Clinical trial NCT03338569
Conditions: Septic Shock Sepsis
Sponsor: University of Minnesota
Start date: 2017-12-20; Completion date: 2020-08-10
Enrollment: 125 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, placebo-controlled clinical trial to compare Vitamin C versus placebo for patients presenting to the ICU with a diagnosis of septic shock.

Detailed description:
This is a multi-site, randomized, double-blind, placebo-controlled trial comparing a regimen of moderate-dose (6000 mg per day) Vitamin C supplementation versus placebo for the treatment of patients presenting to the ICU with septic shock. Both groups will continue to receive all other standard of care measures for septic shock as clinically indicated. Groups will be enrolled and receive study drug/placebo for 4 days (96 hours) or until 24 hours post-last pressor dose, whichever is sooner.

Arms: arm 1: Placebo designed to mimic intervention arm 2: 6000 mg per day Vitamin C supplement
Interventions: intervention 1: Vitamin C intervention 2: Placebo
Intervention descriptions: intervention 1: Continuous infusion of vitamin C intervention 2: Placebo designed to mimic intervention

Protocol documents:
Prot_SAP_001.pdf: 
PROTOCOL TITLE:  Evaluating Vitamin C in Septic Shock: A Randomized Double Blind Control 
Trial 
VERSION DATE: March 17, 2020 
STUDY00000625 
Page 1 of 25 
PROTOCOL TITLE: 
Evaluating Vitamin C in Septic Shock: A Randomized Double Blind Control Trial 
PRINCIPAL INVESTIGATOR: 
Ronald Reilkoff, MD 
Division of Pulmonary, Allergy, Critical Care and Sleep Medicine 
Department of Medicine 
University of Minnesota 
612 624-0999 
rreilkof@umn.edu 
VERSION NUMBER/DATE: 
Version 9 – March 17, 2020 
NCT03338569 


PROTOCOL TITLE:  Evaluating Vitamin C in Septic Shock: A Randomized Double Blind Control 
Trial 
VERSION DATE: March 17, 2020 
STUDY00000625 
Page 2 of 25 
VERSION HISTORY 
 
Version # 
Version Date 
Summary of Changes 
Consent Change? 
1 
11/08/2017 
Initial Protocol 
N/A 
2 
11/21/2017 
Biobanking is convenience sample only. 
Yes 
3 
02/16/2018 
Add fluid collection during standard of care 
BAL or Tracheal Aspirate for assay. Add 
additional references to risk section. 
No 
4 
03/20/2018 
Update names for DSMB, infection disease 
testing 
No 
5 
07/24/2018 
Update UMMC MICU to UMMC ICU 
No 
6 
05/30/2019 
Update withdrawal conditions 
No 
7 
07/18/2019 
Clarification to inclusion criteria; add Essentia 
Health as external site location 
Yes 
8 
08/06/2019 
Clarification to inclusion criteria (units of 
procalcitonin) 
No 
9  
3/17/2020 
Add option of eConsenting 
No 
 
 
 
 


PROTOCOL TITLE:  Evaluating Vitamin C in Septic Shock: A Randomized Double Blind Control 
Trial 
VERSION DATE: March 17, 2020 
STUDY00000625 
Page 3 of 25 
TABLE OF CONTENTS 
 
1.0 
Objectives 
6 
2.0 
Background 
6 
3.0 
Study Endpoints/Events/Outcomes 
8 
4.0 
Study Intervention(s)/Investigational Agent(s) 
9 
5.0 
Procedures Involved 
10 
6.0 
Data and Specimen Banking 
13 
7.0 
Sharing of Results with Participants 
13 
8.0 
Study Duration 
13 
9.0 
Study Population 
13 
10.0 Vulnerable Populations 
14 
11.0 Local Number of Participants 
15 
12.0 Local Recruitment Methods 
15 
13.0 Withdrawal of Participants 
16 
14.0 Risks to Participants 
16 
15.0 Potential Benefits to Participants 
17 
16.0 Data Management 
17 
17.0 Confidentiality 
18 
18.0 Provisions to Monitor the Data to Ensure the Safety of Participants 
19 
19.0 Provisions to Protect the Privacy Interests of Participants 
21 
20.0 Compensation for Research-Related Injury 
21 
21.0 Consent Process 
21 
22.0 Setting 
22 
23.0 Multi-Site Research 
22 
24.0 Resources Available 
23 
25.0 References 
24 
 
 


PROTOCOL TITLE:  Evaluating Vitamin C in Septic Shock: A Randomized Double Blind Control 
Trial 
VERSION DATE: March 17, 2020 
STUDY00000625 
Page 4 of 25 
ABBREVIATIONS/DEFINITIONS 
 
BAL: Bronchoalveolar lavage 
 
BDAC: Biostatical Design and Analysis Center 
 
DSMB: Data and Safety Monitoring Board 
 
ICU: intensive care unit 
 
LAR: legally authorized representative 
 
TA: Tracheal aspirate 
 
Vitamin C: also known as ascorbic acid 
 
 


PROTOCOL TITLE:  Evaluating Vitamin C in Septic Shock: A Randomized Double Blind Control 
Trial 
VERSION DATE: March 17, 2020 
STUDY00000625 
Page 5 of 25 
STUDY SUMMARY 
 
Study Title 
Evaluating Vitamin C in Septic Shock: A Randomized 
Double Blind Control Trial 
Study Design 
Phase 3, randomized double-blind 
Primary Objective 
Evaluate effect of  Vitamin C supplementation on survival in 
patients presenting with septic shock 
Secondary Objective(s) 
Evaluate effect of Vitamin C supplementation on resolution 
of shock 
Research Intervention(s)/ 
Investigational Agents 
Vitamin C (ascorbic acid)  
IND/IDE # (if applicable) 
N/A: Exempt 
Study Population 
Patients admitted to ICU with septic shock 
Sample Size (number of 
participants) 
Approximately 140 
Approximately 70 per group (study drug or placebo) 
Study Duration for Individual 
Participants 
Up to 4 days, plus a Day 28 chart review with no participant 
interaction 
 
 
 


PROTOCOL TITLE:  Evaluating Vitamin C in Septic Shock: A Randomized Double Blind Control 
Trial 
VERSION DATE: March 17, 2020 
STUDY00000625 
Page 6 of 25 
1.0 
Objectives 
1.1 Purpose:  
This is a randomized, double-blind, placebo-controlled clinical trial to compare Vitamin C versus 
placebo for patients presenting to the ICU with a diagnosis of septic shock.  
Specific Aim 1: Determine if patient survival is improved with the use of Vitamin C.  
Hypothesis Aim 1: Compared to placebo, moderate-dose Vitamin C will improve survival.  
Specific Aim 2: Determine whether Vitamin C improves secondary clinical outcomes including 
but not limited to: duration of vasopressor therapy, duration of ICU stay, lactate clearance, and 
organ failure.  
Hypothesis Aim 2: Compared to placebo, moderate-dose Vitamin C will improve clinical 
outcomes.  
Specific Aim 3: Identify individual and clinical characteristics associated with responses to 
Vitamin C.  
Hypothesis Aim 3: Specific characteristics exist that can identify those with a greater chance for 
a therapeutic response.  
2.0 
Background 
2.1 Significance of Research Question/Purpose:  
Sepsis is defined as life threatening organ dysfunction caused by a dysregulated response to 
infection. Sepsis and septic shock, the latter defined as persistent hypotension refractory to 
volume resuscitation and requiring vasopressor therapy to maintain adequate blood pressure, are 
common reasons for admission to the intensive care unit1. It is estimated that approximately 1 
million Americans are diagnosed every year2. Despite concerted efforts focused on early 
recognition and stabilization of septic patients, mortality rates of patients admitted with septic 
shock remain high at 25%-50%1 and survival is still associated with significant comorbidity3. 
This is of particular importance when sepsis-associated organ failure is prolonged, as the 
extended recovery period keeps patients vulnerable to adverse effects associated with prolonged 
ICU stays (e.g., myopathy, delirium). All of this highlights the need for novel effective therapies. 
The main tenets of therapy in sepsis have been focused on early recognition, hemodynamic 
stabilization (correction of low blood pressure) and antimicrobial therapies. This involves early 
aggressive fluid resuscitation and vasopressor therapy (medications such as epinephrine which 
increase blood pressure), as well as early empiric antibiotic therapy and effective source control, 
the latter of which consistently correlates with survival1,3,4.  Over the last two decades, most 
efforts to improve outcomes in sepsis have focused on resuscitation at the systemic level (e.g. 
blood pressure and cardiac output goals). Unfortunately, although several ‘targeted’ systemic 
resuscitation studies have shown promise during early studies (e.g. early goal directed therapy 
protocol5, large-scale confirmatory studies of these treatments have been disappointing6-10).  As 
a result, renewed attention has shifted towards identification of sepsis-induced abnormalities at 
the cellular and microcirculation level, such as dysfunction of mitochondria (the parts of cells 
which generate energy), endothelium (the lining of blood vessels which plays a role in controlling 
blood supply to tissues) and cellular oxygen metabolism despite adequate tissue blood supply11.  


PROTOCOL TITLE:  Evaluating Vitamin C in Septic Shock: A Randomized Double Blind Control 
Trial 
VERSION DATE: March 17, 2020 
STUDY00000625 
Page 7 of 25 
Therapies aiming to correct oxygen metabolism, mitochondrial, and endothelial dysfunction have 
been dubbed “metabolic resuscitation”12,13. 
2.2 Preliminary Data:  
Clinical studies of Vitamin C in critical illness date back 40 years13. More recent work in burn 
victims had demonstrated that Vitamin C supplementation was able to reduce fluid volume 
resuscitation to achieve hemodynamic (blood pressure) resuscitative goals14. Subsequent studies 
have demonstrated trends in decreased multiorgan failure support with broad antioxidant 
supplementation15. 
Further studies expand on the positive therapeutic potential of Vitamin C supplementation for 
sepsis.  Fowler et al performed a Phase 1 randomized controlled trial of 24 patients admitted to 
the Intensive care unit with sepsis. Subjects received either low dose or high dose Vitamin C 
supplementation or placebo. Whilst the primary endpoint of safety and tolerability was met, most 
intriguing was the finding of a dose dependent improvement in SOFA score (surrogate for organ 
failure) as well improvement in inflammatory markers16. These findings were expanded upon by 
Zabet et al in 2016, who tested the effect of Vitamin C supplementation had upon vasopressor 
dose and duration of therapy. Twenty four patients admitted to a surgical ICU were randomized 
to receive placebo or Vitamin C supplementation. Not only did the cohort receiving Vitamin C 
experience significant reduction in dosing requirement and duration of therapy there was a 
significant reduction in mortality17. Most recently a before-and-after retrospective study of a 
combination of Vitamin C, thiamine and hydrocortisone supplementation in severe sepsis and 
septic shock patient also demonstrated a remarkable survival benefit in the supplemented patients 
compared to usual care18.  
Together, these preliminary results suggest that supplementation of Vitamin C may play an 
important role in the metabolic resuscitation of patients with septic shock.  While intriguing, the 
limitations of the non-blinded before-and-after study combined with a history of false-positive 
results in adjuvant therapy trials in sepsis (e.g. activated protein C administration19,20, atorvastatin 
administration21) temper these dramatic results, and further validation via prospective analysis is 
justified and necessary to clarify a possible novel therapeutic approach. 
2.3 Existing Literature:  
The pathophysiological abnormalities in sepsis and septic shock which are the targets of 
metabolic resuscitation include diminished vascular tone (improper relaxation of the muscles 
controlling blood vessel diameter), porous microvascular junctions caused by barrier dysfunction 
(leakiness of the cell layer surrounding blood vessels), and inappropriate leukocyte adhesion with 
activation of inflammation microvascular coagulation cascades (dysregulated immune system 
activation)22.  While the pathophysiology of sepsis is multifaceted, metabolic derangements are 
common, including several antioxidant vitamin levels which invariably fall during sepsis23. 
These deficiencies include Vitamin C (Vitamin C), and thiamine with low levels of each 
correlating with progressive multiorgan failure and death24-27. Emerging clinical data (as outlined 
in section 2.2) as well as laboratory findings suggest that supplementation of Vitamin C during 
septic shock may play a key role in metabolic resuscitation by resolving microvascular 
dysfunction28,29, augmenting vascular tone, and providing a cofactor for catecholamine (steroids 
such as adrenaline) synthesis30.  


PROTOCOL TITLE:  Evaluating Vitamin C in Septic Shock: A Randomized Double Blind Control 
Trial 
VERSION DATE: March 17, 2020 
STUDY00000625 
Page 8 of 25 
3.0 
Study Endpoints/Events/Outcomes 
3.1 Primary Endpoint/Event/Outcome:  
First outcome endpoint for Specific Aim 1: all-cause mortality measured at ICU discharge.  
Second outcome endpoint for Specific Aim 1: all-cause mortality measured at 28 days post Day 
0.  
3.2 Secondary Endpoint(s)/Event(s)/Outcome(s):  
Outcome endpoint for Specific Aim 2: Difference in clinical outcomes between both groups at 
ICU discharge. Specific secondary endpoints may include, depending on power and final 
enrollment: 
a. Duration of vasopressor therapy post administration of Vitamin C (or placebo).  Conclusion 
of vasopressor therapy will be defined as the time point when pressors are stopped, following 
which they are not restarted for 24 hours. 
b. Duration of ICU stay post administration of Vitamin C (or placebo). 
c. Time to lactate clearance post administration of Vitamin C (or placebo).  Time of lactate 
clearance will be defined as the first time point at which measured lactate level drops below 
the normal level as defined by the measuring laboratory. 
d. Rate of lactate and procalcitonin clearance over 24, 48 and 96 hours following Vitamin C (or 
placebo) administration (in patients for whom values are available).  Defined as the change 
in lactate and procalcitonin level from the initial measurement to the measurement at the 
designated time point if available, or closest measurement within 4 hours of the designated 
time point. 
e. Duration of mechanical ventilation post administration of Vitamin C (or placebo).  Cessation 
of mechanical ventilation will be defined as the time of extubation following which re-
intubation is not required for a full 24 hours. 
f. Incidence of need for renal replacement therapy during the 96 hour drug administration 
period 
g. Change in serum creatinine at 24, 48, 72, and 96 hours after Vitamin C (or placebo) 
administration compared to level at enrollment (in patients for whom values are available).  
The measurement closest in time to the designated time-point (within 12 hours) will be used.  
Patients who are dialysis-dependent at baseline or are currently receiving renal replacement 
therapy will be excluded from this endpoint. 
h. Change to SOFA and/or APACHE scores from initiation of Vitamin C (or placebo) as 
measured at 24, 48, 72, and 96 hours. 
i. Total intravenous fluid administered from presentation until various intervals (3 hours, 6 
hours, and 24hours), until resolution of shock, and from Vitamin C (or placebo) 
administration until resolution of shock. 
j. Effect of standard of care medications including corticosteroids as an sub-group analysis.  
 
Outcome endpoint for Specific Aim 3: In general, clinical and biochemical characteristics 
associated with Vitamin C responsiveness will be examined. Specifics include:  
a. Assessment of whether time from onset of septic shock to receipt of Vitamin C (or placebo) 
influences effectiveness of Vitamin C therapy. 
b. Treatment effects as associated with or without initial presentation of inflammatory response 


PROTOCOL TITLE:  Evaluating Vitamin C in Septic Shock: A Randomized Double Blind Control 
Trial 
VERSION DATE: March 17, 2020 
STUDY00000625 
Page 9 of 25 
● Fever versus hypothermia 
● Leukocytosis versus leukopenia 
● Surgical versus medical source control 
c. Biobanking of blood specimens for future assessment of: 
● Vitamin C levels  
● Cytokine and chemokine levels 
● Danger associated molecular patterns (DAMPS) 
● Markers of necroptosis (RIP1 and RIP3) 
● Mitochondrial DNA and RNA for gene expressions 
● Genetic features favorable to Vitamin C therapy 
 
4.0 
Study Intervention(s)/Investigational Agent(s) 
4.1 Description: 
This is a multi-center, randomized, double-blind, placebo-controlled clinical trial to compare 
Vitamin C versus placebo for patients presenting to the ICU with a diagnosis of septic shock. 
The investigational product is parenteral Vitamin C (also known as ascorbic acid); 1000 mg bolus 
IV followed by a continuous infusion at 250 mg/hr or matched placebo.  
4.2 Drug/Device Handling:  
Investigational Drug Services and the research pharmacist will handle all drug requirements 
including randomization, blinding, and dispensing. Study clinicians as listed on the Delegation 
of Authority Log will manage ordering and prescribing. Clinical care staff will administer study 
drug/placebo infusions to the participant.   
Vitamin C is available parenterally in a single dose 50 mL vial (500mg/mL).   One 50 mL vial 
will be drawn up into five x 10 mL syringes containing 5000 mg of Vitamin C.  These syringes 
will be refrigerated, protected from light, and given 9 day beyond use dating per USP 797 as a 
low-risk compounding product.  The 5000mg/10mL pre-drawn syringes will be utilized in the 
preparation of the continuous infusion. 
Total, Approximate Infusion Amounts 
  6875mg in first 24 hours, including initial bolus 
 6000mg per day for all following 24 hour periods 
o 7000mg maximum allowable per 24 hour period 
 25 grams per study period 
Total infusion daily amount would be approximately 6000mg. More or less than 6000mg is 
acceptable given prioritization for septic shock treatment, body habitus concerns, or other 
clinically relevant decision made by the study clinician with the treating clinician. No more than 
7000mg daily would be allowed, as a maximum amount of infusion. There will be no minimum 
amount provided as the infusion could be stopped early. 


PROTOCOL TITLE:  Evaluating Vitamin C in Septic Shock: A Randomized Double Blind Control 
Trial 
VERSION DATE: March 17, 2020 
STUDY00000625 
Page 10 of 25 
1. Preparation of Active Drug 
a. The Vitamin C infusion will be prepared as a 10mg/mL continuous infusion by adding 
the 5000mg (10 mL) syringe of Vitamin C to a 500 ml Normal Saline infusion bag.   
b. The Vitamin C 5000mg/500mL infusion bag will last 20 hours when running at the 
study rate of 250 mg/hour (25 ml/hour).  The 1st infusion bag will last less than 20 
hours since the initial bolus is administered from the infusion bag. 
c. The infusion bag will be given a 24 hour expiration date.  At room temperature and 
protected from light, Vitamin C is compatible in Normal Saline for 24 hours.   
d. The infusion will be protected from light with an amber bag.  IV tubing will not be 
protected from light. 
2. Preparation of Placebo 
a. The placebo infusion bag will be a 500 mL Normal Saline Infusion bag.   
b. The placebo infusion will be protected from light with a brown bag in the same 
manner as the active drug. IV tubing will not be protected from light. 
3. Drug Administration 
a. The 1000mg bolus (100 ml) of active drug or placebo will be administered over 30 
minutes from the active drug or placebo continuous infusion bag, respectively. 
b. After the initial bolus is complete, the continuous infusion will run at a rate of 
250mg/hr (25 mL/hour). 
c. A dedicated line for the Ascorbic Acid or placebo infusions is not required.  IV 
compatibility with other IV solutions should be checked per standard of practice. 
d. Infusion can be administered peripherally. 
e. Infusion will be stopped if the participant transitions to comfort care measures only 
4.3 IND/IDE:  
Not applicable, exempt. There is no intent to report to the FDA for a new indication, nor intent 
of this study is to support a significant change in the advertisement of Vitamin C. The 
administration of Vitamin C or placebo in septic shock population does not significantly increase 
risk or decrease acceptability of risk with its proposed route of administration and dosing. 
5.0 
Procedures Involved 
5.1 Study Design:  
This is a multi-site, randomized, double-blind, placebo-controlled trial comparing a regimen of 
moderate-dose (6000 mg per day) Vitamin C supplementation versus placebo for the treatment 
of patients presenting to the ICU with septic shock. Both groups will continue to receive all other 
standard of care measures for septic shock as clinically indicated. Groups will be enrolled and 
receive study drug/placebo for 4 days (96 hours) or until 24 hours post-last pressor dose, 
whichever is sooner.  
5.2 Study Procedures:  
When a potentially eligible participant is identified, the PI or other clinical research team member 
will approach the individual with floor staff permission and coordination to explain the research. 


PROTOCOL TITLE:  Evaluating Vitamin C in Septic Shock: A Randomized Double Blind Control 
Trial 
VERSION DATE: March 17, 2020 
STUDY00000625 
Page 11 of 25 
After signing the consent and completing eligibility procedures, IDS will be notified. IDS will 
perform randomization and dispense appropriate study drug/placebo infusion materials.  
Infusions must be started within 24 hours post-presentation of septic shock. Those participants 
who consent but cannot start an infusion within 24 hours will still follow all research procedures 
related to data collection except for banking of biospecimens.  
Participants randomized to Vitamin C will receive IV parenteral Vitamin C; with a 1000 mg 
bolus to start and followed by a continuous infusion at 250 mg/hr for four days or off pressors 
for 24 hours, whichever is sooner. Placebo will be given as a matched infusion on the same 
schedule.  
Chart review will take place at 24 hour time periods (Day 0, 1, 2, 3, and 4).  
 
Blood draws for biobanking will occur at Day 0, 1, and 3 (0, 24 and 72 hours), 25 mL on day 0, 
and then 20 mL on days 1 and 3.  Patients discharged from the hospital will not undergo blood 
draws following discharge. Those still in the hospital, any floor or unit, will have blood drawn if 
clinically possible. Blood draw will be based on a convenience sample only. Blood draw will 
only be done when study clinician is available and when time is available for processing and 
transporting. Not all participants will have all, or any, blood draw done for biobanking.  
 
Excessive biospecimens will be collected during routine, standard of care procedures for use in 
refinement of an infectious disease laboratory analysis.  Remaining sputum, tracheal aspirate, 
bronchoalveolar lavage specimens, blood, serum, urine or other bodily fluid will be obtained 
from standard of care procedures and shipped to an outside laboratory for assay refinement.  
 
The biospecimens will be used to compare concurrently collected specimen culture growth with 
those findings from this specific assay. This assay is FDA-approved, and will only be used to 
refine the algorithm that defines something as pathological. It is not meant to diagnose or aid in 
any way treatment procedures. Results from this assay refinement test will not be shared with the 
patient, their provider, or placed in their medical record.  Specimens will be collected on a 
convenience sample only.  
 
5.3 Follow-Up:  
28 days following Day 0 (time of first infusion), a chart review for final outcomes will be 
performed. Chart review will include both medical record data as well as CTSI’s Clinical Data 
Repository to collect non-hospital mortality information and other clinical information that might 
not be available in the medical record.   


PROTOCOL TITLE:  Evaluating Vitamin C in Septic Shock: A Randomized Double Blind Control Trial 
VERSION DATE: March 17, 2020 
STUDY00000625 
Page 12 of 25 
 
 
Screening2 
(-24 hours to +0 hours) 
Day 03 
 (+0 hours) 
Day 1 
(+24 hours) 
Day 2 
(+48 
hours) 
Day 3 
(+72 
hours) 
Day 4 
(+96 hours) Day 28 
Septic Shock 
Identification1 
X 
 
 
 
 
 
 
Consent 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
Eligibility Review 
X 
 
 
 
 
 
 
Study Drug or 
Placebo 
 
X 
X 
X 
X 
X4 
 
Blood Banking 
Specimen5  
 
X 
(25ml) 
X 
(20ml) 
 
X 
(20ml) 
 
 
Baseline Chart 
Review 
 
X 
 
 
 
 
 
Daily Chart Review 
 
 
X 
X 
X 
X 
 
Follow-Up Chart 
Review 
 
 
 
 
 
 
X 
1: Identification is defined as: onset of shock if already in hospital OR presentation to hospital/emergency department 
2: All screening procedures must be completed in 24 hour window between identification and infusion start 
3: Infusion of study drug/placebo must happen within 24 hours of septic shock identification 
4: Day 4 or 24 hours post last pressor dose, whichever comes first 
5: Will occur at alltime points stated even if participant is off infusion but still in hospital. Only done when possible given clinician and time 
constraints. 


