Conditions: Covid19
Allocation: RANDOMIZED | Intervention model: FACTORIAL
Enrollment: 142
Healthy volunteers: no

Brief summary:
The purpose of this study is to explore the impact of two medications-colchicine and low-dose naltrexone (LDN)-relative to standard of care (SOC) on COVID-19 disease progression to severe/critical illness and/or intubation in patients hospitalized with moderate COVID-19. As researchers have learned, COVID-19's clinical course suggests that the hyperinflammatory response seen in severe/critical cases is involved in the pathogenesis of associated adverse sequelae such as acute respiratory distress syndrome (ARDS), thromboembolic disease, and acute cardiac injury. Given colchicine has demonstrated clinical utility in inflammatory syndromes within these systems (e.g. endothelial/vascular/myocardial), and LDN acts both to boost the immune system, and limit an excessive response; they may prove useful in minimizing the risk of disease progression and associated adverse sequelae.

Detailed description:
In December 2019, a novel coronavirus caused a cluster of pneumonia cases in Wuhan, China. The identified virus was officially named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated illness named coronavirus disease (COVID-19) (WHO). In the months since its discovery, the spread of SARS-CoV-2 has led to tens of millions of cases worldwide. In the United States alone, there have been over 11.6 million cases of COVID-19, with over 340,000 attributed deaths reported as of December 31, 2020 (CDC Cases in the US). Despite the recent availability of a preventative vaccine, there are limited pharmacotherapeutic treatment options for those with an active infection, the majority of which remain investigational.

Common symptoms among patients with mild disease include fever, altered senses of smell or taste, fatigue, or cough. More severe cases of COVID-19 may lead to hypoxemia and pneumonia. When compared to those with less-severe disease, severe/critical COVID-19 pneumonia generally results in an increase in circulating proinflammatory chemokines and cytokines. The SARS-CoV-2 virus has specific structural components (e.g. viroporin E and viroporins 3a and 8A) that have been shown to activate NLRP3 inflammasomes NLRP3 has been found to be a major pathophysiologic component in developing ARDS; and inflammasome activation along with subsequent cytokine production is seen with myocardial injury, which may provide mechanistic insight to SARS-CoV-2's ability to cause cardiac insult. Additionally, aberrant activation of neutrophils and formation of excessive neutrophil extracellular traps (NETs) were found to be associated with ARDS, and recently to be the potential central cause of severe/critical COVID-19.

Treatments that influence neutrophil recruitment to sites of inflammation and hyper-inflammatory response may prove beneficial for reduction in disease progression, adverse sequelae, and mortality associated with COVID-19 infections. Agents under investigation to mitigate this detrimental host response include the IL-6 receptor antagonists. However, their extreme expense, scarce availability, and high-risk for severe adverse effects relegate the use of these injectable agents to cases that have already progressed to critical illness.

Colchicine is an oral anti-inflammatory agent that is relatively inexpensive, readily available, and has been used for generations. Approved for treatment and prophylaxis of gout flares and Mediterranean fever, it is also used in a variety of other inflammatory conditions. Colchicine binds to tubulin causing depolymerization, which interferes with neutrophil chemotaxis, adhesion, and mobilization to sites of inflammation, and contributes to reduction in superoxide production; through interference of the NLRP3 inflammasome protein complex, colchicine inhibits IL-1b, IL-6, and IL-18 production. These are recognized as playing an important role in acute coronary syndrome, pericarditis, and ARDS. Colchicine also has an anti-apoptotic action on endothelial cells that may provide benefit in minimizing extravasation, capillary leak, and therefore progression or development of ARDS. Lastly, coronavirus replication, virion particle assembly, and subsequent exocytosis from the host cell, have been shown to rely on cytoplasmic structural proteins (microtubules) for trafficking during its lifecycle. Disrupting microtubule trafficking has the potential to interfere with these key viral replication steps, and therefore introduction of a microtubule depolymerizing agent may help treat a coronavirus infection through decreased viral replication.

The use of colchicine in patients hospitalized with COVID-19 has been studied in several small uncontrolled case series and comparative cohort studies, as well as small, randomized controlled trials. Results have been unanimously favorable thus far, though they have substantial limitations. Some were performed during local COVID-19 surges, rates of intubation and mortality were likely inflated as a result, and therefore the benefits of colchicine may be overestimated.

Most well known as an opioid antagonist, or a treatment for alcohol dependence, naltrexone also possesses immunomodulatory effects. Seen exclusively at low doses, this attribute is being employed in the pain community as a novel anti-inflammatory agent that has been shown to reduce symptom severity in fibromyalgia, Crohn's disease, and multiple sclerosis. Naltrexone is a 50:50 racemic mixture of both L and R isomers - in theory, these isomers allow it to act in a dualistic fashion, both boosting the immune system yet limiting an excessive immune response. The L isomer is a competitive inhibitor of the Mu and Kappa opioid receptor, resulting in elevated levels of endogenous endorphins and enkephalins, which in turn, functions as an immune enhancer. The R isomer blocks the toll like receptor and modulates T and B cell activity; the downstream effects limit the release of inflammatory cytokines including IL-6, IL-12, TNF alpha, and NF-KB. A study in 2017 demonstrated a significant reduction in cytokines after eight weeks of therapy in eight female patients.

While preliminary LDN studies demonstrate success in Crohn's disease, multiple sclerosis, and fibromyalgia, there is still a need for follow-up trials to establish definitive evidence of benefit. The lack of proprietary value in a generic medication with no industry backing has hampered widespread adoption and FDA approval. Thus, clinical efficacy data is slowly forthcoming on LDN. At the same time, the safety profile of naltrexone is well established and very well tolerated in alcohol use disorder. Considering that is a high-risk population, and the dose used is significantly higher (25-100mg versus 1-4.5mg for LDN), it stands to reason that LDN should have little to no toxicity. Hepatic function has to be monitored at higher doses, and the drug should be stopped if necessary. However, with LDN the majority of adverse drug effects are constitutional (headache, dizziness, nausea etc.), with no end organ damage and no evidence for opportunistic infections.

As previously outlined, available evidence demonstrates that excessive immune response in the form of a "cytokine storm" plays a key role in the pathophysiology of COVID-19 offering this process as a possible target for drug therapy. Known immunomodulatory effects of LDN suggest that this drug could be used to reduce this exaggerated immune response. While the efficacy of LDN is being studied in COVID-19 (NCT04604704, NCT04604678, NCT04365985) in combination with a nutritional supplement, metformin, and ketamine (respectively), only the latter trial is recruiting at this time, and none includes colchicine.

The proposed study will investigate whether or not the colchicine and naltrexone (used alone or in combination) can slow the progression of COVID-19 patients hospitalized with mild illness. A modified version of the World Health Organization's R\&D Blueprint Ordinal Clinical Scale will be used to assess this outcome. Patients enrolled in the study will follow the schedule of events outlined below. If randomized to receive study drug (colchicine only, naltrexone only, or both colchicine and naltrexone) patients will continue to take the medication until discharge form the hospital (but not more than 28 days).

Baseline Enrollment Information collection

* Inclusion \& Exclusion Criteria Assessment
* Informed consent, randomization
* Demographics-Documentation of patient characteristics
* Past medical history-Documentation of diagnoses at baseline
* Documentation of need for supplemental home oxygen therapy at baseline
* Rule out pregnancy for female participants of child-bearing age Clinical Course Monitoring - Performed daily until discharge
* Safety assessment and reporting-Review of chart for AEs by study staff
* Concomitant medications-Review of medications taken in hospital in addition to study drugs
* New Drug-Drug Interactions-Assessment of new/updated medications to determine risk of new drug interactions
* Documentation of Colchicine dose frequency (Daily/BID, with rationale if changed)
* Study Drug Administration-For interventional arms: Documentation of date and time of study drug administration
* Maximum O2 needs for continuous 12-hour periods beginning at hospital admission
* Tmax-Maximum recorded temperature patient reached during the study day
* Chest imaging (yes/no)-Documentation of whether patient received SOC chest imaging on study day
* EKG or continuous telemetry (yes/no)-Documentation of whether patient received an SOC EKG or is on continuous telemetry on study day
* LMWH \> 0.5 mg/kg/dose (not cumulative daily dose) or heparin drip? (yes/no)-Documentation of need for more than .5mg/kg total dose of Low Molecular Weight Heparin on study day
* Level of care-Documentation of clinical scale score; hospital unit through which patient is being treated
* Length of hospitalization Mortality-Documentation of patient death at any time during the hospital stay Laboratory Monitoring
* BNP (B-Type Natriuretic Peptide)-Documented during patient's hospital stay as performed per SOC
* CBC with differential-Documented during patient's hospital stay as performed per SOC with supplemental research-only labs added as needed
* C-reactive protein-Documented during patient's hospital stay as performed per SOC with supplemental research-only labs added as need
* D-dimer-Documented during patient's hospital stay as performed per SOC with supplemental research-only labs added as need
* Ferritin-Documented during patient's hospital stay as performed per SOC with supplemental research-only labs added as need
* Hepatic Function Panel-Documented during patient's hospital stay as performed per SOC with supplemental research-only labs added as need
* Procalcitonin-Documented during patient's hospital stay as performed per SOC -Serum Creatinine (SCr)-Documented during patient's hospital stay as preformed per SOC/as needed for research
* Troponin-Documented during patient's hospital stay as performed per SOC up to discharge

Dosing strategy-Colchicine Patients randomized to a colchicine-containing treatment arm will receive colchicine 0.6 mg twice daily for up to 28 days. On the day of enrollment, provided the first dose can be given prior to 16:00 that day, patients are eligible to receive two doses; the second dose will be scheduled for 22:00. Patients experiencing gastrointestinal side effects (nausea, vomiting, and diarrhea) on twice daily dosing may have the dose decreased to 0.6 mg daily. Dosing will continue twice daily unless there is a change that requires a dose adjustment or an exclusion criterion is met. Dosing deviations above the study protocol will be allowed if medically necessary for the treatment of an additional indication (e.g. colchicine for viral pericarditis).

Renal dosing:

* CrCl\* ≥50 mL/min: colchicine 0.6 mg twice daily
* CrCl\* 30-49 mL/min: colchicine 0.6 mg every 24 hours
* CrCl\* 11-29 mL/min\*\*: colchicine 0.6 mg every 48 hours
* CrCl\* ≤10 mL/min: doses will be held

Drug interactions: To ensure patients are properly screened and identified as eligible/ineligible with respect to prescribed medications, this research team will identify a group of study pharmacists and physicians (including the PI, Dr. Daniel Delaney, and a pain specialist, Dr. Joseph Johnson), who will be available as-needed to field questions regarding any medications a patient is taking during or prior to their hospital stay that may or may not preclude study participation.

Arms:
arm 1: Patients randomized to a colchicine-containing treatment arm will receive colchicine 0.6 mg twice daily for up to 28 days. On the day of enrollment, provided the first dose can be given prior to 16:00 that day, patients are eligible to receive two doses; the second dose will be scheduled for 22:00. Patients experiencing gastrointestinal side effects (nausea, vomiting, and diarrhea) on twice daily dosing may have the dose decreased to 0.6 mg daily. Dosing will continue twice daily unless there is a change that requires a dose adjustment or an exclusion criterion is met. Dosing deviations above the study protocol will be allowed if medically necessary for the treatment of an additional indication (e.g. colchicine for viral pericarditis).

Patients in this arm will also receive the investigating institution's current standard of care (described in detail in the "standard of care" arm) for patients with COVID-19. arm 2: Patients randomized to a colchicine-containing treatment arm (including the "combined arm") will receive colchicine 0.6 mg twice daily for up to 28 days. On the day of enrollment, provided the first dose can be given prior to 16:00 that day, patients are eligible to receive two doses; the second dose will be scheduled for 22:00.

Patients in the "combined" arm will also receive naltrexone. Patients randomized to an LDN-containing treatment arm (including the "combined arm") will receive naltrexone 4.5 mg once daily. The first dose can be given at any time during the day of enrollment/randomization, and will be timed at 08:00 daily thereafter (with AM colchicine dose, if in combined colchicine/LDN arm) for up to 28 days (unless new contraindication or exclusion criteria met).

Patients in this arm will also receive the investigating institution's current standard of care (described in detail in the "standard of care" arm) for patients with COVID-19. arm 3: Patients randomized to an LDN-containing treatment arm (including the "combined arm") will receive naltrexone 4.5 mg once daily. The first dose can be given at any time during the day of enrollment/randomization, and will be timed at 08:00 daily thereafter (with AM colchicine dose, if in combined colchicine/LDN arm) for up to 28 days (unless new contraindication or exclusion criteria met).

Patients in this arm will also receive the investigating institution's current standard of care (described in detail in the "standard of care" arm) for patients with COVID-19. arm 4: Patients in this arm will receive the investigating institution's current standard of care for patients with COVID-19. For example, all patients requiring supplemental oxygen (assuming no contraindications) would be candidates for both remdesivir 200 mg x 1 IV dose followed the next day by 100 mg q24h IV x up to 4 doses, as well as dexamethasone 6 mg q24h x 10 up to 10 doses.

Interventions: intervention 1: Colchicine 0.6 mg intervention 2: Naltrexone
Intervention descriptions: intervention 1: Colchicine is an oral anti-inflammatory agent that is relatively inexpensive, readily available, and has been used for generations. Approved for treatment and prophylaxis of gout flares and Mediterranean fever, it is also used in a variety of other inflammatory conditions (e.g. pericarditis and diffuse vascular inflammation such as Behcet syndrome). Colchicine binds to tubulin causing depolymerization, which interferes with neutrophil chemotaxis, adhesion, and mobilization to sites of inflammation, and contributes to reduction in superoxide production; through interference of the NLRP3 inflammasome protein complex, colchicine inhibits IL-1b, IL-6, and IL-18 production.

For this study, patients enrolled in a colchicine containing arm will receive 0.6mg of colchicine BID (unless renal function/gastrointestinal issues require adjustments described in the protocol) intervention 2: Most well known as an opioid antagonist, or a treatment for alcohol dependence, naltrexone also possesses immunomodulatory effects. Seen exclusively at low doses, this attribute is being employed in the pain community as a novel anti-inflammatory agent that has been shown to reduce symptom severity in fibromyalgia, Crohn's disease, multiple sclerosis, and complex regional pain syndrome.

For this study, patients enrolled in a naltrexone-containing arm will take their daily dose of the medication (4.5mg) by oral suspension.

Protocol document:
Prot_SAP_001.pdf: 
 
Approved by HealthPartners IRB on 17MAR2021  
Impact of colchicine and low-dose naltrexone 
on COVID-19 disease progression and 
clinical course in hospitalized patients 
Daniel Delaney, PharmD; Elie Gertner, MD; Sadia Ali, MD; Christine Behrendt, PharmD; Joseph 
Johnson, MD; Alison Knutson, PharmD; Marek Kokoszka, MD; Meghan O’Brien, MPH; Tawatchai 
Paisansinsup, MD; Rebecca Peglow, MD; Anne Schullo-Feulner, PharmD; Daniel Sandgren, 
PharmD;  Michael Schnaus, MD;  Paula Skarda, MD. 
 
1. Summary 
The purpose of this study is to explore the impact of two medications—colchicine and low-dose 
naltrexone (LDN)—relative to standard of care (SOC) on COVID-19 disease progression to 
severe/critical illness and/or intubation in patients hospitalized with moderate COVID-19. As we have 
learned, COVID-19’s clinical course suggests that the hyperinflammatory response seen in 
severe/critical cases is involved in the pathogenesis of associated adverse sequelae such as acute 
respiratory distress syndrome (ARDS), thromboembolic disease, and acute cardiac injury. Given 
colchicine has demonstrated clinical utility in inflammatory syndromes within these systems (e.g. 
endothelial/vascular/myocardial), and LDN acts both to boost the immune system, and limit an 
excessive response; they may prove useful in minimizing the risk of disease progression and 
associated adverse sequelae. 
2. Study Aims 
Primary Outcome 
Relative to standard supportive care, the primary aim of this study is to determine the impact of 
colchicine and LDN, administered alone or in combination, on the progression of moderate COVID-
19 to more severe/critical disease. We also aim to determine whether the addition of LDN to 
colchicine changes the odds of progression towards more severe/critical COVID-19 versus 
colchicine or naltrexone alone.  Moderate illness is defined as patients requiring hospitalization due 
to laboratory confirmed COVID-19, and a clinical score of 2 or 3 (see below). Additionally, to prevent 
enrollment of patients with incidental COVID-19 findings, they must meet one or more of the 
following criteria at some point in the 48 hours preceding enrollment: 
- 
Dyspnea limiting usual activities on baseline O2 needs 
- 
Respiratory rate ≥ 30/min at or above baseline O2 needs  
- 
Blood oxygen saturations ≤94% on room air (or on baseline O2 needs if on home 
oxygen therapy prior to presentation at the hospital). 
-     Requiring supplemental O2 above baseline needs (i.e. new receipt of supplemental  


 
Approved by HealthPartners IRB on 17MAR2021  
- 
O2 or an increase over typical oxygen requirements in patients on existing O2 
regimen)COVID-19 contributed to the current hospital admission, per attending 
provider’s clinical assessment of the patient.  
For the purposes of our primary outcome, progression of moderate COVID-19 (score of 2-3) 
to severe/critical illness (score of 4-6) is defined as an increase of two or more points on a 6-
point ordinal scale. Patients enrolled in the study with a baseline score of 2 must progress to 
at least 4 in order to meet the primary outcome. Similarly, those enrolled in the study with a 
baseline score of 3 must progress to at least a 5 in order to meet the primary outcome. 
Patients who progress from a moderate score of 3 to a severe score of 4 will not be 
considered to have met the primary outcome. This will ensure comparability across severity 
groups, as both 2s and 3s will be required to move the same number of points on the ordinal 
scale to meet the primary outcome.   
 
Clinical Score Scale 
Severity 
Score
Definition 
N/A 
1 
Discharged or ready for discharge (i.e. not requiring further medical care 
or monitoring - afebrile, O2 sats >94% on room air or baseline O2 needs, 
respiratory rate < 24 per minute [all x 48 hours]) 
Hospitalized, 
moderate 
disease 
2 
Hospitalized, not requiring supplemental O2 (but requiring ongoing 
medical care or monitoring). If decreasing from a 3, must be at baseline 
O2 requirements for 24 hours. 
3 
Hospitalized requiring supplemental oxygen via  nasal cannula (for a 
minimum of 24 hours if score increasing from 2 or decreasing from a 4) 
Hospitalized, 
severe disease
4 
Hospitalized on high-flow nasal cannula (HFNC) or noninvasive positive-
pressure ventilation (NIPPV) support, (for a minimum of 24 hours if score 
is increasing from 3 or decreasing from a 5).  Patients with baseline use 
of NIPPV, e.g. nocturnal CPAP/BiPAP for obstructive sleep apnea must 
also require qualifying O2 support during the day to obtain a score of 4. 
Hospitalized, 
critical disease 
5 
Mechanically ventilated, or a required transfer for ECMO 
N/A 
6 
Death 
Secondary Outcomes 
To investigate the effects of colchicine, alone or in combination with LDN, relative to standard 
supportive care on the following: 
- 
Obtained via Epic 
- 
Composite in-hospital mortality 


 
Approved by HealthPartners IRB on 17MAR2021  
- 
Total duration of hospitalization (hours) from first dose of any study medication (or 
when first dose would be for standard of care arm) to hospital discharge (or when 
ready for discharge but remains hospitalized for non-medical reasons [e.g. transitional 
care unit placement delays]) 
- 
Total duration of ICU admission (hours) 
- 
Total duration of intubation (hours) 
- 
Total duration of HFNC or NIPPV (hours), (excluding baseline NIPPV use, as above) 
from first dose of study drug (or anticipated first dose, if in standard of care arm) to 
discharge  
- 
Total time above baseline oxygen requirements (hours) from first dose of study drug 
(or anticipated study drug, if in SOC arm) to discharge (i.e. patients not on 
supplemental oxygen prior to presentation at the hospital = time on any supplemental 
oxygen  after first dose/anticipated dose of study drug to discharge); for patients on 
home oxygen therapy of two liters per minute via nasal cannula = time on oxygen >2 
liters per minute via nasal cannula or any other oxygen delivery device from first drug 
dose/anticipated dose to discharge). 
- 
In-hospital days with a fever ≥38 degrees Celsius (00:00 to 23:59:59) from start of first 
dose of study drug (or anticipated first dose, if in standard of care arm) to discharge. 
- 
Adverse events related to colchicine or LDN 
- 
Incidence of significant adverse outcomes associated with/attributable to COVID-19; 
including ARDS, thromboembolic disease, myocardial injury, and acute kidney injury.  
Must be documented in patient’s problem list during their hospitalization, but not 
present or clinically suspected prior to receiving the first dose of any study medication 
(or when a dose would be due if randomized to standard of care). 
- 
Lab values (captured and recorded per the Schedule of Events below) obtained 
during hospital admission and coded as low, normal, high per hospital reference 
range  
- 
Cumulative dose of corticosteroids received in ED/hospital (excluding prior to 
admission/pre-existing use of steroids for an alternative indication); converted to a 
single equivalent unit. 
- 
Cumulative dose of remdesivir received 
- 
Discharge anticoagulation needs (i.e. number of patients discharged on a direct oral 
anticoagulant specifically prescribed for prophylaxis of increased venous 
thromboembolism risk due to COVID-19) 
3. Background and Rationale 
In December 2019, a novel coronavirus caused a cluster of pneumonia cases in Wuhan, China.  The 
identified virus was officially named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
and the associated illness named coronavirus disease (COVID-19) (WHO).  In the months since its 
discovery, the spread of SARS-CoV-2 has led to tens of millions of cases worldwide.  In the United 
States alone, there have been over 11.6 million cases of COVID-19, with over 340,000 attributed 
deaths reported as of December 31, 2020 (CDC Cases in the US).  As is common with emerging 
infectious diseases, the magnitude of their novelty is inverse to the quality of accessible treatment 


 
Approved by HealthPartners IRB on 17MAR2021  
options.  COVID-19 is no exception to this, and despite the recent availability of a preventative 
vaccine, there are limited pharmacotherapeutic treatment options for those with an active infection, 
the majority of which remain investigational. 
Common symptoms among patients with mild disease include fever, altered senses of smell or taste, 
fatigue, or cough.  More severe cases of COVID-19 may lead to hypoxemia and pneumonia.  When 
compared to those with less-severe disease, severe/critical COVID-19 pneumonia generally results 
in an increase in circulating proinflammatory chemokines and cytokines.  These changes have been 
implicated in the pathogenesis of a hyperinflammatory response, and disease severity has been 
shown to correlate with the level of these markers (1-7).  Hyperinflammation is apparent with 
evidence of increased circulating levels of IL-1b, IL-6, IL-8, IL-12, IL-17, IL-18, TNF-α, and IFNγ (1-2, 
4-5, 8), and this “cytokine storm” plays a role in the development of adverse sequelae seen with 
COVID-19, such as ARDS (8-10), thromboembolic disease (9, 11-14), and myocardial injury (15-20).   
The SARS-CoV-2 virus has specific structural components (e.g. viroporin E and viroporins 3a and 
8A) that have been shown to activate NLRP3 inflammasome (21-22).  NLRP3 has been found to be 
a major pathophysiologic component in developing ARDS (23-25); and inflammasome activation 
along with subsequent cytokine production is seen with myocardial injury, which may provide 
mechanistic insight to SARS-CoV-2’s ability to cause cardiac insult (26-27).  Additionally, aberrant 
activation of neutrophils and formation of excessive neutrophil extracellular traps (NETs) were found 
to be associated with ARDS, and recently to be the potential central cause of severe/critical COVID-
19 (10).   
Treatments that influence neutrophil recruitment to sites of inflammation and hyper-inflammatory 
response may prove beneficial for reduction in disease progression, adverse sequelae, and mortality 
associated with COVID-19 infections.  Agents under investigation to mitigate this detrimental host 
response include the IL-6 receptor antagonists (28).  However, their extreme expense, scarce 
availability, and high-risk for severe adverse effects relegate the use of these injectable agents to 
cases that have already progressed to critical illness.   
Colchicine 
Colchicine is an oral anti-inflammatory agent that is relatively inexpensive, readily available, and has 
been used for generations.  Approved for treatment and prophylaxis of gout flares and 
Mediterranean fever, it is also used in a variety of other inflammatory conditions (e.g. pericarditis and 
diffuse vascular inflammation such as Behcet syndrome) (29-31).  Colchicine binds to tubulin 
causing depolymerization, which interferes with neutrophil chemotaxis, adhesion, and mobilization to 
sites of inflammation, and contributes to reduction in superoxide production; through interference of 
the NLRP3 inflammasome protein complex, colchicine inhibits IL-1b, IL-6, and IL-18 production.  As 
described, these are recognized as playing an important role in acute coronary syndrome (32-33), 
pericarditis, and ARDS.  In addition to these anti-fibrotic and cardio-protective features, colchicine 
has an anti-apoptotic action on endothelial cells (34, 35) that may provide benefit in minimizing 
extravasation, capillary leak (36), and therefore progression or development of ARDS.  Lastly, 
coronavirus replication, virion particle assembly, and subsequent exocytosis from the host cell, have 
been shown to rely on cytoplasmic structural proteins (microtubules) for trafficking during its lifecycle 


