Study of Immunomodulation Using Naltrexone and Ketamine for COVID-19 (SINK COVID-19)

• ClinicalTrials.gov Identifier: NCT04365985
• Recruitment Status: Terminated
• First Posted: April 28, 2020
• Results First Posted: January 26, 2022
• Last Update Posted: January 26, 2022
• Sponsor: William Beaumont Hospitals
• Information provided by (Responsible Party): Matthew Sims, MD, PhD, William Beaumont Hospitals

Tracking Information

• First Submitted Date: April 26, 2020
• First Posted Date: April 28, 2020
• Results First Submitted Date: January 12, 2022
• Results First Posted Date: January 26, 2022
• Last Update Posted Date: January 26, 2022
• Actual Study Start Date: April 29, 2020
• Actual Primary Completion Date: April 1, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 12, 2022)

Progression of Oxygenation Needs [ Time Frame: up to 1 month ]

Count of participants initially presenting with mild/moderate disease who progress to requiring advanced oxygenation (high flow nasal canula, non-rebreather, continuous positive airway pressure (CPAP), bilevel positive airway pressure (BIPAP), or intubation)

Original Primary Outcome Measures (submitted: April 26, 2020)

Progression of oxygenation needs [ Time Frame: up to 1 month ]

Count of participants initially presenting with mild/moderate disease who progress to requiring advanced oxygenation (high flow nasal canula, non-rebreather, continuous positive airway pressure (CPAP), bilevel positive airway pressure (BIPAP), or intubation)

Current Secondary Outcome Measures (submitted: January 12, 2022)

• Renal Failure [ Time Frame: up to 1 month ]
  Count of participants who develop or experience worsened renal failure as defined by RIFLE criteria, a 5-point scale where the categories are labeled: Risk-Injury-Failure-Loss-End stage renal disease, with Risk being the least severe and End stage renal disease being the most severe. The criteria for determination of stage are factors of serum creatinine and urine output. Numbers of participants worsening one or more RIFLE stages will be reported.
• Liver Failure [ Time Frame: up to 1 month ]
  Count of participants who develop or experience worsened liver failure as defined by serum transaminases five times normal limits
• Cytokine Storm [ Time Frame: up to 1 month ]
  Count of participants who develop cytokine storm as measured by elevated markers of inflammation (elevated D-dimer, hypofibrinogenemia, hyperferritinemia), evidence of acute respiratory distress syndrome (ARDS) measured by imaging findings and mechanical ventilator requirements, and/or continuous fever (≥ 38.1 ° Celsius unremitting)
• COVID Mortality [ Time Frame: up to 1 month post hospital discharge ]
  Count of participants who die from COVID-19
• Length of Hospital Stay [ Time Frame: up to 1 month ]
  Length of hospital stay in days
• Intensive Care Unit (ICU) Admission [ Time Frame: up to 1 month ]
  Count of patients admitted to the ICU at any time during index hospitalization
• Intensive Care Unit (ICU) Duration [ Time Frame: up to 1 month ]
  Length of ICU stay in days
• Intubation [ Time Frame: up to 1 month ]
  Count of participants requiring intubation
• Intubation Duration [ Time Frame: up to 1 month ]
  Length of intubation, measured in days
• Time Until Recovery [ Time Frame: up to 1 month ]
  Time measured in days from hospital admission to determination patient is stable for discharge

Original Secondary Outcome Measures (submitted: April 26, 2020)

• Renal failure [ Time Frame: up to 1 month ]
  Count of participants who develop or experience worsened renal failure as defined by RIFLE criteria, a 5-point scale where the categories are labeled: Risk-Injury-Failure-Loss-End stage renal disease, with Risk being the least severe and End stage renal disease being the most severe. The criteria for determination of stage are factors of serum creatinine and urine output. Numbers of participants worsening one or more RIFLE stages will be reported.
• Liver failure [ Time Frame: up to 1 month ]
  Count of participants who develop or experience worsened liver failure as defined by serum transaminases five times normal limits
• Cytokine Storm [ Time Frame: up to 1 month ]
  Count of participants who develop cytokine storm as measured by elevated markers of inflammation (elevated D-dimer, hypofibrinogenemia, hyperferritinemia), evidence of acute respiratory distress syndrome (ARDS) measured by imaging findings and mechanical ventilator requirements, and/or continuous fever (≥ 38.1 ° Celsius unremitting)
• Mortality [ Time Frame: up to 1 month post hospital discharge ]
  Count of participants who die from COVID-19
• Length of hospital stay [ Time Frame: up to 1 month ]
  Length of hospital stay in days
• Intensive Care Unit (ICU) admission [ Time Frame: up to 1 month ]
  Count of patients admitted to the ICU at any time during index hospitalization
• Intensive Care Unit (ICU) duration [ Time Frame: up to 1 month ]
  Length of ICU stay in days
• Intubation [ Time Frame: up to 1 month ]
  Count of participants requiring intubation
• Intubation duration [ Time Frame: up to 1 month ]
  Length of intubation, measured in days
• Time until recovery [ Time Frame: up to 1 month ]
  Time measured in days from hospital admission to determination patient is stable for discharge

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Immunomodulation Using Naltrexone and Ketamine for COVID-19
• Official Title: Study of Immunomodulation Using Naltrexone and Ketamine for COVID-19
• Brief Summary: Ideal new treatments for Novel Coronavirus-19 (COVID-19) would help halt the progression disease in patients with mild disease prior to the need for artificial respiration (ventilators), and also provide a rescue treatment for patients with severe disease, while also being affordable and available in quantities sufficient to treat large numbers of infected people. Low doses of Naltrexone, a drug approved for treating alcoholism and opiate addiction, as well as Ketamine, a drug approved as an anesthetic, may be able to interrupt the inflammation that causes the worst COVID-19 symptoms and prove an effective new treatment. This study will investigate their effectiveness in a randomized, blinded trial versus standard treatment plus placebo.

Detailed Description

There is an urgent need to develop new treatments for Novel Coronavirus-19 (COVID-19) infection using easily available and affordable medications. We need to develop a treatment protocol which prevents progression of the disease and a treatment protocol to rescue those with advanced disease. In addition to anti-viral therapeutics currently under investigation in other trials, the addition of immunomodulators to the treatment regimen appears have to potential to act as agents which can reduce the pathogenicity of this disease by reducing the dysregulation of autoimmunity which is destructive of normal tissue and when unchecked rapidly leads to mortality.

COVID-19 infection has three stages and 80% of infected people stay in stage 1 or stage 2A (viral response and early pulmonary effects), however 20% of patients progress to stage 2B (late pulmonary effects), and of those about 20% progress to stage 3 (hyper-inflammation). An ideal treatment for COVID-19 would have a two-pronged strategy: a treatment that would slow or interrupt the progression of the disease from mild/moderate (stage 1-2A) to severe (stage 2B-3), and a treatment to rescue patients who have become severe. Promising data using tocilizumab, an monoclonal antibody targeting the cytokine Interleukin-6 (IL-6), suggests that interrupting IL-6 is one of the potential pathways to accomplish this.

Low-dose naltrexone has been used off-label for treatment of pain and inflammation in multiple sclerosis, Crohn's disease, fibromyalgia and other pain conditions. Lower than standard doses of naltrexone inhibit cellular proliferation of T- and B- cells and block Toll-like receptor 4 (TLR4), providing pain relief and anti-inflammatory benefit. Naltrexone at doses below the normal therapeutic dose appears to reduce production of multiple cytokines including IL-6 in a steady pace and is available as an oral preparation. As such it is ideal to use to attempt to modify progression to stage 2B as it can easily be given to both hospitalized patients and patients in the community.

Ketamine at low doses, below the normal anesthetic dose, appears to rapidly reduce the production of pro-inflammatory cytokines, especially IL-6 and tumor necrosis factor alpha (TNFα), for hours after an event which would induce the inflammatory response. This drug is given intravenously (IV), either by drip or push, and is easily given in a hospital environment. This could not easily be used in the community but could act as a rescue drug with lower cost and easier availability than tocilizumab, a monoclonal antibody targeting IL-6. Ketamine has been extensively studied in a variety of settings and indications with a well-established side-effect and dosing profile. Ketamine is generally well tolerated and remains inexpensive and widely available on the U.S. market and available for immediate use.

The trial will measure the ability of low dose naltrexone to reduce the progression of participants with COVID-19. In this study, naltrexone or placebo will be given to participants in early stages of COVID-19 infection in a randomized, double blinded manner, whereas the use of ketamine will be unblinded and given as a rescue agent should a participant progress. Additionally, should a participant be ineligible for the randomized portion of the study due to already being in a more advanced stage of the disease, they will be given the opportunity to enter the trial to receive ketamine without being randomized to naltrexone vs placebo.

Participants will continue to receive any standard of care COVID-19 treatment during their participation in this study. Laboratory blood tests such as IL-6 concentration, blood counts, liver and renal function panels as well as close physician supervision will be used to monitor participant condition during hospitalization. Participants will be contacted 1 month post discharge to evaluate outcomes and potential side effects.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Factorial Assignment
Intervention Model Description:

Prospective, single center, randomized, double blinded study of naltrexone with an open label extension using ketamine as a rescue drug for patients who progress in their disease

Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:

No other parties blinded

Primary Purpose: Treatment

Condition

• COVID-19
• Acute Respiratory Distress Syndrome
• Severe Acute Respiratory Syndrome (SARS)
• Coronavirus Infections

Intervention

• Drug: Naltrexone
  Low dose naltrexone, 4.5 mg by mouth, given from date of admission through time participant is stable for discharge for inpatient participants with mild/moderate COVID-19 infection stages. Naltrexone will continue for 1 month post hospital discharge. Patients progressing to requirement for advanced oxygenation will be reassess when sedation and assigned to Ketamine arm. Naltrexone may be reduced to 1.5 mg/day if interfering with sedation and can be held when sedation and symptoms of withdrawal is an issue..
  Other Names:

  • ReVia
  • Vivitrol
• Drug: Ketamine
  Low dose ketamine hydrochloride given intravenously at a dosage of 0.15 mg/kg body weight for maximum 20 mg every 6 hours, to inpatient participants with advanced oxygenation requirements from either time of admission or time of progression of mild/moderate disease until time participant is stable for discharge, as a rescue treatment. If patient is transferred from the naltrexone or placebo arm, they will continue to receive naltrexone/placebo. Dosage of ketamine may be increased to 0.3 mg/kg body weight, maximum 30 mg every 6 hours, if participant does not respond at the lower dosage. Ketamine can be reduced back to 0.15 mg/kg at the clinical decision of the investigator and when patient has hypertensive emergency, the dose can be held until hypertensive emergency is controlled.
  Other Name: Ketalar
• Other: Placebo
  Oral placebo, given from date of admission through time participant is stable for discharge for inpatient participants in mild/moderate COVID-19 infection stages. Placebo will continue for 1 month post discharge. Participants progressing to requirement for advanced oxygenation will be reassigned to Ketamine arm.
  Other Name: sugar pill

Study Arms

• Placebo Comparator: Placebo
  Placebo by mouth 1 time per day for patients with stage I or stage 2A COVID-19
  Intervention: Other: Placebo
• Experimental: Naltrexone
  Naltrexone 4.5 mg by mouth 1 time per day for patients with stage I or stage 2A COVID-19.
  Intervention: Drug: Naltrexone
• Experimental: Ketamine
  Ketamine IV infusion (0.15 mg/kg based on total body weight for maximum 20 mg every 6 hours) for patients with stage 2B or stage 3 COVID-19; may be increased to 0.3 mg/kg based on total body weight for a maximum of 30 mg every 6 hours if needed. Patients entering this arm from the placebo or naltrexone arms remain on those medications as well.
  Interventions:

  • Drug: Naltrexone
  • Drug: Ketamine
  • Other: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: September 2, 2021): 70
• Original Estimated Enrollment (submitted: April 26, 2020): 500
• Actual Study Completion Date: April 1, 2021
• Actual Primary Completion Date: April 1, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Positive for COVID -19
• Admitted to Beaumont Hospital - Royal Oak, Michigan
• Age ≥18
• Receiving ≤ 6 liters/minute oxygen by nasal cannula for randomization to either placebo or naloxone arm OR receiving ≥ 6 liters/minute oxygen by nasal cannula or requiring advanced oxygenation for placement in ketamine arm

Exclusion Criteria:

• Known allergy to naltrexone
• Known allergy to ketamine
• Diagnosis of schizophrenia or psychosis
• Pregnancy based on available medical history, existing labs, or verbal report
• On chronic high dose opioids > 90mg morphine mg equivalence
• Use of naltrexone or Vivitrol within 90 days

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04365985
• Other Study ID Numbers: 2020-097
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Matthew Sims, MD, PhD, William Beaumont Hospitals
• Original Responsible Party: Same as current
• Current Study Sponsor: William Beaumont Hospitals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Matthew Sims, MD PhD; Beaumont Health

• PRS Account: William Beaumont Hospitals
• Verification Date: January 2022