Use of Ascorbic Acid in Patients With COVID 19
Phase: NA
Conditions: Hospitalized Patients With Covid-19 Pneumonia
Sponsor: University of Palermo

Palermo, Italy 
March 12, 2020 
 
 
 
 
 
Use of ascorbic acid in patients 
with covid-19 pneumonia  
Azienda Ospedaliera di Rilievo Nazionale e di Alta Specializzazione 
ARNAS Civico-Di Cristina-Benfratelli di Palermo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator:  
Prof. Salvatore Corrao  
Direttore Medicina Interna ad indirizzo Geriatrico- Riabilitativo ARNAS Civico, Palermo 
Tel + 390916662717 
Email: s.corrao@tiscali.it  
 
 

 
Title 
Use of ascorbic acid in patients with covid-19 
pneumonia 
Rationale for the 
Study 
Different studies showed that ascorbic acid (vitaminC) 
positively affects the development and maturation of T-
lymphocytes, in particular NK (natural Killer) cells 
involved in the immune response to viral agents. It also 
contributes to the inhibition of ROS production and to the 
remodulation of the cytokine network typical of systemic 
inflammatory syndrome. 
Recent studies have also demonstrated the effectiveness 
of vitamin C administration in terms of reducing mortality, 
in patients with sepsis hospitalized in intensive care 
wards. 
Given this background, in the light of the current COVID-
19 emergency, since the investigators cannot carry out a 
randomized controlled trial, it is their intention to conduct 
a study in the cohort of hospitalized patients with covid-
19 pneumonia, administering 10 gr of vitamin C 
intravenously in addition to conventional therapy. 
Main end-point 
 In-hospital mortality 
Surrogate end-points 
• Reduction of PCR levels > 50% in comparison with 
PCR levels at the admission, within 72 hours after 
the administration 
• Lactate Clearance 
• Hospital stay 
• Resolution of symptoms 
• Duration of positive swab 
• Resolution of tomography imaging 
Study design 
Uncontrolled open label longitudinal study 
Setting 
Azienda Ospedaliera di Rilievo Nazionale e di Alta 
Specializzazione ARNAS Civico-Di Cristina-Benfratelli di 
Palermo  
Duration of the study  Undefined 
Sample size 
Consecutive 
patients 
with 
COVID-19 
pneumonia 
admitted 
to 
ARNAS 
Civico-Di 
Cristina-Benfratelli, 
Palermo  

Data Collection 
For each patient will be considered: 
• Sex 
• Age 
• Origin 
• Comorbidities 
• Drugs 
• PAO 
• Sp02 
• BUN 
• Creatinine 
• Electrolytes 
• Glicaemia 
• Blood count 
• PCR 
• PCT 
• SOFA score at the admission  
• Liver function 
• Coaugulation 
• Hemogasanalysis 
• Thorax tomography 
• Lactate Clearance  
• Lenght of hospital stay 
 
Inclusion criteria 
• In case of doubt of interstitial pneumonia with 
indications for intubation  
• Positive swab test of SARS-CoV-2  
• Interstitial pneumonia 
• Signature of informed consent 
Exclusion criteria 
• Unsigned informed consent 
• Negative swab test of SARS-CoV-2  
Statistical analysis 
Stata Statistical Software: Release 14.1. College Station, 
TX: StataCorp LP) was used for database management 
and analysis. 
Ethics 
 
The data will be collected in accordance to art. 13 and 23 
of D. L.gs. n. 196/2003 and current regulations.  
The study will be conducted according to the rules 
established by the standards of Good Clinical Practice 
and according to the "Helsinki Declaration". Medical 
practices are carried out according to the most recent 
recommendations of the World Medical Assembly 
(Helsinki 
Declaration, 
1964, 
and 
subsequent 
amendments). 
 