 
Approved by HealthPartners IRB on 17MAR2021  
(37).  Perhaps most importantly, this includes the constitutive exocytic pathway responsible for 
releasing newly synthesized virions (38).  Disrupting microtubule trafficking has the potential to 
interfere with these key viral replication steps, and therefore introduction of a microtubule 
depolymerizing agent may help treat a coronavirus infection through decreased viral replication (37-
40).   
Considered together, colchicine’s anti-inflammatory benefits, well-known and minimal toxicity profile, 
in conjunction with the pharmacologic properties detailed above, justify the investigation of colchicine 
as a treatment option to minimize disease progression for patients hospitalized with moderate 
COVID-19.   
The use of colchicine in patients hospitalized with COVID-19 has been studied in several small 
proof-of-concept, uncontrolled case series, and comparative cohort studies, as well as small, 
randomized controlled trials (41-46).  Results have been unanimously favorable thus far, though they 
have substantial limitations, and two remain unpublished pre-prints (43, 46).  Some were performed 
during local COVID-19 surges, rates of intubation and mortality were likely inflated as a result, and 
therefore the benefits of colchicine may be overestimated.   
Low-Dose Naltrexone 
Most well known as an opioid antagonist, or a treatment for alcohol dependence, naltrexone also 
possesses immunomodulatory effects.  Seen exclusively at low doses, this attribute is being 
employed in the pain community as a novel anti-inflammatory agent that has been shown to reduce 
symptom severity in fibromyalgia, Crohn’s disease, multiple sclerosis, and complex regional pain 
syndrome (47-49).  Naltrexone is a 50:50 racemic mixture of both L and R isomers - in theory, these 
isomers allow it to act in a dualistic fashion, both boosting the immune system yet limiting an 
excessive immune response.  The L isomer is a competitive inhibitor of the Mu and Kappa opioid 
receptor, resulting in elevated levels of endogenous endorphins and enkephalins, which in turn, 
functions as an immune enhancer.  The R isomer blocks the toll like receptor and modulates T and B 
cell activity; the downstream effects limit the release of inflammatory cytokines including IL-6, IL-12, 
TNF alpha, and NF-KB (47).  A study in 2017 demonstrated a significant reduction in cytokines after 
eight weeks of therapy in eight female patients (50). 
While preliminary LDN studies demonstrate success in Crohn’s disease, multiple sclerosis, and 
fibromyalgia, there is still a need for follow-up trials to establish definitive evidence of benefit (47-49).  
The lack of proprietary value in a generic medication with no industry backing has hampered 
widespread adoption and FDA approval.  Thus, clinical efficacy data is slowly forthcoming on LDN.  
At the same time, the safety profile of naltrexone is well established and very well tolerated in alcohol 
use disorder.  Considering that is a high-risk population, and the dose used is significantly higher 
(25-100mg versus 1-4.5mg for LDN), it stands to reason that LDN should have little to no toxicity.  
Hepatic function has to be monitored at higher doses, and the drug should be stopped if necessary.  
However, with LDN the majority of adverse drug effects are constitutional (headache, dizziness, 
nausea etc.), with no end organ damage and no evidence for opportunistic infections.   


 
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From a neurological standpoint, LDN has an affinity for microglial cells, which has been shown to 
reduce neuroinflammation (47).  A study of 214 CoVID-19 patients in Wuhan China found that 45.5% 
(40/88) of severe patients had neurological symptoms (51).  This was defined in three categories as 
(A) central: headache, dizziness, impaired consciousness, ataxia, acute cerebrovascular disease, 
and epilepsy; or (B) peripheral: hypogeusia, hyposmia, hypopsia, and neuralgia, and (C) skeletal 
muscular symptoms.  The authors did note possible confounding factors such as hypoxia or 
hypercarbia (51).  Interestingly, during the SARS-CoV outbreak in 2002-2004, post-mortem 
pathological evaluation in animals and patients demonstrated a high viral presence in the brainstem, 
demonstrating invasion into the medullary cardiorespiratory center (52).  Whether or not SARS-CoV2 
carries the same capabilities remains to be seen, but early evidence indicates 30-50% of patients 
hospitalized with COVID-19 will have neurological manifestations (53). 
As previously outlined, available evidence demonstrates that excessive immune response in the 
form of a “cytokine storm” plays a key role in the pathophysiology of COVID-19 offering this process 
as a possible target for drug therapy.  Known immunomodulatory effects of LDN suggest that this 
drug could be used to reduce this exaggerated immune response.  Additionally, the frequency of 
neurologic symptoms associated with COVID-19 implies that there may be a treatment role for a 
drug with neuro-anti-inflammatory properties, such as LDN. 
In summary, the proposed actions of LDN in the treatment of SARS-CoV-2include its potential to act 
as an immune enhancer via the upregulation of the endogenous opioid system, with increased 
endorphins and enkephalins, decrease multiple inflammatory cytokines, including IL-6, IL12, TNF 
alpha, and NF- KB.  Combined, this may blunt the hyperinflammatory response and subsequent 
injury that can lead to, and has been observed in, critically ill COVID-19 patients  
While the efficacy of LDN is being studied in COVID-19 (NCT04604704, NCT04604678, 
NCT04365985) in combination with a nutritional supplement, metformin, and ketamine (respectively), 
only the latter trial is recruiting at this time, and none includes colchicine. 
Summary 
An important step in mitigating the morbidity and mortality of COVID-19, both from an individual and 
community standpoint, is minimizing the duration of hospitalization to extend healthcare capacity, 
frequency of disease progression to more severe illness, and need for more invasive, finite, 
respiratory support (mechanical ventilation).  Treatment modalities aimed to reduce severe, 
resource-intense cases of COVID-19 should be prioritized to alleviate an overburdened healthcare 
infrastructure. 
To that end, this work will specifically determine if there is clinical utility of colchicine and low dose 
naltrexone (alone or in combination), relative to SOC in decreasing the incidence of both 1) 
progression of moderate COVID-19 to severe/critical illness, and 2) its subsequent complications.   
The above rationale for the use of these two agents specifically notes that combining them is not yet 
being investigated elsewhere.  The combination is worthy of inclusion in this research for multiple 
reasons.  Chiefly: there is no evidence to suggest that combining these agents would be harmful, 


 
Approved by HealthPartners IRB on 17MAR2021  
there are no known drug interactions, and we have decades of clinical experience and safety data 
available for both of these well-tolerated, low-toxicity agents.  Outside of its novelty, their 
pharmacologic actions in blunting a hyperinflammatory response act independently of each other, 
with similar downstream effects (e.g. decreased cytokine production).  Their complementary 
mechanisms may therefore have an additive, potentially synergistic, impact.  Further, their 
mechanisms work independently of the anti-inflammatory agents used in COVID-19 that come with 
significant potential for toxicity, namely glucocorticoids.  This may provide further anti-inflammatory 
benefit, and potentially generate additional hypotheses for research regarding ways to minimize the 
need/use of higher-risk anti-inflammatory agents. 
As described, the available evidence and rationale to assess colchicine and LDN for use in COVID-
19 are currently found within distinct areas of clinical and pharmacologic knowledge.  To ethically 
test this novel intervention and bridge this siloed information, a clinical trial that measures their 
potential impact on COVID-19’s clinical course is required.   
4. Approach 
a. Study Design 
This will be a four arm, prospective, randomized, open label trial in patients hospitalized with 
moderate COVID-19. 
b. Population 
i. 
Inclusion/Exclusion Criteria 
To be eligible for this study, patients must meet the following Inclusion criteria at 
enrollment:  
 
1) Male and (non-pregnant, non-breastfeeding) females aged 18 years or older 
2) Requiring admission to Methodist or Regions Hospital due to laboratory-confirmed 
COVID-19  
3) Meets criteria of only up to moderate COVID-19 disease as defined by a clinical score 
of 2 or 3 at the time of enrollment, and one or more of the following noted at some 
point in the 48 hours preceding enrollment: 
a) Dyspnea limiting usual activities on baseline O2 needs 
b) Respiratory rate ≥30/min on O2 or room air  
c) Blood oxygen saturations ≤94% on room air (or on baseline O2 needs if on 
supplemental oxygen prior to presentation at the hospital for a condition 
unrelated to COVID-19). 
d) Requiring supplemental 02 above baseline needs (i.e. prior to presentation at 
hospital) 
e) COVID-19 contributed to the current hospital admission, per attending provider’s 
clinical assessment of the patient.  
 


 
Approved by HealthPartners IRB on 17MAR2021  
4) Ability to provide written informed consent, or has identifiable LAR that is able to do 
so on the patient’s behalf as defined by study protocol, prior to performing study 
procedures. 
 
They cannot meet any of the following exclusion criteria at enrollment: 
 
1) Patients meeting criteria for severe/critical COVID-19 as defined by study protocol or 
requiring O2 supplementation ≥10L nasal cannula at screening 
2) Patients currently in shock as defined by hemodynamic instability requiring 
vasopressors 
3) Patients with a current hospitalization for COVID-19 that is >/=7 days at the time of 
screening.  
4) Clinical estimation of attending physician that the patient will require mechanical 
respiratory support within 48 hours of enrollment 
5) Patients in which EITHER symptom onset OR a positive COVID-19 laboratory test 
occurred ≥14 days prior to enrollment. 
6) Patients with concomitant influenza A or B at time of hospitalization if tested as part of 
ED/hospital admission.  
7) Female patients who are pregnant or breastfeeding at time of hospital admission 
8) Diagnosis of Chronic Kidney Disease stage ≥4 as documented in the patient’s 
problem list (not based on CrCI calculations alone) 
9) CrCl < 30 mL/min or requiring renal replacement therapy (e.g. intermittent 
hemodialysis, continuous renal replacement therapy, peritoneal dialysis) at screening 
10) History of cirrhosis or advanced liver disease, or active hepatic viral infection 
11) Transplant of kidney, lung, heart, or liver in the past 2 years 
12) Uncontrolled severe gastrointestinal disorders, Crohn’s disease, ulcerative colitis, 
chronic diarrhea, diarrhea predominant irritable bowel syndrome, active stomach or 
intestinal ulcer, or one that was treated within the last 6 months 
13) Patients currently receiving agents that are p-glycoprotein AND strong CYP3A4 
inhibitors with CrCl < 60 mL/min, or any combination of drug interactions that is not 
amenable to dosage adjustment (refer to list of medications with potential Colchicine 
and Naltrexone interactions). 
14) Patients actively undergoing chemotherapy for an active malignancy, or history of a 
hematologic malignancies 
15) Chronic or current use of colchicine or any mu-opioid antagonist. 
16) Chronic, scheduled opioid therapy (i.e. not intermittent as needed use), or, prior to 
enrollment, an acute condition requiring continued pain control that is unattainable 
without ongoing opioid therapy. 
17) Pre-existing condition that is being treated with tocilizumab, anakinra, sarilumab, 
other interleukin-antagonists, TNF-inhibitors, or JAK inhibitors.  
18) NOTE: Patients treated with tocilizumab will be permitted to enroll if their care team is 
us prescribing it for COVID-19. Use of tocilizumab at baseline for another indication 
will continue to be excluded.  


 
Approved by HealthPartners IRB on 17MAR2021  
19)    Participation in any other clinical trial of an experimental treatment for COVID-19, 
note: 
a) While convalescent plasma is no longer recommended within HP, it can be 
given if deemed appropriate by the medical team once ≥ 24 hours has elapsed 
since enrollment 
b) Patients previously enrolled in the C3PO study can enroll in this study, as any 
convalescent plasma received would have been outpatient 
c) Remdesivir is allowed per standard protocol 
d) Dexamethasone is allowed per standard protocol 
 
20) Patients actively enrolled in hospice or on palliative care 
21) History of hypersensitivity reaction to colchicine or its inactive ingredients 
22) History of hypersensitivity reaction to naltrexone or its inactive ingredients 
23) Incarcerated or a ward of the state 
24) Any patient considered an unsuitable candidate, for any reason, by study 
investigators. 
ii. 
Sample Size  
We will enroll up to 180 (136--168 estimated) patients between both sites (Methodist and 
Regions hospitals).  Once enrollment has reached ~25% of anticipated sample size in 
each arm, an informal interim assessment will be performed to assess intervention futility. 
Due to current strains on staffing, we do not want to add any unnecessary burden for 
hospital staff including enrolling and consenting patients in the proposed study if the 
intervention doesn’t have a noticeable positive effect. If this initial look shows no obvious 
difference in rate of severe/critical disease progression, the research team and clinicians 
providing care will be involved in deciding whether to terminate the study and will 
promptly alert the IRB if this determination is made. See Power Analysis section for more 
information.  If we do move forward, another interim assessment may be recommended 
when enrollment reaches ~50% in each arm.  We will update the IRB either way. 
 
c. Data Collection Process 
i. 
Process for Identification 
Using the system-wide Epic report for COVID-19 testing, the research team will screen 
for patients.  All patients with a pending or positive result will be screened for inclusion.  
Emergency room physicians, attending physicians, infectious diseases physicians, and 
clinical pharmacists may also contact the research team to refer a patient for enrollment. 
ii. 
Recruitment 
Upon verification of eligibility based on inclusion and exclusion criteria, the research team 
will contact the patient’s attending provider to discuss if the patient is a viable candidate, 
and if they would like the patient to be approached for consent into the research study.  If 


