Upadacitinib treatment withdrawal and retreatment in patients with moderate-to-severe atopic dermatitis: Results from a phase 2b, randomized, controlled trial.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritic eczematous lesions. The effect of treatment withdrawal after response to upadacitinib oral treatment is not fully characterized. OBJECTIVES: Assess the effect of upadacitinib withdrawal on skin clearance and itch improvement in adult patients with moderate-to-severe AD and evaluate the kinetics of recovery on rescue treatment. METHODS: Data from a phase 2b randomized, placebo-controlled trial (NCT02925117) of upadacitinib in patients with moderate-to-severe AD were analysed. Patients were randomized 1:1:1:1 to receive upadacitinib 7.5 mg, 15 mg, 30 mg or placebo, and then at Week 16, patients were re-randomized 1:1 to receive the same dose of upadacitinib (upadacitinib 30 mg for patients initialized to placebo) or placebo. From Week 20, those who experienced loss of response defined as Eczema Area and Severity Index <50% improvement from baseline (EASI 50) received rescue treatment with upadacitinib 30 mg. RESULTS: Patients who withdrew from upadacitinib experienced a rapid loss of skin clearance response, while those who switched from placebo to upadacitinib gained response. Loss of skin clearance response occurred within 4 weeks and worsening of itch occurred within 5 days. In patients who originally received placebo or a lower dose of upadacitinib leading to a loss of EASI response, rescue treatment with upadacitinib 30 mg resulted in rapid recovery or improvement of both skin and itch responses; most patients who were re-randomized to placebo achieved EASI 75 and IGA 0/1 by 8 weeks of rescue treatment. No new safety risks were observed. CONCLUSIONS: Continuous treatment with upadacitinib is suggested to maintain skin clearance and antipruritic effects.

Patient preferences for atopic dermatitis treatments: a discrete choice experiment.

BACKGROUND: Patients with moderate-to-severe atopic dermatitis (AD) experience skin lesions and intense itch that substantially affect quality of life. Patients have choices among systemic AD treatments that offer varied benefit-risk profiles. OBJECTIVE: Measure patients' willingness to trade off the risks and benefits of systemic treatments among individuals with a physician-confirmed diagnosis of moderate-to-severe AD. METHODS: Patients participated in a discrete choice experiment online survey with a series of choices between hypothetical AD treatments defined by six attributes reflecting benefits and risks of treatments (itch reduction, time until noticeable itch reduction, chance of clear or almost clear skin, risk of serious infection, risk of developing acne, and need for prescription topical steroids). Data were analyzed with a random parameters logit model to quantify preferences and the relative importance of attributes for treatment alternatives. RESULTS: Respondents (n = 200) placed the highest relative importance on itch reduction, speed of itch reduction, and skin clearance, and were generally willing to accept clinically relevant levels of risk of serious infection and acne in exchange for treatment benefits. CONCLUSIONS: Patients with moderate-to-severe AD were willing to trade clinically relevant treatment risks for greater or more rapid itch reduction and skin clearance offered by systemic therapies.

Characterization of acne associated with upadacitinib treatment in patients with moderate-to-severe atopic dermatitis: A post hoc integrated analysis of 3 phase 3 randomized, double-blind, placebo-controlled trials.

BACKGROUND: Acne is the most frequent adverse event associated with upadacitinib treatment in patients with moderate-to-severe atopic dermatitis. OBJECTIVE: To characterize the adverse event of acne associated with upadacitinib. METHODS: This was a post hoc integrated analysis of 3 phase 3 randomized, double-blind, placebo-controlled trials of upadacitinib, alone (NCT03569293 and NCT03607422) or in combination with topical corticosteroids (NCT03568318). Data included were from the 16-week placebo-controlled period. RESULTS: Over 16 weeks, 84 of 857 (9.8%), 131 of 864 (15.2%), and 19 of 862 (2.2%) patients randomized to receive upadacitinib 15 mg, upadacitinib 30 mg, and placebo, respectively, experienced acne. All cases of acne, except 1, were mild/moderate in severity; 2 patients discontinued treatment due to moderate acne. Acne occurred at higher rates among younger, female, and non-White patients. Acne required no intervention in 40.5% and 46.6% of patients receiving upadacitinib 15 and 30 mg, respectively; most remaining cases were managed with topical antibiotics, benzoyl peroxide, and/or retinoids. Acne also had no impact on patient-reported outcomes. LIMITATIONS: This study was relatively short in duration and had a small patient population. CONCLUSIONS: Acne associated with upadacitinib for atopic dermatitis treatment is usually mild/moderate in severity and managed with topical therapies or no intervention.

A randomized, placebo-controlled, multicenter study of divalproex sodium extended-release in the acute treatment of mania.

OBJECTIVE: Divalproex sodium extended-release (ER) was examined for the treatment of acute mania in adults in 2 randomized, placebo-controlled clinical trials. One study demonstrated statistically significant improvements in mania symptoms compared to placebo, while an earlier study did not. Results of the earlier study are presented here. METHOD: A total of 225 DSM-IV-diagnosed bipolar I disorder patients were randomly assigned in a 2:1 ratio to 21 days of double-blind treatment with divalproex ER (n = 147) or placebo (n = 78). The daily divalproex ER dosage was initiated at 20 mg/kg. The primary efficacy variable was the change from baseline to final evaluation in Mania Rating Scale (MRS) score. Subjects were discontinued from the study if they were discharged from the hospital or if they met prespecified improvement criteria. The study was conducted from May 1998 to July 1999 at centers in the United States. RESULTS: There was no statistically significant difference in MRS score change from baseline to final for patients treated with divalproex ER compared with those treated with placebo. With the exception of back pain and constipation, adverse event rates between placebo and divalproex ER were very similar. A large proportion of patients prematurely discontinued study treatment (divalproex ER: 83%, placebo: 82%). The mean daily dose of divalproex ER was 2,211 mg with a mean maximum serum valproic acid concentration of 77.9 microg/mL. CONCLUSIONS: The results of the current study did not demonstrate statistically significant improvement in mania symptoms associated with divalproex ER treatment compared to placebo. A number of methodological considerations may have contributed to the negative findings, including allowance for early study discontinuation and lower than optimal dosing. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00060905.

Divalproex sodium in children with partial seizures: 12-month safety study.

This phase III, open-label, multicenter, outpatient study evaluated the 12-month safety of valproate using divalproex sodium sprinkle capsules for partial seizures, with or without secondary generalization, in children aged 3-10 years (n = 169). Laboratory parameters and vital signs were assessed, and the Wechsler Scales of Intelligence, the Developmental Profile-II, movement-related items from the Udvalg for Kliniske Undersøgelser, and the Behavior Assessment System for Children were administered. Efficacy was measured by the 4-week seizure rate. The most common treatment-emergent adverse events in the 169 study patients were typical childhood illnesses: pyrexia (18%), cough (17%), and nasopharyngitis (14%). The most common adverse events not considered typical childhood illnesses were vomiting (14%), tremor (9%), somnolence (8%), and diarrhea (8%). Of the 169 patients, 11 (6.5%) were hospitalized with serious treatment-emergent adverse events. Although elevated ammonia levels were observed in 31 treated patients, and mean increases in uric acid concentrations and decreases in platelets were observed, the majority of patients were asymptomatic. Except for tremor, no increases in movement-related adverse effects were observed. Small numeric improvements were reported in the Wechsler Scales and the Behavior Assessment System for Children. The safety findings in this 12-month study are generally consistent with previous reports of valproate in adult and pediatric epilepsy patients.

A double-blind, randomized, placebo-controlled trial of divalproex extended-release in the treatment of bipolar disorder in children and adolescents.

OBJECTIVE: To compare the efficacy and safety of divalproex extended-release (ER) to placebo in a 28-day double-blind study of bipolar disorder in children and adolescents and evaluate the safety of divalproex ER in a 6-month open-label extension study. METHOD: In the double-blind study, 150 patients (manic or mixed episode, aged 10-17 years) with baseline Young Mania Rating Scale (YMRS) score of 20 or higher were randomized to once-daily placebo or divalproex ER, which was titrated to clinical response or serum valproate concentration of 80 to 125 microg/mL. Sixty-six patients enrolled in the extension study. RESULTS: In the double-blind study, a treatment effect was not observed with divalproex ER based on change in mean YMRS score (divalproex ER -8.8 [n = 74]; placebo -7.9 [n = 70]) or secondary measures. Divalproex was similar to placebo based on incidence of adverse events. Four subjects treated with divalproex ER and three treated with placebo discontinued because of adverse events. Mean ammonia levels increased in the divalproex ER group, but only one patient was symptomatic. In the long-term study, YMRS scores decreased modestly (2.2 points from baseline). The most common adverse events were headache and vomiting. CONCLUSIONS: The results of the study do not provide support for the use of divalproex ER in the treatment of youths with bipolar I disorder, mixed or manic state. Further controlled trials are required to confirm or refute the findings from this study.

Long-term safety of divalproex sodium extended-release in children and adolescents with bipolar I disorder.

OBJECTIVE: The objective of this open-label study was to assess the safety of divalproex sodium extended-release in the treatment of children and adolescents with acute mania associated with bipolar I disorder. METHODS: This was a 6-month, Phase 3, open-label study in healthy subjects aged 9-17 years with a current Diagnostic and Statistical Manual of Mental Disorders, 4(th) edition, Text Revision (DSM-IV-TR) diagnosis of bipolar I disorder manic or mixed episode. Divalproex sodium extended-release (DVPX-ER) was initiated at 15 mg/kg per day on day 1 (not to exceed 750 mg/day) with increases allowed to a maximum of 35 mg/kg per day. Study visits were conducted on day 1 and at months 1, 2, 3, and 6. Assessments included standard safety evaluations and appropriate rating scales for clinical effect. RESULTS: A total of 226 subjects were enrolled; 109 subjects completed the study. The most common adverse events were weight gain (16%), nausea (9%), and increased appetite (8%). Nonsymptomatic elevations of mean ammonia levels in plasma were observed. The mean Young Mania Rating Scale (YMRS) decreased 12.4 from baseline to final visit; small improvements were seen in behavior and caregiver stress ratings. CONCLUSIONS: DVPX-ER was generally well tolerated in children and adolescents with acute mania, with a side-effect profile similar to that observed in adults.