Oral Isotretinoin Versus Topical Tretinoin for Actinic Keratosis

Actinic Keratosis Clinical Trial

— ARISOAK  

Official title:

Low Dose Oral Isotretinoin Versus Topical Tretinoin for Prevention of Actinic Keratosis in Immunocompetent Patients: a Randomized, Comparative Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02278861
• Other study ID #: UFG 133/11
• Status: Completed
• Phase: Phase 2
• First received: October 28, 2014
• Last updated: October 29, 2014
• Start date: November 2011
• Est. completion date: May 2014

Study information

• Verified date: October 2014
• Source: Universidade Federal de Goias
• Contact: n/a
• Is FDA regulated: No
• Health authority: Brazil: Ethics Committee
• Study type: Interventional

Clinical Trial Summary

Actinic keratosis (AKs) are premalignant disorders that can evolve into skin cancer. To prevent their development, a study is being conducted with oral isotretinoin and topical tretinoin to verify what drug is the most effective and has the best security profile for these patients. Along with these treatments, cryotherapy with liquid nitrogen and sunscreens will be part of the treatment. The study will have the duration of 10 months. In the first four months, the AKs will be counted and treated with cryotherapy (face and arms) and sunscreens FPS 60 will be used. After it, the patients will return (the AKs will be counted), a new session of cryotherapy will be performed and they will be randomized into two groups: one group using oral isotretinoin 10mg/day ( ISO: 30 patients) and the other one using tretinoin 0,05% cream (AR: 30 patients) applied on face and arms. Skin biopsies will be done for all 60 patients at the beginning of the treatment with retinoids (isotretinoin and tretinoin). After six months of treatment with retinoids, the study will be stopped, AKs will be counted again and skin biopsies will be done. Patients in the group ISO (oral isotretinoin) also have to make blood tests at the beginning, two months and after six months of the treatment. Clinical (AK counting), histological (improvement of parts of the skin) and immunohistochemical parameters will be evaluated to see what drug is more effective for prevention of AKs.

Description:

This study is a randomized controlled trial with 60 men and women (already in menopause for at least one year), aged 50-75 years. At the beginning, the number of actinic keratosis (AKs) of face and forearms will be counted and treated with cryotherapy with liquid nitrogen (LN).The patients will be randomized in two groups: one receiving oral isotretinoin 10mg/day every day and other receiving tretinoin 0,05% cream applied in the face and arms every other night, for six months. Along with these treatments, patients will use sunscreens FPS 60 with UVA and UVB protection. The inclusion criteria will be the presence of at least 10 and maximum 40 AKs (visible or palpable). Skin biopsies will be performed twice (before and after treatment with retinoids) for all patients, in the left forearm at a standardized site. Histological and immunohistochemical with blinded- evaluator analysis will be done. The main objective of the study is to evaluate clinical, histological and immunohistochemical effects of retinoids for AK prevention on face and forearms of immunocompetent individuals. Efficacy evaluation will be measured by improving clinical (AK counting before and after treatments), histopathological (Hematoxilin-eosin and Verhoeff staining) and immunohistochemical parameters (markers for carcinogenesis - p53 protein, Bcl-2 and Bax). The secondary objective is evaluate the tolerability and safety of the drugs and their impact in quality of life. The safety analysis will be related to adverse events of the two drugs and the blood tests will be performed in the ISO group patients. Indirectly, by decreasing the number of AKs and the expression of cutaneous carcinogenesis markers, a decrease in the risk of squamous cell carcinoma could be infered . This principle is used by many drugs called chemoprophylactic drugs, and the retinoids are considered in this group.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: May 2014
• Est. primary completion date: April 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 50 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Signature of the Free and Clarified Consent Term before any procedure of the study;

2. Men and women, aged 50-75 years, in good health;

3. Women in menopause for 1 year or more;

4. Phototypes I-IV by Fitzpatrick classification;

5. Glogau photodamage classification scale from moderate to severe

6. At least 10 and maximum 60 visible and/or palpable actinic keratosis, in the face and forearms, in a standardized distribution;

7. Absence of topical treatment in the face and forearms, except sunscreens, with:

• tretinoin in the last 6 months;

• alphahydroxyacids, polyhydroxyacids, betahydroxyacids and ascorbic acid in the last 3 months;

• drugs or procedures that may change the natural evolution of actinic keratosis, such as imiquimod 5% cream, diclofenac 3% in hyauronic acid gel, photodynamic therapy, 5-FU, in the last 6 months;

8. Absence of previous treatment in the face and forearms with chemical peels and microdermabrasion, in the last 6 months;

9. Absence of previous treatment with oral retinoids in the last 6 months;

10. Absence of anti-cancer chemotherapy in the last 3 months;

11. Absence of hypersensitivity to parabens (present in the majority of drugs as a preserving agent);

12. Absence of infectious or inflammatory diseases in the face and forearms;

13. Absence of immunossupression;

14. Absence of photodermatosis;

15. Agreement in avoiding sun exposure during the research;

16. Agreement in not performing any other kind of treatment that could change the natural history of actinic keratosis; and

17. Agreement with the study conditions, ability to understand and follow strictly the given orientations, availability to attend the periodical evaluations.

For the isotretinoin group (ISO):

1. Absence of history of isotretinoin hypersensitivity;

2. Avoid alcohol intake and;

3. Absence of previous and actual history of rheumatologic diseases.

For the tretinoin group (AR):

1. Absence of history of tretinoin hypersensitivity;

Exclusion Criteria:

For all patients:

1. Men and women who dón't agree with the terms of the research or without ability to understand and/or follow strictly the conditions of the study, without availability to understand and attend the periodical evaluations or who decline to sign the Free and Clarified Consent Term;

2. Patients with less than 10 and more than 60 actinic keratosis in the face and forearms;

3. Fertile, pregnant or lactating women;

4. Fitzpatrick phototypes V e VI ;

5. Topical treatment in the face and forearms, except sunscreens, with:

• tretinoin in the last 6 months;

• alphahydroxyacids, polyhydroxyacids, betahydroxyacids and ascorbic acid in the last 3 months;

• drugs or procedures that may change the natural evolution of actinic keratosis, such as imiquimod 5% cream, diclofenac 3% in hyauronic acid gel, photodynamic therapy, 5-FU, in the last 6 months;

6. Previous treatment in the face and forearms with chemical peels and microdermabrasion, in the last 6 months;

8. Previous treatment with oral retinoids in the last 6 months

For the isotretinoin group (ISO):

1. Presence of significative hepatic laboratory alterations (elevated liver enzymes twice ashigh as the upper normal limit;

2. Diabetic patients, with fast glucose values superior to 110mg/dl;

3. Significant lipid profile alterations (triglycerides > 300 mg/dl; total cholesterol> 250 mg/dl);

4. Low count of white blood cells (leukocytes < 3000/mm3);

5. History of hypersensitivity to isotretinoin and parabens;

6. Alcohol intake;

7. Previous or actual history of rheumatologic diseases;

8. Anticancer chemotherapy in the last 3 months;

9. Previous history of hypervitaminosis A;

10. Previous history of bone or muscular diseases;

11. Patients who are in use or may use the following drugs (risk of drug interaction):

• tetracyclines and derivatives - in the last 7 days;

• vitamin A - in the last 30 days;

• carbamazepine - in the last 7 days.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Actinic Keratosis
• Keratosis
• Keratosis, Actinic

Intervention

Drug:
• Oral isotretinoin
Oral isotretinoin - 10mg/day (one pill) after lunch for six months
• Tretinoin 0,05% cream
Topical tretinoin 0,05% cream - applied every other night in the face and forearms for six months
• Sunscreen FPS 60
Sunscreen FPS 60 applied on sun exposed areas every 3 hours daily

Locations

Country	Name	City	State
Brazil	Dermatology Outpatient Clinic - Hospital das Clínicas - Federal University of Goias (UFG)	Goiânia	Goiás

Sponsors (4)

Lead Sponsor	Collaborator
Universidade Federal de Goias	Conselho Nacional de Desenvolvimento Científico e Tecnológico, Germed Pharma, Theraskin

Country where clinical trial is conducted

Brazil, 

References & Publications (2)

Ianhez M, Fleury LF Jr, Miot HA, Bagatin E. Retinoids for prevention and treatment of actinic keratosis. An Bras Dermatol. 2013 Jul-Aug;88(4):585-93. doi: 10.1590/abd1806-4841.20131803. Review. — View Citation

Weinstock MA, Bingham SF, Cole GW, Eilers D, Naylor MF, Kalivas J, Taylor JR, Gladstone HB, Piacquadio DJ, DiGiovanna JJ. Reliability of counting actinic keratoses before and after brief consensus discussion: the VA topical tretinoin chemoprevention (VATT — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Reduction in the Dermatology Life Quality Index (DLQI)	The Dermatology Life Quality Index (DLQI) questionnaire is performed for every patient at the time frames specified. With the reduction of actinic keratosis and use of retinoids it is expected for retinoids to reduce points of the questionnaire.	at the beginning, with 4 months (T120) and 10 months (T300) of the study	Yes
Other	Clinical adverse events of tretinoin	The clinical adverse events with tretinoin 0,05% cream are: erythema, burning sensation, desquamation, irritation The clinical adverse events with oral isotretinoin are: cheilitis, xerophthalmia, xerostomia, dry skin, epistaxis, and other mucocutaneous side effects	4 months (T120) and 10 months (T300) of the study	Yes
Other	Laboratory alterations in patients treated with low dose oral isotretinoin (10mg/day)	At day 120 (4 months) the patients of isotretinoin group (ISO) were submitted to laboratory tests: complete blood count, alanine and aspartate aminotransferase, fasting plasma glucose test and lipid profile tests.; At day 180 (6 months) the laboratory tests were repeated, except fasting plasma glucose test At day 300 (10 months) the laboratory tests were asked and repeated after 1 month, except fasting plasma glucose test	4 months (T120), 6 months (T180) and 10 months (T300). If there were alterations, the laboratory tests were done monthly	Yes
Primary	Reduction in the counting of actinic keratosis in the face and forearms	The actinic keratosis (AKs) will be counted by the same evaluator twice, in different moments at the same day, at the beginning of the study, after 4 months and at the end (10 months)	at the beginning (T0), 120 days (T120) and 300 days (T300)	Yes
Secondary	Reduction in the thickness of the stratum corneum	Skin biopsies will be taken from patients at the time of randomization (T120) and after the treatment with retinoids (T300) and stained with hematoxilin-eosin (HE)	4 months (T120) and 10 months (T300) of the study	Yes
Secondary	Increase in the epithelium thickness	Skin biopsies will be taken from patients at the time of randomization (T120) and after the treatment with retinoids (T300) and stained with hematoxilin-eosin (HE)	4 months (T120) and 10 months (T300) of the study	Yes
Secondary	Reduction in the expression of p53 protein	Skin biopsies will be taken from patients at the time of randomization (T120) and after the treatment with retinoids (T300). Retinoids are known to reduce the expression of this marker of carcinogenesis.	4 months (T120) and 10 months (T300) of the study	Yes
Secondary	Reduction in the expression of the Bcl-2 protein	Skin biopsies will be taken from patients at the time of randomization (T120) and after the treatment with retinoids (T300). Retinoids are known to reduce the expression of this marker of carcinogenesis.	4 months (T120) and 10 months (T300) of the study	Yes
Secondary	Increase in the expression of Bax protein	Skin biopsies will be taken from patients at the time of randomization (T120) and after the treatment with retinoids (T300). Retinoids are known to increase the expression of this marker of carcinogenesis.	4 months (T120) and 10 months (T300) of the study	Yes