title: Histological examination confirms clinical clearance of actinic keratoses following treatment with ingenol mebutate 0·05% gel.
abstract: BACKGROUND
  To date, studies with ingenol mebutate gel have used clinical clearance, not histological clearance, as a primary efficacy endpoint.
  
  
  OBJECTIVE
  This phase I, multicentre, single-arm, open-label study sought to confirm histologically the clinical clearance of actinic keratoses (AKs) to support a treatment effect deep in the epidermis.
  
  
  METHODS
  Patients (n = 108) aged ≥ 18 years with histologically confirmed AK within a 25-cm2contiguous treatment area on the trunk and extremities received ingenol mebutate 0·05% gel for two consecutive days and were followed up on day 3 and week 8. One AK was randomly preselected at day 1 for clinical and histological evaluation at week 8 and for reflectance confocal microscopy (RCM) in a subset of patients. The primary endpoint was clinical and histological clearance of AKs at week 8.
  
  
  RESULTS
  The observed agreement rate between clinical and histological assessments of clearance of a single AK was 81·9% and the positive predictive value of a clinical assessment of clearance was 87%. Agreement between the two pathologists was 88%. The common composite 8-week complete clearance rate was 41% (95% confidence interval 32-50). Observed agreement rates between RCM and pathologist I and II assessments of clearance were 72·9% and 81·4%, respectively. Overall, 30 patients (27·8%) experienced 38 adverse events (AEs). Application-site pain (four patients, 3·7%) was the most common treatment-related AE inside the treatment area.
  
  
  CONCLUSIONS
  Ingenol mebutate achieves histopathological clearance of AKs that correlates with observed clinical clearance. Clinical clearance is a good predictor for histological clearance.
authors: Charité Universitätsmedizin Berlin, Department of Dermatology, Charitéplatz 1, Berlin, Germany.|Dermatologie am Regierungsviertel/Collegium Medicum, Berlin, Germany.
authors: M
authors: M
authors: Ulrich
authors: Department of Dermatology, Dermatological Center Bonn Friedensplatz, Friedensplatz, Bonn, Germany.
authors: U
authors: U
authors: Reinhold
authors: LEO Pharma A/S, Ballerup, Denmark.
authors: T
authors: T
authors: Skov
authors: LEO Pharma A/S, Ballerup, Denmark.
authors: R
authors: R
authors: Elvang Søndergaard
authors: Sydney Melanoma Diagnostic Centre and Melanoma Institute Australia, Discipline of Dermatology, The University of Sydney, Sydney, NSW, Australia.
authors: P
authors: P
authors: Guitera
mesh_terms: D000279:Administration, Cutaneous; D000368:Aged; D003879:Dermatologic Agents / Q000008:administration & dosage*; D004224:Diterpenes / Q000008:administration & dosage*; D005260:Female; D005782:Gels; D006801:Humans; D055623:Keratosis, Actinic / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D018613:Microscopy, Confocal; D015588:Observer Variation; D016896:Treatment Outcome
chemical_list: C486592:3-ingenyl angelate; D003879:Dermatologic Agents; D004224:Diterpenes; D005782:Gels