Safety and Efficacy of Escalating Doses of Ingenol Mebutate for Field Treatment of Actinic Keratosis on the Full Face, Full Balding Scalp, or Chest.

Background: Actinic keratosis (AK) can affect large skin areas. Ingenol mebutate (IngMeb) gel (0.015% and 0.05%) is approved for topical treatment of AK in a single contiguous area of ~25 cm2.

Objective: The study sought to determine the maximum tolerated dose (MTD), efficacy, and tolerability of IngMeb applied to AK on a contiguous area less than equal to 250 cm2.

Methods: Part 1 determined the MTD of IngMeb at 7 concentrations for 2 or 3 days. Part 2 assessed efficacy and tolerability at the MTD and one dose lower for 2 or 3 days vs vehicle.

Results: Four dosing regimens with an acceptable benefit-to-risk ratio were identified: 0.018% and 0.027% once daily for 2 or 3 days. Complete clearance at 8 weeks was achieved by 21.3% to 39.1% of IngMeb-treated patients vs 0% to 3.2% treated with vehicle. Composite local skin response scores peaked on the day after the last application, rapidly declined, and were near baseline at 2 weeks. Adverse events were predominantly mild or moderate.

Limitations: The study evaluated a limited number of doses in a population of only white patients.

Conclusion: IngMeb gel was effective and well tolerated as field treatment of AK on the full face, full scalp, and up to 250 cm2 on the chest.

J Drugs Dermatol. 2017;16(5):438-444.

Fixed-Combination Calcipotriene Plus Betamethasone Dipropionate Aerosol Foam Is Well Tolerated in Patients with Psoriasis Vulgaris: Pooled Data from Three Randomized Controlled Studies.

The authors performed a pooled analysis of three randomized, 4-week, phase II/III studies in adult patients with mild to severe psoriasis and assessed the safety/tolerability of aerosol foam fixed-combination calcipotriene 0.005% (Cal) plus betamethasone dipropionate 0.064% (BD) versus different comparators. Overall, 1104 patients were randomized to Cal/BD aerosol foam (n=564), Cal aerosol foam (n=101), BD aerosol foam (n=101), aerosol foam vehicle (n=152), Cal/BD ointment (n=135), or ointment vehicle (n=51). A total of 543 Cal/BD patients in the aerosol foam group (96.3%) completed the studies, with only two patients (0.4%) withdrawing as a result of adverse events (AEs). Ninety-five AEs were reported in 78 patients (13.8%) receiving Cal/BD aerosol foam; similar event rates were observed in other groups. The most common AEs with Cal/BD aerosol foam were nasopharyngitis (n=6, 1.1%) and application-site pain (n=4, 0.7%); most AEs were mild (n=71/95; 74.7%). Adverse drug reactions (ADRs) experienced by two or more patients receiving Cal/BD aerosol foam were application-site pain (n=4; 0.7%) and application-site pruritus (n=2; 0.4%). There were no clinically relevant changes in calcium homeostasis. Cal/BD aerosol foam has a positive benefit-risk profile for the treatment of psoriasis vulgaris; the superior efficacy versus Cal/BD ointment and the individual active ingredients is not associated with poorer tolerability.

Aerosol Foam Formulation of Fixed Combination Calcipotriene Plus Betamethasone Dipropionate is Highly Efficacious in Patients With Psoriasis Vulgaris: Pooled Data From Three Randomized Controlled Studies.

BACKGROUND: Calcipotriene 0.005% (Cal)/betamethasone dipropionate 0.064% (BD) aerosol foam was developed as a new treatment option for patients with psoriasis. This pooled analysis evaluated the efficacy of this formulation for 4 weeks of treatment.
METHODS: Patients aged ≥18 years with mild-severe psoriasis were enrolled into three Phase II/III studies (nCT01536886, nCT01536938, nCT01866163); each study evaluated Cal/BD aerosol foam versus different comparators. Endpoints included: proportion of patients clear/almost clear with ≥2-step improvement in physician's global assessment of disease severity ('treatment success'); modified (excluding head) psoriasis area and severity index (mPASI); proportion of patients with ≥75% reduction in mPASI (PASI75); change in itch (according to visual analog scale [VAS]).
RESULTS: 1104 patients were included in the pooled analysis: Cal/BD aerosol foam (n=564), Cal/BD ointment (n=135), BD aerosol foam (n=101), Cal aerosol foam (n=101), aerosol foam vehicle (n=152), ointment vehicle (n=51). At week 4, 51% of Cal/BD aerosol foam patients achieved treatment success, a higher proportion than in all other groups (Cal/BD ointment, 43%; BD aerosol foam, 31%; Cal aerosol foam, 15%; aerosol foam vehicle, 5%; ointment vehicle, 8%). Greater percentage mean decrease in mPASI with Cal/BD aerosol foam was noted versus other treatments at week 4 (72% vs 63%, 53%, 43%, 32%, and 33%, respectively); week 4 PASI75 rate was also greater (51% vs 41%, 34%, 18%, 7%, and 10%, respectively). Cal/BD aerosol foam was efficacious irrespective of baseline disease severity and on all body areas assessed (arms, legs, trunk). Cal/BD aerosol foam alleviated itch as early as week 1 (change in itch VAS: -30 mm), maintained to week 4 (change in itch VAS: -41 mm).
CONCLUSIONS: Cal/BD aerosol foam was significantly more effective than Cal/BD ointment and the individual active ingredients for treating psoriasis vulgaris, resulting in greater and faster reduction in disease severity and rapid, effective relief of itch.

J Drugs Dermatol. 2016;15(8):951-957.

Calcipotriene plus betamethasone dipropionate topical suspension for the treatment of mild to moderate psoriasis vulgaris on the body: a randomized, double-blind, vehicle-controlled trial.

BACKGROUND/OBJECTIVES: A combination topical suspension/gel containing calcipotriene plus betamethasone dipropionate has been developed as a safe and effective treatment for patients with psoriasis vulgaris of the scalp. This same preparation has the potential to be a convenient, effective, and cosmetically appealing formulation for psoriasis on the body. This trial evaluated the efficacy and safety of a topical suspension containing calcipotriene plus betamethasone dipropionate compared with its constituent components and topical suspension vehicle in the treatment of mild to moderate psoriasis on the trunk and limbs. METHODS: This was a randomized, double-blind, vehicle-controlled, 4-arm trial in 1,152 subjects. The co-primary efficacy end points were the proportion of subjects achieving controlled disease based on the Investigators' Global Assessment of disease severity at weeks 4 and 8. Adverse events, vital signs, and clinical laboratory measurements were also assessed. RESULTS: At week 4, a greater proportion of subjects in the calcipotriene plus betamethasone group achieved controlled disease compared with subjects in the calcipotriene-only and vehicle-only treatment groups. At week 8, a statistically significantly (P<.01) greater proportion of subjects in the calcipotriene plus betamethasone group achieved controlled disease compared with subjects in the 3 other treatment groups. Adverse events and other safety assessments were similar between the groups. CONCLUSION: The topical suspension containing calcipotriene plus betamethasone dipropionate traditionally used for scalp psoriasis is also a safe and effective once-daily treatment for psoriasis vulgaris on the body.

Warts in a cohort of Danish kidney transplanted patients: impact on quality of life.

There are no published clinical studies evaluating the impact of warts on quality of life after transplantation. The aim of this study was to determine the frequency of self-reported skin warts and skin cancer and their impact on quality of life in kidney transplanted patients, as measured with the Dermatology Life Quality Index (DLQI). Of 740 patients with a functioning renal allograft and were free of dialysis who were surveyed, 568 returned the questionnaires. Patients were asked about general health issues, with a focus on transplantation history, cutaneous warts and whether they had ever had cutaneous cancer. A total of 285 (52%) patients replied that they had warts, and these increased with time since last transplantation, with a p-value < 0.0001. A total of 101 patients (18%) reported that they had ever had skin cancer. The median DLQI was 0 for patients not having warts, 1 for patients with warts, and 2 for patients having warts and skin cancer. In conclusion, renal transplant recipients experience increasing numbers of warts and skin cancer over time, and having skin cancer impairs patients' quality of life to a greater degree than warts.

Pharmacokinetics of ingenol mebutate gel under maximum use conditions in large treatment areas.

PURPOSE: Actinic keratoses (AKs) exist on a continuum with squamous cell carcinoma and can occur as sub-clinical and clinically visible lesions in cancerized fields on sun-damaged skin. Ingenol mebutate effectively treats AKs on areas up to 25 cm2, but actinic keratosis can affect larger areas of skin. This trial evaluated systemic exposure and safety of ingenol mebutate gel on larger areas of skin under maximum use conditions. METHODS: Phase I, multicenter, open-label, uncontrolled, non-randomized trial. Patients received ingenol mebutate gel for three consecutive days on approximately 250 cm2 of sun-damaged skin on the full face (0.027%), the scalp (0.027%), or arm (0.06%). RESULTS: Of 61 patients, 10 (face =8; arm =2) had ingenol mebutate in whole blood at subnanomolar levels (0.235-0.462 nM). The assayed metabolites were below the lower limit of quantification. Local skin responses increased during Days 1-4 and declined thereafter, approaching baseline by Day 16. Most adverse events were pain/pruritus of mild or moderate intensity. CONCLUSIONS: Subnanomolar systemic exposure to ingenol mebutate was measured after application of the gel to approximately 250 cm2 on the full face, scalp, or arm under maximum use conditions. No clinically relevant systemic adverse reactions were observed, and local skin responses were manageable.

Calcipotriol Plus Betamethasone Dipropionate Aerosol Foam is Effective, Independent of Body Mass Index and the Extent and Severity of Psoriasis.

INTRODUCTION: Good treatment adherence is important in the effective management of psoriasis and is related to both the frequency of applications and the amount of product used versus the recommended dose. The efficacy and safety of fixed combination calcipotriol 50 µg/g (Cal) and betamethasone 0.5 mg/g as dipropionate (BD) in the treatment of psoriasis is well established; an aerosol foam formulation has been developed to enhance adherence. This subanalysis from the Phase III PSO-FAST study evaluates the amount of Cal/BD foam used during treatment and the association between the extent and severity of baseline disease. METHODS: Patients (≥18 years) with mild-to-severe body psoriasis were randomized 3:1 to once-daily Cal/BD foam or vehicle. The amount of Cal/BD foam and vehicle used over the 4-week study period was evaluated according to three baseline disease assessments: extent of body surface area (BSA) affected by psoriasis, physician's global assessment of disease severity (PGA) and modified psoriasis area and severity index (mPASI). Treatment success and mPASI75 rates were assessed according to body mass index (BMI) and body weight. RESULTS: 323 patients were randomized to Cal/BD foam and 103 to vehicle. At week 4, the mean total amount of Cal/BD foam used was 120.8 g (n = 293), which was similar to the amount of vehicle used (128.9 g; n = 98). The total amount of Cal/BD foam used at week 4 was greater with increasing BSA and increasing severity of baseline PGA and mPASI. Throughout the study, 93.1% of patients in the Cal/BD foam group and 99.0% of patients in the vehicle group missed ≤10% of treatment applications. Treatment success and mPASI75 rates were generally similar when stratified according to BMI and body weight. CONCLUSIONS: This subanalysis demonstrates that Cal/BD aerosol foam is used appropriately and is effective for the treatment of psoriasis, independent of BMI and the extent or severity of disease. CLINICAL TRIALS NUMBER: NCT01866163. FUNDING: LEO Pharma A/S.

Superior efficacy of calcipotriene and betamethasone dipropionate aerosol foam versus ointment in patients with psoriasis vulgaris--A randomized phase II study.

BACKGROUND: An aerosol foam formulation of fixed combination calcipotriene 0.005% (as hydrate; Cal) plus betamethasone dipropionate 0.064% (BD) was developed to improve psoriasis treatment. OBJECTIVES: To compare the efficacy and safety of Cal/BD aerosol foam with Cal/BD ointment after 4 weeks. METHODS: In this Phase II, multicenter, investigator-blind, 4-week trial, adult patients with psoriasis vulgaris were randomized to Cal/BD aerosol foam, Cal/BD ointment, aerosol foam vehicle or ointment vehicle (3:3:1:1). The primary efficacy endpoint was the proportion of patients at week 4 who achieved treatment success (clear or almost clear with at least a two-step improvement) according to the physician's global assessment of disease severity. RESULTS: In total, 376 patients were randomized. At week 4, significantly more patients using Cal/BD aerosol foam achieved treatment success (54.6% versus 43.0% [ointment]; p = 0.025); mean modified (excluding the head, which was not treated) psoriasis area and severity index score was significantly different between Cal/BD aerosol foam and Cal/BD ointment (mean difference -0.6; p = 0.005). Rapid, continuous itch relief occurred with both active treatments. One adverse drug reaction was reported with Cal/BD aerosol foam (application site itch). CONCLUSIONS: Cal/BD aerosol foam demonstrates significantly greater efficacy and similar tolerability compared with Cal/BD ointment for psoriasis treatment.

Efficacy of an innovative aerosol foam formulation of fixed combination calcipotriol plus betamethasone dipropionate in patients with psoriasis vulgaris.

BACKGROUND AND OBJECTIVE: The antipsoriatic effect of an innovative aerosol foam formulation of fixed combination calcipotriol 50 µg/g (as hydrate; Cal) and betamethasone 0.5 mg/g (as dipropionate; BD) was explored in order to compare the effect with that of the first-line treatment Cal/BD ointment. METHODS: This was a Phase IIa, single-centre, investigator-blinded, exploratory study, with intra-individual comparison using a modified psoriasis plaque test. Patients were treated once daily (6 days/week) for 4 weeks with Cal/BD foam, Cal/BD ointment, BD foam and Cal/BD foam vehicle, randomized to four plaque test sites (5 cm(2) each). The primary efficacy endpoint was change in total clinical score (TCS; sum of erythema, scaling and lesional thickness). Secondary endpoints included ultrasonographic changes in total skin thickness and echo-poor band thickness, and adverse events. RESULTS: Twenty-four patients, median age 52.5 years (range 21-75), completed this study. At week 4, test sites treated with Cal/BD foam had a significantly greater decrease in mean (±SD) TCS (-6.00 ± 1.27) versus those treated with Cal/BD ointment (-5.25 ± 1.78; difference -0.75; 95 % CI -1.46 to -0.04; p = 0.038), BD foam (-4.96 ± 1.85; difference -1.04; 95 % CI -1.75 to -0.33; p = 0.005) or foam vehicle (-1.88 ± 1.12; difference -4.13; 95 % CI -4.83 to -3.42; p < 0.001). Total skin thickness and echo-poor band thickness of Cal/BD foam-treated sites were reduced to a greater extent than those treated with comparators. Eleven patients reported 17 adverse events, the most frequent being headache (five patients). There were no lesional/perilesional adverse events or adverse drug-related events. CONCLUSIONS: Cal/BD foam demonstrated a significant improvement in antipsoriatic effect over Cal/BD ointment, BD foam and foam vehicle alone.

A 6-months, randomised, placebo-controlled evaluation of efficacy and tolerability of a low-dose 7-day buprenorphine transdermal patch in osteoarthritis patients naïve to potent opioids.

Objective Patients with osteoarthritis (OA) pain often have insufficient pain relief from non-opioid analgesics. The aim of this trial was to study efficacy and tolerability of a low dose 7-day buprenorphine transdermal delivery system, added to a NSAID or coxib regimen, in opioid-naïve patients with moderate to severe OA pain. Methods A 6 months randomised, double-blind, parallel-group study at 19 centres in Denmark, Finland, Norway, and Sweden, in which OA patients (>40 years) with at least moderate radiographic OA changes and at least moderate pain in a hip and/or knee while on a NSAID or a coxib were randomised to a 7-day buprenorphine patch (n = 100) or an identical placebo patch (n = 99). The initial patch delivered buprenorphine 5 µg/h. This was titrated to 10 or 20 µg/h, as needed. Rescue analgesic was paracetamol 0.5-4 g daily. Statistical analysis of outcome data was mainly with a general linear model, with treatment as factor, the primary joint of osteoarthritis, baseline scores, and season as covariates. Results Most patients had OA-radiographic grade II (moderate) or grade III (severe), only 8 in each group had very severe OA (grade IV). The median buprenorphine dose was 10 µg/h. 31 buprenorphine-treated patients and 2 placebo-treated patients withdrew because of side effects. Lack of effect caused 12 placebo-treated and 7 buprenorphine-treated patients to withdraw. The differences in effects between treatments: Daytime pain on movement, recorded every evening on a 0-10 numeric rating scale decreased significantly more (P = 0.029) in the buprenorphine group. Patients' Global Impression of Change at the end of the double blind period was significantly improved in the buprenorphine group (P = 0.017). The chosen primary effect outcome measure, the Western Ontario and McMaster Universities (WOMAC) OA Index for Pain (P = 0.061), and secondary outcome measures, the WOMAC OA score for functional abilities (P = 0.055), and the WOMAC total score (P = 0.059) indicated more effects from buprenorphine than placebo, but these differences were not statistically significant. In a post-hoc, subgroup analysis with the 16 patients with radiographic grad IV (very severe) excluded, WOMAC OA Index for Pain was significantly (P = 0.039) reduced by buprenorphine, compared with placebo. WOMAC OA score for stiffness and the amount of rescue medication taken did not differ. Sleep disturbance, quality of sleep, and quality of life improved in both groups. Side effects: Typical opioid side effects caused withdrawal at a median of 110 [corrected] days before completing the 168 days double blind trial in 1/3 of the buprenorphine group. Mostly mild local skin reactions occurred equally often (1/3) in both groups. Conclusions Although the 24 hours WOMAC OsteoArthritis Index of pain was not statistically significantly superior to placebo, day-time movement-related pain and patients' global impression of improvement at the end of the 6-months double blind treatment period were significantly better in patients treated with buprenorphine compared with placebo. Opioid side effects caused 1/3 of the buprenorphine-patients to withdraw before the end of the 6-months double blind study period. Implications A low dose 7-days buprenorphine patch at 5-20 µg/h is a possible means of pain relief in about 2/3 of elderly osteoarthritis patients, in whom pain is opioid-sensitive, surgery is not possible, NSAIDs and coxibs are not recommended, and paracetamol in tolerable doses is not effective enough. Vigilant focus on and management of opioid side effects are essential.

Weight loss produced by tesofensine in patients with Parkinson's or Alzheimer's disease.

OBJECTIVE: Tesofensine (TE) is a norepinephrine, dopamine, and serotonin reuptake inhibitor. We conducted a meta-analysis of TE's effect on body weight in trials investigating its potential for treatment of Parkinson's or Alzheimer's disease. METHODS AND PROCEDURES: Four randomized, double-blind, multicenter trials compared TE (n = 740) and placebo (n = 228), two in each disease. Patients received oral TE or placebo once daily for 14 weeks without any weight loss program. Results were adjusted for baseline values, age, and study. RESULTS: In the placebo group, 14% were obese and 21% were in the TE group. In the total cohort, weight change after 14 weeks was +0.5, -0.5, -0.9, -1.8, -2.8% in the placebo, 0.125, 0.25, 0.5 and 1.0 mg in the TE groups, respectively (P = 0.015 for dose effect). In the obese subgroup, weight changes were -0.2, -1.7, -1.6, -1.5, -3.7%, and 2.1, 8.2, 14.1, 20.9, 32.1% of the obese patients achieved > or = 5% weight loss (P < 0.001 for 0.25, 0.5, and 1.0 mg vs. placebo for both end points). Changes in heart rate were -0.4, 2.1, 4.2, 6.0, and 6.8 bpm after 14 weeks (TE vs. placebo: P < 0.001 from 0.25 mg), but no effect on blood pressure was observed. DISCUSSION: TE produced a placebo-subtracted weight loss of approximately 4% for >14 weeks without any diet and lifestyle therapy, which is similar to that of sibutramine, but with no effect on blood pressure. On the basis of these results, TE is now being developed for obesity management.

Lower urinary tract symptoms after total and subtotal hysterectomy: results of a randomized controlled trial.

The aim of this Danish multicenter trial was to compare the proportion of women with lower urinary tract symptoms after total abdominal hysterectomy (TAH) and subtotal abdominal hysterectomy (SAH) for benign uterine disorders. A total of 319 women were randomized to TAH (n = 158) or SAH (n = 161). Women were followed up for 1 year by strict data collection procedures, including postal questionnaires. Results were analyzed by intention-to-treat analyses. Urinary incontinence was found less often among TAH women than among SAH women. This was due to a larger reduction of the number of women with stress and urinary incontinence in the TAH group. No other differences were found between the two operation methods. The number of women with urinary incontinence and frequency was reduced from study entry for follow-up, while double/triple voiding was increased. Incontinent women had significantly lower quality of life scores than continent women