Secukinumab in moderate-to-severe hidradenitis suppurativa (SUNSHINE and SUNRISE): week 16 and week 52 results of two identical, multicentre, randomised, placebo-controlled, double-blind phase 3 trials.

BACKGROUND: Few therapeutic options are available for patients with moderate-to-severe hidradenitis suppurativa. We aimed to assess the efficacy of secukinumab in patients with moderate-to-severe hidradenitis suppurativa in two randomised trials. METHODS: SUNSHINE and SUNRISE were identical, multicentre, randomised, placebo-controlled, double-blind phase 3 trials done in 219 primary sites in 40 countries. Patients aged 18 years old or older with the capacity to provide written informed consent and with moderate-to-severe hidradenitis suppurativa (defined as a total of ≥5 inflammatory lesions affecting ≥2 distinct anatomical areas) for at least 1 year were eligible for inclusion. Included patients also agreed to daily use of topical over-the-counter antiseptics on the areas affected by hidradenitis suppurativa lesions while on study treatment. Patients were excluded if they had 20 or more fistulae at baseline, had ongoing active conditions requiring treatment with prohibited medication (eg, systemic biological immunomodulating treatment, live vaccines, or other investigational treatments), or met other exclusion criteria. In both trials, patients were randomly assigned (1:1:1) by means of interactive response technology to receive subcutaneous secukinumab 300 mg every 2 weeks, subcutaneous secukinumab 300 mg every 4 weeks, or subcutaneous placebo all via a 2 mL prefilled syringe in a double-dummy method as per treatment assignment. The primary endpoint was the proportion of patients with a hidradenitis suppurativa clinical response, defined as a decrease in abscess and inflammatory nodule count by 50% or more with no increase in the number of abscesses or in the number of draining fistulae compared with baseline, at week 16, assessed in the overall population. Hidradenitis suppurativa clinical response was calculated based on the number of abscesses, inflammatory nodules, draining fistulae, total fistulae, and other lesions in the hidradenitis suppurativa affected areas. Safety was assessed by evaluating the presence of adverse events and serious adverse events according to common terminology criteria for adverse events, which were coded using Medical Dictionary for Regulatory Activities terminology. Both the SUNSHINE, NCT03713619, and SUNRISE, NCT03713632, trials are registered with ClinicalTrials.gov. FINDINGS: Between Jan 31, 2019, and June 7, 2021, 676 patients were screened for inclusion in the SUNSHINE trial, of whom 541 (80%; 304 [56%] women and 237 [44%] men; mean age 36·1 years [SD 11·7]) were included in the analysis (181 [33%] in the secukinumab every 2 weeks group, 180 [33%] in the secukinumab every 4 weeks group, and 180 [33%] in the placebo group). Between the same recruitment dates, 687 patients were screened for inclusion in the SUNRISE trial, of whom 543 (79%; 306 [56%] women and 237 [44%] men; mean age 36·3 [11·4] years) were included in the analysis (180 [33%] in the secukinumab every 2 weeks group, 180 [33%] in the secukinumab every 4 weeks group, and 183 [34%] in the placebo group). In the SUNSHINE trial, significantly more patients in the secukinumab every 2 weeks group had a hidradenitis suppurativa clinical response (rounded average number of patients with response in 100 imputations, 81·5 [45%] of 181 patients) compared with the placebo group (60·7 [34%] of 180 patients; odds ratio 1·8 [95% CI 1·1-2·7]; p=0·0070). However, there was no significant difference between the number of patients in the secukinumab every 4 weeks group (75·2 [42%] of 180 patients) and the placebo group (1·5 [1·0-2·3]; p=0·042). Compared with the placebo group (57·1 [31%] of 183 patients), significantly more patients in the secukinumab every 2 weeks group (76·2 [42%] of 180 patients; 1·6 [1·1-2·6]; p=0·015) and the secukinumab every 4 weeks group (83·1 [46%] of 180 patients; 1·9 [1·2-3·0]; p=0·0022) had a hidradenitis suppurativa clinical response in the SUNRISE trial. Patient responses were sustained up to the end of the trials at week 52. The most common adverse event by preferred term up to week 16 was headache in both the SUNSHINE (17 [9%] patients in the secukinumab every 2 weeks group, 20 [11%] in the secukinumab every 4 weeks group, and 14 [8%] in the placebo group) and SUNRISE (21 [12%] patients in the secukinumab every 2 weeks group, 17 [9%] in the secukinumab every 4 weeks group, and 15 [8%] in the placebo group) trials. No study-related deaths were reported up to week 16. The safety profile of secukinumab in both trials was consistent with that previously reported, with no new or unexpected safety findings detected. INTERPRETATION: When given every 2 weeks, secukinumab was clinically effective at rapidly improving signs and symptoms of hidradenitis suppurativa with a favourable safety profile and with sustained response up to 52 weeks of treatment. FUNDING: Novartis Pharma.

New insights on hidradenitis suppurativa phenotypes and treatment response: An exploratory automated analysis of the SUNSHINE and SUNRISE trials.

BACKGROUND: Defining hidradenitis suppurativa (HS) subtypes was previously limited by small sample sizes and poor interrater reliability; no study has investigated subtype treatment responses. The objective of this analysis was to characterize HS clusters in adult patients with moderate to severe HS and evaluate secukinumab treatment responses between clusters. METHODS: Clusters were identified via an unsupervised machine learning clustering analysis using baseline data from the randomized, placebo-controlled SUNSHINE (NCT03713619) and SUNRISE (NCT03713632) phase 3 trials. To assess treatment responses, patients received secukinumab every 2 (SECQ2W) or 4 weeks (SECQ4W) or placebo, for 16 weeks, after which, placebo patients randomly switched to SECQ2W/SECQ4W, and SECQ2W/SECQ4W patients maintained their original treatment, until week 52. Baseline outcomes included patient characteristics, disease characteristics and severity, HS-associated comorbidities and previous treatment exposures. Treatment response was assessed via the HS clinical response (HiSCR), abscess and inflammatory nodule (AN) count, flares and NRS30 (skin pain). RESULTS: Based on baseline data, three clusters were identified from 1084 patients (Cluster 1: 54.1%, Cluster 2: 17.8%, Cluster 3: 28.1%). Cluster 1 was predominantly female (65.4%) and was characterized by milder HS. Cluster 2 had more patients from the Asia Pacific, Middle East and Africa region (58.5%) and was characterized by moderate HS. Cluster 3 had the highest rates of previous exposure to biologics (45.9%) and prior HS-related surgeries (47.5%) and was characterized by severe HS. SECQ2W and SECQ4W demonstrated efficacy versus placebo in all clusters at week 16; SECQ2W and SECQ4W efficacy was maintained to week 52. SECQ2W treatment showed a trend for greater efficacy versus SECQ4W in Cluster 3 through week 52. CONCLUSIONS: Three HS clusters were identified. Secukinumab demonstrated benefit over placebo in all clusters. However, patients with more severe disease may take longer to respond and more frequent secukinumab dosing may be required for these patients. TRIAL REGISTRATION: SUNSHINE (NCT03713619) and SUNRISE (NCT03713632).

Chronic kidney disease and cognitive decline in patients with type 2 diabetes at elevated cardiovascular risk.

AIMS: We addressed the question whether chronic kidney disease (CKD) may contribute to cognitive decline in type 2 diabetes. METHODS: Participants with type 2 diabetes with elevated cardiovascular risk or CKD from cognition substudies of two large trials were studied prospectively (CARMELINA: n = 2666, mean ± SD age 68.1 ± 8.7 years, CAROLINA: n = 4296; 64.7 ± 9.4 years). Estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) at baseline were related to cognitive performance (Mini-Mental State Examination (MMSE) and attention and executive functioning score (A&E)) in linear regression analyses, adjusted for demographics, cardiovascular risk factors and treatment, at baseline and follow-up. RESULTS: CKD at baseline was more common in CARMELINA than CAROLINA (eGFR<60 in 72.6 % and 19.6 %, macroalbuminuria in 35.0 % and 4.1 %, respectively). Baseline eGFR was related to A&E in CARMELINA (b = 0.02 per 10 ml/min/1.73m2, 95%CI [0.01,0.03]). Baseline UACR was related to A&E in CAROLINA (b = -0.01 per doubling of UACR mg/g, 95%CI [-0.02,-0.002]). Baseline UACR predicted decline in A&E in CAROLINA (median 6.1 years follow-up; b = -0.01, 95%CI [-0.03,-0.0001] per doubling of UACR mg/g). CONCLUSIONS: eGFR and UACR were associated with A&E in two cohorts with type 2 diabetes, enriched for CKD and cardiovascular disease. The small effect size estimates indicate limited impact of kidney dysfunction on cognition in this setting. GOV IDENTIFIERS: NCT01897532 NCT01243424.

Effect of Linagliptin on Cognitive Performance in Patients With Type 2 Diabetes and Cardiorenal Comorbidities: The CARMELINA Randomized Trial.

OBJECTIVE: Type 2 diabetes is associated with cognitive dysfunction and an increased dementia risk, particularly in individuals with concomitant cardiovascular and/or kidney disease. Incretin therapies may modulate this risk via glycemic and nonglycemic pathways. We explored if the dipeptidyl peptidase 4 inhibitor linagliptin could prevent cognitive decline in people with type 2 diabetes with cardiorenal disease. RESEARCH DESIGN AND METHODS: The CArdiovascular and Renal Microvascular outcomE study with LINAgliptin (CARMELINA)-COG substudy was an integral part of CARMELINA (NCT01897532) that randomized participants with cardiorenal disease to linagliptin 5 mg or placebo once daily (1:1), in addition to standard of care. The primary cognitive outcome was the occurrence of accelerated cognitive decline at the end of treatment, defined as a regression-based index score ≤16th percentile on the Mini-Mental State Examination (MMSE) or a composite measure of attention and executive functioning and analyzed in participants with a baseline MMSE ≥24. Effects across subgroups by baseline factors, as well as absolute cognitive changes, were also assessed. RESULTS: Of the 6,979 participants in CARMELINA, CARMELINA-COG included 1,545 (mean ± SD age, 68 ± 8 years; MMSE, 28.3 ± 1.7; estimated glomerular filtration rate, 52 ± 23 mL/min/1.73 m2; and HbA1c, 7.8 ± 0.9% [61.4 ± 10.1 mmol/mol]). Over a median treatment duration of 2.5 years, accelerated cognitive decline occurred in 28.4% (linagliptin) vs. 29.3% (placebo) (odds ratio 0.96 [95% CI 0.77, 1.19]). Consistent effects were observed across subgroups by baseline characteristics. Absolute cognitive performance changes were also similar between treatment groups. CONCLUSIONS: In a large international cardiovascular outcome trial in people with type 2 diabetes and cardiorenal disease, linagliptin did not modulate cognitive decline over 2.5 years.