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.
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.
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 Name: Array
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
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
William Beaumont Hospital
Royal Oak, Michigan, United States
Matthew Sims, MD PhD, Principal Investigator
Beaumont Health