Clinical trial NCT02734147
Conditions: Sepsis
Sponsor: Christiana Care Health Services
Start date: 2016-04-01; Completion date: 2017-11-23
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Despite an organized treatment approach outlined in expert-consensus guidelines for sepsis with fluid resuscitation to treat hypovolemia, antibiotics to target the infectious insult, and vasopressors for hypotension, mortality rates for sepsis remain high and the incidence continues to rise, making sepsis the most expensive inpatient disease.

1. Recent research has described the therapeutic benefits associated with ascorbic acid treatment for sepsis.
2. Researchers objectives are to perform a randomized-controlled clinical trial investigating the ability of ascorbic acid(vitamin C) administration to decrease organ dysfunction in severe sepsis. The widespread occurrence of microvascular dysfunction in sepsis leading to tissue hypoxia, mitochondrial dysfunction, and adenosine triphosphate (ATP) depletion, gives rise to organ failure.
3. Patients with organ failure and sepsis (severe sepsis) are at a higher risk of death than patients with organ failure alone. Critically ill patients may have an increased requirement for ascorbic acid in sepsis and these patients frequently have levels below normal. Ascorbic acid administration, has been shown to correlate inversely with organ failure (human literature) and directly with survival (animal studies).

4,5 Intravenous ascorbic acid therapy decreases organ failure by providing a protective effect on several microvascular functions including improving capillary blood flow, decreasing microvascular permeability, and improving arteriolar responsiveness to vasoconstrictors. Defining the utility of novel agents to augment researchers care for severe sepsis is an important task as investigators continue the institutional focus on sepsis care.

Detailed description:

Arms: arm 1: Patients will receive 67 mg/kg IV ascorbic acid in 100 ml normal saline over 30 minutes every 8 hours (200 mg/kg/day) for 72 hours. arm 2: The placebo group will receive 100 ml 0.9% NaCl over 30 minutes every 8 hours for 72 hours.
Interventions: intervention 1: Ascorbic Acid intervention 2: Normal Saline
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Protocol Title: High Dose Intravenous Ascorbic Acid in Severe Sepsis 
NCT02734147 
Principal Investigator: 
Ryan Arnold, MD 
Protocol Version: 01.11.2017 


NEW PROTOCOL DEVELOPMENT FORM 
Page 1 of 9 
Emergency Medicine Research 
Ascorbic Acid and Sepsis DDD# 603204 Version Date 01.11.2017 
 
 
Part A 
Date of Request:  
12/21/15  
Name of Project/Study:  
The efficacy of intravenous ascorbic acid in patients with severe sepsis 
Principal Investigator:  
Ryan Arnold, MD 
 
Sub-Investigators:  
Jamie M. Rosini, PharmD  
Matthew Barrett, MD 
Colleen Ellis, FNP-C,MSN 
Brett Schuchardt 
Andrea Passarelli, PharmD 
Debra Marco, RN 
 
Category (Admin/Critical Care/Resident 
Education, Ultrasound, Other):   
Critical Care 
Lead Content Expert:  
Ryan Arnold, MD 
Target Start Date: 1/2016 
Target Date of Completion: 1/2017 
 
Part B 
1. Study Question 
a) Clearly define the reason(s) for the study:  
A phase I safety trial of intravenous (IV) ascorbic acid in patients with severe sepsis demonstrated 
that ascorbic acid may positively impact the extent of multiple organ failure. Our phase 2 study will 
investigate those efficacy findings through evaluating the ability of ascorbic acid to decrease organ 
dysfunction using a modified SOFA (mSOFA) score in severe sepsis.  
b) Clearly define the goal(s) for the study:  
This is a randomized, double-blind, placebo-controlled study that will evaluate the efficacy 
of high dose IV ascorbic acid in severe sepsis (mSOFA score, , hospital length of stay, 
mortality) 
 
c) Hypothesis Statement:  
Severe sepsis patients administered high dose IV ascorbic acid (200 mg/kg/day) will have 
improvements in their mSOFA scores compared to patients who receive placebo 
 
 
 
2. Background Information and Literature Review:   
Despite an organized treatment approach outlined in expert-consensus guidelines for sepsis with fluid 
resuscitation to treat hypovolemia, antibiotics to target the infectious insult, and vasopressors for 
hypotension, mortality rates for sepsis remain high and the incidence continues to rise, making sepsis the 
most expensive inpatient disease.i Recent research has described the therapeutic benefits associated with 
ascorbic acid treatment for sepsis.ii Our objectives are to perform a randomized-controlled clinical trial 


NEW PROTOCOL DEVELOPMENT FORM 
Page 2 of 9 
Emergency Medicine Research 
Ascorbic Acid and Sepsis DDD# 603204 Version Date 01.11.2017 
 
 
investigating the ability of ascorbic acid administration to decrease organ dysfunction in severe sepsis. The 
widespread occurrence of microvascular dysfunction in sepsis leading to tissue hypoxia, mitochondrial 
dysfunction, and ATP depletion, gives rise to organ failure.iii  Patients with organ failure and sepsis 
(severe sepsis) are at a higher risk of death than patients with organ failure alone. Critically ill patients 
may have an increased requirement for ascorbic acid in sepsis and these patients frequently have levels 
below normal. Ascorbate, the redox state of ascorbic acid, has been shown to correlate inversely with 
organ failure (human literature) and directly with survival (animal studies).iv,v Intravenous ascorbic 
acid therapy decreases organ failure by providing a protective effect on several microvascular functions 
including improving capillary blood flow, decreasing microvascular permeability, and improving arteriolar 
responsiveness to vasoconstrictors. Defining the utility of novel agents to augment our care for severe 
sepsis is an important task as we continue our institutional focus on sepsis care.   
 
 
3. Study Plan/Design/Methodology 
The primary goal of this interventional pilot study is to apply positive initial efficacy data with ascorbic 
acid in the severe sepsis patient population to calculate the effect size necessary to power a multi-center 
randomized controlled trial. The sample size estimate is of critical importance for the randomized 
controlled trial that will be powered to show the superiority of IV ascorbic acid compared to standard care 
in the severe sepsis population to decrease the incidence of organ failure and death. 
 
This is a prospective, double-blind, placebo-controlled study. Patients will be randomized within 
12 hours from ED arrival using block randomization per 10 patients with pre-randomization 
envelopes generated using an online randomizer. The study blind will be established and 
maintained by the pharmacy department where the study drug will be prepared and dispensed. 
Subjects will be assigned to one of two groups: placebo or ascorbic acid. The ascorbic acid group 
will receive 67 mg/kg IV ascorbic acid in approximately 115 ml normal saline over 30 minutes 
three times a day (TID) (200 mg/kg/day) for 72 hours. Actual body weight or patient stated weight 
will be used to calculate a dose with a maximum daily dose of 25 grams.  The placebo group will 
receive approximately 115  ml 0.9% NaCl over 30 minutes TID for 72 hours. The study intends on 
enrolling 20 patients in each group.  
 
 
 
 
 
4. Definition of the Study Population 
a) What patients meet the criteria for inclusion into this study? 
Inclusion criteria 
Patients with: 
1) A suspected or confirmed infection with an order for intravenous antibiotics or antiviralsvi,vii 
2)  
≥ 2 Quick SOFA (qSOFA) score OR a PIRO (Predisposition, Infection, Response, and Organ 
Failure) score ≥ 10 
Definition of qSOFA 
a) altered mentation 
b) respiratory rate ≥22 breaths per minute 
c) systolic blood pressure ≤ 100 mmHg 


NEW PROTOCOL DEVELOPMENT FORM 
Page 3 of 9 
Emergency Medicine Research 
Ascorbic Acid and Sepsis DDD# 603204 Version Date 01.11.2017 
 
 
Exclusion criteria 
1) Age < 18 years 
2) Pregnancy or breastfeeding 
3) Requirement for immediate surgery within the treatment protocol timeframe 
4) Inability to obtain written informed consent from subject or surrogate 
5) Patient to receive comfort measures only 
6) Patient diagnosed with G6PD 
7) Patient diagnosed with active Hepatitis B 
8) Patient with known  history of Kidney Stones 
 
b) Clearly define time period:  
We intended to enroll for a one year time period or until 40 patients are enrolled. 
     
c) Based on criteria in a) and b) – what potential information sources could the study   
population be derived from:. 
Patients will be screened in the emergency department for inclusion and exclusion criteria 
and if met, will be provided with informed consent. 
 
 
6. Develop Data Collection Plan 
a) Develop data dictionary:  
Data will be collected and managed using REDCap (Research Electronic Data Capture).  Organ 
failure will be assessed using a modified Sequential Organ Failure Assessment (mSOFA) score (see 
below). Scores will be calculated at enrollment, at 24, 48, and 72 hours. Laboratory data and 
physiological measures for calculating mSOFA scores will be monitored daily and recorded. Plasma 
ascorbic acid levels will be collected at enrollment and at 32 hours or prior to the 5th dose). Ascorbic 
acid levels will be sent out for analysis as per standard send out laboratory procedures for ascorbic 
acid levels.   The mSOFA calculation will be performed at time 0 and daily.  The investigative team 
will monitor for adverse events such as hypotension (defined as a systolic blood pressure < 90 
mmHg), tachycardia (defined as an increase in heart rate of 20 beats per min), nausea, vomiting, or 
allergic reactions (rash, urticaria, hives, etc) prior to infusion (+/- 30 mins) and post infusion (+/- 30 
mins). If an adverse event listed above is observed, the drug infusion will be stopped. If the patient 
becomes unstable, a rapid response team (RRT) alert will be called (floor patients) or a higher level of 
care consultation will be placed (ICU patients) as per hospital protocol.  If the event resolves, the drug 
infusion will be restarted at 50% of the original infusion rate. If the event reoccurs, the patient will be 
removed from the study. A physical exam (see attached form) will be performed within the scope of 
practice of a practitioner caring for the patient or investigative practitioner and reviewed by one of the 
investigative practitioners prior to the first infusion and daily during the study period. Adverse events 
including hypernatremia (defined as > 146 mmol/L) will be monitored daily and documented by the 
investigators for 4 days after initial infusion. The investigators will assess these events to determine if 
clinically significant and relevant to the study drug.  The patient will be followed until discharge for 
serious adverse events and death. Because high doses of ascorbic acid interact with point of care 
glucose testing (falsely elevates glucose reading), nurses will be educated that if a patient is on a 


NEW PROTOCOL DEVELOPMENT FORM 
Page 4 of 9 
Emergency Medicine Research 
Ascorbic Acid and Sepsis DDD# 603204 Version Date 01.11.2017 
 
 
sliding scale insulin regimen, that the glucose labs should be sent to the lab and point of care 
measurements avoided for insulin administration. 
A Data Monitoring Safety Board (DSMB) will review all outcome and safety data at 6 months or after 
the enrollment of 20 patients whichever comes first. The DSMB will meet again if needed based on 
the findings of their initial data review. Mortality (all-cause in-hospital mortality) will also be 
measured. Each patient will also be followed for the secondary outcome assessment of resource 
utilization 1) ICU length of stay; 2) In-hospital length of stay; and 3) In-hospital charges. 
Data elements to be collected: age, gender, race, source of sepsis, systemic inflammatory 
response (temperature, heart rate, white blood cell count, bands), mSOFA score (see below), 
ascorbic acid levels at baseline and approximately 31:30 hours (30 minutes prior to 5th dose), 
hospital length of stay, ICU length of stay, in-hospital mortality, in-hospital charges. 
 
PIRO: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Points 
Points
Points
Points
Age < 65
0 Pneumonia
4 Respiratory rate > 20
3 BUN > 20
2
Age 65-80
1 Skin/soft tissue infection
0 Band > 5%
1
Respiratory failure- intubated, 
CPAP, BiPaP
OR
Hypoxemia- oxygen 
requirement higher than 
baseline
3
Age > 80
2 Any other infection
2 Heart rate > 120
2 Lactate > 4.0
3
COPD
1
SBP < 70
4
Liver disease
2
SBP 70-90
2
Nursing home resident
2
SBP > 90
0
Malignancy without metastases
1
Platetlet < 150,000
2
Malignany with metastases
2
Total possible points
9
4
6
14
P  score
I score
R score
O score


NEW PROTOCOL DEVELOPMENT FORM 
Page 5 of 9 
Emergency Medicine Research 
Ascorbic Acid and Sepsis DDD# 603204 Version Date 01.11.2017 
 
 
mSOFA (bilirubin removed): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0
1
2
3
4
Respiration
SPO2/FiO2
> 400
< 400
< 300
< 200
< 100
Coagulation
Plateles x 103/mm3
> 150
< 150
< 100
< 50
< 20
Cardiovascular
Hypotension, dose mcg/kg/min
MAP > 70 MAP < 70
Dopamine ≤ 5  
ANY Dobutamine
Dopamine > 5
Norepinephrine ≤ 0.1
Epinephrine ≤ 0.1
Phenylephrine ≤ 0.8
Dopamine > 15
Norepinephrine > 0.1
Epinephrine > 0.1
Phenylephrine > 0.8
ANY Vasopressin
CNS
Glasgow Coma Score
15
13 - 14
10 - 12
6 - 9
<6
Renal
Creantinine (mg/dL)
<1.2
1.2 - 1.9
2.0 - 3.4
3.5 - 4.9
≥ 5.0


NEW PROTOCOL DEVELOPMENT FORM 
Page 6 of 9 
Emergency Medicine Research 
Ascorbic Acid and Sepsis DDD# 603204 Version Date 01.11.2017 
 
 
 
Protocol procedures: 
 
 
 
 
 
 
Hours 
Activity 
Baseline 
Enrollment 
(prior to study 
drug) 
0 
8 
16 
24 
31.5 
32 
40 
48 
56 
64 
72 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Study Drug/Placebo 
Infusion 
 
 
X X 
X 
X 
 
X 
X 
X 
X 
X 
X 
mSOFA Score 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Plasma ascorbic level 
 
 
X 
 
 
 
 
X 
 (30 mins 
prior to 
5th dose) 
 
 
 
 
 
 
H&P 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs  
(0-30 minutes PRE 
and POST study drug 
infusion) 
 
 
X X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
Adverse 
Events/Serious 
Adverse Events 
 
 
X X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
d) Location of study records and database.  
REDCap (a secure, web-based data collection and storage tool) and secured CCHS hard drive 
 
a) Determine if database will be used for data collection/entry: If so, which one.  
REDCap 
 
 
b) Sampling considerations:  
A sample size of 40 patients was determined to be adequate to determine initial efficacy data 
with ascorbic acid in severe sepsis patients and define a sample size needed to study this 


NEW PROTOCOL DEVELOPMENT FORM 
Page 7 of 9 
Emergency Medicine Research 
Ascorbic Acid and Sepsis DDD# 603204 Version Date 01.11.2017 
 
 
outcome through a multicenter trial. 
 
e) Define how and when data will be collected:   
Data will be collected at CCHS using PowerChart. 
 
 
7. Develop Analysis Plan (Consultations w/ Value Institute or Mia Papas) 
Data analysis of all assimilated data will take place over 2 months with statistical review of the primary 
outcome assessment and secondary endpoints associated with the intervention by a Value Institute 
biostatistician. We will perform an intention to treat analysis with a planned secondary analysis of patients 
with low initial ascorbic acid levels. 
 
 
 
 
8. Risks/Benefits 
a) What are the potential risks to the study population?   
Risks associated with ascorbic acid include nausea/vomiting, , false elevations in point 
of care blood glucose testing, and hyperoxaluria  
b) What are the benefits of this study?  
Expected benefits of this study are decreased rates of organ dysfunction and mortality 
with preliminary data to study this population in a larger multicenter study.  
 
 
 
9. Data Communication Plan (Where will results be presented?) 
We intend on submitting our results to the Society of Academic Emergency Medicine or the 
Society of Critical Care Medicine annual research conference and then publishing the manuscript 
in a relevant journal.  
 
 
 
10. References 
1. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: 
international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 
2013;41:580-637. 
2. Fowler AA, Syed AA, Knowlson S, Schulthorpe R, Farthing D, DeWilde C, et al. Phase I safety trial of 
intravenous ascorbic acid in patients with severe sepsis. J Translat Med. 2014.12:32. 
3. Wilson JX. Mechanism of action of vitamin C in sepsis: ascorbate modulates redox signaling in endothelium. 
Internat Union Biochem Molec Biol. 35(1):5-13. 
4. Borrelli E, Roux-Lombard P, Graua GE, Girardin E,  Ricou B, Dayer J, 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):392-7. 
5. Wu F, Wilson JX, Tyml K. Ascorbate protects against impaired arteriolar constriction in sepsis by inhibiting 
inducible nitric oxide synthase expression. Free Rad Biol Med. 2004;37(8):1282-9. 
6. Grissom CK, Brown SM, Kuttler KG, Boltax JP, et al. A modified sequential organ failure assessment (MSOFA) 
score for critical care triage. Disaster Med Public Health Prep. 2010;4(4): doi:10.1001/dmp.2010.40 


NEW PROTOCOL DEVELOPMENT FORM 
Page 8 of 9 
Emergency Medicine Research 
Ascorbic Acid and Sepsis DDD# 603204 Version Date 01.11.2017 
 
 
 
11. Timeline and Publication Plan  
 
Date 
Task 
12/2015 
Present proposal to EM Faculty/Content Expert 
12/2015 
Present proposal to Research Governance 
*Research Governance meets the 1st and 3rd Thursday of each month 
12/2015 
Submit proposal to IRB 
01/2016 
Initiate study; Enrollment/Data collection  
01/2016 
Complete first sections of the manuscript 
06/2016 
DSMB review 
01/2017 
Complete data collection 
01/2017 
Data analysis 
02/2017 
Abstract submission/Communication of results 
04/2017 
Complete draft manuscript 
05/2017 
Present project at regional/national forum 
*Note:  Travel and conference expenses will be paid according to 
program SOPs upon receipt of draft manuscript. 
07/2017 
Submit manuscript to journal and close out project with IRB 
 
 
 
 
 
 
 
NOTABLE RESEARCH FORUMS and SUBMISSION DEADLINES 
FORUM 
DEADLINE 
CONFERENCE 
Society of Academic 
Emergency Medicine 
(SAEM) 
 
Early December 
 
Mid May 
American College of 
Emergency Physicians 
Early April 
End October 
National Association of 
EMS Physicians 
(NAEMSP) 
 
Mid August 
 
Mid January 
American Academy of 
Emergency Medicine 
(AAEM) 
 
Mid October 
 
January/February 
Council of Emergency 
Medicine Residency 
Directors (CORD) 
 
December 
 
 
March/April 
 


NEW PROTOCOL DEVELOPMENT FORM 
Page 9 of 9 
Emergency Medicine Research 
Ascorbic Acid and Sepsis DDD# 603204 Version Date 01.11.2017 
 
 
                                                          
i Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: 
international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 
2013;41:580-637. 
ii Fowler AA, Syed AA, Knowlson S, Schulthorpe R, Farthing D, DeWilde C, et al. Phase I safety trial of 
intravenous ascorbic acid in patients with severe sepsis. J Translat Med. 2014.12:32. 
iii Wilson JX. Mechanism of action of vitamin C in sepsis: ascorbate modulates redox signaling in 
endothelium. Internat Union Biochem Molec Biol. 35(1):5-13. 
iv Borrelli E, Roux-Lombard P, Graua GE, Girardin E,  Ricou B, Dayer J, 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):392-7. 
v Wu F, Wilson JX, Tyml K. Ascorbate protects against impaired arteriolar constriction in sepsis by 
inhibiting inducible nitric oxide synthase expression. Free Rad Biol Med. 2004;37(8):1282-9. 
vi Kaukonen KM, Bailey M, Pilcher D, Cooper DJ, Bellomo R. Systemic inflammatory response syndrome 
criteria in defining severe sepsis. N Engl J Med. 2015;372:1629-38. 
vii Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 
SCCM/ESICM/SCCP/ATS/SIS international sepsis definitions conference. Intens Care Med. 2003;29:530-
8.