Impact of Colchicine and Low-dose Naltrexone on COVID-19
Condition: Covid19
MeSH terms: COVID-19
Intervention: Colchicine 0.6 mg; Naltrexone
Intervention description: Colchicine is an oral anti-inflammatory agent that is relatively inexpensive, readily available, and has been used for generations. Approved for treatment and prophylaxis of gout flares and Mediterranean fever, it is also used in a variety of other inflammatory conditions (e.g. pericarditis and diffuse vascular inflammation such as Behcet syndrome). Colchicine binds to tubulin causing depolymerization, which interferes with neutrophil chemotaxis, adhesion, and mobilization to sites of inflammation, and contributes to reduction in superoxide production; through interference of the NLRP3 inflammasome protein complex, colchicine inhibits IL-1b, IL-6, and IL-18 production.
For this study, patients enrolled in a colchicine containing arm will receive 0.6mg of colchicine BID (unless renal function/gastrointestinal issues require adjustments described in the protocol); 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.
Intervention MeSH terms: Colchicine; Naltrexone
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Factorial Assignment
Intervention model description: This will be a four arm, prospective, randomized, open label trial in patients hospitalized with moderate COVID-19. Randomization will be stratified by baseline severity score (2 or 3) to ensure balanced baseline severities between the four arms. Block randomization will be used to ensure equal group sizes. As the final sample size is unknown, study staff will use small blocks of eight for randomization. This is being done in an effort to ensure evenly distributed treatment arms.
Masking: None (Open Label)
Enrollment: 142.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to explore the impact of two medications-colchicine and low-dose
      naltrexone (LDN)-relative to standard of care (SOC) on COVID-19 disease progression to
      severe/critical illness and/or intubation in patients hospitalized with moderate COVID-19. As
      researchers have learned, COVID-19's clinical course suggests that the hyperinflammatory
      response seen in severe/critical cases is involved in the pathogenesis of associated adverse
      sequelae such as acute respiratory distress syndrome (ARDS), thromboembolic disease, and
      acute cardiac injury. Given colchicine has demonstrated clinical utility in inflammatory
      syndromes within these systems (e.g. endothelial/vascular/myocardial), and LDN acts both to
      boost the immune system, and limit an excessive response; they may prove useful in minimizing
      the risk of disease progression and associated adverse sequelae.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male and (non-pregnant, non-breastfeeding) females aged 18 years or older

          2. Requiring admission to Methodist or Regions Hospital due to laboratory-confirmed
             COVID-19

          3. 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:

               1. Dyspnea limiting usual activities on baseline O2 needs

               2. Respiratory rate >/= 30/min on O2 or room air

               3. 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).

               4. Requiring supplemental 02 above baseline needs (i.e. prior to presentation at
                  hospital)

               5. COVID-19 contributed to the current hospital admission, per attending provider's
                  clinical assessment of the patient.

          4. 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:

          1. Patients meeting criteria for severe/critical COVID-19 as defined by study protocol or
             requiring O2 supplementation ≥10L nasal cannula at screening

          2. Patients currently in shock as defined by hemodynamic instability requiring
             vasopressors

          3. Patients with a current hospitalization for COVID-19 that is >/=7 days at the time of
             screening.

          4. Clinical estimation of attending physician that the patient will require mechanical
             respiratory support within 48 hours of enrollment

          5. Patients in which EITHER symptom onset OR a positive COVID-19 laboratory test occurred
             >14 days prior to enrollment.

          6. Patients with concomitant influenza A or B at time of hospitalization if tested as
             part of ED/hospital admission.

          7. Female patients who are pregnant or breastfeeding at time of hospital admission

          8. Diagnosis of Chronic Kidney Disease stage ≥4 as documented in the patient's problem
             list (not based on CrCI calculations alone)

          9. CrCl < 30 mL/min or requiring renal replacement therapy (e.g. intermittent
             hemodialysis, continuous renal replacement therapy, peritoneal dialysis) at screening

         10. History of cirrhosis or advanced liver disease, or active hepatic viral infection

         11. Transplant of kidney, lung, heart, or liver in the past 2 years

         12. 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

         13. 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).

         14. Patients actively undergoing chemotherapy for an active malignancy, or history of a
             hematologic malignancies

         15. Chronic or current use of colchicine or any mu-opioid antagonist.

         16. 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.

         17. Pre-existing condition that is being treated with tocilizumab, anakinra, sarilumab,
             other interleukin-antagonists, TNF-inhibitors, or JAK inhibitors.

         18. 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.

         19. Participation in any other clinical trial of an experimental treatment for COVID-19,
             note:

               1. 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;

               2. Patients previously enrolled in the C3PO study can enroll in this study, as any
                  convalescent plasma received would have been outpatient;

               3. Remdesivir is allowed per standard protocol;

               4. Dexamethasone is allowed per standard protocol

         20. Patients actively enrolled in hospice or that are DNI or on palliative care

         21. History of hypersensitivity reaction to colchicine or its inactive ingredients

         22. History of hypersensitivity reaction to naltrexone or its inactive ingredients

         23. Incarcerated or a ward of the state

         24. Any patient considered an unsuitable candidate, for any reason, by study
             investigators.