PROTOCOL TITLE:  Evaluating Vitamin C in Septic Shock: A Randomized Double Blind Control 
Trial 
VERSION DATE: March 17, 2020 
STUDY00000625 
Page 13 of 25 
6.0 
Data and Specimen Banking 
6.1 Storage and Access:  
Blood will be obtained at three different time points (0, 24 hours, and 72 hours) and will be 
coupled with clinical care blood draws when possible. These samples will be stored in a -80◦C 
freezer in lab space utilized by the PACCS division at the University of Minnesota for future 
analysis. Serum, RNA, and cell lysates will be separated and stored with study code only.  
6.2 Data: 
Specimens will be stored by study code. All study data will be associated with the specimen 
through the study code link. 
6.3 Release/Sharing:  
Data will be shared with other researchers who request it, under the following conditions:  
● Requester provides protocol and IRB approval or Determination of Non-Human Subjects 
Research.  
● Requester completes Data Use Agreement form as developed by the Health Information 
Privacy and Compliance Office at the University of Minnesota.  
● Any data or specimen can be shared but all identifiers will be stripped. Requester will not be 
provided with link between identity and study code.  
7.0 
Sharing of Results with Participants 
Not applicable. No results will be shared with participants.  
8.0 
Study Duration 
Each participant will be on the study drug for up to four days. There is a final data collection time 
point at 28 days but no participant interaction is needed for this; it will be chart review only.  
It is expected that it will take up to 1.5 years to enroll all study participants. It is expected that it 
will take up to 2 years to complete all study procedures and data analysis. 
9.0 
Study Population 
9.1 Inclusion Criteria:  
 Capability to provide written consent from participant or legally authorized representative 
(LAR) if the participant is unable or incapacitated due to severity of illness.  
 Age ≥ 18 years  
 Septic shock as pragmatically defined as:  
o Order for intravenous antimicrobials with either procalcitonin > 2 ng/mL within 24 
hours of enrollment OR other clinical suspicion of infection or confirmed infection  
AND 
 Hypotension requiring vasopressor therapy, despite fluid resuscitation of at least 
30 mL/kg ideal body weight AND  
 Lactate > 2 mmol/L 24 hr prior to enrollment AND 


PROTOCOL TITLE:  Evaluating Vitamin C in Septic Shock: A Randomized Double Blind Control 
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 Presence of sepsis defined as equal to or greater than 2 SIRS criteria and/or acute 
increase in qSOFA score of 2 points or more. 
o 
SIRS criteria:  1) Temperature greater than 38° or less than 36° 
Celsius.  2) Heart rate greater than 90 beats per minute.  3) 
Respiratory rate greater than 20 breaths per minute OR arterial 
carbon dioxide tension less than 32 mmHg.  4) White blood cell 
count greater than 12,000 cell/µL, less than 4,000 cells/µL, OR 
band cells greater than 10% of the total white blood cell 
population. 
o 
qSOFA:  1 point each is assigned for: 1) systolic blood pressure 
below 100, 2) respiratory rate greater than 22, and 3) mental 
status not at baseline. 
9.2 Exclusion Criteria:  
 Unable to start infusion within 24 hours of septic shock identification 
 Currently pregnant or breastfeeding  
 Patient to receive comfort measures only 
 Cardiac Arrest 
 Cardiovascular Surgery patients receiving prophylactic peri-operative antibiotics < 48 hours 
post-operation 
 Participation in another study involving an investigational product within 30 days of the 
baseline visit 
 Allergy to Vitamin C 
 History of nephrolithiasis 
 History of G6PD deficiency 
 ESRD patients, transplant eligible on dialysis currently taking vitamin C supplementation 
 Clinical course that treating clinician decides would preclude safe participation 
 
9.3 Screening:  
Potential participants will be identified by clinic staff at sites identified in Section 23.0. Once 
identified, the study team will review the medical record for basic eligibility and research opt-
out status. Once the medical record has been reviewed, the investigator or coordinator and floor 
staff will approach the potential participant to explain the study. 
10.0 Vulnerable Populations 
10.1 Vulnerable Populations:  
☐ Children 
☐ Pregnant women/Fetuses/Neonates 
☐ Prisoners 
☒ Adults lacking capacity to consent and/or adults with diminished capacity to consent, 
including, but not limited to, those with acute medical conditions, psychiatric disorders, 
neurologic disorders, developmental disorders, and behavioral disorders 
☒ Approached for participation in research during a stressful situation such as emergency 
room setting, childbirth (labor), etc. 


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☐ Disadvantaged in the distribution of social goods and services such as income, housing, or 
healthcare 
☐ Serious health condition for which there are no satisfactory standard treatments 
☐ Fear of negative consequences for not participating in the research (e.g. institutionalization, 
deportation, disclosure of stigmatizing behavior) 
☐ Any other circumstance/dynamic that could increase vulnerability to coercion or exploitation 
that might influence consent to research or decision to continue in research 
☐ Undervalued or disenfranchised social group 
☐ Members of the military 
☐ Non-English speakers 
☐ Those unable to read (illiterate) 
☐ Employees of the researcher 
☐ Students of the researcher 
☐ None of the above 
10.2 Adults lacking capacity to consent and/or adults with diminished capacity to consent: 
Patients who are in septic shock often have brain dysfunction or encephalopathy. This 
dysfunction is part of the sepsis syndrome and medical care often involves the use of surrogates 
to make urgent medical decisions for them. The same surrogates will act as an LAR for this study 
so they will be well versed in what this means, consenting to something for the participant. Those 
experiencing brain dysfunction are often those who are experiencing more severe symptoms of 
septic shock and thus, are those who would be most benefited by the use of this treatment. There 
are no additional risks for enrolling participants who cannot consent for themselves. 
10.3 Additional Safeguards: Not applicable.  
No individuals (pregnant women, neonates, nor prisoners) required additional safeguards will be 
enrolled.  
11.0 Local Number of Participants 
11.1 Local Number of Participants to be Consented:  
Approximately 140 (70 per group) will be enrolled for an expected 124 (62 per group) for the 
final analysis. As there is a rolling startup for the sites, it is expected that the largest number of 
participants will be from Fairview Southdale.  
12.0 Local Recruitment Methods 
12.1 Recruitment Process:  
Potential participants will be recruited from the ICU by study investigator after identified by 
intensivist physician on the floor or made aware of septic patient elsewhere in the hospital. 
Recruitment will take place at any time when a study investigator or trained coordinator is 
available for a consenting discussion and eligibility review. The investigator or other study team 
member will review opt-out status and medical records for basic eligibility before approaching 
the candidate. Once basic eligibility has been established, the investigator or coordinator and 
floor staff as necessary will approach the candidate. 
12.2 Source of Participants:  


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Potential participants will be sourced from all patients admitted to the adult ICU with diagnostic 
criteria for septic shock who have not opted out of research. It is expected that participants could 
present to the ICU from either the emergency department or another floor or unit in the hospital. 
Please see Section 23.0 for list of sites.  
12.3 Identification of Potential Participants:  
Potential participants will be identified by the intensivist physician and study clinicians as those 
already admitted to the hospital for septic shock or suspicion of septic shock. Medical records 
will be reviewed for research opt-out status.  
12.4 Recruitment Materials:  
Not applicable. No recruitment materials to be used.  
12.5 Payment:  
No compensation or other payment will be provided to participants.  
13.0 Withdrawal of Participants 
13.1 Withdrawal Circumstances:  
Participants can be withdrawn from the infusion or the study completely at any time by the study 
clinician or their personal clinician for:  
1. A serious adverse event suspected to be related to the study drug.  
2. Any suspicion that further involvement would jeopardize medical care.  
3. Transitioning to comfort care measures only  
Unblinding of treatment allocation will occur when such information would be critical to the 
ongoing care of the participant. Researchers will work with IDS and the research pharmacist on 
the unblinding procedures.  
13.2 Withdrawal Procedures:  
At the point of a participant-requested withdrawal, the infusion will be halted and no further 
direct interaction will occur. Data collection including Day 28 medical record review will still be 
conducted.  
13.3 Termination Procedures:  
Data will continue to be used and analyzed after withdrawal or termination.  
14.0 Risks to Participants 
14.1 Foreseeable Risks: 
Vitamin C risks: Vitamin C has a good safety profile as evidenced in the background section of 
this proposal. Participants will be educated about potential adverse effects as part of the consent 
process, including inquiries about daily use of multi-vitamins, nutritional supplements or 
powders, or anything else that might contain vitamin C. Investigators will include known 
comorbidities that could affect vitamin C risk including kidney stones, diabetes, and cancer in 
their review of general eligibility. These would not make somebody automatically ineligible but 
would factor into a general clinical decision on whether or not it would be safe to enroll them.   
 


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There are no known major risks at the dose used in this study, approximately 6,000 milligrams 
per day to a total culminated dose of 25 grams. A tolerable upper limit of 2,000 milligrams per 
day oral administration was published in 200031.  At ingestions higher than 3,000 milligrams per 
day the most common adverse effect is diarrhea, but can include nausea, vomiting, heartburn, 
stomach cramps, and headaches. Clinical studies  using dosing greater than 100,000 milligrams 
per day intravenously14, administered as quickly as 1g/min32 have been well tolerated, with no 
indication of harm following administration14. Hyperoxaluria and oxalate nephropathy have been 
reported in an individual status post renal transplant who previously had taken daily vitamin c 
supplementation whilst on dialysis33., though additional studies suggest that ascorbic acid does 
not contribute to renal oxalate stone formation34,35.  
 
Blood draw risks and IV: The risks associated with the blood draw include minimal discomfort, 
and/or bruising.  In very rare cases, a small blood clot can form at the site of the needle insertion. 
The risks of the intravenous line are similar to a blood draw but because it is kept in the vein for 
a longer period of time, the risk of bruising and discomfort are slightly higher. All participants 
will have an peripheral or central intravenous line catheter placed for standard of care 
medications and will have clinical blood drawn on at least a daily basis. Any research blood draw 
or IV placed for the infusion will be coupled with clinical care when possible.  
 
General participation risks: There is always the risk for a breach of confidentiality during the 
course of any research study. 
14.2 Reproduction Risks:  
Not applicable. Because Vitamin C in doses exceeding RDA recommendations is classified as 
category C in pregnancy (insufficient evidence to determine safety), pregnant and breast-feeding 
women will be excluded. 
14.3 Risks to Others:  
Not applicable. No risk to others.  
15.0 Potential Benefits to Participants 
15.1 Potential Benefits:  
No direct guaranteed benefit to individual participants.  
16.0 Data Management 
16.1 Data Analysis Plan:  
Patient baseline characteristics will be summarized and presented using means and standard 
deviations for continuous variables and frequencies and percentages for categorical variables. 
Treatment groups will be compared using two-sample t test for continuous variables and Chi-
square test for categorical variables. 
Analysis plan for Aim 1: Mortality rates between treatment groups will be compared using Chi-
square test. Logistic regression model will be used to model the probability of death. Model will 
include treatment group and covariates determined by the investigators to impact mortality 
and/or those that are significantly different between groups at baseline. 


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Analysis plan for Aim 2: Clinical outcomes at ICU discharge will be compared between groups 
using two-sample t test for continuous variables and Chi-square test for categorical variables. 
Multivariate linear and logistic regression analysis will be performed for continuous outcomes 
and dichotomous outcomes respectively to adjust for covariates. 
Analysis plan for Aim 3: Correlation analysis will be conducted to examine the association 
between clinical characteristics and Vitamin C responsiveness. 
Intention-to-treat analysis will be used. Analysis will be performed using Statistical Analysis 
Software (version 9.3, SAS Institute Inc., Cary, NC).   
16.2 Power Analysis:  
The trial will enroll enough participants to demonstrate a 20% mortality difference in between 
treatment groups. Based on this information, 124 patients, 62 patients in each arm, would be 
needed to have an 80% power to detect a 20 % decrease in hospital mortality between the two 
groups with a two-tailed alpha error of 0.05.  To account for potential dropout of participants, 
planned enrollment will be 70 per arm, 140 total.    
16.3 Data Integrity: 
REDCap™ data will be periodically reviewed by the regulatory specialist and project manager 
or coordinator; to occur at the request of the PI and before final analysis occurs. Standard data 
quality checks will be run using REDCap™’s integrated programs.  
17.0 Confidentiality 
17.1 Data Security:  
All standard confidentiality procedures will be observed for this study and all research staff will 
be trained on protocol and GCP standards before they will be allowed contact with participants 
or data. Any paper data, source or CRF or logs, will be kept in locked research offices. All 
University of Minnesota data protection policies will be reviewed and followed.  
Electronic data will be entered into a REDCap™ database, which uses a MySQL database via 
secure web interface with data checks used during data entry to ensure data quality. REDCap™ 
includes a complete suite of features to support HIPAA compliance, including a full audit trail, 
user-based privileges, and integration with the institutional LDAP server. The MySQL database 
and the web server will both be hosted on the secure servers operated by the University of 
Minnesota Academic Health Center’s Information Systems group (AHC-IS). The servers are in 
a physically secure location on campus and are backed up nightly, with the backups stored in 
accordance with the AHC-IS retention schedule of daily, weekly, and monthly tapes retained for 
1 month, 3 months, and 6 months, respectively. Weekly backup tapes are stored offsite. The 
AHC-IS servers provide a stable, secure, well-maintained, and high-capacity data storage 
environment, and both REDCap™  and MySQL are widely-used, powerful, reliable, well-
supported systems. Access to the study’s data in REDCap™ will be restricted to the members of 
the study team by username and password.  
Access to data exports will be limited with no member of staff given the ability to download full 
data sets; all exports will be limited to the “remove all tagged identifier fields” option when 
setting user rights. Additionally, all dates will be marked for date-shifting during the export 
process.  


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REDCap™ data files will be exported to shared drives housed under HIPAA-compliant AHC-IS 
servers on the MedDerm (\\med.ahc.umn.edu\med)(N:) shared drive.  
Any other identifiable electronic data, including logs, will be stored on Box. Access to the study 
files on Box will be limited to those members of the study team.  
Spreadsheets of data in aggregate form (summary statistics only, no individual data) will be 
electronically kept and may be electronically transmitted between study investigators only.  
Documentation of research involvement will be recorded in the participant’s medical record. 
Consents will not be placed in medical record.  
18.0 Provisions to Monitor the Data to Ensure the Safety of Participants 
18.1 Data Integrity Monitoring.  
While there will be no planned full, interim data analysis, the PI will periodically review data for 
completeness and to ensure that all procedures are being followed as detailed in the protocol. The 
assigned Regulatory Specialist or CTSI monitor will also perform periodic quality assurance 
monitoring at any point requested by the PI or otherwise mandated by local policy. 
18.2 Data Safety Monitoring.  
Participants enrolled in this study will be monitored for adverse outcomes including adverse drug 
reactions, hospitalizations, and death. In addition, participants will be given contact information 
for the study team and will be counseled to report any adverse effects for duration of therapy.  
The Principal Investigator will oversee the safety of the study, including careful assessment and 
appropriate reporting of adverse events. All adverse and serious adverse events will be discussed 
with the PI within 48 hours for standard assessments (causality, expectedness, severity, and 
seriousness). IRB and other regulatory reporting requirements will be reviewed by study staff 
and followed with assistance of the Regulatory Specialist assigned to the study. 
A Data Safety and Monitoring Board (DSMB) will be formed as a part of this study.  Two 
physicians, with adequate clinical knowledge of the subject matter and research experience, 
along with one statistician will make up the DSMB. No member will have any affiliation with 
the study or data other than their responsibilities on the DSMB. Members will sign a Statement 
of Confidentiality.  
 
DSMB members:  
 Craig Weinert, MD MPH: Associate Professor of Medicine, Division of Pulmonary, 
Allergy, Critical Care and Sleep Medicine, Department of Medicine 
 Greg Beilman, MD: Professor, Department of Surgery 
 Ashley Peterson, PhD: Assistant Professor, Division of Biostatistics, School of Public 
Health 
 
Safety Data Collection:  
All adverse events will be collected with particular attention paid towards those listed as most 
frequent risks of Vitamin C, including nausea, vomiting, headaches, stomach cramps, and 
headaches. Adverse events will be collected on case report forms as completed within 
REDCap™. Three different types of events will be differentiated: those expected and/or related 
to study drug, those expected and/or related to any other research procedure, and those expected 


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and/or related to underlying septic shock condition.  All safety data will be collected from the 
time of consent to the final 28 day chart review visit. All events will be followed until either 
resolution or 30 days-post last study visit, whichever comes first.  
 
Mortality Data Review:  
All mortality data will be collected when site becomes aware of death. This could happen while 
participant is still in hospital or during the 28-day final chart review or at any other time point. 
All deaths will be reviewed by PI and Regulatory Specialist for IRB prompt reporting guidelines.  
 
Information Provided to DSMB 
Reports to DSMB will be prepared in coordination with an independent statistician from BDAC. 
Data provided includes:  
 Cumulative 
o Safety data (including adverse events) 
o Primary outcome data for Specific Aim 1 (mortality data) 
o Primary outcome data for Specific Aim 2 (clinical endpoints) 
 Since last DSMB meeting 
o Relevant IRB submissions, including Reportable New Information and 
Modifications 
o Monitoring reports 
 
DSMB Meeting Schedule 
 6 Months Post First Randomization 
o All data will be sent to DSMB. 
o Case report forms and paper documents, including consents, will be reviewed by 
Regulatory Specialist or CTSI monitor. Monitoring reports will be made available 
to DSMB.   
 Annually Post First Randomization 
o All data will be sent to DSMB. 
o Case report forms and paper documents, including consents, will be reviewed by 
Regulatory Specialist or CTSI monitor. Monitoring reports will be made available 
to DSMB.   
 
DSMB Meeting Components 
The DSMB members will be provided with data reports before the meeting date, with sufficient 
time to allow for review. Reports and all necessary information will be electronically provided 
to DSMB members through email. DSMB members will meet either in-person or 
telephonically/electronically as necessary to allow for clinical schedule restraints. The 
Regulatory Specialist will attend all DSMB meetings to compile minutes. This individual will 
also prepare all DSMB Summaries.  
 
DSMB IRB Reporting 
All DSMB Summaries will be submitted to the IRB per local guidelines.  


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19.0 Provisions to Protect the Privacy Interests of Participants 
19.1 Protecting Privacy:  
Participants will sign a consent form and a HIPAA Authorization which will detail what data and 
under what circumstances will be shared with research staff and non-research staff. Study 
procedures will be explained in full detail in the consent so that participants can make informed 
decisions before they enroll. The consent will also detail under which conditions any information 
may be shared with those outside of the internal research staff. 
19.2 Access to Participants:  
Participants will sign a consent and HIPAA authorization. 
20.0 Compensation for Research-Related Injury 
20.1 Compensation for Research-Related Injury:  
In the event that this research activity results in an injury, treatment will be available, including 
first aid, emergency treatment and follow-up care as needed. Care for such injuries will be billed 
in the ordinary manner to the subject or their insurance company. 
20.2 Contract Language:  
Not applicable.  
21.0 Consent Process 
21.1 Consent Process (when consent will be obtained):  
In-person consent will be obtained by the delegated research staff within the participant’s private 
hospital room. It is expected that this will be the PI or a Co-I (all ICU clinicians) the vast majority 
of the time. This study will employ a nurse-coordinator who could assist with consenting.  Any 
waiting period will only be for necessary clinical procedures; priority for clinical treatments will 
always take priority over research.  
Consent may also be done using an electronic informed consent document (eICD). This will 
occur either in-person or by remote in conjunction with telemedicine. The eICD will be presented 
as a REDCap survey on a device provided by the research study or on a participant/LAR’s 
personal device. The investigator will conduct the consent process with the participant/LAR via 
the telemedicine system by way of face-to-face video or via telephone if the LAR is unable to be 
physically present at the telemedicine site. The consenting investigator will review the consent 
document in the same manner as a paper consent document.  The UMN Medical School 
Department of Emergency Medicine Standard Operating Procedures - Electronic Informed 
Consent (eConsent) will be followed.  
All those consenting will be trained on the MacArthur Competence Assessment tool. 
21.2 Waiver or Alteration of Consent Process:  
Not applicable. No waiver or alteration of consent. 
21.3 Non-English Speaking Participants:  
Not applicable. Non-English speaking patients will not be enrolled.  


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21.4 Participants Who Are Not Yet Adults:  
Not applicable. No individual under the age of 18 will be enrolled.  
21.5 Cognitively Impaired Adults, or adults with fluctuating or diminished capacity to consent: 
For those patients with known capacity issues who are already using a clinical surrogate or LAR 
to consent to clinical procedures, these individuals will automatically be consented using the 
LAR, including those who are currently sedated. For those patients with questionable capacity, 
the MacArthur Competence Assessment Tool will be used to assess their ability to consent. Study 
clinicians will work with floor staff to assess current clinical presentation to ensure that the 
recruitment and consenting procedures do not take place during any period of greater than normal 
(for septic shock) impairment. This could include, but is not limited to, periods of greater stress 
due to medical treatments or intake procedures. As part of the clinical staff caring for the patient, 
the study clinicians will have the greatest ability to understand current and up-to-date patient 
temperament, cognitive abilities, and treatments.  
21.6 Adults Unable to Consent: 
● 
Permission:  
In order of priority for acting as an LAR, the established healthcare power of attorney, 
spouse, parent, adult children, and then adult sibling will be included in the consent process 
to obtain permission for the research study. In the case that this disagrees with the current 
surrogate providing permission for clinical care, the clinical care surrogate will be used.  
● 
Assent:  
Informal, verbal assent will be attempted on those participants who might have some 
cognitive ability to understand what is being asked of them. This will be a clinical decision 
made between the study investigator and floor staff and will only be a verbal discussion of 
what is already included in the consent. No script or written document will be used during 
the assent process.  
22.0 Setting 
22.1 Research Sites:  
Identification, recruitment, screening, and research visits will all take place within hospital ICUs. 
All research procedures will take place in the participant’s private hospital room. 
23.0 Multi-Site Research 
This is a multi-site study that will have a phased rollout at Fairview Hospitals and HealthEast 
Hospitals.  
1. Fairview Southdale ICU: this will be the pilot site and the study will be started at this location 
first. The PI is the director of the ICU at this location.  
2. Fairview UMMC ICU (includes MICU and SICU) and Ridges ICU: these sites will be 
secondary sites and will be initiated after Southdale.  
3. HealthEast St. Joseph’s Hospital ICU: this site will be last and require additional IRB 
approval from the local human ethics board. This site will only be initiated if additional 
recruitment is necessary. If and when the site is initiated and receives IRB approval, those 
documents would be submitted to the UMN IRB, if necessary.  


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4. Essentia Health: this site will require additional IRB approval from the local IRB. This site 
will be initiated once local-IRB is secured.  
23.1 Study-Wide Number of Participants:  
140 participants.  
23.2 Study-Wide Recruitment Methods:  
Each local site will rely on internal study clinicians and floor staff to identify candidates for the 
study.  
23.3 Study-Wide Recruitment Materials:  
Not applicable. No recruitment materials.  
23.4 Communication Among Sites:  
The study will employ a lead Regulatory Specialist who will coordinate all communication and 
regulatory efforts. Box will be utilized to manage study-wide documents so that team members 
can easily obtain the most current version of all documents. The Regulatory Specialist will 
manage IRB reporting at all sites and will work with the PI to ensure all non-compliance, adverse 
events, and other reportable events are reviewed and reported in accordance with local policies. 
There will be three IRBs involved, UMN, HealthEast, and Essentia Health. 
All study data will be entered into REDCap™ with each site being assigned a specific group so 
that staff at one site cannot see participant data from another site.  
23.5 Communication to Sites:  
The PI, the Project Manager, and the Regulatory Specialist will work together to release site-
wide communications. As the study begins enrollment at each new site, it is expected to have 
semi-often meetings (telephone or in-person) to ensure an efficient and appropriate start-up.  
24.0 Resources Available 
24.1 Resources Available:  
This study will include a PI, several co-investigators, project manager, coordinator, and a 
regulatory specialist. Bedside nursing will be used to assist PI with clinical assessments as 
necessary and as available. In the case of any medical or psychological event, clinical staff will 
be immediately available for assessment or treatment.  
All staff will be trained on research procedures before being allowed access to participants or 
data. All training will be documented within the regulatory binder and reviewed by the PI and 
project manager. 
As this study will involve staff at several sites, the Project Manager and the Regulatory Specialist 
will coordinate training efforts as required by each site.  
 
This study will take place at Fairview Southdale, UMMC, Ridges, HealthEast St. Joseph’s and 
Essentia Health in Duluth.  


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25.0 References 
1. 
Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines 
for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017;45(3):486-552. 
2. 
Hall MJ, Williams SN, DeFrances CJ, Golosinskiy A. Inpatient care for septicemia or sepsis: a 
challenge for patients and hospitals. NCHS data brief. 2011(62):1-8. 
3. 
Linder A, Lee T, Fisher J, et al. Short-Term Organ Dysfunction Is Associated With Long-Term 
(10-Yr) Mortality of Septic Shock. Crit Care Med. 2016;44(8):e728-736. 
4. 
Liu VX, Fielding-Singh V, Greene JD, et al. The Timing of Early Antibiotics and Hospital 
Mortality in Sepsis. American journal of respiratory and critical care medicine. 2017. 
5. 
Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe 
sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377. 
6. 
Angus DC, Barnato AE, Bell D, et al. A systematic review and meta-analysis of early goal-
directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. Intensive 
Care Med. 2015;41(9):1549-1560. 
7. 
Investigators P, Rowan KM, Angus DC, et al. Early, Goal-Directed Therapy for Septic Shock - 
A Patient-Level Meta-Analysis. N Engl J Med. 2017;376(23):2223-2234. 
8. 
Pro CI, Yealy DM, Kellum JA, et al. A randomized trial of protocol-based care for early septic 
shock. N Engl J Med. 2014;370(18):1683-1693. 
9. 
Investigators A, Group ACT, Peake SL, et al. Goal-directed resuscitation for patients with early 
septic shock. N Engl J Med. 2014;371(16):1496-1506. 
10. 
Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic 
shock. N Engl J Med. 2015;372(14):1301-1311. 
11. 
Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective 
antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care 
Med. 2006;34(6):1589-1596. 
12. 
Leite HP, de Lima LF. Metabolic resuscitation in sepsis: a necessary step beyond the 
hemodynamic? Journal of thoracic disease. 2016;8(7):E552-557. 
13. 
Bradley JA, King RF, Schorah CJ, Hill GL. Vitamins in intravenous feeding: a study of water-
soluble vitamins and folate in critically ill patients receiving intravenous nutrition. The British 
journal of surgery. 1978;65(7):492-494. 
14. 
Tanaka H, Matsuda T, Miyagantani Y, Yukioka T, Matsuda H, Shimazaki S. Reduction of 
resuscitation fluid volumes in severely burned patients using ascorbic acid administration: a 
randomized, prospective study. Archives of surgery. 2000;135(3):326-331. 
15. 
Nathens AB, Neff MJ, Jurkovich GJ, et al. Randomized, prospective trial of antioxidant 
supplementation in critically ill surgical patients. Annals of surgery. 2002;236(6):814-822. 
16. 
Fowler AA, 3rd, Syed AA, Knowlson S, et al. Phase I safety trial of intravenous ascorbic acid 
in patients with severe sepsis. Journal of translational medicine. 2014;12:32. 
17. 
Zabet MH, Mohammadi M, Ramezani M, Khalili H. Effect of high-dose Ascorbic acid on 
vasopressor's requirement in septic shock. Journal of research in pharmacy practice. 
2016;5(2):94-100. 
18. 
Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and 
Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After 
Study. Chest. 2017;151(6):1229-1238. 
19. 
Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated 
protein C for severe sepsis. N Engl J Med. 2001;344(10):699-709. 


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20. 
Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa (activated) in adults with septic 
shock. N Engl J Med. 2012;366(22):2055-2064. 
21. 
Patel JM, Snaith C, Thickett DR, et al. Randomized double-blind placebo-controlled trial of 40 
mg/day of atorvastatin in reducing the severity of sepsis in ward patients (ASEPSIS Trial). Crit 
Care. 2012;16(6):R231. 
22. 
Ince C. The microcirculation is the motor of sepsis. Crit Care. 2005;9 Suppl 4:S13-19. 
23. 
Koekkoek WA, van Zanten AR. Antioxidant Vitamins and Trace Elements in Critical Illness. 
Nutr Clin Pract. 2016;31(4):457-474. 
24. 
Wilson JX. Mechanism of action of vitamin C in sepsis: ascorbate modulates redox signaling in 
endothelium. BioFactors. 2009;35(1):5-13. 
25. 
Borrelli E, Roux-Lombard P, Grau GE, et al. Plasma concentrations of cytokines, their soluble 
receptors, and antioxidant vitamins can predict the development of multiple organ failure in 
patients at risk. Crit Care Med. 1996;24(3):392-397. 
26. 
Schorah CJ, Downing C, Piripitsi A, et al. Total vitamin C, ascorbic acid, and dehydroascorbic 
acid concentrations in plasma of critically ill patients. The American journal of clinical 
nutrition. 1996;63(5):760-765. 
27. 
Manzanares W, Hardy G. Thiamine supplementation in the critically ill. Current opinion in 
clinical nutrition and metabolic care. 2011;14(6):610-617. 
28. 
Mohammed BM, Fisher BJ, Huynh QK, et al. Resolution of sterile inflammation: role for 
vitamin C. Mediators of inflammation. 2014;2014:173403. 
29. 
Fisher BJ, Kraskauskas D, Martin EJ, et al. Attenuation of sepsis-induced organ injury in mice 
by vitamin C. JPEN Journal of parenteral and enteral nutrition. 2014;38(7):825-839. 
30. 
Carr AC, Shaw GM, Fowler AA, Natarajan R. Ascorbate-dependent vasopressor synthesis: a 
rationale for vitamin C administration in severe sepsis and septic shock? Crit Care. 
2015;19:418. 
31. 
. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington 
(DC)2000. 
32. 
Stephenson CM, Levin RD, Spector T, Lis CG. Phase I clinical trial to evaluate the safety, 
tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with 
advanced cancer. Cancer Chemother Pharmacol. 2013;72(1):139-146. 
33. 
Nankivell BJ, Murali KM. Images in clinical medicine. Renal failure from vitamin C after 
transplantation. N Engl J Med. 2008;358(4):e4. 
34. 
Gerster H. No contribution of ascorbic acid to renal calcium oxalate stones. Ann Nutr Metab. 
1997;41(5):269-282. 
35. 
Morgan SH, Maher ER, Purkiss P, Watts RW, Curtis JR. Oxalate metabolism in end-stage 
renal disease: the effect of ascorbic acid and pyridoxine. Nephrol Dial Transplant. 
1988;3(1):28-32. 
 

ICF_002.pdf: 
Approved for use by UMN IRB
Effective on 1/28/2020
IRB Study Number: STUDY00000625
Consent Form
Version 5 – January 23, 2020 
Page 1 of 9
Title of Research Study: Evaluating Vitamin C and Septic Shock: 
A Randomized Double Blind Control Trial (EVICT)
Researcher Team Contact Information: 
Ron Reilkoff, MD
Division of Pulmonary, Allergy, Critical Care and Sleep Medicine
Department of Medicine
University of Minnesota
For questions about research appointments, the research study, research results, or other concerns, call the 
study team at: 
Researcher Name: Ron Reilkoff, MD
Phone Number: 612-624-0999
Email Address: rreilkof@umn.edu
Supported By: This research is supported by the Fairview Foundation and Critical Care Grant.
Your doctor, who is also responsible for this research study, is interested in both your clinical care and the 
conduct of this research study. You have the right to discuss this study with another person who is not part of 
the research team before deciding whether to participate in the research.
What is research?
Doctors and researchers are committed to your care and safety. There are important differences between 
research and treatment plans:
●
The goal of research is to learn new things in order to help groups of people in the future. Researchers
learn things by following the same plan with a number of participants, so they do not usually make changes
to the plan for individual research participants. You, as an individual, may or may not be helped by
volunteering for a research study.
●
The goal of treatment is to help you get better or to improve your quality of life. Doctors can make changes
to your treatment plan as needed.
Why am I being asked to take part in this research study?
We are asking you to take part in this research study because you are in the intensive care unit (ICU) with a 
diagnosis of septic shock
What should I know about a research study?
●
Someone will explain this research study to you.
●
Whether or not you take part is up to you.
●
You can choose not to take part.
●
You can agree to take part and later change your mind.
●
Your decision will not be held against you.
●
You can ask all the questions you want before you decide.
NCT03338569


Approved for use by UMN IRB
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IRB Study Number: STUDY00000625
Consent Form
Version 5 – January 23, 2020 
Page 2 of 9
Why is this research being done?
The purpose of this research is to learn if Vitamin C can help treat septic shock. During septic shock, vitamin 
levels in general can fall and are associated with organ failure. It is thought that Vitamin C can help the body 
during septic shock by having an anti-oxidant and anti-inflammatory effect. 
This study involves the use of an infusion of Vitamin C for septic shock. The FDA has not approved Vitamin C for 
this treatment. 
How long will the research last?
We expect that you will be in this research study for about 4 days. If your septic shock gets better and you stop 
vasopressor medications (standard of care) for at least 24 hours, the infusion will be stopped at that point. 
Vasopressors are medication that are used to raise blood pressure and are considered to be a vital part of 
treatment of septic shock. 
At 28 days, we will do a follow-up review of your medical chart but you do not need to come in for a visit. 
How many people will be studied?
We expect about 140 people here in Minnesota will be in this research study. The research is being done at 
several hospitals in the region; Fairview Southdale, University of Minnesota Medical Center, Ridges, HealthEast 
St. Joseph’s and Essentia Health in Duluth.
What happens if I say “Yes, I want to be in this research”?
The treatment you get will be chosen by chance, like flipping a coin. Neither you nor the study doctor or anybody 
else treating you will choose what treatment you get. You will have an equal chance of being given either 
treatment. 
Neither you nor the study doctor or anybody else treating you will know which treatment you are getting. You 
will be given either Vitamin C or placebo. It will be given to you by an infusion in an intravenous (IV) line placed 
in your arm. You will most likely already have a line placed for other medications and we will use that same line 
for the study medication. 

