Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617000783325
Ethics application status
Approved
Date submitted
23/05/2017
Date registered
29/05/2017
Date last updated
1/12/2020
Date data sharing statement initially provided
2/08/2019
Date results information initially provided
1/12/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Probiotics to reduce infection in patients admitted to the Intensive Care Unit
Scientific title
Restoration Of gut miCroflora in CrITical Illness (The ROCIT trial): A multicentre Randomised controlled trial of probiotic therapy to reduce nosocomial infection and increase days alive and out of hospital in critically ill patients admitted to the intensive care unit.
Secondary ID [1] 292027 0
nil known
Universal Trial Number (UTN)
Trial acronym
ROCIT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
hospital acquired infection 303418 0
Condition category
Condition code
Infection 302830 302830 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention
Participants randomised to probiotics will receive a once daily administration of a single capsule of probiotic therapy containing 20 billion colony forming units of Lactobacillus plantarum strain 299v. Participants receiving oral antibiotics will not receive administration of the study drug within two hours of a dose of oral antibiotics. In vitro testing of the product has been completed locally confirming viable bacteria at a colony count within 0.1 log10 of the expected value. Participants will be discouraged from initiating any additional probiotic therapy after discharge from index hospitalisation until study completion (day-60). All other treatment will remain at the discretion of the treating team. Minimisation of contamination by development of an SOP for the handling and administration of probiotics based on published standard.
Participants will be provided a study drug diary to record adherence and requested to return study drug bottles at the end of the study period for pill counts and reconciliation.

Intervention code [1] 298156 0
Treatment: Other
Comparator / control treatment
Placebo
The trial will be placebo-controlled. Participants randomised to placebo will receive an identically packaged capsule and will not receive any probiotic therapy whilst hospitalised. Participants will be discouraged from initiating any additional probiotic therapy after discharge from index hospitalisation until study completion (day-60). All other treatment will remain at the discretion of the treating team.
Control group
Placebo

Outcomes
Primary outcome [1] 302221 0
Days alive and out of hospital
Timepoint [1] 302221 0
day 60
Secondary outcome [1] 335189 0
* All-cause nosocomial infection to hospital discharge. Assessed by two independent blinded infectious diseases clinicians review of medical records.
Timepoint [1] 335189 0
hospital discharge, censored at day 60
Secondary outcome [2] 335190 0
* ventilator-associated pneumonia. Assessed by two independent blinded infectious diseases clinicians review of medical records.
Timepoint [2] 335190 0
ICU discharge, censored at day 60
Secondary outcome [3] 335191 0
* hospital-acquired pneumonia. Assessed by two independent blinded infectious diseases clinicians review of medical records.
Timepoint [3] 335191 0
hospital discharge, censored at day 60
Secondary outcome [4] 335192 0
* urinary tract infection. Assessed by two independent blinded infectious diseases clinicians review of medical records.
Timepoint [4] 335192 0
hospital discharge, censored at day 60
Secondary outcome [5] 335193 0
* surgical site infection. Assessed by two independent blinded infectious diseases clinicians review of medical records.
Timepoint [5] 335193 0
hospital discharge, censored at day 60
Secondary outcome [6] 335194 0
* blood stream infection. Assessed by two independent blinded infectious diseases clinicians review of medical records.
Timepoint [6] 335194 0
hospital discharge, censored at day 60
Secondary outcome [7] 335195 0
* clostridium difficile infection. Assessed by two independent blinded infectious diseases clinicians review of medical records.
Timepoint [7] 335195 0
hospital discharge, censored at day 60
Secondary outcome [8] 335196 0
* Antibiotic free days. Blinded assessment of medical records.
Timepoint [8] 335196 0
hospital discharge, censored at day 60
Secondary outcome [9] 335197 0
* Composite out come of antibiotic, antiviral and antifungal free days. Blinded assessment of medical records.
Timepoint [9] 335197 0
to hospital discharge, censored at day 60
Secondary outcome [10] 335198 0
* Ventilator-free days. Blinded assessment of medical records.
Timepoint [10] 335198 0
ICU discharge, censored at day 60
Secondary outcome [11] 335199 0
* Vasopressor-free days. Blinded assessment of medical records.
Timepoint [11] 335199 0
ICU discharge, censored at day 60
Secondary outcome [12] 335200 0
* Incident renal replacement therapy.Blinded assessment of medical records.
Timepoint [12] 335200 0
ICU discharge, censored at day 60
Secondary outcome [13] 335201 0
* Renal replacement-free days. Blinded assessment of medical records.
Timepoint [13] 335201 0
ICU discharge, censored at day 60
Secondary outcome [14] 335202 0
* ICU mortality. Blinded assessment of medical records.
Timepoint [14] 335202 0
icu discharge, censored at day 60
Secondary outcome [15] 335203 0
* Hospital mortality. Blinded assessment of medical records.
Timepoint [15] 335203 0
hospital discharge, censored at day 60
Secondary outcome [16] 335204 0
* day 60 mortality. Blinded assessment of medical records and phone contact where necessary.
Timepoint [16] 335204 0
day 60
Secondary outcome [17] 335205 0
* Quality of life via EQ5D5L. Phone contact.
Timepoint [17] 335205 0
at day 60
Secondary outcome [18] 335206 0
* Per protocol analysis of days alive and out of hospital including those with >80% compliance to daily administration of study drug. Blinded assessment of medical records.
Timepoint [18] 335206 0
day 60
Secondary outcome [19] 335207 0
* Per protocol analysis of all cause nosocomial infection including those with >80% compliance to daily administration of study drug. Blinded assessment of medical records.
Timepoint [19] 335207 0
day 60

Eligibility
Key inclusion criteria
* Admitted to the ICU or high dependency area for less than 48 hours
* Anticipated to require intensive care or high dependency area care beyond the next calendar day
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. less than 18 years of age
2. Absolute contraindication to receiving medication via the enteral route
3. Known to be receiving probiotic therapy at time of index hospitalisation
4. Acute pancreatitis as a cause or complication of current admission
5. Immunosuppressed, e.g. chemotherapy within four weeks of admission, receiving greater than or equal to 1.5mg/kg methylprednisolone daily or equivalent for more than four days
6. Neutropenia (neutrophil count less than 1x109/L)
7. Prosthetic heart valve or permanent pace maker
8. Death is deemed to be inevitable as a result of the current acute illness AND either the treating clinician, the patient, or the substitute decision maker are not committed to full active treatment
9. Enrolment not considered in the patient’s best interest
10. Previously enrolled in the ROCIT study
11. Unlikely to be residing in the Perth Metropolitan area in 60 days time
12. Participating in a competing interventional study
13. Pregnancy
14. Admitted to hospital from a high level nursing facility or rehabilitation facility

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)
sequentially numbered, otherwise identical vials of study drug and placebo
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
central, variable block size via online randomisation engine
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering 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
Normally and non-normally distributed data will be presented as mean and standard deviation (SD), and median and interquartile range (IQR), respectively. Between-group comparison of parametric data will be provided as mean difference and confidence interval and analysed using Student’s t test. Between-group comparison of non-parametric data will be presented at median difference and analysed using the Mann-Whitney U test. For dichotomous data, frequencies and percentages will be presented and between-group analysis will use Fischer’s Exact or Chi-squared test as appropriate. The numbers at risk in each group and the number and proportion of events observed will be reported, as well as the equivalent absolute risk difference, relative risk ratio and corresponding 95% confidence intervals. Survival time from randomisation until day 60, according to treatment group will be displayed as Kaplan-Meier curves and analysed using a log-rank test. Estimates of hazard ratios for survival, with corresponding 95% CI and P values, will be obtained from the Cox proportional hazards models incorporating treatment group alone, and independent covariates used in the multivariate models. Secondary analysis will also be conducted adjusting the primary outcome variable for prespecified baseline covariates (age, gender, APACHE-II score, IVAB therapy) in a transformed multivariable linear regression model including baseline univariate variables with a p<0.25. For all outcome analyses a two-sided P value of <0.05 will be considered significant.

Pre-specified subgroups will be:
1. Antibiotic therapy vs no antibiotic therapy at enrolment
2. Emergency vs Elective admission
3. Surgical vs medical admission
4. Microbiota diversity (Shannon Index<4 vs Shannon Index >4)
5. Trauma vs non trauma admission

Subgroup analyses will be performed on the pre-specified subgroups of interest irrespective of whether there is evidence of a treatment effect. Heterogeneity between subgroups will be determined by fitting an interaction between treatment and subgroup.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
23/07/2017
Actual
28/07/2017
Date of last participant enrolment
Anticipated
1/03/2020
Actual
20/12/2019
Date of last data collection
Anticipated
1/06/2020
Actual
28/02/2020
Sample size
Target
220
Accrual to date
Final
220
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 8106 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [2] 8107 0
Royal Perth Hospital - Perth
Recruitment hospital [3] 8108 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [4] 8109 0
St John of God Hospital, Subiaco - Subiaco
Recruitment hospital [5] 8110 0
St John of God Hospital, Murdoch - Murdoch
Recruitment postcode(s) [1] 16164 0
6150 - Murdoch
Recruitment postcode(s) [2] 16165 0
6000 - Perth
Recruitment postcode(s) [3] 16166 0
6009 - Nedlands
Recruitment postcode(s) [4] 16167 0
6008 - Subiaco

Funding & Sponsors
Funding source category [1] 296557 0
Government body
Name [1] 296557 0
State health Research Advisory Council Research Translation Project, Department of Health, government of Western Australia
Country [1] 296557 0
Australia
Primary sponsor type
Hospital
Name
Fiona Stanley Hospital
Address
Murdoch Drive, Murdoch, WA, 6065
Country
Australia
Secondary sponsor category [1] 295508 0
None
Name [1] 295508 0
Address [1] 295508 0
Country [1] 295508 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297772 0
South Metropolitan Human Research Ethics Committee
Ethics committee address [1] 297772 0
Fiona Stanley Hospital, Murdoch Drive, Murdoch, Perth, WA, 6065
Ethics committee country [1] 297772 0
Australia
Date submitted for ethics approval [1] 297772 0
01/12/2016
Approval date [1] 297772 0
21/04/2017
Ethics approval number [1] 297772 0
RGS000000004

Summary
Brief summary
The primary purpose of this study is to determine whether probiotic therapy in critically ill patients admitted to an ICU reduces hospital-acquired infection, and hence reduces risk of death and time in hospital.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 75070 0
Dr Edward Litton
Address 75070 0
Intensive Care Unit
Fiona Stanley Hospital
Murdoch Drive
Murdoch
Perth
WA
6065
Country 75070 0
Australia
Phone 75070 0
+61415293281
Fax 75070 0
Email 75070 0
[email protected]
Contact person for public queries
Name 75071 0
Dr Edward Litton
Address 75071 0
Intensive Care Unit
Fiona Stanley Hospital
Murdoch Drive
Murdoch
Perth
WA
6065
Country 75071 0
Australia
Phone 75071 0
+61415293281
Fax 75071 0
Email 75071 0
[email protected]
Contact person for scientific queries
Name 75072 0
Dr Edward Litton
Address 75072 0
Intensive Care Unit
Fiona Stanley Hospital
Murdoch Drive
Murdoch
Perth
WA
6065
Country 75072 0
Australia
Phone 75072 0
+61415293281
Fax 75072 0
Email 75072 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Plain language summaryNo Not yet available

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseStudy protocol for the safety and efficacy of probiotic therapy on days alive and out of hospital in adult ICU patients: The multicentre, randomised, placebo-controlled Restoration of gut microflora in Critical Illness Trial (ROCIT).2020https://dx.doi.org/10.1136/bmjopen-2019-035930
N.B. These documents automatically identified may not have been verified by the study sponsor.