Efficacy and safety of ingenol mebutate gel in field treatment of actinic keratosis on full face, balding scalp, or approximately 250 cm2 on the chest: A phase 3 randomized controlled trial.

BACKGROUND: Ingenol mebutate (IngMeb) 0.015% or 0.05% is approved for actinic keratosis (AK) areas of 25 cm2 or less; some patients require treatment of larger fields. OBJECTIVE: To determine efficacy and safety of IngMeb 0.027% in areas of AK of up to 250 cm2 during an 8-week initial assessment period and extended 12-month follow-up. METHODS: This phase 3, randomized, double-blind, vehicle-controlled trial (NCT02361216) enrolled adult patients with 5 to 20 AK lesions on the face/scalp (25-250 cm2) or chest (approximately 250 cm2). Patients received once-daily IngMeb or vehicle for 3 consecutive days on the full face, full balding scalp, or approximately 250 cm2 on the chest. The primary endpoint was complete AK clearance (AKCLEAR 100; week 8). Additional endpoints included partial AK clearance (AKCLEAR 75), recurrence, patient satisfaction, cosmetic outcome, and safety. RESULTS: IngMeb was superior to vehicle for complete AK clearance (21.4% vs 3.4%, P < .001) and AK clearance of 75% or greater (59.4% vs 8.9%, P < .001) at week 8. Probability of sustained clearance during the 12-month follow-up was 22.9% for patients treated with IngMeb. Increased treatment satisfaction and cosmetic outcomes were observed with IngMeb versus vehicle. No unexpected safety signals were identified. LIMITATIONS: Localized skin responses hindered maintenance of double-blinding. CONCLUSIONS: IngMeb 0.027% was superior to vehicle for treatment of AK areas of up to 250 cm2. The safety profile of IngMeb was as expected.

Three-Day Field Treatment with Ingenol Disoxate (LEO 43204) for Actinic Keratosis: Cosmetic Outcomes and Patient Satisfaction from a Phase II Trial.

Objective: To report cosmetic outcomes and patient satisfaction with ingenol disoxate (LEO 43204) used in a once-daily, three-day field treatment regimen in patients with actinic keratosis. Design: This was a phase II, multicenter, open-label trial (ClinicalTrials.gov: NCT02305888) involving 20 trial sites in the United States. Participants: Patients with between five and 20 clinically typical actinic keratoses lesions on the full face/250cm2 on the chest, 25cm2 to 250cm2 on the scalp, or 250cm2 on the trunk/extremities were included. Measurements: The assessment methods in this study included the examination of global photo-damage at Week 8; a cosmetic outcome questionnaire to evaluate the overall appearance and feel of the skin following treatment at Week 8; and a treatment satisfaction questionnaire for medication (TSQM) to evaluate patient satisfaction with treatment at Week 8. Results: Treatment adherence was high, with 97 percent of patients overall applying the full three-day regimen. Global photo-damage improvement was seen in 66, 69, and 72 percent of patients in the face/chest, scalp, and trunk/extremities groups, respectively. Improved overall appearance of the treatment area was reported by 95, 97, and 80 percent of patients in the face/chest, scalp, and trunk/extremities groups, respectively. In addition, overall feel of the treatment area was reported as improved by 92, 95, and 70 percent of patients in the face/chest, scalp, and trunk/extremities groups, respectively. Overall, the mean scores for all four treatment satisfaction questionnaires for medication domains were high in each treatment group, ranging from 66.7/100 to 91.3/100. In particular, mean scores for global satisfaction were 73.9/100, 79.7/100, 66.7/100 for the face/chest, scalp, and trunk/extremities groups, respectively. Conclusion: Actinic keratosis field treatment with ingenol disoxate provided favorable cosmetic benefits and high treatment satisfaction.

Three-day Field Treatment with Ingenol Disoxate (LEO 43204) for Actinic Keratosis: A Phase II Trial.

OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of ingenol disoxate gel using a once-daily, three-day field treatment regimen in patients with actinic keratosis. DESIGN: This was a Phase II, multicenter, open-label trial (clinicaltrials.gov: NCT02305888). SETTING: The study was conducted in 20 trial sites in the United States. PARTICIPANTS: Participants included patients with 5 to 20 clinically typical actinic keratosis lesions on the full face/chest (250cm2), scalp (25-250cm2), or the trunk/extremities (250cm2). MEASUREMENTS: We measured incidence of dose-limiting events based on local skin responses. Percentage reduction in actinic keratosis lesion count from baseline, complete clearance, and partial clearance (≥75%) of actinic keratosis lesions were assessed at Week 8. RESULTS: Nine of 63 (14.3%) patients in the face/chest group reported dose-limiting events; zero of 63 patients in the scalp group reported dose-limiting events; and 11 of 62 (17.7%) patients in the trunk/extremities group reported dose-limiting events. Mean composite local skin response scores peaked at Day 4, then rapidly declined, reaching or approaching baseline levels by Week 4. Less than five percent of patients reported severe adverse events; the most common treatment-related adverse events were application site pain and pruritus. The reduction in actinic keratosis lesion count was 78.9, 76.3, and 69.1 percent for the face/chest, scalp, and trunk/extremities groups, respectively. Complete clearance was achieved in 36.5, 39.7, and 22.6 percent of patients in the face/chest, scalp, and trunk/extremities groups, respectively. Partial clearance was achieved in 71.4, 65.1, and 50.0 percent of patients in the face/chest, scalp, and trunk/extremities groups, respectively. CONCLUSION: Ingenol disoxate demonstrated adverse events and local skin reaction profiles similar to results seen in trials evaluating shorter two-day regimens and was effective in patients with actinic keratosis. These data support the use of ingenol disoxate gel for actinic keratosis field treatment.

Biological Effects of Ingenol Mebutate Gel in Moderate to Severe Actinic Fields Assessed by Reflectance Confocal Microscopy: A Phase I Study.

Ingenol mebutate represents a topical treatment for fields with actinic keratosis (AK). The biological effects of ingenol mebutate in AK, subclinical (SC)-AK, and reference-skin were assessed and graded by in vivo reflectance confocal microscopy (RCM) and histology. Patients with AK and SC-AK lesions in one 25 cm2 field on hands or forearms, and with an area of reference skin on the inner upper arm, were included. The two fields were each treated with ingenol mebutate 0.05% gel (n=16), or vehicle (n=8), on 2 consecutive days; clinical and RCM assessments were performed on days 1, 2, 3, 8, and 57, and biopsies on day 3. Local skin responses were more pronounced in AK fields (6.1 (mean) ± 2.6 (SD)) compared with reference skin (3.5 ± 1.5). The clinical AK lesion reduction was 43.8% and 6.3% with ingenol mebutate and vehicle, respectively. RCM and histology evaluations showed that ingenol mebutate induced a significant pronounced cell death and immune response in AK and SC-AK lesions, compared with reference skin. Ingenol mebutate induced RCM-measured reduction in (investigator-1/investigator-2): AK lesions (34/28%), SC-AK lesions (72/56%), and solar elastosis in AK fields (mean, -0.22/-0.25). In conclusion, ingenol mebutate showed selective pronounced biological responses in AK and SC-AK as compared with reference skin.

J Drugs Dermatol. 2016;15(10):1181-1189.

The Aerosol Foam Formulation of the Fixed Combination Calcipotriene Plus Betamethasone Dipropionate Improves the Health-Related Quality of Life in Patients With Psoriasis Vulgaris: Results from the Randomized PSO-FAST Study.

INTRODUCTION: Psoriasis has a major impact on patient quality of life, similar to that seen in other chronic diseases, eg, diabetes. Health-related quality of life (HRQoL) measures are commonly included in clinical trial designs, capturing the disease burden and therapeutic success of a treatment. In the randomized, double-blind, phase III PSO-FAST (Psoriasis vulgaris, a Four-week, vehicle-controlled, efficacy And Safety Trial) study (nCT01866163), fixed combination calcipotriene (Cal) 0.005% plus betamethasone dipropionate (BD) 0.064% aerosol foam was compared with vehicle. By treatment end, 53% of patients using Cal/BD foam achieved treatment success.
OBJECTIVE: To compare the impact on HRQoL of Cal/BD foam vs vehicle in patients with mild-to-severe psoriasis.
METHOD: HRQoL was assessed by dermatology life-quality index (DLQI; baseline, weeks 1, 2, 4) and EQ-5D-5L (EQ-5D; baseline, week 4) questionnaires. A DLQI score of 0 (range, 0-30) indicates no effect on the patient's life; an EQ-5D utility score of 1 (range, 0-1) and an EQ-5D visual analog scale (VAS) score of 100 (range, 1-100) indicate perfect health.
RESULTS: 426 patients were randomized (Cal/BD foam, n=323; vehicle, n=103). Baseline mean DLQI scores were 9.9 (Cal/BD foam) and 10.3 (vehicle). The impact of psoriasis on HRQoL (EQ-5D utility score) at baseline was primarily driven by pain/discomfort (Cal/BD foam: 69.9%; vehicle: 65.0%) and anxiety/depression (Cal/BD foam: 45.3%; vehicle 44.7%). There was a greater improvement from baseline in DLQI score for Cal/BD foam vs vehicle at week 4 (-7.0 vs -4.4; P<.001); increased improvement was also seen in EQ-5D scores. At week 4, 48.1% of patients using Cal/BD foam reported no effect of psoriasis on their lives (DLQI = 0/1), and of patients using Cal/BD foam with baseline DLQI scores ≥5, 81.2% achieved a ≥5-point improvement.
CONCLUSION: Cal/BD aerosol foam improved HRQoL after 4 weeks, with most patients experiencing a clinically meaningful improvement and almost 50% reporting no impairment.

J Drugs Dermatol. 2016;15(8):981-987.

Efficacy and Safety of Calcipotriene Plus Betamethasone Dipropionate Aerosol Foam in Patients With Psoriasis Vulgaris--a Randomized Phase III Study (PSO-FAST).

INTRODUCTION: An innovative aerosol foam formulation of calcipotriene 0.005% (Cal) plus betamethasone dipropionate 0.064% (BD) designed to improve treatment outcomes. OBJECTIVE: To compare the efficacy and safety of Cal/BD aerosol foam with aerosol foam vehicle in patients with psoriasis. DESIGN: Phase III, double-blind, randomized PSO-FAST (Cal/BD foam in PSOriasis vulgaris, a Four-week, vehicle-controlled, efficacy And Safety Trial) study recruited patients with ≥ mild severity psoriasis of the trunk and/or limbs from 27 US outpatient sites (NCT01866163). Patients were randomized (3:1) to Cal/BD foam or vehicle once-daily for 4 weeks. PRIMARY OUTCOME: proportion of patients at week 4 who achieved treatment success according to physician's global assessment. SECONDARY OUTCOMES: modified (excluding head) psoriasis area and severity index (mPASI) and patient's assessment of itch (visual analog scale). Safety was monitored by adverse events/calcium homeostasis. RESULTS: 426 patients enrolled between June and October 2013 (Cal/BD foam, n=323; vehicle, n=103). At week 4, significantly more patients using Cal/BD foam achieved treatment success versus vehicle (53.3 versus 4.8%; OR 30.3, 95% CI 9.7,94.3; P < .001) and mean mPASI score was significantly lower for patients using Cal/BD foam than vehicle (2.0 versus 5.5; adjusted difference -3.3, P <.001). Significantly greater itch relief was observed for patients using Cal/BD foam than vehicle (P = .010 at day 3, P < .001 from day 5). Adverse drug reactions were reported in 10 Cal/BD foam patients (3.1%) and two vehicle patients (1.9%); events occurred in one patient each except application site pain (Cal/BD foam, two patients; vehicle, one patient). There were no clinically significant changes in calcium homeostasis. CONCLUSIONS: Cal/BD foam was efficacious, achieved rapid itch relief and was well tolerated in patients with body psoriasis. This innovative aerosol foam formulation is expected to become a valuable treatment option.

Calcipotriol plus betamethasone dipropionate gel compared with tacalcitol ointment and the gel vehicle alone in patients with psoriasis vulgaris: a randomized, controlled clinical trial.

OBJECTIVE: To establish the efficacy and safety of once daily treatment of Daivobet®/Dovobet® gel in patients with psoriasis vulgaris, relative to tacalcitol ointment and the gel vehicle alone. METHODS: 458 patients with at least moderately severe disease were randomized in 3 treatment arms for an 8-week period. Treatment was investigator blinded, and treatment success was defined as patients with an Investigator's Global Assessment of 'clear' or 'almost clear' at week 8. RESULTS: The proportion of patients who were 'clear or almost clear' was significantly higher in the 2-compound gel group (39.9%) compared with 17.9% in the tacalcitol group and 5.5% in the gel vehicle group: p < 0.001 in both comparisons. The proportion of patients with at least 1 adverse drug reaction was significantly lower in the 2-compound gel group compared to the other 2 treatment groups. CONCLUSIONS: Once-a-day treatment with the 2-compound Daivobet/Dovobet gel is a safe and efficacious therapeutic regimen for individuals with psoriasis on the body.

Leisure-time physical activity in pregnancy and risk of postpartum depression: a prospective study in a large national birth cohort.

OBJECTIVE: To explore the association between physical activity during pregnancy and postpartum depression (PPD) in a large, prospective cohort. METHOD: Exposure information from the Danish National Birth Cohort, a large, prospective cohort with information on more than 100,000 pregnancies (1996-2002), was linked to the Danish Psychiatric Central Register and the Danish Register for Medicinal Product Statistics for data on clinically identified cases of depression up to 1 year postpartum. A total of 70,866 women from the Danish National Birth Cohort were included in the analyses. Duration, frequency, and type of physical activity were assessed by a telephone interview at approximately week 12 of gestation. Admission to hospital due to depression (PPD-admission) and prescription of an antidepressant (PPD-prescription) were treated as separate outcomes. RESULTS: Through linkage to national registers, we identified 157 cases of PPD-admission and 1,305 cases of PPD-prescription. Women engaging in vigorous physical activity during pregnancy had a lower risk of PPD-prescription compared to women who were not physically active (adjusted odds ratio, 0.81; 95% CI, 0.66-0.99). No association was observed between physical activity and PPD-admission; but, in women who were underweight prior to pregnancy, physical activity was associated with increased risk of PPD-admission. CONCLUSIONS: Our data are compatible with a protective effect of vigorous physical activity, but not for other measures of physical activity, against postpartum depression requiring antidepressant therapy. No protective effect could be detected on PPD leading to hospitalization.

Associations of maternal fish intake during pregnancy and breastfeeding duration with attainment of developmental milestones in early childhood: a study from the Danish National Birth Cohort.

BACKGROUND: Few studies have examined the overall effect of maternal fish intake during pregnancy on child development or examined whether the developmental benefits of maternal fish intake are greater in infants breastfed for a shorter duration. OBJECTIVE: We aimed to study associations of maternal prenatal fish intake and breastfeeding duration with child developmental milestones. DESIGN: We studied 25 446 children born to mothers participating in the Danish National Birth Cohort, a prospective population-based cohort study including pregnant women enrolled between 1997 and 2002. Mothers reported child development by a standardized interview, which we used to generate developmental scores at ages 6 and 18 mo. We used multivariate cumulative ordinal logistic regression to evaluate the odds of higher developmental scores associated with maternal fish intake and breastfeeding, after adjustment for child age, sex, and growth; maternal size and pregnancy characteristics; and parental education and social status. RESULTS: Higher maternal fish intake and greater duration of breastfeeding were associated with higher child developmental scores at 18 mo [odds ratio: 1.29 (95% CI: 1.20, 1.38) for the highest versus the lowest quintile of fish intake, and 1.28 (1.18, 1.38) for breastfeeding for > or =10 mo compared with breastfeeding for < or =1 mo]. Associations were similar for development at 6 mo. Associations of fish intake with child development did not differ by breastfeeding duration. CONCLUSIONS: Maternal fish intake during pregnancy and the duration of breastfeeding are independently associated with better early child development. Future research and consumption guidelines, incorporating nutritional benefits as well as contaminant risks, should consider the overall effect of prenatal fish consumption on child development.

Fish oil intake compared with olive oil intake in late pregnancy and asthma in the offspring: 16 y of registry-based follow-up from a randomized controlled trial.

BACKGROUND: Evidence suggests that asthma is rooted in the intrauterine environment and that intake of marine n-3 polyunsaturated fatty acids (n-3 PUFAs) in pregnancy may have immunomodulatory effects on the child. OBJECTIVE: Our aim was to examine whether increasing maternal intake of n-3 PUFAs in pregnancy may affect offspring risk of asthma. DESIGN: In 1990, a population-based sample of 533 women with normal pregnancies were randomly assigned 2:1:1 to receive four 1-g gelatin capsules/d with fish oil providing 2.7 g n-3 PUFAs (n = 266); four 1-g, similar-looking capsules/d with olive oil (n = 136); or no oil capsules (n = 131). Women were recruited and randomly assigned around gestation week 30 and asked to take capsules until delivery. Among 531 live-born children, 528 were identified in registries and 523 were still alive by August 2006. Diagnoses from the International Coding of Diseases version 10 were extracted from a mandatory registry that recorded diagnoses reported from hospital contacts. RESULTS: During the 16 y that passed since childbirth, 19 children from the fish oil and olive oil groups had received an asthma-related diagnosis; 10 had received the diagnosis allergic asthma. The hazard rate of asthma was reduced by 63% (95% CI: 8%, 85%; P = 0.03), whereas the hazard rate of allergic asthma was reduced by 87% (95% CI: 40%, 97%; P = 0.01) in the fish oil compared with the olive oil group. CONCLUSION: Under the assumption that intake of olive oil in the dose provided here was inert, our results support that increasing n-3 PUFAs in late pregnancy may carry an important prophylactic potential in relation to offspring asthma.

Mediterranean-type diet and risk of preterm birth among women in the Norwegian Mother and Child Cohort Study (MoBa): a prospective cohort study.

BACKGROUND: Mediterranean diet has been shown to reduce the incidence of preterm birth. We wanted to investigate whether a Mediterranean-type diet (MD) could be associated with a lower risk of preterm birth in the Norwegian Mother and Child Cohort Study (MoBa). METHODS: The data collection was conducted as part of MoBa at the Norwegian Institute of Public Health. In MoBa, women answer a Food Frequency Questionnaire (FFQ) at week 18-22 of pregnancy. The MD criteria were intake of fish > or =2 times a week, fruit and vegetables > or =5 times a day, use of olive/canola oil, red meat intake < or = times 2 a week, and < or =2 cups of coffee a day. RESULTS: A total of 569 women (2.2%) met the MD criteria, 25,397 women (97.2%) met 1-4 criteria, and 159 women (0.01%) met none of the MD criteria. The number of preterm births in the MD group was 26 (4.6%), in those who met 1-4 criteria it was 1,148 (4.5%), and in those who met none of the criteria it was 10 (6.3%). The women who met the MD criteria did not have reduced risk of preterm birth compared with women meeting none of the MD criteria (OR: 0.73; 95% CI: 0.32, 1.68). Intake of fish twice or more a week was associated with a lower risk of preterm birth (OR: 0.84; 95% CI: 0.74, 0.95). CONCLUSIONS: The women who fulfilled the criteria of a MD did not have a reduced risk of preterm birth.

Association between a Mediterranean-type diet and risk of preterm birth among Danish women: a prospective cohort study.

BACKGROUND: Thus far, few factors with a causal relation to preterm birth have been identified. Many studies have focused on the woman's diet, but most have been discouraging. The aim of the present study was to examine if maternal intake of a Mediterranean-type diet (MD) is associated with reduced risk of preterm birth. METHODS: The Danish National Birth Cohort assessed diet in mid-pregnancy by food frequency questionnaires (FFQ). Women consuming MD were those who ate fish twice a week or more, used olive or rape seed oil, consumed 5+ fruits and vegetables a day, ate meat (other than poultry and fish) at most twice a week, and drank at most 2 cups of coffee a day. RESULTS: Of 35,530 non-smoking women, 1,137 (3.2%) fulfilled all MD criteria, and 540 (1.5%) none. Odds ratios for preterm birth and early preterm birth were 0.61 (95% Confidence Interval (CI): 0.35-1.05) and 0.28 (0.11-0.76), respectively, in MD women compared to women fulfilling none of the MD criteria. CONCLUSION: Shifting towards a MD during pregnancy may reduce the risk of early delivery in Danish women.

Validity of preeclampsia-related diagnoses recorded in a national hospital registry and in a postpartum interview of the women.

In a population-based sample, the authors examined the validity of preeclampsia and related diagnoses recorded in a mandatory Danish national hospital discharge registry and in a standardized telephone interview of women who gave birth between 1998 and 2002. Using a "gold standard" for preeclampsia defined in accordance with the guidelines from the American College of Obstetricians and Gynecologists, the authors reviewed hospital charts of 3,039 women and found that 61 of 88 preeclampsia cases (69.3%) and 24 of 55 cases of serious subtypes of preeclampsia (43.6%) were recorded as such by the registry. A total of 21 of 2,951 women without preeclampsia (0.71%) had a preeclampsia diagnosis in the registry. All registrations of serious subtypes of preeclampsia reflected true cases. The positive predictive value of a preeclampsia diagnosis in the registry was 74.4%. Including interview data reduced the sample size to 2,307 women. In this sample, of 62 women with preeclampsia, 45 (72.6%) reported in the interview to have had preeclampsia. Of 2,245 women with no preeclampsia, 31 (1.4%) reported to have had preeclampsia. The positive predictive value of the women's own report on preeclampsia was 59.2%. The authors conclude, for the purpose of etiologic studies, that the registry had acceptable validity, whereas the usefulness of self-reported information may be limited.

Data collected on maternal dietary exposures in the Danish National Birth Cohort.

Recent research suggests that the diet consumed in, or shortly before, pregnancy can potentially lead to maldevelopment and diseases in the offspring, which may become apparent at any time from the embryonic stage until old age. For example, maternal diet may affect the chance of twinning (and associated complications), malformation risk, brain development, and the offspring's fecundity and risk of contracting cardiovascular diseases and cancer in adult life. Prospectively designed longitudinal studies with sufficient size and data quality are much needed to substantiate or refute these hypotheses. At present, the Danish National Birth Cohort is likely to be the largest epidemiological database containing extensive information on maternal dietary exposures. By October 2002, 100 000 women had been recruited in early pregnancy, for long-term follow-up of themselves and their offspring. The present paper details the information available in the database on early nutritional exposures with emphasis on maternal dietary intake. We also present distributions of selected nutritional exposures.

Duration of pregnancy in relation to seafood intake during early and mid pregnancy: prospective cohort.

We examined the association between exposure to seafood intake during two periods of pregnancy on the one hand and risks of preterm delivery and postterm delivery on the other. In a prospective cohort of 8729 pregnant Danish women, we assessed frequency of fish meals during the first and second trimester of pregnancy by questionnaires completed around gestation weeks 16 and 30, respectively. When fish intake was based solely on intake reported for the early period of pregnancy, mean gestation length was shorter by 3.91 (95% CI: 2.24-5.58) days and odds of preterm delivery were increased 2.38 (1.23-4.61) times in those who never consumed fish (n = 308) vs. those who consumed both fish as main meal and fish in sandwiches at least once per week (n = 785). These measures were similar when fish intake was based solely on intake reported for mid-pregnancy. In the subgroup of women reporting same intake in the two trimesters, those who never consumed fish (n = 165) had 8.57 (5.46-11.7) days shorter mean gestation and 19.6 (2.32-165) times increased odds of preterm delivery, compared to high fish consumers (n = 127); odds of elective and postterm delivery were reduced by a factor 0.33 (0.11-1.02) and 0.34 (0.12-0.95), respectively, in zero fish consumers. All analyses were adjusted for potential confounding by factors such as maternal smoking, height, and prepregnant weight. We conclude that never consuming fish in the first two trimesters of pregnancy was an extremely strong risk factor for preterm delivery but was also associated with reduced risks of elective delivery and postterm delivery.