 
 
 
 

Rationale for the Study 
The Sars-COV-2, has spread all over the world, in two months after its discovery in 
China. Outbreaks have been reported in more than 50 countries with more than 118,223 
confirmed cases and 4,291 deaths worldwide. In Italy, the scenario is progressively 
worsening with 8514 confirmed cases and 631 deaths at 10/3/2020. 
Along with the spread of this new virus there has been an increase in the number of 
pneumonia identified with the term novel coronavirus (2019-nCoV)-infected pneumonia 
(NCIP), which are characterized by fever, asthenia, dry cough, lymphopenia, prolonged 
prothrombin time, elevated lactic dehydrogenase, and a tomographic imaging indicative 
of interstitial pneumonia (ground glass and patchy shadows). 
Recent studies have shown the efficacy of vitamin C and thiamine administration in 
patients hospitalized for sepsis in the setting of intensive wards in terms of mortality 
reduction. The use of intravenously vitamin C arises from the experimental evidence of 
its anti-inflammatory and antioxidant properties. Vitamin C causes a greater 
proliferation of natural killers without affecting their functionality. Moreover, the vitamin 
C reduces the production of ROS (reactive oxygen species) that contribute to the 
activation of the inflammosomi and, in particular, the NLRP3 that affetcs the maturation 
and secretion of cytokines such as IL1beta and IL-18 that are involved in the 
inflammatory systemic syndrome that characterized sepsis. Vitamin C blocks the 
expression of ICAM-1 and activation of NFKappaB that are involved in inflammatory, 
neoplastic, and apoptotic processes by the inhibition of TNFalfa. 
For this reason, the use of vitamin C could be effective in terms of mortality and 
secondary outcomes in the cohort of patients with covid-19 pneumonia. 
In view of the emergency of SARS-VOC-2 and the impossibility of carrying out a 
randomized controlled study, it is their intention to conduct an intervention protocol 
(administration of 10 grams of vitamin C intravenously in addition to conventional 
therapy) involving the cohort of hospitalized patients with covid-19 pneumonia. 

 
Methods 
An uncontrolled longitudinal study will be conducted at the Arnas Civico-di Cristina-
Benfratelli National Relevance Hospital in Palermo. This study will include all patients 
consecutively hospitalized with positive swab test of SARS-CoV-2 and interstitial 
pneumonia or with interstitial pneumonia with indication of intubation. At the admission, 
data will be collected: personal and anamnestic information, clinical and laboratory 
findings such as Gender, Age, Ethnicity, Comorbidities, Drugs, blood urea nitrogen, 
Creatinine, Electrolytes, Blood cell count, Clearance of the lactates, PCR, PCT, SOFA 
score, liver function, Coagulation, Blood gas analysis, Systolic and Diastolic Blood 
Pressure, Sp02, Glycaemia, Body Mass Index (BMI). Length of hospital stay will be 
recorded. After written informed consent, 10 grams of vitamin C in 250 ml of saline to 
infuse at a rate of 60 drops / minute will be administered. In-hospital mortality, 
reduction of PCR levels > 50% in comparison with PCR levels at the admission within 
72 hours after the administration, lactate clearance, length of hospital stay, resolution 
of symptoms, duration of positive swab (days). Resolution of the CT imaging will be 
analysed. Stata Statistical Software: Release 14.1. College Station, TX: StataCorp LP) 
was used for database management and analysis. 
 
Ethics 
The data will be collected in accordance to art. 13 and 23 of D. L.gs. n. 196/2003 and 
current regulations. The study will be conducted according to the rules established by 
the standards of Good Clinical Practice and according to the "Helsinki Declaration". 
Medical practices are carried out according to the most recent recommendations of the 
World Medical Assembly (Helsinki Declaration, 1964, and subsequent amendments). 
 
 

Bibliography 
  
1) http://www.salute.gov.it/portale/nuovocoronavirus/dettaglioContenutiNuovoCor
onavirus.jsp?lingua=italiano&id=5338&area=nuovoCoronavirus&menu=vuoto 
accesso 11/03/2020 
2) http://www.salute.gov.it/portale/nuovocoronavirus/dettaglioContenutiNuovoCor
onavirus.jsp?lingua=italiano&id=5351&area=nuovoCoronavirus&menu=vuoto 
accesso 11/03/2020 
3) Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, 
Zhao Y, Li Y, Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients 
With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 
Feb 7. doi: 10.1001/jama.2020.1585 
4) Byerly S, Parreco J, Soe-Lin H, Parks J, Lee EE, Shnaydman I, Mantero A, Yeh 
DD, Namias N, Rattan R. Vitamin C and Thiamine Are Associated with Lower 
Mortality in Sepsis. J Trauma Acute Care Surg. 2020 Feb 7. doi: 
10.1097/TA.0000000000002613. [Epub ahead of print] 
5) Kawade N, Tokuda Y, Tsujino S, Aoyama H, Kobayashi M, Murai A, Horio F. 
Dietary Intake of Ascorbic Acid Attenuates Lipopolysaccharide-Induced Sepsis 
and Septic Inflammation in ODS Rats. J Nutr Sci Vitaminol (Tokyo). 
2018;64(6):404-411. 
6) Tyml K. Vitamin C and Microvascular Dysfunction in Systemic Inflammation. 
Antioxidants (Basel). 2017 Jun 29;6(3). 
7) Huijskens MJ, Walczak M, Sarkar S, Atrafi F, Senden-Gijsbers BL, Tilanus MG, 
Bos GM, Wieten L, Germeraad WT. Ascorbic acid promotes proliferation of natural 
killer cell populations in culture systems applicable for natural killer cell therapy. 
Cytotherapy. 2015 May;17(5):613-20 

8) Mao K., Chen S., Chen M., Ma Y., Wang Y., Huang B., He Z., Zeng Y., Hu Y., Sun 
S., et al., Nitric oxide suppresses NLRP3 inflammasome activation and protects 
against LPS-induced septic shock, Cell research, 2013, 23, 201-212. 
9) Fisher B.J., Kraskauskas D., Martin E.J., Farkas D., Puri P., Massey H.D., Idowu 
M.O., Brophy D.F., Voelkel N.F., Fowler A.A., 3rd, et al., Attenuation of sepsis-
induced organ injury in mice by vitamin C, JPEN. Journal of parenteral and enteral 
nutrition, 2014, 38, 825-839. 
10) Sang Xuesong, Wang Hongbin, Chen Yihui, Guo Qiuhong, Lu Ailing, Zhu Xiaoli, 
Meng Guangxun.. Vitamin C inhibits the activation of the NLRP3 inflammasome 
by scavenging mitochondrial ROS. Inflammasome. 2016, 2. 10.1515/infl-2016-
0001. 
11) Mo SJ, Son EW, Rhee DK, Pyo S. Modulation of TNF-alpha-induced ICAM-1 
expression, NO and H2O2 production by alginate, allicin and ascorbic acid in 
human endothelial cells. Arch Pharm Res. 2003 Mar;26(3):244-251 
12) Bowie AG, O'Neill LA. Vitamin C inhibits NF-kappa B activation by TNF via the 
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15;165(12): 7180-7188. 
 
 
 
 
 
 
 
 
 

ATTACHMENT 1 
Method for administration of Ascorbic Acid (Vitamin C). 
1. Introduce yourself to the patient; 
2. Check personal data; 
3. Verify that the patient is suitable for treatment. Inform the patient before signing the consent. Ask 
for the presence of allergies to vitamin C or its excipients (methyl parahydroxybenzoate, 
propyl parahydroxybenzoate, sodium hydroxide); 
4. Make sure that informed consent is signed in all its parts; 
5. Prepare the patient by cannulating a vein with a cannula-over-needle device, preferably green (18G) 
or pink (20G); 
6. Dilute, according to sterile procedure, 10 grams of vitamin C in 250 cc of physiological solution; 
7. Administer the solution by infusing at a rate of 60 drops / minute. 
8. In the absence of incompatibility studies, this medicine should not be mixed with other products; 
9. Monitor the patient for at least half an hour after the infusion; 
10. Observe patient-reported signs and symptoms. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Attachment 2 
  
INFORMED CONSENT FORM FOR VITAMIN TREATMENT C 
  
Dear Madam / Dear Sir, 
  
This document, which we invite you to read carefully, is intended to inform you about the benefits and possible 
negative effects associated with the administration of Vitamin C, a water-soluble antioxidant vitamin, intravenously. 
  
  
To facilitate its understanding, we report some definitions and information regarding the aforementioned therapy. 
  
  
Possible side effects related to prolonged administration of vitamin C 
- gastric acidity with heartburn and reflux; 
-a ument excretion urine of oxalates 
  
We therefore invite you, during the day of administration, to take at least 1.5 liters of water per day by drinking 
little and often. 
  
  
The undersigned: Surname _________________________   Name  ___________________________ 
  
Clinical record n ° ________________ 
declares to have been informed in detail about the benefits and potential negative effects associated with 
the intravenous infusion therapeutic treatment with Vitamin C at high doses and to have understood that this 
treatment may lead to the onset of undesirable effects. 
On the basis of the information received, I grant my free and voluntary consent to the treatment with vitamin C. 
  
Date: ________________ 
  
        Doctor’s signature                                                                                          Patient's signature