Mean Percentage Change Research Articles

Evaluating the Safety and effectivenesS in adult KorEaN patients treated with Tolvaptan for management of autosomal domInAnt poLycystic kidney disease (ESSENTIAL): final report.

Tolvaptan, a selective vasopressin V2 receptor antagonist, was first approved by the Korean Ministry of Food and Drug Safety in 2015 as a treatment option for autosomal dominant polycystic kidney disease (ADPKD). To prescribe tolvaptan safely and effectively, we designed the phase 4 clinical trial among Korean ADPKD patients with chronic kidney disease stages 1 to 3. A total of 117 Korean patients aged 19 to 50 years with rapidly progressing ADPKD were enrolled in the study. Tolvaptan was prescribed for 24 months with the maximum tolerable dose up to 120 mg/day. The primary outcome was the incidence of treatment-emergent adverse events (TEAEs) including hepatic adverse events. The secondary outcomes were the annual mean percent change of total kidney volume (TKV) and the annual mean change of estimated glomerular filtration rate (eGFR). A total of 489 TEAEs occurred in 106 patients (90.6%). A total of 17 cases of hepatic adverse events (14.5%) occurred during the study period and mostly within the first 18-month period. However, liver enzymes were normalized after drug discontinuation. Although it was not statistically significant, patients with a previous history of liver disease as well as those with mild elevation of liver enzyme showed a higher frequency of hepatic adverse events. Compared with the predicted value from the calculation, tolvaptan attenuated both TKV growth and eGFR decline rate. Although the incidence of hepatic adverse events was higher in Korean ADPKD patients compared to the previous studies, tolvaptan can be prescribed safely and effectively using meticulous titration and 1-month interval monitoring.

Liraglutide for Children 6 to

No medications are currently approved for the treatment of nonmonogenic, nonsyndromic obesity in children younger than 12 years of age. Although the use of liraglutide has been shown to induce weight loss in adults and adolescents with obesity, its safety and efficacy have not been established in children. In this phase 3a trial, which consisted of a 56-week treatment period and a 26-week follow-up period,we randomly assigned children (6 to <12 years of age) with obesity, in a 2:1 ratio, to receive either once-daily subcutaneous liraglutide at a dose of 3.0 mg (or the maximum tolerated dose) or placebo, plus lifestyle interventions. The primary end point was the percentage change in the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters). The confirmatory secondary end points were the percentage change in body weight and a reduction in BMI of at least 5%. A total of 82 participants underwent randomization; 56 were assigned to the liraglutide group and 26 to the placebo group. At week 56, the mean percentage change from baseline in BMI was -5.8% with liraglutide and 1.6% with placebo, representing an estimated difference of -7.4 percentage points (95% confidence interval [CI], -11.6 to -3.2; P<0.001). The mean percentage change in body weight was 1.6% with liraglutide and 10.0% with placebo, representing an estimated difference of -8.4 percentage points (95% CI, -13.4 to -3.3; P = 0.001), and a reduction in BMI of at least 5% occurred in 46% of participants in the liraglutide group and in 9% of participants in the placebo group (adjusted odds ratio, 6.3 [95% CI, 1.4 to 28.8]; P = 0.02). Adverse events occurred in 89% and 88% of participants in the liraglutide and placebo groups, respectively. Gastrointestinal adverse events were more common in the liraglutide group (80% vs. 54%); serious adverse events were reported in 12% and 8% of participants in the liraglutide and placebo groups, respectively. Among children (6 to <12 years of age) with obesity, treatment with liraglutide for 56 weeks plus lifestyle interventions resulted in a greater reduction in BMI than placebo plus lifestyle interventions. (Funded by Novo Nordisk; SCALE Kids ClinicalTrials.gov number, NCT04775082.).

Improvement Across Dimensions of Disease with Lebrikizumab Use in Atopic Dermatitis: Two Phase 3, Randomized, Double-Blind, Placebo-Controlled Monotherapy Trials (ADvocate1 and ADvocate2).

Atopic dermatitis is a complex, chronic, inflammatory skin disease thatrequires long-term control of symptoms like itch and sleep loss and improvement in quality of life, in addition to reduction of clinical signs. Lebrikizumab is a selective interleukin-13 inhibitor approved in the European Union, United Kingdom, United Arab Emirates, Canada, and Japan for treatment of moderate-to-severe atopic dermatitis in adults and adolescents. Here, we assess the magnitude of changes across signs and symptoms of atopic dermatitis with lebrikizumab monotherapy over the 16-week induction period in two phase 3 studies, ADvocate1 and ADvocate2. Eligible adults (aged≥18years) and adolescents (aged 12 to<18years and weighing≥40kg) with moderate-to-severe atopic dermatitis were randomized to receive either 250mg of lebrikizumab or placebo subcutaneously every two weeks. Least squares mean percentage change from baseline through week 16 was compared between lebrikizumab and placebo using mixed model repeated measure analysis for the following endpoints: Eczema Area and Severity Index (EASI), Pruritus Numeric Rating Scale (NRS), Sleep-Loss Scale, Patient-Oriented Eczema Measure (POEM), and Dermatology Life Quality Index (DLQI). In both trials, significant (P<0.05) improvements were observed for lebrikizumab treatment compared with placebo at each 2-week timepoint for EASI, Pruritus NRS, Sleep-Loss Scale, and POEM, and at each 4-week timepoint for DLQI, through week 16. Statistically significant (P<0.001) improvements were observed at 16weeks for lebrikizumab treatment versus placebo in ADvocate1/ADvocate2 for EASI (71.9%/75.0% vs. 35.6%/43.3%), Pruritus NRS (53.3%/46.3% vs. 21.4%/18.0%), Sleep-Loss Scale (57.7%/55.6% vs. 23.9%/25.5%), POEM (54.4%/45.8% vs. 18.8%/16.9%), and DLQI (64.2%/60.5% vs. 28.5%/32.2%). Patient photos show improvements in skin appearance when disease measures improve. Lebrikizumab monotherapy resulted in significant and fast improvements in multiple dimensions of disease (clinical signs, symptoms, and quality of life) over 16weeks in patients with moderate-to-severe atopic dermatitis. ClinicalTrials.gov identifiers, NCT04146363; NCT04178967.

Dietary Counseling Outcomes in Patients with Lung Cancer in an Upper-Middle-Income Country: An Open-Label Randomized Controlled Trial.

Background: Malnutrition harms treatment outcomes, QoL, and survival in lung cancer patients. Effective dietary counseling can improve nutrition, but few randomized controlled trials have focused on lung cancer patients. The objective of this study was to determine if dietary counseling improves nutritional and treatment outcomes when compared to routine care. Methods: This open-label parallel RCT was conducted at Maharaj Nakorn Chiang Mai Hospital in Thailand. The investigators used computer-generated blocked randomization to assign patients to dietary counseling by a nutritionist or routine care. The nutritionist sessions occurred before treatment, with follow-ups at 3-4 weeks and 12 weeks. The primary outcome was the mean percentage change in the body weight of patients at 12 weeks. Secondary outcomes included changes in the BMI, nutrition score, QoL, serum albumin level, lymphocyte count, energy and protein intake, treatment response, PFS, and OS. Results: Between April 2020 and May 2022, after completing recruitment, 80 lung cancer patients were randomized: 43 to dietary counseling and 37 to routine care. The dietary counseling group showed significant benefits, with smaller decreases in body weight at 3-4 weeks (-0.8% vs. -2.6%, p = 0.05) and 12 weeks (-1.1% vs. -4.3%, p = 0.05). They also had higher energy and protein intake levels and better treatment response rates. The secondary outcomes and significant adverse events did not differ significantly between the groups. Conclusions: Dietary counseling helps to maintain body weight, maintain dietary intake, and enhance treatment responses in lung cancer patients. Although not all nutritional markers or survival outcomes were affected, these findings highlight the importance of early nutritional interventions.

A randomized, open-label, clinical trial examined the effects of canagliflozin on albuminuria and eGFR decline using an individual pre-intervention eGFR slope

Demonstrating drug efficacy in slowing kidney disease progression requires large clinical trials when targeting participants with an early stage of chronic kidney disease (CKD). In this randomized, parallel-group, open-labeled trial (CANPIONE study), we assessed the effect of the sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin using the individual’s change in estimated glomerular filtration rate (eGFR) slope before (pre-intervention slope) and during treatment (chronic slope).We randomly assigned (1:1) participants with type 2 diabetes, urinary albumin-to-creatinine ratio (UACR) of 50 to under 300 mg/g, and an eGFR of at least 45 ml/min/1.73m2 to receive canagliflozin or guideline-recommended treatment except for SGLT2inhibitors (control). The first and second primary outcomes were the geometric mean percentage change from baseline in UACR and the change in eGFR slope, respectively. Of 98 randomized participants, 96 received at least one study treatment. The least-squares mean change from baseline in log-transformed geometric mean UACR was significantly greater in the canagliflozin group than the control group (between group-difference, −30.8% (95% confidence interval −42.6 to −16.8). The between-group difference (canagliflozin group – control group) of change in eGFR slope (chronic – pre-intervention) was 4.4 (1.6 to 7.3) ml/min/1.73 m2 per year, which was more pronounced in participants with faster eGFR decline. In summary, canagliflozin reduced albuminuria and the participant-specific natural course of eGFR decline in participants with type 2 diabetes and microalbuminuria. Thus, the CANPIONE study suggest that the within-individual change in eGFR slope may be a novel approach to determine the kidney protective potential of new therapies in early stages of CKD.

Efficacy and safety of gefapixant in women with chronic cough and cough-induced stress urinary incontinence: a phase 3b, randomised, multicentre, double-blind, placebo-controlled trial

Approximately two-thirds of women with chronic cough have cough-induced stress urinary incontinence (CSUI). We aimed to evaluate the efficacy and safety of gefapixant in reducing CSUI episodes in women with refractory or unexplained chronic cough. This phase 3b, double-blind, randomised, placebo-controlled trial done at 90 sites in 12 countries enrolled women aged 18 years or older who had chronic cough for at least 1 year, a diagnosis of refractory or unexplained chronic cough, a cough severity visual analogue scale score of 40 mm or more (100 mm maximum), and CSUI for 3 months or more. Participants were randomised 1:1 to oral gefapixant or placebo for 12 weeks. The primary outcome was percentage change from baseline in daily CSUI episodes (7-day average) at week 12. This study is registered with ClinicalTrials.gov (NCT04193176). From May 10, 2020, to Sept 2, 2022, 375 participants were randomised to and treated with gefapixant 45 mg twice daily (n=185) or placebo (n=190). Mean age was 56·4 years (SD 11·4), with mean chronic cough duration of 5·2 years (SD 6·6) and SUI duration of 4·0 years (SD 5·9). Least-squares mean percentage change from baseline in daily CSUI episodes was -52·8% (95% CI -58·4 to -47·1%) for gefapixant and -41·1% (-46·7 to -35·4%) for placebo (estimated treatment difference: -11·7% [95% CI -19·7 to -3·7]; p=0·004). 129 (70%) of 185 participants who received gefapixant and 71 (37%) of 190 participants who received placebo had at least one adverse event. Safety and tolerability were consistent with previous trials of gefapixant; the most frequent adverse events were taste related. Gefapixant 45 mg twice daily is the first treatment to show efficacy versus placebo in reducing CSUI episodes in participants with refractory or unexplained chronic cough. Merck Sharp & Dohme, a subsidiary of Merck & Co.

Characterization of the circulating markers of the renin-angiotensin-aldosterone system in telmisartan- or enalapril-treated dogs with proteinuric chronic kidney disease.

Effects of the renin-angiotensin-aldosterone system (RAAS) inhibitors enalapril and telmisartan on circulating RAAS in dogs with proteinuric chronic kidney disease (pCKD) are undescribed. To characterize the RAAS in untreated dogs with pCKD compared to healthy, life-stage- and sex-matched controls, and in dogs with pCKD after 30 days of treatment with enalapril or telmisartan. Dogs with pCKD (n = 36) and healthy controls (n = 20). Retrospective study of banked samples and previously collected data. Day 0 serum equilibrium concentrations of angiotensin I, II, III, IV, 1-5, and 1-7, and aldosterone, and urinary aldosterone-to-creatinine ratio (UACR) from pCKD dogs were compared to values on day 30 of treatment with enalapril (0.5 mg/kg PO q12) or telmisartan (1 mg/kg PO q24h) and to those of healthy dogs. Data were analyzed using linear mixed models. Compared with healthy dogs, pCKD dogs had significantly higher Ang I, III, 1-5, and 1-7 concentrations, and UACR. Relative to pretreatment values, day 30 Ang II concentrations were significantly increased and decreased in telmisartan- and enalapril-treated pCKD dogs, respectively (both P < .001). Mean (95% confidence interval) percentage change from pretreatment value in serum Ang 1-7 concentration was significantly greater in telmisartan- (753% [489%-1134%]) versus enalapril-treated (149% [69%-268%]) dogs (P < .001). Serum aldosterone decreased with treatment (P = .02 for enalapril, P < .001 for telmisartan), with no difference between groups at day 30. Circulating RAAS activity is higher in dogs with pCKD. Compared with enalapril, treatment with telmisartan caused significantly greater increases in the presumed beneficial peptide Ang 1-7.

Study protocol for the ROLEX-DUO randomised placebo-controlled trial: ROmosozumab Loaded with EXercise – DUal effects on bone and muscle in postmenopausal Osteoporosis and Osteopenia

IntroductionNovel strategies are needed to address the rising burden of osteoporosis and fragility fractures. High-intensity resistance and impact (HiRIT) exercise has shown benefit in improving bone density in postmenopausal women...

Intraoperative Intracranial Pressure Changes in Children With Craniosynostosis Undergoing Endoscopic-Assisted Strip Craniectomy.

Craniosynostosis can lead to progressive cranial and skull base deformities and can be associated with increased intracranial pressure (ICP), ophthalmological manifestations, behavioral changes, and developmental delay. Most published data on the incidence of elevated ICP include older children undergoing open surgical correction. Endoscopic-assisted release of fused sutures with postoperative helmet therapy is an established method for managing craniosynostosis presenting at an early age; however, the immediate effect of this approach on ICP in a young cohort has not been previously reported. Prospective data on 52 children undergoing endoscopic-assisted release of stenosed cranial sutures were included. Individuals were excluded if they underwent open correction or had previous cranial surgery. Individuals underwent a standardized endoscopic approach for each suture type. ICP was measured using an intraparenchymal sensor both before creation of the neosuture and after complete release of the stenosed suture. An ICP reading of >10 mm Hg was considered elevated. The mean age was 5.3 months, range 1 to 32 months, and 94% was younger than 12 months. The mean opening pressure was 12.7 mm Hg, and the mean closing pressure was 2.9 mm Hg. Opening ICP ≥10 mm Hg was present in 58%, ≥15 mm Hg was present in 31%, and ≥20 mm Hg was present in 23%. No patient had an ICP above 10 mm Hg at closing. The mean percentage change in ICP among all craniosynostosis cases was a 64% decrease. Optic disk swelling was identified in 28 children preoperatively and improved in 22 children at follow-up. Elevated ICP may occur in infants with craniosynostosis at higher rates than previously reported. Endoscopic-assisted craniectomy has an immediate effect on lowering ICP and improving postoperative ophthalmological findings.

Orthodontic treatment protocol versus Peer Assessment Rating: Assessing the quality of orthodontic treatment.

To apply the Peer Assessment Rating (PAR) to cases that have been assessed by the NHS Business Service Authority (NHSBSA) using the orthodontic treatment protocol (OTO), then compare the NHSBSA outcome assessment with weighted (W) and unweighted (U) PAR scores. Cross-sectional study. UK. Anonymised orthodontic cases submitted to the NHSBSA. A sample of 30 reports from 2021/2022 were randomly selected to include different standard of treatment grades. The records were de-identified and the pre- and post-treatment study models were PAR scored by a calibrated assessor. The mean percentage change in PAR was higher in cases from green reports (W: 78%; U: 79%) than amber (W: 68%; U: 67%) and red reports (W: 65%; U: 65%). Alignment and poor buccal segment interdigitation were the most reported concerns for cases included in the red and amber graded reports. A residual increased overjet was the most common occlusal feature leading to PAR scores not being more than 70% improved. Only slight agreement was shown between OTP and PAR using the kappa statistic, and the chi-square statistical test found that outcome measures are statistically significantly different. There are fundamental differences between OTP and PAR, and general agreement between them has not been demonstrated. The NHSBSA Report provides a more critical outcome assessment than PAR, identifying elements that are not assessed or measured by the PAR index.

Effect of the presence of cysts in the hip joint on hip arthroscopy.

The aim of this study was to investigate whether the presence and size of fibrous cysts affected postoperative results in patients undergoing hip arthroscopy. Between January 2010 and December 2019, a total of 261 patients (138 males, 123 females; mean age: 39.5±11.9 years; range, 18 to 66 years) who underwent hip arthroscopy with the diagnosis of cam-pincer-mixed-type femoroacetabular impingement (FAI) and labral pathologies were retrospectively analyzed. The study groups (impingements and labral pathologies) and the presence of cyst (or cyst size: <5 mm, 5-8 mm, >8 mm) were used as the fixed effects, and the analysis was adjusted for baseline age, sex, and preoperative scores. Pre- and postoperative modified Harris Hip Score (mHHS) and Visual Analog Scale (VAS) scores that were applied to all patients were used as an indication of clinical results. The mean preoperative mHHS score of the patients with a cyst was significantly lower compared to the patients without a cyst (56.8±12.3 vs. 60.3±12.7, p=0.026). The mean change in the mHHS score and the mean percentage change in VAS score were significantly higher in the patients with a cyst compared to the patients without a cyst (mHHS score: 28.1±14.0 vs. 22.5±14.1, p=0.002; VAS score: 61.9±30.2 vs. 52.6±47.4, p=0.038). The increase in mHHS score over time for patients with a cyst was significantly higher than the patients without cysts in the pincer group (38.1±11.1 vs. 19.3±13.5, p<0.001). The patients with a cyst size of >8 mm had a significantly higher increase in the mHHS scores compared to the patients with a cyst size of <5 mm (29.5±12.9 vs. 23.5±13.8, p=0.043). Subchondral cysts in the femoral head and neck junction accompanied cam-type and mixed-type FAI, while subchondral cysts in the acetabulum accompanied pincer-type impingement. In all groups, the mean increase in mHHS scores and the mean decrease in VAS scores were higher in patients with subchondral cysts than in patients without cysts. In patients with subchondral cysts, if the lesion causing FAI is treated arthroscopically, it can positively affect the functional results.

Treatment of moderate-to-severe canine atopic dermatitis with modified-release mycophenolate (OKV-1001): A pilot open-label, single-arm multicentric clinical trial.

Mycophenolate is an immunomodulating agent successfully used for the treatment of moderate-to-severe atopic dermatitis (AD) in people. Mycophenolate is an effective steroid-sparing treatment option for use in dogs with inflammatory skin diseases. To evaluate whether once-daily modified-release mycophenolate (OKV-1001) is safe and effective for treating moderate-to-severe canine AD. Client-owned atopic dogs (n = 9) were enrolled. In an open-label multicentre pilot study, OKV-1001 (30 mg/kg every 24 h) was given orally for ≤84 days. Concomitant tapering doses of glucocorticoids were administered up to Day (D)28. Clinicians assessed Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI-04) on D0, D14, D28, D56 and D84. Body weight and clinical pathological parameters were measured at baseline and at the end of the study. Treatment with OKV-1001 combined with glucocorticoids significantly reduced the severity of AD within two weeks in seven of nine (77.8%) dogs. The mean percentage change from baseline in the CADESI-04 score was 29% (p = 0.009) at D14 (n = 9), 39% (p = 0.008) at D28 (n = 9) and 49% (p = 0.03) at D56 (n = 7) at which point glucocorticoids had been withdrawn. In two dogs the improvement in CADESI-04 was 62% and 23% (respectively) on D84. No significant adverse events including clinical pathological findings were reported. Modified-release mycophenolate (OKV-1001) may represent a promising alternative treatment option for dogs with moderate-to-severe AD. The safety and efficacy profile of OKV-1001 will need to be established in larger, placebo-controlled clinical trials.

Efficacy and Safety of TAS-303 in Female Patients With Stress Urinary Incontinence: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial.

We aimed to evaluate the therapeutic efficacy and safety of TAS-303, a highly selective noradrenaline reuptake inhibitor, in Japanese women with stress urinary incontinence (SUI). A double-blind, placebo-controlled, phase 2 study randomized women with SUI symptoms to once-daily oral administration of TAS-303 18 mg or placebo for 12 weeks. The primary endpoint was percent change from baseline to Week 12 in mean SUI episode frequency per 24 hours (SUIEF) in the per-protocol set. The secondary endpoints were the proportion of patients with ≥ 50% reduction in mean SUIEF, incontinence episode frequency, incontinence amount, health-related quality of life, and safety in the full analysis set. In total, 231 patients were randomized to TAS-303 (n = 116) or placebo (n = 115). At Week 12, TAS-303 had superior efficacy to placebo, with a least squares mean percent change in mean SUIEF of -57.7% vs -46.9%, respectively, in the per-protocol set (least squares mean difference -10.8%; P = .036). TAS-303 showed some evidence of improved incontinence episode frequency, incontinence amount, and health-related quality of life (although not statistically significant) at Week 12 vs placebo in the full analysis set. The between-group difference in SUIEF improvement was more clearly confirmed in patients with ≥ 2 SUI episodes daily at baseline. All adverse events (AEs) with TAS-303 were mild or moderate; there were no serious AEs, AEs leading to discontinuation, or nervous system- or gastrointestinal-related (eg, nausea or vomiting) adverse drug reactions. Once-daily TAS-303 18 mg showed superior efficacy to placebo for the treatment of SUI in Japanese women, with an adequate safety profile. ClinicalTrials.gov: NCT04512053; Japan Registry of Clinical Trials: jRCT2080225307 (JapicCTI-205403 before site integration).

Are Two Gliflozins Different: A Prospective Multicenter Randomized Study to Assess Effect of Remogliflozin Compared With Empagliflozin on Biomarkers of Heart Failure in Indian Patients With Type 2 Diabetes Mellitus with Chronic Heart Failure (REMIT-HF Study)

BackgroundThere is limited data comparing two gliflozins on their effect on biomarkers in diabetic patients with chronic heart failure. MethodsA prospective, multicenter, active controlled, double-arm, investigator-initiated, interventional study enrolled 250 adults with T2DM and comorbid CHF (LVEF<40%; NT-proBNP >600pg/ml). 125 patients were allocated each to Remogliflozin (R) and Empagliflozin (E) group and followed up for 24 weeks. The primary endpoint was the mean percentage change from baseline in NT-proBNP level after 24 weeks. ResultsThere was significant improvement from baseline in mean NT-proBNP level in both groups after 24 weeks however there was no significant difference between the two groups (p= 0.214). The mean NT-proBNP level improved from 2078.15±1764.70 pg/ml at baseline to 1185.06±1164.21 pg/ml at 6 months in R-group (p≤0.001) and from 2283.98±1759.15 pg/ml at baseline to 1395.33±1304.18 pg/ml at 6 months in E-group (p= <0.001). Left ventricular ejection fraction (LVEF) and LV volumes improved in both the groups. The glycemic parameters (HbA1c, FPG and PPG) demonstrated a significant reduction from baseline to week 24 in both groups. Similar improvement was seen in heart rate, blood pressure and weight reduction over 6 months in both groups. There was no drug related serious adverse event in any group. ConclusionRemogliflozin and Empagliflozin significantly improves glycemic parameters and NT-proBNP levels as the index of the therapeutic effects in T2DM patients with CHF. The positive effects are comparable in both groups.

Cilofexor in Patients With Compensated Cirrhosis Due to Primary Sclerosing Cholangitis: An Open-Label Phase 1B Study.

This proof-of-concept, open-label phase 1b study evaluated the safety and efficacy of cilofexor, a potent selective farnesoid X receptor agonist, in patients with compensated cirrhosis due to primary sclerosing cholangitis. Escalating doses of cilofexor (30 mg [weeks 1-4], 60 mg [weeks 5-8], 100 mg [weeks 9-12]) were administered orally once daily over 12 weeks. The primary endpoint was safety. Exploratory measures included cholestasis and fibrosis markers and pharmacodynamic biomarkers of bile acid homeostasis. Eleven patients were enrolled (median age: 48 years; 55% men). The most common treatment-emergent adverse events (TEAEs) were pruritus (8/11 [72.7%]), fatigue, headache, nausea, and upper respiratory tract infection (2/11 [18.2%] each). Seven patients experienced a pruritus TEAE (one grade 3) considered drug-related. One patient temporarily discontinued cilofexor owing to peripheral edema. There were no deaths, serious TEAEs, or TEAEs leading to permanent discontinuation. Median changes (interquartile ranges) from baseline to week 12 (predose, fasting) were -24.8% (-35.7 to -7.4) for alanine transaminase, -13.0% (-21.9 to -8.6) for alkaline phosphatase, -43.5% (-52.1 to -30.8) for γ-glutamyl transferase, -12.7% (-25.0 to 0.0) for total bilirubin, and -21.2% (-40.0 to 0.0) for direct bilirubin. Least-squares mean percentage change (95% confidence interval) from baseline to week 12 at trough was -55.3% (-70.8 to -31.6) for C4 and -60.5% (-81.8 to -14.2) for cholic acid. Fasting fibroblast growth factor 19 levels transiently increased after cilofexor administration. Escalating doses of cilofexor over 12 weeks were well tolerated and improved cholestasis markers in patients with compensated cirrhosis due to primary sclerosing cholangitis (NCT04060147).

Real-time monitoring of middle cerebral artery blood flow using intraoperative transcranial doppler during trans-carotid artery revascularization

ObjectiveTranscarotid artery revascularization (TCAR) has emerged as a safe and effective method for carotid revascularization, offering several key advantages over carotid endarterectomy (CEA) and carotid artery stenting (CAS). Intraoperative transcranial Doppler (TCD) monitoring plays a pivotal role in assessing cerebral hemodynamics and detecting embolic signals during TCAR at our institution. MethodsThis review synthesizes the current literature and provides guidance for TCD monitoring throughout the various phases of TCAR, from preoperative assessment to postoperative management. Key considerations include probe placement, waveform evaluation, interpreting monitoring parameters such as mean flow velocity (MFV), pulsatility index (PI), and percentage change in the MFV (Δ%). Techniques for maintaining the insonation of the middle cerebral artery (MCA) M1 segment and optimal parameter settings for intraoperative TCD monitoring are detailed. ResultsTCAR phases are highlighted, including transcarotid access and vessel control, sheath insertion, the establishment of flow reversal, pre-dilation, stent placement, post-dilation, and closure, while emphasizing the importance of real-time feedback provided by TCD monitoring in identifying embolic signals and assessing changes in cerebral perfusion. The review discusses limitations of TCD monitoring, such as inadequate temporal windows, incorrect vessel identification and reliability issues with automatic emboli detection counters. Furthermore, practical advice is provided on how to navigate common pitfalls encountered during intraoperative TCD monitoring. ConclusionBy understanding the nuances of TCD monitoring and its application in TCAR, intraoperative TCD monitoring may aid to minimize the low but potential risk of intraprocedural embolic events, periprocedural hypoperfusion and postoperative hyperperfusion. Finally, we suggest opportunities for further research in embolization quantification and additional strategies to optimize quality control in TCAR.

