP3A4 inhibitors with CrCl < 60 mL/min, or any combination of drug interactions that is not amenable to dosage adjustment (refer to list of medications with potential Colchicine and Naltrexone interactions).
Patients actively undergoing chemotherapy for an active malignancy, or history of a hematologic malignancies
Chronic or current use of colchicine or any mu-opioid antagonist.
Chronic, scheduled opioid therapy (i.e. not intermittent as needed use), or, prior to enrollment, an acute condition requiring continued pain control that is unattainable without ongoing opioid therapy.
Pre-existing condition that is being treated with tocilizumab, anakinra, sarilumab, other interleukin-antagonists, TNF-inhibitors, or JAK inhibitors.
NOTE: Patients treated with tocilizumab will be permitted to enroll if their care team is prescribing it for COVID-19. Use of tocilizumab at baseline for another indication will continue to be excluded.

Participation in any other clinical trial of an experimental treatment for COVID-19, note:

While convalescent plasma is no longer recommended within HP, it can be given if deemed appropriate by the medical team once ≥ 24 hours has elapsed since enrollment;
Patients previously enrolled in the C3PO study can enroll in this study, as any convalescent plasma received would have been outpatient;
Remdesivir is allowed per standard protocol;
Dexamethasone is allowed per standard protocol
Patients actively enrolled in hospice or that are DNI or on palliative care
History of hypersensitivity reaction to colchicine or its inactive ingredients
History of hypersensitivity reaction to naltrexone or its inactive ingredients
Incarcerated or a ward of the state
Any patient considered an unsuitable candidate, for any reason, by study investigators.