Proof-of-concept study exploring the effect of spesolimab in patients with moderate-to-severe hidradenitis suppurativa: A randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease with a considerable disease burden. Existing treatment options are limited and often suboptimal; a high unmet need exists for effective targeted therapies. OBJECTIVE: To explore the effects of spesolimab treatment in patients with HS. METHODS: This randomized, double-blind, placebo-controlled, proof-of-clinical-concept study was conducted at 25 centers across 12 countries from May 3, 2021, to April 21, 2022. Patients had moderate-to-severe HS for ≥1 year before enrollment. Patients were randomized (2:1) to receive a loading dose of 3600 mg intravenous spesolimab (1200 mg at Weeks 0, 1, and 2) or matching placebo, followed by maintenance with either 1200 mg subcutaneous spesolimab every 2 weeks from Week 4-10 or matching placebo. The primary endpoint was the percentage change from baseline in total abscess and inflammatory nodule (AN) count at Week 12. Secondary endpoints were the absolute change from baseline in International Hidradenitis Suppurativa Severity Score System (IHS4), percentage change from baseline in draining tunnel (dT) count, the proportion of patients achieving a dT count of zero, absolute change from baseline in revised Hidradenitis Suppurativa Area and Severity Index (HASI-R), the proportion of patients achieving Hidradenitis Suppurativa Clinical Response (HiSCR50), the proportion of patients with ≥1 flare (all at Week 12), and patient-reported outcomes (PROs). RESULTS: In this completed trial, randomized patients (N=52) received spesolimab (n=35) or placebo (n=17). The difference (95% confidence interval) versus placebo in least squares mean are reported. At Week 12, the percentage change in total AN count was similar between treatment arms: -4.1% (-31.7, 23.4). There was greater numerical improvement in the spesolimab arm, as measured by IHS4: -13.9 (-25.6, -2.3); percentage change from baseline in dT count: -96.6% (-154.5, -38.8); and the proportion of patients achieving a dT count of zero: 18.3% (-7.9, 37.5). Spesolimab treatment also improved HASI-R and HiSCR50 versus placebo. Spesolimab demonstrated a favorable safety profile, similar to that observed in trials in other diseases. CONCLUSIONS: This exploratory proof-of-clinical-concept study supports the development of spesolimab as a new therapeutic option in HS. ClinicalTrials.gov identifier: NCT04762277.

Validity and responsiveness of the Daily- and Clinical visit-PROactive Physical Activity in COPD (D-PPAC and C-PPAC) instruments.

BACKGROUND: The Daily-PROactive and Clinical visit-PROactive Physical Activity (D-PPAC and C-PPAC) instruments in chronic obstructive pulmonary disease (COPD) combines questionnaire with activity monitor data to measure patients' experience of physical activity. Their amount, difficulty and total scores range from 0 (worst) to 100 (best) but require further psychometric evaluation. OBJECTIVE: To test reliability, validity and responsiveness, and to define minimal important difference (MID), of the D-PPAC and C-PPAC instruments, in a large population of patients with stable COPD from diverse severities, settings and countries. METHODS: We used data from seven randomised controlled trials to evaluate D-PPAC and C-PPAC internal consistency and construct validity by sex, age groups, COPD severity, country and language as well as responsiveness to interventions, ability to detect change and MID. RESULTS: We included 1324 patients (mean (SD) age 66 (8) years, forced expiratory volume in 1 s 55 (17)% predicted). Scores covered almost the full range from 0 to 100, showed strong internal consistency after stratification and correlated as a priori hypothesised with dyspnoea, health-related quality of life and exercise capacity. Difficulty scores improved after pharmacological treatment and pulmonary rehabilitation, while amount scores improved after behavioural physical activity interventions. All scores were responsive to changes in self-reported physical activity experience (both worsening and improvement) and to the occurrence of COPD exacerbations during follow-up. The MID was estimated to 6 for amount and difficulty scores and 4 for total score. CONCLUSIONS: The D-PPAC and C-PPAC instruments are reliable and valid across diverse COPD populations and responsive to pharmacological and non-pharmacological interventions and changes in clinically relevant variables.

Efficacy and Safety of 5-Fluorouracil 0.5%/Salicylic Acid 10% in the Field-Directed Treatment of Actinic Keratosis: A Phase III, Randomized, Double-Blind, Vehicle-Controlled Trial.

INTRODUCTION: Due to the high prevalence of actinic keratosis (AK) and potential for lesions to become cancerous, clinical guidelines recommend that all are treated. The objective of this study was to evaluate the efficacy and safety of 5-fluorouracil (5-FU) 0.5%/salicylic acid 10% as field-directed treatment of AK lesions. METHODS: This multicenter, double-blind, vehicle-controlled study (NCT02289768) randomized adults, with a 25 cm2 area of skin on their face, bald scalp, or forehead covering 4-10 clinically confirmed AK lesions (grade I/II), 2:1 to treatment or vehicle applied topically once daily for 12 weeks. The primary endpoint was the proportion of patients with complete clinical clearance (CCC) of lesions in the treatment field 8 weeks after the end of treatment. Secondary endpoints included partial clearance (PC; ≥75% reduction) of lesions. Safety outcomes were assessed. RESULTS: Of 166 patients randomized, 111 received 5-FU 0.5%/salicylic acid 10% and 55 received vehicle. At 8 weeks after the end of treatment, CCC was significantly higher with 5-FU 0.5%/salicylic acid 10% than with vehicle [49.5% vs. 18.2%, respectively; odds ratio (OR) 3.9 (95% CI) 1.7, 8.7; P = 0.0006]. Significantly more patients achieved PC of lesions with treatment than with vehicle [69.5% vs. 34.6%, respectively; OR 4.9 (95% CI 2.3, 10.5); P < 0.0001]. Treatment-emergent adverse events, predominantly related to application- and administration-site reactions, were more common with 5-FU 0.5%/salicylic acid 10% than with vehicle (99.1% vs. 83.6%). CONCLUSIONS: Compared with vehicle, field-directed treatment of AK lesions with 5-FU 0.5%/salicylic acid 10% was effective in terms of CCC. Safety outcomes were consistent with the known and predictable safety profile. TRIAL REGISTRATION: NCT02289768. FUNDING: Almirall S.A.

The PROactive instruments to measure physical activity in patients with chronic obstructive pulmonary disease.

No current patient-centred instrument captures all dimensions of physical activity in chronic obstructive pulmonary disease (COPD). Our objective was item reduction and initial validation of two instruments to measure physical activity in COPD.Physical activity was assessed in a 6-week, randomised, two-way cross-over, multicentre study using PROactive draft questionnaires (daily and clinical visit versions) and two activity monitors. Item reduction followed an iterative process including classical and Rasch model analyses, and input from patients and clinical experts.236 COPD patients from five European centres were included. Results indicated the concept of physical activity in COPD had two domains, labelled "amount" and "difficulty". After item reduction, the daily PROactive instrument comprised nine items and the clinical visit contained 14. Both demonstrated good model fit (person separation index >0.7). Confirmatory factor analysis supported the bidimensional structure. Both instruments had good internal consistency (Cronbach's α>0.8), test-retest reliability (intraclass correlation coefficient ≥0.9) and exhibited moderate-to-high correlations (r>0.6) with related constructs and very low correlations (r<0.3) with unrelated constructs, providing evidence for construct validity.Daily and clinical visit "PROactive physical activity in COPD" instruments are hybrid tools combining a short patient-reported outcome questionnaire and two activity monitor variables which provide simple, valid and reliable measures of physical activity in COPD patients.

Safety, efficacy, and immunogenicity of a live, quadrivalent human-bovine reassortant rotavirus vaccine in healthy infants.

OBJECTIVES: To investigate safety, efficacy, and immunogenicity of live quadrivalent rotavirus vaccine (QRV) containing human-bovine (WC3) reassortant rotavirus serotypes G1, G2, G3, and P1a. STUDY DESIGN: This was a randomized, double-blinded, placebo-controlled trial. During 1993 to 1994, at 10 US study sites, 439 healthy infants approximately 2 to 6 months of age, were enrolled to receive 3 doses of oral QRV or placebo at approximately 8-week intervals. RESULTS: The vaccine was generally well tolerated; no serious vaccine-related adverse experiences were reported. Risk differences and 95% confidence intervals suggested no differences between vaccine and placebo recipients in the incidences of fever, irritability, vomiting, or diarrhea during the 14 days after any dose. QRV was 74.6% efficacious (95% CI: 49.5%, 88.3%) in preventing rotavirus acute gastroenteritis (AGE), regardless of severity and 100% efficacious (95% CI: 43.5%, 100%) in preventing severe rotavirus AGE through one rotavirus season. Serotype G1 was identified in most infants with rotavirus AGE. A >or=3-fold rise in serum neutralizing antibody to G1 was observed in 57% (45/79) of vaccinees. A >or=3-fold rise in serum anti-rotavirus IgA and fecal anti-rotavirus IgA was observed in 88% (162/185) and 65% (104/159) of vaccinees, respectively. CONCLUSIONS: QRV was generally well tolerated, immungenic, and highly effective against rotavirus gastroenteritis.