ANZCTR - Registration

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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]

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

Condition category

Condition code

Infection

Other infectious diseases

Respiratory

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]

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]

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]

30 days post-treatment initiation

Secondary outcome [1]

Rate of recruitment of patients hospitalised with moderate/severe community acquired pneumonia (CURB-65 >1).

Timepoint [1]

Overall trial period-18 months

Secondary outcome [2]

Length of hospital stay as assessed by data-linkage to medical records

Timepoint [2]

censored at day 30 post-treatment initiation

Secondary outcome [3]

Admission to ICU as assessed by data-linkage to medical records

Timepoint [3]

censored at day 30 post-treatment initiation

Secondary outcome [4]

Readmission to hospital as assessed by data-linkage to medical records

Timepoint [4]

censored at 90 days post-treatment initiation

Secondary outcome [5]

Hospital mortality as assessed by data-linkage to medical records

Timepoint [5]

30 and 90 days post-treatment initiation

Secondary outcome [6]

Days until death as assessed by data-linkage to medical records

Timepoint [6]

censored at 90 days post-treatment initiation

Secondary outcome [7]

Quality of life as assessed by study-specific questionnaire

Timepoint [7]

30 days post-treatment initiation

Secondary outcome [8]

Resolution of symptoms as assessed by study-specific questionnaire

Timepoint [8]

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

Sex

Both males and females

Can healthy volunteers participate?

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

1/05/2019

Actual

Date of last participant enrolment

Anticipated

1/11/2020

Actual

Date of last data collection

Anticipated

1/12/2020

Actual

Sample size

Target

140

Accrual to date

Final

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Canterbury

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

Health Research Council

Address [1]

Level 3 - ProCARE Building, Grafton Mews, at 110 Stanley Street
Grafton, Auckland 1010

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Northern B Health and Disability Ethics Committee

Ethics committee address [1]

Health and Disability Ethics Committees
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington, 6011

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

15/10/2018

Approval date [1]

17/12/2018

Ethics approval number [1]

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

Prof Stephen Chambers

Address

University of Otago, Christchurch
2 Riccarton Avenue
Christchurch Central
Christchurch, 8011

Country

New Zealand

Phone

+64 3 3640649

Fax

steve.chambers@otago.ac.nz

Contact person for public queries

Name

Stephen Chambers

Address

University of Otago, Christchurch
2 Riccarton Avenue
Christchurch Central
Christchurch, 8011

Country

New Zealand

Phone

+64 3 3640649

Fax

steve.chambers@otago.ac.nz

Contact person for scientific queries

Name

Stephen Chambers

Address

University of Otago, Christchurch
2 Riccarton Avenue
Christchurch Central
Christchurch, 8011

Country

New Zealand

Phone

+64 3 3640649

Fax

steve.chambers@otago.ac.nz

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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 Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Vitamin C supplementation for prevention and treatment of pneumonia.	2020	https://dx.doi.org/10.1002/14651858.CD013134.pub2
Embase	Vitamin C supplementation for prevention and treatment of pneumonia.	2021	https://dx.doi.org/10.1002/14651858.CD013134.pub3
Dimensions AI	Low Vitamin C Concentrations in Patients with Community-Acquired Pneumonia Resolved with Pragmatic Administration of Intravenous and Oral Vitamin C	2023	https://doi.org/10.3390/antiox12081610

N.B. These documents automatically identified may not have been verified by the study sponsor.

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Documents added manually

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