Vitamin C Infusion for Treatment in Sepsis Induced Acute Lung Injury (CITRIS-ALI)

Hypothesis 1A: Vitamin C infusion will significantly attenuate sepsis-induced systemic organ failure as measured by Sequential Organ Failure Assessment (SOFA) score,

Hypothesis 1B: Vitamin C infusion will attenuate sepsis-induced lung injury as assessed by the oxygenation index and the VE40

Hypothesis 1C: Vitamin C infusion will attenuate biomarkers of inflammation (C-Reactive Protein, Procalcitonin), vascular injury (Thrombomodulin, Angiopoietin-2), alveolar epithelial injury (Receptor for Advanced Glycation Products), while inducing the onset of a fibrinolytic state (Tissue Factor Pathway Inhibitor).

Study Overview

• Status: Completed
• Conditions: Sepsis; Acute Lung Injury
• Intervention / Treatment: Drug: Ascorbic Acid; Drug: Placebo: 5% Dextrose in water

• Study Type: Interventional
• Enrollment (Actual): 170
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University and Grady Memorial Hospital
  • Kentucky
    • Lexington, Kentucky, United States, 40506
      • University of Kentucky
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • The Cleveland Clinic
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University Health System
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert and the Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must have suspected or proven infection, and meet 2 out of 4 of the criteria for Systemic Inflammatory Response (SIRS) due to infection, and be accompanied by at least 1 criterion for sepsis-induced organ dysfunction, and meet all 5 criteria for Acute Respiratory Distress Syndrome (ARDS).
• Suspected or proven infection: (e.g., thorax, urinary tract, abdomen, skin, sinuses, central venous catheters, and central nervous system, see Appendix A).
• The presence of a systemic inflammatory response: Defined as: fever: >38ºC (any route) or hypothermia: <36ºC (core temp only), tachycardia: heart rate > 90 beats/min or receiving medications that slow heart rate or paced rhythm, leukocytosis: >12,000 WBC/µL or leukopenia: <4,000 WBC/µL or >10% band forms. Respiratory rate > 20 breaths per minute or PaCO2 < 32 or invasive mechanical ventilation.
• The presence of sepsis associated organ dysfunction: (any of the following thought to be due to infection)
• Sepsis associated hypotension (systolic blood pressure (SBP) < 90 mm Hg or an SBP decrease > 40 mm Hg unexplained by other causes or use of vasopressors for blood pressure support (epinephrine, norepinephrine, dopamine =/> 5mcg, phenylephrine, vasopressin)
• Arterial hypoxemia (PaO2/FiO2 < 300) or supplemental O2 > 6LPM.
• Lactate > upper limits of normal laboratory results
• Urine output < 0.5 ml/kg/hour for > two hours despite adequate fluid resuscitation
• Platelet count < 100,000 per mcL
• Coagulopathy (INR > 1.5)
• Bilirubin > 2 mg/dL
• Glasgow Coma Scale < 11 or a positive CAM ICU score
• ARDS characterized by all the following criteria
• Lung injury of acute onset, within 1 week of an apparent clinical insult and with progression of respiratory symptoms
• Bilateral opacities on chest imaging not explained by other pulmonary pathology (e.g. pleural effusions, lung collapse, or nodules)
• Respiratory failure not explained by heart failure or volume overload
• Decreased arterial PaO2/FiO2 ratio ≤ 300 mm Hg
• Minimum PEEP of 5 cmH2O (may be delivered noninvasively with CPAP to diagnose mild ARDS

Exclusion Criteria:

