Sepsis, Septic Shock
Conditions
Brief summary
This is a randomized, double-blind, placebo-controlled clinical trial to compare Vitamin C versus placebo for patients presenting to the ICU with a diagnosis of septic shock.
Detailed description
This is a multi-site, randomized, double-blind, placebo-controlled trial comparing a regimen of moderate-dose (6000 mg per day) Vitamin C supplementation versus placebo for the treatment of patients presenting to the ICU with septic shock. Both groups will continue to receive all other standard of care measures for septic shock as clinically indicated. Groups will be enrolled and receive study drug/placebo for 4 days (96 hours) or until 24 hours post-last pressor dose, whichever is sooner.
Interventions
DRUGVitamin C
Continuous infusion of vitamin C
DRUGPlacebo
Placebo designed to mimic intervention
Sponsors
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* • Capability to provide written consent from participant or legally authorized representative (LAR) if the participant is unable or incapacitated due to severity of illness. * Age ≥ 18 years * Septic shock as pragmatically defined as: o Order for intravenous antimicrobials with either procalcitonin \> 2 mg/dL within 24 hours of enrollment OR other clinical suspicion of infection or confirmed infection AND * Hypotension requiring vasopressor therapy, despite fluid resuscitation of at least 30 cc/kg AND * Lactate \> 2 mmol/L 24 hr prior to enrollment AND * Presence of sepsis defined as equal to or greater than 2 SIRS criteria and/or acute increase in qSOFA score of 2 points or more. * SIRS criteria: 1) Temperature greater than 38° or less than 36° Celsius. 2) Heart rate greater than 90 beats per minute. 3) Respiratory rate greater than 20 breaths per minute OR arterial carbon dioxide tension less than 32 mmHg. 4) White blood cell count greater than 12,000 cell/µL, less than 4,000 cells/µL, OR band cells greater than 10% of the total white blood cell population. * qSOFA: 1 point each is assigned for: 1) systolic blood pressure below 100, 2) respiratory rate greater than 22, and 3) mental status not at baseline.
Exclusion criteria
* • Unable to start infusion within 24 hours of septic shock identification * Currently pregnant or breastfeeding * Patient to receive comfort measures only * Cardiac Arrest * Cardiovascular Surgery patients receiving prophylactic peri-operative antibiotics \< 48 hours post-operation * Participation in another study involving an investigational product within 30 days of the baseline visit * Allergy to Vitamin C * History of nephrolithiasis * History of G6PD deficiency * ESRD patients, transplant eligible on dialysis currently taking vitamin C supplementation * Clinical course that treating clinician decides would preclude safe participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With ICU Mortality | 28 days | Outcome is reported as the number of patients who expired while receiving care in the intensive care unit (ICU). |
| All Cause Mortality at 28 Days | 28 days | Outcome is reported as the number of participants who have expired at 28 days post intervention |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Lactate Clearance Post Intervention Administration | 28 days | — |
| Rate of Lactate Clearance Post Intervention Administration | 24, 48, 72, and 96 hours post intervention | Outcome is reported as the number of participants who clear lactate from the bloodstream at 24, 48, 72, and 96 hours post intervention. Clearance is defined as a serum concentration of 2.0 mmol/l or less. |
| Rate of Procalcitonin Clearance Post Intervention Administration | 4 days | — |
| Number of Participants With Need for Renal Replacement Therapy | 4 days | Outcome is reported as the number of participants who require renal replacement therapy |
| Duration of Vasopressor Therapy | 28 days | Outcome is reported as the duration in hours of vasopressor therapy post intervention administration |
| Change in Sequential Organ Failure Assessment (SOFA) Score | Baseline and 4 days | SOFA score is a mortality prediction score that is based on the degree of dysfunction of 6 organ systems. Total scores range from 0 to 24, with higher scores indicating higher likely mortality. |
| Change in Acute Physiology and Chronic Health Evaluation (APACHE) Scores | Baseline and 4 days | APACHE score is a severity-of-disease classification system that is calculated from a patient's age and 12 routine physiological measurements. Total scores are computed based on several measurements and range from 0 to 71 with higher scores corresponding to more severe disease and a higher risk of death. |
| Total Intravenous Fluid Administered | 24 hours | Outcome is reported as the total volume of intravenous fluid (in liters) administered to participants during 24 hours following the initiation of study treatment. |
| Change in Serum Creatinine | Baseline and 4 days | Outcome is report as the change in serum creatinine between baseline and 4 days following treatment. Outcome is reported in units of mg/dl. |
| Duration of ICU Stay Post Intervention Administration | 28 days | Outcome is reported as the duration (in days) that participants require care in the intensive care unit (ICU) post intervention administration |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo designed to mimic intervention
Placebo: Placebo designed to mimic intervention | 64 |
| Intervention Vitamin C
Vitamin C: Continuous infusion of vitamin C | 61 |
| Total | 125 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 8 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Intervention |
|---|---|---|---|
| Age, Continuous | 73 years | 71 years | 68.9 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 59 Participants | 118 Participants | 59 Participants |
| Region of Enrollment United States | 64 participants | 125 participants | 61 participants |
| Sex: Female, Male Female | 31 Participants | 62 Participants | 31 Participants |
| Sex: Female, Male Male | 33 Participants | 63 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 26 / 64 | 16 / 61 |
| other Total, other adverse events | 9 / 64 | 8 / 61 |
| serious Total, serious adverse events | 3 / 64 | 4 / 61 |
Outcome results
Primary
All Cause Mortality at 28 Days
Outcome is reported as the number of participants who have expired at 28 days post intervention
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | All Cause Mortality at 28 Days | 26 Participants |
| Intervention | All Cause Mortality at 28 Days | 16 Participants |
Primary
Number of Participants With ICU Mortality
Outcome is reported as the number of patients who expired while receiving care in the intensive care unit (ICU).
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With ICU Mortality | 20 Participants |
| Intervention | Number of Participants With ICU Mortality | 14 Participants |
Secondary
Change in Acute Physiology and Chronic Health Evaluation (APACHE) Scores
APACHE score is a severity-of-disease classification system that is calculated from a patient's age and 12 routine physiological measurements. Total scores are computed based on several measurements and range from 0 to 71 with higher scores corresponding to more severe disease and a higher risk of death.
Time frame: Baseline and 4 days
Population: All participants for whom APACHE scores at baseline and 4 days post intervention were available are included.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change in Acute Physiology and Chronic Health Evaluation (APACHE) Scores | 7 score on a scale |
| Intervention | Change in Acute Physiology and Chronic Health Evaluation (APACHE) Scores | 5 score on a scale |
Secondary
Change in Sequential Organ Failure Assessment (SOFA) Score
SOFA score is a mortality prediction score that is based on the degree of dysfunction of 6 organ systems. Total scores range from 0 to 24, with higher scores indicating higher likely mortality.
Time frame: Baseline and 4 days
Population: All participants for whom baseline and 96-hour SOFA scores were available are included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change in Sequential Organ Failure Assessment (SOFA) Score | 4 score on a scale |
| Intervention | Change in Sequential Organ Failure Assessment (SOFA) Score | 4 score on a scale |
Secondary
Change in Serum Creatinine
Outcome is report as the change in serum creatinine between baseline and 4 days following treatment. Outcome is reported in units of mg/dl.
Time frame: Baseline and 4 days
Population: All participants for whom baseline and 96-hour creatinine data is available are included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change in Serum Creatinine | 0.5 mg/dl |
| Intervention | Change in Serum Creatinine | .4 mg/dl |
Secondary
Duration of ICU Stay Post Intervention Administration
Outcome is reported as the duration (in days) that participants require care in the intensive care unit (ICU) post intervention administration
Time frame: 28 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Duration of ICU Stay Post Intervention Administration | 2.6 days |
| Intervention | Duration of ICU Stay Post Intervention Administration | 2.9 days |
Secondary
Duration of Vasopressor Therapy
Outcome is reported as the duration in hours of vasopressor therapy post intervention administration
Time frame: 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Duration of Vasopressor Therapy | 27.1 hours |
| Intervention | Duration of Vasopressor Therapy | 27.7 hours |
Secondary
Number of Participants With Need for Renal Replacement Therapy
Outcome is reported as the number of participants who require renal replacement therapy
Time frame: 4 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Need for Renal Replacement Therapy | 2 Participants |
| Intervention | Number of Participants With Need for Renal Replacement Therapy | 10 Participants |
Secondary
Rate of Lactate Clearance Post Intervention Administration
Outcome is reported as the number of participants who clear lactate from the bloodstream at 24, 48, 72, and 96 hours post intervention. Clearance is defined as a serum concentration of 2.0 mmol/l or less.
Time frame: 24, 48, 72, and 96 hours post intervention
Population: All participants who completed 96 hours of testing are included.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Rate of Lactate Clearance Post Intervention Administration | 24 hours | 13 Participants |
| Placebo | Rate of Lactate Clearance Post Intervention Administration | 48 hours | 18 Participants |
| Placebo | Rate of Lactate Clearance Post Intervention Administration | 72 hours | 18 Participants |
| Placebo | Rate of Lactate Clearance Post Intervention Administration | 96 hours | 19 Participants |
| Intervention | Rate of Lactate Clearance Post Intervention Administration | 96 hours | 18 Participants |
| Intervention | Rate of Lactate Clearance Post Intervention Administration | 24 hours | 12 Participants |
| Intervention | Rate of Lactate Clearance Post Intervention Administration | 72 hours | 18 Participants |
| Intervention | Rate of Lactate Clearance Post Intervention Administration | 48 hours | 16 Participants |
Secondary
Rate of Procalcitonin Clearance Post Intervention Administration
Time frame: 4 days
Population: Outcome was not collected.
Secondary
Time to Lactate Clearance Post Intervention Administration
Time frame: 28 days
Population: Measure was not collected
Secondary
Total Intravenous Fluid Administered
Outcome is reported as the total volume of intravenous fluid (in liters) administered to participants during 24 hours following the initiation of study treatment.
Time frame: 24 hours
Population: All participants for whom total intravenous fluid administration data was available are included.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Total Intravenous Fluid Administered | 6 hours post initiation of study treatment | .76 liters |
| Placebo | Total Intravenous Fluid Administered | 24 hours post initiation of study treatment | 3.37 liters |
| Intervention | Total Intravenous Fluid Administered | 6 hours post initiation of study treatment | 1.07 liters |
| Intervention | Total Intravenous Fluid Administered | 24 hours post initiation of study treatment | 3.59 liters |