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Oral Isotretinoin Versus Topical Tretinoin for Actinic Keratosis (ARISOAK)

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ClinicalTrials.gov Identifier: NCT02278861
Recruitment Status : Completed
First Posted : October 30, 2014
Last Update Posted : October 30, 2014
Sponsor:
Collaborators:
Conselho Nacional de Desenvolvimento Científico e Tecnológico
Theraskin
Germed Pharma
Information provided by (Responsible Party):
Mayra Ianhez, Universidade Federal de Goias

Tracking Information
First Submitted Date  ICMJE October 28, 2014
First Posted Date  ICMJE October 30, 2014
Last Update Posted Date October 30, 2014
Study Start Date  ICMJE November 2011
Actual Primary Completion Date April 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 29, 2014)
Reduction in the counting of actinic keratosis in the face and forearms [ Time Frame: at the beginning (T0), 120 days (T120) and 300 days (T300) ]
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)
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: October 29, 2014)
  • Reduction in the thickness of the stratum corneum [ Time Frame: 4 months (T120) and 10 months (T300) of the study ]
    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)
  • Increase in the epithelium thickness [ Time Frame: 4 months (T120) and 10 months (T300) of the study ]
    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)
  • Reduction in the expression of p53 protein [ Time Frame: 4 months (T120) and 10 months (T300) of the study ]
    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.
  • Reduction in the expression of the Bcl-2 protein [ Time Frame: 4 months (T120) and 10 months (T300) of the study ]
    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.
  • Increase in the expression of Bax protein [ Time Frame: 4 months (T120) and 10 months (T300) of the study ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: October 29, 2014)
  • Reduction in the Dermatology Life Quality Index (DLQI) [ Time Frame: at the beginning, with 4 months (T120) and 10 months (T300) of the study ]
    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.
  • Clinical adverse events of tretinoin [ Time Frame: 4 months (T120) and 10 months (T300) of the study ]
    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
  • Laboratory alterations in patients treated with low dose oral isotretinoin (10mg/day) [ Time Frame: 4 months (T120), 6 months (T180) and 10 months (T300). If there were alterations, the laboratory tests were done monthly ]
    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
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Oral Isotretinoin Versus Topical Tretinoin for Actinic Keratosis
Official Title  ICMJE Low Dose Oral Isotretinoin Versus Topical Tretinoin for Prevention of Actinic Keratosis in Immunocompetent Patients: a Randomized, Comparative Trial
Brief 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.
Detailed 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE Actinic Keratosis
Intervention  ICMJE
  • Drug: Oral isotretinoin
    Oral isotretinoin - 10mg/day (one pill) after lunch for six months
    Other Name: Acnova
  • Drug: Tretinoin 0,05% cream
    Topical tretinoin 0,05% cream - applied every other night in the face and forearms for six months
    Other Name: Vitacid 0,05% cream
  • Drug: Sunscreen FPS 60
    Sunscreen FPS 60 applied on sun exposed areas every 3 hours daily
    Other Name: Skin Block 60 Fluide Extreme
Study Arms  ICMJE
  • Active Comparator: Oral isotretinoin 10mg/day
    Oral isotretinoin 10mg/day for 6 months The dose could be reduced if there were any significant laboratory alterations or clinical adverse events, along with sunscreen FPS 60 every 3 hours during the day.
    Interventions:
    • Drug: Oral isotretinoin
    • Drug: Sunscreen FPS 60
  • Active Comparator: Tretinoin 0,05% cream

    An every other night application of tretinoin 0,05% cream in the face and forearms for 6 months, along with sunscreen FPS 60 every 3 hours during the day.

    If there were any clinical adverse events the drug could be reduced to twice a week.

    Interventions:
    • Drug: Tretinoin 0,05% cream
    • Drug: Sunscreen FPS 60
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 29, 2014)
60
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE May 2014
Actual Primary Completion Date April 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 50 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Brazil
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02278861
Other Study ID Numbers  ICMJE UFG 133/11
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Mayra Ianhez, Universidade Federal de Goias
Study Sponsor  ICMJE Universidade Federal de Goias
Collaborators  ICMJE
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico
  • Theraskin
  • Germed Pharma
Investigators  ICMJE
Study Chair: Edileia Bagatin, MD, PhD Federal University of São Paulo (UNIFESP)
Study Chair: Hélio A Miot, MD, PhD University of Paulista State - Julio de Mesquita Filho, UNESP
PRS Account Universidade Federal de Goias
Verification Date October 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP