Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000812897p
Ethics application status
Submitted, not yet approved
Date submitted
27/01/2021
Date registered
28/06/2021
Date last updated
28/06/2021
Date data sharing statement initially provided
28/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Does vitamin C decrease post-operative pain in surgery to the foot and ankle?
Scientific title
Can Vitamin C prevent Complex Regional Pain Syndrome in adults undergoing surgery to the foot and ankle? A double-blinded randomised, multi-centre, controlled feasibility study.
Secondary ID [1] 302053 0
nil known
Universal Trial Number (UTN)
U1111-1257-0633
Trial acronym
V-CILLS Trial
(Vitamin C In Lower Limb Surgery)
Linked study record
Nil

Health condition
Health condition(s) or problem(s) studied:
Complex Regional Pain Syndrome 318649 0
Patients who have foot and ankle pathology (such as fracture, arthritis and ligament injuries) who require surgical treatment to treat the pathology. 318650 0
Condition category
Condition code
Musculoskeletal 316665 316665 0 0
Other muscular and skeletal disorders
Surgery 319750 319750 0 0
Other surgery
Injuries and Accidents 319751 319751 0 0
Fractures
Injuries and Accidents 319752 319752 0 0
Other injuries and accidents
Anaesthesiology 319753 319753 0 0
Pain management
Neurological 319754 319754 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Vitamin C 500mg daily orally for fifty days.

Vitamin C will commence within 72 hours following surgery (to allow for weekend and overnight admissions), and continuing for fifty days after commencement.

Patients will be reviewed two, six, twelve and twenty-six weeks following surgery. They will be asked directly about adherence to the medication as well as any adverse effects.
Intervention code [1] 318357 0
Treatment: Other
Comparator / control treatment
Active substance: Lactobacillus acidophilus and Bifidoobacterium animalis
Trade or Generic name: Blackmores Acidophilus
Dosage form: Capsule
Route of administration: Oral one capsule daily for fifty days
Control group
Placebo

Outcomes
Primary outcome [1] 326315 0
Recruitment capability:
• Successful recruitment of pre-determined patient numbers
This will be done via audit of patient databases via RedCap.
Timepoint [1] 326315 0
Patients are reviewed two, six, twelve and twenty-six weeks following surgery. The final assessment and discharge from the trial is twenty-six weeks following surgery.

Please note patients are reviewed at two, six, twelve and twenty-six weeks following surgery as this is the usual timing of orthopaedic review following foot and ankle surgery. Using the timing ‘at the conclusion of the study’ may not fit in with the patient’s follow up, thus deviating from standard clinical practice.
Primary outcome [2] 327611 0
Data collection procedure:
• Successful follow up at established time-points
• Qualitative clinical feedback about ease of assessment/data collection
• Lost to follow up rate
Data collection procedure outcomes will be assessed as a composite of:
*Successful follow up at established time-points assessed by audit of the study database
*A semi-structured interview with researchers to gauge ease of data collection.
*Follow up rate will be assessed by an audit of the study database
Timepoint [2] 327611 0
Patients are reviewed two, six, twelve and twenty-six weeks following surgery. The final assessment and discharge from the trial is twenty-six weeks following surgery.
Primary outcome [3] 327612 0
Suitability of intervention:
• Patient-reported compliance with medication
• Patient-reported complication
• Qualitative assessment of patient feedback
Data collection procedure outcomes will be assessed as a composite of:
*Adherence to medication is asked at each time point
*Patients are asked if they have had any side effects
*Patients will undergo a semi-structured interview to ask about ease of medication and feedback regarding participation in the trial
*Follow up rate will be assessed by an audit of the study database
Timepoint [3] 327612 0
Patients are reviewed two, six, twelve and twenty-six weeks following surgery. The final assessment and discharge from the trial is twenty-six weeks following surgery.
Secondary outcome [1] 391020 0
Proportion of participants presenting with Complex Regional Pain Syndrome will be assessed according to the 'Budapest criteria'. This is a combination of asking patients about their symptoms and examining them for positive signs as per the below criteria:
A: continuing pain, which is disproportional to any inciting event
B: The patient must report at least one symptom in three of the four following categories:
• Sensory- reports of hyperaesthesia and/or allodynia
• Vasomotor – reports of temperature asymmetry and/or skin colour changes and/or skin colour asymmetry
• Sudomotor/oedema – reports of oedema and/or sweating changes and/or sweating asymmetry
• Motor/trophic – reports of decreased range of motion and/or motor dysfunction (weakness/tremor/dystonia) and/or trophic changes (hair/nail/skin)
C: The clinician must observe at least one sig at the time of the evaluation in two or more of the following categories:
• Sensory- evidence of hyperalgesia (to pinprick) and/or allodynia and/or deep somatic pressure and/or joint movement
• Vasomotor – evidence of temperature asymmetry and/or skin colour changes and/or skin colour asymmetry
• Sudomotor/oedema – evidence of oedema and/or sweating changes and/or sweating asymmetry
• Motor/trophic – evidence of decreased range of motion and/or motor dysfunction (weakness/tremor/dystonia) and/or trophic changes (hair/nail/skin)
D: There is no other diagnosis that better explains the signs and symptoms

