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Green tea in DEB
(epigallocathechin 3 gallate)
C. Chiaverini1, E. Fontas5, C. Roger5, E. Bourrat2, J. Mazerreuw3, C. Labreze4, P. Vabres6,C. Bodemer2, JP. Lacour1
EB center of 1Nice, 2Paris (MAGEC), 3Toulouse, 4Bordeaux and department of 5clinical research, Nice, 6dermatology
Dijon
Fundings
National program for medical research (PHRC) 2009
Capsules of epigallocathechin 3 gallate (EGCG) and placebo were provided by Polyphenon
Pharma/Mitsui Norin company
Participants
DEBRA France help us to inform patients and families
3 French reference centres for EB and one competence centre participated to this study
Why use green tea for DEB?
No curative treatment
DEB patients with the most severe phenotype have elevated level of activated MMP in skin
Efficiency in vitro of epigallocatechin 3 gallateon dermal MMP activity
EGCG is available in oral form and has been tested for various conditions (cancer,
inflammatory disease)
Selection criteria
Diagnosis of DEB with documented collagen type VII deficiency by: Antigenic mapping (LH7.2 antibody)
DNA mutation analysis when available
Performance status: >50% Karnofsky
Adequate organ function Renal: glomerular filtration rate > 60ml/min/1.73m2 patients
aged 10 years
Hepatic: bilirubin, aspartate aminotransferase/alanine aminotransferase (AST/ALT), Alkaline phosphatase (ALP) < 5 x upper limit of normal
Both sex
Older than 4 years
From France
Study design
Multicentric, national, randomized, double blind controlled versus placebo, cross over study
Group 1
Polyphnon E
Group 2
placebo
Groupe1
placebo
Group 2
Polyphnon E
Period 2Period 1
M10 M12M6M4M1
M0
inclusionM7
Study design
Before each visit patients need to
Count the number of new blisters during seven dresses
Evaluate the duration of wound healing of 3 blisters
At each visit, investigator evaluated:
Surface involved (scheme)
Pruritus, mucosal involvement, skin fragility (VAS)
Blood exam
AE
Epigallocatechin 3 gallate
Capsules of 200mg to open
Dosage depend on weight and was estimated on previous studies but no data available in
young children and for skin disease
> 40kg: 400mg twice a day
> 20-40kg: 400mg and 200mg
< 20kg: 200mg twice a day
Primary outcome
Number of patients in therapeutic success after each period of 4 months of treatment.
Therapeutic success was defined by a decrease of at least 20% of the mean number
of blisters counted by patients seven dresses
before each visit.
Secondary outcomes
At each visit following items were evaluated:
Surface of skin involved (blisters and erosions)
Pruritus (visual analog scale)
Mucosal involvement (visual analog scale)
Skin fragility (VAS)
Duration of wound healing of 3 blisters
Others
Compliance of patients was evaluated by the comparison for each patient of the number of
residual treatment returned to central
pharmacy in Nice with the prevised number of
residual treatment.
Adverse events were search at each visit by questionnaire and by blood analysis
Statistical analysis
Primary outcome (qualitative value) : Prescott test (to analyse a period effect)
Secondary outcomes (continue values): procedure MIXED of SAS.
Results
17 (instead of 22 as initially planned) were included in this study, 12 females and 5 males, mean age 19,35 years (16,22 SD)
1 patient did not start the treatment (stolen with his bag) and was not included in statistical analysis
Only 10/16 patients had available data for each visit of both periods of treatment for the main outcome
Results
8 patients /16 had a decrease of almost 20% of mean number of new blisters per day during the Polyphenon E period of treatment and 5 /16 for the placebo treatment period (Test de Prescott, p = 0,37)
6 patients /10 had a decrease of almost 20% of mean number of new blisters per day during the Polyphenon E period of treatment and 5 /10 for the placebo treatment period (Test de Prescott, p = 0,019)
Results
Similar results were obtained primary outcome was 30% of decrease of daily blisters
Similar results were obtained when patients (1) with poor compliance were exclude of
analysis
Results: duration of wound healing
Polyphenon E
Moy ET (N)
Placebo
Moy ET (N)p value
Mean duration of wound
healing (end of period
beginning of the period)
-14,62 18,76 (7)1,78 14,65
(9)0,2068
Results: other criteria
Evolution of score (end of
the period - beginning of
the period)
Polyphenon E
Moy ET (N)
Placebo
Moy ET (N)p value
Surface -4,07 7,62 (12) -4,42 9,84 (14) 0,9254
Skin fragility -0,90 2,46 (12) -0,64 2,06 (14) 0,7508
Mucosal involvement 0,55 1,12 (8) 1,97 1,64 (6) 0,0708
Pruritus-1,17 3,53 (12) 0 2,16 (14) 0,3776
Population Totale (n=42) Placebo (n=16)Polyphenon E
(n=26)p value*
N % N % N %
Evnements 0,2588
AINHUM ANNULAIRE GAUCHE+ 1 2,38 0 0,00 1 3,85
ANGINE+ 2 4,76 1 6,25 1 3,85
ASTHENIE 1 2,38 0 0,00 1 3,85
BRONCHITE 2 4,76 0 0,00 2 7,69
CARCINOME SPINOCELLULAIRE+ 3 7,14 2 12,50 1 3,85
CHUTE 2 4,76 1 6,25 1 3,85
VOMISSEMENT 2 4,76 0 0,00 2 1,69
CONSTIPATION CHRONIQUE 1 2,38 0 0,00 1 3,85
DIARRHEES/SELLES MOLLES 3 7,14 1 6,25 2 7,69
DIARRHEES GLAIREUSES 1 2,38 1 6,25 0 0,00
DOULEUR SOPHAGE 2 4,76 2 12,50 0 0,00
FISSURE ANALE 1 2,38 0 0,00 1 3,85
GASTROENTERITE 3 7,14 0 0,00 3 11,54
HOSPITALISATION POUR BULLES
OESOPHAGIENNES+1 2,38 0 0,00 1 3,85
INTERVENTION SUR PIED+ 1 2,38 1 6,25 0 0,00
LUMBAGO 1 2,38 0 0,00 1 3,85
ODYNOPHAGIE ET APHAGIE + 1 2,38 0 0,00 1 3,85
POUSSEE BULLEUSE 1 2,38 1 6,25 0 0,00
POUSSEE DE DERMATITE ATOPIQUE 1 2,38 0 0,00 1 3,85
PRURIT 1 2,38 0 0,00 1 3,85
RHUME 5 15,90 3 18,75 2 7,69
SURINFECTION CUTANEE 3 7,14 1 6,25 2 7,69
TOUX, SYNDROME VIRAL 1 2,38 1 6,25 0 0,00
VIROSE (FIEVRE+HERPES) 1 2,38 0 0,00 1 3,85
VULVITE 1 2,38 1 6,25 0 0,00
Gravit de lEI 0,3514
Grave 8 19,05 4 25,00 4 15,38
Non Grave 34 80,95 12 75,00 22 84,62
Actions sur le Traitement de lessai 0,8160
Aucune 10 23,81 4 25,00 6 23,08
Hospitalisation 6 14,29 3 18,75 3 11,54
Traitement symptomatique 26 61,90 9 56,25 17 65,38
Imputabilit
Non valuable 3 7,14 0 0,00 3 11,54
Douteuse 5 11,90 0 0,00 5 19,23
Possible 8 19,05 5 31,25 3 11,54
Exclue 26 61,90 11 68,75 15 57,69
What this study tell us?
ECGC (Polyohenon) seems to be efficient on:
The number of new blisters per day
The duration of wound healing
In patient with DEB
However the low number of patients who have completed the study did not allow us to
definitively affirm it
Tolerance is good
What this study tell us?
Randomized controlled versus placebo and double blind studies in DEB patients are very difficult (very few studies published) due to:
The rarity and the severity of the disease
The difficulty for patients and/or families to go to hospital for many visits even with financial compensation
The number of associated diseases/events
Difficulty to include and high level of premature termination of study
What this study tell us?
The variable course of the disease with time
difficulty to find a good and reproductible
primary outcome
The heterogeneity of patients with various severity and for our study probably various
level of activation of MPP1 in skin
difficulty to have a sufficient number of
patients for statistical analysis
What this study tell us?
Cross over study have : Some advantages
A comparison of treatments on the same subject is expected to be more precise and allowed smaller sample size.
Patient enrollment into the study is easier because each patient will receive both treatments.
Many disadvantages The statistical analysis of a cross-over experiment is more
complex than a parallel-group experiment and requires additional assumptions. It may be difficult to separate the treatment effect from the time effect , the period effect and the carry-over effect of the previous treatment.
Because subjects must be measured at least twice, it may be more difficult to keep patients enrolled in the study.
Lack of data in a small population has big repercussions on results.
What this study tell us?
The perfect EB study: Is controlled versus placebo, randomized and
double blind
International to have enough patients
Avoid cross over design
Have well defined target population (polymorphism of MMP1?)
Propose an improvement of lesions of at least 30%
Avoid summer to initiate treatment.
Conclusion
Polyphenon E is a promising treatment to improved DEB, waiting for a curative
treatment
A new perfect international study is requested with the help of all EB centres,
DEBRA international, Mitsui Norin company
and.patients!