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Integrated Safety Analysis of Abrocitinib for the Treatment of Moderate-to-Severe Atopic Dermatitis From the Phase II and Phase III Clinical Trial Program.
Simpson, EL, Silverberg, JI, Nosbaum, A, Winthrop, KL, Guttman-Yassky, E, Hoffmeister, KM, Egeberg, A, Valdez, H, Zhang, M, Farooqui, SA, et al
American journal of clinical dermatology. 2021;(5):693-707
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Abstract
BACKGROUND Pivotal phase III studies demonstrated that abrocitinib, an oral, once-daily, JAK1-selective inhibitor, is effective treatment for moderate-to-severe atopic dermatitis (AD) as monotherapy and in combination with topical therapy. OBJECTIVE The aim of this study was to evaluate the long-term safety of abrocitinib 200 mg and 100 mg in an integrated analysis of a phase IIb study, four phase III studies, and one long-term extension study. METHODS Two cohorts were analyzed: a placebo-controlled cohort from 12- to 16-week studies and an all-abrocitinib cohort including patients who received one or more abrocitinib doses. Adverse events (AEs) of interest and laboratory data are reported. RESULTS Total exposure in the all-abrocitinib cohort (n = 2856) was 1614 patient-years (PY); exposure was ≥ 24 weeks in 1248 patients and ≥ 48 weeks in 606 (maximum 108 weeks). In the placebo-controlled cohort (n = 1540), dose-related AEs (200 mg, 100 mg, placebo) were nausea (14.6%, 6.1%, 2.0%), headache (7.8%, 5.9%, 3.5%), and acne (4.7%, 1.6%, 0%). Platelet count was reduced transiently in a dose-dependent manner; 2/2718 patients (200-mg group) had confirmed platelet counts of < 50 × 103/mm3 at week 4. Incidence rates (IRs) were 2.33/100PY and 2.65/100 PY for serious infection, 4.34/100PY and 2.04/100PY for herpes zoster, and 11.83/100PY and 8.73/100PY for herpes simplex in the 200-mg and 100-mg groups, respectively. IRs for nonmelanoma skin cancer, other malignancies, and major adverse cardiovascular events were < 0.5/100PY for both doses. Five venous thromboembolism events occurred (IR 0.30/100PY), all in the 200-mg group. There were three deaths due to gastric carcinoma (diagnosed at day 43), sudden death, and COVID-19. CONCLUSION Abrocitinib, with proper patient and dose selection, has a manageable tolerability and longer-term safety profile appropriate for long-term use in patients with moderate-to-severe AD. TRIAL REGISTRIES ClinicalTrials.gov: NCT02780167, NCT03349060, NCT03575871, NCT03720470, NCT03627767, NCT03422822.
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Impact of Preoperative Acetaminophen and Carbohydrate Loading on Pain and Functional Status in Patients Undergoing Mohs Micrographic Surgery for Nonmelanoma Skin Cancers.
Aleisa, A, Naccarato, L, Gramz, M, Patel, J, Nguyen, B
Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]. 2020;(7):863-867
Abstract
BACKGROUND Preoperative acetaminophen and carbohydrate loading has been shown to improve the functional recovery of surgical patients. OBJECTIVE To determine the effects of preoperative acetaminophen and carbohydrates on functional outcomes and the use of pain medications after surgery in patients undergoing Mohs Micrographic Surgery (MMS) for nonmelanoma skin cancer (NMSC). MATERIALS AND METHODS One hundred patients treated with MMS for NMSC at an academic center were randomized into a control group receiving standard preoperative care or an intervention group receiving acetaminophen and carbohydrate drinks immediately before surgery. Patients rated levels of pain, thirst, hunger, anxiety, and fatigue on the day of surgery on a scale of 0 to 100, and reported through a phone interview the use of pain medications within 48 hours of surgery. RESULTS There was no significant difference between intervention and control groups in maximum pain score on the day of surgery; maximum pain score 48 hours after surgery; use of nonopioid pain medications; and use of opioids. However, the intervention group had lower anxiety levels during and at the end of surgery. CONCLUSION Patients undergoing MMS for NMSC reported very low levels of pain during and after surgery. Preoperative acetaminophen and carbohydrate loading had no impact on pain levels or the use of pain medications but did reduce levels of anxiety.
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i-Move, a personalised exercise intervention for patients with advanced melanoma receiving immunotherapy: a randomised feasibility trial protocol.
Hyatt, A, Gough, K, Murnane, A, Au-Yeung, G, Dawson, T, Pearson, E, Dhillon, H, Sandhu, S, Williams, N, Paton, E, et al
BMJ open. 2020;(2):e036059
Abstract
INTRODUCTION There is increasing evidence demonstrating the benefits of exercise in counteracting cancer treatment-related fatigue. Immunotherapy is an established treatment for advanced melanoma, and is associated with fatigue in a third of patients. The safety and efficacy of exercise in counteracting treatment-related fatigue in patients with advanced melanoma receiving immunotherapy are yet to be determined. This study aims to assess the safety, adherence to and acceptability of a mixed-methods parallel-group, pilot randomised controlled trial of a personalised, 12-week semi-supervised exercise programme prescribed by an exercise physiologist (iMove) in 30 patients with stage IV melanoma scheduled to commence immunotherapy: single agent ipilimumab, nivolumab or pembrolizumab, or combination ipilimumab and nivolumab. The trial will be used to provide preliminary evidence of the potential efficacy of exercise for managing fatigue. METHODS AND ANALYSIS Thirty participants will be recruited from a specialist cancer centre between May and September, 2019. Participants will be randomised 1:1 to receive iMove, or usual care (an information booklet about exercise for people with cancer). Feasibility data comprise: eligibility; recruitment and retention rates; adherence to and acceptability of exercise consultations, personalised exercise programme and study measures; and exercise-related adverse events. Patient-reported outcome measures assess potential impact of the exercise intervention on: fatigue, role functioning, symptoms and quality of life. Follow-up will comprise five time points over 24 weeks. Physical assessments measure physical fitness and functioning. ETHICS AND DISSEMINATION This study was reviewed and approved by the Peter MacCallum Cancer Centre Human Research Ethics Committee (HREC/48927/PMCC-2019). The findings from this trial will be disseminated via conference presentations and publications in peer-reviewed journals, and by engagement with clinicians, media, government and consumers. In particular, we will promote the outcomes of this work among the oncology community should this pilot indicate benefit for patients. TRIAL REGISTRATION NUMBER ACTRN12619000952145; Pre-results.
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A phase II randomized controlled trial of nicotinamide for skin cancer chemoprevention in renal transplant recipients.
Chen, AC, Martin, AJ, Dalziell, RA, McKenzie, CA, Lowe, PM, Eris, JM, Scolyer, RA, Dhillon, HM, Vardy, JL, Bielski, VA, et al
The British journal of dermatology. 2016;(5):1073-1075
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Smartphone mobile application delivering personalized, real-time sun protection advice: a randomized clinical trial.
Buller, DB, Berwick, M, Lantz, K, Buller, MK, Shane, J, Kane, I, Liu, X
JAMA dermatology. 2015;(5):497-504
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Abstract
IMPORTANCE Mobile smartphones are rapidly emerging as an effective means of communicating with many Americans. Using mobile applications (apps), they can access remote databases, track time and location, and integrate user input to provide tailored health information. OBJECTIVE A smartphone mobile app providing personalized, real-time sun protection advice was evaluated in a randomized clinical trial. DESIGN, SETTING, AND PARTICIPANTS The trial was conducted in 2012 and had a randomized pretest-posttest controlled design with a 10-week follow-up. Data were collected from a nationwide population-based survey panel. A sample of 604 non-Hispanic and Hispanic adults from the Knowledge Panel 18 years or older who owned an Android smartphone were enrolled. INTERVENTIONS The mobile app provided advice on sun protection (ie, protection practices and risk of sunburn) and alerts (to apply or reapply sunscreen and get out of the sun), hourly UV Index, and vitamin D production based on the forecast UV Index, the phone's time and location, and user input. MAIN OUTCOMES AND MEASURES Percentage of days using sun protection and time spent outdoors (days and minutes) in the midday sun and number of sunburns in the past 3 months were collected. RESULTS Individuals in the treatment group reported more shade use (mean days staying in the shade, 41.0% vs 33.7%; P = .03) but less sunscreen use (mean days, 28.6% vs 34.5%; P = .048) than controls. There was no significant difference in number of sunburns in the past 3 months (mean, 0.60 in the treatment group vs 0.62 for controls; P = .87). Those who used the mobile app reported spending less time in the sun (mean days keeping time in the sun to a minimum, 60.4% for app users vs 49.3% for nonusers; P = .04) and using all protection behaviors combined more (mean days, 39.4% vs 33.8%; P = .04). CONCLUSIONS AND RELEVANCE The mobile app improved some sun protection. Use of the mobile app was lower than expected but associated with increased sun protection. Providing personalized advice when and where people are in the sun may help reduce sun exposure.
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Evaluation of immediate and 12-week effects of a smartphone sun-safety mobile application: a randomized clinical trial.
Buller, DB, Berwick, M, Lantz, K, Buller, MK, Shane, J, Kane, I, Liu, X
JAMA dermatology. 2015;(5):505-12
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IMPORTANCE Mobile applications on smartphones can communicate a large amount of personalized, real-time health information, including advice on skin cancer prevention, but their effectiveness may be affected by whether recipients can be convinced to use them. OBJECTIVE To evaluate a smartphone mobile application (Solar Cell) delivering real-time advice about sun protection for a second time in a randomized clinical trial. DESIGN, SETTING, AND PARTICIPANTS A previous trial conducted in 2012 used a randomized pretest-posttest design. For the present trial, we collected data from a volunteer sample of 202 adults 18 years or older who owned a smartphone. Participants were recruited nationwide through online promotions. Screening procedures and a 3-week run-in period were added to increase the use of the mobile application. We conducted follow-ups at 3 and 8 weeks after randomization to examine the immediate and the longer-term effects of the intervention. INTERVENTIONS Use of the mobile application. The application gave feedback on sun protection (ie, sun-safety practices and the risk for sunburn) and alerted users to apply or to reapply sunscreen and to get out of the sun. The application also displayed the hourly UV Index and vitamin D production based on the forecast UV Index, time, and location. MAIN OUTCOMES AND MEASURES Percentage of days with the use of sun protection, time spent outdoors in the midday sun (days and hours), and the number of sunburns in the last 3 months. RESULTS Participants in the intervention group used wide-brimmed hats more at 7 weeks than control participants (23.8% vs 17.4%; F = 4.07; P = .045). Women who used the mobile application reported using all sun protection combined more than men (46.4% vs 43.3%; F = 1.49; P = .04), whereas men and older individuals reported less use of sunscreen (32.7% vs 35.5%; F = 5.36; P = .02) and hats (15.6% vs 17.9%; F = 4.72; P = .03). CONCLUSIONS AND RELEVANCE The mobile application initially appeared to confer weak improvement of sun protection. Use of the mobile application was greater than in a previous trial and was associated with greater sun protection, especially among women. Strategies to increase the use of the mobile application are needed if the application is to be deployed effectively to the general adult population.
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Treated individuals who progress to action or maintenance for one behavior are more likely to make similar progress on another behavior: coaction results of a pooled data analysis of three trials.
Paiva, AL, Prochaska, JO, Yin, HQ, Rossi, JS, Redding, CA, Blissmer, B, Robbins, ML, Velicer, WF, Lipschitz, J, Amoyal, N, et al
Preventive medicine. 2012;(5):331-4
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OBJECTIVE This study compared, in treatment and control groups, the phenomena of coaction, which is the probability that taking effective action on one behavior is related to taking effective action on a second behavior. METHODS Pooled data from three randomized trials of Transtheoretical Model (TTM) tailored interventions (n=9461), completed in the U.S. in 1999, were analyzed to assess coaction in three behavior pairs (diet and sun protection, diet and smoking, and sun protection and smoking). Odds ratios (ORs) compared the likelihood of taking action on a second behavior compared to taking action on only one behavior. RESULTS Across behavior pairs, at 12 and 24 months, the ORs for the treatment group were greater on an absolute basis than for the control group, with two being significant. The combined ORs at 12 and 24 months, respectively, were 1.63 and 1.85 for treatment and 1.20 and 1.10 for control. CONCLUSIONS The results of this study with addictive, energy balance and appearance-related behaviors were consistent with results found in three studies applying TTM tailoring to energy balance behaviors. Across studies, there was more coaction within the treatment group. Future research should identify predictors of coaction in more multiple behavior change interventions.
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Oral nicotinamide reduces actinic keratoses in phase II double-blinded randomized controlled trials.
Surjana, D, Halliday, GM, Martin, AJ, Moloney, FJ, Damian, DL
The Journal of investigative dermatology. 2012;(5):1497-500
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Dose response of retinol and isotretinoin in the prevention of nonmelanoma skin cancer recurrence.
Clouser, MC, Roe, DJ, Foote, JA, Harris, RB, Alberts, DS
Nutrition and cancer. 2010;(8):1058-66
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Using data from a randomized, double blind, study of the efficacy of retinol or isotretinoin vs. placebo on recurrence of nonmelanoma skin cancer in high-risk subjects, a reanalysis of the original intent to treat analysis was performed in a dose-response format. Cox proportional hazards models describe the relationship between dose quartiles of isotretinoin and retinol use and time to first occurrence of squamous cell carcinoma (SCC) or basal cell carcinoma (BCC) in crude and adjusted models. Neither the isotretinoin nor retinol models showed any significance at any quartile for reduction in first BCC or SCC occurrence. Crude and adjusted retinol models show a statistically significant increase in risk of developing an SCC in the first quartile, whereas only the crude model shows a statistically significant increase in risk in the first quartile of the isotretinoin model. For retinol and SCC, hazard ratios (HRs) for the first quartile were as follows: HR = 2.92, 95% confidence interval (CI) = 1.67-5.10 crude; HR = 1.95, 95% CI = 1.00-3.80 adjusted. For isotretinoin and SCC, HRs for the first quartile were as follows: HR = 2.38, 95% CI = 1.35-4.19 crude; HR = 1.69, 95% CI = 0.87-3.31 adjusted. Test for trend was not significant in any of the models. These analyses confirm the results of the original intent to treat analyses and raise an interesting question related to the potential for increased risk for patients in the first quartile of retinol dose.
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Topical tretinoin therapy and all-cause mortality.
Weinstock, MA, Bingham, SF, Lew, RA, Hall, R, Eilers, D, Kirsner, R, Naylor, M, Kalivas, J, Cole, G, Marcolivio, K, et al
Archives of dermatology. 2009;(1):18-24
Abstract
OBJECTIVE To evaluate the relation of topical tretinoin, a commonly used retinoid cream, with all-cause mortality in the Veterans Affairs Topical Tretinoin Chemoprevention Trial (VATTC). The planned outcome of this trial was risk of keratinocyte carcinoma, and systemic administration of certain retinoid compounds has been shown to reduce risk of this cancer but has also been associated with increased mortality risk among smokers. DESIGN The VATTC Trial was a blinded randomized chemoprevention trial, with 2- to 6-year follow-up. Oversight was provided by multiple independent committees. SETTING US Department of Veterans Affairs medical centers. Patients A total of 1131 veterans were randomized. Their mean age was 71 years. Patients with a very high estimated short-term risk of death were excluded. Interventions Application of tretinoin, 0.1%, or vehicle control cream twice daily to the face and ears. MAIN OUTCOME MEASURES Death, which was not contemplated as an end point in the original study design. RESULTS The intervention was terminated 6 months early because of an excessive number of deaths in the tretinoin-treated group. Post hoc analysis of this difference revealed minor imbalances in age, comorbidity, and smoking status, all of which were important predictors of death. After adjusting for these imbalances, the difference in mortality between the randomized groups remained statistically significant. CONCLUSIONS We observed an association of topical tretinoin therapy with death, but we do not infer a causal association that current evidence suggests is unlikely.