RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / NAME OF THE CANDIDATE AND ADDRESS. / Dr. LEELA HUGAR
P.G. IN M.D. (PHARMACOLOGY)
KARNATAKA INSTITUTE OF MEDICAL SCIENCES (K.I.M.S.)
HUBLI-580021
2. / NAME OF THE INSTITUTION. / KARNATAKA INSTITUTE OF MEDICAL SCIENCES (K.I.M.S.) HUBLI-580021
3. / COURSE OF STUDY AND SUBJECT / M.D. - PHARMACOLOGY
4. / DATE OF ADMISSION / 01- JUNE-2012
5. / TITLE OF THE TOPIC / “A COMPARATIVE STUDY OF EFFICACY AND SAFETY OF TOPICAL CALCITRIOL AND TOPICAL CALCIPOTRIOL IN STABLE CHRONIC PLAQUE TYPE PSORIASIS”
6. / BRIEF RESUME OF INTENDED WORK:
6.1 NEED FOR THE STUDY:
Psoriasis is a chronic skin disorder characterized by epidermal hyperproliferation and dermal inflammation1.Although no cure is available, the disease can be effectively controlled by various therapeutic options. The wide number of non-steroidal preparations satisfied the needs of many psoriatic patients and reduced the common use of topical corticosteroids which, after a long term application, may give rise to various side effects. The various non steroidal topical treatments available are: Dithranol, topical retinoids, salicylic acid, tar and more recently vitamin D3 derivatives2.
The vitamin D3 derivatives topically administered for the treatment of psoriasis are: Calcipotriol, Tacalcitol, Maxacalcitol and more recently Calcitriol3,4. Topical formulations of Calcipotriol and other vitamin D3 analogues are probably the most widely prescribed active topical therapy for plaque psoriasis. The mechanism of action of these agents is via vitamin D receptor-mediated effects on the proliferation and differentiation of epidermal keratinocytes and on the immunological features of psoriasis4. Topical Calcipotriol although considered efficient, its superiority over topical Calcitriol is not well established. Therefore this study is undertaken to compare the efficacy and safety of topical Calcitriol with that of Calcipotriol in stable chronic plaque type psoriasis.

6.2. REVIEW OF LITERATURE:

  • Psoriasis is a common, chronic, disfiguring, inflammatory and proliferative condition of the skin, in which both genetic and environmental influences have a critical role4. Worldwideprevalence ranges from 0.1% to 3%. Psoriasis may begin at any age, but it is uncommon under the age of 10 years. Males and females are equally affected5.
  • Chronic stable plaque psoriasis (Psoriasis vulgaris) is the most common form of psoriasis, seen in approximately 90% of patients. Red, scaly, symmetrically distributed plaques are characteristic5.
  • Vitamin D3 analogues bind to the vitamin D receptor, which acts as a heterodimer with the retinoid receptor RXR. Keratinocytes and lymphocytes have vitamin D receptors6.
  • The therapeutic actions of vitamin D3 analogues in psoriasis6,7:
1. Potent antiproliferative effect on keratinocytes.
2.Ability to promote differentiation of keratinocytes.
3.Immunosuppressive activity.
4. Inhibition of IL-2 release, lymphocyte activation, release of IL-8.
5. Antiangiogenic effect.
  • Calcipotriol is a synthetic analogue of vitamin D34. Calcipotriol 50µg/g ointment has been investigated intensively over the past decade8. Systemic reviews of calcipotriol therapy for psoriasis attest to its equivalence or superiority to other available topical therapies apart from potent topical corticosteroids9,10. Side effects of calcipotriol include local irritation, which may affect up to 20% of patients11,12. Calcipotriol (50µg/g) ointment was found to cause no significant changes in serum calcium when used in amounts up to 100g/week13,14.
  • Calcitriol ointment 3µg/g has been made available for the topical treatment of psoriasis vulgaris in recent years8. Long term treatment of chronic plaque psoriasis with calcitriol (3µg/g) ointment confirmed previous shorter term studies indicating the efficacy of this natural vitamin D3 metabolite15. The relative efficacy of this agent compared with topical calcipotriol is currently unclear4. Transient local skin irritation, occasionally necessitates withdrawal of treatment4. No significant changes in serum calcium levels were found, even in patients using large quantities of the ointment to treat upto 35% of the body surface area for 3 months16.
6.3.OBJECTIVES OF THE STUDY:
  • To evaluate the efficacy and safety of topical calcitriol and topical calcipotriol in subjects with stable chronic plaque psoriasis.
  • To compare the efficacy and safety of topical calcitriol with that of topical calcipotriol in subjects with stable chronic plaque psoriasis.

7. / MATERIALS & METHODS:
7.1 SOURCE OF DATA:
Drugs:
  • Calcipotriol 50μg/g ointment3,4,6,8.(Biocon biopharmaceuticals,Bangalore)
  • Calcitriol 3μg/g ointment8,16,17.(Alkem laboratories Ltd,Mumbai)
Patients:
Considering inclusion and exclusion criteria the patients attending dermatology OPD KIMS Hubli are selected for the study.
Inclusion Criteria:
1. Both male and female subjects of age group 18 to 70 years.
2. Subjects with stable chronic plaque psoriasis.
3. Body surface area involvement less than 35%.
Exclusion Criteria:
  1. Patients with unstable, acute guttate, pustular, erythrodermic or orthropathic psoriasis.
  2. Patients with history of hypercalcaemia, renal dysfunction, calcium based calculi, underlying conditions that require the use of systemic supplements of calcium or vitamin D.
  3. Body surface area involvement >35%.
  4. Subjects who had applied topical antipsoriatic medication within past 2 weeks or had used systemic antipsoriatic medication within the past 8 weeks.
  5. Patients who have other extensive skin disease and who have severe systemic illness.
  6. Pregnant women.
7.2 Methods of collection of data
A total of 50 subjects with stable chronic plaque psoriasis (both male and female) will be recruited. These 50 subjects will be divided into two groups (Calcitriol group and Calcipotriol group) with 25 subjects in each group. Alternative subject will be assigned to each group.
Assessment of efficacy and safety:
  • Calcitriol group: Subjects in this group will be treated with Calcitriol 3µg/g ointment twice daily for 12 weeks.
  • Calcipotriol group: Subjects in this group will be treated with Calcipotriol 50µg/g ointment twice daily for 12 weeks.
Subjects will be evaluated at baseline (week 0), week 2, week 4, week 8 and week 12.
Assessment of efficacy8:
It is done by
1. Global assessment of improvement
2. Dermatological sum score.
1.Global assessment of improvement:
a) Primary efficacy criteria- It is the global assessment of improvement done clinically at the end of the study (week 12).
b) Secondary efficacy criteria: It is the global assessment of improvement as assessed by the subject at the end of study (week 12).
Global assessment of improvement will be rated on a 4-point scale.
0 – No change
1 – Some improvement
2 – Marked improvement
3 – Clear or almost clear
Total score will be recorded at baseline (week 0) and at the end of study (week 12).
2.Dermatological sum score(DSS):
It is the sum of erythema, plaque elevation and scaling of target lesion. Each sign will be evaluated on a 5-point scale at each visit.
0-None
1-Mild
2-Moderate
3-Severe
4-Very severe.
The total score will be calculated at baseline (week 0) and at the end of study(week 12).
Assessment of safety8:
It includes
1. Clinical assessment of cutaneous safety.
2. Assessment of cutaneous discomfort by the subject.
1.Clinical assessment of cutaneous safety: It is done on a 5-point scale.
0-None
1-Mild
2-Moderate
3-Severe
4-Very severe
Total score will be recorded on baseline (week 0) and at the end of study (week 12).
2.Assessment of cutaneous discomfort by the subject: It is done on a 5-point scale.
0-No discomfort
1-Mild discomfort
2-Moderate discomfort
3-Severe discomfort
4-Very severe discomfort.
Total score will be recorded on baseline (week 0) and at the end of study (week 12).
  • At each visit blood sample is collected from the subject to estimate serum calcium.
7.3. Does the study require any investigations or interventions to be conducted on patients or other animals? Specify.
Yes, the above study requires investigations on the subjects. Serum calcium to be estimated on each follow up.
7.4 Has ethical clearance been obtained from ethical committee of your institution?
Yes, ethical clearance has been obtained from ethical committee KIMS,Hubli.
7.5. Statistical analysis: Mean±SEM is calculated at baseline and at the end of studyfor each parameter and statistical analysis is done using student-t-test (paired and unpaired).
8. / LIST OF REFERENCES
  1. Ortonne JP. Recent developments in the understanding of the pathogenesis of psoriasis. Br J Dermatol 1999; 140(suppl.54): 1-7.
  2. Ashoff R, Wozel G, Meurer M. Topical treatment of psoriasis: a systemic update. Hautarzt 2003; 54(3): 237-241.
  3. Sweetman SC, editor. Martindale: The complete drug reference. London: Pharmaceutical press; 2009.
  4. Griffiths CEM, Barker JNWN. Psoriasis. In: Burns T, Breathnach S, Cox N, Griffiths C, editors. Rook’s textbook of Dermatology vol 1. 8th ed. UK: Wiley-Blackwell; 2010. p. 20.1-20.60.
  5. Gudjonsson JE, Elder JT. Psoriasis. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, editors. Fitzpatrick’s Dermatology in General Medicine vol 1. 8th ed. USA: McGraw Hill; 2012. p. 197-231.
  6. Guenther L, Campazard F, van de Kerkhof PCM et al. Efficacy and safety of a new combination of calcipotriol and betamethasone dipropionate (once or twice daily ) compared to calcipotriol (twice daily) in the treatment of psoriasis vulgaris: a randomized, double-blind, vehicle controlled clinical trial. Br J Dermatol 2002; 147: 316-323.
  7. Berth-Jones J. Topical therapy. In: Burn T, Breathnach S, Cox N, Griffiths C, editors. Rook’s textbook of Dermatology vol 4. 8th ed. UK: Wiley-Blackwell; 2010. P. 73.1-73.52.
  8. Zhu X, Wang B, Zhao G, et al. An investigator masked comparison on the efficacy and safety of twice daily applications of calcitriol 3µg/g ointment vs calcipotriol 50µg/g ointment in subjects with mild or moderate chronic plaque-type psoriasis. Eur Acad Dermatol Venereol. 2007; 21: 466-472.
  1. Ashcroft DM, Li Wan Po A, Williams HC, Griffiths CEM. Systematic review of comparative efficacy and tolerability of calcipotriol in treating chronic plaque psoriasis. BMJ 2000; 320: 963-967.
  2. Mason J, Mason AR, Cork MJ. Topical preparations for the treatment of psoriasis: a systematic review. Br J Dermatol 2002; 146: 351-364.
  3. Cunliffe WJ, Berth-Jones J, Claudy A et al. Comparative study of calcipotriol (MC903) ointment and betamethasone-17-valerate ointment in patients with psoriasis vulgaris. J Am Acad Dermatol 1992; 26: 736-743.
  4. Berth-Jones J, Chu AC, Dodd WAH et al. A multicentre, parallel group comparison of calcipotriol ointment and short-contact dithranol therapy in chronic plaque psoriasis. Br J Dermatol 1992; 127: 266-271.
  5. Mortensen L, Kragballe K, Wegmann E et al. Treatment of psoriasis vulgaris with topical calcipotriol has no short-term effects on calcium or bone metabolism. Acta Derm Venereol (Stockh) 1993; 73: 300-304.
  6. Berth-Jones J, Bourke JF, Hutchinson PE. Urine calcium excretion during treatment of psoriasis with topical calcipotriol. Br J Dermatol 1993; 129: 411-414.
  7. Langer A, Ashton P, van de Kerkhof PCM et al. A long-term multicentre assessment of the safety and tolerability of calcitriol ointment in the treatment of chronic plaque psoriasis. Br J Dermatol 1996; 135: 385-389.
  8. Barker JNWN, Berth-Jones J, Groves R et al. Calcium homeostasis remains unaffected after 12 weeks therapy with calcitriol 3μg/gm ointment; no correlation with extent of psoriasis. J Derm Treat 2003; 14: 14-21.
  9. Langner A, Stapor W, Ambroziak M. Efficacy and tolerance of topical calcitriol 3μg/g in psoriasis treatment: a review of our experience in Poland. Br J Dermatol 2001; 144(suppl.58): 11-16.

9. / Signature of candidate
10. / Remarks of guide / The data generated by this study will help in the treatment of stable chronic plaque psoriasis.
11. / Name and designation
11.1 Guide / DR. RAMESH. H
ASSOCIATE PROFESSOR
DEPARTMENT OF PHARMACOLOGY
KIMS
HUBLI
11.2 Signature
11.3 Co-Guide / DR. RAVI. M. RATHOD
PROFESSOR
DEPARTMENT OF DERMATOLOGY
KIMS
HUBLI
11.4 Signature
11.5 Head of the department / DR. A. N. DATTATRI
PROFESSOR
DEPARTMENT OF PHARMACOLOGY
KIMS
HUBLI
11.6 Signature
12 / 12.1 Remarks of the Chairman and principal
12.2 Signature