High Dose Intravenous Ascorbic Acid in Severe Sepsis

• ClinicalTrials.gov Identifier: NCT02734147
• Recruitment Status: Terminated
• First Posted: April 12, 2016
• Results First Posted: February 16, 2021
• Last Update Posted: February 16, 2021
• Sponsor: Christiana Care Health Services
• Information provided by (Responsible Party): Christiana Care Health Services

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Sepsis
• Interventions: Drug: Ascorbic Acid; Other: Normal Saline
• Enrollment: 24

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	High Dose IV Ascorbic Acid	Placebo
Arm/Group Description	Patients will receive 67 mg/kg IV ascorbic acid in 100 ml normal saline over 30 minutes every 8 hours (200 mg/kg/day) for 72 hours. Ascorbic Acid Participant Started: 12 Participant Completed: 9	The placebo group will receive 100 ml 0.9% NaCl over 30 minutes every 8 hours for 72 hours. Normal Saline Participant Started: 12 Participant Completed: 11
Period Title: Overall Study
Started	12	12
Completed	9	11
Not Completed	3	1

Baseline Characteristics

Arm/Group Title		High Dose IV Ascorbic Acid	Placebo	Total
Arm/Group Description		Patients will receive 67 mg/kg IV ascorbic acid in 100 ml normal saline over 30 minutes every 8 hours (200 mg/kg/day) for 72 hours. Ascorbic Acid	The placebo group will receive 100 ml 0.9% NaCl over 30 minutes every 8 hours for 72 hours. Normal Saline	Total of all reporting groups
Overall Number of Baseline Participants		12	12	24
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	12 participants	12 participants	24 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	6 50.0%	5 41.7%	11 45.8%
	>=65 years	6 50.0%	7 58.3%	13 54.2%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	12 participants	12 participants	24 participants
		67.6 (13.6)	70.2 (14.4)	68.9 (13.8)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	12 participants	12 participants	24 participants
	Female	5 41.7%	3 25.0%	8 33.3%
	Male	7 58.3%	9 75.0%	16 66.7%
Race and Ethnicity Not Collected [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	0 participants	0 participants	0 participants
				0
		[1] Measure Analysis Population Description: Race and Ethnicity were not collected from any participant.
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	12 participants	12 participants	24 participants
		12	12	24
Ascorbic Acid Concentration, Baseline [1] [2]; Mean (Standard Deviation); Unit of measure: mg/dL
	Number Analyzed	11 participants	11 participants	22 participants
		0.3 (0.3)	0.4 (0.3)	0.3 (0.3)
		[1] Measure Description: Normal Ascorbic Acid Range 0.4-2.0 mg/dL; [2] Measure Analysis Population Description: Missing Data
Ascorbic Acid Concentrations <0.4 mg/dL, Baseline [1] [2]; Measure Type: Number; Unit of measure: Percentage of participants
	Number Analyzed	11 participants	11 participants	22 participants
		72.7	36.6	68.1
		[1] Measure Description: Normal Ascorbic Acid Range 0.4-2.0 mg/dL; [2] Measure Analysis Population Description: Missing data
PIRO Score, Baseline [1]; Mean (Standard Deviation); Unit of measure: Scores on a scale
	Number Analyzed	12 participants	12 participants	24 participants
		15.4 (3.9)	15.9 (4.0)	15.7 (3.9)
		[1] Measure Description: PIRO consists of 4 assessments, Predisposition (scored 0-9), Infection (scored 0-4), Response (scored 0-6), and Organ Failure (scored 0-14). The total PIRO score is the sum of all subscores and ranges from 0-33 with higher scores indicating worse health
Modified SOFA Score, Baseline [1]; Mean (Standard Deviation); Unit of measure: Units on a scale
	Number Analyzed	12 participants	12 participants	24 participants
		5.2 (2.5)	5.0 (2.3)	5.1 (2.3)
		[1] Measure Description: Sequential Organ Failure Assessment (SOFA) Score included the degree of dysfunction of six organ systems (Respiratory, Cardiovascular, Liver, Renal, Coagulation, Neurologic. A modification of the SOFA includes the exclusion of the Liver function. Total score is reported, minimum score = 0 maximum score = 20. Higher scores indicate greater degree of dysfunction.
ICU Admission; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	12 participants	12 participants	24 participants
		5 41.7%	5 41.7%	10 41.7%

Outcome Measures

1. Primary Outcome

Title	Change in Modified SOFA Score
Description	Sequential Organ Failure Assessment (SOFA) Score included the degree of dysfunction of six organ systems (Respiratory, Cardiovascular, Liver, Renal, Coagulation, Neurologic. A modification of the SOFA includes the exclusion of the Liver function. Total score is reported, minimum score = 0 maximum score = 20. Higher scores indicate greater degree of dysfunction.
Time Frame	Baseline and 72 hours

Outcome Measure Data

Analysis Population Description

Data was not available for 3 participants in the treatment group.

Arm/Group Title	High Dose IV Ascorbic Acid	Placebo
Arm/Group Description:	Patients will receive 67 mg/kg IV ascorbic acid in 100 ml normal saline over 30 minutes every 8 hours (200 mg/kg/day) for 72 hours. Ascorbic Acid	The placebo group will receive 100 ml 0.9% NaCl over 30 minutes every 8 hours for 72 hours. Normal Saline
Overall Number of Participants Analyzed	9	12
Mean (Standard Deviation); Unit of Measure: units on a scale
	-1.0 (4.4)	-1.75 (3.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose IV Ascorbic Acid, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.631
	Comments	[Not Specified]
	Method	Other
	Comments	[Not Specified]

2. Secondary Outcome

Title	Modified SOFA Score
Description	Sequential Organ Failure Assessment (SOFA) Score included the degree of dysfunction of six organ systems (Respiratory, Cardiovascular, Liver, Renal, Coagulation, Neurologic. A modification of the SOFA includes the exclusion of the Liver function. Total score is reported, minimum score = 0 maximum score = 20. Higher scores indicate greater dysfunction.
Time Frame	at 72 Hours

Outcome Measure Data

Analysis Population Description

Data was not available for 3 participants in the treatment group.

Arm/Group Title	High Dose IV Ascorbic Acid	Placebo
Arm/Group Description:	Patients will receive 67 mg/kg IV ascorbic acid in 100 ml normal saline over 30 minutes every 8 hours (200 mg/kg/day) for 72 hours. Ascorbic Acid	The placebo group will receive 100 ml 0.9% NaCl over 30 minutes every 8 hours for 72 hours. Normal Saline
Overall Number of Participants Analyzed	9	12
Mean (Standard Deviation); Unit of Measure: units on a scale
	4.1 (4.8)	3.3 (3.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose IV Ascorbic Acid, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.640
	Comments	[Not Specified]
	Method	Other
	Comments	[Not Specified]

3. Secondary Outcome

Title	Ascorbic Acid Concentration at 32 Hours
Description	Ascorbic Acid Concentration Normal Ascorbic Acid Range 0.4-2.0 mg/dL
Time Frame	32 Hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose IV Ascorbic Acid	Placebo
Arm/Group Description:	Patients will receive 67 mg/kg IV ascorbic acid in 100 ml normal saline over 30 minutes every 8 hours (200 mg/kg/day) for 72 hours. Ascorbic Acid	The placebo group will receive 100 ml 0.9% NaCl over 30 minutes every 8 hours for 72 hours. Normal Saline
Overall Number of Participants Analyzed	12	12
Mean (Standard Deviation); Unit of Measure: mg/dL
	13.8 (10.9)	0.22 (0.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose IV Ascorbic Acid, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.006
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

4. Secondary Outcome

Title	ICU Length of Stay
Description	ICU Length of Stay in Hours
Time Frame	Length of ICU stay up to 200 hours

Outcome Measure Data

Analysis Population Description

Data was not available for 7 participants in both groups.

Arm/Group Title	High Dose IV Ascorbic Acid	Placebo
Arm/Group Description:	Patients will receive 67 mg/kg IV ascorbic acid in 100 ml normal saline over 30 minutes every 8 hours (200 mg/kg/day) for 72 hours. Ascorbic Acid	The placebo group will receive 100 ml 0.9% NaCl over 30 minutes every 8 hours for 72 hours. Normal Saline
Overall Number of Participants Analyzed	5	5
Median (Inter-Quartile Range); Unit of Measure: Hours
	29; (6 to 187)	47; (39 to 144)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose IV Ascorbic Acid, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.655
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

5. Secondary Outcome

Title	Hospital Length of Stay
Description	From admission until discharge from ICU in days
Time Frame	From ICU admission through ICU discharge, up to 2 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose IV Ascorbic Acid	Placebo
Arm/Group Description:	Patients will receive 67 mg/kg IV ascorbic acid in 100 ml normal saline over 30 minutes every 8 hours (200 mg/kg/day) for 72 hours. Ascorbic Acid	The placebo group will receive 100 ml 0.9% NaCl over 30 minutes every 8 hours for 72 hours. Normal Saline
Overall Number of Participants Analyzed	12	12
Median (Inter-Quartile Range); Unit of Measure: Days
	7; (5 to 9)	6; (4 to 7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose IV Ascorbic Acid, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.133
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]

6. Secondary Outcome

Title	Change in PIRO Score
Description	PIRO consists of 4 assessments, Predisposition (scored 0-9), Infection (scored 0-4), Response (scored 0-6), and Organ Failure (scored 0-14) (PIRO). The total PIRO score is the sum of all subscores and ranges from 0-33 with higher scores indicating worse health.
Time Frame	Baseline and 72 hours

Outcome Measure Data

Analysis Population Description

Data was not available for 3 participants in the treatment group.

Arm/Group Title	High Dose IV Ascorbic Acid	Placebo
Arm/Group Description:	Patients will receive 67 mg/kg IV ascorbic acid in 100 ml normal saline over 30 minutes every 8 hours (200 mg/kg/day) for 72 hours. Ascorbic Acid	The placebo group will receive 100 ml 0.9% NaCl over 30 minutes every 8 hours for 72 hours. Normal Saline
Overall Number of Participants Analyzed	9	12
Mean (Standard Deviation); Unit of Measure: units on a scale
	-3.7 (3)	-4.5 (3.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose IV Ascorbic Acid, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.566
	Comments	[Not Specified]
	Method	Other
	Comments	[Not Specified]

7. Secondary Outcome

Title	Percentage of Participants Who Died
Description	[Not Specified]
Time Frame	From initial hospital admission through discharge, up to 2 weeks.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose IV Ascorbic Acid	Placebo
Arm/Group Description:	Patients will receive 67 mg/kg IV ascorbic acid in 100 ml normal saline over 30 minutes every 8 hours (200 mg/kg/day) for 72 hours. Ascorbic Acid	The placebo group will receive 100 ml 0.9% NaCl over 30 minutes every 8 hours for 72 hours. Normal Saline
Overall Number of Participants Analyzed	12	12
Measure Type: Number; Unit of Measure: Percentage of participants
	16.7	16.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High Dose IV Ascorbic Acid, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	1.0
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]

Adverse Events

Time Frame	2 weeks
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	High Dose IV Ascorbic Acid		Placebo
Arm/Group Description	Patients will receive 67 mg/kg IV ascorbic acid in 100 ml normal saline over 30 minutes every 8 hours (200 mg/kg/day) for 72 hours. Ascorbic Acid		The placebo group will receive 100 ml 0.9% NaCl over 30 minutes every 8 hours for 72 hours. Normal Saline
All-Cause Mortality
	High Dose IV Ascorbic Acid		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	2/12 (16.67%)		2/12 (16.67%)
Serious Adverse Events
	High Dose IV Ascorbic Acid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/12 (16.67%)		2/12 (16.67%)
General disorders
Death †	2/12 (16.67%)		2/12 (16.67%)
Respiratory, thoracic and mediastinal disorders
Shortness of Breath † [1]	0/12 (0.00%)		1/12 (8.33%)
† Indicates events were collected by systematic assessment; [1] Short of breath during the 48-72 hour post randomization.
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	High Dose IV Ascorbic Acid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/12 (50.00%)		4/12 (33.33%)
Cardiac disorders
Tachycardia (HR increase 20 bpm) †	1/12 (8.33%)	2	2/12 (16.67%)	2
Gastrointestinal disorders
Vomiting †	2/12 (16.67%)	3	0/12 (0.00%)	0
General disorders
Other †	4/12 (33.33%)	8	3/12 (25.00%)	5
Vascular disorders
Hypotension (SBP< 90) †	2/12 (16.67%)	3	0/12 (0.00%)	0
† Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Jamie Rosini, Pharm D
• Organization: Christiana Care Health Services
• Phone: 302-733-6364
• EMail: jrosini@christianacare.org

• Responsible Party: Christiana Care Health Services
• ClinicalTrials.gov Identifier: NCT02734147
• Other Study ID Numbers: 603204
• First Submitted: March 18, 2016
• First Posted: April 12, 2016
• Results First Submitted: March 6, 2020
• Results First Posted: February 16, 2021
• Last Update Posted: February 16, 2021