Impact of Age on Efficacy and Safety of Fixed-Dose Clindamycin Phosphate 1.2%/Adapalene 0.15%/Benzoyl Peroxide 3.1% Gel in Participants with Moderate-to-Severe Acne

Introduction: Topical clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide 3.1% (CAB) gel is the first fixed-dose, triple-combination formulation approved for the treatment of acne. In three clinical studies of participants with moderate-to-severe acne, CAB gel demonstrated superior efficacy to vehicle and component dyads, with good safety/tolerability. As acne pathogenesis and treatment outcomes can vary with age, this post hoc analysis was performed to evaluate the efficacy and safety of CAB in pediatric and adolescent participants (aged 9-24 years) versus adult participants (≥25 years). This age cutoff was chosen as acne in patients aged 18-24 years is more similar to adolescents than adults, and age 25 is often used to define “adult acne”. Methods: In a phase 2 (NCT03170388) and two phase 3 (NCT04214652, NCT04214639) studies, participants aged ≥9 years with moderate-to-severe acne were randomized to once-daily CAB or vehicle gel. Endpoints included percentage of participants achieving treatment success (defined as ≥2-grade reduction from baseline in Evaluator’s Global Severity Score and clear/almost clear skin) and least-squares mean percent change from baseline in inflammatory/noninflammatory lesion counts at week 12. Treatment-emergent adverse events (TEAEs) were also assessed. Pooled data across all three studies were analyzed for participants aged 9-24 years (CAB: n=297; vehicle: n=218) or ≥25 years (n=91; n=51). Results: At week 12, approximately half of CAB-treated participants in both age groups achieved treatment success (9-24 years: 50.6%; ≥25: 49.0%) versus less than one-fourth with vehicle (15.7% and 20.6%; P&lt;0.01, both). Treatment with CAB resulted in &gt;70% reductions from baseline in inflammatory and noninflammatory lesions in both age groups, versus 45%-62% with vehicle (P≤0.001, all). There were no significant differences between CAB-treated participants in the two age groups across any of these efficacy endpoints (P=0.68-0.97). Most TEAEs with CAB were of mild-moderate severity, with no age-related trends in safety/tolerability. Conclusions: Fixed-dose, triple-combination CAB gel was efficacious and well tolerated in participants with moderate-to-severe acne, regardless of age. Approximately half of pediatric/adolescent and adult participants achieved clear/almost clear skin with CAB, and lesion count reductions of &gt;70% were observed. Funding: Ortho Dermatologics

Ritlecitinib, a JAK3/TEC family kinase inhibitor, stabilizes active lesions and repigments stable lesions in vitiligo

The efficacy of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, on active and stable lesions was evaluated in patients with active non-segmental vitiligo in a phase 2b trial (NCT03715829). Patients were randomized to placebo or daily ritlecitinib 50 mg (with or without 4-week 100-mg or 200-mg loading dose), 30 mg, or 10 mg for 24 weeks. Active lesions showed greater baseline expression of inflammatory/immune markers IFNG and CCL5, levels of CD103, and T-cell infiltrates than stable lesions. Patients with more active than stable vitiligo lesions showed higher baseline serum levels of CXCL9 and PD-L1, while patients with more stable than active lesions showed higher baseline serum levels of HO-1. At Week 24, ritlecitinib 50 mg significantly stabilized mean percent change from baseline in depigmentation extent in both active lesions and stable lesions vs. placebo-response, with stable lesions showing greater repigmentation. After 24 weeks of treatment, ritlecitinib 50 mg increased expression of melanocyte markers in stable lesions, while Th1/Th2-related and co-stimulatory molecules decreased significantly in both stable and active lesions. Serum from patients with more active than stable lesions showed decreased levels of ICOS and NK cell activation markers. These data, confirmed at transcription/protein levels, indicate that stable lesion repigmentation occurs early with ritlecitinib, while active lesions require stabilization of inflammation first. ClinicalTrials.gov: NCT03715829.

