Clinical trial NCT03422159
Conditions: Sepsis, Severe Septic Shock
Sponsor: Community Medical Center, Toms River, NJ
Start date: 2018-02-05; Completion date: 2019-08-27
Enrollment: 140 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study has been created to compare the addition of intravenous (IV) vitamin C, thiamine, and hydrocortisone to the usual standard of care of sepsis and septic shock. Sepsis is a possibly life-threatening condition in which a patient may have organ dysfunction due to an infection. Septic shock is defined as low blood pressure and organ dysfunction that do not improve after administering IV fluids. Standard of care for sepsis and septic shock include early administration of IV antibiotics, IV fluids, and vasopressors if need be to provide oxygen to vital organs.

A large amount of experimental data has shown that vitamin C and corticosteroids decrease the release of inflammatory substances which may lead to organ failure seen in sepsis. Vitamin C and corticosteroids also improve blood flow to vital organs and increase the body's ability to respond well to vasopressor medications used in septic shock. Low blood levels of both thiamine and vitamin C are common in sepsis. The study will be placebo controlled, meaning one group will receive vitamin C, thiamine, and hydrocortisone, and the other will receive an inactive substance ("placebo"). The goal of the study is to compare the effects of receiving vitamin C, thiamine, and hydrocortisone (along with the standard sepsis care) versus placebo and standard sepsis care.

Detailed description:
The global burden of sepsis is substantial with an estimated 15 to 19 million cases per year; the vast majority of these cases occur in low income countries. With more timely diagnosis and improvement in supportive care the 28-day mortality from sepsis in high income countries has declined to about 25%, however, the mortality from septic shock remains as high as 45%. Moreover, the mortality from sepsis and septic shock in low income countries is reported to be as high as 60%. In addition to short term mortality, septic patients suffer from a numerous short- and long-term complications and are at an increased risk of death for up to five years following the acute event. Over the last 3 decades over 100 phase II and phase III clinical trial have been performed testing various novel pharmacologic agents and therapeutic intervention in an attempt to improve the outcome of patients with sepsis and septic shock; all of these studies have failed to show an improvement in patient outcomes. New therapeutic approaches to sepsis are desperately required; considering the global burden of sepsis these interventions should be effective, cheap, safe and readily available.

A large body of experimental data has demonstrated that both corticosteroids and intravenous vitamin C reduce activation of nuclear factor ƘB (NFƘB) attenuating the release of pro-inflammatory mediators, reduce the endothelial injury characteristic of sepsis thereby reducing endothelial permeability and improving macrocirculatory flow, augment the release of endogenous catecholamines and enhance vasopressor responsiveness. In animal models these effects have resulted in reduced organ injury and increased survival. Corticosteroids have been evaluated in several clinical trials, with meta-analysis of these trials demonstrating somewhat conflicting outcomes. Low-dose stress corticosteroids have proven to be safe with no increased risk of clinically important complications. While corticosteroids decrease vasopressor dependency the effect on survival is less clear.

Several studies have investigated the use of intravenous vitamin C in critically ill patients. Nathens et al randomized 595 surgical ICU patients (91% trauma patients) to receive intravenous vitamin C and vitamin E for up to 28 days.The vitamin combination was associated with a significant reduction in the incidence of multiple system organ failure (p=0.04) with a trend to reduced mortality and length of ICU stay. No adverse effects were noted with the vitamin combination. Fowler et al performed a pilot study in 24 patients with severe sepsis and septic shock. In this study patients were randomized to placebo (n=8), low dose intravenous vitamin C (50 mg/kg) (n=8) or high dose vitamin C (200mg/kg). Vitamin C attenuated the inflammatory response with both doses of the vitamin being devoid of any side effects. Although the Sequential Sepsis Related Organ Failure Score (SOFA) fell significantly in both treatment arms the study was underpowered to determine any outcome benefit. Zabet and colleagues performed a randomized controlled trial (RCT) in which they evaluated the role of intravenous vitamin C in a dose of 100 mg/kg/day (about 7g/day) in 28 surgical ICU patients with septic shock. In this study the mean dose of norepinephrine and duration of norepinephrine administration were significantly lower in the ascorbic acid than the placebo group. The 28-day mortality was significantly lower in the ascorbic acid than the placebo group (14% vs. 64%, p = 0.009). No side effects related to the vitamin C infusion were reported. Tanaka et al randomized 37 patients with severe burn to very high dose vitamin C (about 110g/day) or placebo. Patients who received vitamin C required less fluid resuscitation with a trend towards reduced length of stay and mortality. No adverse effects were noted with the very high dosages of vitamin C. Several studies have administered vitamin C in doses exceeding 100g/day as adjuvant therapy in patients with cancer with no discernable side effects. Vitamin C appears to be toxic to normal human cells (not cancer cells) at a concentration on greater than 25 millimole (mM). A dose of 6g/day will achieve a steady state serum concentration of about 240 micromole (uM) which is about 100 times less than the dose required to cause cellular toxicity. The package insert for vitamin C lists no contraindications or adverse effects of the drug and states that as much as "6 grams has been administered without evidence of toxicity". The only reported restriction to the use of high dose intravenous vitamin C is in patients with known glucose-6-phosphate deficiency (G6PD) in whom hemolysis has been reported. It is important to recognize that patents with sepsis predictably have very low serum vitamin C levels, which can only be corrected with intravenous vitamin C in a dose of more than 3gm per day. The low or undetectable levels of vitamin C likely result from the metabolic consumption of the molecule as well as increased renal losses. Furthermore, unlike all other mammals, primates and guinea pigs are unable synthesize vitamin C is due to mutations in the L-gulono-\_-lactone oxidase (GLO) gene which codes for the enzyme responsible for catalyzing the last step of vitamin C biosynthesis. In almost all species, except humans and guinea pigs, vitamin C production increases during stress and is secreted by the adrenal gland; in these species vitamin C is best considered a stress "hormone". Vitamin C is an essential cofactor for the production of corticosteroids and catecholamines by the adrenal gland. Vitamin C has been shown to reverse adrenal suppression caused by induction doses of etomidate during anesthesia.

Ascorbate donates a single electron in all its redox reactions, generating the ascorbate radical. This radical is not very reactive with anything but itself. Dismutation of two ascorbate radicals forms a molecule each of ascorbate and dehydroascorbate. Hydrolysis of the lactone ring of dehydroascorbate irreversibly converts it to 2,3-diketo-1-gulonic acid which is then converted to oxalate. Oxalate is normally excreted by the kidney and serum levels will increase with renal impairment. In patients with renal impairment receiving mega-dose vitamin C, supersaturation of serum with oxalate may result in tissue deposition as well as crystallization in the kidney. Glyoxylate, a byproduct of intermediary metabolism, is either reduced to oxalate or oxidized to carbon dioxide (CO2) by the enzyme glyoxylate aminotransferase; thiamine pyrophosphate is a co-enzyme required for this reaction. Thiamine deficiency increases the conversion of glyoxylate to oxalate resulting in hyper- oxalosis. Donnino and colleagues have demonstrated that thiamine deficiency is common (32%) in patients with sepsis and that treatment with thiamine in these patients reduces mortality. In a post-hoc analysis of this study these authors demonstrated that thiamine decreased the risk of acute kidney injury and the required for renal replacement therapy in all treated patients.

It has previously been suggested that "...the best hope for therapeutic advances \[in sepsis\] will depend on broad-base targeting, in which multiple components are targeted at the same time." Such combination "chemo-therapy" targeting multiple biological pathways is the standard approach in the treatment of malignant disease. While the benefits of vitamin C, hydrocortisone, and thiamine alone are likely limited, the investigators believe that these medications act synergistically to reduce the risk of organ failure and death in patients with sepsis. This hypothesis is supported previous research and more recently a set of elegant experiments performed by Barabutis et al. Using a validated pulmonary endothelial monolayer model, these authors demonstrated that hydrocortisone together with vitamin C protected the vascular endothelium from damage by endotoxin while neither agent alone had this effect. Previous research has demonstrated that vitamin C reverses oxidation of the glucocorticoid receptor (GR) a likely manifestation of sepsis. Oxidation of the GR limits binding of the GR to both ligand and DNA responsive units decreasing the activity of glucocorticoids. Furthermore, glucocorticoids increase the expression of the sodium vitamin C transporter-2 (SVCT-2) which is an essential transport protein necessary for vitamin C to be transported intracellularly.

The investigators therefore propose that a "metabolic resuscitation protocol" including vitamin C, corticosteroids and thiamine will limit the development of organ failure and reduce mortality in patients with severe sepsis and septic shock. This postulate is supported by the preliminary findings by Marik et al. In a retrospective before-after clinical study, these authors compared the outcome and clinical course of consecutive septic patients treated with intravenous vitamin C, hydrocortisone and thiamine during a 7-month period (treatment group) compared to a control group treated in during the preceding 7 months. The primary outcome was hospital survival. A propensity score was generated to adjust the primary outcome. There were 47 patients in both treatment and control groups with no significant differences in baseline characteristics between the two groups. The hospital mortality was 8.5% (4 of 47) in the treatment group compared to 40.4% (19 of 47) in the control group (p \< 0.001). The propensity adjusted odds of mortality in the patients treated with the vitamin C protocol was 0.13 (95% CI 0.04-0.48, p=0.002). The SOFA score decreased in all patients in the treatment group with none developing progressive organ failure. Vasopressors were weaned off all patients in the treatment group, a mean of 18.3 ± 9.8 hours after starting treatment with vitamin C protocol. The mean duration of vasopressor use was 54.9 ± 28.4 hours in the control group (p\<0.001). The results of this study provide sufficient information for the design of an adequately powered, pragmatic randomized controlled trial.

Arms: arm 1: Based on published clinical data, vitamin C pharmacokinetic modeling, the package insert as well as the preliminary study by Marik et al, Vitamin C will be administered as an intravenous dose of 6gm per day divided in 4 equal doses. This dosage is reported to be devoid of any complications or side effects. Hydrocortisone will be dosed according to the consensus guidelines of the American College of Critical Care Medicine. Thiamine will be administered according to current recommendations in a dose of 200mg q 12 hourly. This will be continued for 4 days, or less if discharged from the ICU prior. arm 2: Vitamin C placebo will consist of an identical bag of 100mL normal saline (but with no vitamin C) and will be labeled "Vitamin C or Placebo". Placebo will be infused over 30 minutes as per the infusion instructions of the active vitamin and protected from light with a brown bag. Hydrocortisone placebo will be provided as an identical 3mL syringe as 1mL of normal saline.The thiamine placebo will be placed in a 50mL bag of Normal Saline labeled "Thiamine 200mg or Placebo" and run over 30 minutes (100mL/hr) Placebo patients will receive a matching 50mL bag of Normal Saline. All of these will be given for up to 4 days, or less if discharged from the ICU prior.
Interventions: intervention 1: Ascorbic Acid intervention 2: Thiamine intervention 3: Hydrocortisone intervention 4: Sodium Chloride 0.9%
Intervention descriptions: intervention 1: Ascorbic Acid 1.5g IV piggyback every 6 hours for 4 days (or discharge from ICU if prior to 4 days). intervention 2: Thiamine 200mg IV piggyback every 12 hours for 4 days (or discharge from ICU if prior to 4 days). intervention 3: Hydrocortisone 50mg IV push every 6 hours for 4 days (or discharge from ICU if prior to 4 days). intervention 4: Placebo "Ascorbic Acid" 100mL IV piggyback every 6 hours, Placebo "Thiamine" 50mL IV piggyback every 12 hours, and Placebo "Hydrocortisone" IV push every 6 hours for 4 days (or discharge from ICU if prior to 4 days).

Protocol documents:
ICF_005.pdf: 
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INFORMED CONSENT FORM 
TITLE: Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the 
Early Treatment of Sepsis. 
 
NAME OF INSTITUTION: Community Medical Center, Monmouth Medical Center Southern Campus 
 
INSTITUTION ADDRESS:   
Community Medical Center 
99 West Rt 37, Toms River, NJ 08755 
 
Monmouth Medical Center Southern Campus 
600 River Ave, Lakewood, NJ, 08701 
 
NAME OF IRB: Community Medical Center IRB  
 
IRB/EC APPROVAL DATE: June 12th, 2017 
 
 
Introduction: 
You are being invited to take part in a research study (also known as a clinical trial) of three drugs, 
ascorbic acid (Vitamin C), thiamine, and hydrocortisone. To allow you to make an informed decision as 
to whether or not you want to take part in this research study, this document describes the purpose of 
the study, your rights and obligations, the procedures needed by the study, and the possible benefits 
and risks of participating in the study. Please take time to read the following information carefully. Feel 
free to talk with your doctor, nurse, family, or friends before deciding. If you have any questions, you 
may ask your study doctor, Dr. Jose Iglesias, for more explanation. 
 
Study Purpose: 
This study has been created to compare the addition of intravenous (IV) vitamin C, thiamine, and 
hydrocortisone to the usual standard of care of sepsis and septic shock. Sepsis is a possibly life-
threatening condition in which a patient may have organ dysfunction due to an infection. Septic shock is 
defined as low blood pressure and organ dysfunction that do not improve after administering IV fluids. 
Standard of care for sepsis and septic shock include early administration of IV antibiotics, IV fluids 
(sodium chloride), and vasopressors (medications used in the treatment of very low blood pressure) if 
need be to provide oxygen to vital organs.  


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A large amount of experimental data has shown that vitamin C and corticosteroids (hormones in your 
body that react in response to severe sickness) decrease the release of inflammatory substances which 
may lead to organ failure seen in sepsis. Vitamin C and corticosteroids also improve blood flow to vital 
organs and increase the body’s ability to respond well to vasopressor medications used in septic shock. 
Low blood levels of both thiamine and vitamin C are common in sepsis. The study will be placebo 
controlled, meaning one group will receive vitamin C, thiamine, and hydrocortisone, and the other will 
receive an inactive substance (“placebo”). The goal of the study is to compare the effects of receiving 
vitamin C, thiamine, and hydrocortisone (along with the standard sepsis care) versus placebo and 
standard sepsis care.  
 
Who is sponsoring and conducting this research? 
The research is not sponsored by any company and is being run independently by hospital practitioners. 
 
Who has reviewed this research? 
This study has been approved by the Institutional Review Board (IRB) of Community Medical Center, in 
conjunction with the IRB at Monmouth Medical Center as the regional IRB for Monmouth Medical 
Center Southern Campus, an organization that is responsible for protecting the rights and safety of 
participants who take part in research studies.  
 
How many people will take part in the study? 
Approximately 140 to 200 patients will take part in this study at this hospital. 
 
What are my obligations if I take part in this study? 
If you decide to take part in this study, you will be required to do the following: 
 
Inform study personnel about any symptoms you may have during or after administration of 
study medication 
 
Inform study personnel if you believe you might be pregnant 
 
Inform study personnel if you change your mind about participating in the study 
 
Inform your other doctors that you are taking part in this study 
 
Take the study treatment as instructed 
 
How long will I be in the study? 
You will be asked to receive an infusion of vitamin C, thiamine, and IV hydrocortisone or placebo 
immediately after you are enrolled in the study. Your total length of time in the study will be about 28 
days, including screening, study drug dosing, and the follow-up period. 
 


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What will happen if I take part in this research study? 
 
Screening assessments: 
Before you begin the main part of the study, you will need to undergo the following tests or procedures 
to find out if you can be in the main part of the study. Some of these tests or procedures may be part of 
your regular medical care and may be done even if you do not take part in the study. If you have had 
some of them recently, they may not need to be repeated. 
 
Discussion of this study and review and signing of this Informed Consent Form 
 
Recording of your demographic information, including your age, sex, and weight 
 
Review of your medical history 
 
Measurement of your vital signs 
 
Collection of blood for standard laboratory tests (including blood chemistry, blood cultures, and 
blood counts), and a pregnancy test if applicable 
 
Admitting diagnosis and possible site of infection 
 
Study drug dosing: 
You will be randomly assigned to one of the following drug dosing groups: 
1. Treatment group 
 
Vitamin C 1.5g in Normal Saline 100mL every 6 hours for 4 days (or less if discharged from the 
ICU) 
 
Thiamine 200mg in Normal Saline 50mL every 12 hours for 4 days (or less if discharged from the 
ICU) 
 
Hydrocortisone 50mg/1mL every 6 hours for 4 days (or less if discharged from the ICU) 
 
2. Placebo group 
 
Normal saline 100mL every 6 hours for 4 days (or less if discharged from the ICU) 
 
Normal saline 50mL every 12 hours for 4 days (or less if discharged from the ICU) 
 
Normal saline 1mL IV every 6 hours for 4 days (or less if discharged from the ICU) 
If you are placed into the placebo group, you will not receive the test drugs (vitamin c, thiamine, and 
hydrocortisone). If you are placed into the treatment group, you will not receive the placebo. When you 
are “randomized” into the study, this means that you are put into a group by chance (like tossing a coin). 
Neither you nor your study doctor may choose the group you will be in. You will have an equal chance of 
being placed in either group. Neither you nor your study doctor will know which treatment group you 
receive. If your safety is at risk, your study doctor can find out which treatment group you are receiving. 
An IV line (needle in your vein) will be started for the administration of the study drug or placebo. The 
study drug or placebo will be administered to you intravenously.  
 
 


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Assessments during the study: 
If the screening assessments show that you can be in the main part of the study, and you choose to take 
part, you will undergo the following tests and procedures at the following visit time points. Most of 
these tests and procedures are part of your regular medical care, but they may be done more often for 
this study. 
 
Admission order to ICU from attending physician for sepsis or septic shock 
 
Blood tests will be taken for the following: 
o Vitamin C level 
o Thiamine level 
o Procalcitonin 
 
Routine laboratory data for 4 days including: 
o Serum creatinine 
o White cell count (WBC) 
o Platelet count 
o Total bilirubin 
o PaO2/FiO2 ratio 
o Procalcitonin (repeated only on day 4) 
o Lactate level 
o Urine oxalate (day 4) 
 
Review of blood culture results 
 
Assess for acute kidney injury through review of blood chemistry test 
 
Use of vasopressor medication will be recorded 
 
Assessments 
o Acute Physiology and Chronic Health Evaluation (APACHE) II and APACHE IV scores will 
be recorded upon admission, which are scores used in the ICU to predict patient 
outcomes 
o Daily Sepsis-related Organ Failure Assessment (SOFA) score will be recorded for the first 
4 days to describe organ dysfunction or failure 
o Daily urine output (for the first 4 days) 
o Fluid balance after 24 and 72 hours 
 
Length of stay 
o ICU 
o Hospital 
o Discharge location 
 
28-day follow-up via phone call from study doctor or study staff will review if you have had any 
health issues during your time in the study 
 
Can I stop being in the study? 
Yes. You can decide to stop participating at any time. Tell the study doctor if you are thinking about 
stopping or decide to stop. The study doctor will tell you how to stop safely.  


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The study doctor may stop you from taking part in this study at any time, even if you want to continue, 
for reasons that include but are not limited to the following: 
 
Your safety would be at risk if you continued in this study. 
 
You failed to adequately follow instructions or procedures.  
 
You need a treatment that is not allowed by the study. 
 
The study has been cancelled. 
In any case, you will still continue to receive appropriate medical care for your disease.  
 
What are the possible side effects or risks of being in the study? 
You may have side effects from the drugs or procedures used in this study. Side effects can vary from 
mild to very serious, and they may vary from person to person. Everyone taking part in the study will be 
watched carefully for any side effects. However, the study doctor does not know all of the side effects 
that could occur.  
 
Side effects known to be associated with Vitamin C: 
Vitamin C has known to be tolerated well in doses much higher than those used in the treatment group 
of this study. One risk associated with intravenous vitamin C at high doses is the development of oxalate 
crystals which may form in the kidney and can affect its function at doses >40g per day (Buehner 2016). 
Patients who have a hypersensitivity to vitamin C will be excluded from the study.  
 
Side effects known to be associated with Thiamine: 
The safety of 400mg per day of thiamine is well studied and universally accepted. Side effects of 
intravenous thiamine may include flushing, nausea, sweating, itching, or weakness. Patients who have a 
hypersensitivity to thiamine will be excluded from the study.  
 
Side effects known to be associated with Hydrocortisone: 
Patients may experience sleep problems, mood changes, bruising or discoloration, increased sweating, 
headache, dizziness, nausea, stomach pain, heartburn, bloating, convulsions, and/or increased blood 
sugar. Patients who have a hypersensitivity to hydrocortisone will be excluded from the study. 
 
Possible risks and discomfort associated with drawing blood: 
During this study, small amounts of blood (approximately 2 to 3 tablespoons) will be drawn and used for 
tests that allow your study doctors to see how you are doing. Drawing blood may cause pain where the 
needle is inserted. There is a small risk of bruising or infection at the place where the needle is inserted. 
Some people experience dizziness, upset stomach, or fainting when their blood is drawn. 
 


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Possible risks with Placebo:  
Some people in the study will get placebo instead of treatment medications. Placebo is a substance that 
looks like a drug but has no drug in it.  Ask the study doctor or study staff if you have questions about 
placebo. 
 
Possible risks with study drug infusion: 
Treatment medications will be administered intravenously (IV).  While IV’s are used fairly frequently, 
they do run some risks, such as risk for infection or infiltration.  Infiltration occurs when fluid infused 
escapes the vein and begins to swell the tissue around it.  Since this can look dramatic quickly, it usually 
noticed and treated.  Should you see swelling start to occur at or around the IV site, please bring this to 
the attention of a nurse or a study doctor right away. 
Other risks of study drug infusion include: 
 
Irritation of the vein.  Your skin near the vein could become warm, swell, hurt, or get red. 
 
Damage to your vein. 
 
Damage to your skin or tissue around the injection site. 
 
Too much or too little of the study drug may be given to you. 
 
Increase or decrease in electrolyte levels (the amount of certain salts and other chemicals in 
your blood), causing health problems. 
 
A blood clot or an air bubble could form, which could block a blood vessel in another part of 
your body. 
Some of these problems could be very serious. 
 
Are there benefits to taking part in the study? 
There is no guarantee that you will receive any benefits from this study. Taking part in this study may or 
may not cause your health to improve. Information from this study may help doctors learn more about 
vitamin C, thiamine, and hydrocortisone use in sepsis and septic shock. This information may benefit 
other patients with sepsis and septic shock in the future. 
 
Will I be told about new information? 
During the study, you will be told in a timely manner about new information or changes in the study that 
may affect your health or your willingness to continue in this study. When informed of this new 
information, if you agree to continue in the study, you, or your legally authorized representative will be 
asked to sign an updated consent form. 
 
What other choices do I have if I do not take part in this study? 
Your other choices may include the following: 


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 
Getting treatment or care for sepsis / septic shock without being in a study 
 
Taking part in another study 
 
Refusing treatment or care 
Talk to your doctor about your choices, including the risks and benefits of each choice, before you 
decide if you will take part in this study. 
 
Will I be paid if I take part in this study? 
You will not be paid for taking part in this study. You and your family will not receive any financial 
benefits or compensation from or have rights in any developments, inventions, or other discoveries that 
might come from this study. 
 
Will it cost anything to be in this study? 
You or your health plan will need to pay for medicines and clinic, hospital, and doctors’ services that are 
part of your regular medical care. Some health plans will not pay these costs for people taking part in 
research studies. Your study doctor can check with your health plan to find out what they will pay for. 
After your participation in the study ends, you and your health plan will need to pay for medicines and 
clinic, hospital, and doctors’ services that are part of your regular medical care. 
 
What happens if I am injured because I took part in this study? 
It is important that you tell your study doctor, Dr. Jose Iglesias, if you feel that you have been injured 
because of taking part in this study. You can tell the study doctor in person or call him at (609) 978-9940. 
You will get medical treatment if you are injured as a result of taking part in this study. Your study 
doctor will explain the treatment options to you and tell you where you can get treatment. Neither 
Community Medical Center, Monmouth Medical Center Southern Campus, nor the study doctor will pay 
for this medical treatment, and you will not receive any other kind of payment. 
 
What are my rights if I take part in this study? 
Taking part in this study is your choice. You may choose to either take part or not take part in the study. 
If you decide to take part in this study, you may leave the study at any time. No matter what decision 
you make, there will be no penalty to you and you will not lose any of your regular benefits. Leaving the 
study will not affect your medical care. 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment 
by signing this form. 
If you agree to participate in the study, your study doctor will inform your regular doctor about your 
participation in the study. 
 


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Will my health information be kept private? 
Patient information: 
As part of this research study, your study doctor, study staff, Community Medical Center, and/or 
Monmouth Medical Center Southern Campus will collect and record data about you. These data will 
include medical and personal information about you, such as information about your general health, 
how you have responded to the study drug, any side effects you may have experienced, and the results 
of any tests performed during the study. The information collected about you will be held by Community 
Medical Center and Monmouth Medical Center Southern Campus. If information from this study is 
published in medical journals or presented at scientific meetings, you will not be identified by name, 
picture, or any other personally identifying information. 
 
Your medical and personal information will be kept as confidential as possible within the limits of the 
law.  Your medical and personal information may be given out if required by law. 
 
To help ensure that your health information is kept confidential you will be assigned a unique 
participant identification number. Your forms, records, and samples associated with this study will be 
labeled with this identification number; they will not be labeled with your name, picture, or any other 
personally identifying information.  
 
The following people and groups of people may look at and/or copy your medical information to make 
sure that the study is being done properly, to check the quality of the data, and/or for research 
purposes: 
 
Community Medical Center and Monmouth Medical Center Southern Campus monitors and 
representatives 
 
Community Medical Center and Monmouth Medical Center Southern Campus’s collaborators 
and licensees (people and companies who partner with either institution) 
 
The Institutional Review Board or Ethics Committee responsible for protecting the rights and 
safety of the participants who take part in research studies 
 
Regulatory health authorities (government agencies involved in keeping research safe for 
people) 
 
Qualified researches 
o Your medical and personal information may be shared with qualified researchers who 
are not participating in this study, for research purposes and to advance medical care 
and science. In such cases, additional steps will be taken to protect your information 
from being linked to you. Before receiving your medical and personal information, the 
researchers have to agree that they will use it for research purposes only and that they 
will not make any attempts to trace your information back to you. 


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If you agree, your family doctor may be told that you are taking part in this study. 
 
Study results: 
A clinical study report containing the results of this trial will be made available to anyone who requests a 
copy.  Before this report is provided, additional steps will be taken to protect your information from 
being linked to you. 
 
How will my health information be used and disclosed? 
If you sign this consent form, you give permission to Community Medical Center and Monmouth 
Medical Center Southern Campus to use or disclose (share) your health information that identifies you 
only for the purposes of this research study and for research directly related to sepsis / septic shock or 
its symptoms, the use of intravenous vitamin C, thiamine and hydrocortisone therapy and/or the 
development of tests that help with detection or understanding of your disease.  You do not have to 
sign this consent form, but if you do not, you may not take part in this research study. 
 
The health information for which you are giving permission to be used and shared includes all health 
information about you that has been and will be created or received by Community Medical Center or 
Monmouth Medical Center Southern Campus and that is in your medical record kept by Community 
Medical Center or Monmouth Medical Center Southern Campus. 
 
This health information about you may be used by and/or disclosed to study monitor, representatives, 
collaborators, and licensees, the Institutional Review board or Ethics Committee, and representatives of 
the FDA or other national and local health authorities.  Your health information and data may be 
analyzed in any country worldwide.  Those persons who receive your health information may not be 
required by federal privacy laws to protect it and may share your information with others without your 
permission, if permitted by laws that apply to them. 
You have the right to see and get a copy of your medical records kept by Community Medical Center or 
Monmouth Medical Center Southern Campus that are related to the study.  However, by signing this 
consent form, you agree that you generally will not be able to review or receive some of your records 
related to the study until after the entire study has been completed, to protect the scientific integrity of 
the study. 
 
Your authorization (permission) to use and disclose (share) your health information does not have an 
expiration date, but that use and sharing will only be for the  purposes described in this consent form. 
 
You are free at any time to limit Community Medical Center and/or Monmouth Medical Center 
Southern Campus’s use and sharing of your health information, without penalty or other consequence. 
However, you may not be allowed to take part or continue to take part in this research study if at any 


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Version 4 – 31 May 2018 
Pt. Initials: ________ 
time you choose to limit Community Medical Center or Monmouth Medical Center Southern Campus’s 
use and sharing of your health information that is necessary for the completion of this research study. 
 
You may change your mind and revoke (take back) this authorization at any time.  If you revoke this 
authorization, no new health information will be collected about you.  However, Community Medical 
Center and Monmouth Medical Center Southern Campus will still be able to use and disclose any health 
information about you that has already been collected during this research study.  To revoke this 
authorization, you must contact Dr. Jose Iglesias (see contact information in next section). 
 
Federal law requires Community Medical Center and Monmouth Medical Center Southern Campus to 
inform the Centers for Medicare & Medicaid Services (CMS, the agency responsible for administration of 
the Medicare program) when Community Medical Center or Monmouth Medical Center Southern 
Campus is going to reimburse for patient injury expenses for treatment of an injury to Medicare 
beneficiary.  To comply with a Medicare reporting obligation, Community Medical Center or Monmouth 
Medical Center Southern Campus’s representative may need to collect and share with CMS certain 
personal information about you, such as your name, date of birth, sex, social security number, and 
Medicare ID number (if you have one). 
 
Who can answer my questions about the study? 
You can talk to your study doctor if you have any questions or concerns about this study, if you would 
like to withdraw your consent to take part in this study, or if you think you have been injured as a result 
of taking part in the study.  Contact your study doctor, Dr. Jose Iglesias, at (609) 978-9940. 
For questions about your rights while taking part in this study or if at any time during this study you feel 
that you have not been informed enough about your privacy rights about your health information, or 
you feel that the privacy of your health information has not been protected, you may contact the Risk 
Management Department at Community Medical Center, 99 Route 37 West, Toms river, New Jersey, 
08755 or by calling 732-557-8032. You may also contact the regional Risk Management Department for 
Monmouth Medical Center Southern Campus located at Monmouth Medical Center, 300 2nd Ave, Long 
Branch, NJ, 07740 or by calling 732-923-6620. 
 
 
 
 
 
 
 
 


Page 11 of 11 
 
 
 
Version 4 – 31 May 2018 
Pt. Initials: ________ 
 
Signature 
I understand that I will be given a copy of all pages of this form after it has been signed and dated.  I 
have read it, or it has been read to me.  I understand the information and have had my questions 
answered.  I agree to take part in this research study as described above and authorize Community 
Medical Center, Monmouth Medical Center Southern Campus, and Dr. Jose Iglesias to use and disclose 
(share) my health information as described in this Informed Consent Form. 
 
Participant name (print) 
 
If applicable – Name of participant’s legally authorized representative (print) – Relationship to patient 
 
Participant signature or signature of participant’s legally authorized representative  
 Date 
 
I, the undersigned, have fully explained this informed consent to the participant named above and/or 
the participant’s legally authorized representative. 
 
Name of person conducting informed consent discussion (print) 
 
Signature of person conducting informed consent discussion  
 
 
 
 Date 
 
Witness namea (print) 
 
Witness signaturea  
 
 
 
 
 
 
 
 
 Date 
 
a If the Principal Investigator or Institutional Review Board or Ethics Committee deems a witness 
signature is necessary. 
 
 

SAP_006.pdf: 
 
Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, 
and Glucocorticoids in the Early Treatment of Sepsis. 
ORANGES Trial 
NCT#: NCT03422159 
Document Date: May 13th, 2019 
 
Study end-points:  
Primary end-point  
i. Time to vasopressor independence. Defined as the time from starting the active treatment/placebo to 
discontinuation of all pressors 
ii. Delta SOFA score, defined as the initial SOFA score minus the day 4 SOFA score 
Secondary end-points  
iii. 28-day mortality  
iv. Hospital mortality 
v. PCT clearance (PCT-c) calculated using the following formula: initial PCT minus PCT at 96 hours, 
divided by the initial PCT multiplied by 100. [67,68]  
vi. ICU mortality 
vii. ICU length of stay (LOS) and ICU free days. ICU free days is calculated as the number of days alive and 
out of the ICU to day 28 
viii. Hospital LOS 
Power Calculation:  
Based on the results of the preliminary study of Marik et al we project that the combination of 
hydrocortisone, vitamin C and thiamine could reduce time to vasopressor discontinuation from 54 (+/- 
30 hours) versus 30 hours. For the additional primary outcome we projected a greater change of SOFA 


score of 4 (+/- 3) versus 2.  Assuming a type 1 error of 5% (alpha of 0.05) and a power of 80% (the ability 
to detect a difference between two groups when a difference exists) would require a sample size of 94 
patients. To account for dropouts and patients not requiring vasopressor therapy we will therefore aim 
for a sample size of 140 patients.  
Data analysis:  
Summary statistics will be used to describe the clinical data and presented as mean ± SD, median with 
interquartile range (IQR) or percentages as appropriate. Chi squared analysis with Fisher’s exact test 
(when appropriate) and Student’s t test (Mann Whiney U test for non- normal distributions) were used 
to compare data between the active treatment group and the placebo group with statistical significance 
declared for probability values of 0.05 or less.  
 

Prot_003.pdf: 
 
 
Page 1 of 15 
Version 5 – 13 May 2019 
Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, 
and Glucocorticoids in the Early Treatment of Sepsis. 
ORANGES Trial 
NCT#: NCT03422159 
Background and Significance:  
The global burden of sepsis is substantial with an estimated 15 to 19 million cases per year; the vast 
majority of these cases occur in low income countries. [1] With more timely diagnosis and improvement 
in supportive care the 28-day mortality from sepsis in high income countries has declined to about 25%, 
however, the mortality from septic shock remains as high as 45%. [2,3] Moreover, the mortality from 
sepsis and septic shock in low income countries is reported to be as high as 60%.[4-6] In addition to 
short term mortality, septic patients suffer from a numerous short- and long-term complications and are 
at an increased risk of death for up to five years following the acute event.[7] Over the last 3 decades 
over 100 phase II and phase III clinical trial have been performed testing various novel pharmacologic 
agents and therapeutic intervention in an attempt to improve the outcome of patients with sepsis and 
septic shock; all of these studies have failed to show an improvement in patient outcomes. [8] New 
therapeutic approaches to sepsis are desperately required; considering the global burden of sepsis these 
interventions should be effective, cheap, safe and readily available.  
A large body of experimental data has demonstrated that both corticosteroids and intravenous vitamin 
C reduce activation of nuclear factor ƘB (NFƘB) attenuating the release of pro-inflammatory mediators, 
reduce the endothelial injury characteristic of sepsis thereby reducing endothelial permeability and 
improving macrocirculatory flow, augment the release of endogenous catecholamines and enhance 
vasopressor responsiveness.[9-16] In animal models these effects have resulted in reduced organ injury 
and increased survival. Corticosteroids have been evaluated in several clinical trials, with meta-analysis 
of these trials demonstrating somewhat conflicting outcomes. [17-20] Low-dose stress corticosteroids 
have proven to be safe with no increased risk of clinically important complications. [17] While 
corticosteroids decrease vasopressor dependency the effect on survival is less clear.[19,21]  
Several studies have investigated the use of intravenous vitamin C in critically ill patients. Nathens et al 
randomized 595 surgical ICU patients (91% trauma patients) to receive intravenous vitamin C and 
vitamin E for up to 28 days. [22] The vitamin combination was associated with a significant reduction in 
the incidence of multiple system organ failure (p=0.04) with a trend to reduced mortality and length of 
ICU stay. No adverse effects were noted with the vitamin combination. Fowler et al performed a pilot 


 
 