• Known allergy to Vitamin C
• inability to obtain consent;
• age < 18 years;
• No indwelling venous or arterial catheter in patients requiring insulin in a manner that requires glucose being checked more than twice daily (e.g. continuous infusion, sliding scale);
• presence of diabetic ketoacidosis;
• more than 48 hrs since meeting ARDS criteria;
• patient or surrogate or physician not committed to full support (not excluded if patient would receive all supportive care except for cardiac resuscitation);
• pregnancy or breast feeding,
• moribund patient not expected to survive 24 hours;
• home mechanical ventilation (via tracheotomy or noninvasive) except for CPAP/BIPAP used only for sleep-disordered breathing;
• home O2 > 2LPM, except for with CPAP/BIPAP
• diffuse alveolar hemorrhage (vasculitis);
• interstitial lung disease requiring continuous home oxygen therapy;
• Active kidney stone
• Non English speaking;
• Ward of the state (inmate, other)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Ascorbic Acid; 200mg/kg/day divided over 4 doses. Administered every 6 hours for 96 hours	Drug: Ascorbic Acid; Intervention; Other Names: Vitamin C
PLACEBO_COMPARATOR: 5% Dextrose in Water; 50ml every 6 hours for 96 hours	Drug: Placebo: 5% Dextrose in water; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modified Change in Sequential Organ Failure Assessment (mSOFA) Score	mSOFA is a single score based on patient status of five different biological systems: respiratory, cardiovascular, coagulation, renal, and neurological. Scores range from 0 to 20 with higher scores indicated worse status.	96 hours
C-Reactive Protein at Study Hours 0, 48, 96, 168 When Compared to Placebo		up to 168 hours
Thrombomodulin Protein at Study Hours 0, 48, 96, 168 When Compared to Placebo		Up to 168 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oxygenation Score: Pressure	Oxygenation as measure by the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2). Scores range from 100 to 300 with lower values indicating more worse outcomes	Up to hour 168
Coagulation	Coagulation as measured by Platelets per unit of blood. Scores range from less than 20 to more than 150. Lower scores indicate worse outcomes	Up to hour 168
Cardiovascular Function	Cardiovascular function as measured by Mean arterial pressure. Scores less than 70 mmHg indicate worse outcomes.	Up to hour 168
State of Consciousness	State of consciousness as measure by Glasgow Coma Scale which gives a score based on eye, verbal, and motor responses. Scores range from 3 to 15 with lower scores indicating worse outcome	Up to hour 168
Oxygenation Index (FiO2 x Mean Airway Pressure/PaO2) at Study Hour 0, 48, 96, 168 if Still Intubated in Ascorbate Infused Patient Compared to Placebo.		Up to hour 168
VE-40 (Vent RR x TV/Weight) x (PaCO2/40) at Study Hour 0, 48, 96, 168 if Still Intubated, in Ascorbate Infused Patient Compared to Placebo	Estimate of Shunt	Up to hour 168
mSOFA Scores at Hours 0, 48, 96	mSOFA is a single score based on patient status of five different biological systems: respiratory, cardiovascular, coagulation, renal, and neurological. Scores range from 0 to 20 with higher scores indicated worse status.	Up to hour 96
Ascorbate Level at Hour 0, 48, 96, 168		Up to hour 168
Ventilator Free Days to Day 28		Up to Day 28
ICU-free Days at Day 28		Up to Day 28
All Cause Mortality to Day 28		Up to Day 28
Hospital-free Days at Day 60		Up to Day 60
Procalcitonin at Study Hour 0, 48, 96, 168		Up to hour 168
Receptor for Advanced Glycation Endpoints at Study Hour 0, 48, 96, 168		Up to hour 168
Tissue Factor Pathway Inhibitor at Study Hour 0, 48, 96, 168		Up to hour 168
Oxygenation Score: Saturation	Oxygenation as measure by the ratio of arterial oxygen saturation to fraction of inspired oxygen SpO2/FiO2	Up to hour 168
Liver Function	Liver function as measured by Total Bilirubin. Normal levels range from 0.2 - 1.2. Levels greater than 1.2 indicate worse outcomes	Up to hour 168
Renal Function	Renal function as measured by Creatinine. Scores range from less than 1.2 to greater than 5.0 with higher scores indicating worse outcomes	Up to hour 168

Collaborators and Investigators

• Sponsor: Virginia Commonwealth University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Alpha B. Fowler, MD, Virginia Commonwealth University

Publications and helpful links

General Publications

• Fowler AA 3rd, Truwit JD, Hite RD, Morris PE, DeWilde C, Priday A, Fisher B, Thacker LR 2nd, Natarajan R, Brophy DF, Sculthorpe R, Nanchal R, Syed A, Sturgill J, Martin GS, Sevransky J, Kashiouris M, Hamman S, Egan KF, Hastings A, Spencer W, Tench S, Mehkri O, Bindas J, Duggal A, Graf J, Zellner S, Yanny L, McPolin C, Hollrith T, Kramer D, Ojielo C, Damm T, Cassity E, Wieliczko A, Halquist M. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA. 2019 Oct 1;322(13):1261-1270. doi: 10.1001/jama.2019.11825. Erratum In: JAMA. 2020 Jan 28;323(4):379.

Study record dates

Study Major Dates

• Study Start: April 1, 2014
• Primary Completion (ACTUAL): November 16, 2017
• Study Completion (ACTUAL): January 8, 2018

Study Registration Dates

• First Submitted: March 27, 2014
• First Submitted That Met QC Criteria: April 3, 2014
• First Posted (ESTIMATE): April 8, 2014

Study Record Updates

• Last Update Posted (ACTUAL): October 15, 2019
• Last Update Submitted That Met QC Criteria: October 14, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Diseases; Lung Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Thoracic Injuries; Sepsis; Toxemia; Wounds and Injuries; Acute Lung Injury; Lung Injury; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Vitamins; Antioxidants; Ascorbic Acid
• Other Study ID Numbers: HM20000917; 1UM1HL116885-01 (NIH)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No