Clinical trial NCT04365985
Conditions: COVID-19 Acute Respiratory Distress Syndrome Severe Acute Respiratory Syndrome (SARS) Coronavirus Infections
Keywords: naltrexone ketamine cytokine storm Interleukin-2 therapeutic treatment
Sponsor: William Beaumont Hospitals
Start date: 2020-04-29; Completion date: 2021-04-01
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

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.

Arms: arm 1: Placebo by mouth 1 time per day for patients with stage I or stage 2A COVID-19 arm 2: Naltrexone 4.5 mg by mouth 1 time per day for patients with stage I or stage 2A COVID-19. arm 3: 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: intervention 1: Naltrexone intervention 2: Ketamine intervention 3: Placebo
Intervention descriptions: intervention 1: 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.. intervention 2: 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. intervention 3: 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.

Protocol documents:
Prot_SAP_000.pdf: 
TITLE:  
Study of Immunomodulation using Naltrexone and Ketamine for 
COVID-19 (SINK COVID-19) 
 
NCT04365985 
 
Approval date: 09/2/2021 
 
Protocol and Statistical Analysis Plan 


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STUDY OF IMMUNOMODULATION USING NALTREXONE AND KETAMINE FOR COVID-19
(SINK COVID-19)
Investigative Team
Matthew Sims, MD, PhD, FACP, FIDSA (Co-PI): Director Infectious Disease Research, Beaumont Health; 
Professor of Internal Medicine and Foundational Medical Studies, OUWB School of Medicine
Annas Aljassem, MD, MHSA (Co-PI): Director Functional Pain and Rehabilitation Service, Beaumont Health; 
Assistant Professor of Physical Medicine and Rehabilitation, OUWB School of Medicine
Levi Hall, PharmD, BCPS: Clinical Pharmacy Specialist – Pain Medicine, Functional Pain and Rehabilitation 
Service; Assistant Professor of Foundational Medical Studies, OUWB School of Medicine
Carl Lauter, MD, MACP, FIDSA: Section Head Allergy and Immunology, Beaumont Health; Professor of 
Internal Medicine, OUWB School of Medicine
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Research Strategy
1. Significance
1.1 COVID-19: A Major Pandemic Currently Affecting the Entire World
In late 2019 the first cases of what has come to be names COVID-19 were noted in Wuhan China1. 
COVID-19 is caused by a novel coronavirus now designated SARS coronavirus-2 (SARScoV2). As of this 
writing the most current total worldwide is 336,004 with 14,631 deaths and 98,334 recovered2.  In the 
United States there are currently 33,276 cases, 416 deaths, and 178 recovered2. In Michigan there are 
currently 1,037 cases, 9 deaths, and recovered is not currently available2, the first death in Michigan was 
reported from Beaumont, Wayne3. This certainly represents an underestimate given that testing is still 
severely limited at this time. The most common presenting symptoms of COVID-19 are fever, cough, and 
shortness of breath4 and the disease presentation ranges from asymptomatic to mild to an overwhelming 
inflammatory response leading to acute respiratory distress syndrome (ARDS) and cytokine release 
syndrome and ultimately death. The actual mortality of the disease is currently unknown but estimates 
from China give a mortality rate of 3.6% (95% CI 3.5–3.7)5. In the United States mortality estimates to date 
indicate that fatality was highest in persons aged ≥85, ranging from 10% to 27%, followed by 3% to 11% 
among persons aged 65–84 years, 1% to 3% among persons aged 55-64 years, <1% among persons aged 
20–54 years, and no fatalities among persons aged ≤19 years6 with an overall mortality rate ~1.5% which 
varies day to day (0.8%-2.6% depending on the day it is calculated)7. Importantly current mortality 
numbers for the United States are based on a time when the health care system is not overwhelmed. 
When looking at Italy, a country whose health care system can no longer handle the patient load caused 
by this disease, the mortality is currently 9.3%2. Those at high risk for progression to severe illness include 
people over the age of 65, people who live in a long term care facility, people with chronic lung disease, 
people with heart disease, immunocompromised patients, people who are obese (BMI≥40), and people 
with other chronic medical conditions such as diabetes, renal failure, and liver disease8.  At Beaumont 
Health we have noted a trend that severe cases tend to be male, African American, with diabetes and 
hypertension (unpublished data).
1.2 Treatment of COVID-19
There are no approved treatments for COVID-19. There have been numerous approaches tried 
and currently at Beaumont Health the standard treatment is hydroxychloroquine and azithromycin based 
on the study of Gautret et al9. Remdesivir is an experimental medication developed for the treatment of 
Ebola virus and active against RNA viruses which is undergoing clinical trials in COVID10, 11 and was available 
for compassionate use but availability is currently on hold due to overwhelming demand while the 
company organizes an expanded access protocol12. Lopinavir-ritonavir is a repurposed HIV protease 
inhibitor which showed good activity against SARS13 but has failed to show activity again COVID-1914.  
There are several other compounds in research studies, but this is what is currently available and hospitals 
are already having difficulty keeping up with the demands for hydroxychloroquine.
1.3 Immunomodulation as Treatment for COVID-19
One approach for treating severe patients with COVID-19 has been to target the cytokine storm 
seen in the worst patients is the addition of the immunomodulatory tocilizumab. Tocilizumab is a 
monoclonal antibody which targets the IL-6 receptor15. IL-6 is a cytokine which is one of the main drivers 
of cytokine storm and tocilizumab has become a standard treatment for the cytokine release syndrome 
associated with use of CAR-T therapy in cancer16. The existence of a hyperinflammatory state and cytokine 
storm with elevated IL-6, has been reported in severe COVID-19 and were associated with increased 
mortality in patients in China17. A case series of 21 patients treated with tocilizumab between February 5-
14, 2020 in China reported great success, including rapid resolution of fever, decreased oxygen 
requirements, resolution of lung opacities on CT, and reduction of markers of inflammation18. Studies of 
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this compound for COVID in the United States are expected to begin in April and it is currently being used 
off label for the worst cases but there is limited supply and it is quite costly.
1.4 What We Need in a Treatment for COVID-19
Ideally when you consider the treatment of COVID-19 we need a two-pronged strategy. We need 
a treatment that will slow or interrupt the progression of the disease from mild/moderate to severe, and 
we need a treatment to rescue patients who have become severe. COVID-19 infection has three stages 
and 80% of infected people stay in stage 1 or stage 2A, however 20% of patients progress to stage 2B and 
of those about 20% progress to stage 319.
What is needed is a drug to keep people from progressing into stage 2B or stage 3 and a drug to pull 
people out of stage 3. The tocilizumab data suggests that interrupting IL-6 is one of the potential pathways 
to accomplish this.
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2. Innovation
2.1 Naltrexone and Ketamine as Immunomodulatory Agents 
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.  Although approved by the FDA as a 
mu-opioid receptor antagonist for the treatment of opioid and alcohol dependence, it is theorized that 
lower than standard doses of naltrexone inhibit cellular proliferation of T- and B- cells and block Toll-like 
receptor 4 (TLR4).  It is the blocking of cellular proliferation of T- and B-cells and TLR4 that is thought to 
provide pain relief and anti-inflammatory benefit.  A review article evaluated the evidence of the safety, 
tolerability and efficacy of low-dose naltrexone for use in chronic pain and inflammatory conditions20. 
Current evidence supports the safety and tolerability of low-dose naltrexone in multiple sclerosis, 
fibromyalgia, and Crohn’s disease. Other studies focus more on subjective measures like quality of life or 
self-reported pain scores. Studies support a beneficial effect over placebo but evidence for more objective 
measures is limited.
In a study evaluating low-dose naltrexone (LDN) on the effects of IBD, the authors found LDN 
induced clinical improvement in 74.5% and remission in 25.5% of patients.  Naltrexone improved wound 
healing and reduced endoplasmic reticulum stress induced by Tunicamycin, lipopolysaccharide or bacteria 
in the epithelial barriers.  Inflamed mucosa samples from IBD patients showed reduced levels of 
endoplasmic reticulum stress when treated with low-dose naltrexone. The authors concluded that low 
dose naltrexone is effective and safe and could be considered for treatment of therapy refractory IBD 
patients21.
Cant et al concluded that naltrexone has the potential to modulate the secretion of inflammatory 
cytokines in response to intracellular Toll-like receptor activity. In their study naltrexone inhibited 
production of IL-6 and TNF by monocyte, B-cells, and plasmacytoid dendritic cell subsets within the 
peripheral blood mononuclear cells following treatment with Toll-like receptor (TLR) ligands. This supports 
the hypothesis that naltrexone has potential use as an immunomodulatory agent22.
Ketamine has shown in vitro with mice, rats and whole human blood to reduce pro-inflammatory 
cytokines (IL-6).  Elevated levels of IL-6 in the post-operative period were regularly reported to be 
associated with poor outcome23-26.
Ketamine shows pleiotropic (showing multiple effects from a single gene) anti-inflammatory 
effects. Previous researchers have made a strong argument for a very early interaction in the time-course 
of the inflammatory cascade with ketamine.  
The anti-inflammatory effects occur at multiple early steps in the inflammatory process.  Central 
to this argument is nuclear factor NF-b, which is an intracellular protein that activates the transcription 
of genes coding for cytokines (inflammatory mediators). NF-b is activated by pro-type inflammatory 
mediators such as IL-1 and TNF.  Another common pathway is via adenosine receptor systems, such as 
the Wnt5a-signaling pathway. Ketamine blocks Wnt5a-signaling pathway which is critical for endothelium 
activation during inflammation27.
Another study showed patients undergoing cardiac surgery with bypass (procedure known to 
cause significant inflammation), the administration of a single dose of ketamine 0.25 mg/kg at induction 
of anesthesia significantly reduced the production of IL-6 (a proinflammatory cytokine).  The IL-6 pro-
inflammatory cytokine is believed to be significant to the inflammatory process caused by COVID-19. In 
the same study higher doses of 0.5 mg/kg showed reduce C-reactive protein and IL-10 in addition to the 
reduced levels of IL-628.
Yang et al, showed patients undergoing liver transplantation who received ketamine was 
associated with reduced levels of circulating TNF-and IL-629.
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In a meta-analysis by Dale et al six studies consisting of patients undergoing cardiopulmonary 
bypass operations, abdominal, thoracic and cataract surgeries, concluded that patients receiving IV bolus 
dose of at least 0.15 mg/kg before surgery significantly inhibits the early postoperative IL-6 inflammatory 
response30.  Inana et al demonstrated that ketamine for surgical pre-treatment was at least as important 
as receiving pre-treatment with methylprednisolone (30 mg/kg) in cardiopulmonary bypass surgery.  The 
study showed the effect of methylprednisolone was short-lived (approximately 1 hour) in comparison 
with ketamine showing affects lasting up to 6 hours31.
2.2 A Two-Step Approach to Treatment
Naltrexone at low 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 cytokines, especially IL-6 and TNFα, for hours after an event which would induce the 
inflammatory response. This drug is given IV, either by drip or push, and is easily given in a hospital 
environment and is currently used for opioid sparing therapy. This could not easily be used in the 
community but could act as a rescue drug in the same way tocilizumab does but with lower cost and easier 
availability.
2.3 The Benefits and Limits of Naltrexone and Ketamine 
Naltrexone is used for alcohol and opioid use disorder at standard doses.  Proposed benefit of 
naltrexone is slowing progression of pro-inflammatory processes. In clinical trials naltrexone is generally 
well-tolerated. Studies have demonstrated a decreased need for opioid in patients with chronic opioids.  
Further low dose naltrexone has been shown to decrease inflammatory response, reducing symptom 
severity in fibromyalgia, Crohn’s and chronic regional pain syndrome. This benefit may have a delayed 
onset or may occur sooner.  Naltrexone is not habit forming. If a patient is receiving high dose opioids, 
low dose naltrexone may precipitate withdrawal symptoms.  If side-effects occur, a lower dose of this 
medication may be used. This agent is inexpensive and readily available in the U.S. market.
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. With significant percentage of 
patients receiving chronic opioids or that are opioid-dependent, ketamine would provide the direct 
benefit of significantly reducing the requirement for opioids or other medications to manage the 
constellation of pain symptoms patients are experiencing with COVID-19. Proposed benefit of ketamine 
is to slow or halt progression of pro-inflammatory cytokines (IL-6).  A study demonstrated peri-operative 
use of ketamine reduced inflammation post-operatively.
The short half-life of ketamine minimizes the severity of side-effects, if they occur.  Most common 
adverse effects of ketamine are nausea, increasing blood pressure, worsening baseline psychiatric 
condition and dissociation. The risk of dissociation is very low due to the dosage used for 
immunomodulation which is 0.1 to 0.2 mg/kg. Dissociation from ketamine typically occurs at doses 
greater than 0.5-1 mg/kg.  
2.4 A Clinical Trial to Investigate the Use of Naltrexone and Ketamine: Study of 
Immunomodulation using Naltrexone and Ketamine for COVID-19 (SINK COVID-19)
There is an urgent need to develop new treatments for COVID-19 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 
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therapeutics such as discussed above, the addition of immunomodulators to the treatment regimen 
appear to be an excellent choice for 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. The use of naltrexone will be done in a randomized, double blinded manner whereas 
the use of ketamine will be unblinded and given as a rescue agent should a patient progress. Additionally 
should a patient be ineligible for the randomized portion of the study due to already being in stage 2B or 
stage 3 of the disease, they will be given the opportunity to enter the trial to receive ketamine without 
being randomized to naltrexone vs placebo.
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3. Approach
Specific Aims
Aim 1: Determine whether treatment with low dose naltrexone, 4.5 mg by mouth daily, reduces 
progression of patients with COVID-19 from stage 1 or stage 2A to stage 2B or stage 3.
1.1:  Determine the percentage of patients on naltrexone who proceed to requiring advanced 
oxygenation (hiflo nasal canula, non-rebreather, CPAP, BIPAP, or intubation)
1.2: Determine the impact of naltrexone on development of renal failure, liver failure, cytokine 
storm, and ARDS.
1.3:  Determine the impact of naltrexone on mortality, length of stay, admission to ICU, length 
of stay in ICU, intubation, length of intubation, and time till recovery.
Aim 2: Determine if ketamine can improve mortality in patients who progress the need for advanced 
oxygenation.
2.1: Determine the impact of ketamine on development of renal failure, liver failure, cytokine 
storm, and ARDS.
2.2:  Determine the impact of ketamine on mortality, length of stay, admission to ICU, length of 
stay in ICU, intubation, length of intubation, and time till recovery.
3.1 Research Design
To date we have over 100 patients admitted to Beaumont, Royal Oak in the space of 1 week with 
about 25% needing to be admitted to the ICU. Of the first 101 patients admitted 25 ended up admitted to 
the ICU, 12 to the advanced COVID Unit (medical progressive care), and 64 to COVID general floor, these 
numbers can fluctuate and those in the COVID units can still progress to the floors. Approximately 70 of 
the 101 patients were treated with hydroxychloroquine and azithromycin.
This is a prospective, single center, randomized, double blinded study of naltrexone for the 
treatment of COVID-19 with an open label extension using ketamine as a rescue drug for patients who 
progress in their disease. We plan to recruit up to 500 patients. All COVID positive patients will be screened 
by the following criteria:
Inclusion
Exclusion
Positive for COVID -19
Known allergy to naltrexone
Admitted to Royal Oak
Known allergy to ketamine
Age ≥18
Diagnosis of schizophrenia or acute psychosis
On ≤6L Oxygen by nasal cannula A
Pregnancy
On chronic high dose opioids > 90mg morphine 
mg equivalence
Use of naltrexone or Vivitrol within 90 days
A – If on more than 6L oxygen by NC patient can be enrolled as a non-randomized patient directly into the 
ketamine rescue group.
If eligible the patient or their LAR will be approached for inclusion in the study. Given the nature 
of the pandemic and the shortage of personal protective equipment all consenting will take place over 
the phone in the presence of a witness as per IRB emergency safety policy during COVID19.
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Patients who consent will be randomized to one of 2 arms: Arm 1 – low dose naltrexone 4.5 mg 
by mouth per day (can be given via NG tube if needed). Arm 2 – placebo by mouth per day. Treatment 
will be for 30 days past discharge. If the patient develops severe insomnia or shows symptoms of opioid 
withdrawal the dose of naltrexone can be decreased to 3 mg by mouth per day. If the patient continues
to demonstrate issues on the 3 mg reduced dose of naltrexone the dose can be further reduced to 1.5
mg by mouth per day or held temporarily if needed. Reasons it may need to be held include if it is
interfering with sedation, due to the unique issues with sedation in COVID-19 often requiring large
amounts of opioids. Even low dose naltrexone seems to interfere with sedation in some of the patients.
Since opioids, particularly fentanyl, are stored in fat, a patient who is starting on study who has been on
opioid based sedation for 3 days or more can be started on a reduced dose of naltrexone (as above) or
the naltrexone can be held from start and only ketamine used until their sedation is weaned to levels
where clinically is it felt the naltrexone will no longer cause issues with sedation or signs of withdrawal.
A patient should have naltrexone started by the time ketamine is no longer needed.
 Imaging data, flowsheets, and medical notes will be abstracted to generate a daily summary of 
the patient’s status to determine renal failure, liver failure, cytokine storm, ARDS, improvement vs 
progression of disease, need for advanced oxygenation, ICU status, and mortality.
If at any point a patient requires advanced oxygenation (hiflo nasal cannula, non-rebreather, 
CPAP, BIPAP, or intubation) for more than 15 minutes they will then be given ketamine as a rescue 
treatment and remain on the Naltrexone or placebo. Ketamine will initially be given at a dose of 0.15 
mg/kg based on total body weight (max 20 mg) every 6 hours (+/- 1 hour) by intravenous piggyback over 
30 minutes. Ketamine will continue until the patient is deemed stable for low level oxygen. If the patient 
relapses after the ketamine is stopped they can be restarted on the ketamine. If the patient continues to 
worsen or displays evidence of cytokine storm (elevated markers of inflammation, evidence of ARDS, 
continuous fever) the dose of ketamine will be increased to 0.3 mg/kg IV every 6 hours (max 30 mg). The
dose of ketamine can be reduced back to 0.15 mg/kg at the clinical decision of the physician
investigators. If a patient has issues with hypertensive emergency the dose of ketamine can be held until
the hypertensive emergency is controlled.
In addition, a patient can receive ketamine if they are not yet on advanced oxygenation if the 
investigating physician feels they are moving toward cytokine storm based on the markers of 
inflammation and clinical factors such as worsening imaging and unrelenting fever.
If a patient transitions to comfort care the patient will remain in the study for data collection purposes. 
Study medications may be held if requested by the clinical team,  patient, LAR or family.
Patients who at screening are already requiring advanced oxygen can be consented and enrolled 
in the study and immediately will skip the randomization and be placed on naltrexone and receive 
ketamine as the starting treatment in an open label manner.
All patients will have the following labs drawn on a daily basis for the first 5 days after 
randomization and then weekly while in the hospital: IL-6, CBC with differential, CMP, Triglycerides, 
Ferritin, Fibrinogen, ESR, CRP, LDH, CK, Troponin, and D-dimer. An additional IL-6 will be drawn prior to 
the first dose of study drug to establish a baseline. In addition if a patient is placed on ketamine these labs 
will be drawn for the 5 days following initiation of ketamine and then return to once a week. These labs 
are measures of general medical status, renal status, liver status, and markers of inflammation. The use 
of these labs is 2 fold, they may be used up front to help determine when I patient should have the dose 
of ketamine escalated and they will be reviewed retrospectively for the research to determine impact of 
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the study drugs. IL-6 in particular will only be looked at retrospectively as it is a send out test and the 
length of time to get results is 3-5 days. Each patient will have the following vital signs from the prior 
calendar day and related data recorded on a daily basis: maximum temperature, minimum temperature, 
maximum heart rate, minimum heart rate, maximum blood pressure (based on mean arterial pressure), 
minimum blood pressure (based on mean arterial pressure), maximum oxygen patient is on and the 
method of delivery, minimum oxygen patient is on and the method of delivery, maximum respiratory rate, 
minimum respiratory rate. The nurses and physicians participating in this study will also be looking for 
progression of oxygen requirements whenever they access the chart and the floor staff will be instructed 
to call the study team immediately for consideration of ketamine rescue.
After the first five days the labs will be collected once a week (every 7 days +/-1 day) until 
discharge. Any of these labs drawn by the treatment team will be collected if they match the timeframe 
of the study labs additional labs will not need to be ordered for the study.
For all patients we will collect medical history specifically including what COVID-19 symptoms 
were present and for how long, the date and time of the positive COVID test and what lab it was run at, 
demographics, concomitant medications on a daily basis, and any available cardiac markers including CK, 
troponin, myoglobin and echocardiography results.
After discharge patients will be called once a week (+/- 3 days) for 1 month to determine their 
current health status and review their medication compliance. If at the 1 month mark the patient has not 
resolved their symptoms fully the calls will be extended for an additional month, once a week. 
While the exact time the patient will remain in the study is unclear depending on duration of the 
admission and duration of symptoms, we expect it will be approximately 3 months on average.
3.2 Measurements of Outcomes
Primary Outcome Measure:
1. Progression of oxygenation needs
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)
[Time Frame: up to 1 month]
Secondary Outcome Measure:
2. Renal failure
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.
[Time Frame: up to 1 month]
3. Liver failure
Count of participants who develop or experience worsened liver failure as defined by serum
transaminases five times normal limits
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[Time Frame: Daily times 5, then weekly]
4. Cytokine Storm
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)
[Time Frame: 1 month]
5. Mortality
Count of participants who die from COVID-19
[Time Frame: up to 1 month post hospital discharge]
6. Length of hospital stay
Length of hospital stay in days
[Time Frame: 1 month]
7. Intensive Care Unit (ICU) admission
Count of patients admitted to the ICU at any time during index hospitalization
[Time Frame: 1 month]
8. Intensive Care Unit (ICU) duration
Length of ICU stay in days
[Time Frame: 1 month]
9. Intubation
Count of participants requiring intubation
[Time Frame: 1 month]
10. Intubation duration
Length of intubation, measured in days
[Time Frame: 1 month]
11. Time until recovery
Time measured in days from hospital admission to determination patient is stable for discharge
[Time Frame: 1 month post hospital discharge.]
3.2 Statistical Analysis
Descriptive statistics will be provided for all variables collected including patient demographics, 
numbers progressing to requiring more oxygen, and all secondary outcomes. Categorical variables will be 
summarized as counts and percentages. All continuous variables will be summarized as means+/- the 
standard deviation where normal or median and 25th, 75th percentiles if not normal.  The minimum and 
maximum will also be provided.
Analysis Sets: Data analysis will be performed on a full analysis set (FAS), a per protocol set (PPS), 
an intent-to-treat (ITT) set, and a safety analysis (SA) set.
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The FAS will be used for the primary analysis. The FAS will consist of all randomized subjects who 
receive at least one naltrexone/placebo treatment. All analyses using the FAS will group participants 
according to randomized treatment in an intent-to-treat analysis.
The PPS will be used for a supportive analysis and will be defined as all subjects included in the 
FAS who do not have any significant protocol deviations. All analyses using the PPS will group subjects 
according to treatment the subject actually received.
The safety data set will include all subjects with all safety data but will lack any outcome data. This 
data set will be used for reporting to the internal safety committee.
Missing Data: We will evaluate the potential impact of any missing data on analyses before 
deciding how to include missing data. Missing data will not be replaced by substitutions or imputation as 
long as the percent missing for any of the variables is less than 5%. Should the percent missing increase 
above 5%, we will use multiple imputation to replace missing data and conduct any analyses outlined 
below.
Primary Outcome: Progression to requiring more oxygen will be the primary outcome, and we will 
compare the percent patients progressing between the two arms of this study. The primary hypothesis is 
that the percent progressing for those in the naltrexone arm will be less than the percent progressing in 
the placebo arm. We will use the Pearson chi-squared test this hypothesis using a one-sided type 1 error 
rate of 0.05. We will also estimate the difference in proportion progressing using a Bayesian approach 
with independent Jeffrey’s priors for both groups and numerical integration to obtain the credibility 
interval for the difference in proportions.
Sample Size Determination: We assumed that 20% of patients admitted to the hospital will show 
progression to requiring more oxygen, and that we want to detect if naltrexone reduces the progression 
rate to no more than 10%. With these assumptions, a sample size of 154 per arm (308 total) is required 
to have 80% power based on a two-sample t-test, using PASS 16. 
Secondary Outcomes: To examine the potential impact of ketamine on mortality, we will use the 
chi-squared test to evaluate the hypothesis that mortality is reduced in the naltrexone arm. We will also 
estimate the difference in proportions using the Bayesian approach noted above. We will use a type 1 
error rate of 0.05 for this secondary outcome.
For all remaining secondary outcomes, we will estimate the difference between the two arms and 
not test for differences between the two arms since these data will be used in planning future studies. For 
dichotomous outcomes (renal failure, liver failure, cytokine storm, and ARDS), we will use the Bayesian 
approach discussed for estimating the difference in proportions. We will use generalized linear models to 
estimate the difference in durations (number of days in ICU, number of days on a ventilator, and length 
of stay), evaluating the distribution to use based on the data. We will consider using the Poisson, negative-
binomial, and normal distributions. We will use a Bayesian approach, using a flat prior on the difference 
in means parameter. We will calculate 99% credibility intervals for all of these secondary outcomes given 
the multiple outcomes being examined.
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For statistical analysis the biostatisticians and Data analytics teams at Beaumont (Rob Podolsky and Shirley 
Qu) will pull patients who were not on SINK, had COVID-19 with as close to a direct match to patients with 
similar profiles who were treated on the SINK study.  The match to the patients on SINK will aim to 
compare the outcomes of the two groups, to see if there is a difference in the outcomes.  The evaluation 
is a chart analysist aimed at focusing on the outcomes of the study.  
Safety Measures:
There will a full DSMB consisting of an infectious disease physician, two additional physicians, a 
biostatistician, and a pharmacist.  A medical monitor will review safety data weekly (+/- 7 days). Adverse 
event summaries will be emailed to the committee weekly. The DSMB will meet monthly but can choose 
to modify that schedule based on patient recruitment levels. At a minimum they will have quarterly 
meetings no matter what the level of recruitment is. When 20 patients (from the open-label arm) have 
been placed on ketamine enrollment will be held. The DSMB will review the data for safety of using 
ketamine. The DSMB will then present their findings to the IRB to determine if protocol revisions are 
necessary and when enrollment may resume. 
With the completion of the initial safety review, going forward the DSMB will formally meet at least each 
quarter with the option to meet earlier if enrollment is found to be high enough to warrant it. There are 
no further automatic holds to enrollment. PI and study team will monitor study patients at least daily or 
more frequently due to their severe illness risks.  
4. Future Directions
If the SINK COVID-19 study is successful we plan to develop a large multi-center trial to confirm the results 
on a larger scale. 
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