Vitamin C: On the first day, the amount of Vitamin C in the infusion is 6,875 milligrams. This larger amount
on the first day is what is called a “bolus”. A bolus, or larger start dose, is used to more efficiently raise a
medication’s concentration in the body to a level where it can start working. After the first day, the daily
average of the Vitamin C is approximately 6,000milligrams which is given at 250 milligrams per hour. The
maximum Vitamin C would be 7,000 milligrams per day.

Placebo: A matched infusion given at the same amount and same rate as the Vitamin C.
If you get better or leave the ICU, the infusion could be stopped before four days. Your study doctor will discuss 
stopping early with you, if necessary. 
We will collect medical information about you from your hospital record including history, medication usage, 
and laboratory results. This information will be collected at Baseline, and once a day for the four days of the 
infusion. There will be one follow-up chart review 28 days after the infusion has been started. You do not have 
to come in for the visit at 28 days.
Additional blood will be taken to study biomarkers (proteins and molecules in the blood) for septic shock and to 
measure the response to the Vitamin C. We will be looking at genetic and other chemical markers in your blood. 
This blood draw will be taken at Day 0, Day 1, and Day 3. The first blood draw will be about 5 teaspoons. The 


Approved for use by UMN IRB
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IRB Study Number: STUDY00000625
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Version 5 – January 23, 2020 
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two other blood draws will be about 4 teaspoons. The total blood draw amount will be about 13 teaspoons. This 
blood will most likely be taken from the IV that will already be in your arm. Not everybody will have blood drawn 
at all specified time points. Blood will only be drawn when there is a study clinician available and transportation 
to long-term freezer storage is available. 
If a bronchoscopy is performed or if your sputum is collected for clinical purposes, we may collect some of the 
fluid from your lungs or sputum at that time. In addition, we may also collect excess urine, blood or other bodily 
fluids that are collected for a clinical purpose that would otherwise be destroyed or wasted. These samples 
would be used to help refine a laboratory test in determining infections. This laboratory test would only be done 
for research purposes and is not intended to diagnose or help treat you. This fluid collection would not be done 
on everyone, only on those when staffing and standard of care procedures allow for it. 
If you choose to participate, you will still receive the usual standard of care measures for septic shock 
management, just as if you were to choose not to participate.
Screening
Day 0
Day 1
Day 2
Day 3
Day 4
Day 28
Consent
X
Medical History
X
Physical Exam
X
Study Drug or Placebo Infusion
X
X
X
X
X
Blood Draw 
X
X
X
Chart Review
X
X
X
X
X
X
What are my responsibilities if I take part in this research?
As this research will all take place while you are hospitalized, you will not have any responsibilities. You will not 
be asked to come in for research visits after you leave the hospital.  
What happens if I do not want to be in this research?
You will continue to receive all standard of care options for septic shock as prescribed by your clinician. No 
medication or treatment will be withheld because of your participation in this study. 
This research study is IN ADDITION to what you are already receiving or may receive. 
Standard of care for septic shock can include, but is not limited to: 

Medications to raise your blood pressure (vasopressors)

Oxygen supplementation

Mechanical ventilation to support your breathing

Dialysis to support kidney function

Antibiotics

Supportive and preventative cares for critically ill patients

Intravenous hydration

Intravenous steroids

Surgery or drainage of source of infection
Any standard of care that you receive will be prescribed and ordered by your hospital doctor and is separate 
from this study. 


Approved for use by UMN IRB
Effective on 1/28/2020
IRB Study Number: STUDY00000625
Consent Form
Version 5 – January 23, 2020 
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Because the alternative to being in this study is the current standard of care, there are no specific risks or benefits 
associated with declining to participate beyond those related to usual care for septic shock. The benefits of 
therapy for septic shock are to stabilize vital signs, reverse and limit organ failure and prevent death. However 
life sustaining therapies such as vasopressor medications, mechanical ventilation may cause temporary 
discomfort and pain and increase risk of complications. Treatment usually require additional procedures, such 
as placing IVs in large blood vessels to administer medication or for dialysis, placement of drainage catheters or 
placing a breathing tube into a patient’s throat.
What happens if I say “Yes”, but I change my mind later?
You can leave the research at any time. Leaving will not be held against you. 
If you decide to leave the research, contact the investigator so that the investigator can make sure the infusion 
is stopped in a safe manner. 
Choosing not to be in this study or to stop being in this study will not result in any penalty to you or loss of 
benefit to which you are entitled. Meaning, your choice not to be in this study will not negatively affect your 
right to any present or future medical treatment.
If you stop being in the research, already collected information about you will be removed from the study 
database if you request it to be. You will be asked whether the investigator can collect information from your 
routine medical care, such as your medical records. If you agree, this information will be handled the same as 
the information obtained for the research study. 
What are the risks of being in this study?  Is there any way being in this study could be bad 
for me?
This research may hurt you in the following ways:
1.
Vitamin C risks: This study is approximately 6,000 milligrams per day via an IV, with a maximum dose of
7,000 milligrams. At oral doses higher than 3,000 milligrams per day the most common adverse effect is
diarrhea, but can uncommonly include nausea, vomiting, heartburn, stomach cramps, and headaches. At
very high doses (10,000 milligrams up to 100,000 milligrams per day) some studies have shown an increase
risk of kidney problems, including crystal formation, stones and renal failure. It is important to discuss with
the study doctor if you are taking vitamins or supplements which could contain Vitamin C.
2.
Blood draw risks: The risks associated with a blood draw include minimal discomfort, and/or bruising.
Fainting is possible but unlikely.  In very rare cases, a small blood clot can form at the site of the needle
insertion.
3.
Intravenous line: The risks of an intravenous line are similar to a blood draw but because it is kept in the
vein for a longer period of time, the risk of bruising and discomfort are slightly higher. All participants will
already have a peripheral or central intravenous line catheter placed for standard of care medications.
Any blood draw or IV placed for the infusion will be done with clinical care when possible. Having an
indwelling catheter for extended periods can increase risk of secondary infection.
4.
Loss of confidentiality: As part of this research we will be collecting information about your health from
your medical record.  We will take safeguards to protect this information, including removing identifying
information when possible, and storing such information in a locked office.  Should a loss occur, however,
your confidential personal health information may be obtained by unintended parties.  Confidentiality is
not guaranteed.


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IRB Study Number: STUDY00000625
Consent Form
Version 5 – January 23, 2020 
Page 5 of 9
In addition to these risks, this research may hurt you in ways that are unknown. These may be a minor 
inconvenience or may be so severe as to cause death.
Will it cost me anything to participate in this research study?
Taking part in this research study will not lead to any costs to you. All study procedures, including the Vitamin C 
or placebo infusion, will be paid for by the research study. 
You and your insurance company will be charged for the health care services that you would ordinarily be 
responsible to pay. In some cases, insurance will not pay for services ordinarily covered because these services 
were performed in a research study. You should check with your insurance to see what services will be covered 
by your insurance and what you will be responsible to pay.
Will being in this study help me in any way?
There are no benefits to you from your taking part in this research. We cannot promise any benefits to others 
from your taking part in this research. However, possible benefits to others include learning how to treat septic 
shock. 
What happens to the information collected for the research, including my health information?
We try to limit the use and sharing of your information, including research study records, any medical records 
and any other information about you, to people who have a need for  this information.  But we cannot promise 
complete confidentiality.  
If you participate in this study, your information, including your health information, will be used and shared for 
purposes of conducting this research.  As described later in this Consent Form, your information may also be 
used and shared for publishing and presenting the research results, future research, and any optional elements 
of the research you agree to in this Consent Form.   If you sign this Consent Form, you are giving us permission 
to use and share your health information for these purposes, and if we are using your medical records, you are 
giving permission to any health care providers who are treating you to share your medical records with us.  
What health information will be made available?
Health information about you to be used and shared for the research includes those items checked by the 
research team below:
☒Your medical records, which may include records from hospital and clinic visits, emergency room visits,
immunizations, medical history and physical exams, medications, images and imaging reports, progress
notes, psychological tests, EEG/EKG/ECHO reports, lab and pathology reports, dental records and/or
financial records.  These records may be used and shared for as long as this research continues.
☒Information collected as part of this research study, including research procedures, research visits, and
any optional elements of the research you agree to, all as described in this Consent Form.  This information
might not be part of your medical record, and may include things like responses to surveys and
questionnaires, and information collected during research visits described in this Consent Form.


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What about more sensitive health information?
Some health information is so sensitive that it requires your specific permission.  If this research study requires 
any of this sensitive information, the boxes below will be marked and you will be asked to initial to permit this 
information to be made available to the research team to use and share as described in this Consent Form.
☐My drug & alcohol abuse, diagnosis & treatment records ________ (initial)
☐My HIV/AIDS testing records  ________ (initial)
☒My genetic testing records  ________ (initial)
☐My mental health diagnosis/treatment records  ________ (initial)
☐My sickle cell anemia records  ________ (initial)
Who will access and use my health information?
If you agree to participate in this study, your information will be shared with:

The University of Minnesota research team and any institutions or individuals collaborating on the
research with us;

Others at the University of Minnesota and M Health/Fairview who provide support for the research or
who oversee research (such as the Institutional Review Board or IRB which is the committee that provides
ethical and regulatory oversight of research at the University, systems administrators and other technical
and/or administrative support personnel, compliance and audit professionals (such as the Quality
Assurance Program of the Human Research Protection Program (HRPP)), individuals involved in
processing any compensation you may receive for your participation, and others);

Organizations who provide accreditation and oversight for research and the research team, and others
authorized by law to review the quality and safety of the research (such as U.S. government agencies like
the Food and Drug Administration, the Office of Human Research Protections, the Office of Research
Integrity, or government agencies in other countries); and

Organizations that process any payments that may be made to you for participating in this study, and any
other individuals or organizations specifically identified in this Consent Form.

The research sponsor, any affiliates, partners or agents of the sponsor involved in the research,
organizations funding the research, and any affiliates, partners or agents of the funding organization
involved in the research;
Additional sharing of your information for mandatory reporting
If we learn about any of the following, we may be required or permitted by law or policy to report this 
information to authorities:

Current or ongoing child or vulnerable adult abuse or neglect;

Communicable, infectious or other diseases required to be reported under Minnesota’s Reportable
Disease Rule;

Certain wounds or conditions required to be reported under other state or federal law; or

Excessive use of alcohol or use of controlled substances for non-medical reasons during pregnancy.
How will my information be used in publications and presentations?
We may publish the results of this research in scientific, medical, academic or other journals or reports, or 
present the results at conferences.  Information that makes it easy to identify you (such as your name and 
contact information, SSN and medical records number) will not be part of any publication or presentation.  If 


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you have an extremely unique or rare condition that is not shared by many others, it is possible that some 
people may be able to determine your identity even without these identifiers.
What will be done with my data and specimens when this study is over?
Your data and blood specimens will be stored indefinitely.  We will use and may share data and/or specimens 
for future research. They may be shared with researchers/institutions outside of University of Minnesota.  This 
could include for profit companies. We will not ask for your consent before using or sharing them. We will 
remove identifiers from your data and/or specimens, which means that nobody who works with them for 
future research will know who you are.  Therefore, you will not receive any results or financial benefit from 
future research done on your specimens or data.
Do I have to sign this Consent Form and give my permission to make my information, including my 
health information, available for use and sharing?
No, you do not have to sign this Consent Form.  But if you do not sign, you will not be able to participate in 
this research study.  Your decision about signing this Consent Form will not impact treatment options available 
outside of the study, payment for such treatment, enrollment in health insurance plans or eligibility for 
benefits.
Does my permission for making my health information available for use and sharing ever expire?
No, there is no expiration date.
May I cancel my permission for making my health information available for use and sharing?
Yes.  You may cancel your permission at any time by writing to the researcher at the address on the first page 
of this Consent Form.  If you cancel your permission, you will no longer be in the research study. You may also 
want to ask someone on the research team in canceling will affect any research related medical treatment.   If 
you cancel your permission, any health information about you that was already used and shared may continue 
to be used and shared for the research study and any optional elements of the study to which you agree in 
this Consent Form.  
What happens to my health information after it is shared with others?
When we share your information with others as described in this Consent Form, privacy laws may no longer 
protect your information and there may be further sharing of your information.  
Will I be able to look at my records?
It is possible that the research team may not allow you to see the information collected for this study.   
However, you may access any information placed in your medical records after the study is complete.  
What about genetic information?
A federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes it illegal for health 
insurance companies, group health plans, and most employers to discriminate against you based on your 
genetic information. This law generally will protect you in the following ways:

Health insurance companies and group health plans may not request your genetic information that we
get from this research.

Health insurance companies and group health plans may not use your genetic information when making
decisions regarding your eligibility or premiums.

Employers with 15 or more employees may not use your genetic information that we get from this
research when making a decision to hire, promote, or fire you or when setting the terms of your
employment.


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Be aware that this federal law does not protect you against genetic discrimination by companies that sell life 
insurance, disability insurance, or long-term care insurance.
Where can I find out about the study results?
A description of this clinical trial will be available at 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.
The results of the genetic and biomarker tests will not be made available to you because the research is still in 
an early phase and the reliability of the results is unknown.
Who do I contact if I have question, concerns or feedback about my experience?
This research has been reviewed and approved by an Institutional Review Board (IRB) within the Human 
Research Protections Program (HRPP). To share feedback privately with the HRPP about your research 
experience, call the Research Participants’ Advocate Line at 612-625-1650 (Toll Free: 1-888-224-8636) or go to 
z.umn.edu/participants. You are encouraged to contact the HRPP if: 
●
Your questions, concerns, or complaints are not being answered by the research team.
●
You cannot reach the research team.
●
You want to talk to someone besides the research team.
●
You have questions about your rights as a research participant.
●
You want to get information or provide input about this research.
Will I have a chance to provide feedback after the study is over? 
The HRPP may ask you to complete a survey that asks about your experience as a research participant. You do 
not have to complete the survey if you do not want to. If you do choose to complete the survey, your responses 
will be anonymous.
If you are not asked to complete a survey, but you would like to share feedback, please contact the study team 
or the HRPP. See the “Investigator Contact Information” of this form for study team contact information and 
“Whom do I contact if I have questions, concerns or feedback about my experience?” of this form for HRPP 
contact information.
Can I be removed from the research without my OK?
You could be removed from the study or have the infusion stopped at any time for any reason when either the 
research doctor or your personal doctor feels further participation could impact your medical care. Even if the 
infusion is stopped early, we will still continue to collect information from your medical record. 
What happens if I am injured while participating in this research?
In the event that this research activity results in an injury, treatment will be available, including first 
aid, emergency treatment and follow-up care as needed. Care for such injuries will be billed in the ordinary 
manner to you or your insurance company. If you think that you have suffered a research related injury, let the 
study physicians know right away.
Will I be compensated for my participation? 
You will not be compensated for being in this research study. 


Approved for use by UMN IRB
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IRB Study Number: STUDY00000625
Consent Form
Version 5 – January 23, 2020 
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Signature Block for Obtaining Consent Directly from Participant
Your signature documents your permission to take part in this research.  You will be provided a copy of this 
signed document.
_______________________________________________  __________________
Signature of Participant                                                               Date
_______________________________________________
Printed Name of Participant
______________________________________________     __________________
Signature of Person Obtaining Consent                                     Date
_______________________________________________
Printed Name of Person Obtaining Consent
Signature Block for Obtaining Consent from
Legally Authorized Representative
Your signature documents your permission for the named participant to take part in this research. You will 
be provided a copy of this signed document.
_____________________________________________
Printed Name of Participant
_____________________________________________
___________________
Signature of Legally Authorized Representative
Date
_____________________________________________
Printed Name of Legally Authorized Representative
_____________________________________________
___________________
Signature of Person Obtaining Consent
Date
_____________________________________________
Printed Name of Person Obtaining Consent


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Effective on 4/1/2020
IRB Study Number: STUDY00000625
03/18/2020 14:39
projectredcap.org
Confidential
Page 1
EVICT eConsent
Please complete this informed consent. A study team member will be in contact with you to discuss the document
while you complete it.
Evaluating Vitamin C and Septic Shock: 
A Randomized Double Blind Control Trial (EVICT)
Researcher Team Contact Information: 
Ron Reilkoff, MD
Division of Pulmonary, Allergy, Critical Care and Sleep Medicine
Department of Medicine
University of Minnesota
For questions about research appointments, the research study, research results, or other
concerns, call the study team at: 
Researcher Name: Ron Reilkoff, MD
Phone Number: 612-624-0999
Email Address: rreilkof@umn.edu
Supported By: This research is supported by the Fairview Foundation and Critical Care Grant.
Your doctor, who is also responsible for this research study, is interested in both your clinical care and the conduct of
this research study. You have the right to discuss this study with another person who is not part of the research team
before deciding whether to participate in the research.


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projectredcap.org
Confidential
Page 2
What is research? Doctors and researchers are committed to your care and safety. There are important differences
between research and treatment plans:
  The goal of research is to learn new things in order to help groups of people in the future. Researchers learn things
by following the same plan with a number of participants, so they do not usually make changes to the plan for
individual research participants. You, as an individual, may or may not be helped by volunteering for a research
study. The goal of treatment is to help you get better or to improve your quality of life. Doctors can make changes to
your treatment plan as needed.
  Why am I being asked to take part in this research study? We are asking you to take part in this research study
because you are in the intensive care unit (ICU) with a diagnosis of septic shock.
 What should I know about a research study? ● Someone will explain this research study to you.
● Whether or not you take part is up to you.
● You can choose not to take part.
● You can agree to take part and later change your mind.
● Your decision will not be held against you.
● You can ask all the questions you want before you decide.
 Why is this research being done? The purpose of this research is to learn if Vitamin C can help treat septic shock.
During septic shock, vitamin levels in general can fall and are associated with organ failure. It is thought that Vitamin
C can help the body during septic shock by having an anti-oxidant and anti-inflammatory effect.
This study involves the use of an infusion of Vitamin C for septic shock. The FDA has not approved Vitamin C for this
treatment.
 How long will the research last? We expect that you will be in this research study for about 4 days. If your septic
shock gets better and you stop vasopressor medications (standard of care) for at least 24 hours, the infusion will be
stopped at that point. Vasopressors are medication that are used to raise blood pressure and are considered to be a
vital part of treatment of septic shock.
At 28 days, we will do a follow-up review of your medical chart but you do not need to come in for a visit.
 How many people will be studied? We expect about 140 people here in Minnesota will be in this research study. The
research is being done at several hospitals in the region; Fairview Southdale, University of Minnesota Medical Center,
Ridges, HealthEast St. Joseph's and Essentia Health in Duluth.
 What happens if I say "Yes, I want to be in this research"? The treatment you get will be chosen by chance, like
flipping a coin. Neither you nor the study doctor or anybody else treating you will choose what treatment you get.
You will have an equal chance of being given either treatment.
Neither you nor the study doctor or anybody else treating you will know which treatment you are getting. You will be
given either Vitamin C or placebo. It will be given to you by an infusion in an intravenous (IV) line placed in your arm.
You will most likely already have a line placed for other medications and we will use that same line for the study
medication.
  Vitamin C: On the first day, the amount of Vitamin C in the infusion is 6,875 milligrams. This larger amount on the
first day is what is called a "bolus". A bolus, or larger start dose, is used to more efficiently raise a medication's
concentration in the body to a level where it can start working. After the first day, the daily average of the Vitamin C
is approximately 6,000 milligrams which is given at 250 milligrams per hour. The maximum Vitamin C would be
7,000 milligrams per day. Placebo: A matched infusion given at the same amount and same rate as the Vitamin C.  If
you get better or leave the ICU, the infusion could be stopped before four days. Your study doctor will discuss
stopping early with you, if necessary.
We will collect medical information about you from your hospital record including history, medication usage, and
laboratory results. This information will be collected at Baseline, and once a day for the four days of the infusion.
There will be one follow-up chart review 28 days after the infusion has been started. You do not have to come in for
the visit at 28 days.
Additional blood will be taken to study biomarkers (proteins and molecules in the blood) for septic shock and to
measure the response to the Vitamin C. We will be looking at genetic and other chemical markers in your blood. This
blood draw will be taken at Day 0, Day 1, and Day 3. The first blood draw will be about 5 teaspoons. The two other
blood draws will be about 4 teaspoons. The total blood draw amount will be about 13 teaspoons. 
This blood will most likely be taken from the IV that will already be in your arm. Not everybody will have blood drawn
at all specified time points. Blood will only be drawn when there is a study clinician available and transportation to
long-term freezer storage is available.


Approved for use by UMN IRB
Effective on 4/1/2020
IRB Study Number: STUDY00000625
If a bronchoscopy is performed or if your sputum is collected for clinical purposes, we may collect some of the fluid
from your lungs or sputum at that time. In addition, we may also collect excess urine, blood or other bodily fluids that
are collected for a clinical purpose that would otherwise be destroyed or wasted. These samples would be used to
help refine a laboratory test in determining infections. This laboratory test would only be done for research purposes
and is not intended to diagnose or help treat you. This fluid collection would not be done on everyone, only on those
when staffing and standard of care procedures allow for it.
If you choose to participate, you will still receive the usual standard of care measures for septic shock management,
just as if you were to choose not to participate.
 What are my responsibilities if I take part in this research? As this research will all take place while you are
hospitalized, you will not have any responsibilities. You will not be asked to come in for research visits after you leave
the hospital. 
 What happens if I do not want to be in this research? You will continue to receive all standard of care options for
septic shock as prescribed by your clinician. No medication or treatment will be withheld because of your
participation in this study.
This research study is IN ADDITION to what you are already receiving or may receive.
Standard of care for septic shock can include, but is not limited to:
• Medications to raise your blood pressure (vasopressors)
• Oxygen supplementation
• Mechanical ventilation to support your breathing
• Dialysis to support kidney function
• Antibiotics
• Supportive and preventative cares for critically ill patients
• Intravenous hydration
• Intravenous steroids
• Surgery or drainage of source of infection
Any standard of care that you receive will be prescribed and ordered by your hospital doctor and is separate from
this study.
Because the alternative to being in this study is the current standard of care, there are no specific risks or benefits
associated with declining to participate beyond those related to usual care for septic shock. The benefits of therapy
for septic shock are to stabilize vital signs, reverse and limit organ failure and prevent death. However life sustaining
therapies such as vasopressor medications, mechanical ventilation may cause temporary discomfort and pain and
increase risk of complications. Treatment usually require additional procedures, such as placing IVs in large blood
vessels to administer medication or for dialysis, placement of drainage catheters or placing a breathing tube into a
patient's throat.
 What happens if I say "Yes", but I change my mind later? You can leave the research at any time. Leaving will not be
held against you.
If you decide to leave the research, contact the investigator so that the investigator can make sure the infusion is
stopped in a safe manner.
Choosing not to be in this study or to stop being in this study will not result in any penalty to you or loss of benefit to
which you are entitled. Meaning, your choice not to be in this study will not negatively affect your right to any
present or future medical treatment.
If you stop being in the research, already collected information about you will be removed from the study database if
you request it to be. You will be asked whether the investigator can collect information from your routine medical
care, such as your medical records. If you agree, this information will be handled the same as the information
obtained for the research study.
 What are the risks of being in this study? Is there any way being in this study could be bad for me? This research
may hurt you in the following ways:
  Vitamin C risks: This study is approximately 6,000 milligrams per day via an IV, with a maximum dose of 7,000
milligrams. At oral doses higher than 3,000 milligrams per day the most common adverse effect is diarrhea, but can
uncommonly include nausea, vomiting, heartburn, stomach cramps, and headaches. At very high doses (10,000
milligrams up to 100,000 milligrams per day) some studies have shown an increase risk of kidney problems,
including crystal formation, stones and renal failure. It is important to discuss with the study doctor if you are taking
vitamins or supplements which could contain Vitamin C. Blood draw risks: The risks associated with a blood draw
include minimal discomfort, and/or bruising. Fainting is possible but unlikely. In very rare cases, a small blood clot
can form at the site of the needle insertion. Intravenous line: The risks of an intravenous line are similar to a blood


