Mobile health technologies in an interventional hybrid study on actinic keratosis: Results from an early phase randomized controlled trial investigating the safety and efficacy of a cytosolic phospholipase A2 inhibitor gel in photodamaged skin.

Hybrid trials are a new trend in dermatological research that leverage mobile health technologies to decentralize a subset of clinical trial elements and thereby reduce the number of in-clinic visits. In a Phase I/IIa randomized controlled hybrid trial, the safety and efficacy of an anti-proliferative and anti-inflammatory drug inhibiting cytosolic phospholipase A2 (AVX001) was tested using 1%, 3% or vehicle gel in 60 patients with actinic keratosis (AK) and assessed in-clinic as well as remotely. Over the course of 12 weeks, patients were assessed in-clinic at baseline, end of treatment (EOT) and end of study (EOS), as well as 9 times remotely on a weekly to biweekly basis. Safety outcomes comprising local skin reactions (LSR; 0-5), adverse events (AE) and cosmesis, were graded in-clinic and remotely using patient-obtained smartphone photographs (PSPs) and questionnaires; efficacy was assessed in-clinic based on clinically visible clearance of AK target area of >50%. A total of 55 participants (91.7%) completed the treatment course. The average submission rate of PSPs was high (≥85%), of which 93% were of sufficient quality. No serious AE were reported and only two experienced temporary LSR >2 (scale 0-4) and cosmesis remained stable throughout the study. Based on the mild AE and LSR profile, daily application of AVX001 gel for 1 month appears safe, tolerable, and cosmetically acceptable for use in patients with AK. At EOT, AVX001 achieved a subtle treatment response with clearance of AK target area of >50% in 18% of patients. Remote and in-clinic assessments of LSRs were in high agreement, suggesting that the use of mobile health technologies in early-phase hybrid studies of AK does not compromise patient safety.

The Copenhagen Actinic Keratosis Study (COAKS). A decentralised clinical trial to evaluate tolerability, safety and efficacy of daily field-directed topical treatment with cytosolic phospholipase A2 inhibitor, AVX001, in participants with actinic keratosis: protocol for a randomised controlled phase I/IIa trial.

INTRODUCTION: Actinic keratosis (AK) is the most common precancerous skin condition caused by long-term UV exposure. Given the high recurrence rate of 15%-53%, identifying safe and effective treatment options is warranted. AVX001, a cytosolic phospholipase A2α (cPLA2α) enzyme inhibitor, is a novel anti-inflammatory drug for field-directed, self-administered, topical therapy of AK. METHODS AND ANALYSIS: This study is a single-centre, randomised, vehicle-controlled, double-blind, parallel-group hybrid clinical trial in adults with multiple AK lesions Olsen grade 1 or 2. The hybrid design combines decentralised participant tasks and assessments with conventional in-clinic visits. Recruitment using targeted advertising on social media and eligibility prescreening are conducted via the Studies&Me online recruitment platform. Participants (n=60) are randomly assigned to 1 of 3 treatment arms: AVX001 gel 1%, AVX001 gel 3% or vehicle gel. The trial consists of a 4-week treatment period with daily field-directed topical application of the gel and an 8-week follow-up period. Participants attend in-clinic visits at baseline, week 4 and week 12. The remote participant trial tasks include questionnaires and upload of smartphone-obtained photos of the treated skin area using a study-specific web-based app. Both remote and in-clinic assessments of safety and efficacy will be performed. The primary objective is to evaluate the local tolerability of daily application of AVX001 gel (1% or 3%) compared with vehicle gel. Secondary objectives include safety, efficacy, dose-response efficacy relationship, treatment satisfaction and cosmetic outcome. Exploratory objectives include evaluations of tolerability and efficacy assessed by dermatologists using smartphone photos uploaded by participants, comparisons of in-clinic and remote assessments and assessment of AK-related skin changes by non-invasive optical imaging. ETHICS AND DISSEMINATION: Approved by the Ethics Committee of the Capital Region of Denmark (H-21018064) and the Danish Medicines Agency (2021032485). Results will be submitted for publication in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBERS: 2021-000934-32; NCT05164393.

Integrated Management of Childhood Illnesses (IMCI): a mixed-methods study on implementation, knowledge and resource availability in Malawi.

Background: The introduction of the WHO's Integrated Management of Childhood Illnesses (IMCI) guidelines in the mid-1990s contributed to global reductions in under-five mortality. However, issues in quality of care have been reported. We aimed to determine resource availability and healthcare worker knowledge of IMCI guidelines in two districts in Malawi. Methods: We conducted a mixed-methods study, including health facility audits to record availability and functionality of essential IMCI equipment and availability of IMCI drugs, healthcare provider survey and focus group discussions (FGDs) with facility staff. The study was conducted between January and April 2019 in Mchinji (central region) and Zomba (southern region) districts. Quantitative data were described using proportions and χ2 tests; linear regression was conducted to explore factors associated with IMCI knowledge. Qualitative data were analysed using a pragmatic framework approach. Qualitative and quantitative data were analysed and presented separately. Results: Forty-seven health facilities and 531 healthcare workers were included. Lumefantrine-Artemether and cotrimoxazole were the most available drugs (98% and 96%); while amoxicillin tablets and salbutamol nebuliser solution were the least available (28% and 36%). Respiratory rate timers were the least available piece of equipment, with only 8 (17%) facilities having a functional device. The mean IMCI knowledge score was 3.96 out of 10, and there was a statistically significant association between knowledge and having received refresher training (coeff: 0.42; 95% CI 0.01 to 0.82). Four themes were identified in the FGDs: IMCI implementation and practice, barriers to IMCI, benefits of IMCI and sustainability. Conclusion: We found key gaps in IMCI implementation; however, these were not homogenous across facilities, suggesting opportunities to learn from locally adapted IMCI best practices. Improving on-going mentorship, training and supervision should be explored to improve quality of care, and programming which moves away from vertical financing with short-term support, to a more holistic approach with embedded sustainability may address the balance of resources for different conditions.