Oxidative StressPhase 3NCT05327348
Effectiveness of IV Vitamin C in Reducing Oxidative Stress Associated With Free Flap Surgery
A Phase 3 study testing Intravenous Ascorbate and Normal Saline 10 mL Injection in people with Oxidative Stress and Ischemia-reperfusion Injury, run by University of Malaya at 3 sites in Malaysia.
Trial summary
Ischemia and reperfusion injury during free flap reconstructive surgery creates a state of increased oxidative stress that can adversely affect the flap outcomes. Ascorbic acid (AA) had been proven to have beneficial effect on end-organ protection and flap survival from ischemia-reperfusion injury via its antioxidant… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Oxidative Stress, Ischemia-reperfusion Injury
- What is being tested?
- Intravenous Ascorbate and Normal Saline 10 mL Injection
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 34 participants
- Where
- 3 sitesMalaysia
- Study dates
- 25 Sep 2022to 31 Jul 2023
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adults (age 18 years and older, male or female) who are planned for elective free flap reconstructive surgery.
Who cannot join
- Hypersensitivity to vitamin C
- Oliguria (urine output <400mL/day) or anuria (urine output <100mL/day)
- Renal failure (serum creatinine level ≥175.0 %mol/L)
- Hemodialysis
- Renal calculi
- Thalassemia
Show all 11Show fewer
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency
- Unfit for surgery
- Pregnancy or lactating
- Hemochromatosis
- Hyperoxaluria
Trial locations and contacts
3 sites in 1 country.
Malaysia3 sites, 3 recruiting
- Recruiting
Hospital Kuala Lumpur
Kuala Lumpur, 50586
Chai Siew Cheng, MD, +60326155555 ext. 1060/1059, scchai513@gmail.com
Raymond Yii Shi Liang, MBBS, +60379494422 ext. 2441, raymond.yii@ummc.edu.my
- Recruiting
University of Malaya Medical Centre
Kuala Lumpur, 59100
Raymond Yii Shi Liang, MBBS, +60379494422 ext. 2441, raymond.yii@ummc.edu.my
Alizan B Abdul Khalil, MBBS, +60379494422 ext. 2441, alizankhalil@gmail.com
- Not yet recruiting
Hospital Universiti Sains Malaysia
Kubang Kerian, Kelantan, 16150
Wan Azman Wan Sulaiman, MD, +6097676894, wazman@usm.my
Raymond Yii Shi Liang, MBBS, +60379494422 ext. 2441, raymond.yii@ummc.edu.my
About this study
Official title: The Efficacy of Perioperative Parenteral Ascorbic Acid in Reducing Oxidative Stress Among Patients Undergoing Free Flap Reconstructive Surgery: A Prospective Multicenter Randomized Controlled Pilot Trial
Ischemia and reperfusion injury during free flap reconstructive surgery creates a state of increased oxidative stress that can adversely affect the flap outcomes. Ascorbic acid (AA) had been proven to have beneficial effect on end-organ protection and flap survival from ischemia-reperfusion injury via its antioxidant properties.
The investigators hypothesise that perioperative parenteral ascorbic acid treatment may reduce oxidative stress among participants undergoing free flap reconstructive surgery along with reduction in inflammatory markers, improved rate of flap viability and wound healing at both donor and recipient sites.
Read the detailed description
Temporary cessation of blood supply to the flap tissues from clamping of donor vascular pedicle (ischemia) followed by restoration of flap tissue perfusion (reperfusion) after micro-anastomosis are inevitable in any free flap surgery. In combination, the ischemia and reperfusion process during free flap tissue transfers induce a state of increased oxidative stress, which may lead to complications such as flap failure and non-healing wounds at either donor or recipient sites. The negative impacts of which include additional wounds from flap loss, higher costs and increased duration of hospital stay.
Previous studies had demonstrated the beneficial effects of ascorbic acid in end-organ protection against ischemia and reperfusion injury. In addition, parenteral ascorbic acid has been shown to be remarkably safe even at high dose in both clinical and nonclinical models. Nonetheless, the data on efficacy of ascorbic acid in free flap survival in human is very limited.
The aims of this prospective, multicentre, double-blind, randomized, placebo-controlled pilot study are to measure the extent of oxidative stress in participants undergoing free flap reconstructive surgery before and after administration of parenteral ascorbic acid; and to evaluate its efficacy on modulation of inflammation, flap viability and wound healing.
Eligible participants will be randomized to receive 1 gram of parenteral ascorbic acid and 0.9% normal saline (as placebo) 8 hourly for 7 days (from pre-operative day 2 until post-operative day 5). Blood sampling will be performed on day 0 (pre-operative), day 3 (post-operative day 1) and day 5 (post-operative day 3) of intravenous ascorbic acid or placebo infusion for measurement of i) oxidative stress biomarkers, including isoprostane level, gene expression of glutamate-cystein ligase (GCL) and total glutathione level) ii) inflammatory markers, including leucocytes count and gene expression of TNF-α and IL-1. Post-operative outcomes of free flap surgery, up to post-operative 14 days, including flap viability, wound healing at both donor and recipient sites and duration of ICU and hospital stay will be evaluated.
The investigators estimate that a total sample of 28 participants (14 on each arm) will be necessary for 80% power to detect a 33% oxidative stress reduction with medium effect size (0.5) at 5% level of significance (α) between treatment (intravenous ascorbic acid) and placebo group (0.9% normal saline). A total of 34 participants are required to account for 20% of dropouts.
Primary analysis of this study utilizes an intention-to-treat approach and includes all randomized participants undergoing elective free flap reconstructive surgery. The mean difference between the baseline (pre-operative) and post-operative oxidative stress and inflammatory levels will be analyzed and compared between the intravenous ascorbic acid and placebo group using analysis of variance (ANOVA) for all normally distributed dataset whilst the non-parametric Kruskal-Wallis test is used, if otherwise. The effect size of such difference will be determined and compared. Subsequently, correlation between reduction of oxidative stress and post-operative flap outcomes in the intravenous ascorbic acid group will be evaluated. The secondary outcomes such as flap viability (percentage of flap necrosis), wound healing at both recipient and donor sites (percentage of wound dehiscence and percentage of skin graft failure to take/loss), duration of hospital and ICU stay and wound infection rate will be presented as mean with standard deviation (SD) or median with interquartile range (IQR) based on their normality distribution and are compared with Student's t-test or Mann-Whitney U test.
- Conditions
- Oxidative Stress, Ischemia-reperfusion Injury
- Being tested
- Intravenous Ascorbate, Normal Saline 10 mL Injection
- Keywords
- Free Flap Reconstructive Surgery, Perioperative Parenteral Ascorbic Acid
- Medical subject headings
- Reperfusion Injury
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Intravenous AscorbateDrug
Also called Ascorbic Acid Injection
Intravenous ascorbic acid 1 gram 8 hourly (3 grams per day) over 15 minutes for 7 days since pre-operative day 1 until post-operative day 5.
Normal Saline 10 mL InjectionDrug
Also called 0.9% Normal Saline
Intravenous 0.9% normal saline 8 hourly bolus infusion over 15 minutes for 7 days since pre-operative day 1 until post-operative day 5.
| Study group | Role | What they receive |
|---|---|---|
| Parenteral Ascorbic Acid | Experimental | Intravenous ascorbic acid 1 gram 8 hourly (3 grams per day) for 7 days Receives: Drug: Intravenous Ascorbate |
| 0.9% Normal Saline | Placebo comparator | Intravenous 0.9% normal saline 10 mL 8 hourly for 7 days Receives: Drug: Normal Saline 10 mL Injection |
What is being measured
The primary outcome is the main question the study is designed to answer.
Oxidative stress biomarker: Plasma isoprostane level
Plasma isoprostane level will be analyzed using a competitive ELISA assay and expressed in unit of pg/ml.
Measured: Change from preoperative baseline level at day 5 of infusion (post-operative)
Oxidative stress biomarker: Gene expression of glutamate-cystein ligase (GCL)
The expression of glutamate cysteine ligase (GCL) will be quantitated using real time quantitative polymerase chain reaction (qRT-CR). The differences in gene expression, expressed as fold-change, will be calculated using the 2 -DΔCt algorithm where GAPDH will be used as the housekeeping gene.
Measured: Change from preoperative baseline level at day 5 of infusion (post-operative)
Oxidative stress biomarker: Total glutathione level
Total glutathione level (GSSG + GSH) will be determined using a Glutathione Assay Kit, which will be expressed in unit of µM.
Measured: Change from preoperative baseline level at day 5 of infusion (post-operative)
Secondary outcomes (7)
Inflammatory biomarkers levels: Leucocytes counts
Leucocytes count will be measured through flow cytometry White blood cells Differential Fluorescence (WDF) scattergram using Sysmex XN-10 (Sysmex Corporation TM , Kobe, Japan) and expressed in unit of X10^9/L.
Measured: Change from preoperative baseline level at day 5 of infusion (post-operative)
Inflammatory biomarkers levels: Gene expression of TNF-α
The expression of TNF-α will be quantitated using real time quantitative polymerase chain reaction (qRT-CR). The differences in gene expression, expressed as fold-change, will be calculated using the 2 -DΔCt algorithm where GAPDH will be used as the housekeeping gene.
Measured: Change from preoperative baseline level at day 5 of infusion (post-operative)
Inflammatory biomarkers levels: Gene expression of IL-1
The expression of IL-1 will be quantitated using real time quantitative polymerase chain reaction (qRT-CR). The differences in gene expression, expressed as fold-change, will be calculated using the 2 -DΔCt algorithm where GAPDH will be used as the housekeeping gene.
Measured: Change from preoperative baseline level at day 5 of infusion (post-operative)
Post-operative outcomes: Flap viability
Flap viability is the survival of flap without tissue loss. For flap viability assessment, total flap loss is defined as complete necrosis (death) of flap (100% flap loss), whilst partial flap loss refers to incomplete necrosis of flap. By using simple tracing technique, the percentage of flap necrosis is calculated as:
[Necrotic flap surface area (cm^2)/Total flap surface area (cm^2)] × 100%
Measured: From post-operative day 1 until day 14 (2 weeks)
Post-operative outcomes: Wound dehiscence
Surgical wound dehiscence is defined as separation of the margins of a closed surgical incision that has been made in skin, with or without exposure or protrusion of underlying tissue, organs or implants. Wound dehiscence is assessed upon suture removal. It is categorized as either partial (1-99%) or complete (100%), depending on the depth/thickness of skin layers involvement. Partial wound dehiscence is defined as separation of wound edge up to level of epidermis and dermis layer of sutured wounds, whereas complete wound dehiscence refers to complete separation of wound edge involving the full thickness of skin. The percentage of wound dehiscence in relative to the total wound size is calculated.
Measured: From post-operative day 1 until day 14 (2 weeks)
Post-operative outcomes: Graft loss
Skin graft recipient area is inspected at post-operative day 5 for assessment of graft take. Graft loss is categorized as partial (1-99%) or complete (100%). The percentage of skin graft failure to take/loss is calculated as:
[Graft failure to take or loss surface area (cm^2)/Total skin graft area surface area (cm^2)] X 100%
Measured: From post-operative day 1 until day 14 (2 weeks)
Post-operative outcomes: Wound infection
Wound infection is defined by presence of clinical sign and symptoms of infection associated with wound, including:
- Local signs: Erythema - localized or spreading (cellulitis); Pus/purulent or haemopurulent exudate; Abscess; Swelling/induration; Local warmth; Malodour; Crepitus; Dehiscence; Unexpected pain or tenderness. ii) Systemic signs: Malaise; Loss of appetite; Pyrexia or hypothermia; Tachycardia; Tachypnoea; Elevated C-reactive protein (CRP); Elevated or suppressed white blood cell count; Sepsis or Septic Shock.
Measured: From post-operative day 1 until day 14 (2 weeks)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Apr 2022
- Study start25 Sep 2022
- Primary completion31 Jul 2023 (estimated)
- Study completion31 Jul 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (13)Papers the sponsor has linked to this study.
- Other trials for Oxidative StressStudies of the same condition, open and under way.
- More trials run by University of MalayaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 34 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Malaya
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Raymond Yii Shi Liang, MBBS, Principal investigator, University of Malaya Medical Centre
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05327348
- Sponsor's protocol ID
- MECID No,UMMC: 202086-8956
- Other IDs
- PV042-2021, NMRR-21-1378-60482 (IIR), USM/JEPeM/21070522
- Status last verified
- Nov 2022
- First submitted
- 28 Mar 2022
- Last updated
- 25 Nov 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Ballestin A, Casado JG, Abellan E, Vela FJ, Alvarez V, Uson A, Lopez E, Marinaro F, Blazquez R, Sanchez-Margallo FM. Ischemia-reperfusion injury in a rat microvascular skin free flap model: A histological, genetic, and blood flow study. PLoS One. 2018 Dec 27;13(12):e0209624. doi: 10.1371/journal.pone.0209624. eCollection 2018.
PubMed 30589864Schafer M, Werner S. Oxidative stress in normal and impaired wound repair. Pharmacol Res. 2008 Aug;58(2):165-71. doi: 10.1016/j.phrs.2008.06.004. Epub 2008 Jun 19.
PubMed 18617006Siemionow M, Arslan E. Ischemia/reperfusion injury: a review in relation to free tissue transfers. Microsurgery. 2004;24(6):468-75. doi: 10.1002/micr.20060.
PubMed 15378577Stepanovs J, Ozoliņa A, Rovīte V, Mamaja B, Vanags I. Factors Affecting the Risk of Free Flap Failure in Microvascular Surgery. Proc Latv Acad Sci Sect B Nat Exact, Appl Sci. 2016;70(6):356-364. doi:10.1515/prolas-2016-0039.
Tsai MS, Huang CH, Tsai CY, Chen HW, Lee HC, Cheng HJ, Hsu CY, Wang TD, Chang WT, Chen WJ. Ascorbic acid mitigates the myocardial injury after cardiac arrest and electrical shock. Intensive Care Med. 2011 Dec;37(12):2033-40. doi: 10.1007/s00134-011-2362-6. Epub 2011 Sep 28.
PubMed 21953354Azari O, Kheirandish R, Azizi S, Farajli Abbasi M, Ghahramani Gareh Chaman S, Bidi M. Protective Effects of Hydrocortisone, Vitamin C and E Alone or in Combination against Renal Ischemia-Reperfusion Injury in Rat. Iran J Pathol. 2015 Fall;10(4):272-80.
PubMed 26351497Lee WY, Lee JS, Lee SM. Protective effects of combined ischemic preconditioning and ascorbic acid on mitochondrial injury in hepatic ischemia/reperfusion. J Surg Res. 2007 Sep;142(1):45-52. doi: 10.1016/j.jss.2006.08.043. Epub 2007 Jun 7.
PubMed 17559880Wang ZJ, Hu WK, Liu YY, Shi DM, Cheng WJ, Guo YH, Yang Q, Zhao YX, Zhou YJ. The effect of intravenous vitamin C infusion on periprocedural myocardial injury for patients undergoing elective percutaneous coronary intervention. Can J Cardiol. 2014 Jan;30(1):96-101. doi: 10.1016/j.cjca.2013.08.018.
PubMed 24365194Zaccaria A, Weinzweig N, Yoshitake M, Matsuda T, Cohen M. Vitamin C reduces ischemia-reperfusion injury in a rat epigastric island skin flap model. Ann Plast Surg. 1994 Dec;33(6):620-3. doi: 10.1097/00000637-199412000-00010.
PubMed 7880053Fowler AA 3rd, Syed AA, Knowlson S, Sculthorpe R, Farthing D, DeWilde C, Farthing CA, Larus TL, Martin E, Brophy DF, Gupta S; Medical Respiratory Intensive Care Unit Nursing; Fisher BJ, Natarajan R. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014 Jan 31;12:32. doi: 10.1186/1479-5876-12-32.
PubMed 24484547Padayatty SJ, Sun AY, Chen Q, Espey MG, Drisko J, Levine M. Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects. PLoS One. 2010 Jul 7;5(7):e11414. doi: 10.1371/journal.pone.0011414.
PubMed 20628650Stephenson CM, Levin RD, Spector T, Lis CG. Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer. Cancer Chemother Pharmacol. 2013 Jul;72(1):139-46. doi: 10.1007/s00280-013-2179-9. Epub 2013 May 14.
PubMed 23670640Hoffer LJ, Robitaille L, Zakarian R, Melnychuk D, Kavan P, Agulnik J, Cohen V, Small D, Miller WH Jr. High-dose intravenous vitamin C combined with cytotoxic chemotherapy in patients with advanced cancer: a phase I-II clinical trial. PLoS One. 2015 Apr 7;10(4):e0120228. doi: 10.1371/journal.pone.0120228. eCollection 2015.
PubMed 25848948
Study at a glance
From the registry record, last updated by the sponsor on 25 Nov 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Efficacy of Perioperative Parenteral Ascorbic Acid in Reducing Oxidative Stress Among Patients Undergoing Free Flap Reconstructive Surgery: A Prospective Multicenter Randomized Controlled Pilot Trial
- ClinicalTrials.gov ID
- NCT05327348
- Acronym / sponsor ID
- MECID No,UMMC: 202086-8956
- Conditions
- Oxidative Stress, Ischemia-reperfusion Injury
- Keywords
- Free Flap Reconstructive Surgery, Perioperative Parenteral Ascorbic Acid
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 34 participants (estimated)
- Lead sponsor
- University of MalayaUniversity, hospital or other
- Study start
- 25 Sep 2022 (actual)
- Primary completion
- 31 Jul 2023 (estimated)
- Study completion
- 31 Jul 2023 (estimated)
- First posted
- 14 Apr 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Ischemia and reperfusion injury during free flap reconstructive surgery creates a state of increased oxidative stress that can adversely affect the flap outcomes. Ascorbic acid (AA) had been proven to have beneficial effect on end-organ protection and flap survival from ischemia-reperfusion injury via its antioxidant properties.
The investigators hypothesise that perioperative parenteral ascorbic acid treatment may reduce oxidative stress among participants undergoing free flap reconstructive surgery along with reduction in inflammatory markers, improved rate of flap viability and wound healing at both donor and recipient sites.
Detailed description
Temporary cessation of blood supply to the flap tissues from clamping of donor vascular pedicle (ischemia) followed by restoration of flap tissue perfusion (reperfusion) after micro-anastomosis are inevitable in any free flap surgery. In combination, the ischemia and reperfusion process during free flap tissue transfers induce a state of increased oxidative stress, which may lead to complications such as flap failure and non-healing wounds at either donor or recipient sites. The negative impacts of which include additional wounds from flap loss, higher costs and increased duration of hospital stay.
Previous studies had demonstrated the beneficial effects of ascorbic acid in end-organ protection against ischemia and reperfusion injury. In addition, parenteral ascorbic acid has been shown to be remarkably safe even at high dose in both clinical and nonclinical models. Nonetheless, the data on efficacy of ascorbic acid in free flap survival in human is very limited.
The aims of this prospective, multicentre, double-blind, randomized, placebo-controlled pilot study are to measure the extent of oxidative stress in participants undergoing free flap reconstructive surgery before and after administration of parenteral ascorbic acid; and to evaluate its efficacy on modulation of inflammation, flap viability and wound healing.
Eligible participants will be randomized to receive 1 gram of parenteral ascorbic acid and 0.9% normal saline (as placebo) 8 hourly for 7 days (from pre-operative day 2 until post-operative day 5). Blood sampling will be performed on day 0 (pre-operative), day 3 (post-operative day 1) and day 5 (post-operative day 3) of intravenous ascorbic acid or placebo infusion for measurement of i) oxidative stress biomarkers, including isoprostane level, gene expression of glutamate-cystein ligase (GCL) and total glutathione level) ii) inflammatory markers, including leucocytes count and gene expression of TNF-α and IL-1. Post-operative outcomes of free flap surgery, up to post-operative 14 days, including flap viability, wound healing at both donor and recipient sites and duration of ICU and hospital stay will be evaluated.
The investigators estimate that a total sample of 28 participants (14 on each arm) will be necessary for 80% power to detect a 33% oxidative stress reduction with medium effect size (0.5) at 5% level of significance (α) between treatment (intravenous ascorbic acid) and placebo group (0.9% normal saline). A total of 34 participants are required to account for 20% of dropouts.
Primary analysis of this study utilizes an intention-to-treat approach and includes all randomized participants undergoing elective free flap reconstructive surgery. The mean difference between the baseline (pre-operative) and post-operative oxidative stress and inflammatory levels will be analyzed and compared between the intravenous ascorbic acid and placebo group using analysis of variance (ANOVA) for all normally distributed dataset whilst the non-parametric Kruskal-Wallis test is used, if otherwise. The effect size of such difference will be determined and compared. Subsequently, correlation between reduction of oxidative stress and post-operative flap outcomes in the intravenous ascorbic acid group will be evaluated. The secondary outcomes such as flap viability (percentage of flap necrosis), wound healing at both recipient and donor sites (percentage of wound dehiscence and percentage of skin graft failure to take/loss), duration of hospital and ICU stay and wound infection rate will be presented as mean with standard deviation (SD) or median with interquartile range (IQR) based on their normality distribution and are compared with Student's t-test or Mann-Whitney U test.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Parenteral Ascorbic Acid | Experimental | Drug: Intravenous AscorbateIntravenous ascorbic acid 1 gram 8 hourly (3 grams per day) for 7 days |
| 0.9% Normal Saline | Placebo comparator | Drug: Normal Saline 10 mL InjectionIntravenous 0.9% normal saline 10 mL 8 hourly for 7 days |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Adults (age 18 years and older, male or female) who are planned for elective free flap reconstructive surgery.
Key exclusion criteria (11 listed)
- Hypersensitivity to vitamin C
- Oliguria (urine output <400mL/day) or anuria (urine output <100mL/day)
- Renal failure (serum creatinine level ≥175.0 %mol/L)
- Hemodialysis
- Renal calculi
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Intravenous AscorbateAlso: Ascorbic Acid InjectionIntravenous ascorbic acid 1 gram 8 hourly (3 grams per day) over 15 minutes for 7 days since pre-operative day 1 until post-operative day 5. | Drug | Parenteral Ascorbic Acid |
| Normal Saline 10 mL InjectionAlso: 0.9% Normal SalineIntravenous 0.9% normal saline 8 hourly bolus infusion over 15 minutes for 7 days since pre-operative day 1 until post-operative day 5. | Drug | 0.9% Normal Saline |
Primary outcome
Oxidative stress biomarker: Plasma isoprostane level
Time frame: Change from preoperative baseline level at day 5 of infusion (post-operative)
Plasma isoprostane level will be analyzed using a competitive ELISA assay and expressed in unit of pg/ml.
Oxidative stress biomarker: Gene expression of glutamate-cystein ligase (GCL)
Time frame: Change from preoperative baseline level at day 5 of infusion (post-operative)
The expression of glutamate cysteine ligase (GCL) will be quantitated using real time quantitative polymerase chain reaction (qRT-CR). The differences in gene expression, expressed as fold-change, will be calculated using the 2 -DΔCt algorithm where GAPDH will be used as the housekeeping gene.
Oxidative stress biomarker: Total glutathione level
Time frame: Change from preoperative baseline level at day 5 of infusion (post-operative)
Total glutathione level (GSSG + GSH) will be determined using a Glutathione Assay Kit, which will be expressed in unit of µM.
7 secondary outcomes
Inflammatory biomarkers levels: Leucocytes counts
Time frame: Change from preoperative baseline level at day 5 of infusion (post-operative)
Inflammatory biomarkers levels: Gene expression of TNF-α
Time frame: Change from preoperative baseline level at day 5 of infusion (post-operative)
Inflammatory biomarkers levels: Gene expression of IL-1
Time frame: Change from preoperative baseline level at day 5 of infusion (post-operative)
Post-operative outcomes: Flap viability
Time frame: From post-operative day 1 until day 14 (2 weeks)
Post-operative outcomes: Wound dehiscence
Time frame: From post-operative day 1 until day 14 (2 weeks)
Post-operative outcomes: Graft loss
Time frame: From post-operative day 1 until day 14 (2 weeks)
Post-operative outcomes: Wound infection
Time frame: From post-operative day 1 until day 14 (2 weeks)
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Nov 2022.
- Background: PubMed 30589864Ballestin A, Casado JG, Abellan E, Vela FJ, Alvarez V, Uson A, Lopez E, Marinaro F, Blazquez R, Sanchez-Margallo FM. Ischemia-reperfusion injury in a rat microvascular skin free flap model: A histological, genetic, and blood flow study. PLoS One. 2018 Dec 27;13(12):e0209624. doi: 10.1371/journal.pone.0209624. eCollection 2018.
- Background: PubMed 18617006Schafer M, Werner S. Oxidative stress in normal and impaired wound repair. Pharmacol Res. 2008 Aug;58(2):165-71. doi: 10.1016/j.phrs.2008.06.004. Epub 2008 Jun 19.
- Background: PubMed 15378577Siemionow M, Arslan E. Ischemia/reperfusion injury: a review in relation to free tissue transfers. Microsurgery. 2004;24(6):468-75. doi: 10.1002/micr.20060.
- BackgroundStepanovs J, Ozoliņa A, Rovīte V, Mamaja B, Vanags I. Factors Affecting the Risk of Free Flap Failure in Microvascular Surgery. Proc Latv Acad Sci Sect B Nat Exact, Appl Sci. 2016;70(6):356-364. doi:10.1515/prolas-2016-0039.
- Background: PubMed 21953354Tsai MS, Huang CH, Tsai CY, Chen HW, Lee HC, Cheng HJ, Hsu CY, Wang TD, Chang WT, Chen WJ. Ascorbic acid mitigates the myocardial injury after cardiac arrest and electrical shock. Intensive Care Med. 2011 Dec;37(12):2033-40. doi: 10.1007/s00134-011-2362-6. Epub 2011 Sep 28.
- Background: PubMed 26351497Azari O, Kheirandish R, Azizi S, Farajli Abbasi M, Ghahramani Gareh Chaman S, Bidi M. Protective Effects of Hydrocortisone, Vitamin C and E Alone or in Combination against Renal Ischemia-Reperfusion Injury in Rat. Iran J Pathol. 2015 Fall;10(4):272-80.
- Background: PubMed 17559880Lee WY, Lee JS, Lee SM. Protective effects of combined ischemic preconditioning and ascorbic acid on mitochondrial injury in hepatic ischemia/reperfusion. J Surg Res. 2007 Sep;142(1):45-52. doi: 10.1016/j.jss.2006.08.043. Epub 2007 Jun 7.
- Background: PubMed 24365194Wang ZJ, Hu WK, Liu YY, Shi DM, Cheng WJ, Guo YH, Yang Q, Zhao YX, Zhou YJ. The effect of intravenous vitamin C infusion on periprocedural myocardial injury for patients undergoing elective percutaneous coronary intervention. Can J Cardiol. 2014 Jan;30(1):96-101. doi: 10.1016/j.cjca.2013.08.018.
- Background: PubMed 7880053Zaccaria A, Weinzweig N, Yoshitake M, Matsuda T, Cohen M. Vitamin C reduces ischemia-reperfusion injury in a rat epigastric island skin flap model. Ann Plast Surg. 1994 Dec;33(6):620-3. doi: 10.1097/00000637-199412000-00010.
- Background: PubMed 24484547Fowler AA 3rd, Syed AA, Knowlson S, Sculthorpe R, Farthing D, DeWilde C, Farthing CA, Larus TL, Martin E, Brophy DF, Gupta S; Medical Respiratory Intensive Care Unit Nursing; Fisher BJ, Natarajan R. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014 Jan 31;12:32. doi: 10.1186/1479-5876-12-32.
- Background: PubMed 20628650Padayatty SJ, Sun AY, Chen Q, Espey MG, Drisko J, Levine M. Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects. PLoS One. 2010 Jul 7;5(7):e11414. doi: 10.1371/journal.pone.0011414.
- Background: PubMed 23670640Stephenson CM, Levin RD, Spector T, Lis CG. Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer. Cancer Chemother Pharmacol. 2013 Jul;72(1):139-46. doi: 10.1007/s00280-013-2179-9. Epub 2013 May 14.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Raymond Yii Shi Liang, MBBS principal investigator
University of Malaya Medical Centre
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Intravenous Ascorbate and Normal Saline 10 mL Injection in people with Oxidative Stress and Ischemia-reperfusion Injury, run by University of Malaya at 3 sites in Malaysia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 25 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Malaysia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Raymond Yii Shi Liang, MBBS (+60379494422 ext. 2441, raymond.yii@ummc.edu.my), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Oxidative stress biomarker: Plasma isoprostane level (time frame: Change from preoperative baseline level at day 5 of infusion (post-operative)). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05327348, which also lists 13 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Nov 2022; AzTrials last refreshed its copy on 7 Nov 2026.