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

• ClinicalTrials.gov Identifier: NCT02106975
• Recruitment Status: Completed
• First Posted: April 8, 2014
• Results First Posted: October 15, 2019
• Last Update Posted: October 15, 2019
• Sponsor: Virginia Commonwealth University
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Virginia Commonwealth University

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Acute Lung Injury; Sepsis	Drug: Ascorbic Acid; Drug: Placebo: 5% Dextrose in water	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 170 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Vitamin C Infusion for Treatment in Sepsis Induced Acute Lung Injury
• Study Start Date: April 2014
• Actual Primary Completion Date: November 16, 2017
• Actual Study Completion Date: January 8, 2018

Arms and Interventions

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 Name: Vitamin C
Placebo Comparator: 5% Dextrose in Water; 50ml every 6 hours for 96 hours	Drug: Placebo: 5% Dextrose in water; Placebo

Outcome Measures

Primary Outcome Measures :

1. Modified Change in Sequential Organ Failure Assessment (mSOFA) Score [ Time Frame: 96 hours ]
   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.
2. C-Reactive Protein at Study Hours 0, 48, 96, 168 When Compared to Placebo [ Time Frame: up to 168 hours ]
3. Thrombomodulin Protein at Study Hours 0, 48, 96, 168 When Compared to Placebo [ Time Frame: Up to 168 hours ]

Secondary Outcome Measures :

1. 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. [ Time Frame: Up to hour 168 ]
2. 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 [ Time Frame: Up to hour 168 ]
   Estimate of Shunt
3. mSOFA Scores at Hours 0, 48, 96 [ Time Frame: Up to hour 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.
4. Ascorbate Level at Hour 0, 48, 96, 168 [ Time Frame: Up to hour 168 ]
5. Ventilator Free Days to Day 28 [ Time Frame: Up to Day 28 ]
6. ICU-free Days at Day 28 [ Time Frame: Up to Day 28 ]
7. All Cause Mortality to Day 28 [ Time Frame: Up to Day 28 ]
8. Hospital-free Days at Day 60 [ Time Frame: Up to Day 60 ]
9. Procalcitonin at Study Hour 0, 48, 96, 168 [ Time Frame: Up to hour 168 ]
10. Receptor for Advanced Glycation Endpoints at Study Hour 0, 48, 96, 168 [ Time Frame: Up to hour 168 ]
11. Tissue Factor Pathway Inhibitor at Study Hour 0, 48, 96, 168 [ Time Frame: Up to hour 168 ]
12. Oxygenation Score: Pressure [ Time Frame: Up to hour 168 ]
    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
13. Oxygenation Score: Saturation [ Time Frame: Up to hour 168 ]
    Oxygenation as measure by the ratio of arterial oxygen saturation to fraction of inspired oxygen SpO2/FiO2
14. Coagulation [ Time Frame: Up to hour 168 ]
    Coagulation as measured by Platelets per unit of blood. Scores range from less than 20 to more than 150. Lower scores indicate worse outcomes
15. Liver Function [ Time Frame: Up to hour 168 ]
    Liver function as measured by Total Bilirubin. Normal levels range from 0.2 - 1.2. Levels greater than 1.2 indicate worse outcomes
16. Cardiovascular Function [ Time Frame: Up to hour 168 ]
    Cardiovascular function as measured by Mean arterial pressure. Scores less than 70 mmHg indicate worse outcomes.
17. State of Consciousness [ Time Frame: Up to hour 168 ]
    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
18. Renal Function [ Time Frame: Up to hour 168 ]
    Renal function as measured by Creatinine. Scores range from less than 1.2 to greater than 5.0 with higher scores indicating worse outcomes

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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)

Contacts and Locations

Locations

United States, Georgia

Emory University and Grady Memorial Hospital

Atlanta, Georgia, United States, 30322

United States, Kentucky

University of Kentucky

Lexington, Kentucky, United States, 40506

United States, Ohio

The Cleveland Clinic

Cleveland, Ohio, United States, 44106

United States, Virginia

Virginia Commonwealth University Health System

Richmond, Virginia, United States, 23298

United States, Wisconsin

Froedtert and The Medical College of Wisconsin

Milwaukee, Wisconsin, United States, 53226

Sponsors and Collaborators

Virginia Commonwealth University

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Alpha B. Fowler, MD; Virginia Commonwealth University

  Study Documents (Full-Text)

Documents provided by Virginia Commonwealth University:

Study Protocol and Statistical Analysis Plan  [PDF] February 20, 2017

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Virginia Commonwealth University
• ClinicalTrials.gov Identifier: NCT02106975
• Other Study ID Numbers: HM20000917; 1UM1HL116885-01 ( U.S. NIH Grant/Contract )
• First Posted: April 8, 2014
• Results First Posted: October 15, 2019
• Last Update Posted: October 15, 2019
• Last Verified: October 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Sepsis; Toxemia; Lung Injury; Acute Lung Injury; Wounds and Injuries; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Lung Diseases; Respiratory Tract Diseases; Thoracic Injuries; Ascorbic Acid; Vitamins; Micronutrients; Physiological Effects of Drugs; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents