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Trial registered on ANZCTR


Registration number
ACTRN12619000256178
Ethics application status
Approved
Date submitted
14/02/2019
Date registered
20/02/2019
Date last updated
20/02/2019
Date data sharing statement initially provided
20/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Vitamin C in Community Acquired Pneumonia: A pilot study
Scientific title
Vitamin C administration in community acquired pneumonia (CURB-65 >1): a feasibility study for a randomised controlled trial
Secondary ID [1] 297381 0
Nil
Universal Trial Number (UTN)
U1111-1222-3105
Trial acronym
CAP-C study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Community Acquired Pneumonia 311533 0
Condition category
Condition code
Infection 310169 310169 0 0
Other infectious diseases
Respiratory 310170 310170 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Vitamin C: Intravenous infusion of 2.5 g /8 hours will be started as soon as possible, but not later than 72 hours after hospital admission and within 24 hours of the documentation of a community acquired pneumonia CURB-65 severity score >1.
Intravenous vitamin C will be provided while the patient is receiving intravenous antimicrobial therapy and will continue until the patient is changed to oral antimicrobial therapy or for a maximum of 7 days.
Following the cessation of intravenous vitamin C therapy the patient will receive a further 7 days of oral vitamin C at a dose of 1 g (2 x 500 mg chewable tablets) three times per day. This may be administered via nasogastric tube if the patient cannot swallow.
The intravenous infusion of vitamin C will be made up by the attending nurse just prior to administering the agent. Five milliliters of a 500 mg/mL vitamin C IV solution (2.5 g total dose) will be drawn up and added to a 100 mL bag of normal saline and will be administered over a 20-30 minute period. A new solution will be made up and administered every 8 hours while the patient is on intravenous antimicrobial therapy or for a maximum of 7 days.
Participants will receive vitamin C for a minimum of 8 days and a maximum of 14 days.
Intervention code [1] 313641 0
Treatment: Drugs
Comparator / control treatment
Placebo: Intravenous infusion of normal saline/8 hours will be started as soon as possible, but not later than 72 hours after hospital admission and within 24 hours of the documentation of a community acquired pneumonia CURB-65 severity score >1.
Intravenous normal saline will be provided while the patient is receiving intravenous antimicrobial therapy and will continue until the patient is changed to oral antimicrobial therapy or for a maximum of 7 days.
Following the cessation of intravenous normal saline administration the patient will receive a further 7 days of oral placebo (2 x chewable tablets) three times per day. The tablets will be orange flavoured microcellulose with citric acid and adipic acid to give a sour taste and will also contain some sodium cholride to duplicate salty notes. The tablets may be administered via nasogastric tube if the subject cannot swallow.
The intravenous infusion of normal saline will be made up by the attending nurse just prior to administering the agent. Five milliliters of normal saline will be drawn up and added to a 100 mL bag of normal saline and will be administered over a 20-30 minute period. A new solution will be made up and administered every 8 hours while the patient is on intravenous antimicrobial therapy or for a maximum of 7 days.
Participants will receive placebo for a minimum of 8 days and a maximum of 14 days.
The vitamin C and normal saline vials used by the attending nurse to make up the patient intravenous solutions will be visibly different, however the vials will be covered and de-identified with sticky opaque paper labels. The vitamin C and placebo tablets will be indistinguishable both visibly and by taste.
Control group
Placebo

Outcomes
Primary outcome [1] 319068 0
All-cause mortality in hospitalised patients with moderate/severe community acquired pneumonia (CURB-65 >1) as assessed by data-linkage to medical records.
Timepoint [1] 319068 0
30 days post-treatment initiation
Secondary outcome [1] 366931 0
Rate of recruitment of patients hospitalised with moderate/severe community acquired pneumonia (CURB-65 >1).
Timepoint [1] 366931 0
Overall trial period-18 months
Secondary outcome [2] 366934 0
Length of hospital stay as assessed by data-linkage to medical records
Timepoint [2] 366934 0
censored at day 30 post-treatment initiation
Secondary outcome [3] 367058 0
Admission to ICU as assessed by data-linkage to medical records
Timepoint [3] 367058 0
censored at day 30 post-treatment initiation
Secondary outcome [4] 367059 0
Readmission to hospital as assessed by data-linkage to medical records
Timepoint [4] 367059 0
censored at 90 days post-treatment initiation
Secondary outcome [5] 367060 0
Hospital mortality as assessed by data-linkage to medical records
Timepoint [5] 367060 0
30 and 90 days post-treatment initiation
Secondary outcome [6] 367061 0
Days until death as assessed by data-linkage to medical records
Timepoint [6] 367061 0
censored at 90 days post-treatment initiation
Secondary outcome [7] 367124 0
Quality of life as assessed by study-specific questionnaire
Timepoint [7] 367124 0
30 days post-treatment initiation
Secondary outcome [8] 367125 0
Resolution of symptoms as assessed by study-specific questionnaire
Timepoint [8] 367125 0
30 days post-treatment initiation

Eligibility
Key inclusion criteria
1) Community acquired pneumonia (CAP) defined as: a new inflammatory infiltrate on chest radiograph and the presence of at least one of the following acute respiratory signs and symptoms: cough, sputum production, dyspnoea, core body temperature of 38.0°C or higher, auscultatory findings of abnormal breathing sounds or rales, leucocyte count > 104 cells/µL or < 4x104 cells/µL.
2) Aged > 17 years;
3) Able to provide informed consent
4) Requiring IV antibiotic therapy;
5) Moderate or severe pneumonia with a CURB-65 score > 1 at any time during their admission.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Pneumonia is not the principal reason for admission;
2) CURB-65 score 0-1;
3) Pneumonia associated with bronchial obstruction, bronchiectasis, cystic fibrosis, or active tuberculosis;
4) Cannot provide informed consent
5) Previous hospitalisation within 2 weeks so that hospital-acquired pneumonia cannot be ruled out;
6) Severe immunosuppression ( eg neutropenia 350 cells/µL, or HIV positive and a CD4 cell count below 350 cells/µL, receiving cancer chemotherapy, receiving prednisone > 20 mg daily or anti-rejection medication);
7) Chronic kidney disease with a creatinine clearance <10 mls/sec), or receiving dialysis;
8) Known or suspected G6PD deficiency.
9) Pregnancy and breast feeding
10) Haemachromatosis


Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The intervention and placebo treatments (48 hours intravenous solution and 7 days oral preparations) will be prepared and packaged (covered and de-identifed with sticky opaque paper labels prior to storage) by a hospital pharmacist independent from the study. These will then be labelled with the study identifiers according to the randomisation list, patients sticky labels taken form the clinical notes and dispensed to clinical staff. A further 5 days of covered and de-identified intravenous solutions that have been labelled with the study identifiers will be held at the hospital pharmacy and dispensed to clinical staff as required.
Participants shall be allocated a study identifier in the order they are enrolled, and provided with the corresponding treatment pack. Neither the hospital pharmacist nor study statistician will have any contact with patients or ability to influence treatment assignment.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A computer generated randomisation list, comprising of study identifiers and allocated treatment group at a 1:1 ratio, will be prepared by the study statistician. The list will be unstratified and blocked with blocks of size 2 to 4. The complete list will be provided directly to the hospital pharmacist.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
This is a feasibility study with the primary objective of determining the required sample size for a full-scale randomised, double-blind, placebo-controlled trial, thus sample size calculations have not been conducted. However, there are some sample size considerations such as having a sample size that is sufficient to identify all major threats to the success of a full-scale study. The study period will run for 18 months over two winter seasons, allowing time to accurately assess recruitment rates and implement strategies to improve them if necessary. Assuming recruitment rates reach nominal targets of around 95 participants a year, a total of 140 patients will be recruited into the study. This would provide sufficient information to estimate parameter means, variance, and proportions with acceptable precision, and makes it highly likely (greater than or equal to 95%) that even rare (probability of occurrence < 0.03) problems will be detected.
Descriptive analysis will be performed for all data, including measures of central tendency and spread for continuous outcomes and counts and proportions for binary outcomes. Differences between treatment groups in 30-day mortality rates will be explored by calculating rate ratios with confidence intervals, although it is acknowledged that this feasibility study is too small to detect even very large effect sizes. All reported CIs will be two-sided 95% intervals, and tests will be done at the two-sided 5% significance level.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 21279 0
New Zealand
State/province [1] 21279 0
Canterbury

Funding & Sponsors
Funding source category [1] 301951 0
Government body
Name [1] 301951 0
Health Research Council
Address [1] 301951 0
Level 3 - ProCARE Building, Grafton Mews, at 110 Stanley Street
Grafton, Auckland 1010
Country [1] 301951 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
362 Leith Street
North Dunedin
Dunedin 9016
Country
New Zealand
Secondary sponsor category [1] 301717 0
None
Name [1] 301717 0
Address [1] 301717 0
Country [1] 301717 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302633 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 302633 0
Health and Disability Ethics Committees
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington, 6011
Ethics committee country [1] 302633 0
New Zealand
Date submitted for ethics approval [1] 302633 0
15/10/2018
Approval date [1] 302633 0
17/12/2018
Ethics approval number [1] 302633 0
18/NTB/218

Summary
Brief summary
Community acquired pneumonia (CAP) is responsible for more than 14,000 hospital admissions in New Zealand each year, more than a thousand deaths, and thousands of days lost from work, education and leisure activities. Vitamin C is required for immune response, protects tissues from oxidative stress and is an essential enzyme cofactor for the synthesis of the hormones noradrenaline and vasopressin, which are central to the stress
response. We have found that on admission 60% of patients have hypovitaminosis C and 96% have levels below normal (<50micromol). Two recent randomised controlled trials in intensive care units have shown that adjunctive vitamin C therapy administered to patients with sepsis and septic shock, (including CAP), reduced mortality and two old, and limited, studies in CAP and CAP/acute bronchitis had reduced length of hospital stay (LOS). Because vitamin C is consumed in higher quantities during acute inflammatory and stress responses we hypothesize that the resultant deficiency in patients with severe CAP results in an increased risk of death or delayed recovery.
Aim: To determine the feasibility of performing a clinical trial of early vitamin C administration (intravenous while on IV antimicrobial therapy changing to oral when on oral antibiotics), in combination with standard antimicrobial therapy and supportive care, on the outcome of moderate/severe CAP (CURB-65 >1) in a randomised, double blind, placebo-controlled trial (RDBPCT).
The issues assessed in this feasibility study will be: (1) Estimation of the effect size of vitamin C intervention on mortality in CAP to facilitate power calculations and (2) Determination of the rate of recruitment and accrual of patients hospitalised with severe CAP (CURB-65 >1).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 90886 0
Prof Stephen Chambers
Address 90886 0
University of Otago, Christchurch
2 Riccarton Avenue
Christchurch Central
Christchurch, 8011
Country 90886 0
New Zealand
Phone 90886 0
+64 3 3640649
Fax 90886 0
Email 90886 0
steve.chambers@otago.ac.nz
Contact person for public queries
Name 90887 0
Prof Stephen Chambers
Address 90887 0
University of Otago, Christchurch
2 Riccarton Avenue
Christchurch Central
Christchurch, 8011
Country 90887 0
New Zealand
Phone 90887 0
+64 3 3640649
Fax 90887 0
Email 90887 0
steve.chambers@otago.ac.nz
Contact person for scientific queries
Name 90888 0
Prof Stephen Chambers
Address 90888 0
University of Otago, Christchurch
2 Riccarton Avenue
Christchurch Central
Christchurch, 8011
Country 90888 0
New Zealand
Phone 90888 0
+64 3 3640649
Fax 90888 0
Email 90888 0
steve.chambers@otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
As this is a feasibility study we do not anticipate that much of the individual level data will merit submission. There are also some potential privacy concerns that the relevant institutions and governmental agencies need to resolve around what we can and are allowed to share before we can agree to sharing individual participant data.
What supporting documents are/will be available?
No other documents available
Summary results
No Results