2-point Reduction Research Articles

Setmelanotide in patients aged 2-5 years with rare MC4R pathway-associated obesity (VENTURE): a 1 year, open-label, multicenter, phase 3 trial.

Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, has been shown to reduce hunger and weight in patients aged 6 years and older with proopiomelanocortin (POMC) deficiency (including biallelic variants in proprotein convertase subtilisin/kexin type 1 [PCSK1]), leptin receptor (LEPR) deficiency, or Bardet-Biedl syndrome (BBS). No approved therapies for patients younger than 6 years old currently exist. The phase 3, open-label VENTURE trial aimed to evaluate the efficacy and safety of setmelanotide in patients aged 2-5 years with POMC or LEPR deficiency or BBS. This phase 3, open-label, multicentre trial, conducted across six sites in the USA, the UK, Spain, and Australia, enrolled eligible patients aged 2-5 years who had hyperphagia and obesity due to biallelic POMC (including PCSK1) or LEPR variants or genetically confirmed BBS. Open-label subcutaneous setmelanotide was administered once daily for 52 weeks, starting at 0·5 mg with doses increasing every 2 weeks in 0·5 mg increments until reaching the maximum dose based on weight. The co-primary endpoints at week 52 were the percentage of patients reaching a 0·2-point decrease or greater in BMI Z score (a statistical measure used to assess BMI in paediatric patients considering a patient's BMI and comparing it to reference values for the same age and sex) and mean percent change in BMI. Additional endpoints measured safety, hunger, weight-related outcomes, and caregiver burden. The study is registered at ClinicalTrials.gov (NCT04966741) and is complete. Between March 8, 2022, and Sept 18, 2023, 13 patients were screened at the six sites, and 12 patients were enrolled in the study (seven with POMC or LEPR and five with BBS); one patient with BBS was excluded as their BMI was not at the 97th percentile or above. Of the 12 patients enrolled, most were male (seven [58%] vs five [42%] for female) and the mean age was 3·6 years (SD 0·9). 11 patients completed the trial. Ten (83%) of the 12 overall participants reached a 0·2-point reduction or more in BMI Z score per WHO methodology at week 52 (95% CI 58·7-99·8). The mean percent change in BMI from baseline at week 52 was -18% (SD 13) in the overall safety population. Mean percent change in BMI at week 52 was -26% (SD 11) in patients with POMC or LEPR deficiency and -10% (9) in patients with BBS. Mean reductions in secondary endpoints of BMI Z score (3·4 [2·5]) and percent of the BMI 95th percentile (32·5 [22·9]) were seen at Week 52. 91% of caregivers reported that patients were less hungry than at baseline. All adverse events were mild or moderate; skin hyperpigmentation, vomiting, nasopharyngitis, upper respiratory tract infection, and injection site reactions were most common. No serious adverse events or adverse events leading to study discontinuation or death were reported. To our knowledge this is the first trial of setmelanotide in patients younger than 6 years old. These results support the benefit of the drug as an early intervention to manage obesity in this population. Rhythm Pharmaceuticals.

Post-hoc analyses from the ADAPT clinical study demonstrate aggregate sustained benefit of Efgartigimod in generalized myasthenia gravis

ObjectivesThis post-hoc analysis evaluates the long-term efficacy of efgartigimod versus placebo in adult patients with generalized myasthenia gravis (gMG) with acetylcholine-receptor autoantibodies (AChR-Ab+), based on data from the ADAPT RCT and its open-label extension ADAPT+. MethodsChanges from baseline in Quantitative Myasthenia Gravis (QMG) and Myasthenia Gravis-Activities of Daily Living (MG-ADL) scores were assessed by treatment group over the ADAPT (up to 20 weeks) and ADAPT+ time horizon (extended to 64 weeks for efgartigimod group patients). Response to treatment was defined as (Meriggioli, 2009 [3])5-point reduction in QMG or (Meriggioli, 2009 [3])3-point reduction in MG-ADL vs. baseline values. ResultsAChR-Ab+ patients treated with efgartigimod spent a substantially greater percentage of time in response in ADAPT based on at least a 5-point change in QMG compared to the placebo group (44 % versus 13 % respectively, p = 0.0034). Analyses based on a 3-point change in MG-ADL in ADAPT showed the percentage of time in response was nearly double for efgartigimod versus placebo (59 % versus 30 % respectively, p = 0.010). These trends were also maintained using different response definitions, as well as in patients with and without prior immune therapy exposure and by time from diagnosis (<7 years versus ≥7 years). ConclusionsThe clinical benefit of efgartigimod was sustained over repeat treatment cycles and maintained over the long term. Response to treatment was consistent regardless of response definition and was repeated in different patient subgroups. Overall, the results of this analysis indicate that efgartigimod is an effective therapeutic option, demonstrating a robust benefit among AChR-Ab+ patients with gMG.

Risk-Benefit Analysis of Novel Treatments for Patients with Generalized Myasthenia Gravis.

This study used network meta-analysis (NMA) to inform and compare the number needed to treat (NNT), number needed to harm (NNH), and cost per improved outcome (CPIO) associated with more recently approved treatments for anti-acetylcholine receptor antibody-positive (anti-AChR Ab+) generalized myasthenia gravis (gMG). Clinical trials of neonatal Fc receptor (FcRn) inhibitors, efgartigimod intravenous (IV) and rozanolixizumab, and complement inhibitors, ravulizumab and zilucoplan, versus placebo (with background conventional treatment) were included in the primary NMA to compare efficacy and safety outcomes. The outputs from the NMAs were used to estimate NNT and NNH of each treatment versus placebo. CPIO (2024 USD) was estimated for a≥3- or≥5-point reduction from baseline in Quantitative Myasthenia Gravis (QMG) and Myasthenia Gravis-Activities of Daily Living (MG-ADL) scores. Sensitivity analyses were performed adding efgartigimod PH20 subcutaneous (SC) and eculizumab to the NMA. Efgartigimod IV had the lowest NNT versus placebo for achieving a≥3- and≥5-point reduction in QMG, as well as a≥5-point reduction in MG-ADL, whereas rozanolixizumab had the lowest NNT for a≥3-point reduction in MG-ADL. The NNH versus placebo was similar across comparator treatments. Efgartigimod IV had the lowest CPIO among all treatments for all assessed efficacy outcomes. Sensitivity analyses yielded results consistent with primary analysis and indicated that efgartigimod PH20 SC had comparable NNT and CPIO values to efgartigimod IV, whereas eculizumab had comparable NNT and higher CPIO values compared to other complement inhibitors. FcRn inhibitors and complement inhibitors assessed in this study all demonstrated clinical benefit in terms of NNT as well as an acceptable safety profile in terms of NNH. Within the limitations of this meta-analysis, efgartigimod was associated with a favorable benefit-risk profile as well as a better economic value compared to ravulizumab, rozanolixizumab, and zilucoplan as treatments for anti-AChR Ab+gMG.

Long-term efficacy and safety of stapokibart for moderate-to-severe atopic dermatitis: 52-week results from a phase 3 trial.

Management of moderate-to-severe atopic dermatitis (AD) needs long-term therapy. Stapokibart is a humanized monoclonal antibody targeting interleukin-4 receptor α subunit (IL-4Rα), a shared receptor for IL-4 and IL-13 which are key pathogenic drivers of AD. In a pivotal phase 3 trial (NCT05265923), significant higher proportions of adult AD patients receiving stapokibart than placebo achieved ≥75% improvement from baseline in Eczema Area and Severity Index (EASI-75; 66.9% vs. 25.8%) and Investigator's Global Assessment (IGA) score of 0/1 with ≥2-point reduction (44.2% vs. 16.1%) at Week 16. Herein, we report long-term (52 weeks) efficacy and safety of stapokibart from this trial. After 16-week double-blind treatment completed, patients in both stapokibart and placebo groups entered a 36-week maintenance treatment period and received stapokibart 300 mg every 2 weeks. Concomitant use of topical medications for AD was permitted throughout the maintenance period. Of 476 patients entering maintenance period, 430 completed the treatment. At Week 52, EASI-75 was achieved in 92.5% of patients continuing stapokibart and 88.7% of those switching from placebo to stapokibart, respectively; an IGA score of 0 or 1 with a ≥2-point reduction was achieved in 67.3% and 64.2% of patients, respectively; a ≥4-point reduction in weekly average of daily Peak Pruritus Numerical Rating Scale (PP-NRS) was achieved in 67.3% and 60.5% of patients, respectively. Over the 52-week treatment period, 88.1% of patients reported treatment-emergent adverse events, most were mild or moderate. Long-term treatment with stapokibart demonstrated a sustained efficacy and favorable safety profile in adults with moderate-to-severe AD.

DaxibotulinumtoxinA for injection to treat moderate or severe glabellar lines: A randomized, multicenter, Phase III, double-blind, placebo-controlled trial in China

