ORANGES: Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in Sepsis.
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 2 |
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Treatment Arm 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. |
Drug: Ascorbic Acid
Ascorbic Acid 1.5g IV piggyback every 6 hours for 4 days (or discharge from ICU if prior to 4 days).
Other Names:
Drug: Thiamine
Thiamine 200mg IV piggyback every 12 hours for 4 days (or discharge from ICU if prior to 4 days).
Drug: Hydrocortisone
Hydrocortisone 50mg IV push every 6 hours for 4 days (or discharge from ICU if prior to 4 days).
Other Names:
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Placebo Comparator: Placebo Arm 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. |
Drug: Sodium Chloride 0.9%
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).
Other Names:
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Outcome Measures
Primary Outcome Measures
- Time to Vasopressor Independence (Hours) [From start of vasopressor medication to final discontinuation of vasopressor medication, up to 7 days.]
Defined as the time from starting the active treatment/placebo to discontinuation of all pressors.
- Change in Sequential Organ Failure Assessment (SOFA) Score [4 days post-randomization]
Defined as the day 4 post-randomization SOFA score minus the initial SOFA score. The Sequential Organ Failure Assessment (SOFA) Score is a mortality prediction score that is based on the degree of dysfunction of six organ systems. The score is calculated on admission and every 24 hours until discharge using the worst parameters measured during the prior 24 hours SOFA score ranges from 0 (no organ dysfunction) to 24 (highest possible score / organ dysfunction).
Secondary Outcome Measures
- Procalcitonin (PCT) Clearance [4 days post-randomization]
PCT at 96 hours minus initial PCT, divided by the initial PCT multiplied by 100.
- ICU Mortality [From admission to hospital until final discharge from the ICU, up to 28 days.]
ICU mortality rate
- ICU Length of Stay [From admission to the ICU until final discharge from the ICU, up to an average of 7 days.]
Time from admitting to ICU to discharge.
- Ventilator Free Days [28 Days post-randomization]
Number of days alive and off of the ventilator at day 28.
- Hospital Length of Stay [From admission to the hospital until final discharge, up to 28 days.]
Time from admitting to discharge of hospital stay.
- Hospital Mortality [Survival until hospital discharge, up to 28 days.]
In-hospital mortality rate.
Eligibility Criteria
Criteria
Inclusion Criteria:
- 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
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Broad spectrum antibiotics given after obtaining blood cultures
Exclusion Criteria:
- Age < 18 years ii. Pregnant 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
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Monmouth Medical Center, Southern Campus | Lakewood | New Jersey | United States | 08701 |
2 | Community Medical Center | Toms River | New Jersey | United States | 08755 |
Sponsors and Collaborators
- Community Medical Center, Toms River, NJ
Investigators
None specified.Study Documents (Full-Text)
More Information
Publications
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- Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Mar;43(3):304-377. doi: 10.1007/s00134-017-4683-6. Epub 2017 Jan 18.
- Ruiz-Rodríguez JC, Caballero J, Ruiz-Sanmartin A, Ribas VJ, Pérez M, Bóveda JL, Rello J. Usefulness of procalcitonin clearance as a prognostic biomarker in septic shock. A prospective pilot study. Med Intensiva. 2012 Oct;36(7):475-80. doi: 10.1016/j.medin.2011.11.024. Epub 2012 Jan 16.
- Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ, Ayers D; VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008 Feb 28;358(9):877-87. doi: 10.1056/NEJMoa067373.
- Sales Júnior JA, David CM, Hatum R, Souza PC, Japiassú A, Pinheiro CT, Friedman G, Silva OB, Dias MD, Koterba E, Dias FS, Piras C, Luiz RR; Grupo de Estudo de Sepse do Fundo AMIB. [An epidemiological study of sepsis in Intensive Care Units: Sepsis Brazil study]. Rev Bras Ter Intensiva. 2006 Mar;18(1):9-17. Portuguese.
- Sidhu H, Gupta R, Thind SK, Nath R. Oxalate metabolism in thiamine-deficient rats. Ann Nutr Metab. 1987;31(6):354-61.
- Silva E, Pedro Mde A, Sogayar AC, Mohovic T, Silva CL, Janiszewski M, Cal RG, de Sousa EF, Abe TP, de Andrade J, de Matos JD, Rezende E, Assunção M, Avezum A, Rocha PC, de Matos GF, Bento AM, Corrêa AD, Vieira PC, Knobel E; Brazilian Sepsis Epidemiological Study. Brazilian Sepsis Epidemiological Study (BASES study). Crit Care. 2004 Aug;8(4):R251-60. Epub 2004 Jun 15.
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- Stephenson CM, Levin RD, Spector T, Lis CG. Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer. Cancer Chemother Pharmacol. 2013 Jul;72(1):139-46. doi: 10.1007/s00280-013-2179-9. Epub 2013 May 14.
- Tanaka H, Matsuda T, Miyagantani Y, Yukioka T, Matsuda H, Shimazaki S. Reduction of resuscitation fluid volumes in severely burned patients using ascorbic acid administration: a randomized, prospective study. Arch Surg. 2000 Mar;135(3):326-31.
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- Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, Reinhart CK, Suter PM, Thijs LG. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996 Jul;22(7):707-10.
- Wandzilak TR, D'Andre SD, Davis PA, Williams HE. Effect of high dose vitamin C on urinary oxalate levels. J Urol. 1994 Apr;151(4):834-7.
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- Welsh JL, Wagner BA, van't Erve TJ, Zehr PS, Berg DJ, Halfdanarson TR, Yee NS, Bodeker KL, Du J, Roberts LJ 2nd, Drisko J, Levine M, Buettner GR, Cullen JJ. Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial. Cancer Chemother Pharmacol. 2013 Mar;71(3):765-75. doi: 10.1007/s00280-013-2070-8. Epub 2013 Feb 5.
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- 17-004
Study Results
Participant Flow
Recruitment Details | Between February 14th, 2018 and April 29th, 2019, 256 patients were evaluated within two community hospital intensive care units. |
---|---|
Pre-assignment Detail | Patients excluded from enrollment based on their diagnosis upon admission (ineligible unless they were admitted to the ICU for sepsis, 33 patients), end stage disease (20), had a DNR/DNI (17), or required immediate surgery (11). |
Arm/Group Title | Treatment Arm | Placebo Arm |
---|---|---|
Arm/Group Description | 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. Ascorbic Acid: Ascorbic Acid 1.5g IV piggyback every 6 hours for 4 days (or discharge from ICU if prior to 4 days). Thiamine: Thiamine 200mg IV piggyback every 12 hours for 4 days (or discharge from ICU if prior to 4 days). Hydrocortisone: Hydrocortisone 50mg IV push every 6 hours for 4 days (or discharge from ICU if prior to 4 days). | 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. Sodium Chloride 0.9%: 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). |
Period Title: Overall Study | ||
STARTED | 70 | 70 |
COMPLETED | 68 | 69 |
NOT COMPLETED | 2 | 1 |
Baseline Characteristics
Arm/Group Title | Treatment | Comparator | Total |
---|---|---|---|
Arm/Group Description | 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. Ascorbic Acid: Ascorbic Acid 1.5g IV piggyback every 6 hours for 4 days (or discharge from ICU if prior to 4 days). Thiamine: Thiamine 200mg IV piggyback every 12 hours for 4 days (or discharge from ICU if prior to 4 days). Hydrocortisone: Hydrocortisone 50mg IV push every 6 hours for 4 days (or discharge from ICU if prior to 4 days). | 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. Sodium Chloride 0.9%: 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). | Total of all reporting groups |
Overall Participants | 68 | 69 | 137 |
Age (years) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [years] |
70
(12)
|
67
(14)
|
68
(13)
|
Sex: Female, Male (Count of Participants) | |||
Female |
36
52.9%
|
42
60.9%
|
78
56.9%
|
Male |
32
47.1%
|
27
39.1%
|
59
43.1%
|
Race/Ethnicity, Customized (Count of Participants) | |||
Caucasian |
66
97.1%
|
65
94.2%
|
131
95.6%
|
Non-Caucasian |
2
2.9%
|
4
5.8%
|
6
4.4%
|
Comorbidities (Count of Participants) | |||
Coronary Artery Disease (CAD) |
25
36.8%
|
21
30.4%
|
46
33.6%
|
Diabetes |
24
35.3%
|
33
47.8%
|
57
41.6%
|
Dementia |
