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!