Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2).

BACKGROUND: Tralokinumab, a fully human monoclonal antibody, specifically neutralizes interleukin-13, a key cytokine driving peripheral inflammation in atopic dermatitis (AD). In phase II studies, tralokinumab combined with topical corticosteroids provided early and sustained improvements in AD signs and symptoms. OBJECTIVES: To evaluate the efficacy and safety of tralokinumab monotherapy in adults with moderate-to-severe AD who had an inadequate response to topical treatments. METHODS: In two 52-week, randomized, double-blind, placebo-controlled, phase III trials, ECZTRA 1 and ECZTRA 2, adults with moderate-to-severe AD were randomized (3 : 1) to subcutaneous tralokinumab 300 mg every 2 weeks (Q2W) or placebo. Primary endpoints were Investigator's Global Assessment (IGA) score of 0 or 1 at week 16 and ≥ 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16. Patients achieving an IGA score of 0 or 1 and/or EASI 75 with tralokinumab at week 16 were rerandomized to tralokinumab Q2W or every 4 weeks or placebo, for 36 weeks. The trials were registered with ClinicalTrials.gov: NCT03131648 and NCT03160885. RESULTS: At week 16, more patients who received tralokinumab vs. placebo achieved an IGA score of 0 or 1: 15·8% vs. 7·1% in ECZTRA 1 [difference 8·6%, 95% confidence interval (CI) 4·1-13·1; P = 0·002] and 22·2% vs. 10·9% in ECZTRA 2 (11·1%, 95% CI 5·8-16·4; P < 0·001) and EASI 75: 25·0% vs. 12·7% (12·1%, 95% CI 6·5-17·7; P < 0·001) and 33·2% vs. 11·4% (21·6%, 95% CI 15·8-27·3; P < 0·001). Early improvements in pruritus, sleep interference, Dermatology Life Quality Index, SCORing Atopic Dermatitis and Patient-Oriented Eczema Measure were observed from the first postbaseline measurements. The majority of week 16 tralokinumab responders maintained response at week 52 with continued tralokinumab treatment without any rescue medication (including topical corticosteroids). Adverse events were reported in 76·4% and 61·5% of patients receiving tralokinumab in ECZTRA 1 and ECZTRA 2, respectively, and in 77·0% and 66·0% of patients receiving placebo in ECZTRA 1 and ECZTRA 2, respectively, in the 16-week initial period. CONCLUSIONS: Tralokinumab monotherapy was superior to placebo at 16 weeks of treatment and was well tolerated up to 52 weeks of treatment.

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.

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.

A seamless phase I/II dose-finding trial assessing ingenol disoxate (LEO 43204) for field treatment of actinic keratosis on the scalp.

BACKGROUND: Actinic keratosis (AK) is a common sun-related skin condition, which can progress to squamous cell carcinoma and occur in cancerized fields. OBJECTIVES: To investigate in a phase I/II trial the safety and efficacy of ingenol disoxate as topical field therapy for patients with AK on the balding scalp. METHODS: Part 1 was a phase I, open-label, dose-escalation trial investigating up to six doses of ingenol disoxate to determine the maximum tolerated dose (MTD). Part 2 was a phase II, randomized, double-blind, parallel group, vehicle-controlled trial. Patients were randomized 2 : 2 : 1 to receive ingenol disoxate 0·037%, 0·05% or vehicle gel once daily for two consecutive days. Percentage reduction in AK count from baseline, complete clearance (AKCLEAR 100) and partial clearance (≥ 75% AK count reduction; AKCLEAR 75) were assessed at week 8. RESULTS: The MTD in part 1 was 0·075% based on a dose-dependent increase in the number and severity of adverse events. Two lower doses of ingenol disoxate gel (0·037%, 0·05%) were assessed in part 2, which showed a reduction in AK count from baseline to week 8 (0·037%, 72·7%; 0·05%, 78·5% vs. vehicle 12·6; P < 0·001), and rates of AKCLEAR 100 and AKCLEAR 75 were significantly higher in active treatment groups compared with vehicle (P ≤ 0·007). Local skin responses peaked at day 3 and declined rapidly. Adverse events were generally mild to moderate in intensity, and were most commonly application site pain/pruritus. CONCLUSIONS: Ingenol disoxate 0·037% and 0·05% gel was effective and superior to vehicle, and well tolerated as field therapy for AK on the balding scalp.

A randomized, phase IIa exploratory trial to assess the safety and preliminary efficacy of LEO 43204 in patients with actinic keratosis.

BACKGROUND: LEO 43204 is a novel ingenol derivative in development for the treatment of actinic keratosis. OBJECTIVES: To compare the safety and preliminary efficacy of three doses of LEO 43204 with ingenol mebutate in actinic keratoses (AKs). METHODS: Patients with at least three visible, discrete, nonkeratotic AKs on four separate selected treatment areas on the forearms received LEO 43204 gel (0·025%, 0·05% and 0·075%) and ingenol mebutate 0·05% gel, by investigator-blinded, randomized allocation, for 2 consecutive days. Patients were assessed at 8 weeks. Primary outcomes included maximum composite local skin response (LSR) score and adverse events (AEs). Secondary outcomes included a reduction in the number of visible AKs. RESULTS: Forty patients completed the trial. For all treatments, mean LSR scores peaked at week 1, and were below baseline by week 8. Mean maximum composite LSR scores for LEO 43204 0·025%, 0·05% and 0·075% were 9·2 (Dunnett adjusted P = 0·02), 10·1 (Dunnett adjusted P = 0·90) and 11·2 (Dunnett adjusted P < 0·01), respectively, vs. ingenol mebutate 0·05% gel (10·0). The most frequent AEs across all treatments were application site pruritus, burning sensation and tenderness. Mean reduction in the number of AKs was comparable for ingenol mebutate and the two lowest doses of LEO 43204 (71·9-73·1%), but LEO 43204 0·075% gave a significantly larger reduction (81·8%; Dunnett adjusted P = 0·04). CONCLUSIONS: LEO 43204 had a similar safety profile to ingenol mebutate and a dose-response relationship for LSRs was demonstrated. The highest LEO 43204 dose (0·075%) significantly reduced the AK count when compared with ingenol mebutate.

Efficacy and safety of follow-up field treatment of actinic keratosis with ingenol mebutate 0·015% gel: a randomized, controlled 12-month study.

BACKGROUND: Ingenol mebutate (IngMeb) is a novel patient-applied topical field therapy for actinic keratosis. OBJECTIVES: To demonstrate the efficacy and safety of follow-up IngMeb field treatment of actinic keratoses (AKs) present at 8 weeks after initial treatment or emerging in a previously cleared field. METHODS: In this phase III, randomized, double-blind study in patients with 4-8 clinically visible AKs within a contiguous 25-cm(2) treatment area on the face or scalp, all patients were treated initially with IngMeb 0·015% gel for three consecutive days. If lesions were present in the field at 8 weeks, or emerged at weeks 26 or 44, patients were randomized (2 : 1) to follow-up IngMeb or vehicle gel for three consecutive days. The main outcome was complete clearance rates of AKs 8 weeks after randomization. RESULTS: Of 450 patients who received initial treatment with IngMeb, 61·6% demonstrated complete clearance at 8 weeks. Patients with AKs present at 8 weeks or emerging at weeks 26 or 44 were randomized to IngMeb (n = 134) or vehicle (n = 69). IngMeb achieved a higher complete clearance rate than vehicle 8 weeks after randomization in AKs present at 8 weeks (46·7% vs. 18·4%; P < 0·01) and in emergent AKs (59·5% vs. 25·0%; P = 0·01). Based on those who completed 12 months of follow-up (n = 340), the overall 12-month clearance rate was estimated at 50·0%. Follow-up IngMeb treatment was well tolerated. CONCLUSIONS: This study demonstrated the long-term benefit of IngMeb 0·015% gel for initial and follow-up therapy of AKs.

Intake of vitamin C and E in pregnancy and risk of pre-eclampsia: prospective study among 57 346 women.

OBJECTIVE: It has been suggested that vitamin C, alone or in combination with vitamin E, may protect against pre-eclampsia, whereas the safety of high-dose vitamin E supplements has been questioned. We investigated dietary intakes of vitamins C and E to see if they correlated with the incidence of pre-eclampsia. DESIGN: Prospective cohort study. SETTING: The Danish National Birth Cohort; a population-based pregnancy cohort; analyses were based on 57 346 pregnancies. METHODS: Vitamin intake was estimated from a food frequency questionnaire completed in gestational week 25, recording intake from diet and supplements during the previous four weeks. Pre-eclampsia diagnoses were obtained from the Danish National Patient Registry; we worked with two entities, 'pre-eclampsia (all types)' and 'severe pre-eclampsia/eclampsia/HELLP'. We adjusted for confounding factors by logistic regression. MAIN OUTCOME MEASURES: A small increase in the incidence of severe disease was also seen in the group of women (64, n = 49 373) with a high intake of vitamin E from supplements and dietary sources. RESULTS: The incidence of 'pre-eclampsia (all types)' did not correlate with dietary vitamin C and E intake. There was a decreasing trend (P = 0.01) in the incidence of 'severe pre-eclampsia/eclampsia/HELLP' with increasing dietary vitamin C intake; with an intake of 130-170 mg/day as reference, odds ratios ranged from 1.21 (95% confidence interval 0.83 to 1.75) for an intake below 70 mg/day to 0.70 (0.40 to 1.23) for an intake exceeding 275 mg/day (total n = 57 346). For vitamin E intake aggregated from diet and supplements (n = 49 373), with an intake of 10.5-13.5 mg/day as reference, the 'severe pre-eclampsia/eclampsia/HELLP' odds ratio was 1.46 (1.02 to 2.09) for an intake exceeding 18 mg/day. CONCLUSIONS: Low dietary intake of vitamin C was associated with a trend towards an increased incidence of either severe pre-eclampsia, eclampsia or HELLP. A small increase in the incidence of severe disease was also seen in the group of women with a high intake of vitamin E from supplements and dietary sources.

Does leisure time physical activity in early pregnancy protect against pre-eclampsia? Prospective cohort in Danish women.

OBJECTIVE: To examine the association between physical activity in early pregnancy and risk of pre-eclampsia. DESIGN: Prospective cohort. SETTING: Denmark. POPULATION: A total of 85,139 pregnant Danish women, recruited between 1996 and 2002. METHODS: The authors assessed leisure time physical activity in first trimester by a telephone interview and categorised women a priori into seven groups: 0 (reference), 1-44, 45-74, 75-149, 150-269, 270-419 and 420+ minutes/week. Pre-eclampsia diagnoses were extracted from the Danish National Patient Registry. A number of potential confounders were adjusted for by logistic regression. MAIN OUTCOME MEASURES: Pre-eclampsia and severe pre-eclampsia. RESULTS: The two highest physical activity levels were associated with increased risk of severe pre-eclampsia compared with the nonexercising group, with adjusted odds ratios of 1.65 (95% CI: 1.11-2.43) and 1.78 (95% CI: 1.07-2.95), whereas more moderate levels of physical activity (1-270 minutes/week) had no statistically significant association with risk of pre-eclampsia (total n = 85,139). CONCLUSIONS: We were unable to document a protective effect of leisure time physical activity against pre-eclampsia. Our data even suggest that leisure time physical activity exceeding 270 minutes/week in first trimester may increase risk of severe pre-eclampsia.

Duration of pregnancy in relation to fish oil supplementation and habitual fish intake: a randomised clinical trial with fish oil.

OBJECTIVE: To examine the effect of fish oil supplementation on duration of pregnancy, conditional on the woman's habitual fish intake. DESIGN: Multicentre 1:1 randomised clinical trial of effect of fish oil in a high-risk population of pregnant women in whom habitual fish intake was assessed at randomisation. SETTING: Nineteen university delivery wards in seven European countries. SUBJECTS: Pregnant women with preterm delivery, intrauterine growth retardation (IUGR), or pregnancy-induced hypertension (PIH) in a previous pregnancy (group 1, n=495); with twin pregnancies (group 2, n=367); or with suspicion of IUGR or threatening preeclampsia in the current pregnancy (group 3, n=106). Women were stratified into low, middle, or high fish consumers. METHODS: The intervention group received fish oil capsules providing 2.7 g long-chain n-3 fatty acids per day (n-3 poly unsaturated fatty acids (PUFA)) from around week 20 (groups 1 and 2) or 6.3 g n-3 PUFA from week 33 (group 3). The control regimen was capsules with olive oil. Effect on timing of spontaneous delivery was examined by Cox regression, assuming elective delivery (occurring in 40%) as a censoring event. Analyses of effect of fish oil were intention to treat, and all analyses were adjusted for maternal smoking, age, and parity. RESULTS: In group 1, fish oil reduced the hazard rate of spontaneous delivery (HR) by 44% (95% confidence interval 14-64%) and 39% (16-56%) in low and middle fish consumers, respectively, with no detectable effect (-56 to 33%) in high fish consumers. In groups 2 and 3, no significant effect of fish oil was detected in any of the sub-strata defined by baseline fish consumption. CONCLUSIONS: In pregnant women with previous pregnancy complications, fish oil supplementation delayed onset of delivery in low and middle, but not in high, fish consumers. SPONSORSHIP: March of Dimes Birth Defects Foundation, Concerted Action (ERB-BMH1-CT92-1906) and PECO (ERB-CIPD-CT94-0235) programmes of the European Commission, and the Danish National Research Foundation. Lube Ltd donated the oil capsules.

Fish oil in various doses or flax oil in pregnancy and timing of spontaneous delivery: a randomised controlled trial.

OBJECTIVES: To test the earlier suggested hypothesis that intake of long-chain n-3 fatty acids from fish oil may delay the timing of spontaneous delivery and to test if alpha-linolenic acid, provided as flax oil capsules, shows the same effect. DESIGN: Randomised controlled trial including women reporting low dietary fish intake. The women were allocated in the proportions of 1:1:1:1:1:1:2 into six treatment groups and a control group, respectively, from week 17-27 of gestation. The treatment groups received fish oil, in various doses, or flax oil, and the control group did not receive any treatment. SETTING: The Danish National Birth Cohort. SAMPLE: A total of 3098 women allocated into six treatment groups and one control group. METHODS: The six intervention groups were offered fish oil capsules in doses of 0.1, 0.3, 0.7, 1.4 and 2.8 g of eicosapentaenoic acid and docosahexaenoic acid per day or 2.2 g of alpha-linolenic acid (ALA) per day from week 17-27 of gestation until delivery. MAIN OUTCOME MEASURES: Timing of spontaneous delivery. RESULTS: No differences in timing of spontaneous delivery was detected in the fish oil groups or the flax oil group, compared with the control group. The difference in timing of spontaneous delivery in the group receiving the highest fish oil dose compared with the control group was 0.8 days (95% CI: -2.3 to 1.0). Only a minority of the women in the intervention groups took capsules until delivery. CONCLUSION: Possible explanations for these findings include no true effect of n-3 fatty acids on spontaneous delivery or a quick-acting effect not detectable in this trial.