Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001040853
Ethics application status
Approved
Date submitted
20/12/2020
Date registered
9/08/2021
Date last updated
9/08/2021
Date data sharing statement initially provided
9/08/2021
Date results provided
9/08/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
Effectiveness and safety of supplement drug (Linfadren®) in the management of patients with post-trauma/surgery persistent ankle edema: a randomized controlled trial
Scientific title
Effectiveness and safety of supplement drug (Linfadren®) in the management of patients with post-trauma/surgery persistent ankle edema: a randomized controlled trial
Secondary ID [1] 303056 0
none
Universal Trial Number (UTN)
U1111-1263-0034
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
persistent ankle edema following trauma or surgery of ankle or distal leg 320119 0
Condition category
Condition code
Musculoskeletal 318062 318062 0 0
Other muscular and skeletal disorders
Physical Medicine / Rehabilitation 318066 318066 0 0
Physiotherapy
Injuries and Accidents 320086 320086 0 0
Fractures
Surgery 320087 320087 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Once eligible for the trial, participants will be recruited and randomised into one of the following 6-week interventions:
1) conventional rehabilitation treatment (control group)
2) conventional rehabilitation treatment plus Linfadren® (study group)

a) conventional rehabilitation treatment consisting of elevation, cryotherapy, low-compression garments, retrograde massage, and gentle hand movement. These treatments were performed once a day for five days a week for six weeks, Patients will receive sessions with retrograde massage and gentle ankle movement on a one-to-one basis with an experienced physiotherapist who also monitored the patients' adherence to the other treatments

b) Linfadren® is a marketed supplement formulation which contains 200 mg of diosmin, 30.6 mg of coumarin, and 3.7 mg of arbutin.
Coumarin (alpha-benzopyrones), stimulating macrophage activation and proteolysis, favors the reduction of excess stagnant proteins from tissues, with a decrease of edema and chronic inflammation. Diosmin (gamma-benzopyrones) is mainly a vascular-protecting agent, improving venous tone, protecting capillary bed microcirculation, reducing capillary permeability, but being potent inhibitors of inflammatory mediators as prostaglandin E2 (PGE2) and thromboxane A2 (TxA2), also exhibits anti-inflammatory properties. Arbutin is a natural product found in different plants including bearberry (Arctostaphylos uva-ursi) and has diuretic properties that help to reduce water tissue retention.

Patients were instructed to consume one oral capsule of Linfadren® on an empty stomach twice a day (6-hourly: 11a.m. and 5 p.m.) for two weeks, and once a day for four weeks. The dose asministered at each interval (one capsule) contains 200 mg of diosmin, 30.6 mg of coumarin, and 3.7 mg of arbutin.
To improve adherence as far as medication assumption we asked patients to self-compile a daily diary.
Intervention code [1] 319337 0
Rehabilitation
Intervention code [2] 319338 0
Treatment: Other
Comparator / control treatment
Patients in the control group will receive a 6-week conventional rehabilitation treatment consisting of elevation, cryotherapy, low-compression garments, retrograde massage, and gentle ankle movement. These treatments were performed for 1 hour once a day for five days a week for six weeks.
Control group
Active

Outcomes
Primary outcome [1] 326054 0
Our primary outcome measure was the reduction of ankle edema as evaluated by figure-of-eight-20 method, which is a valid and reliable instrument for measurement of ankle edema following trauma or surgery. Its minimal detectable change was of 9.6 mm when performed without skin marks.
Timepoint [1] 326054 0
Baseline, after treatment (6 weeks-primary timepoint), 3 months after the end of treatment
Secondary outcome [1] 389986 0
Italian version of Lower Extremity Functional Scale (LEFS) questionnaire, which is valid and reliable instrument for measurement of lower limb functional status in a wide spectrum of patients with lower extremity conditions of musculoskeletal origin, including ankle. It consists of 20 items designed to measure the degree of difficulty in performing different physical activities because of the problem in the lower extremity, which generate a disability score from 0 (low functional level) to 80 (high functional level)
Timepoint [1] 389986 0
3 months after the end of treatment
Secondary outcome [2] 389987 0
As a self-perceived treatment effectiveness a 5-point Likert scale ranging from “extremely effective” to “not at all effective” was chosen. Success rates were calculated by dichotomizing responses. Patients who referred to treatment effectiveness as “extremely effective” or “very effective” were counted as successes, whereas patients who referred to treatment effectiveness as, “somewhat effective”, “poorly effective” or “not at all effective” were counted as failures.
Timepoint [2] 389987 0
3 months after the end of treatment
Secondary outcome [3] 389988 0
Difference between the two group in the number of rescue medications taken during the study period, as assessed by analysis of self-completed diary. where patients recorded the number of rescue medication consumed each day
Timepoint [3] 389988 0
3 months after the end of treatment
Secondary outcome [4] 397113 0
Adverse events
To evaluate the tolerability of the Linfadren® during the course of treatment, patients underwent a complete laboratory examination, including hematology, blood chemistry and urinalysis both before and after treatment. Patients also underwent a clinical examination to record vital signs and were asked to record all the adverse effects they observed.
Timepoint [4] 397113 0
Baseline, after treatment (6 weeks), 3 months after the end of treatment

Eligibility
Key inclusion criteria
Inclusion criteria were: 18 years or older, diagnosis of post-trauma/surgery persistent ankle edema with a difference greater than or equal to 20 mm between the affected ankle and the unaffected ankle as measured by figure-of-eight-20 method. Persistent edema was an edema that persisted for more than two weeks.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria were: bilateral ankle edema; pulmonary edema; congestive heart failure; coagulation defects; any contraindications limiting clinical evaluation and therapy of the patient.

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)
sealed envelopes prepared by an assistant researcher at the University of L’Aquila, who was independent of the recruitment process
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
The sample size calculation was based on the primary outcome using MedCalc (version 11.1.1.0 for Windows; MedCalc Software, Mariakerke, Belgium). The minimal detectable change when figure-of-eight-20 method was performed without skin marks, was of 9.6 mm. Assuming a level of significance of 5% and a power of 80%, the necessary sample size to detect a difference of 10 mm in figure-of-eight-20 measurements was of 26 patients per group. Assuming a dropout of 15%, 30 patients per group were required.
A two-sample unpaired t-test and Chi-square test were applied to compare the differences in continuous and categorical variables, respectively. A two-way analysis of variance (ANOVA) with group (study vs control) as the between-subject factor and time (baseline–six weeks–three months) as the within-subject factor, followed by a Tukey post hoc comparison, was used to assess the presence of significant differences between the study and control groups for ankle edema measured by figure-of-eight-20 method and for ankle function assessed by LEFS questionnaire. Fisher´s exact test was carried out to compare the percentage of success in Likert rating scale between the study and control groups after treatment and at the 3-month follow-up. The intake of paracetamol (rescue medication) was analyzed by comparing the mean number of tablets taken by the two groups of patients during the study, using a two-sample unpaired t tests.
All analyses of the primary and secondary outcome measures were performed according to the principle of intention-to-treat. The intention-to-treat analysis was carried out according to a “worst-case scenario” analysis. The P values (two sides) less than 0.05 (P less than 0.05) were considered significant. A 95% confidence interval (CI) was also calculated. MedCalc software (version 11.1.1.0 for Windows; MedCalc Software, Mariakerke, Belgium) was used.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
1/10/2018
Date of last participant enrolment
Anticipated
Actual
29/11/2019
Date of last data collection
Anticipated
Actual
21/02/2020
Sample size
Target
60
Accrual to date
Final
60
Recruitment outside Australia
Country [1] 23303 0
Italy
State/province [1] 23303 0
Abruzzo

Funding & Sponsors
Funding source category [1] 307464 0
University
Name [1] 307464 0
University of L'Aquila
Country [1] 307464 0
Italy
Primary sponsor type
University
Name
University of L'Aquila
Address
Via Giuseppe Petrini, "Rita Levi Montalcini" Building 67100 L'Aquila
Country
Italy
Secondary sponsor category [1] 308136 0
None
Name [1] 308136 0
Address [1] 308136 0
Country [1] 308136 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307541 0
Internal Review Board of the University of L'Aquila
Ethics committee address [1] 307541 0
Ethics committee country [1] 307541 0
Italy
Date submitted for ethics approval [1] 307541 0
28/03/2017
Approval date [1] 307541 0
11/07/2017
Ethics approval number [1] 307541 0
Prot. 30262c

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

Contacts
Principal investigator
Name 107602 0
Prof Angelo Cacchio
Address 107602 0
Department of Life, Health & Environmental Sciences
University of L'Aquila
Via Giuseppe Petrini
“Rita Levi Montalcini” Building
67100 Coppito-L'Aquila
Country 107602 0
Italy
Phone 107602 0
+390862434747
Fax 107602 0
Email 107602 0
[email protected]
Contact person for public queries
Name 107603 0
Angelo Cacchio
Address 107603 0
Department of Life, Health & Environmental Sciences
University of L'Aquila
Via Giuseppe Petrini
“Rita Levi Montalcini” Building
67100 Coppito-L'Aquila
Country 107603 0
Italy
Phone 107603 0
+390862434747
Fax 107603 0
Email 107603 0
[email protected]
Contact person for scientific queries
Name 107604 0
Angelo Cacchio
Address 107604 0
Department of Life, Health & Environmental Sciences
University of L'Aquila
Via Giuseppe Petrini
“Rita Levi Montalcini” Building
67100 Coppito-L'Aquila
Country 107604 0
Italy
Phone 107604 0
+390862434747
Fax 107604 0
Email 107604 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Deidentified participant information data will be available including a/ Baseline demographic information, b/Figure-of-Eight-20 , c/Questionnaire information (on ankle function) d/patient’s overall perceived treatment effectiveness based on 5-point Likert Scale
When will data be available (start and end dates)?
available with no end date
Available to whom?
Only researchers who provide a methodologically motivated and sound proposal, and not aimed at producing similar studies
Available for what types of analyses?
Purpose as agreed to by the prinicipal investigator
How or where can data be obtained?
access subject to approvals by Principal Investigator ([email protected])


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
SourceTitleYear of PublicationDOI
EmbaseEfficacy and Safety of the Phytochemical Product Linfadren in the Management of Patients With Persistent Ankle Edema Following Trauma or Surgery: A Randomized Controlled Trial.2023https://dx.doi.org/10.1177/10711007231189679
N.B. These documents automatically identified may not have been verified by the study sponsor.