This document summarizes clinical trials on using growth factors like platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) to treat chronic wounds in patients with diabetes. A trial of EGF involving 57 patients found it significantly accelerated wound closure and healing compared to placebo, with complete healing within 15 weeks in 88% of the EGF group versus only 8% of the control group. The mechanism of action and signaling pathway of EGF is also described. Case studies demonstrate complete wound healing with EGF treatment within 4-8 weeks.

1. Dr. Vijay Viswanathan, M.D, Ph.D., MNAMS
Joint Director
Diabetes Research Centre &
M. V. Hospital for Diabetes
Chennai.
WHO Collaborating Centre for Research,
Education & Training in diabetes

2.  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.

3. Treatment
Modality
Reference No. of
patients
examined
Method
of trial
Method
of action
Results
Platelet –
derived
growth factor
– BB
(Becaplermin)
Becaplermin
0.01%
272
Control - 236
Meta –
analysis of
4 RCT’s
Enhances
granulation
tissue formation
and facilities
epithelialization
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

4.  Epidermal growth factor belongs to:
A family of growth factors that regulate cell
proliferation
 migration
 differentiation through binding to receptor kinases on
target cells

5.  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

6.  Binding of EGF results in:
 EGF receptor dimerization
 autophosphorylation of the receptor
 tyrosine phosphorylation of other proteins

7.  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

8.  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 ]

9. 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.

10. Epidermal Growth Factor : Diabetic Foot Ulcer Trial summary
Total no. of patients - 57
• Group 1 (EGF) - 29
• Group 2 (Control) - 28
Group 1 Group 2 p value
No. of patients 29 28
M / F 22 / 7 20 / 8
Mean 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

11. Week, w
Percentageofpatientscuredbyweekw
282420161284
100
80
60
40
20
0
Figure-5: Efficacy of Regen-D Gel
Cont rol
Test
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.
Percentageofpatientswhohadcomplete
healing(inweeks)

12. 0
10
20
30
40
Condition
Area
Control ControlTest Test
%Healedwithin15weeks
88%
100%
8%
66%
0 - 6 Above 6
Control : Placebo. Test: rhEGF
Comparison of placebo and rhEGF by ulcer area

13. Post – Marketing Survey (PMS) Study comparison with
Phase III Clinical Data
0
20
40
60
80
100
5 10 15 20 25 30
Week (w)
Percentageofpatientscuredbyweek(w)
Cumulative percentages of curing
Control Test PMS

14. •65 year old female
•Ulcer on the dorsum of left foot – one
month duration
•Size: 1 x 2.5 cms
Visit 1

15. • Size: 0.4 x 1.5 cms
Visit 4 (Week 3)

16. • Wound has healed completely
Visit 6 (Week 5)

17. • 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

18. • Size: 2.2 x 1 cms
Visit 6 (Week 5)

19. • The ulcer completely healed in 8
weeks.

20. • 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

21. • Size: 1.3 x 1.3 cms
Visit 3 (Week 2)

22. • Wound measured about 0.4 x 0.3 cms.
• Totally healed in a weeks time.
Visit 5 (Week 4)

23. [Courtesy, Sharad Pendsey, Nagpur]

24. [Courtesy, Sharad Pendsey, Nagpur]

25. “I dressed the wound and God healed it”
Ambrose Pare