Cendakimab in Patients With Moderate to Severe Atopic Dermatitis

Cendakimab selectively targets interleukin (IL)-13, a type 2 cytokine implicated in atopic dermatitis (AD) pathogenesis, by inhibiting binding to its receptors (IL13R-α1 and IL13R-α2). Proof-of-concept work in AD supports using cendakimab for type 2 inflammatory diseases. To evaluate the efficacy and safety of cendakimab compared with placebo in patients with moderate to severe AD. This phase 2, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging clinical trial was conducted from May 2021 to November 2022. Adult patients with moderate to severe AD and inadequate response to topical medications were enrolled at 69 sites in 5 countries (US [n = 26], Japan [n = 17], Canada [n = 9], Poland [n = 9], and Czech Republic [n = 8]). Data were analyzed between April 25, 2023, and October 16, 2023. Patients were randomized (1:1:1:1) to receive subcutaneous cendakimab, 360 mg, every 2 weeks; 720 mg, every 2 weeks; 720 mg, once weekly; or placebo. Mean percentage change in Eczema Area and Severity Index scores from baseline to week 16. Hierarchical testing with multiplicity adjustment was performed for 720 mg, once weekly vs placebo, then 720 mg, every 2 weeks vs placebo, and then 360 mg, every 2 weeks vs placebo. Overall, 221 patients were randomized, and 220 received study drug (95 women [43%]; mean [SD] age, 37.7 [13.9] years; 720 mg, once weekly [54 (24%)]; 720 mg, every 2 weeks [55 (25%)]; 360 mg, every 2 weeks [55 (25%)]; placebo [56 (26%)]). The primary efficacy end point was met for cendakimab, 720 mg, once weekly vs placebo (-84.4 vs -62.7; P = .003) but missed statistical significance for 720 mg, every 2 weeks (-76.0 vs -62.7; P = .06). The treatment effect for 360 mg, every 2 weeks (-16.3; nominal P = .03 vs placebo) was comparable with 720 mg, once weekly (-21.8); however, significance was not claimed because the hierarchical testing sequence was interrupted. Of patients with treatment-emergent adverse events leading to discontinuation, 4 (7.4%) received 720 mg, once weekly; 2 (3.6%) 720 mg, every 2 weeks; 1 (1.8%) 360 mg, every 2 weeks; and 2 (3.6%) placebo. The results of this randomized clinical trial indicated that cendakimab was effective, generally safe, and well-tolerated in patients with moderate to severe AD. The primary end point was met with a significant reduction in Eczema Area and Severity Index scores with 720 mg, once weekly at week 16. Cendakimab demonstrated progressive AD improvement at all doses during 16 weeks of treatment. ClinicalTrials.gov Identifier: NCT04800315.

Investigation of setmelanotide, an MC4R agonist, for obesity in individuals with Smith-Magenis syndrome

BackgroundSmith Magenis Syndrome (SMS) is a rare genetic disorder caused by RAI1 haploinsufficiency. Obesity in people with SMS is believed partially due to dysfunction of the proximal melanocortin 4 receptor (MC4R) pathway. We therefore studied effects of treatment with the MC4R agonist setmelanotide on obesity and hunger, as well as metabolic, cardiac and safety, in individuals with SMS. MethodsPeople with SMS received once-daily setmelanotide injections, with the dose titrated bi-weekly to a maximum of 3 mg over ∼1 month; and a full-dose treatment duration of 3mo. The primary outcome was percent change in body weight. Secondary outcomes included hunger, waist circumference, body composition, and safety. Results12 individuals, ages 11–39 y, enrolled and 10 completed the full-dose treatment phase. Mean percent change in body weight at end-treatment was − 0.28 % [(95 % CI, −2.1 % to 1.5 %; n = 12; P = 0.66]. Participants experienced a significant decrease in total cholesterol associated with a significant decrease in HDL-cholesterol and a trend for lower LDL-cholesterol. Self-reported hunger was reduced at end-treatment (p = 0.011). All participants reported adverse events (AEs), most commonly injection-site reactions and skin hyperpigmentation. No AEs led to withdrawal or death. ConclusionsIn this trial, setmelanotide did not significantly reduce body weight in participants with SMS. Participants reported significant differences in hunger, but such self-reports are difficult to interpret without a placebo-treated group. The changes in lipid profiles require further investigation. Results of this study do not suggest that dysfunction of the proximal MC4R pathway is the main etiology for obesity in people with SMS.