 
Approved by HealthPartners IRB on 17MAR2021  
in agreement, the attending will mention the study to the patient and notify them that they 
are eligible for a research study and that a member of the research team will contact 
them in the near future.  
At this time, the other studies actively enrolling patients for the use of investigational 
agents for the treatment of COVID-19 patients at Methodist and Regions hospital include 
CARDEA and C3PO (the latter of which is outpatient only).  The initiation of this study will 
be unlikely to influence enrollment of these ongoing studies, as they are distinct in their 
enrollment criteria. In the event that a patient simultaneously meets criteria for more than 
one study, the research team will contact the patient’s attending to discuss whether one 
study may be a more appropriate option to present to the patient given their clinical 
status. If, in the attending’s opinion, the patient is an equally good candidate for both 
studies, study staff will present both options to the patient and permit the study participant 
to decide which research study (if any) they would choose to participate in. 
If additional COVID-19 studies are to be initiated, and could potentially conflict with this 
application, IRB will be updated with a plan for mitigating these concerns.  Additionally, 
there is a COVID-19 registry being created locally and these patients will be a part of that 
registry. Study staff involved in the Colchicine/LDN study are also involved in the COVID-
19 registry started in April of 2020. As many of the medical history elements captured in 
the registry are of interest to the investigators of this study, the research team will utilize 
medical history data documented in the COVID-19 registry for the study. This will avoid 
burdening the study staff with excessive data entry responsibilities and permit more 
efficient enrollments. The list of data points that will be extracted from the registry for this 
study are identified in the data collection tool sample that is included with this submission.  
iii. 
Consent 
Considering the highly infectious nature of COVID-19, and the unique strains the 
pandemic is placing on healthcare and supply chain industries, we are requesting 
permission to utilize an altered approach to patient consent.  This altered approach may 
require some patients to provide verbal consent under the supervision of a witness prior 
to obtaining the patient’s signature for consent.  The processes outlined below present 
the best scenarios for obtaining patient consent while minimizing unnecessary patient 
interactions, healthcare worker exposure, and consumption of personal protective 
equipment. This process has been successfully used by the CCRC since March 2020 to 
ensure that research staff does not enter the patient’s room and meets all requirements 
for compliance. The CCRC follows the FDA’s guidance document, “FDA Guidance on 
Conduct of Clinical Trials of Medical Products during COVID-19 Public Health 
Emergency”, to consent patients during the COVID pandemic.  
 
1) Prior to contacting the patient (or the patient’s legally authorized representative/LAR) 
directly, the study team will reach out to the attending to request permission to 
approach the patient. If the attending gives permission, he/she may introduce the 
study prior to research staff outreach.  


 
Approved by HealthPartners IRB on 17MAR2021  
 
-The attending may provide important information about patient’s capacity to consent 
for themselves and, if the patient is unable to do so, may inform the study team of a 
family member or other legal guardian who would be an appropriate LAR who could 
provide consent for research on the patient’s behalf.  
 
-If the patient or LAR primarily speaks a language other than English, study staff will 
procure a copy of the HealthPartners Short Form Consent Form and ensure the 
informed consent process is completed with help from a certified medical interpreter. 
As the consent form will not be translated in full, the study team will ensure that an 
impartial witness is present (listening in by phone) during the entire consent process 
and will attest to this by signing the Short Form Consent Form. This will be a fourth 
individual (other than the study participant/LAR, interpreter, and person obtaining 
informed consent) who is neither (1) part of the study team, nor (2) serving as the 
patient’s primary provider (MD/PA/NP).  
 
2)   Once the team determines what conditions need to be in place to obtain informed  
consent, a research team member will call the patient or LAR to introduce the study 
and assess if the patient/LAR can access a link to the REDCap electronic consent 
form on a cell phone, tablet, or other device. 
 
*Patients who require time to think about the study before making a decision about 
participating, or who want an easy-to-reference guide about what is involved, will be 
given a copy of the participant information sheet. This will have contact information 
about the study team on it so they may reach out with any questions they may have.  
 
3) If the patient or LAR can receive the link to the consent form, the researcher will 
send them the consent link and guide the patient through consent over the phone 
while the patient reviews it on their device.  Patients/LARs will sign consent 
electronically through REDCap if they agree to participate in the research study. Both 
the full informed consent document and the Short Form will be made available 
electronically. Study staff obtaining consent will countersign the form in REDCap. If 
applicable, an impartial witness will also sign the consent form.  
 
If the patient/LAR does not have a device with which they can review and sign the 
consent form via REDCap in real-time: 
 
a) Research staff will provide a paper copy of the full informed consent form (or Short 
Form, if consent is provided through an interpreter) to a member of the patient’s care 
team. This person will enter the room to deliver the form for the patient to sign.  
b) If possible, research staff will stay on the phone with the patient to review the 
signature pages and ensure (as much a possible) that the form has been signed and 
dated appropriately.   


 
Approved by HealthPartners IRB on 17MAR2021  
c) The provider who entered the room to deliver the consent form will collect the signed 
document. Research staff will meet the provider outside the patient’s room and will 
obtain the consent form (using gloves) and place the signed document in a paper 
bag. 
d) The date and time of consent form collection will be noted on the bag, and it will be 
placed in quarantine for a minimum of 3 days to avoid possible COVID-19 infection 
among the research team. 
e) The study staff member completing the consent process will document the method of 
consent as “paper” and will countersign the form electronically in REDCap. 
f) If the consenter is an LAR, depending on hospital visitation restrictions, research staff 
may meet them in person in or outside of the hospital to obtain a signature on the 
paper consent form.  
g) In rare circumstances, an LAR may be able to provide neither an electronic consent 
nor an in-person consent. In this case, a neutral witness privy to the telephone 
consent conversation may sign the witness line of the consent form to attest that the 
LAR was in agreement. 
 
All consents, no matter the form, will include time for patients to ask questions, consult 
with their treating team or family members, and be asked a few comprehension questions 
from the research team to ensure the patient understands what they are consenting to 
take part in. 
iv. 
Data Sources/steps for data acquisition 
Patient data will be collected by the research team members that are listed in the IRB 
personnel section of the application.  With the exception of informed consent, all data will 
be collected through manual chart review/abstraction in Epic.  Any necessary 
correspondence with the patient or care team will happen via phone if possible.  Below is 
the planned schedule of events:  
 
 


 
Approved by HealthPartners IRB on 17MAR2021  
**Screening and Day 1 procedures may occur on the same day
Study time point/activity
Screening
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Up to Discharge
Inclusion & Exclusion Criteria
1
Informed consent, randomization
1
Demographics
1
Past medical history
1
Detailed baseline O2 needs
1
Pregnancy testing (as needed)
1
Safety assessment and reporting
1
1
1
1
1
1
1
1
Concomitant medications
1
1
1
1
1
1
1
1
1
New  Drug-Drug Interactions
1
1
1
1
1
1
1
1
1
Colchicine dose frequency (Daily/BID, 
w ith rationale if changed)
1
1
1
1
1
1
1
1
1
Study Drug Administration
1
1
1
1
1
1
1
1
1
Max O2 needs, SpO2 range, both q12h
1
1
1
1
1
1
1
1
1
Tmax
1
1
1
1
1
1
1
1
1
Chest imaging (yes/no)
1
1
1
1
1
1
1
1
1
EKG or continuous telemetry (yes/no)
1
1
1
1
1
1
1
1
1
LMWH > 0.5 mg/kg/dose (not 
cumulative daily dose) or heparin drip?
1
1
1
1
1
1
1
1
1
Level of care
1
1
1
1
1
1
1
1
1
Length of hospitalization
1
Mortality
1
Study time point/activity
Screen
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Up to Discharge
BNP
1
1
1
1
1
1
1
1
1
CBC w ith differential
1
3
1
1
1
3
3
3
4
C-reactive protein
1
3
1
1
1
3
3
3
4
D-dimer
1
3
1
1
1
1
1
1
4
Ferritin
1
3
1
1
1
1
1
1
4
Hepatic Function Panel
1
3
1
1
1
1
3
1
4
Procalcitonin
1
1
1
1
1
1
1
1
1
SCr
1
2
2
2
2
2
2
2
2
Troponin
1
1
1
1
1
1
1
1
1
Key
1 = Record
2 = Minimum of every 48 hours
3 = unless ordered as standard of care within the 
past two days, order on this study day
4 = unless ordered as part of standard of care, order 
within 24 hours of meeting the primary endpoint
Schedule of Events
Baseline Enrollment Information
Clinical Course Monitoring (can be documented following day)
Laboratory Monitoring
(Serum creatinine) 


 
Approved by HealthPartners IRB on 17MAR2021  
Additional Clarification - Schedule of Events  
Baseline Enrollment Information  
Inclusion & Exclusion Criteria 
Assessment of study eligibility at time of hospital admission  
Informed consent, 
randomization 
Enrollment in study and assignment to study arm 
Demographics 
Documentation of patient characteristics (age, gender, race, 
etc.). See data collection plan for more information  
Past medical history 
Documentation of diagnoses from problems list at baseline; 
relevant medical history data extracted from COVID-19 
registry. See data collection tool sample for more information 
Detailed baseline O2 needs 
Documentation of need for supplemental home oxygen 
therapy at baseline (yes/no); if yes, amount in L 
Pregnancy testing (as needed)
Rule out pregnancy for female participants of child-bearing 
age 
 
Clinical Course Monitoring – Performed daily until discharge  
Safety assessment and 
reporting 
Review of chart for AEs by study staff  
Concomitant medications 
Review of medications taken in hospital in addition to study 
drugs (reviewed by study staff/ study pharmacists) 
New Drug-Drug Interactions 
Assessment of new/updated medications to determine risk of 
new drug interaction based on change in concomitant 
medications/revised information about any medication the was 
previously on. 
Colchicine dose frequency 
(Daily/BID, with rationale if 
changed) 
Documentation regarding any changes in colchicine dosage 
and reason for doing so 
Study Drug Administration  
      
For interventional arms: Administration of colchicine twice per 
day (08:00, or when morning drugs are given, and 20:00, or 
when afternoon drugs are given), unless change in patient’s 
health status warrants temporarily stopping or reducing 
medications. Administration of naltrexone will occur once per 
day at 08:00 (dose on day 1 can be at any time) or when 
morning drugs are given. 
Max O2 needs, SpO2 range, 
both q12h 
Maximum O2 needs for continuous 12-hour periods beginning 
at hospital admission; highest and lowest SpO2 during each 
time period.  
Tmax 
Maximum recorded temperature patient reached during the 
study day 0:00-23:59.  
Chest imaging (yes/no) 
Documentation of whether patient received SOC chest 
imaging on the study day 
EKG or continuous telemetry 
(yes/no) 
Documentation of whether patient received an SOC EKG or is 
on continuous telemetry on study day 
LMWH > 0.5 mg/kg/dose (not 
cumulative daily dose) or 
heparin drip? (yes/no) 
Documentation of need for more than .5mg/kg total dose of 
Low Molecular Weight Heparin on study day  
Level of care 
Documentation of clinical scale score; hospital unit through 
which patient is being treated (Gen Med, ICU) and any 
transfers that occur 


 
Approved by HealthPartners IRB on 17MAR2021  
Length of hospitalization 
Documented time from first study drug dose (or when it be if in 
the SOC arm) to discharge; check daily and document where 
patient discharged to (home, TCU, etc.) 
Mortality 
Documentation of patient death at any time during the hospital 
stay  
 
Laboratory Monitoring  
BNP 
Documented during patient’s hospital stay as performed per SOC 
up to the point of discharge  
CBC with differential 
 Documented during patient’s hospital stay as performed per 
standard of care with supplemental research-only labs added as 
need according to the schedule above 
C-reactive protein 
Documented during patient’s hospital stay as performed per 
standard of care with supplemental research-only labs added as 
need according to the schedule above 
D-dimer 
Documented during patient’s hospital stay as performed per 
standard of care with supplemental research-only labs added as 
need according to the schedule above 
Ferritin 
Documented during patient’s hospital stay as performed per 
standard of care with supplemental research-only labs added as 
need according to the schedule above 
Hepatic Function Panel 
Documented during patient’s hospital stay as performed per 
standard of care with supplemental research-only labs added as 
need according to the schedule above 
Procalcitonin 
 Documented during patient’s hospital stay as performed per 
SOC up to the point of discharge 
Serum Creatinine (SCr) 
Documented during patient’s hospital stay as preformed per SOC 
up to the point of discharge. Research-only labs will be ordered 
as needed to ensure no more than 48 hours passes between 
draws up to the point of discharge. 
Troponin 
Documented during patient’s hospital stay as performed per SOC 
up to the point of discharge 
 
d. Interventions/treatment 
Dosing strategy 
Colchicine  
Patients randomized to a colchicine-containing treatment arm will receive colchicine 0.6 mg twice 
daily for up to 28 days.  On the day of enrollment, provided the first dose can be given prior to 
16:00 that day, patients are eligible to receive two doses; the second dose will be scheduled for 
22:00.  Patients experiencing gastrointestinal side effects (nausea, vomiting, and diarrhea) on 
twice daily dosing may have the dose decreased to 0.6 mg daily.  Dosing will continue twice daily 
unless there is a change that requires a dose adjustment or an exclusion criterion is met.  Dosing 
deviations above the study protocol will be allowed if medically necessary for the treatment of an 
additional indication (e.g. colchicine for viral pericarditis).   
Renal dosing:  


 
Approved by HealthPartners IRB on 17MAR2021  
 
- 
CrCl* ≥50 mL/min: colchicine 0.6 mg twice daily (standard dose timing to cluster cares of 
08:00 and 20:00 will be used. 
- 
CrCl* 30-49 mL/min: colchicine 0.6 mg every 24 hours 
- 
CrCl* 11-29 mL/min**: colchicine 0.6 mg every 48 hours 
- 
CrCl* ≤10 mL/min: doses will be held 
- 
   
*Calculated using the Cockcroft-Gault formula 
**CrCl < 30 mL/min at the time of screening excludes enrollment at that time point 
Hepatic dosing: If severe hepatic function impairment is present, use is not recommended for 
the purpose of this study. 
Drug interactions (54-55): All participants, in all arms of the study will have an evaluation of all 
current medications for drug interactions, as is the standard of care in hospitalized patients at 
Methodist or Regions Hospital.   
The following two lists contain agents with drug-drug interactions with colchicine, and may 
exclude patients from enrollment based on a combination of interactions and renal function.  
Patients requiring continued treatment with medications in the following two lists will require 
study clinical pharmacist review for eligibility and colchicine dosing (if applicable). 
1) Concomitant medications that may be contraindicated due to CYP3A4 and/or P-
glycoprotein metabolic interactions: 
Patients requiring continuation of atazanavir, bocepravir, clarithromycin, cobicistat, cyclosporine, 
darunavir (with ritonavir), dasabuvir, dronedarone, elvitegravir (with ritonavir), erythromycin, 
idelalisib, indinavir (with ritonavir), itraconazole, ketoconazole, lopinavir (with ritonavir), 
nefazodone, nelfinavir, ombitasvir, paritaprevir (with ritonavir), posaconazole, ranolazine, 
ritonavir, saquinavir (with ritonavir), tacrolimus, telaprevir, tipranavir (with ritonavir),  
telithromycin, or voriconazole will require study clinical pharmacist review for eligibility and 
colchicine dosing (if applicable). 
2) Concomitant medications that may pose drug interactions due to CYP3A4 and/or 
P-glycoprotein metabolic interactions: 
Patients requiring continuation of abametapir, amiodarone, amprenavir, aprepitant, crizotinib, 
delavirdine, fluconazole, fluvoxamine, fosnetupitant, imatinib, interferon alfa-2A, lasmiditan, 
letermovir, mibefradil, mifepristone, netupitant, reserpine, tacrolimus, or venetoclax will require 
study clinical pharmacist review for eligibility and dosing (if applicable). 
 
- 
Patients receiving fibrates or gemfibrozil during their hospitalization will need to be discontinued 
prior to the first dose of colchicine (if assigned to either of the two colchicine-containing treatment 
arms) due to increased risk of myopathy and rhabdomyolysis with concomitant use. Study team 
members will consult with the attending physician and/or study pharmacists to see if this is an 
appropriate and safe option for a potential study participant prior to consent and randomization.  
 


 
Approved by HealthPartners IRB on 17MAR2021  
- 
The combination of colchicine and statin therapy (atorvastatin, fluvastatin, lovastatin, pitavistatin, 
pravastatin, rosuvastatin, or simvastatin) may have an increased risk of myopathy and 
rhabdomyolysis.  Our approach for patients receiving statin therapy will follow the standard of 
care for this interaction as follows: 
 
- 
Patients receiving a statin for primary prevention of cardiovascular disease must be, 
in the opinion of the attending physician, an appropriate candidate for discontinuation 
of their statin for the duration of the study to be eligible for enrollment.  If they are 
randomized into a colchicine-containing arm of the study, their statin therapy will be 
held. 
- 
Patients receiving a statin for secondary prevention of cardiovascular disease must 
be, in the opinion of the attending physician, able to tolerate substitution of their 
current statin therapy for rosuvastatin 20 mg once daily. If they are randomized into a 
colchicine-containing arm of the study, statin therapy will be resumed with 
rosuvastatin 20 mg daily. This is being done in an effort to minimize interruptions in 
statin therapy, and drug-drug interaction potential.   
Low-Dose Naltrexone 
Patients randomized to an LDN-containing treatment arm will receive naltrexone 4.5 mg once 
daily.  The first dose can be given at any time during the day of enrollment/randomization, and 
will be timed at 08:00 daily thereafter (with AM colchicine dose, if in combined colchicine/LDN 
arm) for up to 28 days (unless new contraindication or exclusion criteria met).  
 
Naltrexone is most commonly used in the treatment of alcohol and opioid dependence at 
standard doses of 25 to 100 mg daily.  At these doses, naltrexone acts as a non-selective, pure 
opioid receptor antagonist and blocks the effects of opioids by competitively binding to the 
receptors.  However, naltrexone exhibits different effects in relation to its concentration.  LDN is 
considered a daily dose ranging from 1 – 4.5 mg.  At these lower doses, naltrexone antagonizes 
Toll-like receptor 4 on glial cells, reducing the inflammatory immune response (47, 56).   
 
Additional Procedures: Drug Interaction Assessment at Screening/Enrollment 
As previously mentioned, to ensure patients are properly screened and identified as 
eligible/ineligible with respect to prescribed medications, this research team will identify a group 
of study pharmacists and physicians (including the PI, Dr. Daniel Delaney, and a pain specialist, 
Dr. Joseph Johnson), who will be available as-needed to field questions regarding any 
medications a patient is taking during or prior to their hospital stay that may or may not preclude 
study participation. 
Interaction of LDN and Colchicine 
As previously described, the use of LDN and colchicine in combination for study purposes is 
presumed safe, as there are no known drug interactions with these treatments, nor any known 
interactions affecting metabolism. As this study was designed and developed by a team of 
pharmacists, many of whom will be involved in safety monitoring and dosing regimen 
adjustments, all appropriate measures will be taken in response to AEs identified in study 
participants regardless of their assigned arm, including those receiving both colchicine and LDN. 


 
Approved by HealthPartners IRB on 17MAR2021  
Randomization 
Randomization will be stratified by baseline severity score (2 or 3) to ensure balanced baseline 
severities between the four arms. Block randomization will be used to ensure equal group sizes.  
As the final sample size is unknown, we will use small blocks of eight. This is being done in an 
effort to ensure evenly distributed treatment arms.  A research team member will create an Excel 
file to determine randomization assignments.  The Excel file will be numbered from one to 180 
(the largest possible sample size).  Each number will represent a subject ID, for each ordered 
block of 8 rows; they will generate 8 random numbers between 0 and 1 with 3 decimal places 
and no replacement.  The subjects with the smallest two values (tier 4) will receive colchicine + 
standard supportive care (group A), the subjects with the second lowest set of digits (tier 3 ) will 
receive colchicine + LDN + standard supportive care (group B), the two subjects with next 
highest set of digits (tier 2) will receive LDN alone + standard supportive care (group C) and the 
subjects with the largest two values (tier 1) will receive standard supportive care and no drug 
(group D). Separate spreadsheets will be used for patients with a clinical scale score of 2 vs 3 at 
the time of randomization to ensure a balance in baseline in severity among all the arms. When a 
research team member enters a consented subject into this database, the subject will be 
considered randomized.  Any subject who consents but is not randomized will not receive a 
sequential study ID, as this would interrupt the Excel file’s randomization scheme.  Instead, 
subjects who are not randomized may be referred to as subjects a, b, c, etc. and will be tracked 
in a separate file.   
Patients will be randomized in a 1:1:1:1 fashion to the following treatment: 
Randomized Intervention Group 
A 
   B 
C 
D 
*Colchicine 0.6 mg BID + 
low dose naltrexone 
4.5mg daily + standard 
supportive care 
*Colchicine 0.6 
mg BID + 
standard 
supportive care 
Low-dose 
naltrexone 4.5 mg 
daily + standard 
supportive care   
Standard of 
care 
 
*can receive two doses of colchicine on day 1 if enrollment completed/first dose given before 
16:00.    
Once randomized, the research team will place an order for the correct study medication panel 
through Epic to be prepared by pharmacy staff.  The research team will use the subject ID 
generated during randomization to order the correct order panel. 
Nursing staff will receive education on how to administer the medication via the research team.  
This education will include that the study medications should be dosed per the Epic orders.  The 
education will also include a list of side effects to watch for in the study patients and contact 
information to notify the research team 24/7 if any of these adverse events are observed. 
To assess for outcomes and adverse events, patients will continue to be monitored per the 
schedule of events above until they are discharged.  Upon discharge from the hospital, patients 


 
Approved by HealthPartners IRB on 17MAR2021  
will not be prescribed study medications unless for an alternate indication (e.g. continuation of 
colchicine for viral pericarditis). 
Due to feasibility issues, and concerns with unnecessary healthcare worker exposure and 
consumption of personal protective equipment, we will use a standard treatment arm in lieu of a 
placebo-controlled arm.  Daniel Delaney, PharmD will be the pharmacy liaison at Methodist 
Hospital and assist in identifying where study medications will be kept, prepped, and distributed.  
At Regions, study medications will be stored and distributed with the assistance of Jason Sloan, 
PharmD.   
e. Outcome/endpoint and other variable definitions, instruments used 
Primary Outcome 
Relative to standard supportive care, the primary aim of this study is to determine the impact 
of colchicine and LDN, alone or in combination, on the progression of moderate COVID-19 to 
more severe disease.  Moderate illness is defined as patients requiring hospitalization due to 
laboratory confirmed COVID-19, meeting one or more of the following: 
- 
Dyspnea limiting usual activities on baseline O2 needs 
- 
Respiratory rate >/= 30/min at or above baseline O2 needs  
- 
Blood oxygen saturations <94% on room air (or on baseline O2 needs if on home 
oxygen therapy prior to presentation at the hospital). 
-     Requiring supplemental 02 above baseline needs (i.e. new receipt of supplemental  
O2 or an increase over typical oxygen requirements in patients on existing O2 
regimen) 
 
Disease progression measured by severity increase from moderate disease to severe 
disease/critical illness, defined as a minimum 2-point increase within 14 days of enrollment or 
by hospital discharge, whichever occurs first based on the following 6-point scale:   
 
Clinical Score Scale 
Severity 
Score
Definition 
N/A 
1 
Discharged or ready for discharge (i.e. not requiring further medical care 
or monitoring - afebrile, O2 sats >94% on room air or baseline O2 needs, 
respiratory rate < 24 per minute [all x 48 hours]) 
Hospitalized, 
moderate 
disease 
2 
Hospitalized, not requiring supplemental O2 (but requiring ongoing 
medical care or monitoring). If decreasing from a 3, must be at baseline 
O2 requirements for 24 hours. 
3 
Hospitalized requiring supplemental oxygen via  nasal cannula (for a 
minimum of 24 hours if score increasing from 2 or decreasing from a 4 
Hospitalized, 
severe disease
4 
Hospitalized on high-flow nasal cannula (HFNC) or noninvasive positive-
pressure ventilation (NIPPV) support, (for a minimum of 24 hours if score 
is increasing from 3 or decreasing from a 5).  Patients with baseline use 


 
Approved by HealthPartners IRB on 17MAR2021  
of NIPPV, e.g. nocturnal CPAP/BiPAP for obstructive sleep apnea must 
also require qualifying O2 support during the day to obtain a score of 4. 
Hospitalized, 
critical disease 
5 
Mechanically ventilated, or a required transfer for ECMO 
N/A 
6 
Death 
 
 
This scale is a modified version of the World Health Organization R&D Blueprint Ordinal 
Clinical Scale (57).  Modifications were made to fit the study population, as this study focuses 
on patients requiring hospitalization for laboratory confirmed COVID-19, and does not 
delineate severity among those requiring mechanical ventilation (patients will have already 
met primary outcome). 
 
Based on inclusion/exclusion criteria, at minimum patients will have a score of 2 at the time of 
enrollment, and a maximum score of 3.The primary endpoint is met with progression in 
severity that is correlated to a 2-point increase, i.e. progression to at least requiring 
HFNC/NIPPV for patients with an admission score of 2 (2 to 4) or intubation for a patient with 
an admissions score of 3 (3 to 5) would designate them as “progressed to severe/critical 
disease”.  As described, randomization will be stratified by baseline severity score (2 or 3) to 
ensure balanced baseline severities between the four arms 
Secondary Outcomes 
To investigate the effects of colchicine with or without LDN relative to standard supportive 
care on the following: 
- 
Obtained via Epic 
- 
Composite in-hospital mortality 
- 
Total duration of hospitalization (hours) from first dose of any study medication (or 
when first dose would be for standard of care arm) to hospital discharge (or when 
ready for discharge but remains hospitalized for non-medical reasons [e.g. transitional 
care unit placement delays]) 
- 
Total duration of ICU admission (hours) 
- 
Total duration of intubation (hours) 
- 
Total duration of HFNC or NIPPV (hours), (excluding baseline NIPPV use, as above) 
from first dose of study drug (or anticipated first dose) to discharge.  
- 
Total time above baseline oxygen requirements (hours) from first dose of study drug 
(or anticipated study drug, if in SOC arm) to discharge (i.e. patients not on 
supplemental oxygen prior to presentation at the hospital = time on any supplemental 
oxygen  after first dose/anticipated dose of study drug to discharge); for patients on 
home oxygen therapy of two liters per minute via nasal cannula = time on oxygen >2 
liters per minute via nasal cannula or any other oxygen delivery device from first drug 
dose/anticipated dose to discharge). 
- 
In-hospital days with a fever ≥38 degrees Celsius (00:00 to 23:59:59) from first dose 
of study drug (or anticipated first dose) to discharge. 


 
Approved by HealthPartners IRB on 17MAR2021  
- 
Adverse events related to colchicine or LDN 
- 
Incidence of significant adverse outcomes associated with/attributable to COVID-19; 
including ARDS, thromboembolic disease, myocardial injury, and acute kidney injury.  
Must be documented in patient’s problem list during their hospitalization, but not 
present or clinically suspected prior to receiving the first dose of any study medication 
(or when a dose would be due if randomized to standard of care). 
- 
Lab results (captured and recorded per the Schedule of Events below) obtained 
during hospital admission and coded as low, normal, high per hospital reference 
range  
- 
Cumulative dose of corticosteroids received in ED/hospital (excluding prior to 
admission/pre-existing use of steroids for an alternative indication); converted to 
single equivalent units 
- 
Cumulative dose of remdesivir received 
- 
Discharge anticoagulation needs (i.e. number of patients discharged on a direct oral 
anticoagulant specifically prescribed for prophylaxis of increased venous 
thromboembolism risk due to COVID-19) 
f. Statistical analysis plan 
Primary Aim:  
 
For the primary aim, to determine if Colchicine and LDN effect the odds of progression towards 
severe/critical COVID-19, we will use logistic regression with intent to treat (ITT) analysis for all 
randomized subjects. We will also determine whether the concurrent administration of both 
colchicine and LDN changes the odds of progression towards severe/critical COVID-19 versus 
each alone. A 2X2 factorial design, rather than an analysis of 4 parallel arms, will be employed. 
The table below indicates the treatment provided to each group: A will receive both colchicine 
and LDN, B will receive only colchicine, C will receive only LDN, and D will receive neither 
(standard of care group).  
 
 
 
 
Colchicine 
LDN 
 
Yes 
No 
Yes 
A 
C 
No 
B 
D 
 
The study will examine the main effect for both colchicine alone (Group B compared to Group 
D) and naltrexone alone (Group C compared to group D). We will also look for a potential 
interaction effect of using both medications together. All analysis for the primary aim will be 
performed using logistic regression. Our outcome variable will be whether a patient 
experienced clinical deterioration during hospitalization as defined by an increase of at least 2 
points on the clinical score/levels of care scale (see above) relative to their baseline score at 
enrollment.  
 
The effect on disease progression from Colchicine and LDN as compared to SOC, along with 
the interaction of the two interventions will be estimated with the following model: 


 
Approved by HealthPartners IRB on 17MAR2021  
𝑙𝑜𝑔𝑖𝑡൫Ε(𝑌|𝑋)൯= 𝛼+ 𝛽ଵ(𝐶𝑜𝑙𝑐ℎ𝑖𝑐𝑖𝑛𝑒) + 𝛽ଶ(𝐿𝐷𝑁) +  𝛽ଷ[(𝐶𝑜𝑙𝑐ℎ𝑖𝑐𝑖𝑛𝑒) ∗(𝐿𝐷𝑁)] +
𝛽ସ  (𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑆𝑒𝑣𝑒𝑟𝑖𝑡𝑦) +  𝛽ହ(𝑎𝑔𝑒) + 𝛽଺ (𝑠𝑒𝑥) + 𝛽଻(𝑟𝑎𝑐𝑒) +  𝜀  
This model will result in log odds and p-value estimates for the effect of colchicine (𝛽ଵ
෢) and 
LDN (𝛽ଶ
෢) on experiencing clinical deterioration during hospitalization. The interaction term (𝛽ଷ
෢)  
will allow us to determine if administering LDN and colchicine together significantly changes the 
odds of severe/critical progression compared to the additive effect of each intervention alone. 
The model will include adjustments for patient age, biological sex, race, and baseline severity. 
  
The results from the model above will be used to create contrast statements that allow for a 
pairwise comparison of the four study arms and their estimated odds of experiencing clinical 
deterioration. Odds ratios, confidence intervals, ratio of ratios, as well as the directionality of 
the effect will be used to describe any differences in effect between each intervention arm and 
the SOC group.  
 
Effect 
Group Comparison 
Odds Ratios 
Colchicine alone vs. SOC 
B vs D 
𝑒ఉభ
෢ 
LDN alone vs SOC 
C vs D 
𝑒ఉమ
෢ 
Colchicine and LDN vs SOC 
A vs D 
𝑒ఉభ
෢ାఉమ
෢ାఉయ
෢ 
 
Secondary Aims  
 
For our secondary aim, we will use the modeling steps described in our primary aim to assess 
the effect of Colchicine and LDN relative to SOC, along with the interaction effect on each of 
the many secondary outcome measures. One model will be run for each outcome to estimate 
the differences between the single-drug intervention groups and SOC with the final step of 
comparing the interaction effects. These comparisons are considered exploratory and are 
unpowered: 
 
Outcome 
Model 
Mortality, adverse events, and 
categorical lab results 
Logistic regression 
Duration of hospitalization, ICU 
admission, intubation, and HFNC or 
NIPPV; Total time above baseline 
oxygen requirements; days with fever; 
cumulative dose of corticosteroids 
received; cumulative does of remdesivir 
OLS or x- and/or y- transformed 
regression, as appropriate depending 
on the spread of the data 


 
Approved by HealthPartners IRB on 17MAR2021  
received; discharge anticoagulation 
needs; continuous lab results 
 
All analysis will be performed in SAS 9.4 with two-sided alphas of 0.05 
g. Power analysis or statement of precision  
The use of colchicine +/- LDN to prevent COVID-19 disease progression requiring HFNC, 
NIPPV, or intubation is an unstudied area, particularly in the context of concomitant 
administration of our current SOC (if not otherwise contraindicated, remdesivir and 
dexamethasone in patients requiring supplemental oxygen).  It can be estimated that roughly 
20% of hospitalized patients will require ICU-level care, approximately half of which (~10% 
overall) will require mechanical ventilation.  Noting that not all patients needing HFNC or 
NIPPV require ICU-level care, the proportion of patients reaching a clinical score of ≥4 during 
their admission will be estimated at 40%. We expect that the majority of these patients will 
initially present with moderate symptoms, therefore our estimated rate of progression to 
severe/critical care for moderate COVID-19 patients receiving SOC is 30% to 40%.  
Using the assumption that colchicine would reduce the proportion of patients who progress in 
clinical score by 20% (raw difference), with an alpha 0.05 and 80% power, we will require a 
sample of at least 136 (34 per arm, 68 patients receiving colchicine, groups A and B). Similarly, 
we expect a 20% difference in proportion of patients progressing to critical status when 
receiving LDN as compared to SOC, requiring 68 patients total receiving LDN (34 per arm, 
groups A and C).   
Although our study contains four arms, the analysis plan is powered off of a comparison of two 
unadjusted main effects rather than a formal comparison of each of the three intervention arms 
to the SOC [A, B, and C to the SOC arm (D)]. Because this is not a parallel-arms study, we will 
not be able to compare the LDN-only arm with the combined arm (A and C) or the colchicine-
only arm with the combined arm (A and B). However, the decision to use a 2X2 factorial design 
permits us to compare larger pools of study participants and still be appropriately powered to 
detect a significant difference associated with each intervention and determine if the use of 
both interventional drugs together changes the odds of progressing to severe/critical disease 
compared to the use of each alone. The study team acknowledges that any statements about 
the interaction effect of both medications will necessarily be less precise than those of the main 
effects. 
 It is important to emphasize that with the unknowns (disease trajectory, actual effect of study 
drugs, and population of consentable patients); this is a very rough estimate.  If there is a true 
effect, we may observe it at a much smaller n, or not observe it at all even if we reach our goal 
recruitment.  Thus, our interim assessments will be very important in conducting this study 
when enrollment hits at least 10 in each arm. At this point, the sample will likely be 
underpowered to observe an effect if there is one. Absolute rate of progression to 
severe/critical care will be calculated for the SOC and pooled intervention groups. If there is < 


 
Approved by HealthPartners IRB on 17MAR2021  
10% difference in absolute progression rates between the SOC arm and the pooled 
intervention patients, we will take into account resources, rate of recruitment, futility, and ethical 
considerations when deciding whether to move forward with recruitment at this point. Next 
steps will be evaluated/determined at that time including a possible second interim assessment 
when enrollment exceeds 20 per arm.  As we are in desperate need of inexpensive, safe, orally 
administrable, and commercially available treatment options for COVID-19, we are hopeful the 
IRB will understand this. 
Sample size per arm needed to detect effect sizes shown 
 
Rate of 
Progression to 
Severe/Critical 
No Effect 
(H0) 
Effect 
(Reject H0) 
N per arm/Total 
N 
0.3 
0.1 
34/136 
0.4 
0.2 
42/168 
h. Strengths and limitations 
The study team is composed of multiple clinical pharmacists, physicians from infectious 
diseases, hospital medicine, anesthesiology, cardiology, and rheumatology, many of whom 
have been caring for hospitalized COVID-19 patients for almost 10 months.  As a result, the 
team is very well acquainted with the patient population, the current practices for managing 
COVID-19 in the hospital, and is motivated to find an oral treatment option that has a favorable 
safety profile, is inexpensive, and commercially available.  The Critical Care Research Center 
(CCRC) is also familiar with working in the acute care setting and carrying out research 
protocols like the one proposed.  As such, we have a well-rounded group to carry out this 
robust study.  We will have access to patients from two large hospitals allowing a large patient 
pool to enroll from (see setting/environment/organizational feasibility). 
Ideally, our study would be double blind and placebo-controlled, but that was not feasible given 
limited resources and time during the current COVID-19 surge.  As such, we opted to use a 
SOC control group.  While the study is not blinded, we will attempt to have a second blinded 
physician assess AE’s.  We will be limited in our sample size due to locations, funds, and 
availability of patients and study medications.  As previously noted, there are many unknowns 
and calculating a sample size estimate is very challenging and may need to be adjusted as the 
study progresses.  We could improve the study by assessing for viral clearance, but due to the 
lack of widely available testing, and testing shortages in general, we are unable to include this. 
5. Setting/environment/organizational feasibility 
This study will be conducted at Methodist Hospital and Regions Hospital in collaboration with clinical 
pharmacy, infectious diseases, and hospital medicine groups at each location.  Dr. Daniel Delaney 
will serve as the overall PI of the trial, as well as the PI of the Methodist site, supported by Drs. Sadia 
Ali and Michael Schnaus. Dr. Gertner will serve as the PI at Regions with support from Dr. Schnaus 


 
Approved by HealthPartners IRB on 17MAR2021  
who also sees patients at Regions Hospital, as well as Drs. Rebecca Peglow and Paula Skarda. 
Enrollment at both of these large hospitals will give us access to a larger and potentially more 
diverse patient population, and as of December 2020 have had multiple weeks of a combined 
COVID-19 census of 100-150+ patients.  The CCRC will assist with research efforts at both sites 
and will collaborate with other research staff in the Park Nicollet and Methodist system to carry out 
this protocol. 
Regarding coordination of inpatient care, Dr. Schnaus has been tasked with leading research efforts 
from the Hospital Medicine perspective, Drs. Ali and Peglow for infectious diseases, and Drs. Daniel 
Delaney and Jason Sloan for pharmacy.  Many of these individuals, in addition to the rest of the 
research team, are members of the COVID-19 Clinical Research Expert Panel for HealthPartners. 
As COVID-19 research leaders within the Care Group, they are up to date on current practices, and 
have access to necessary groups for input and collaboration to carry out these efforts successfully. 
As this study seeks to answer questions being asked around the world for patients suffering from 
COVID-19, we hope the results not only influences our local care teams and patients, but also the 
medical community at large.   
6. Risks and benefits 
Risks 
Each medication has a well-known safety profile and is generally well tolerated.  With the appropriate 
monitoring, avoidance of important drug-drug interactions, and dosing adjustments provided by this 
protocol, we do not anticipate a notable difference, in adverse events between the treatment and 
SOC arms (including the combined LDN and colchicine arm).   
Colchicine 
As gastrointestinal side effects (most commonly diarrhea, potentially nausea, and vomiting) are 
occasionally seen with colchicine, this may be a specific exception to observed differences in 
adverse effects, and should be noted even though it is uncommon at low doses of 0.6-1.2 mg/day.  
Less common (<1%) adverse drug events include hepatotoxicity, bone marrow suppression, and 
myotoxicity.  Renal insufficiency and drug interactions leading to increased colchicine levels are the 
primary risk factor for side effects; the enrollment process is designed to preclude or minimize this 
risk, and will be monitored for in enrolled patients regardless (58). 
Low-Dose Naltrexone 
The medication is well tolerated at much higher doses than outlined in this protocol (25-100 mg vs 
4.5 mg daily).  At the higher doses, hepatotoxicity can occur; this will be monitored for as part of the 
study protocol.  Trials using LDN for its anti-inflammatory properties have found it to be uniformly 
well tolerated by participants, and if side effects do occur they’re generally mild and constitutional 
(headache, dizziness, nausea, insomnia or sedation, anxiety, abnormal dreams) (43).  In terms of 
drug interactions, the primary concern would be avoiding opioid withdrawal in patients receiving 
chronic opioid therapy, and the enrollment process will exclude patients in which this is a concern.  
For patients requiring management of acute pain with opioids following enrollment, pain control may 
still be achieved with concomitant LDN and opioid administration, though it may require a higher total 


 
Approved by HealthPartners IRB on 17MAR2021  
dose of opioids, intentionally separating administration times of the opioid and study medication, or 
the use of an alternative agent (e.g. ketamine).  If there are challenges with pain control during 
treatment, continued study participation will of course remain voluntary, and a pain specialist, Dr. 
Joseph Johnson, will be available to provide pain management recommendations as needed.   
Benefits 
As this is novel research, it cannot guarantee benefit to the patients enrolled.  It is our hope that the 
information gathered will have broad implications in a variety of care settings - which could include, 
uniquely, rural and underserved communities (not just to those hospitalized in resource rich regions, 
or those with access to larger, academic/research hospital systems).  If proven beneficial, colchicine 
+/- LDN would be the first treatment option that: has an existing supply chain with broad commercial 
availability, is generally well tolerated with a very well-known and favorable safety profile, and can be 
administered orally.   
Additionally, the medications considered “standard of care” at this point are in stark contrast to those 
used in published literature.  For example, per our institution’s current treatment algorithm, all 
patients requiring supplemental oxygen (assuming no contraindications) would be candidates for 
both remdesivir 200 mg x 1 IV dose followed the next day by 100 mg q24h IV x up to 4 doses, as 
well as dexamethasone 6 mg q24h x 10 up to 10 doses.  None of the patients received remdesivir in 
the aforementioned studies (42-46).  Additionally, the 614 patients received azithromycin and 
hydroxychloroquine two and three times more often, respectively, than steroids (which was only 
given to 30.3% of patients). 
Confirmation of the potential benefits of colchicine alongside the current SOC within our Care Group 
is needed.  In addition to having the potential to provide a new treatment option to a more diverse 
patient population, it may mitigate initiation of higher risk (dexamethasone, anticoagulation), more 
expensive therapies (remdesivir).  Taken together with the fact that there are no registered clinical 
trials investigating the combination of LDN with colchicine, each of the study’s treatment arms will 
provide novel, actionable information that may prove useful in optimizing patient outcomes and 
resource utilization (beds, ventilators, and capital). 
7. Data Confidentiality and Privacy 
All data collected in this study will be stored on servers that only the research team from 
HealthPartners has access to such as REDCap and the CCRC drive.  Data will not be shared with 
anyone outside of HealthPartners without prior authorization.  Only those directly involved with the 
study will have access to screening and participant information.  All data will be de-identified once 
the team is finished with data collection and identifiers will be destroyed. 
8. Timeline 
November 2020 -Early January 2021: Study development, IRB application creation, IRB submission, 
IRB review and approval 
January 2021: First patient in 
January 2021 - mid 2021: Patient enrollment and data collection 
Q3 2021: Statistical analysis 


 
Approved by HealthPartners IRB on 17MAR2021  
Q4 2021: Manuscript Preparation and Submission 
9. Dissemination/Sharing Results/Integration and Impact 
This information will be shared with the Infectious Disease and Hospital Medicine groups, and the 
COVID-19 Command Center. We hope the results can guide the continued use of these medications 
for more patients with COVID-19 or eliminate them as an option. 
After completion of the study, we will attempt to submit our results for publication and presentation in 
the relevant public health, infectious disease, and hospital medicine journals and conferences.  
10.  References: 
1. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients 
from Wuhan, China 
2. COVID-19: consider cytokine storm syndromes and immunosuppression. 
3. Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-
19 patients 
4. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China 
5. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus 
disease 2019 (COVID-19): The Perspectives of clinical immunologists from China 
6. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-
2019 (COVID-19): The epidemic and the challenges. 
7. Hypothesis for potential pathogenesis of SARS-CoV-2 infection-a review of immune changes 
in patients with viral pneumonia 
8. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients 
With Coronavirus Disease 2019 Pneumonia in Wuhan, China 
9. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, 
China: a retrospective cohort study. 
10. Targeting potential drivers of COVID-19: Neutrophil extracellular traps. 
11. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, 
Antithrombotic Therapy, and Follow-up 
12. Acute pulmonary embolism and COVID-19 pneumonia: a random association? 
13. COVID-19 Complicated by Acute Pulmonary Embolism 
14. Acute Pulmonary Embolism in COVID-19 Patients on CT Angiography and Relationship to D-
Dimer Levels 
15. COVID-19 and the cardiovascular system. 
16. Association of Coronavirus Disease 2019 (COVID-19) With Myocardial Injury and Mortality 
17. SARS-CoV-2 inflames the heart.  The importance of awareness of myocardial injury in 
COVID-19 patients. 
18. Potential Effects of Coronaviruses on the Cardiovascular System: A Review. 
19. Coronaviruses and the cardiovascular system: acute and long-term implications. 
20. COVID-19 and cardiovascular disease: What we know, what we think we know, and what we 
need to know. 
21. Severe acute respiratory syndrome coronavirus E protein transports calcium ions and 
activates the NLRP3 inflammasome 


 
Approved by HealthPartners IRB on 17MAR2021  
22. Severe Acute Respiratory Syndrome Coronavirus Viroporin 3a Activates the NLRP3 
Inflammasome 
23. Critical Role for the NLRP3 Inflammasome during Acute Lung Injury 
24. The NLRP3 Inflammasome Is Required for the Development of Hypoxemia in 
LPS/Mechanical Ventilation Acute Lung Injury 
25. Inflammasome-regulated Cytokines Are Critical Mediators of Acute Lung Injury 
26. Colchicine Acutely Suppresses Local Cardiac Production of Inflammatory Cytokines in 
Patients With an Acute Coronary Syndrome 
27. Colchicine therapy in acute coronary syndrome patients acts on caspase-1 to suppress 
NLRP3 inflammasome monocyte activation 
28. Why tocilizumab could be an effective treatment for severe COVID-19? 
29. Update on colchicine, 2017. 
30. Colchicine: An Impressive Effect on Posttransplant Capillary Leak Syndrome and Renal 
Failure 
31. Colchicine--Update on mechanisms of action and therapeutic uses. 
32. Low-dose colchicine for secondary prevention of cardiovascular disease (LoDoCo). 
33. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction (Colcot). 
34. Effects of colchicine on renal fibrosis and apoptosis in obstructed kidneys. 
35. Initial evidence of endothelial cell apoptosis as a mechanism of systemic capillary leak 
syndrome. 
36. Colchicine: An Impressive Effect on Posttransplant Capillary Leak Syndrome and Renal 
Failure 
37. Human Coronavirus: host-pathogen interaction 
38. Viral stop-and-go along microtubules: taking a ride with dynein and kinesins 
39. Update on colchicine, 2017 
40. Tubulins interact with porcine and human S proteins of the genus alphacoronavirus and 
support successful assembly and release of infectious viral particles. 
41. Treating COVID-19 with colchicine in community healthcare setting 
42. Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical 
outcomes in patients hospitalized with coronavirus disease 2019; the GRECCO-19 
randomized clinical trial.   
43. Beneficial effects of colchicine for moderate to severe COVID-19: an interim analysis of a 
randomized, double-blinded, placebo controlled clinical trial.  MedRxiv.  (Pre-print) 
44. Association between treatment with colchicine and improved survival in a single-centre 
cohort of adult hospitalised patients with COVID-19 pneumonia and acute respiratory distress 
syndrome 
45. A case control study to evaluate the impact of colchicine on patients admitted to the hospital 
with moderate to severe COVID-19 infection. 
46. The Impact of Colchicine on The COVID-19 Patients; A Clinical Trial Study (Pre-Print) 
47. Low-Dose Naltrexone (LDN)—Review of Therapeutic Utilization 
48. Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn's 
disease: a randomized placebo-controlled trial 
49. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, 
double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. 


 
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50. Reduced Pro-Inflammatory Cytokines after Eight Weeks of Low-Dose Naltrexone for 
Fibromyalgia 
51. Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: a 
retrospective case series study 
52. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of 
COVID-19 patients 
53. Neurobiology of COVID-19 
54. Novel evidence-based colchicine dose-reduction algorithm to predict and prevent colchicine 
toxicity in the presence of cytochrome P450 3A4/P-glycoprotein inhibitors. 
55. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers 
56. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain 
57. WHO R&D Blueprint and COVID-19 
58. Adverse events during oral colchicine use: a systematic review and meta-analysis of 
randomised controlled trials 
 

ICF_000.pdf: 
 
 
IRB Approved March 3, 2021 - TK 
 
INFORMED CONSENT TO PARTICIPATE IN A RESEARCH STUDY 
 
 
Page 1 of 9 
 
 
 
HealthPartners, Inc.  
Consent to Participate in a Research Study 
 
Study Title 
Impact of colchicine and low-dose naltrexone on COVID-19 disease 
progression and clinical course in hospitalized patients 
Study Investigator 
Dan Delaney, PharmD 
Department: Pharmacy (Methodist Hospital) 
Daytime Phone: 952-993-7197 
24-hour contact number: 651-254-9900 
Study Team 
Coordinator 
Meghan O’Brien  
Daytime Phone: 651-254-5303 
 
Introduction 
You are invited to participate in a research study. In order to participate, you must be at least 18 of age 
and currently hospitalized with COVID-19 (corona virus). Taking part in this research study is 
voluntary. 
To make reading this consent form easier, please note that the word “you” refers either to you if 
you are the patient (research participant), or to the patient (research participant) if you are his/her 
family member. 
 
Important Information about the Research Study 
Things you should know: 
● The purpose of the study is to find out if two different drugs, naltrexone and colchicine (taken 
alone or together), reduce the chance that patients with moderate COVID-19 will develop more 
severe symptoms when compared to the usual course of care. 
If you choose to participate, you will be asked to allow us to randomly assign you to one of four 
study groups: (1) one that will receive two study drugs, (colchicine + naltrexone), (2) one that 
will receive only colchicine, (3) one that will receive only naltrexone, (4) and one that will 
receive no study drugs. All patients, no matter which group, will also receive the usual care 
provided to patients with COVID-19. While the specific treatment patients with COVID-19 
receive will depend on their symptoms, those who are hospitalized will often be given antiviral 
drugs and corticosteroids to help slow production of the virus and prevent an excessive 
immune response. Patients may also receive supplemental oxygen therapy, and medications to 
prevent complications of COVID-19, such as blood clots.  
If you are in any of the three groups receiving study drugs, you will be asked to take these 
medications until you are discharged from the hospital, but no longer than 28 days. If you are 
not receiving study drug, you will not be asked to do anything different during the study. Some 
extra labs may be collected. These include labs that are drawn to monitor the condition of 
patients with COVID-19, and will help us understand how your body is responding to the 
virus. These labs help us understand how your liver (hepatic panel), immune system (CBC with 
differential) and kidneys (serum creatinine) are functioning, and if there are concerns for blood 


 
 
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clotting problems (d-dimer) or iron deficiency (ferritin).We will also review your medical 
records for information about the course of your treatment until the time of your discharge 
from the hospital.  
● Risks and discomforts from this research include those related to taking the study drugs, as well 
as those related to research in general. Colchicine can cause nausea, diarrhea, and vomiting. 
Low dose naltrexone can cause headaches, dizziness, anxiety, and insomnia. There is also the 
risk of the loss of the confidentiality of your health information, but the study team will take 
measures to prevent this from happening.  
● The study may or may not benefit you directly, but this cannot be guaranteed. By being in this 
study, you are helping us learn more about the study drugs and whether the study drugs help 
to effectively treat other patients with COVID-19. 
● Taking part in this research study is voluntary. You don’t have to participate and you can stop 
at any time. 
● Alternative procedures or course of treatment include:  
o Receiving the usual care provided to patients with COVID-19 as described above. 
Please take time to read this form and ask questions before deciding whether to take part. You may 
discuss your decision with your friends and family. You can also discuss it with your health care team. 
If you decide to take part in this study, you will be asked to sign and date this form and will be given a 
copy of the signed and dated consent form. 
 
Why am I being asked to participate? 
You are being asked whether you would like to participate in a research study about moderate COVID-
19 because you recently tested positive for this virus and are hospitalized due to your symptoms, or 
you were diagnosed with COVID-19 after your admission to the hospital and your doctor believes this 
finding contributes to your current hospitalization.  
 
What is the purpose of this study? 
In this study, we want to find out if the drugs colchicine and naltrexone, either alone or combined, 
reduce the chance that patients with moderate COVID-19 will develop more severe symptoms 
compared to the usual care. A second goal of the study is to find out if there is a difference between the 
groups who receive colchicine or naltrexone alone (compared to those who get colchicine and 
naltrexone together) on overall patient outcomes and treatment needs.  
 
Although colchicine and naltrexone are approved by the FDA for certain uses, they have not been 
approved specifically for use in patients with COVID-19. Colchicine is a medication that has been used 
to treat symptoms of gout, a condition that causes joint pain and swelling. Naltrexone helps people 
with alcohol or narcotic dependence reduce or stop their use of these drugs. Both of these medications 
interfere with cytokines, or proteins that are responsible for the extreme immune response seen in 
severe COVID-19 cases. While Colchicine restricts the production of cytokines, naltrexone limits their 
release. This study will investigate the use of these drugs for a new indication (use) and will help us 
determine if using them together is better than each alone for the treatment of COVID-19.  
 


 
 
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Where will this study take place? 
This study will take place at both Regions Hospital in St. Paul, MN and Park Nicollet Methodist 
Hospital in St. Louis Park, MN.  We expect to enroll up to 180 subjects.   
 
What is involved if I take part? 
 
 
If you agree to take part in this study, you will be asked to sign this consent form before any study-
related procedures are performed.  The investigator and research team will ask you questions and 
review your medical records to see if you qualify to be in the study. 
 
If you meet all criteria to be in this study, you will be randomized to one of 4 groups. Randomized 
means being assigned to a group by chance, like flipping a coin or drawing names out of a hat. You 
have a 25%, or one in four, chance of being assigned to each group.  
 
Group 1 will receive 0.6mg of colchicine orally twice a day, along with usual care. Group 2 will receive 
0.6mg of colchicine orally twice a day, 4.5mg of naltrexone once daily, and usual care. Group 3 will 
receive 4.5mg of naltrexone orally once daily and usual care. Group 4 will receive usual care and no 
study drugs. You cannot choose which group you will be in. 
 
As a subject, you will be responsible for: 
● telling the investigator if you are feeling bad or worse than before 
● following the directions of the investigator and research team 
 
What will happen during the study? 
All study participants will be screened, enrolled, and randomized. The schedule of future events will 
be based on your length of stay at the hospital and study group. After randomization, some study-
specific labs may be done if they are not ordered by your doctor as part of your usual care. 
 
Time Point 
Study Events 
How long 
will this 
take? 
Reminders 
Screening/ 
Enrollment – 
Day 1 
● Answer questions about yourself to 
help the study team make sure you are 
eligible to participate. 
● Review and sign this consent form 
 
60-90 
minutes 
 
Randomization– 
Day 1 
● Be randomized to a study drug group 
or usual care 
● Receive initial dose of study drug (if 
assigned to one of three treatment 
groups) 
15 minutes 
 
Days 2-28 
● Receive study medication 1-2 times a 
day if in one of the treatment groups 
● Study team will draw study labs (in 
addition to usual care) to monitor 
illness/assess safety 
30 minutes 
Will continue up to 28 
days, but may stop 
sooner if discharged. 


 
 
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Are there any risks to me? 
There may be side effects from the study drug.  Many side effects go away, but sometimes they can be 
serious, long-lasting, or may never go away.  There may be other side effects that we don’t know about 
yet, so be sure to tell the investigator about any unusual symptoms. 
 
Risks of Colchicine 
Common risks of colchicine, reported in about 20% of users, affect the stomach and gastrointestinal 
system. These may include: diarrhea, nausea, and vomiting, but are not often seen at the low doses 
used for this study. If you experience these issues, the study team may reduce your dosage for this 
study to one 0.6mg tablet per day.  
 
Rare side effects (<1%) include damage to the liver (hepatotoxicity), reduced ability of the bones to 
make immune cells (bone marrow suppression), and muscle damage (myotoxicity)    
 
Poor kidney function is another potential risk, and this most likely to happen in patients taking certain 
medications. The study team will tell you if you are not eligible for this study if the medications you 
are taking would make it unsafe for you to do so.  
 
Risks of Naltrexone  
Common risks of naltrexone, affecting more than 10% of users, include: headaches, dizziness, nausea, 
insomnia, and anxiety. These side effects are typically seen at higher doses than what is being given for 
this study. 
 
Naltrexone is well-tolerated at higher doses than what is used for this study, but study team members 
will monitor patients for rare risks like damage to the liver (hepatotoxicity).  
 
Opioid withdrawal is another potential issue, and this most likely to happen in patients who are 
receiving chronic opioid therapy. The study team will tell you if you are not eligible for this study if the 
medications you are taking would make it unsafe for you to do so.  
 
The risks of colchicine and naltrexone for an embryo, fetus, or nursing infant, are not well know at this 
time. If you are pregnant or breast feeding, you should not participate in this study. If you discover you 
are pregnant during the study, you must tell the investigator immediately.  
 
Are there any benefits to me? 
You may or may not benefit from being in this study.  Your disease or condition could improve in the 
following ways: lessening of COVID-19 symptoms or shorter recovery time from your current illness. 
 
It is also possible that your condition could stay the same or even get worse. We hope the information 
learned will help other patients with COVID-19 in the future. 
 
How is this study being funded?  
This research is supported by a grant from the Park Nicollet Foundation. 
 


 
 
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How much will it cost to participate? 
You will not need to pay for the study drugs or any lab tests done solely for research purposes. Any 
procedures and tests performed while you are in the hospital that will be for your routine medical care 
(and not specifically for research) will be charged to you or your insurance company as they normally 
would. 
 
Will I be paid to participate? 
You will not be paid to participate in this study. 
 
How long will I be in the study? 
You will be in the study for the duration of your hospital stay for COVID-19. If you are randomized to 
a group receiving one or more study drugs, you will be asked to take medication until you are 
discharged, but no more than 28 days. 
 
The study may be stopped early by the investigator. You could be asked to stop being in the study for 
any of the following reasons:  
● for your safety 
● if you do not follow our directions for this study 
● if you become pregnant 
 
Do I have to be in this study? 
You do not have to be in this study.  If you start the study, you may stop at any time.  There is no 
penalty or loss of benefits if you don't want to participate, and your decision won't affect your regular 
medical care.  
 
You may decide to participate now, but change your mind and withdraw from the study anytime 
without penalty or loss of benefits.  If you decide to withdraw before the  study ends, let the 
investigator and/or study team know. You may do so by contacting the investigator at the number on 
this consent form (a copy of which will be provided to you) or study coordinator and stating your 
intention to stop participating. Although we will no longer collect data on your hospital stay after your 
withdrawal, there may be special procedures to follow for your safety. 
 
Your only choices are to participate, or not to participate.  It is up to you whether you want to be in this 
study. 
 
What if I am harmed from being in the study? 
If you get hurt or sick from being in this study, you should let the investigator/study team know as 
soon as possible. If you are in the hospital at the time of your injury, your providers will ensure you 
receive the care that you need. The study team will not cover the cost of treatment provided to you for 
harm caused by your participation in this study. You will be responsible for the cost of any medical 
services provided to you in the study-related illness or injury.  By signing this form, you are not giving 
up any of your legal rights. 
 


 
 
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Will my records be kept confidential? 
Your study records will be kept as confidential as possible.  This is further described in the HIPAA 
Authorization. Please know that at any time, your study records may be reviewed by the United States 
Food and Drug Administration (FDA), the HealthPartners IRB, or the study team. 
 
Any information we collect on you for this study, even if identifiers are removed, will not be used or 
distributed for future research studies. 
 
All tests, assessments, and procedures done as part your hospital stay (other than your use of the study 
drug, if applicable) will be done as part of your treatment for COVID-19 and not solely for research. If 
you would like to know the results of any tests performed during your hospital stay, consult with your 
care provider.  
 
What if there is new information about this study? 
If we learn any new information about this study that might make you change your mind about 
participating, we will tell you. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law.  This Web site will not include information that can identify you.  At most, the Web site will 
include a summary of the results.  You can search this Web site at any time. 
 
Who oversees this study? 
HealthPartners Institutional Review Board (IRB) has approved this study.  The IRB is a committee of 
people who review all research studies at HealthPartners to check that they meet federal laws and 
ethical standards. 
 
IRB approval only means it is ok for the study to begin.  Only you can decide if being in this study is the 
right decision.  Feel free to talk about this study with your family, friends and personal doctor before 
you decide. 
 
Who do I contact? 
If … 
You should contact 
Contact information 
You are harmed by the research 
or have questions about clinical 
procedures in the study 
Dan Delaney, PharmD 
(24 Hour Phone Line) 
651-254-9900 
You have questions about your 
rights as a research subject 
IRB office 
952-967-5025 
 
 
 


 
 
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Information about Confidentiality and HIPAA Authorization 
 
The Privacy Rule of the federal Health Insurance Portability & Accountability Act (HIPAA) is a law 
that protects the confidentiality of your personal health information.  This Authorization describes 
your rights and explains how your health information will be used and disclosed. 
 
Why is access to my health information being requested? 
To help answer the research questions, the investigator and research team will use and store personal 
health information about you.  We are asking your permission to use and share it with others, as 
explained below. If you don’t give this permission, you won’t be able to take part in the research study. 
 
What information will be collected and used? 
When you are a subject, we will collect health information about you that also includes your name, 
address, telephone number, or other data that could identify the health information as yours.  Under 
HIPAA, this health information is protected and can’t be used without your permission, unless 
otherwise permitted by law.  If you sign this authorization, you are giving permission for 
HealthPartners to use and disclose your personal health information as described below. 
 
The following are examples of personal health information that may be collected for this study: 
● results of tests and procedures 
● information about your medical conditions and history 
 
The collected information may contain your name, address, telephone number, social security number, 
health plan number, date of birth, medical record numbers, dates relating to various medical 
procedures, and/or other identifying information.  
 
Who will see my protected health information? 
By signing this Authorization, you allow the research team to use your personal health information to 
carry out and evaluate this study.  You also allow access to your personal health information (including 
direct access to your medical records at HealthPartners/or Dental Clinic) to the following: 
Who may have access: 
Purpose: 
HealthPartners consultants and employees, 
including IRB members 
To protect the rights and safety of subjects and 
make sure the study information is correct 
Organizations that regulate research (such as the 
FDA, Office for Human Research Protections 
(OHRP), or similar government agencies in the 
US and other countries) 
To make sure applicable laws are being followed 
Organizations that grant accreditation to 
hospitals and research programs 
For HealthPartners to remain accredited 
 
Will you keep my health information confidential? 
We will keep your personal health information as confidential as possible. We will only share it as 
described above or if required or permitted by law.  It is not likely your information will be given to 
others without your permission.  However, once your information leaves HealthPartners, we can’t 
control how it is used, and it will no longer be covered by the HIPAA Privacy Rule. 


 
 
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Will other people know that I was in this study? 
If the results of this study are published, your name or other personal information will not be included. 
 
How long will my personal health information be used? 
Access to your personal health information begins as soon as you sign this form. This authorization 
expires when the study is finished, data analysis is complete, and the study records have been 
destroyed. 
 
What if I change my mind? 
If you don’t want us to use and disclose your personal health information anymore, you must let the 
investigator know in writing. If you need help with this, you can ask the research team or call the 
HealthPartners IRB office at 952-967-5025.  
 
If you withdraw permission for us to use your personal health information: 
● you can’t continue in the research study 
● we will stop collecting health information from you 
● we will still use and disclose any information that we gathered while you were a subject 
● there will not be any penalty or loss of benefits to which you are otherwise entitled 
 
Can I see my study records? 
 
You can see your study records at any time. 
 
Subject name:  
 
● I have read this form and the research study has been explained to me. 
● I have been given the chance to ask questions, and my questions have been answered.  I have been 
told who to call if I have more questions. 
● I agree to be in the research study described above. 
● I will receive a copy of this consent form after I sign it.  A copy will be put in my medical record 
and/or study record. 
● I am not giving up any of my legal rights by signing this form.  
 
 
Subject signature 
Date 
 
 
Witness signature (if applicable*) 
Date 
*Use when the subject or legally authorized representative cannot read the consent (for example, subject is blind, illiterate, or 
does not speak English).  The witness must be present for the entire consent discussion.  The witness signature means that 
the information in this document was presented to the subject, and the subject appeared to understand it. 
 
 
Representative signature 
Date 
 
Relationship to Subject:                                                                                                                                               
 


 
 
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For Site Use only: 
● I have carefully explained to the subject the nature and purpose of this study. 
● The subject has been given enough time and an adequate place to read and review this form. 
● The subject has had a chance to ask questions and receive answers about this study. 
● I have explained and discussed the nature of the research 
● I have explained and discussed potential risks and benefits 
● The alternate treatments available to the subject and the benefits and risks of each 
 
 
 
Name of person obtaining informed consent (print) 
Title 
Phone number 
 
 
Signature of person obtaining informed consent 
Date