Impact of Colchicine and Low-dose Naltrexone on COVID-19 (COLTREXONE)
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|ClinicalTrials.gov Identifier: NCT04756128|
Recruitment Status : Enrolling by invitation
First Posted : February 16, 2021
Last Update Posted : February 18, 2021
|First Submitted Date ICMJE||January 28, 2021|
|First Posted Date ICMJE||February 16, 2021|
|Last Update Posted Date||February 18, 2021|
|Actual Study Start Date ICMJE||January 25, 2021|
|Estimated Primary Completion Date||December 31, 2021 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Progression of COVID-19 from "moderate" classification to "severe/critical" [ Time Frame: Assessed from time of hospitalization until (1) 14 days after enrollment, while still hospitalized (or until discharge, which may be less than 14 days) ]
Moderate illness is defined as patients requiring hospitalization due to laboratory confirmed COVID-19, and a clinical score of 2 or 3 on a modified version of the World Health Organization's R&D Blueprint Ordinal Clinical Scale. A score of 4 or 5 will be defined as severe/critical illness. An increase of 2 or more points over the baseline scale will constitute progression to the primary endpoint. The study will determine if the odds of progression from moderate to severe/critical illness is different among the four treatment arms.
|Original Primary Outcome Measures ICMJE||Same as current|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Impact of Colchicine and Low-dose Naltrexone on COVID-19|
|Official Title ICMJE||Impact of Colchicine and Low-dose Naltrexone on COVID-19 Disease Progression and Clinical Course in Hospitalized Patients|
|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.|
In December 2019, a novel coronavirus caused a cluster of pneumonia cases in Wuhan, China. The identified virus was officially named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated illness named coronavirus disease (COVID-19) (WHO). In the months since its discovery, the spread of SARS-CoV-2 has led to tens of millions of cases worldwide. In the United States alone, there have been over 11.6 million cases of COVID-19, with over 340,000 attributed deaths reported as of December 31, 2020 (CDC Cases in the US). Despite the recent availability of a preventative vaccine, there are limited pharmacotherapeutic treatment options for those with an active infection, the majority of which remain investigational.
Common symptoms among patients with mild disease include fever, altered senses of smell or taste, fatigue, or cough. More severe cases of COVID-19 may lead to hypoxemia and pneumonia. When compared to those with less-severe disease, severe/critical COVID-19 pneumonia generally results in an increase in circulating proinflammatory chemokines and cytokines. The SARS-CoV-2 virus has specific structural components (e.g. viroporin E and viroporins 3a and 8A) that have been shown to activate NLRP3 inflammasomes NLRP3 has been found to be a major pathophysiologic component in developing ARDS; and inflammasome activation along with subsequent cytokine production is seen with myocardial injury, which may provide mechanistic insight to SARS-CoV-2's ability to cause cardiac insult. Additionally, aberrant activation of neutrophils and formation of excessive neutrophil extracellular traps (NETs) were found to be associated with ARDS, and recently to be the potential central cause of severe/critical COVID-19.
Treatments that influence neutrophil recruitment to sites of inflammation and hyper-inflammatory response may prove beneficial for reduction in disease progression, adverse sequelae, and mortality associated with COVID-19 infections. Agents under investigation to mitigate this detrimental host response include the IL-6 receptor antagonists. However, their extreme expense, scarce availability, and high-risk for severe adverse effects relegate the use of these injectable agents to cases that have already progressed to critical illness.
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. 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. These are recognized as playing an important role in acute coronary syndrome, pericarditis, and ARDS. Colchicine also has an anti-apoptotic action on endothelial cells that may provide benefit in minimizing extravasation, capillary leak, and therefore progression or development of ARDS. Lastly, coronavirus replication, virion particle assembly, and subsequent exocytosis from the host cell, have been shown to rely on cytoplasmic structural proteins (microtubules) for trafficking during its lifecycle. Disrupting microtubule trafficking has the potential to interfere with these key viral replication steps, and therefore introduction of a microtubule depolymerizing agent may help treat a coronavirus infection through decreased viral replication.
The use of colchicine in patients hospitalized with COVID-19 has been studied in several small uncontrolled case series and comparative cohort studies, as well as small, randomized controlled trials. Results have been unanimously favorable thus far, though they have substantial limitations. Some were performed during local COVID-19 surges, rates of intubation and mortality were likely inflated as a result, and therefore the benefits of colchicine may be overestimated.
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, and multiple sclerosis. Naltrexone is a 50:50 racemic mixture of both L and R isomers - in theory, these isomers allow it to act in a dualistic fashion, both boosting the immune system yet limiting an excessive immune response. The L isomer is a competitive inhibitor of the Mu and Kappa opioid receptor, resulting in elevated levels of endogenous endorphins and enkephalins, which in turn, functions as an immune enhancer. The R isomer blocks the toll like receptor and modulates T and B cell activity; the downstream effects limit the release of inflammatory cytokines including IL-6, IL-12, TNF alpha, and NF-KB. A study in 2017 demonstrated a significant reduction in cytokines after eight weeks of therapy in eight female patients.
While preliminary LDN studies demonstrate success in Crohn's disease, multiple sclerosis, and fibromyalgia, there is still a need for follow-up trials to establish definitive evidence of benefit. The lack of proprietary value in a generic medication with no industry backing has hampered widespread adoption and FDA approval. Thus, clinical efficacy data is slowly forthcoming on LDN. At the same time, the safety profile of naltrexone is well established and very well tolerated in alcohol use disorder. Considering that is a high-risk population, and the dose used is significantly higher (25-100mg versus 1-4.5mg for LDN), it stands to reason that LDN should have little to no toxicity. Hepatic function has to be monitored at higher doses, and the drug should be stopped if necessary. However, with LDN the majority of adverse drug effects are constitutional (headache, dizziness, nausea etc.), with no end organ damage and no evidence for opportunistic infections.
As previously outlined, available evidence demonstrates that excessive immune response in the form of a "cytokine storm" plays a key role in the pathophysiology of COVID-19 offering this process as a possible target for drug therapy. Known immunomodulatory effects of LDN suggest that this drug could be used to reduce this exaggerated immune response. While the efficacy of LDN is being studied in COVID-19 (NCT04604704, NCT04604678, NCT04365985) in combination with a nutritional supplement, metformin, and ketamine (respectively), only the latter trial is recruiting at this time, and none includes colchicine.
The proposed study will investigate whether or not the colchicine and naltrexone (used alone or in combination) can slow the progression of COVID-19 patients hospitalized with mild illness. A modified version of the World Health Organization's R&D Blueprint Ordinal Clinical Scale will be used to assess this outcome. Patients enrolled in the study will follow the schedule of events outlined below. If randomized to receive study drug (colchicine only, naltrexone only, or both colchicine and naltrexone) patients will continue to take the medication until discharge form the hospital (but not more than 28 days).
Baseline Enrollment Information collection
Dosing strategy-Colchicine 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).
Drug interactions: To ensure patients are properly screened and identified as eligible/ineligible with respect to prescribed medications, this research team will identify a group of study pharmacists and physicians (including the PI, Dr. Daniel Delaney, and a pain specialist, Dr. Joseph Johnson), who will be available as-needed to field questions regarding any medications a patient is taking during or prior to their hospital stay that may or may not preclude study participation.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 2|
|Study Design ICMJE||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)
Primary Purpose: Treatment
|Study Arms ICMJE||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Enrolling by invitation|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE||Same as current|
|Estimated Study Completion Date ICMJE||December 31, 2021|
|Estimated Primary Completion Date||December 31, 2021 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years and older (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT04756128|
|Other Study ID Numbers ICMJE||X2103400|
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Responsible Party||Daniel P. Delaney, PharmD, BCIDP, HealthPartners Institute|
|Study Sponsor ICMJE||HealthPartners Institute|
|Collaborators ICMJE||Park Nicollet Foundation|
|PRS Account||HealthPartners Institute|
|Verification Date||February 2021|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP