Phase IV Head-to-head Randomized Controlled Trial Comparing Ingenol Mebutate 0·015% Gel With Diclofenac Sodium 3% Gel for the Treatment of Actinic Keratosis on the Face or Scalp

E. Stockfleth; C.A. Harwood; C. Serra-Guillén; T. Larsson; M.L. Østerdal; T. Skov


The British Journal of Dermatology. 2018;178(2):433-442. 

In This Article

Abstract and Introduction


Background Ingenol mebutate (IngMeb) and diclofenac sodium (DS) are approved treatments for actinic keratosis (AK).

Objectives To compare the efficacy and safety of IngMeb 0·015% gel with DS 3% gel (NCT02406014).

Methods Patients with 4–8 visible, discrete AK lesions on the face/scalp in a 25 cm2 contiguous area of skin were randomized 1:1 to IngMeb once-daily for three consecutive days or DS twice-daily for 90 days. Patients with AK lesions at Week 8 following IngMeb were offered a second IngMeb course. Primary end point was complete clearance of AK lesions (AKCLEAR 100) at end of first treatment course (Week 8, IngMeb; Week 17, DS). Secondary end points included AKCLEAR 100 at end of last treatment course and Week 17; adverse events (AEs) were assessed at these time points. Patients completed treatment satisfaction questionnaires for medication (TSQM; Week 17).

Results AKCLEAR 100 at end of first treatment course was higher with IngMeb (34%) vs. DS (23%; P = 0·006). AKCLEAR 100 at end of last IngMeb course (53%) and Week 17 (45%) was higher than DS (both P < 0·001). The most frequent AE was application-site erythema (IngMeb 19%; DS 12%). Treatment-related AE (TRAE) duration was shorter with IngMeb. TRAE withdrawals were lower for IngMeb (2%) vs. DS (6%). TSQM scores for global satisfaction (P < 0·001) and effectiveness (P = 0·002) were higher with IngMeb, as was dosing instruction adherence (≥ 90% vs. 70%)

Conclusions AKCLEAR 100, patient treatment satisfaction and effectiveness were significantly higher with IngMeb compared with DS, demonstrating superiority of IngMeb for AK treatment on face/scalp.


Actinic keratosis (AK) is a common, chronic skin condition primarily caused by exposure to ultraviolet (UV) radiation.[1] AK is characterized by atypical epithelial differentiation, appearing as red, scaly papules or plaques known as actinic keratoses or AK lesions.[1,2] AK lesions coexist with, and can progress to, squamous cell carcinoma (SCC) through dysregulation of pathways that regulate cell growth and differentiation, including the p53 pathway; areas of sun-exposed skin may harbour fields with preneoplastic and neoplastic changes, leading to clinically visible and subclinical invisible AK lesions.[1,3–5] Individual AK lesions can resolve spontaneously; however, the area of skin will remain damaged and new lesions can emerge over time in the cancerized field.[3,5–8] Trials have shown that irrespective of grading or thickness, an increasing number of AK lesions is an indicator of higher risk of developing SCC, which can emerge from type 1, as well as more severe, AK lesions.[9,10] The chronic nature of AK coupled with potential lesion recurrence, emergence of new lesions in the cancerized field and potential progression to malignancy may warrant follow-up and repeated intervention to reduce clinically visible and emerging AK lesions.[6,7,11,12]

Lesion-directed therapies, such as cryotherapy, target visible AK lesions but leave subclinical lesions in the cancerized field untreated, from which new lesions may emerge.[13] Effective field treatments may have a therapeutic advantage over lesion-directed therapies in that they can also address subclinical and emerging AK lesions.[12–16] Furthermore, timely intervention with follow-up field treatment has been shown to provide sustained clearance of AK lesions.[12]

Diclofenac sodium (DS) in a 3% topical gel formulation with 2·5% hyaluronic acid is used to treat AK.[17] DS is a nonsteroidal anti-inflammatory drug; however, its mechanism of action in AK has not been fully elucidated. It may involve the inhibition of cyclooxygenase 2, reducing angiogenesis and cellular proliferation, as well as inducing apoptosis.[18,19] The regimen for treating AK is twice daily for 90 days, which may reduce patients' ability to tolerate local skin reactions (LSRs) and contribute to poor adherence.[14,17,20,21]

Ingenol mebutate (IngMeb) gel is a field therapy indicated for the treatment of AK on the face or scalp in an area up to 25 cm2.[22] In vitro data suggest multiple mechanisms of action for IngMeb, including induction of rapid cell death and stimulation of a proinflammatory response via activation of the protein kinase C (PKC) pathway.[23] This has been corroborated in the clinical setting through both pharmacodynamic and histopathological evaluations of patients treated with IngMeb 0·05% gel. IngMeb has been shown to target clinical and subclinical AK lesions, inducing infiltration of neutrophils, macrophages, CD4+ and CD8+ T cells and activation of endothelial intercellular adhesion molecule 1.[15,24] In phase III trials, IngMeb was an effective and well-tolerated treatment for AK when applied once daily for two or three consecutive days depending on body location.[25]

The potential mechanism of action of IngMeb may result in superior clinical outcomes and favourable tolerability, which, along with the short treatment duration, may lead to higher treatment adherence and patient satisfaction than with DS treatment. In this phase IV multicentre, open-label trial (NCT02406014), we tested this hypothesis by comparing the efficacy, safety and patient satisfaction of IngMeb gel with a standard DS gel treatment course in patients with AK on the face or scalp.