Impact of Colchicine and Low-dose Naltrexone on COVID-19

NCT04756128 | Completed Phase 2 Results FDA Drug

• 1 other identifier: X2103400
• Study Type: interventional
• Target: 142
• Locations: 1 country
• Sites: 2

Brief 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.

Conditions

Covid19

Outcome Measures

Primary Outcomes (1)

• In Patients Hospitalized With Moderate COVID-19, the Impact of Colchicine and LDN, Alone or in Combination, on Achieving Disease Recovery by Day 5.

  Disease recovery from moderate COVID-19 was defined as achieving a clinical scale score of 1 (indicating the patient no longer required hospital-level care for COVID-19. Attainment of a score of 1 by study day 5 was chosen based on initial experience treating COVID-19 within this specific health system-patients with similar disease severity were typically hospitalized for 6-7 days, and time from admission to enrollment in preceding COVID-19 studies was generally 1-2 days.

  Assessed from time of hospitalization until (1) 5 days after enrollment, while still hospitalized (or until discharge, which may be less than 5 days)

Secondary Outcomes (8)

• Total Duration of Hospitalization

  Assessed from time of hospitalization until discharge, calculated after patient completes hospital stay - approximately 7 days on average

• Total Duration of Hospitalization (From First Dose of Study Drug to Discharge)

  Assessed from time of study drug administration to discharge, calculated after patient completes hospital stay; 7 days after admission on average)

• In Patients Hospitalized With Moderate COVID-19, Subjects Who Required Remdesivir

  Assessed from time of study drug administration to discharge, calculated after patient completes hospital stay; 7 days after admission on average)

• The Number of Doses of Remdesivir Required In Patients Hospitalized With Moderate COVID-19

  Assessed from time of study drug administration to discharge, calculated after patient completes hospital stay; 7 days after admission on average)

• In Patients Hospitalized With Moderate COVID-19, Subjects Who Required Corticosteroids

  Assessed from time of study drug administration to discharge, calculated after patient completes hospital stay; 7 days after admission on average)

Study Arms (4)

Colchicine-Only Arm

EXPERIMENTAL

Patients randomized to a colchicine-containing treatment arm will receive colchicine 0.6 mg twice daily for up to 28 days. On the day of enrollment, provided the first dose can be given prior to 16:00 that day, patients are eligible to receive two doses; the second dose will be scheduled for 22:00. Patients experiencing gastrointestinal side effects (nausea, vomiting, and diarrhea) on twice daily dosing may have the dose decreased to 0.6 mg daily. Dosing will continue twice daily unless there is a change that requires a dose adjustment or an exclusion criterion is met. Dosing deviations above the study protocol will be allowed if medically necessary for the treatment of an additional indication (e.g. colchicine for viral pericarditis). 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.

Drug: Colchicine 0.6 mg

Colchicine and Naltrexone ("Combined") Arm

EXPERIMENTAL

Patients randomized to a colchicine-containing treatment arm (including the "combined arm") will receive colchicine 0.6 mg twice daily for up to 28 days. On the day of enrollment, provided the first dose can be given prior to 16:00 that day, patients are eligible to receive two doses; the second dose will be scheduled for 22:00. Patients in the "combined" arm will also receive naltrexone. 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.

Drug: Colchicine 0.6 mg; Drug: Naltrexone

Naltrexone-Only Arm

EXPERIMENTAL

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.

Drug: Naltrexone

Standard of Care Arm

NO INTERVENTION

Patients in this arm will receive the investigating institution's current standard of care for patients with COVID-19. For example, all patients requiring supplemental oxygen (assuming no contraindications) would be candidates for both remdesivir 200 mg x 1 IV dose followed the next day by 100 mg q24h IV x up to 4 doses, as well as dexamethasone 6 mg q24h x 10 up to 10 doses.

Interventions

Colchicine 0.6 mg DRUG

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)

Also known as: Colcrys

Colchicine and Naltrexone ("Combined") Arm; Colchicine-Only Arm

Naltrexone DRUG

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.

Also known as: Vivitrol

Colchicine and Naltrexone ("Combined") Arm; Naltrexone-Only Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• HealthPartners Institute: lead
• Park Nicollet Foundation: collaborator

Study Sites (2)

Park Nicollet Methodist Hospital

Saint Louis Park, Minnesota, 55426, United States

Location

Regions Hospital

Saint Paul, Minnesota, 55101, United States

Location

MeSH Terms

Conditions

COVID-19

Interventions

Colchicine; Naltrexone; vivitrol

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Alkaloids; Heterocyclic Compounds; Naloxone; Morphinans; Opiate Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Limitations and Caveats

Limitations include use of a SOC control in place of placebo given the limited time and resources during the COVID-19 surge. Incidence of disease recovery for both study drugs could be impacted by the rapidly improving standard of care for treating patients as the study progressed (remdesivir, glucocorticoids, and tocilizumab).

Results Point of Contact

• Title: Daniel Delaney, PharmD
• Organization: Methodist Hospital

daniel.delaney@parknicollet.com

952-993-5442

Study Officials

• Dan Delaney, PharmD

  Park Nicollet Methodist Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: January 28, 2021
• First Posted: February 16, 2021
• Study Start: January 25, 2021
• Primary Completion: November 26, 2021
• Study Completion: December 12, 2021
• Last Updated: July 25, 2023
• Results First Posted: July 25, 2023

Record last verified: 2022-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)