7
10.3%
|
4
5.8%
|
11
8%
|
Heart failure |
18
26.5%
|
13
18.8%
|
31
22.6%
|
Malignancy |
15
22.1%
|
11
15.9%
|
26
19%
|
Chronic Obstructive Pulmonary Disease (COPD) |
23
33.8%
|
17
24.6%
|
40
29.2%
|
Cirrhosis |
0
0%
|
3
4.3%
|
3
2.2%
|
End Stage Renal Disease (ESRD) |
3
4.4%
|
0
0%
|
3
2.2%
|
Chronic Kidney Disease (CKD) |
10
14.7%
|
4
5.8%
|
14
10.2%
|
Morbid Obesity (BMI >40) |
16
23.5%
|
13
18.8%
|
29
21.2%
|
Immunocompromised |
6
8.8%
|
5
7.2%
|
11
8%
|
Primary diagnosis (Count of Participants) | |||
Pneumonia |
29
42.6%
|
30
43.5%
|
59
43.1%
|
Urinary tract infection |
18
26.5%
|
25
36.2%
|
43
31.4%
|
Primary bacteremia |
9
13.2%
|
11
15.9%
|
20
14.6%
|
Gastrointestinal/biliary |
9
13.2%
|
8
11.6%
|
17
12.4%
|
Other |
13
19.1%
|
9
13%
|
22
16.1%
|
Other Baseline Characteristics (Count of Participants) | |||
Need for mechanical ventilation |
34
50%
|
35
50.7%
|
69
50.4%
|
Vasopressor usage during hospital admission |
56
82.4%
|
47
68.1%
|
103
75.2%
|
Acute Kidney Injury (Stage 1 or higher based on KDIGO definitions) |
54
79.4%
|
52
75.4%
|
106
77.4%
|
Positive blood cultures |
22
32.4%
|
23
33.3%
|
45
32.8%
|
Baseline Labs (mg/dL) [Mean (Standard Deviation) ] | |||
Creatinine (mg/dL) |
2.1
(1.5)
|
2
(1.51)
|
2
(0)
|
Ascorbic acid level (mg/dL) |
0.52
(1)
|
0.48
(0.4)
|
0.5
(0)
|
Thiamine (mg/dL) |
193
(144)
|
148
(53)
|
170
(0)
|
Baseline White Blood Cell Count (WBC) x10^9/L (x10^9 cells/L) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [x10^9 cells/L] |
16
(10)
|
19
(9.7)
|
17.5
(0)
|
Baseline Lactate (mM/L) (mM/L) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [mM/L] |
4.45
(3.5)
|
4.8
(4.2)
|
4.6
(0)
|
Baseline Procalcitonin (ng/mL) (ng/mL) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [ng/mL] |
44
(72)
|
23
(38)
|
33.5
(0)
|
Baseline Sequential Organ Failure Assessment (SOFA) Score (scores on a scale) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [scores on a scale] |
8.3
(3)
|
7.9
(3.5)
|
8.1
(0)
|
Acute Physiology And Chronic Health Evaluation (APACHE) II (scores on a scale) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [scores on a scale] |
24
(7.6)
|
24.9
(8.7)
|
24.5
(0)
|
Acute Physiology And Chronic Health Evaluation (APACHE) IV (scores on a scale) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [scores on a scale] |
88
(28.3)
|
87.5
(29.7)
|
87.8
(0)
|
APACHE IV predicted mortality (%) (percentage of predicted mortality) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [percentage of predicted mortality] |
34
(3)
|
33.6
(2.6)
|
33.8
(0)
|
Outcome Measures
Title | Time to Vasopressor Independence (Hours) |
---|---|
Description | Defined as the time from starting the active treatment/placebo to discontinuation of all pressors. |
Time Frame | From start of vasopressor medication to final discontinuation of vasopressor medication, up to 7 days. |
Outcome Measure Data
Analysis Population Description |
---|
Patients on vasopressor therapy in each group. |
Arm/Group Title | HAT Treatment | Comparator |
---|---|---|
Arm/Group Description | Receiving Hydrocortisone, Ascorbic Acid, and Thiamine | Receiving placebo |
Measure Participants | 60 | 57 |
Mean (Standard Deviation) [hours] |
27
(22)
|
53
(38)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | HAT Treatment, Comparator |
---|---|---|
Comments | ||
Type of Statistical Test | Non-Inferiority | |
Comments | Based on the results of the preliminary study of Marik et al, 5 we projected that the combination of ascorbic acid, thiamine, and hydrocortisone could reduce time to vasopressor discontinuation from 54 (+/-30 hours) vs 30 hours. For the additional primary outcome, we projected a greater change of SOFA score of 4 (+/-3) vs 2. Assuming a type 1 error of 5% (alpha of 0.05) and a power of 80%, this study would require a sample size of 94 patients. | |
Statistical Test of Hypothesis | p-Value | <0.001 |
Comments | ||
Method | t-test, 2 sided | |
Comments |
Title | Change in Sequential Organ Failure Assessment (SOFA) Score |
---|---|
Description | Defined as the day 4 post-randomization SOFA score minus the initial SOFA score. The Sequential Organ Failure Assessment (SOFA) Score is a mortality prediction score that is based on the degree of dysfunction of six organ systems. The score is calculated on admission and every 24 hours until discharge using the worst parameters measured during the prior 24 hours SOFA score ranges from 0 (no organ dysfunction) to 24 (highest possible score / organ dysfunction). |
Time Frame | 4 days post-randomization |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Treatment Arm | Placebo Arm |
---|---|---|
Arm/Group Description | 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. Ascorbic Acid: Ascorbic Acid 1.5g IV piggyback every 6 hours for 4 days (or discharge from ICU if prior to 4 days). Thiamine: Thiamine 200mg IV piggyback every 12 hours for 4 days (or discharge from ICU if prior to 4 days). Hydrocortisone: Hydrocortisone 50mg IV push every 6 hours for 4 days (or discharge from ICU if prior to 4 days). | 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. Sodium Chloride 0.9%: 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). |
Measure Participants | 68 | 69 |
Mean (Standard Deviation) [score on a scale] |
2.9
(3.3)
|
1.93
(3.5)
|
Title | Procalcitonin (PCT) Clearance |
---|---|
Description | PCT at 96 hours minus initial PCT, divided by the initial PCT multiplied by 100. |
Time Frame | 4 days post-randomization |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Treatment Arm | Placebo Arm |
---|---|---|
Arm/Group Description | 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. Ascorbic Acid: Ascorbic Acid 1.5g IV piggyback every 6 hours for 4 days (or discharge from ICU if prior to 4 days). Thiamine: Thiamine 200mg IV piggyback every 12 hours for 4 days (or discharge from ICU if prior to 4 days). Hydrocortisone: Hydrocortisone 50mg IV push every 6 hours for 4 days (or discharge from ICU if prior to 4 days). | 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. Sodium Chloride 0.9%: 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). |
Measure Participants | 68 | 69 |
Mean (Standard Deviation) [Percent] |
63
(170)
|
58
(66)
|
Title | ICU Mortality |
---|---|
Description | ICU mortality rate |
Time Frame | From admission to hospital until final discharge from the ICU, up to 28 days. |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Treatment Arm | Placebo Arm |
---|---|---|
Arm/Group Description | 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. Ascorbic Acid: Ascorbic Acid 1.5g IV piggyback every 6 hours for 4 days (or discharge from ICU if prior to 4 days). Thiamine: Thiamine 200mg IV piggyback every 12 hours for 4 days (or discharge from ICU if prior to 4 days). Hydrocortisone: Hydrocortisone 50mg IV push every 6 hours for 4 days (or discharge from ICU if prior to 4 days). | 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. Sodium Chloride 0.9%: 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). |
Measure Participants | 68 | 69 |
Count of Participants [Participants] |
6
8.8%
|
10
14.5%
|
Title | ICU Length of Stay |
---|---|
Description | Time from admitting to ICU to discharge. |
Time Frame | From admission to the ICU until final discharge from the ICU, up to an average of 7 days. |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Treatment Arm | Placebo Arm |
---|---|---|
Arm/Group Description | 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. Ascorbic Acid: Ascorbic Acid 1.5g IV piggyback every 6 hours for 4 days (or discharge from ICU if prior to 4 days). Thiamine: Thiamine 200mg IV piggyback every 12 hours for 4 days (or discharge from ICU if prior to 4 days). Hydrocortisone: Hydrocortisone 50mg IV push every 6 hours for 4 days (or discharge from ICU if prior to 4 days). | 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. Sodium Chloride 0.9%: 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). |
Measure Participants | 68 | 69 |
Mean (Standard Deviation) [days] |
4.76
(4.3)
|
4.66
(3.45)
|
Title | Ventilator Free Days |
---|---|
Description | Number of days alive and off of the ventilator at day 28. |
Time Frame | 28 Days post-randomization |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Treatment Arm | Placebo Arm |
---|---|---|
Arm/Group Description | 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. Ascorbic Acid: Ascorbic Acid 1.5g IV piggyback every 6 hours for 4 days (or discharge from ICU if prior to 4 days). Thiamine: Thiamine 200mg IV piggyback every 12 hours for 4 days (or discharge from ICU if prior to 4 days). Hydrocortisone: Hydrocortisone 50mg IV push every 6 hours for 4 days (or discharge from ICU if prior to 4 days). | 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. Sodium Chloride 0.9%: 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). |
Measure Participants | 68 | 69 |
Mean (Standard Deviation) [Days] |
22
(6.2)
|
22.4
(4.3)
|
Title | Hospital Length of Stay |
---|---|
Description | Time from admitting to discharge of hospital stay. |
Time Frame | From admission to the hospital until final discharge, up to 28 days. |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Treatment Arm | Placebo Arm |
---|---|---|
Arm/Group Description | 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. Ascorbic Acid: Ascorbic Acid 1.5g IV piggyback every 6 hours for 4 days (or discharge from ICU if prior to 4 days). Thiamine: Thiamine 200mg IV piggyback every 12 hours for 4 days (or discharge from ICU if prior to 4 days). Hydrocortisone: Hydrocortisone 50mg IV push every 6 hours for 4 days (or discharge from ICU if prior to 4 days). | 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. Sodium Chloride 0.9%: 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). |
Measure Participants | 68 | 69 |
Mean (Standard Deviation) [Days] |
11.5
(6.8)
|
11
(6.2)
|
Title | Hospital Mortality |
---|---|
Description | In-hospital mortality rate. |
Time Frame | Survival until hospital discharge, up to 28 days. |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Treatment Arm | Placebo Arm |
---|---|---|
Arm/Group Description | 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. Ascorbic Acid: Ascorbic Acid 1.5g IV piggyback every 6 hours for 4 days (or discharge from ICU if prior to 4 days). Thiamine: Thiamine 200mg IV piggyback every 12 hours for 4 days (or discharge from ICU if prior to 4 days). Hydrocortisone: Hydrocortisone 50mg IV push every 6 hours for 4 days (or discharge from ICU if prior to 4 days). | 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. Sodium Chloride 0.9%: 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). |
Measure Participants | 68 | 69 |
Count of Participants [Participants] |
11
16.2%
|
13
18.8%
|
Adverse Events
Time Frame | Each participant was assessed for adverse events up to hospital discharge, or up to 28 days. | |||
---|---|---|---|---|
Adverse Event Reporting Description | ||||
Arm/Group Title | Treatment Arm | Placebo Arm | ||
Arm/Group Description | 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. Ascorbic Acid: Ascorbic Acid 1.5g IV piggyback every 6 hours for 4 days (or discharge from ICU if prior to 4 days). Thiamine: Thiamine 200mg IV piggyback every 12 hours for 4 days (or discharge from ICU if prior to 4 days). Hydrocortisone: Hydrocortisone 50mg IV push every 6 hours for 4 days (or discharge from ICU if prior to 4 days). | 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. Sodium Chloride 0.9%: 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). | ||
All Cause Mortality |
||||
Treatment Arm | Placebo Arm | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 11/68 (16.2%) | 13/69 (18.8%) | ||
Serious Adverse Events |
||||
Treatment Arm | Placebo Arm | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/68 (0%) | 0/69 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
Treatment Arm | Placebo Arm | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/68 (0%) | 0/69 (0%) |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Jose Iglesias, DO |
---|---|
Organization | Community Medical Center Department of Critical Care, Department of Nephrology |
Phone | 732-557-8070 |
jiglesias23@gmail.com |
- 17-004