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draw but because it is kept in the vein for a longer period of time, the risk of bruising and discomfort are slightly
higher. All participants will already have a peripheral or central intravenous line catheter placed for standard of care
medications. Any blood draw or IV placed for the infusion will be done with clinical care when possible. Having an
indwelling catheter for extended periods can increase risk of secondary infection. Loss of confidentiality: As part of
this research we will be collecting information about your health from your medical record. We will take safeguards
to protect this information, including removing identifying information when possible, and storing such information in
a locked office. Should a loss occur, however, your confidential personal health information may be obtained by
unintended parties. Confidentiality is not guaranteed.  
In addition to these risks, this research may hurt you in ways that are unknown. These may be a minor inconvenience
or may be so severe as to cause death.
 Will it cost me anything to participate in this research study? Taking part in this research study will not lead to any
costs to you. All study procedures, including the Vitamin C or placebo infusion, will be paid for by the research study.
You and your insurance company will be charged for the health care services that you would ordinarily be
responsible to pay. In some cases, insurance will not pay for services ordinarily covered because these services were
performed in a research study. You should check with your insurance to see what services will be covered by your
insurance and what you will be responsible to pay.
 Will being in this study help me in any way? There are no benefits to you from your taking part in this research. We
cannot promise any benefits to others from your taking part in this research. However, possible benefits to others
include learning how to treat septic shock.


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 What happens to the information collected for the research, including my health information? We try to limit the use
and sharing of your information, including research study records, any medical records and any other information
about you, to people who have a need for this information. But we cannot promise complete confidentiality. 
If you participate in this study, your information, including your health information, will be used and shared for
purposes of conducting this research. As described later in this Consent Form, your information may also be used
and shared for publishing and presenting the research results, future research, and any optional elements of the
research you agree to in this Consent Form. If you sign this Consent Form, you are giving us permission to use and
share your health information for these purposes, and if we are using your medical records, you are giving
permission to any health care providers who are treating you to share your medical records with us. 
 What health information will be made available? Health information about you to be used and shared for the
research includes those items checked by the research team below:
☒ Your medical records, which may include records from hospital and clinic visits, emergency room visits,
immunizations, medical history and physical exams, medications, images and imaging reports, progress notes,
psychological tests, EEG/EKG/ECHO reports, lab and pathology reports, dental records and/or financial records. These
records may be used and shared for as long as this research continues.
☒ Information collected as part of this research study, including research procedures, research visits, and any
optional elements of the research you agree to, all as described in this Consent Form. This information might not be
part of your medical record, and may include things like responses to surveys and questionnaires, and information
collected during research visits described in this Consent Form.
 Who will access and use my health information? If you agree to participate in this study, your information will be
shared with:
• The University of Minnesota research team and any institutions or individuals collaborating on the research with us;
• Others at the University of Minnesota and M Health/Fairview who provide support for the research or who oversee
research (such as the Institutional Review Board or IRB which is the committee that provides ethical and regulatory
oversight of research at the University, systems administrators and other technical and/or administrative support
personnel, compliance and audit professionals (such as the Quality Assurance Program of the Human Research
Protection Program (HRPP)), individuals involved in processing any compensation you may receive for your
participation, and others);
• Organizations who provide accreditation and oversight for research and the research team, and others authorized
by law to review the quality and safety of the research (such as U.S. government agencies like the Food and Drug
Administration, the Office of Human Research Protections, the Office of Research Integrity, or government agencies
in other countries); and
• Organizations that process any payments that may be made to you for participating in this study, and any other
individuals or organizations specifically identified in this Consent Form.
• The research sponsor, any affiliates, partners or agents of the sponsor involved in the research, organizations
funding the research, and any affiliates, partners or agents of the funding organization involved in the research;
 Additional sharing of your information for mandatory reporting If we learn about any of the following, we may be
required or permitted by law or policy to report this information to authorities:
• Current or ongoing child or vulnerable adult abuse or neglect;
• Communicable, infectious or other diseases required to be reported under Minnesota's Reportable Disease Rule;
• Certain wounds or conditions required to be reported under other state or federal law; or
• Excessive use of alcohol or use of controlled substances for non-medical reasons during pregnancy.
 How will my information be used in publications and presentations? We may publish the results of this research in
scientific, medical, academic or other journals or reports, or present the results at conferences. Information that
makes it easy to identify you (such as your name and contact information, SSN and medical records number) will not
be part of any publication or presentation. If you have an extremely unique or rare condition that is not shared by
many others, it is possible that some people may be able to determine your identity even without these identifiers.
 What will be done with my data and specimens when this study is over? Your data and blood specimens will be
stored indefinitely. We will use and may share data and/or specimens for future research. They may be shared with
researchers/institutions outside of University of Minnesota. This could include for profit companies. We will not ask for
your consent before using or sharing them. We will remove identifiers from your data and/or specimens, which
means that nobody who works with them for future research will know who you are. Therefore, you will not receive
any results or financial benefit from future research done on your specimens or data.
 Do I have to sign this Consent Form and give my permission to make my information, including my health
information, available for use and sharing? No, you do not have to sign this Consent Form. But if you do not sign, you
will not be able to participate in this research study. Your decision about signing this Consent Form will not impact
treatment options available outside of the study, payment for such treatment, enrollment in health insurance plans
or eligibility for benefits.
 Does my permission for making my health information available for use and sharing ever expire? No, there is no
expiration date.


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 May I cancel my permission for making my health information available for use and sharing? Yes. You may cancel
your permission at any time by writing to the researcher at the address on the first page of this Consent Form. If you
cancel your permission, you will no longer be in the research study. You may also want to ask someone on the
research team in canceling will affect any research related medical treatment. If you cancel your permission, any
health information about you that was already used and shared may continue to be used and shared for the research
study and any optional elements of the study to which you agree in this Consent Form. 
 What happens to my health information after it is shared with others? When we share your information with others
as described in this Consent Form, privacy laws may no longer protect your information and there may be further
sharing of your information. 
 Will I be able to look at my records? It is possible that the research team may not allow you to see the information
collected for this study. However, you may access any information placed in your medical records after the study is
complete. 
 What about genetic information? A federal law, called the Genetic Information Nondiscrimination Act (GINA),
generally makes it illegal for health insurance companies, group health plans, and most employers to discriminate
against you based on your genetic information. This law generally will protect you in the following ways:
• Health insurance companies and group health plans may not request your genetic information that we get from
this research.
• Health insurance companies and group health plans may not use your genetic information when making decisions
regarding your eligibility or premiums.
• Employers with 15 or more employees may not use your genetic information that we get from this research when
making a decision to hire, promote, or fire you or when setting the terms of your employment.
Be aware that this federal law does not protect you against genetic discrimination by companies that sell life
insurance, disability insurance, or long-term care insurance.
 Where can I find out about the study results? A description of this clinical trial will be available at
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.
The results of the genetic and biomarker tests will not be made available to you because the research is still in an
early phase and the reliability of the results is unknown.
 Who do I contact if I have question, concerns or feedback about my experience? This research has been reviewed
and approved by an Institutional Review Board (IRB) within the Human Research Protections Program (HRPP). To
share feedback privately with the HRPP about your research experience, call the Research Participants' Advocate
Line at 612-625-1650 (Toll Free: 1-888-224-8636) or go to z.umn.edu/participants. You are encouraged to contact the
HRPP if:
● Your questions, concerns, or complaints are not being answered by the research team.
● You cannot reach the research team.
● You want to talk to someone besides the research team.
● You have questions about your rights as a research participant.
● You want to get information or provide input about this research.
 Will I have a chance to provide feedback after the study is over? The HRPP may ask you to complete a survey that
asks about your experience as a research participant. You do not have to complete the survey if you do not want to.
If you do choose to complete the survey, your responses will be anonymous.
If you are not asked to complete a survey, but you would like to share feedback, please contact the study team or
the HRPP. See the "Investigator Contact Information" of this form for study team contact information and "Whom do I
contact if I have questions, concerns or feedback about my experience?" of this form for HRPP contact information.
 Can I be removed from the research without my OK? You could be removed from the study or have the infusion
stopped at any time for any reason when either the research doctor or your personal doctor feels further
participation could impact your medical care. Even if the infusion is stopped early, we will still continue to collect
information from your medical record.
 What happens if I am injured while participating in this research? In the event that this research activity results in an
injury, treatment will be available, including first aid, emergency treatment and follow-up care as needed. Care for
such injuries will be billed in the ordinary manner to you or your insurance company. If you think that you have
suffered a research related injury, let the study physicians know right away.
 Will I be compensated for my participation? You will not be compensated for being in this research study.


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What about more sensitive health information? Some
health information is so sensitive that it requires
your specific permission. If this research study
requires any of this sensitive information, the
__________________________________________
boxes below will be marked and you will be asked to
initial to permit this information to be made
available to the research team to use and share as
described in this Consent Form.
☐ My drug & alcohol abuse, diagnosis & treatment
records
☐ My HIV/AIDS testing records 
☒ My genetic testing records
☐ My mental health diagnosis/treatment records 
☐ My sickle cell anemia records
The table below shows what will happen at each visit:
Signing the Consent and HIPAA form
I have read (or someone has read to me) this form and I am aware that I am being asked to participate in a research
study.  I have had the opportunity to ask questions and have had them answered to my satisfaction.  I voluntarily
agree to participate in this study. 
I am not giving up any legal rights by signing this form.  I will be given a copy of this signed combined consent and
HIPAA research authorization form.
Is the patient able to give consent for the study?
Yes
No/Using Legally Authorized
Representative
Is the Legally Authorized Representative signing
consent?
Yes
No
Are you signing this consent in person (at the
In-person
hospital with study staff) or remotely?
Remote/via tele-medicine
All of my questions have been answered, and I have
Yes
been given the opportunity to decline this research.
No
Full Name of Study Participant
__________________________________


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E-mail
__________________________________
Phone number
__________________________________
Full name of Legally Authorized Representative
__________________________________
Legally Authorized Representative Relationship to the
Healthcare Power of Attorney
Participant?
Spouse
Parent
Adult Child
Adult Sibling
Other
If "Other" was selected above, please explain:
__________________________________
Signature of Participant
__________________________________________
(Participant Signature only. LAR to sign in below
section!)
Time and date
__________________________________
Signature of Legally Authorized Representative
__________________________________________
Date and time
__________________________________
Investigator/Research Staff
 I have explained the research to the participant or his/her representative before requesting the signature(s) above. 
There are no blanks in this document. All questions and concerns have been discussed prior to requesting signatures
in this document. A copy of this form has been given to the participant or his/her representative. No research
procedures or assessments were completed prior to the completion of the informed consent conversation. If this
consent was completed via telemedicine or remotely, a Remote Consent Attestation will be completed.
If the study participant is consenting, how was
capacity for consent assessed?
No concern
MacCAT-CR assessment
completed
Printed name of person obtaining consent
__________________________________
Signature of person obtaining consent
__________________________________________
Investigator date and time
__________________________________


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Witness(es)
Only required if subject does not read/write the language of the consent document
Are witness(es) required?
Yes
No
(Only required if consenting a participant or LAR
that does not read the language of the consent)
Witness 1
Printed name of witness
__________________________________
Signature of witness
__________________________________________
Date and time
__________________________________
Adapted from Combined Consent & HIPAA Authorization Template
(http://orrp.osu.edu/irb/investigator-guidance/consent/)