Clinical trial NCT03592277
Conditions: Sepsis Septic Shock
Keywords: Sepsis Septic Shock Vitamin C Thiamine
Sponsor: Trinity Health Of New England
Start date: 2018-09-14; Completion date: 2021-02-22
Enrollment: 120 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Investigators propose to investigate the use of IV vitamins B1 and C in a randomized, double-blinded, prospective trial to determine if these medications decrease mortality rates in patients with severe sepsis or septic shock.

Detailed description:
Investigators propose to investigate the use of IV vitamins B1 and C in a randomized, double-blinded, prospective trial to determine if these medications decrease mortality rates in patients with severe sepsis or septic shock. Patients experiencing evidence-based diagnoses of sepsis and severe sepsis and septic shock will be randomized to the two study arms for care, and all other care left to decisions of intensive care teams.

Arms: arm 1: Patients in the Vitamins C and B1 arm will receive 1.5g of vitamin C in 100mL of 0.9% sodium chloride (normal saline) every six hours for four days or until discharge from the ICU, whichever happens first (seventeen dose maximum). In addition, they will receive 200 mg IV vitamin B1 every 12 hours in 50 mL of normal saline for four days or until ICU discharge (whichever happens first, nine dose maximum). arm 2: Patients in the placebo (control group) arm will receive the 100 mL of 0.9% sodium chloride every six hours and 50 mL of 0.9% sodium chloride every 12 hours to act as placebos for the vitamins C and B1 respectively.
Interventions: intervention 1: Vitamin C intervention 2: Vitamin B1
Intervention descriptions: intervention 1: Patients will receive 1.5g of vitamin C in 100mL of 0.9% sodium chloride (normal saline) every six hours for four days or until discharge from the ICU, whichever happens first (seventeen dose maximum). intervention 2: Patients will also receive 200 mg of IV vitamin B1 every 12 hours in 50 mL of normal saline for four days or until ICU discharge (whichever happens first, nine dose maximum).

Protocol documents:
Prot_SAP_000.pdf: 
Vitamins B1 and C to Improve Outcomes in 
Patients With Severe Sepsis 
NCT  number    NCT03592277
Document Date 08/19/2020


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Vitamins B1 and C to Improve Outcomes in 
Patients With Severe Sepsis 
Peter Sandor, PA-C, FCCM1,4
Jamey Dodge, RPh, BCPS, BCCCP2
Brendan Gontarz, MD1,3
Usman Siddiqui, MD1
David S. Shapiro, MD, FACS, FCCM1,3,4*
1.Saint Francis Hospital and Medical Center
Department of Surgery
114 Woodland Street
Hartford, Connecticut
2. Saint Francis Hospital and Medical Center
Department of Pharmacy
114 Woodland Street
Hartford, Connecticut
3. University of Connecticut School of Medicine
263 Farmington Avenue
Farmington, Connecticut
4. Quinnipiac University 
275 Mount Carmel Avenue
Hamden, CT 06518
*corresponding author
Introduction and Need
Despite continued advances in medical science, the management of sepsis remains a 
challenge. Sepsis is the presence of a systemic infection creating a cascade of downstream effects, 
manifesting in a patient as acute end organ dysfunction. Estimates of upwards of 750,000 cases of 
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severe sepsis were identified annually in the United States and more than half of these patients 
required management in an intensive care unit (ICU). Severe sepsis remains highly morbid and 
costly with a national mortality rate of 28.6% and an estimated $16.7 billion invested in the care 
of these patients.1 Internationally the disease is even more widespread with an estimated 19 
million people affected annually.2 These numbers likely underestimate the magnitude of the 
disease and its repercussions. Iwashyna et al. studied the long term effects of surviving sepsis and 
found that people who survived this acute illness exhibited more severe cognitive decline and 
functional dependence than their previously healthy counterparts.3 Given the massive burden of 
this disease, it is prudent to seek out novel approaches to treat severe sepsis and septic shock.
Background and Rationale
Extensive research in animal models has shown a benefit to using intravenous (IV) 
vitamin C in sepsis.4,5 It is a cofactor for multiple enzymatic functions.6 In addition, one study in 
particular found that critically ill patients, including those with sepsis have significantly lower 
levels of circulating vitamin C during their acute illness than their healthy counterparts. 
Furthermore,  the investigators found critically ill patients who were administered an infusion of 
vitamin C every six hours maintained normal plasma levels for the largest amount of time.6 One 
study showed that critically ill patients required up to 3 grams per day of vitamin C just to return 
their plasma concentrations to normal baseline levels.7 Additional research indicates that critically 
ill patients are often thiamine-deficient which is frequently missed and not treated by their 
clinicians.8,9
Marik et al. published a novel study implicating the use of IV vitamin C, vitamin B1, and 
hydrocortisone resulted in a significantly lower mortality rate for their septic patients. His team 
explored the utility of these medications as compared to historical controls of their previously 
treated septic patients.10 This study, while novel and inspiring, was designed with the acceptance 
of multiple confounders and potential for bias including the retrospective nature, the lack of 
randomization, and the lack of blinding. We propose investigating the use of IV vitamins B1 and 
C in a randomized, prospective trial, eliminating the potential for selection bias.
Hypotheses
1. Primary Hypothesis: Septic patients in the ICU who receive IV vitamins B1 and C will 
demonstrate a decreased mortality rate compared to septic patients who do not receive IV 
vitamins B1 and C.
2. Secondary Hypotheses: Patients receiving IV vitamins B1 and C
a.
will have shorter hospital length of stays (HLOS)
b. will have shorter ICU length of stays (ICU LOS)
c.
will demonstrate a lower 30-day readmission rate 
d. will have fewer ventilator days
e.
will have fewer hours on vasopressors
f.
in addition to IV hydrocortisone for refractory septic shock will have a more 
profound reduction in mortality when as compared to those receiving IV vitamins 
B1 and C alone
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g. who also record to higher Sequential Organ Failure Assessment (SOFA) scores 
will have a more significant reduction in mortality than patients who record lower 
SOFA scores
Objectives
The objective of this study is to determine if the administration of IV vitamins B1 and C 
are effective in decreasing the mortality rates of patients with severe sepsis or septic shock. In 
addition, we will investigate if there are benefits to those patients who also receive hydrocortisone 
in an effort to explore the synergistic relationship that vitamins B1 and C have with 
hydrocortisone.
 Overview of Study Design
Patient Selection Criteria
1. Inclusion Criteria: Patients admitted to the ICU at Saint Francis Hospital and Medical 
Center who are:
a.
Between the ages of 18 and 90 years old
b. Have severe sepsis or septic shock
i. Severe sepsis and septic shock will be defined by the Surviving Sepsis 
2012 guidelines11
c.
Weight more than 30 kg
d. Full code
2. Exclusion Criteria: Patients 
a.
Not diagnosed with severe sepsis or septic shock
b. Younger than 18 or older than 90 years old
c.
Who are pregnant
d. Weigh less than 30 kg
Patients diagnosed with severe sepsis or 
septic shock in the ICU
Control Group: Patients not receiving 
vitamins B1 and C
Intervention Group: Patients receiving 
vitamins B1 and C
Evaluation of age, gender, ICU LOS, HLOS, 30-day readmission 
rates, operative interventions, comorbidities, mortality, Body 
Mass Index (BMI)ventilator days, vasopressor hours, renal 
function, procalcitonin levels, enteral nutrition, SOFA scores, 
discharge destination, and hydrocortisone use.
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e.
Currently on hemodialysis
f.
Not located in the ICU
g. Do not resuscitate (DNR) or do not intubate (DNI), no escalation of care, or 
comfort measures only (CMO)
Enrollment/Randomization
Once identified, patients who meet inclusion criteria will be approached. The majority of 
patients are likely to be intubated and sedated at the time of their diagnosis of severe sepsis or 
septic shock. In these cases, the next of kin or consenting party will be approached for each 
patient. The providers in the ICU, mainly physician’s assistants (PAs) and residents, always 
contact patient’s family members for consent for central lines and other invasive procedures while 
in the ICU. The study staff will speak to this same consenting person (in person or on the phone) 
and will ask them about the potential enrollment of their loved one in the study. In the absence of 
documentation of a healthcare proxy or conservator (as is often the case with septic patients, as it 
is an unexpected illness), priority will be given to the patient’s spouse, followed by an adult child, 
followed by a parent, followed by an adult sibling. .
Due to the impact of the COVID-19 pandemic and associated restrictions and worry, it has 
been increasingly challenging to provide informed consent in person with legally authorized 
representatives. Hospital restrictions combined with a general reluctance of LAR’s desire to come 
to the hospital and risk exposure makes in-person consent problematic.  Consent will be obtained 
via one of two methods: (1) obtained in-person and documented by double signature, or (2) 
obtained telephonically with an additional hospital signatory witness. The research team will then 
memorialize written consent by post (mail) or electronic mail, when possible, but telephonic 
consent will be sufficient for recruitment of subjects and protocol start. If the consenting party is 
only available via phone, the study will be discussed with this Legally Authorized Representative, 
and additional family member as desired, thoroughly, and the research staff will then return a call 
at a reasonable interval, usually in two hours, to respond to any questions. Questions provided 
immediately will be answered in real time. During the two hour interval, the consent form will be 
faxed or emailed to the legally authorized representative for review. This telephonic consent will 
be witnessed by another member of the hospital team to ensure that the study is clear to the family 
member and all questions have been answered. We will then randomize the patient and begin 
treatment. If and when the subject has regained the mental capacity to participate in the informed 
consent process, s/he will be approached by the research staff and consented clarified. If the 
patient does not continue consent, they will be withdrawn from the study. 
Prior to the recruitment process the pharmacy will enter numbers 1-120 in ascending order 
into a randomizing website.  This randomly assigned each number to either placebo or 
intervention.  Prior to recruitment, kits in blocks of 10, containing either the placebo or unmixed 
forms of vitamin B1 and C are made and placed in identical packages labeled with their 
corresponding number. These numbers will be assigned in ascending order corresponding to the 
order in which they are consented. Once ordered by the providers the pharmacy with open the 
identical kits and, if it is the intervention, mix the vitamin B1 and C for IV administration. This 
process will ensure the study coordinators, healthcare providers, and the patients remain blinded. 
Vitamins B1 and C will be ordered for all patients in Epic, giving the impression that all of those 
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enrolled are in the intervention group.  However half the kits will contain the intervention and half 
will contain the placebo.  This is being done due to logistical issues with preparing and storing the 
vitamin B1 and C.  Having premade kits allows the pharmacy to more easily prepare and 
distribute the vitamin B1 and C.  These also need to be refrigerated and given limited space kits 
will be made in blocks of 10 to limit crucial storage space the pharmacy needs for other 
medications.
We plan to enroll 120 patients; 60 in the control arm and 60 in the intervention arm. Our 
current mortality rate is 35% at Saint Francis Hospital and Medical Center for patients with severe 
sepsis and septic shock. We expect our mortality rate to decrease to 30% with this intervention. 
We believe this is a reasonable expectation given that Marik et al. demonstrated that his 
intervention group’s mortality rate dropped from 40.4% to 8.5% after a similar intervention.10 In 
order to demonstrate this difference, 120 patients are needed according to our power calculation.
Informed Consent/Ethical Issues
We anticipate a full board IRB approval, as this is a prospective study involving vitamins 
B1 and C as the intervention. Appropriate patients will be approached and consented (often via 
proxy consent) by members of the research team. Patients will then be randomized by computer 
to receive vitamin C and vitamin B1, or normal saline (control). The treating physicians, the 
research team, and the patients will all be blinded. The pharmacist mixing the drugs will be the 
only non-blinded team member.
Data will be kept on an encrypted, password-protected computer behind two locked doors. 
Data will be managed by the investigators who will each have their own login.
Study Workflow
Patients admitted to the ICU who have severe sepsis or septic shock will be identified by 
the nursing staff, PAs, or physicians caring for them. These patients’ consenting party will be 
approached within 24 hours of their presentation to the ED in an attempt to obtain informed 
consent. Following consent, the pharmacy will be notified of the study patient, randomization will 
occur, and the mixed medications (control or intervention) will be delivered to the patient’s 
bedside in the ICU. Consented patients will receive 1.5g of vitamin C in 100mL of 0.9% sodium 
chloride (normal saline) every six hours for four days or until discharge from the ICU, whichever 
happens first (seventeen dose maximum). In addition, they will receive 200 mg IV vitamin B1 
every 12 hours in 100 mL of normal saline for four days or until ICU discharge (whichever 
happens first, nine dose maximum). Patients in the control arm will receive the 100 mL of 0.9% 
sodium chloride every six hours and 100 mL of 0.9% sodium chloride every 12 hours to act as 
placebos for the vitamin C and B1 respectively. Doses up to 200 mg/kg/day were found to be safe 
in humans in one study.6 Several studies have been conducted in human subjects using IV vitamin 
B1 and C, often at higher doses than proposed here, and have not seen serious side effects.10,12-14
Some patients may receive hydrocortisone IV for refractory septic shock outside of this 
study protocol. This will be at the discretion of the treating physician and will not be included in 
the randomized and blinded intervention. Hydrocortisone has been shown in some studies to help 
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in patients with refractory septic shock.15,16 However, it is not uniformly employed. Patients 
receiving hydrocortisone will undergo a subgroup analysis to better elucidate the synergistic 
effects of hydrocortisone with vitamins B1 and C.
After discharge, patients will be followed for 30 days to track hospital readmissions. 
Reporting of Adverse Events
The study personnel will report adverse events as soon as they become aware of them and 
within 24 hours of them being informed. All adverse events or unanticipated problems will be 
reported to the IRB. If the adverse event is thought to be related to the intervention, the 
medication will be stopped and the patient will be withdrawn from the study. They will be 
monitored closely for resolution of the adverse event. In order to ensure that the patient receives 
the ideal treatment for their adverse reaction and their newly-discovered allergy is documented 
appropriately, the research staff will un-blind the ICU staff and themselves. This will be 
accomplished by keeping duplicate sealed randomization envelopes. In the case of an adverse 
event, the research staff will open this additional envelope and inform the treating physicians.
Side Effects
Possible side effects for patients receiving IV vitamin C include diarrhea, nausea, 
vomiting, heartburn, headache, insomnia, and nephrolithiasis. Possible side effects for patients 
receiving IV vitamin B1 include nausea, hives, wheezing, or angioedema. In the event of these 
reactions, the patients will be treated immediately for their allergic reaction by the primary team 
and will be withdrawn from the trial as previously mentioned.
Study Withdrawal
All patients who have a serious adverse event thought to be directly related to the 
intervention will be withdrawn from the study. The patient or their consenting proxy may revoke 
consent and withdraw from the study at any point as participation is completely voluntary.
Statistical Issues
The intervention arm (vitamin B1 and C) and the control arm (sodium chloride 0.9%) will 
be compared statistically for demographics and patient characteristics; including age, gender, 
comorbidities, need for operative intervention, enteral nutrition, and Body Mass Index (BMI). 
Outcomes between these two groups will also be compared including hours of vasopressor use, 
ventilator days, HLOS, ICU LOS, comorbidities, renal function measured by patients’ GFR and 
creatinine levels, procalcitonin levels, SOFA scores, discharge destination, readmission rates, and 
mortality rates. We will do a subgroup analysis of patients with septic shock as compared to those 
with severe sepsis. We will also do a subgroup analysis of the patients who receive 
hydrocortisone as opposed to those who do not.
Fisher’s exact test will be used to compare gender, operative intervention, rate of mortality 
and the 30-day readmission rate. Average BMI and average age will be evaluated via student’s t-
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test. Median number of ventilator days, average hours of vasopressor use, median daily SOFA 
scores, average procalcitonin levels, average creatinine levels, median GFR, median ICU LOS 
and median HLOS will all be compared via Mann-Whitney U test. A contingency table will be 
used to analyze the different types of enteral nutrition and patients’ discharge destination. A 
multivariate regression analysis will be conducted to analyze patients’ comorbidities.
Duration of Review 
We will start recruiting patients on September 10,, 2018. We expect recruitment and data 
collection to take 12 months. Data analysis and completion of a manuscript is expected to take 
another 12 months. 
All data will be kept on a password-protected and encrypted computer located behind two 
locked doors. We will retain all data for three years after the completion of the study. Following 
this, all data will be deleted from the hard drive where they will be kept.
Publication Plan
We plan to write and submit a manuscript for publication in a peer-reviewed journal.
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