Dr. Vijay Viswanathan, M.D, Ph.D., MNAMSJoint Director

Diabetes Research Centre &M. V. Hospital for Diabetes

Chennai.

WHO Collaborating Centre for Research, Education & Training in diabetes

Chronic wounds provide a more complex

challenge:

fluxes in the local non – healing wound

environment in which growth factors can quickly

become trapped

degraded by the proteolytic extracellular milieu.

[Trengove NJ et al., Wound Repair Regen 1999; 7: 442 – 452]

Certain growth factors are selectively inhibited in the

ulcer environment.

Treatment Modality

Reference No. of patients

examined

Method of trial

Method of

action

Results

Platelet – derived growth

factor – BB (Becaplermi

n)

Becaplermin 0.01% 272 Control -

236

Meta – analysis

of 4 RCT’s

Enhances granulation

tissue formation and

facilities epithelializatio

n

A significant reduction in

healing time. Significantly

more healing in wounds < 5 cm

Epidermal growth factor (EGF)

EGF – 21 Placebo -

19

RCT A potent dose –

dependent mitogen for granulation fibroblasts contributing to wound healing and

closure

Significantly faster wound closure and healing after 12 weeks of

therapy

Tsang MW et al.,

Diabetes Care 2003; 26: 1856 –

1861

RCT’s and clinical trials published on growth factors

Smiell JM et al., Wound

Repair Regen 1999; 7: 335 - 346

Epidermal growth factor belongs to:

A family of growth factors that regulate

cell proliferation

migration

differentiation through binding to receptor

kinases on target cells

Epidermal growth factor peptide induces

cellular proliferation through the EGF receptor:

EGF receptor:

Has a tyrosine kinase cytoplasmic

domain

Extracellular domain involved in EGF

binding and receptor dimerization.

Mechanism of action

Binding of EGF results in:

EGF receptor dimerization

autophosphorylation of the receptor

tyrosine phosphorylation of other proteins

Epidermal growth factor receptor activates

MAP kinase pathway

ultimately causing phosphorylation of

transcription factors such as c – Fos

to create AP – 1

ELK – 1 that contribute to proliferation

Healthy male or female patients between 18 – 65 years at the time of consent Patients with controlled diabetes mellitus having foot ulcers The target ulcer is no less than 2 cm2 and no more than 50 cm2

Patients with ABI > 0.8 Ulcers, which remain opened without healing for more than 2 – 3 weeks

A Phase III Study to Evaluate the Safety and Efficacy of Recombinant Human

Epidermal Growth Factor ( REGEN-D TM – 150 ) in Healing Diabetic foot Ulcers

Vijay Viswanathan, Sharad Pendsey, N.Sekar, G.S.R. Murthy

[ WOUNDS:,Vol.18, No.7 July 2006 ]

EXCLUSION CRITERIA

Patients with > Wagner’s grade III classification

Pregnant women and nursing mothers

Uncontrolled diabetes mellitus

Treatment with a dressing containing other growth factors or biological dressings within 30 days prior to the screening visit.

Epidermal Growth Factor : Diabetic Foot Ulcer Trial summary Total no. of patients - 57

• Group 1 (EGF) -29

• Group 2 (Control) - 28Group 1 Group 2 p valueNo. of patients 29 28

M / F 22 / 7 20 / 8Mean age (in

yrs)58 1.9 59 2.0

Ulcer size (in cm2)

13.3 ± 3.1 12.5± 2.2

No of Healed cases

at 15 weeks

25 12 < 0.01

Mean healing time (days)

56.8 ± 4.7 81± 4.4 < 0.01

Values are Mean SD

Week, w

Perc

enta

ge o

f pat

ients

cure

d by

wee

k w

282420161284

100

80

60

40

20

0

Figure-5: Efficacy of Regen-D Gel

ControlTest

Figure 5 :  The healing takes place before the end of the 8th week in 50% of the patients under test; and it takes nearly 15 weeks to cure 50% of the patients under control.

Perc

enta

ge o

f pat

ient

s who

had

com

plet

e he

alin

g (in

wee

ks)

0

10

20

30

40

Condition Area

Control ControlTest

Test

% H

eale

d w

ithi

n 15

wee

ks

88%

100%

8%

66%

0 - 6 Above 6

Control : Placebo. Test: rhEGF

Comparison of placebo and rhEGF by ulcer area

Post – Marketing Survey (PMS) Study comparison with Phase III Clinical Data

0

2 0

4 0

6 0

8 0

1 00

5 10 15 20 25 30

Week (w)

Perc

enta

ge o

f pat

ient

s cur

ed b

y w

eek

(w) Cumulative percentages of curing

Control Test PMS

•65 year old female •Ulcer on the dorsum of left foot – one month duration•Size: 1 x 2.5 cms

Visit 1

• Size: 0.4 x 1.5 cms

Visit 4 (Week 3)

• Wound has healed completely

Visit 6 (Week 5)

• 65 year old male • Chronic non healing ulcer for 2 months duration over the lateral malleolus of the right foot •Size: 5 x 6.5 cms

Visit 1

• Size: 2.2 x 1 cms

Visit 6 (Week 5)

• The ulcer completely healed in 8 weeks.

• 63 year old female

• Tropic ulcer in the region of left fifth metatarsal

• Duration of the ulcer: 1 month

• Size: 2.5 x 2 cms

Visit 1

• Size: 1.3 x 1.3 cms

Visit 3 (Week 2)

• Wound measured about 0.4 x 0.3 cms.

• Totally healed in a weeks time.

Visit 5 (Week 4)

[Courtesy, Sharad Pendsey, Nagpur]

[Courtesy, Sharad Pendsey, Nagpur]

“I dressed the wound and God healed it”

Ambrose Pare