All components of the Budapest Criteria will be assessed as a composite outcome.
Timepoint [1] 391020 0
Patients are reviewed two, six, twelve and twenty-six weeks following surgery. The final assessment and discharge from the trial is twenty-six weeks following surgery.
Secondary outcome [2] 395941 0
Resource availability:
• Establishing paid and unpaid labour costs required for the trial
• Availability of medication and placebo
Resource availability will be assessed as a composite of:
Establishing paid and unpaid labour costs required for the trial - hours undertaken as part of this project will be assessed by researchers as part of a semi-structured interview and determination of hours required by a research assistant in the future made. The costs of Vitamin C and placebo will also be confirmed with hospital pharmacy.
Timepoint [2] 395941 0
Patients are reviewed two, six, twelve and twenty-six weeks following surgery. The final assessment and discharge from the trial is twenty-six weeks following surgery.
Secondary outcome [3] 395942 0
Participant response:
• Qualitative participant feedback
• Participant engagement/follow up
Participant response will be assessed as a composite of:
*Qualitative participant feedback assessed during a semi-structured one-on-one interview
*Assessment of adherence to medication protocol
*Audit of database to assess follow up
Timepoint [3] 395942 0
The final assessment and discharge from the trial is twenty-six weeks following surgery. Patients will undergo a semi-structured interview at this time to obtain any feedback about participation in the trial, and in particular feedback for a potential larger, multi-centred trial in the future.

Eligibility
Key inclusion criteria
• Patients need to be aged 18 and over to participate in the trial. This is because most fractures in the lower limb in children are treated non-operatively. In addition, most sites have limited numbers of younger patients who have surgery for foot or ankle problems, recruitment of people under the age of 18 is unfeasible.
• Patients need to be able to provide informed consent for the trial via a signed and dated consent form. Patients who are unable to provide informed consent because of (for example) cognitive impairment will be excluded.
• Patients who present to Peninsula Health, Frankston Private Hospital, Holmesglen Private Hospital, Beleura Private Hospital or Cabrini Brighton Private Hospital for surgery of the foot and ankle, either elective or emergency, will be eligible to participate.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Current or recent (ie less than three months prior to randomization) use of vitamin C, either as an isolated substance or as part of a multi-vitamin tablet. This is because the vitamin C dosing will not be standardized if patients are also taking the vitamin, and there is potential for overdosing. Vitamin C has a half-life of 10-20 days and therefore a long exclusion period is required.
• Patients who are pregnant or breastfeeding will be excluded due to the unknown safety risks in this patient population.
• Patients who are unable to commence taking the placebo/vitamin C medication within 72 hours after their surgery will be excluded from the trial
• Patients unable or unwilling to take oral medications.
• Patients who are vegan (as the placebo acidophilus is dairy based)

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
An investigator not directly involved in the analysis of the trial results will prepare the randomisation schedule using block randomisation to maintain balance between treatment arms. This will be Associate Professor Cylie Williams as she will not be directly involved in the analysis. The schedule will be provided to the pharmacist and sealed envelopes containing the treatment allocation of each randomisation code will be provided to the investigator in case of emergency.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block randomisation will be used.
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
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
The two secondary aims of this feasibility study will be addressed statistically. For the first secondary aim, diagnosis of CRPS will be ascertained in the form of time-to-event data, and rate ratios will be calculated using univariate Cox proportional hazards regression to directly compare diagnosis rates between the treatment and control groups.
Given the small sample size of this feasibility study, we anticipate randomization may inadequately balance the baseline characteristics of participants in the two treatment groups (e.g, age, trauma vs elective surgery). If necessary, a secondary set of analyses will be performed to adjust for baseline characteristics found to be imbalanced between groups to the extent of a 0.25 standard deviation difference in means (quantitative measures) or an odds ratio of 1.5 (binary measures). These analyses will be conducted using multivariate Cox proportional hazards regression models.
In the survival analyses, loss to follow-up will be considered a censoring event. This equates to an assumption that data is missing at random given the participant’s treatment group and the timing of their loss to follow-up. The adequacy of this assumption will be checked in sensitivity analyses that will include both a multiple imputation by chained equations (MICE) approach and adjustment for baseline covariates predictive of propensity for dropout.
A sensitivity analysis will repeat the proportional hazards regression to compare rates of CRPS as diagnosed by the presence of individual Budapest criteria, rather than 3 out of 4 patient-reported symptoms or 2 out of 4 clinician-observed symptoms as required for formal CRPS diagnosis.
For the second secondary aim, the incidence risk of CRPS 6 months post surgery for lower limb extremity trauma patients will be reported as a proportion of the study sample.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
12/07/2021
Actual
Date of last participant enrolment
Anticipated
12/12/2021
Actual
Date of last data collection
Anticipated
31/05/2022
Actual
Sample size
Target
100
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 18506 0
Frankston Hospital - Frankston
Recruitment hospital [2] 18507 0
Frankston Private Hospital - Frankston
Recruitment hospital [3] 18508 0
Holmesglen Private Hospital - Moorabbin
Recruitment hospital [4] 18509 0
Cabrini Brighton - Brighton
Recruitment hospital [5] 18510 0
Beleura Private Hospital - Mornington
Recruitment postcode(s) [1] 32825 0
3199 - Frankston
Recruitment postcode(s) [2] 32826 0
3189 - Moorabbin
Recruitment postcode(s) [3] 32827 0
3186 - Brighton
Recruitment postcode(s) [4] 32828 0
3931 - Mornington

Funding & Sponsors
Funding source category [1] 306473 0
Hospital
Name [1] 306473 0
Frankston Hospital
Country [1] 306473 0
Australia
Primary sponsor type
Hospital
Name
Frankston Hospital
Address
Hastings Road
Frankston
Vic 3199
Country
Australia
Secondary sponsor category [1] 306997 0
None
Name [1] 306997 0
n/a
Address [1] 306997 0
n/a
Country [1] 306997 0
Other collaborator category [1] 281623 0
University
Name [1] 281623 0
Monash University
Address [1] 281623 0
Monash University
Clayton Campus
Wellington Rd,
Clayton VIC 3800
Country [1] 281623 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 306681 0
Monash Health Human Resources and Ethics Committee
Ethics committee address [1] 306681 0
Ethics committee country [1] 306681 0
Australia
Date submitted for ethics approval [1] 306681 0
04/05/2021
Approval date [1] 306681 0
Ethics approval number [1] 306681 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 104654 0
Dr Amy Touzell
Address 104654 0
Frankston Private Hospital Consulting Suites
7 Foot St
Frankston
Vic 3199
Country 104654 0
Australia
Phone 104654 0
+61 484739550
Fax 104654 0
Email 104654 0
c2005514@hotmail.com
Contact person for public queries
Name 104655 0
Amy Touzell
Address 104655 0
Frankston Private Hospital Consulting Suites
7 Foot St
Frankston
Vic 3199
Country 104655 0
Australia
Phone 104655 0
+61 484739550
Fax 104655 0
Email 104655 0
c2005514@hotmail.com
Contact person for scientific queries
Name 104656 0
Amy Touzell
Address 104656 0
Frankston Private Hospital Consulting Suites
7 Foot St
Frankston
Vic 3199
Country 104656 0
Australia
Phone 104656 0
+61 484739550
Fax 104656 0
Email 104656 0
c2005514@hotmail.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified data will be available regarding patient demographics, development of CRPS and any adverse affects detected.
Data regarding patient adherence to the medication, recruitment numbers and costs of the study will be available.
When will data be available (start and end dates)?
Data will be available following conclusion of the trial (expected to be twelve months after commence date). There is no end date for data availability.
Available to whom?
Only researchers who provide a methodologically sound proposal.
Available for what types of analyses?
To achieve the aims in the approved proposal
For Individual Patient Data meta-analyses
How or where can data be obtained?
Access subject to approvals by Principal Investigator, via email amy.touzell@monash.edu.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
10349Study protocol    380399-(Uploaded-17-06-2021-11-22-43)-Study-related document.pdf
10350Informed consent form    380399-(Uploaded-23-05-2021-17-34-33)-Study-related document.doc



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.