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Trial registered on ANZCTR


Registration number
ACTRN12618001033235
Ethics application status
Approved
Date submitted
12/06/2018
Date registered
20/06/2018
Date last updated
20/06/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
Effectiveness and safety of a mixture of diosmin, coumarin and arbutin (Linfadren®) in addition to conventional treatment, in the management of patients with persistent hand edema following trauma or surgery of distal forearm or hand. A randomized controlled trial.
Scientific title
Effectiveness and safety of a mixture of diosmin, coumarin and arbutin (Linfadren®) in addition to conventional treatment, in the management of patients with persistent hand edema following trauma or surgery of distal forearm or hand. A randomized controlled trial.
Secondary ID [1] 295169 0
None
Universal Trial Number (UTN)
U1111-1215-4810
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
persistent hand edema following trauma or surgery of distal forearm or hand 308294 0
Condition category
Condition code
Musculoskeletal 307300 307300 0 0
Other muscular and skeletal disorders
Physical Medicine / Rehabilitation 307301 307301 0 0
Physiotherapy
Injuries and Accidents 307327 307327 0 0
Other injuries and accidents
Surgery 307328 307328 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 hand 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 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.
To improve adherence as far as medication assumption we asked patients to self-compile a daily diary.
Intervention code [1] 301505 0
Treatment: Drugs
Intervention code [2] 301506 0
Rehabilitation
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 hand movement. These treatments were performed once a day for five days a week for six weeks.
Control group
Active

Outcomes
Primary outcome [1] 306260 0
Our primary outcome measure was the reduction of hand edema as evaluated by figure-of eight method, which is a valid and reliable instrument for measurement of hand edema following trauma or surgery.
Timepoint [1] 306260 0
Baseline, after treatment (6 weeks-primary timepoint), 3 months after the end of treatment
Secondary outcome [1] 347998 0
Quick Disabilities of Arm, Shoulder and Hand (QuickDASH) questionnaire, which has also been validated in patients undergoing rehabilitation after hand injuries. It consists of 11 core items designed to measure physical function, symptoms and social function, and 2 optional items (musical or sport performance and work), which generate a disability score, ranging from 0 (no disability) to 100 (the most severe disability).
Timepoint [1] 347998 0
Baseline, after treatment (6 weeks-primary timepoint), 3 months after the end of treatment
Secondary outcome [2] 347999 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] 347999 0
Baseline, after treatment (6 weeks-primary timepoint), 3 months after the end of treatment
Secondary outcome [3] 348103 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] 348103 0
Baseline, after treatment (6 weeks-primary timepoint), 3 months after the end of treatmentafter treatment

Eligibility
Key inclusion criteria
Inclusion criteria was: persistent hand edema with a difference of greater than or equal to 20mm between the affected hand and the unaffected hand in figure-of-eight measurement
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 hand edema, pulmonary edema, congestive heart failure, coagulation defects, history of inflammatory, metabolic, or neuropathic arthropathies, treatment with anticoagulant drugs, 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 opaque envelopes
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 receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The calculation of the number of patients was based on the primary outcome. It was assumed that, at the end of treatment, the patients in the study group would have a mean reduction of 25 mm, and the patients in the control group, a mean reduction of 10 mm, with a common SD of 15 mm. On this basis, and assuming a level of significance of 5% and a power of 95%, the number of patients necessary was calculated to be 26 per group. Assuming a dropout of 15%, 30 patients per group were required. Statistical analyses were performed, by an independent statistician, using MedCalc (version 11.1.1.0 for Windows; MedCalc Software, Mariakerke, Belgium). All analyses of the primary and secondary outcome measures were performed according to the principle of intention-to-treatment. The intention-to-treat analysis was carried out according to a "worst-case scenario" analysis: subjects who did not complete the treatment or had not undergone the post-treatment or final follow-up assessments were assigned a poor outcome, corresponding to the final average change recorded in the per-protocol completer population in the control group.
A 2-sample unpaired t test and Chi-square test were applied to compare the differences of continuous and categorical variables, respectively, of the baseline data.
A 2-way analysis of variance (ANOVA) with group (study versus control) as the between-subjects factor and time (before-after-follow-up) as the within-subjects factor was used to assess the presence of significant differences between the study and control groups and within each group before and after treatment and at the 3-month follow-up. A Tukey post hoc comparison was used to determine significant differences between mean values when a significant main effect and interaction were found for the outcome measures.
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.
A two-sample paired t tests was done to compare the differences of mean values of clinical and laboratory examinations before and after treatment. Rates of adverse events between groups were compared using Chi-square test.
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.
For all analysis the p values (2-sides) less than 0.05 (p=0.05) were considered significant.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
17/07/2017
Date of last participant enrolment
Anticipated
Actual
28/01/2018
Date of last data collection
Anticipated
Actual
7/05/2018
Sample size
Target
60
Accrual to date
Final
60
Recruitment outside Australia
Country [1] 10547 0
Italy
State/province [1] 10547 0

Funding & Sponsors
Funding source category [1] 299756 0
University
Name [1] 299756 0
University of L'Aquila
Country [1] 299756 0
Italy
Primary sponsor type
Individual
Name
Angelo Cacchio
Address
University of L'Aquila - P.le San Salvatore 1- Edificio Delta 6 Medicina - 67100 L'Aquila, Italy.
Country
Italy
Secondary sponsor category [1] 299135 0
None
Name [1] 299135 0
Address [1] 299135 0
Country [1] 299135 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300646 0
Ethics committee of University of L'Aquila
Ethics committee address [1] 300646 0
University of L'Aquila - Ethics Committee -
Via Giovanni Di Vincenzo n. 1618 - 67100 L'Aq u ila, Italy
Ethics committee country [1] 300646 0
Italy
Date submitted for ethics approval [1] 300646 0
28/03/2017
Approval date [1] 300646 0
11/07/2017
Ethics approval number [1] 300646 0
Prot. 30262

Summary
Brief summary
This is a randomized, active-controlled, assessor- and statistician-blinded clinical study, with the purpose to assess the effectiveness and safety of oral administration of a mixture of diosmin, coumarin and arbutin (Linfadren®) in addition to conventional treatment, in the management of patients with post-trauma/surgery persistent hand edema.
We hypothesize that managing patients with persistent hand edema following surgery/trauma is more effective by adding Linfadren supplementation to conventional treatment respect to conventional treatment alone
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 84330 0
Prof Angelo Cacchio
Address 84330 0
Università dell'Aquila, P.le San Salvatore 1- Edificio Delta 6 Medicina - 67100 L'Aquila, Italy.
Country 84330 0
Italy
Phone 84330 0
+390862434747
Fax 84330 0
Email 84330 0
[email protected]
Contact person for public queries
Name 84331 0
Prof Angelo Cacchio
Address 84331 0
Università dell'Aquila, P.le San Salvatore 1- Edificio Delta 6 Medicina - 67100 L'Aquila, Italy.
Country 84331 0
Italy
Phone 84331 0
+390862434747
Fax 84331 0
Email 84331 0
[email protected]
Contact person for scientific queries
Name 84332 0
Prof Angelo Cacchio
Address 84332 0
Università dell'Aquila, P.le San Salvatore 1- Edificio Delta 6 Medicina - 67100 L'Aquila, Italy.
Country 84332 0
Italy
Phone 84332 0
+390862434747
Fax 84332 0
Email 84332 0
[email protected]

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