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study in 24 patients with severe sepsis and septic shock. [23] In this study patients were randomized to 
placebo (n=8), low dose intravenous vitamin C (50 mg/kg) (n=8) or high dose vitamin C (200mg/kg). 
Vitamin C attenuated the inflammatory response with both doses of the vitamin being devoid of any 
side effects. Although the Sequential Sepsis Related Organ Failure Score (SOFA) fell significantly in both 
treatment arms the study was underpowered to determine any outcome benefit. Zabet and colleagues 
performed a RCT in which they evaluated the role of intravenous vitamin C in a dose of 100 mg/kg/day 
(about 7g/day) in 28 surgical ICU patients with septic shock. [24] In this study the mean dose of 
norepinephrine and duration of norepinephrine administration were significantly lower in the ascorbic 
acid than the placebo group. The 28-day mortality was significantly lower in the ascorbic acid than the 
placebo group (14% vs. 64%, p = 0.009). No side effects related to the vitamin C infusion were reported. 
Tanaka et al randomized 37 patients with severe burn to very high dose vitamin C (about 110g/day) or 
placebo.[25] Patients who received vitamin C required less fluid resuscitation with a trend towards 
reduced length of stay and mortality. No adverse effects were noted with the very high dosages of 
vitamin C. Several studies have administered vitamin C in doses exceeding 100g/day as adjuvant therapy 
in patients with cancer with no discernable side effects. [26-33] Vitamin C appears to be toxic to normal 
human cells (not cancer cells) at a concentration on greater than 25 mM. [33] A dose of 6g/day will 
achieve a steady state serum concentration of about 240uM [34-36] which is about 100 times less than 
the dose required to cause cellular toxicity. The package insert for vitamin C [37] lists no 
contraindications or adverse effects of the drug and states that as much as “6 grams has been 
administered without evidence of toxicity”. The only reported restriction to the use of high dose 
intravenous vitamin C is in patients with known glucose-6-phospahte deficiency (G6PD) in whom 
hemolysis has been reported. [38,39] It is important to recognize that patents with sepsis predictably 
have very low serum vitamin C levels, which can only be corrected with intravenous vitamin C in a dose 
of more than 3gm per day. [23,34,36] The low or undetectable levels of vitamin C likely result from the 
metabolic consumption of the molecule as well as increased renal losses. Furthermore, unlike all other 
mammals, primates and guinea pigs are unable synthesize vitamin C is due to mutations in the L-gulono-
_-lactone oxidase (GLO) gene which codes for the enzyme responsible for catalyzing the last step of 
vitamin C biosynthesis. [40] In almost all species, except humans and guinea pigs, vitamin C production 
increases during stress and is secreted by the adrenal gland; in these species vitamin C is best 
considered a stress “hormone”. [40] Vitamin C is an essential cofactor for the production of 
corticosteroids and catecholamines by the adrenal gland. [13,41] Vitamin C has been shown to reverse 
adrenal suppression caused by induction doses of etomidate during anesthesia.[42,43]  
Ascorbate donates a single electron in all its redox reactions, generating the ascorbate radical. This 
radical is not very reactive with anything but itself. Dismutation of two ascorbate radicals forms a 
molecule each of ascorbate and dehydroascorbate. Hydrolysis of the lactone ring of dehydroascorbate 


 
 
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irreversibly converts it to 2,3-diketo-1-gulonic acid which is then converted to oxalate. Oxalate is 
normally excreted by the kidney and serum levels will increase with renal impairment. In patients with 
renal impairment receiving mega-dose vitamin C, supersaturation of serum with oxalate may result in 
tissue deposition as well as crystallization in the kidney. [44,45] Glyoxylate, a byproduct of intermediary 
metabolism, is either reduced to oxalate or oxidized to CO2 by the enzyme glyoxylate aminotransferase; 
thiamine pyrophosphate is a co-enzyme required for this reaction. [46] Thiamine deficiency increases 
the conversion of glyoxylate to oxalate resulting in hyper- oxalosis. [47,48] Donnino and colleagues have 
demonstrated that thiamine deficiency is common (32%) in patients with sepsis and that treatment with 
thiamine in these patients reduces mortality. [49] In a post-hoc analysis of this study these authors 
demonstrated that thiamine decreased the risk of acute kidney injury and the required for renal 
replacement therapy in all treated patients. [50]  
It has previously been suggested that “...the best hope for therapeutic advances [in sepsis] will depend 
on broad-base targeting, in which multiple components are targeted at the same time.”[51] Such 
combination “chemo-therapy” targeting multiple biological pathways is the standard approach in the 
treatment of malignant disease. While the benefits of vitamin C, hydrocortisone, and thiamine alone are 
likely limited,[23,49,50,52] we believe that these medications act synergistically to reduce the risk of 
organ failure and death in patients with sepsis. This hypothesis is supported previous research [53,54] 
and more recently a set of elegant experiments performed by Barabutis et al. [55] Using a validated 
pulmonary endothelial monolayer model, these authors demonstrated that hydrocortisone together 
with vitamin C protected the vascular endothelium from damage by endotoxin while neither agent alone 
had this effect. Previous research has demonstrated that vitamin C reverses oxidation of the 
glucocorticoid receptor (GR) a likely manifestation of sepsis.[53] Oxidation of the GR limits binding of the 
GR to both ligand and DNA responsive units decreasing the activity of glucocorticoids. [53] Furthermore, 
glucocorticoids increase the expression of the sodium vitamin C transporter-2 (SVCT-2) which is an 
essential transport protein necessary for vitamin C to be transported intracellularly.[54]  
We therefore propose that a “metabolic resuscitation protocol” including vitamin C, corticosteroids and 
thiamine will limit the development of organ failure and reduce mortality in patients with severe sepsis 
and septic shock. This postulate is supported by the preliminary findings by Marik et al. [56] In a 
retrospective before-after clinical study, these authors compared the outcome and clinical course of 
consecutive septic patients treated with intravenous vitamin C, hydrocortisone and thiamine during a 7-
month period (treatment group) compared to a control group treated in during the preceding 7 
months.[56] The primary outcome was hospital survival. A propensity score was generated to adjust the 
primary outcome. There were 47 patients in both treatment and control groups with no significant 
differences in baseline characteristics between the two groups. The hospital mortality was 8.5% (4 of 47) 


 
 
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in the treatment group compared to 40.4% (19 of 47) in the control group (p < 0.001). The propensity 
adjusted odds of mortality in the patients treated with the vitamin C protocol was 0.13 (95% CI 0.04-
0.48, p=0.002). The SOFA score decreased in all patients in the treatment group with none developing 
progressive organ failure. Vasopressors were weaned off all patients in the treatment group, a mean of 
18.3 ± 9.8 hours after starting treatment with vitamin C protocol. The mean duration of vasopressor use 
was 54.9 ± 28.4 hours in the control group (p<0.001). The results of this study provide sufficient 
information for the design of an adequately powered, pragmatic randomized controlled trial.  
Study Design: 
Specific Aims of the Study:  
The aim of this study is to determine the effect of the combination of intravenous vitamin C, 
hydrocortisone and thiamine on the clinical course and outcome of patients with sepsis and septic 
shock.  
This study will be performed at Community Medical Center and Monmouth Medical Center Southern 
Campus. All patients admitted to the ICU with the primary diagnosis of sepsis or septic shock will be 
screened for inclusion into this study. The diagnosis of sepsis and septic shock will be based on the 2016 
Surviving Sepsis Campaign definitions.[63]  
Inclusion Criteria: 
i. Diagnosis of sepsis or septic shock within 12 hours of admission to the ICU  
ii. Informed consent as dictated by IRB and local practice.  
iii. Compliance with the 3 hour sepsis bundle  
 
30ml/kg of intravenous crystalloid fluid (e.g.: sodium chloride 0.9%) for lactic acid >4 
and/or systolic blood pressure <90mmHg / mean arterial pressure <65mmHg 
 
Lactic acid level drawn 
 
Broad spectrum antibiotics given after obtaining blood cultures 
Exclusion criteria:  
i. Age < 18 years  
ii. Pregnant  


 
 
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iii. DNR/DNI with limitations of care on admission 
iv. Patients with terminal end stage disease (i.e. stage IV cancer, end stage heart failure) that are unlikely 
to survive to hospital discharge  
v. Patients with a primary admitting diagnosis of an acute cerebral vascular event, acute coronary 
syndrome, active gastrointestinal bleeding, burn or trauma [64-66]  
vi. Requirement for immediate surgery [64-66]  
vii. Patients with HIV and a CD4 < 50 mm2 [64-66]  
viii. Patients with known glucose-6 phosphate dehydrogenase (G-6PD) deficiency.[39]  
ix. Patients with sepsis/septic shock transferred from another hospital  
x. Patients with features of sepsis/septic shock > 24 hours after admission 
Study end-points:  
Primary end-point  
i. Time to vasopressor independence. Defined as the time from starting the active treatment/placebo to 
discontinuation of all pressors 
ii. Delta SOFA score, defined as the initial SOFA score minus the day 4 SOFA score 
Secondary end-points  
iii. 28-day mortality  
iv. Hospital mortality 
v. PCT clearance (PCT-c) calculated using the following formula: initial PCT minus PCT at 96 hours, 
divided by the initial PCT multiplied by 100. [67,68]  
vi. ICU mortality 
vii. ICU length of stay (LOS) and ICU free days. ICU free days is calculated as the number of days alive and 
out of the ICU to day 28 
viii. Hospital LOS 


 
 
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Vitamin C, Hydrocortisone and Thiamine dosing protocol and randomization  
Medication dosing.  
Based on published clinical data, vitamin C pharmacokinetic modeling, the package insert as well as the 
preliminary study by Marik et al, Vitamin C will be administered as an intravenous dose of 6gm per day 
divided in 4 equal doses. [22-24,34-37] This dosage is reported to be devoid of any complications or side 
effects. Hydrocortisone will be dosed according to the consensus guidelines of the American College of 
Critical Care Medicine.[52] Thiamine will be administered according to current recommendations in a 
dose of 200mg q 12 hourly. [69]  
This is a double-blind placebo controlled study. Only the dispensing pharmacist will be aware of the 
treatment allocation. Patients will be randomized to receive either vitamin C/hydrocortisone/thiamine 
or triple placebo using a random number table provided to the dispensing pharmacists. Each patient will 
be allocated a unique subject ID which will be linked to the randomization sequence. Only the 
dispensing pharmacists will have a record of the subject ID and randomization sequence. The vitamin C, 
vitamin C-placebo, hydrocortisone, hydrocortisone-placebo, thiamine, and thiamine-placebo will be 
formulated as follows:  
Vitamin C:  Vitamin C is provided by the manufacturer as a 50 ml vial at a concentration of 500mg/ml. 
Three (3) ml of vitamin C will be placed in a 50 ml bag of Normal Saline (1500 mg vitamin C in 50ml bag)  
which will then be infused over 30 minutes (100mL/hr). The bag will be labeled by the pharmacy as 
“Vitamin C 1.5g or Placebo”. The dosing schedule is 1500mg every 6 hours for 4 days (or discontinued 
earlier if discharged from the ICU).  
Once the vial is open, it is only stable for 6 hours. The resulting product is given 12 hour stability. When 
first ordered, 2 doses are made then and sent to the nurse. For next 12 hours, they will wait until 1 hour 
prior to make the next batch.  
Vitamin C placebo will consist of an identical bag of 50mL normal saline (but with no vitamin C) and will 
be labeled “Vitamin C or Placebo”. Placebo will be infused over 30 minutes as per the infusion 
instructions of the active vitamin. 
Hydrocortisone:  Patients will be treated with hydrocortisone 50mg IV push every 6 hours for 4 days (or 
discontinued earlier if discharged from the ICU). Pharmacists will prepare hydrocortisone 50mg/1mL for 
the nurse in a 3mL syringe which will be labeled “Hydrocortisone 50mg or Placebo”. Hydrocortisone 
placebo will be provided as an identical 3mL syringe as 1mL of normal saline. Two doses of study 
medication will be prepared at a time. 


 
 
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Thiamine:  Intravenous thiamine will be given in a dose of 200mg q 12 hourly for 4 days (or discontinued 
earlier if discharged from the ICU). This will be placed in a 50mL bag of Normal Saline labeled “Thiamine 
200mg or Placebo” and run over 30 minutes (100mL/hr) Placebo patients will receive a matching 50mL 
bag of Normal Saline. One dose will be prepared at a time.  
Power Calculation:  
Based on the results of the preliminary study of Marik et al we project that the combination of 
hydrocortisone, vitamin C and thiamine could reduce time to vasopressor discontinuation from 54 (+/- 
30 hours) versus 30 hours. For the additional primary outcome we projected a greater change of SOFA 
score of 4 (+/- 3) versus 2.  Assuming a type 1 error of 5% (alpha of 0.05) and a power of 80% (the ability 
to detect a difference between two groups when a difference exists) would require a sample size of 94 
patients. To account for dropouts and patients not requiring vasopressor therapy we will therefore aim 
for a sample size of 140 patients.  
Data Collection:  
The following de-identified demographic and clinical data will be collected.  
i. Age  
ii. Sex  
iii. Weight  
iv. Admitting diagnosis and possible site of infection  
v. Blood culture results  
vi. Co-morbidities, including diabetes, hypertension, cardiac failure, COPD, malignancy  
vii. Requirement for mechanical ventilation (Y/N).  
viii. Use of vasopressor agents (Y/N). The hourly dosage of vasopressors will be recorded as the 
norepinephrine equivalent dosage. [70,71]  
ix. Duration of vasopressor use  
x. Time to vasopressor independence from start of active drug/placebo  
xi. Daily urine output (for first 4 days)  


 
 
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xii. Fluid balance after 24 and 72 hours  
xiii. Presence of acute kidney injury (AKI). Presence of AKI: Acute kidney injury (AKI) will be defined using 
the KDIGO criteria; namely, an increase of the s-creatinine > 0.3 mg/dl or a level > 1.5 times the baseline 
value. [27] If the baseline s-creatinine is not known a value > 1.5 mg/dl will be regarded as diagnostic of 
AKI.  
xiv. Length of ICU and hospital stay  
xv. ICU, hospital, and 28-day mortality 
xvi. Routine laboratory data for 4 days including:  
a. serum creatinine  
b. white cell count (WBC)  
c. platelet count  
d. total bilirubin  
e. PaO2/FiO2 ratio  
f. Procalcitonin (PCT) – on days 1 and 4 
g. lactate level  
h. urine oxalate level (day 4) 
xvii. HostDx Sepsis genetic testing (day 1) if consent is provided for additional sub-study. 
xviii. The patients’ admission APACHE II and APACHE IV scores will be recorded. The APACHE IV score 
allows calculation of the predicted hospital mortality and predicted ICU length of stay (LOS).  
ixx. The daily SOFA (Sepsis-related Organ Failure Assessment) score will be recorded for the first 4 
treatment days.  
The APACHE II score (incrementing score of 0-71) and APACHE IV score (incrementing score 0-286) are 
standardized measures of disease severity that are used to predict hospital mortality and ICU LOS. 
[72,73] The SOFA score was designed to sequentially assess the severity of organ dysfunction in patients 
who are critically ill from sepsis (incrementing score 0-24). [74]. The SOFA scores is calculated 24 hours 


 
 
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after admission to the ICU and daily thereafter. SOFA scores that increase by about 30 percent are 
associated with a mortality of at least 50 percent.[75]  
 
Data will be collected in the attached Excel spreadsheet (Appendix A – Sepsis Data spreadsheet). No 
personal identifiers will be recorded on the spreadsheet. We will not be recording names, dates of birth, 
social security or EMR numbers or any other HPI data in the data collection spreadsheet. Each record 
will be assigned a unique study ID number (subject ID key). A separate password protected spreadsheet 
will have a list of subject ID number and the corresponding medical record numbers (Subject ID Key data 
sheet). This spreadsheet will only be accessible to the principle investor and sub-PI. The pharmacist will 
have a copy of the “Research Randomization and Dispensing Log” with an additional field which will 
include the randomization code to active vitamin protocol or placebo. Only the pharmacist will have 
access to the “Research Randomization and Dispensing Log” until after the study is completed, when it 
will be made available to the principle investor and sub-PI.  
Data analysis:  
Summary statistics will be used to describe the clinical data and presented as mean ± SD, median with 
interquartile range (IQR) or percentages as appropriate. Chi squared analysis with Fisher’s exact test 
(when appropriate) and Student’s t test (Mann Whiney U test for non- normal distributions) were used 
to compare data between the active treatment group and the placebo group with statistical significance 
declared for probability values of 0.05 or less.  
Data Safety & storage:  
The main risk to subjects is the accidental release of PHI. Careful record management methods will be in 
place to ensure this type of privacy breach does not occur.  
Subject ID Key: Each subject will be given a unique subject ID number. A subject ID key will be used to 
match the subjects Financial Identification Number (FIN). The subject ID key, linking the subject ID 
numbers to the FIN will be kept in a password-protected file on the pharmacy IV room and pharmacy co-
investigator computer. Only the research team (PI, sub PI and research pharmacists) will have access to 
this information, and they will not disclose this information to any other person or entity. The subject ID 
key will be destroyed as soon as possible after the data set has been completely abstracted and 
validated for accuracy and completeness.  
Data set: Similarly, the data set will be kept in a password-protected file and stored separately from the 


 
 
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subject ID key in the locked office of the study coordinator. Only the research team will have access to 
this information, and they will not disclose this information to any other person or entity. Three years 
after the completion of the study, all collected data will be destroyed by permanently deleting electronic 
copies. 
References  
1. Adhikari NK, Fowler RA, Bhagwanjee S et al. Critical care and the global burden of critical illness in 
adults. Lancet 2010; 376:1339-46.  
2. Kaukonen KM, Bailey M, Suzuki S et al. Mortality related to severe sepsis and septic shock among 
critically ill patients in Australia and New Zealand, 2000-2012. JAMA 2014; 311:1308-16.  
3. Gaieski DF, Edwards JM, Kallan MJ et al. Benchmarking the incidence and mortality of severe sepsis in 
the United States. Crit Care Med 2013; 41:1167-74.  
4. Silva E, de Almeida Pedro M, Beltrami Sogayar AC et al. Brazilian Sepsis Epidemiological Study (BASES 
study). Crit Care 2004; 8:R251-R260.  
5. Sales JA, David CM, Hatum R et al. Sepse Brasil: Estudo Epidemiologico da Sepse em Unidades de 
Terapia Intensiva Brasileiras. An epidemiological study of sepsis in Intensive Care Units. Sepsis Brazil 
Study. Rev Bras Ter Int 2006; 18:9-17.  
6. The 10 leading causes of death by country income group 2012. WHO factsheets. 
http://www.who.int/mediacentre/factsheets/fs310/en/index1.html . 2015. World Health Organization. 
5-24-2016.  
7. Wang HE, Szychowski JM, Griffin R et al. Long term mortality after sepsis. Chest 2013.  
8. Artenstein AW, Higgins TL, Opal SM. Sepsis and scientific revolutions. Crit Care Med 2013; 41:2770-
2772.  
9. Fisher BJ, Seropian IM, Masanori Y et al. Ascorbic acid attenuates lipopolysaccharide-induced acute 
lung injury. Crit Care Med 2011; 39:1454-60.  
10. Fisher BJ, Kraskauskas D, Martin EJ et al. Attenuation of sepsis-induced organ injury in mice by 
vitamin C. JPEN 2014; 38:825-39.  
11. Han M, Pendem S, Teh SL et al. Ascorbate protects endothelial barrier function during septic insult: 
Role of protein phosphatase type 2A. Free Radic Biol Med 2010; 48:128.  


 
 
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12. Kim SR. Ascorbic acid reduces HMGB1 secretion in lipopolysaccharide-activated RAW 264.7 cells and 
improves survival rate in septic mice by activation of Nrf2/HO- 1 signals. Biochemical Pharmacology 
2015; 95:279-89.  
13. Bornstein SR, Yoshida-Hiroi M, Sotiriou S et al. Impaired adrenal catecholamine system function in 
mice with deficiency of the ascorbic acid transporter (SVCT2). FASEB Journal 2003; 17:1928-30.  
 14. Wilson JX. Mechanism of action of vitamin C in sepsis: ascorbate modulates redox signaling in 
endothelium. Biofactors 2009; 35:5-13.  
15. Wilson JX. Evaluation of vitamin C for adjuvant sepsis therapy. Antioxidants & Redox Signaling 2013; 
19:2129-40.  
16. Marik PE. Critical illness related corticoseroid insufficiency. Chest 2009; 135:181- 93.  
17. Annane D, Bellisant E, Bollaert PE et al. Corticosteroids for treating sepsis (Review). Cochrane 
Database of Syst Rev 2015.  
18. Minneci PC, Deans KJ, Eichacker PQ et al. The effects of steroids during sepsis depend on dose and 
severity of illness: an updated meta-analysis. Clin Microbiol Infect 2009; 15:308-18.  
19. Volbeda M, Wetterslev J, Gluud C et al. Glucocorticosteroids for sepsis: systematic review with meta-
analysis and trial sequential analysis. Intensive Care Med 2015; 41:1220-1234.  
20. Kalil AC, Sun J. Low-dose steroids for septic shock and severe sepsis; the use of Bayesian statistics to 
resolve clinical trial controversies. Intensive Care Med 2011; 37:420-429.  
21. Sprung CL, Annane D, Keh D et al. Hydrocortisone therapy for patients with septic shock. N Engl J 
Med 2008; 358:111-24.  
22. Nathens AB, Neff MJ, Jurkovich GJ et al. Randomized, prospective trial of antioxidant 
supplementation in critically ill surgical patients. Ann Surg 2002; 236:814-22.  
23. Fowler AA, Syed AA, Knowlson S et al. Phase 1 safety trial of intravenous ascorbic acid in patients 
with severe sepsis. J Transl Med 2014; 12:32.  
24. Zabet MH, Mohammadi M, Ramezani M et al. Effect of high-dose ascorbic acid on vasopressor 
requirement in septic shock. J Res Pharm Pract 2016; 5:94-100.  
25. Tanaka H, Matsuda T, Miyagantani Y et al. Reduction of resuscitation fluid volumes in severely 


 
 
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