Impact of Colchicine and Low-dose Naltrexone on COVID-19 Disease Progression and Clinical Course in Hospitalized Patients
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 142
- 试验地点
- 2
- 主要终点
- In Patients Hospitalized With Moderate COVID-19, the Impact of Colchicine and LDN, Alone or in Combination, on Achieving Disease Recovery by Day 5.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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-
- •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.
研究组 & 干预措施
Colchicine-Only Arm
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.
干预措施: Colchicine 0.6 mg (Drug)
Colchicine and Naltrexone ("Combined") Arm
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.
干预措施: Colchicine 0.6 mg (Drug)
Colchicine and Naltrexone ("Combined") Arm
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.
干预措施: Naltrexone (Drug)
Naltrexone-Only Arm
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.
干预措施: Naltrexone (Drug)
结局指标
主要结局
In Patients Hospitalized With Moderate COVID-19, the Impact of Colchicine and LDN, Alone or in Combination, on Achieving Disease Recovery by Day 5.
时间窗: Assessed from time of hospitalization until (1) 5 days after enrollment, while still hospitalized (or until discharge, which may be less than 5 days)
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.
次要结局
- 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))
- The Dosage Amount (in Milligrams) of Corticosteroids 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, The Need for High Flow Nasal Cannula (HFNC) or Non-Invasive Positive Pressure Ventilation (NIPPV)(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, Patients Who Required ICU or ICU Stepdown Cares(Assessed from time of study drug administration to discharge, calculated after patient completes hospital stay; 7 days after admission on average))