Clinical trial NCT04365985: Study of Immunomodulation Using Naltrexone and Ketamine for COVID-19
Official title: Study of Immunomodulation Using Naltrexone and Ketamine for COVID-19
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: COVID-19
Acute Respiratory Distress Syndrome
Severe Acute Respiratory Syndrome (SARS)
Coronavirus Infections
Keywords: naltrexone
ketamine
cytokine storm
Interleukin-2
therapeutic treatment
Lead sponsor: William Beaumont Hospitals
Sponsor class: OTHER
First posted: 2020-04-28
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
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
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Progression of Oxygenation Needs
timeFrame: up to 1 month
Secondary outcomes:
measure: Renal Failure
timeFrame: up to 1 month
measure: Liver Failure
timeFrame: up to 1 month
measure: Cytokine Storm
timeFrame: up to 1 month
measure: COVID Mortality
timeFrame: up to 1 month post hospital discharge
measure: Length of Hospital Stay
timeFrame: up to 1 month
measure: Intensive Care Unit (ICU) Admission
timeFrame: up to 1 month
measure: Intensive Care Unit (ICU) Duration
timeFrame: up to 1 month
measure: Intubation
timeFrame: up to 1 month
measure: Intubation Duration
timeFrame: up to 1 month
measure: Time Until Recovery
timeFrame: up to 1 month
Other outcomes:
Locations:
city: Royal Oak
country: United States
facility: William Beaumont Hospital
state: Michigan
Study officials:
affiliation: Beaumont Health
name: Matthew Sims, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: