Clinical trial NCT04363437: COlchicine in Moderate-severe Hospitalized Patients Before ARDS to Treat COVID-19
Official title: COlchicine in Moderate-severe Hospitalized Patients Before ARDS to Treat COVID-19 (the COMBAT-COVID-19 Pilot Study)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Coronavirus Infection
Keywords: colchicine
anti-inflammatory
Lead sponsor: Maimonides Medical Center
Sponsor class: OTHER
First posted: 2020-04-27
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The most prevalent complication of COVID-19 infection is respiratory failure from severe acute respiratory syndrome (SARS), the leading cause of mortality. There is increasing indication that the decompensation in severe COVD-19 infection may be due to a cytokine storm syndrome. This hyperinflammatory syndrome results in a fulminant and fatal hypercytokinemia and multiorgan failure.

Approximately 15% of patients with COVID-19 infection are hospitalized and 20-30% of these hospitalized patients require ICU care and/or mechanical ventilation. Overall mortality in hospitalized patients is approximately 20-25%. There is significant interest in therapies that can be given upstream to reduce the rate of mechanical ventilation and thus mortality.

We hypothesize that treatment with colchicine in COVID-19 moderate-severe patients may decrease the risk of progression into ARDS requiring increased oxygen requirements, mechanical ventilation, and mortality.

Detailed description: Prospective, completely randomized, open labeled, controlled study. Patients will be randomized into two groups (A and B). Patients of group A will be treated under what is considered current standard of care at Maimonides Medical Center while group B patients will receive colchicine in addition to standard of care.

Treatment arm

In addition to the local standard of care for COVID 19 patients, the patient will receive colchicine PO as such:

* Loading dose of 1.2 mg followed by 0.6mg after 2 hours if without significant gastrointestinal symptoms (day 1)
* The next day 0.6mg bid for 14 days or until discharge

Patients who are on HMG-Co A Reductase Inhibitors (atorvastatin, fluvastatin, pravastatin, simvastatin), fibrates, genfibrozil, amiodarone, dronedarone or digoxin should have the colchicine dosage reduced to a loading dose of 0.6mg followed by 0.3mg after two hours (day 1) followed by 0.3mg BID for 14 days or until discharge.

If patients have significant gastrointestinal symptoms after loading, the dosage may be reduced to 0.3mg BID for the rest of the 14 day course or until discharge. If gastrointestinal symptoms continue, the medication should then be discontinued. Patients who experience sensory motor neuropathy, or symptoms and laboratory findings consistent with rhabdomyolysis should prompt immediate discontinuation of the drug. If renal function deteriorates during the treatment course and CrCl \<30ml/min, colchicine should also be discontinued.

Control arm Usual medical therapy (can include medications such as hydroxychloroquine, azithromycin)

Patients should NOT receive, Remdesivir, IL-6 inhibitors (Tociluzimab, Sarilumab), JAK inhibitors, IL-1 inhibitors, or other immunomodulators for COVID-19 before randomization. Since the primary clinical endpoint is progression of disease, if the patient requires beyond 8L nasal cannula, eg. high flow O2 or mechanical ventilation, the primary clinical endpoint is met and the above experimental medications will be permitted. To rephrase, the patient will be allowed, Remdesivir, IL-6 inhibitors and other immunomodulators if then deemed medically necessary by the treating physician.

Eligibility criteria: * Males and females \>=18 years of age
* Willing and able to provide written informed consent prior to performing study procedures
* Currently hospitalized and requiring medical care for COVID-19
* Significant COVID-19 symptom, or judged by the treating provider to be at high risk of progression to severe COVID-19 infection
* Significant COVID-19 symptoms are defined by one or more of the following:

  1. Dyspnea
  2. Respiratory frequency ≥ 30/min
  3. Blood oxygen saturation ≤ 93%
* AND one or more of the following: (positive PCR test or positive antibodies) or (CT/Chest X-ray consistent with COVID19 infection) or (anosmia).

Exclusion Criteria:

* Requirement of oxygen supplementation \>8L nasal cannula
* Pregnancy
* Known hypersensitivity to colchicine
* Patient currently in shock or with hemodynamic instability requiring pressors
* History of cirrhosis
* Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) \> 5X upper limit of normal (ULN)
* Patients with severe renal disease, CrCl \<30ml/min
* Patients requiring invasive mechanical ventilation at screening or Clinical estimation that the patient will require mechanical respiratory support within 24 hours
* Patient is currently taking colchicine for other indications (gout or Familial Mediterranean Fever)
* Patient received Remdesivir, Sarilumab, Tociluzimab, Lopinavir/Ritonavir or other immunomodulator given for COVID-19 treatment (Note: Convalescent plasma infusion is not an exclusion)
* Patient is on (and cannot discontinue) a strong CYP3A4 inhibitor (eg clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, atazanavir), a moderate CYP3A4 inhbitor (eg diltiazem, verapamil, fluconazole, amprenavir, aprepitant, fosamprenavir) or a P-gp Inhibitor (eg cyclosporine, ranolazine)
* Patient is undergoing chemotherapy for cancer
* Patient is considered by the investigator, for any reason, to be unsuitable candidate for the study

Primary outcomes:
measure: Percentage of Patients Requiring Supplemental Oxygen Beyond 8L Nasal Cannula
timeFrame: through study completion, estimated 2 months
Secondary outcomes:
measure: Percentage of Patients Who Will Require Mechanical Ventillation
timeFrame: through study completion, estimated 2 months
measure: Mortality
timeFrame: through study completion, estimated 2 months
Other outcomes:
Locations:
city: Brooklyn
country: United States
facility: Maimonides Medical Center
state: New York
Study officials:
affiliation: Maimonides Medical Center
name: Felix Yang, MD
role: PRINCIPAL_INVESTIGATOR
References: