Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT04088591 |
| Other study ID # |
HM20018390 |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
October 2022 |
| Est. completion date |
December 2023 |
Study information
| Verified date |
October 2022 |
| Source |
Virginia Commonwealth University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This feasibility study serves to determine if it is possible to perform a powered randomized
control trial of high-dose intravenous vitamin C (ascorbic acid) as an adjunctive medication
in the management of sepsis and septic shock in Rwanda. Further data will be collected
including Sequential Organ Failure Assessment (SOFA) score, Universal Vital Assessment (UVA)
score, duration of vasopressors, mortality and other key indicators to possibly determine the
impact of vitamin C on organ failure and clinical course. A total of 24 patients with a
diagnosis of sepsis or septic shock will be recruited after obtaining informed consent at the
University Teaching Hospital of Kigali (CHUK) and will be randomized in a 1:1 fashion to
receive drug or placebo. Both treatment arms will receive standard treatment (intravenous
fluids, antibiotics, vasopressors as needed, etc.) in addition to study drug or placebo.
During the course of the study, any difficulties encountered will be recorded and will inform
process improvements for a full randomized control, if it is indeed considered possible to
perform the definitive trial.
Description:
General objectives:
This study will primarily determine if it is possible to perform a powered randomized control
trial of the administration of intravenous high-dose vitamin C for the treatment of sepsis or
septic shock in the tertiary care setting in Rwanda. Additionally, the study will also
attempt to assess any impact vitamin C has on morbidity and mortality.
Specific objectives:
This feasibility study will determine the possibility of and any difficulties encountered
with:
- Storage of vitamin C solution
- Obtaining informed consent
- Pharmaceutical preparation of vitamin C for intravenous administration
- Protection of Vitamin C solution from light during administration
- Nursing acquisition of vital signs during course of administration
- Acquisition of key labs
- Retrieval of data from patient chart for analysis
Hypothesis:
It is expected that the study will be feasible. We also believe that a difference indicating
benefit will be seen when comparing the patients receiving the study drug compared to placebo
in such key areas as hospital length of stay, duration of mechanical ventilation or
vasopressors, and mortality.
Primary outcome:
The primary outcome of this study is the determination of the feasibility of performing a
randomized control trial of high-dose intravenous vitamin C in the management of septic
shock.
Methodology:
Institutional Review Board approval will be sought at he University of Rwanda College of
Medicine and Health Sciences (UR CMHS), at the study site University Teaching Hospital of
Kigali (CHUK), and at Virginia Commonwealth University. This feasibility study will be
carried out in a double-blind randomized control trial format. The clinical trial will be
registered with ClincalTrials.gov and with the Pan African Clinical Trial Registry (PACTR).
Adult patients admitted to the emergency department, medicine ward, surgery ward, obstetrics
and gynecology ward, and intensive care unit (ICU) at CHUK will be screened by study
personnel for possible inclusion on weekdays from 8:00 A.M. to 5:00 P.M. Patients will be
screened for sepsis or septic shock with the following criteria to determine if they are
eligible to participate in the study:
1. Presence of organ dysfunction brought on by sepsis. This defined by an increase of two
or more points in the qSOFA score
2. Strong suspicion or confirmation of infection If a patient meets both of these criteria,
informed consent will be sought from the patient-if the patient is not able to consent,
consent will be obtained from family members of the patient (further details of informed
consent addressed below).
If informed consent is obtained, the patient will receive either intravenous placebo or
intravenous vitamin C. Placebo will be 50ml of 5% dextrose in water and will be administered
4 doses per day over a total duration of 96 hours. The study drug will be obtained from
McGuff Pharmaceuticals (Santa Ana, California, USA) and will be intravenous vitamin C
(ascorbic acid) 200mg/kg/day divided over 4 doses and delivered in 50 ml of 5% dextrose and
water over a total duration of 96 hours. In order to properly store and prepare the study
drug, assistance will be sought from pharmacy at CHUK and the manufacturer's instructions
will be followed. Patients will be randomized in a 1:1 fashion to receive study drug or
placebo using Research Randomizer. Both placebo and study drug will be administered in
shrouding material to protect the ascorbic acid and to preserve blinding. The study drug will
be administered within two to four hours of diagnosis of sepsis or septic shock.
Patients in both arms will receive the standard of care regarding intravenous fluid
resuscitation, but the antibiotic regimen will be altered from the standard of care (but the
regimen will be the same in both trial arms). The standard of care for sepsis and the
standard of care in prior studies that assessed high-dose intravenous vitamin C in sepsis and
septic shock is prompt infusion of broad-spectrum intravenous antibiotics and prompt infusion
of intravenous fluids. Sepsis still tends to be treated with ceftriaxone (with or without
metronidazole) at CHUK yet very high levels of resistance have been shown.15 Therefore, for
patients who participate in this study, the empiric antibiotic will be meropenem (with or
without anti-tuberculosis and antimalarial drugs if indicated) and pharmacy will coordinate
with this study to ensure meropenem is available at all times. In the event a patient is
unable to afford meropenem, this will be covered by the study (this has now been added to the
budget). Regarding intravenous fluid resuscitation, in prior studies of high-dose intravenous
ascorbic acid, prompt administration of high-volume intravenous normal saline was employed;
however, it has been shown that this mode of fluid resuscitation results in a greater
mortality compared to standard of care in a randomized controlled trial in sub-Saharan Africa
reported in the Journal of the American Medical Association in 2017.16 Therefore, the
standard of care in terms of intravenous fluid resuscitation in Rwanda will not be altered.
Prior to administration of the vitamin C, the patient's blood will be drawn and collected in
order to assess the following values: creatinine, total bilirubin, white blood cell count,
platelet count, PaO2, lactate, and ascorbic acid level and these labs will be drawn at 24,
48, 72, and 96 hours, with the exception of plasma ascorbic acid level, which will be drawn
at enrollment and at 24 hours. Glasgow Coma Scale score, respiratory rate, and blood pressure
will be measured at enrollment and at 24, 48, 72, and 96 hours. When a patient with diabetes
is enrolled, venous samples must be drawn to assess glucose levels-fingerstick blood glucose
levels have been shown to be not accurate for patient with hyperglycemia. Of note, neither
the patients nor their family members will be responsible for payment for the laboratory
assays and these will all be funded by this study.
The safety profile of high-dose ascorbic acid has been well verified and side effects have
been shown to be minimal. A metanalysis of five clinical trials of high-dose intravenous
vitamin C, which included the studies performed by Fowler et al. and Zabet et al.
demonstrated that no adverse reactions occurred in the 76 patients who received high-dose
intravenous vitamin C. In the study performed by Nathans et al., 301 patients received
high-dose intravenous vitamin C and no adverse events were reported.
The ascorbic acid package insert from McGuff Pharmaceuticals indicates that possible adverse
reactions include oxalate nephropathy, hemolysis in patients with glucose-6-phosphate
dehydrogenase deficiency, and pain and swelling at the infusion site.
While there is a theoretical risk of hyperoxaluria and oxalate nephropathy, this has not been
seen in clinical trials of high-dose intravenous vitamin C; yet, patients with a history of
kidney stones will be excluded. The study participant will have his/her renal function
monitored daily during the study period. Patients with a known history of
glucose-6-phosphatase-dehydrogenase (G6PD) deficiency will be excluded and every patient will
have his/her hemoglobin measured daily. Patients will be monitored for pain and swelling at
the infusion site and if this occurs the infusion will be stopped, a cold compress will be
applied, and the infusion will be restarted at 50% of the prior rate.
While it is not likely that an adverse reaction will occur, in the event an adverse reaction
occurs, the study recruiter/coordinator will stop the infusion, notify the PI immediately,
and complete an incident report form (included in the IRB application packet) will be
completed. The incident report sheet will be available in all clinical care areas where the
patient may receive intravenous high-dose ascorbic acid (e.g., internal medicine ward,
intensive care unit, etc.). If the adverse event occurs outside the study
recruiter/coordinator's work hours, the in-charge nurse will perform these duties. The
UR-CMHS IRB and other IRBs will be notified of the event as well.
Study site:
University Teaching Hospital of Kigali (CHUK)
Study design:
Feasibility double-blind randomized control trial
Data collection:
Key metrics as per above, including SOFA and UVA scores and laboratory values, will be
recorded in the patient's chart by nursing or study personnel and will be entered into REDCap
(a secure web-based application for storage and management of data) at the time of patient
discharge or death.
Study period:
The study will be conducted from November 2019 until 24 patients have been recruited and
complete the study-it is expected that the study will conclude in November 2020.
Sample size:
The sample size will be 24 patients, with 12 patients in the treatment arm of the trial and
12 patients in the placebo arm.
Ethical considerations:
Informed consent:
Patients or surrogate decision maker (in the event of patient's incapacity to make decisions
and provide consent, in most circumstances family members) will be fully informed of all
risks and benefits of participating in the trial. Risk of intravenous high-dose vitamin C
have been shown to be minimal. The decision maker will be informed that the patient may
receive placebo or study drug. The informed consent form will be available in both English
and Kinyarwanda and if the decision maker is illiterate the form will be read to him or her.
All questions will be answered in full.
Confidentiality measures:
During the study we will make sure that the privacy and confidentiality of participants are
respected. All research team members will avoid discussing sensitive information concerning
individuals where they may be overheard or leave individual's information, either on paper or
on computer screens, where they can be seen by other patients/subjects, unauthorized health
care staff or the public.
Regarding data collection and storage, the investigator will create a dataset key and assign
a unique identifier to each patient selected for chart review for recording individual
patient study data. Resultant study data will therefore be de-identified and will then be
stored electronically in password protected files on an encrypted computer. The PI will be
responsible for overseeing data management.
Data will be accessible only by the research team, overseen by the Principal Investigator,
who will possess passwords and keys to enter. Only de-identified data untraceable to study
participants will be retained after study completion by the study investigators.
Subsequently, only the named study investigators will have access to the de-identified data.
De-identified data may be shared with the health facility leadership and regulatory bodies as
may be required for oversight.