BackgroundDaxibotulinumtoxinA for injection (DAXI), a novel botulinum toxin Type A treatment, is FDA-approved for glabellar lines treatment. Its clinical efficacy has been demonstrated in two Phase III trials (SAKURA 1 and SAKURA 2). ObjectiveTo evaluate DAXI efficacy and safety in Chinese adults with moderate/severe glabellar lines. MethodsIn this Phase III, randomized (2:1), double-blind trial, Chinese adults with moderate/severe glabellar lines received 40U DAXI or placebo into corrugator muscles bilaterally and the procerus. Glabellar line severity was evaluated by investigators (Investigator Global Assessment Frown Wrinkle Severity [IGA-FWS] scale) and participants (Patient Frown Wrinkle Severity [PFWS] scale) for ≥24 to 36 weeks. The primary endpoint was the proportion of 2-point composite responders achieving ≥2-point reduction in both IGA-FWS and PFWS scores at Week 4 post-treatment. ResultsOverall, 307 participants received study treatment (DAXI, 205; placebo, 102). A significantly greater proportion of participants in the DAXI arm versus placebo achieved a 2-point composite response at Week 4: 125 (61.0%) versus 1 (1.0%); difference, 60.0% [95% confidence interval 49.40–66.46]; 2-sided p<0.0001). At Week 4, 94.1% of DAXI-treated participants achieved an IGA-FWS score 0/1 (none/mild) and 86.3% achieved PFWS 0/1; median time to loss of none/mild on both IGA-FWS and PFWS was 23.9 weeks. Benefit of DAXI over placebo through Week 24 occurred regardless of baseline IGA-FWS score, prior BoNTA exposure, sex, or age. DAXI was well tolerated with no new safety signals. ConclusionDAXI provided durable efficacy and acceptable safety for treatment of moderate/severe glabellar lines in Chinese participants.

Chronic kidney disease-associated pruritus and quality of life with difelikefalin treatment: a post hoc analysis of phase 3 data using the Skindex-10 questionnaire.

Pruritus is a common condition in chronic kidney disease (CKD), especially for patients receiving haemodialysis. CKD-associated pruritus (CKD-aP) can be distressing and have a negative impact on quality of life (QoL). This post hoc analysis aimed to assess the relationship between pruritus relief and QoL. Data from phase 3 trials [(NCT03422653, NCT03636269 grouped), and NCT03998163] of the novel antipruritic difelikefalin (N=914) were used to assess the relationship between reductions in pruritus intensity at Week 12 (24-h Worst Itching Intensity Numeric Rating Scale; WI-NRS), perceived improvement in itch (Patient Global Impression of Change, PGI-C) and pruritus-related QoL (Skindex-10 questionnaire). Patients receiving difelikefalin had greater improvements in Skindex-10 total scores than those receiving placebo [LS mean treatment difference -3.4; 95% confidence interval (CI) -5.5, -1.3; P=.002] and greater improvements across Skindex-10 domains (disease, mood and social functioning) at Week 12. In patients receiving difelikefalin, those with clinically meaningful improvements in pruritus (≥3-point reduction in WI-NRS score) at Week 12 had a greater improvement in Skindex-10 total score (mean difference 14.2; 95% CI 11.0, 17.3; P<.001) and Skindex-10 domains than those with a <3-point reduction in WI-NRS score. Improvements in Skindex-10 total scores correlated with PGI-C. Improvements in pruritus intensity following 12 weeks of treatment with difelikefalin were associated with improvements in QoL. Larger improvements in Skindex-10 scores were seen in patients with a greater reduction in pruritus intensity, indicating that improvements in pruritus are associated with a range of factors, such as mood and social functioning, that affect pruritus-related QoL.

Achievement of Endoscopic Remission After Induction Reduces Hospitalization Burden in Crohn's Disease: Findings From a Pooled Post Hoc Analysis of Risankizumab and Upadacitinib Phase III Trials.

Endoscopic remission has emerged as an important treatment target in Crohn's disease (CD) and has been associated with improvement in long-term outcomes. We examined the relationship between achievement of endoscopic remission and hospitalizations using pooled 52-week Phase III risankizumab and upadacitinib maintenance trials for patients with moderate-to-severely active CD. Included patients received maintenance therapy after achieving a clinical response following a 12-week induction with risankizumab or upadacitinib. Endoscopic remission defined as a Simple Endoscopic Score for CD no greater than 4 with at least a 2-point reduction versus induction baseline and no subscore greater than 1. All subsequent hospitalization events were recorded until completion of the maintenance trial or discontinuation. Exposure-adjusted negative binomial regression models were estimated to assess the relationship between post-induction endoscopic remission and long-term hospitalization, controlling for demographics, clinical variables, and treatment arm. Post-induction hospitalization rates were lower in patients who achieved endoscopic remission at the end of the induction period. In multivariable models, post-induction endoscopic remission was independently associated with an IRR of 0.45 (95% CI [0.22-0.95], p=0.036) and 0.71 (95% CI [0.44-1.14], p=0.156) for long-term disease-related and all-cause hospitalizations, respectively. Week 12 endoscopic remission is independently associated with reducing 52-week disease-related hospitalizations. However, achieving this stringent endpoint within 12 weeks of therapy may be challenging. Endoscopic response may be a more realistic early endoscopic target in the post-induction timeframe. Additional research is needed to evaluate early achievement of alternative endoscopic endpoints in CD.

Erenumab versus topiramate: migraine-related disability, impact and health-related quality of life.

HER-MES was the first head-to-head study of erenumab against topiramate (standard of care). This post hoc analysis of the HER-MES study evaluated the effect of erenumab versus topiramate on patient-reported outcomes at week 24. Adult patients with episodic or chronic migraine (n = 777) were randomized (1:1) to monthly subcutaneous erenumab (n = 389) or daily oral topiramate (n = 388). Migraine-related disability, as measured by the Headache Impact Test 6 (HIT-6) and Short Form 36 Health Survey version 2 (SF-36v2), was analysed in the entire study cohort and true completers. In the erenumab group (vs. topiramate), significant improvements were reported in Headache Impact Test 6 total scores (composite populations, -10.88 vs. -7.72; true completers, -11.92 vs. -10.61) and a higher proportion of patients achieved a ≥5-point reduction from baseline with erenumab (composite populations, 72.2% vs. 53.9%; true completers, 79.64% vs. 71.43%). The adjusted mean change from baseline in the SF-36v2 score was greater with erenumab for both physical component summary (composite population, 5.48 vs. 3.63; true completers, 5.95 vs. 5.23) and mental component summary (composite populations, 1.00 vs. -1.18; true completers, 1.74 vs. -0.33). A higher proportion of patients on erenumab versus topiramate had a ≥5-point improvement in SF-36v2 for the physical component summary (composite populations, 47.7% vs. 37.4%; true completers, 52.1% vs. 48.9%) and mental component summary (composite populations, 25.3% vs. 16.8%; true completers, 27.3% vs. 17.7%). This post hoc analysis demonstrated that patients treated with erenumab had significant improvements in headache impact and quality of life as measured by patient-reported outcomes versus patients treated with topiramate.

A randomized phase 3b study evaluating the safety and efficacy of risankizumab in adult patients with moderate-to-severe plaque psoriasis with non-pustular palmoplantar involvement

BackgroundIn plaque psoriasis, palmoplantar areas are more difficult to treat. ObjectiveEvaluate the safety and efficacy of risankizumab (RZB) versus placebo (PBO) for the treatment of palmoplantar psoriasis (PPPsO). MethodsPatients were randomized to RZB or PBO for 16 weeks followed by RZB through week 52. The primary and secondary endpoints were achievement of palmoplantar Investigator’s Global Assessment of “clear” or “almost clear” with ≥2-point reduction from baseline (ppIGA 0/1), achievement of ≥75%, ≥90% and 100% improvement in Palmoplantar Psoriasis Area and Severity Index (PPASI 75, PPASI 90, PPASI 100) and achievement of static Physician Global Assessment of "clear" or "almost clear" with ≥2-point reduction from baseline (sPGA 0/1) at week 16. Safety was based on treatment-emergent adverse events (TEAEs). ResultsRZB demonstrated significant efficacy compared to PBO at week 16 in the patients achieving ppIGA 0/1 (33.3% vs 16.1% [P = .006]), PPASI 75 (42.5% vs 14.9% [P < .001]), PPASI 90 (27.6% vs 5.7% [P < 0.001]), sPGA 0/1 (32.2% vs 11.5% [P < .001]) and PPASI 100 (17.2% vs 1.1% [P < .001]). Results improved through week 52 with no new safety signals. LimitationNo biologic comparator ConclusionsRZB demonstrated safety and efficacy in PPPsO.

Long-Term Efficacy and Safety of Stapokibart in Adults with Moderate-to-Severe Atopic Dermatitis: An Open-Label Extension, Nonrandomized Clinical Trial.

Stapokibart/CM310, a humanized monoclonal antibody targeting the interleukin-4 receptor α chain, has shown promising treatment benefits in patients with moderate-to-severe atopic dermatitis in previous phase II clinical trials. We aimed to evaluate the long-term efficacy and safety of stapokibart in adults with moderate-to-severe atopic dermatitis. Enrolled patients who previously completed parent trials of stapokibart received a subcutaneous stapokibart 600-mg loading dose, then 300mg every 2weeks up to 52weeks. Efficacy outcomes included the proportions of patients with ≥50%/75%/90% improvements from baseline of parent trials in the Eczema Area and Severity Index, Investigator's Global Assessment, and weekly average of the daily Peak Pruritus Numerical Rating Scale. In total, 127 patients were enrolled, and 110 (86.6%) completed the study. At week52, the Eczema Area and Severity Index-50/75/90 response rates were 96.3%, 87.9%, and 71.0%, respectively. An Investigator's Global Assessment 0/1 with a ≥2-point reduction was achieved in 39.3% of patients at week16, increasing to 58.9% at week52. The proportions of patients with ≥3-point and ≥4-point reductions in the weekly average of daily Peak Pruritus Numerical Rating Scale scores were 80.2% and 62.2%, respectively, at week52. Improvement in patients' quality of life was sustained over a 52-week treatment period. Treatment-emergent adverse events occurred in 88.2% of patients, with an exposure-adjusted event rate of 299.2 events/100 patient-years. Coronavirus disease 2019, upper respiratory tract infection, and conjunctivitis were the most common treatment-emergent adverse events. Long-term treatment with stapokibart for 52weeks showed high efficacy and good safety profiles, supporting its use as a continuous long-term treatment option for atopic dermatitis. ClinicalTrials.gov identifier: NCT04893707 (15 May, 2021).

Multicenter external validation of prediction models for clinical outcomes after spinal fusion for lumbar degenerative disease

BackgroundClinical prediction models (CPM), such as the SCOAP-CERTAIN tool, can be utilized to enhance decision-making for lumbar spinal fusion surgery by providing quantitative estimates of outcomes, aiding surgeons in assessing potential benefits and risks for each individual patient. External validation is crucial in CPM to assess generalizability beyond the initial dataset. This ensures performance in diverse populations, reliability and real-world applicability of the results. Therefore, we externally validated the tool for predictability of improvement in oswestry disability index (ODI), back and leg pain (BP, LP).MethodsProspective and retrospective data from multicenter registry was obtained. As outcome measure minimum clinically important change was chosen for ODI with ≥ 15-point and ≥ 2-point reduction for numeric rating scales (NRS) for BP and LP 12 months after lumbar fusion for degenerative disease. We externally validate this tool by calculating discrimination and calibration metrics such as intercept, slope, Brier Score, expected/observed ratio, Hosmer–Lemeshow (HL), AUC, sensitivity and specificity.ResultsWe included 1115 patients, average age 60.8 ± 12.5 years. For 12-month ODI, area-under-the-curve (AUC) was 0.70, the calibration intercept and slope were 1.01 and 0.84, respectively. For NRS BP, AUC was 0.72, with calibration intercept of 0.97 and slope of 0.87. For NRS LP, AUC was 0.70, with calibration intercept of 0.04 and slope of 0.72. Sensitivity ranged from 0.63 to 0.96, while specificity ranged from 0.15 to 0.68. Lack of fit was found for all three models based on HL testing.ConclusionsUtilizing data from a multinational registry, we externally validate the SCOAP-CERTAIN prediction tool. The model demonstrated fair discrimination and calibration of predicted probabilities, necessitating caution in applying it in clinical practice. We suggest that future CPMs focus on predicting longer-term prognosis for this patient population, emphasizing the significance of robust calibration and thorough reporting.

A Fair Investment Environment: The Impact of the Shadow Economy, the Harshness of the Courts Against Corrupt Officials, Tax Pressure and Restrictions on Business

Creating a fair investment environment is crucial for economic growth and attracting domestic and foreign investors. The purpose of this study is to find out how the shadow economy, harshness of courts against corrupt officials, tax pressure, and restrictions on business affect the fair investment environment. Therefore, two economic-mathematical models are built using multiple least squares regression analysis, in which the outcome variables are: in model 1 ‒ control over corruption, which is a component of the Global Governance Index; in model 2 ‒ the European Business Association’s Investment Attractiveness Index. The composition of the factor attributes in both models is the same: Corruption Perceptions Index by Transparency International; level of shadow economy according to the Ministry of Economy of Ukraine; the number of criminal cases in courts under the article “Acceptance of an offer, promise or receipt of an undue benefit by an official” using open data from the Unified State Register of Court Decisions; total tax and fee rate, which reflects taxes and mandatory payments as a percentage of commercial profit, determined by the World Bank Group methodology; assessment of “Starting Business” by Doing Business, according to the methodology of the World Bank Group. The modeling is based on the example of Ukraine for 2012‒2022. Calculations based on Model 1 show that restrictions on business have the greatest impact on the corruption control indicator (a 10% reduction in restrictions leads to a 3-point reduction in the need to control corruption), the shadow economy and tax pressure have an average impact (a one-point increase in them will increase the level of corruption by 0.4 points). The harshness of the courts against corrupt officials has the least impact (most corruption cases in Ukraine do not reach the courts). Calculations based on Model 2 show that the complexity of starting a business exerts the greatest impact on investment attractiveness (if it decreases by 15%, investment attractiveness will increase by almost 1 unit). The average impact is exerted by the increase in the shadow economy (a 10% increase in the shadow economy leads to a rise in investment attractiveness by 0.4 units). The insignificant impact is exerted by the tax burden and judicial punishment of corrupt officials.

Measurement properties of the Inclusion Body Myositis Functional Rating Scale

ObjectivesTo evaluate the validity, reliability, responsiveness and meaningful change threshold of the Inclusion Body Myositis (IBM) Functional Rating Scale (FRS).MethodsData from a large 20-month multicentre, randomised, double-blind, placebo-controlled trial in...

Re-examining the factor structure of the Insomnia Severity Index (ISI) and defining the meaningful within-individual change (MWIC) for subjects with insomnia disorder in two phase III clinical trials of the efficacy of lemborexant

BackgroundThe Insomnia Severity Index (ISI) is a widely used measure of insomnia severity. Various ISI research findings suggest different factor solutions and meaningful within-individual change (MWIC) to detect treatment response in patients with insomnia. This study examined an ISI factor solution and psychometric indices to define MWIC in a robust patient sample from clinical trial settings.MethodsWe endeavored to improve upon previous validation of ISI by examining structural components of confirmatory factor analysis (CFA) models using two large, placebo-controlled clinical trials of lemborexant for insomnia. Using the best-fitting two-factor solution, we evaluated anchor-based, distribution-based and receiver operating characteristic (ROC) curve methods to derive an estimate of the MWIC.ResultsThe model structure for the 7-item scale proposed in other research did not fit the observed data from our two lemborexant clinical trials (N = 1956) as well as a two-factor solution based on 6 items did. Using triangulation of anchor-based, distribution-based, and ROC methods, we determined that a 5-point reduction using 6 items best represented a clinically meaningful improvement in individuals with insomnia in our patient sample.ConclusionsA 6-item two-factor scale had better psychometric properties than the 7-item scale in this patient sample. On the 6-item scale, a reduction of 5 points in the ISI total score represented the MWIC. Generalizability of the proposed MWIC may be limited to patient populations with similar demographic and clinical characteristics.

The impact of cannabidiol (CBD) on aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS).

e24060 Background: Although treatment with an AI for 5-10 years decreases 10-year breast cancer (BC) mortality by about 40%, up to 25% of patients will stop treatment early because of treatment-related, intolerable joint and muscle pain and stiffness, called AIMSS. Only acupuncture, duloxetine, and exercise have been shown to reduce AIMSS. While the exact underlying mechanism is unknown, it is thought to be due in part to ongoing systemic inflammation. CBD has anti-nociceptive and anti-inflammatory properties, making it a potential treatment option for AIMSS. Methods: Women with stage 0-3 hormone receptor-positive BC experiencing AIMSS (defined as worst joint pain ≥4/10 during prior 7 days that developed or worsened since starting AI therapy) were eligible for enrollment in this single arm, single center phase 2 open label clinical trial (NCT04754399). Patients received an FDA-approved formulation of CBD (Epidiolex), titrated over 4 weeks from 25 mg BID to 100 mg BID and then continued at maximum tolerated dose for a total of 15 weeks. Patient-reported outcomes (PRO) data were collected serially, including the Brief Pain Inventory (BPI) and the PROMIS Profile 29+2 v2.1. The primary endpoint was the number of CBD-treated patients with at least a 2-point reduction (minimal clinically important difference) in worst pain from baseline to 15 weeks. Statistical analysis was completed using paired t-tests and linear mixed models. Results: Of 39 eligible patients (Table 1), 11 discontinued participation early due to patient discretion (n = 6) or adverse event (n = 5). There were no grade 3-4 toxicities. Analyzing data from all 39 patients, there was an improvement in BPI worst pain (0-10 scale) of 0.13 per week of treatment after baseline (p &lt; 0.001), resulting in an average improvement in worst pain of 1.95 at the end of 15 weeks. Of the 28 patients who completed the study, 17 (60.7%) reported a ≥2-point improvement in BPI worst pain between baseline and week 15. There was a significant improvement in PROMIS T score at week 15 in both physical function (2.34, p = 0.01) and ability to participate in social roles and activities (2.71, p = 0.02). Conclusions: Treatment with CBD was associated with an improvement in joint pain for a subset of patients. Additional analyses are ongoing to further investigate the impact of CBD on AIMSS and to explore which patients are most likely to benefit from treatment with CBD. Clinical trial information: NCT04754399 . [Table: see text]

Sustained Treatment Response and Global Improvements With Long-term Valbenazine in Patients With Tardive Dyskinesia.

Using data from KINECT® 4, a phase 3, 48-week study of valbenazine, post hoc analyses were conducted to assess long-term outcomes that are relevant to the real-world management of tardive dyskinesia (TD). Post hoc analyses of the participants of the KINECT 4 study who completed 48 weeks of open-label valbenazine (40 or 80 mg) treatment were conducted. Valbenazine effects on TD were evaluated using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD (CGI-TD), and Patient Global Impression of Change (PGIC). Of 103 participants completing 48 weeks of treatment, 55% experienced clinically meaningful improvement (defined as ≥2-point reduction in AIMS total score [sum of items 1 - 7, evaluated by site raters]) by week 4; at week 48, 97% met this threshold. The percentage of completers who achieved AIMS total score response thresholds of ≥10% to ≥90% increased over time, with 86% of completers reaching ≥50% improvement. Of the 40 (39%) completers with AIMS ≥50% response at week 8, 38 (95%) sustained this response at week 48; 81% of those who did not meet this threshold at week 8 had achieved it by week 48. At week 48, more than 85% of completers achieved CGI-TD and PGIC ratings of "much improved" or "very much improved." The majority of participants who completed 48 weeks of treatment with once-daily valbenazine experienced substantial clinically meaningful and sustained TD improvements. These findings indicate that valbenazine can be a highly effective long-term treatment in patients with TD.

Economic Evaluation of a Web Application Implemented in Primary Care for the Treatment of Depression in Patients With Type 2 Diabetes Mellitus: Multicenter Randomized Controlled Trial.

Depressive disorder and type 2 diabetes mellitus (T2DM) are prevalent in primary care (PC). Pharmacological treatment, despite controversy, is commonly chosen due to resource limitations and difficulties in accessing face-to-face interventions. Depression significantly impacts various aspects of a person's life, affecting adherence to medical prescriptions and glycemic control and leading to future complications and increased health care costs. To address these challenges, information and communication technologies (eg, eHealth) have been introduced, showing promise in improving treatment continuity and accessibility. However, while eHealth programs have demonstrated effectiveness in alleviating depressive symptoms, evidence regarding glycemic control remains inconclusive. This randomized controlled trial aimed to test the efficacy of a low-intensity psychological intervention via a web app for mild-moderate depressive symptoms in individuals with T2DM compared with treatment as usual (TAU) in PC. This study aimed to analyze the cost-effectiveness and cost-utility of a web-based psychological intervention to treat depressive symptomatology in people with T2DM compared with TAU in a PC setting. A multicenter randomized controlled trial was conducted with 49 patients with T2DM, depressive symptoms of moderate severity, and glycosylated hemoglobin (HbA1c) of 7.47% in PC settings. Patients were randomized to TAU (n=27) or a web-based psychological treatment group (n=22). This web-based treatment consisted of cognitive behavioral therapy, improvement of diabetes self-care behaviors, and mindfulness. Cost-effectiveness analysis for the improvement of depressive symptomatology was conducted based on reductions in 3, 5, or 50 points on the Patient Health Questionnaire-9 (PHQ-9). The efficacy of diabetes control was estimated based on a 0.5% reduction in HbA1c levels. Follow-up was performed at 3 and 6 months. The cost-utility analysis was performed based on quality-adjusted life years. Efficacy analysis showed that the web-based treatment program was more effective in improving depressive symptoms than TAU but showed only a slight improvement in HbA1c. Incremental cost-effectiveness ratios of 186.76 for a 3-point reduction in PHQ-9 and 206.31 for reductions of 5 and 50 percentage points were obtained. In contrast, the incremental cost-effectiveness ratio for improving HbA1c levels amounted to €1510.90 (€1=US $1.18 in 2018) per participant. The incremental cost-utility ratio resulted in €4119.33 per quality-adjusted life year gained. The intervention, using web-based modules incorporating cognitive behavioral therapy tools, diabetes self-care promotion, and mindfulness, effectively reduced depressive symptoms and enhanced glycemic control in patients with T2DM. Notably, it demonstrated clinical efficacy and economic efficiency. This supports the idea that eHealth interventions not only benefit patients clinically but also offer cost-effectiveness for health care systems. The study emphasizes the importance of including specific modules to enhance diabetes self-care behaviors in future web-based psychological interventions, emphasizing personalization and adaptation for this population. ClinicalTrials.gov NCT03426709; https://clinicaltrials.gov/study/NCT03426709. RR2-10.1186/S12888-019-2037-3.

Role of Resmetirom, a Liver-Directed, Thyroid Hormone Receptor Beta-Selective Agonist, in Managing Nonalcoholic Steatohepatitis: A Systematic Review and Meta-Analysis

BackgroundResmetirom, a liver-directed, thyroid hormone receptor beta-selective agonist, has recently been approved to treat nonalcoholic steatohepatitis (NASH). This meta-analysis aimed to summarize the efficiency and safety of resmetirom in treating NASH. MethodsElectronic databases were searched for randomized controlled trials (RCTs) of resmetirom vs placebo in patients with NASH. The primary outcomes were the changes from baseline in hepatic fat content, liver histology, including NASH resolution, and noninvasive markers of hepatic fibrosis. ResultsThree randomized controlled trials (n = 2231) met the inclusion criteria. Compared to placebo, resmetirom achieved greater reductions from baseline in hepatic fat content assessed by magnetic resonance imaging proton density fat fraction (for resmetirom 80 mg: MD −27.76% [95%CI: −32.84, −22.69]; for resmetirom 100 mg: MD −36.01% [95%CI: −41.54, −30.48]; P < .00001 for both) and FibroScan controlled attenuation parameter (for resmetirom 80 mg: MD −21.45 dBm [95%CI: −29.37, −13.52]; for resmetirom 100 mg: MD −25.51 dBm [95%CI: −33.53, −17.49]; P < .00001 for both). Resmetirom 80 mg outperformed placebo in NASH resolution and ≥2-point nonalcoholic fatty liver disease activity score reduction. Moreover, resmetirom 80 mg and 100 mg were superior to placebo in cytokeratin-18 (M30) reduction. Greater reductions in liver enzymes, lipids, and reverse triiodothyronine were observed in the resmetirom arms with no impact on triiodothyronine. Nausea and diarrhea were more common with resmetirom than with placebo; other adverse events were comparable. ConclusionResmetirom improves hepatic fat content, liver enzymes, and fibrosis biomarkers in NASH patients. Resmetirom generally does not affect thyroid function and is well-tolerated.

The Challenge of Lorazepam Failure: Malignant Catatonia Treated Successfully with Valproate

IntroductionDespite the unclear nature of catatonia, the treatment response of catatonia to benzodiazepines is widely known for its typical, dramatic recovery. The neurobiological correlates of this phenomenon regarding specific receptors and neurotransmitters are unclear, as are the potential treatment options. This is important to consider when the most commonly recommended treatments of catatonia with Lorazepam or Electroconvulsive Therapy (ECT) are unavailable or unsuccessful. In this report, we describe a case of severe, malignant catatonia and psychosis mostly unresponsive to Lorazepam during two different hospitalizations, but with eventual return to baseline after successful treatment with Valproate.Objectives-To describe a unique case of malignant catatonia that was unresponsive to Lorazepam-To illustrate the potential utility of Valproate as an alternative treatment strategy for catatonia MethodsThis is a case report.ResultsA 19-year-old Hispanic male presented to our hospital initially with family reports of severe and sudden depression with bizarre behavior. Prior to this admission, the patient had been discharged recently from another tertiary hospital following a 2-week admission for severe catatonia. Chart review from that admission scored the patient’s Bush-Francis Catatonia Rating Scale (BFCRS) at 16, which remained mostly unchanged after numerous additional intramuscular doses and standing oral doses of Lorazepam, with a reduction of BFCRS the next day of only 2. During the patient’s admission at our hospital, the patient endorsed bizarre, guilt-related delusions, and his catatonia was more severe and malignant with a BFCRS of 19, with tachycardia and diaphoresis. The patient was initially given a total of seven doses of a mix of intramuscular and oral Lorazepam (total 18mg), with a minimal 2-point reduction in BFCRS. As ECT was unavailable, Lorazepam was discontinued in favor of a trial of oral Valproate 500mg twice daily, and after his catatonia subsided (with a serum level of 60.8), he was started on oral Risperidone 0.5mg once at night, titrated up to 3mg twice daily, and eventually returned to baseline as confirmed by his family members.ConclusionsThe treatment of catatonia with Lorazepam is usually reliable and has been found to be up to 80% effective, but when the recommended use of benzodiazepines and ECT fail or are unavailable, there are few studies exploring the viability of alternative treatment options. With the use of Valproate, previous studies have shown it can treat even severe catatonia (KrÜger, J Neuropsychiatry 2001; 13:303-304), or can actually be its cause (Lauterbach, Neuropsychiatry, Neuropsychology, and Behavioral Neurology. 1998 Jul;11(3):157-163). As such, this case report highlights the importance of exploring alternative treatments for catatonia, including Valproate, in order to better tailor the management of this unique syndrome.Disclosure of InterestNone Declared

Efficacy and safety of tildrakizumab for the treatment of moderate-to-severe plaque psoriasis of the scalp: A multicenter, randomized, double-blind, placebo-controlled, Phase 3b study

Scalp psoriasis is common and difficult to treat. To evaluate efficacy and safety of tildrakizumab for the treatment of scalp psoriasis. In this Phase 3b, randomized, double-blind, placebo (PBO)-controlled study (NCT03897088), patients with moderate-to-severe plaque psoriasis affecting the scalp (Investigator Global Assessment modified [IGA mod] 2011 [scalp] ≥3, Psoriasis Scalp Severity Index [PSSI] ≥12, ≥30% scalp surface area affected) received tildrakizumab 100mg or PBO at W0 and W4. The primary endpoint was IGA mod 2011(scalp) score of "clear" or "almost clear" with ≥2-point reduction from baseline at W16 (IGA mod2011 [scalp] response). Key secondary endpoints were PSSI 90 response at W12 and W16 and IGA mod 2011 (scalp) response at W12. Safety was assessed from adverse events. Of patients treated with tildrakizumab (n=89) vs PBO (n=82), 49.4% vs 7.3% achieved IGA mod 2011 (scalp) response at W16 (primary endpoint) and 46.1% vs 4.9% at W12; 60.7% vs 4.9% achieved PSSI 90 response at W16 and 48.3% vs 2.4% at W12 (all P<.00001). No serious treatment-related adverse events occurred. Only short-term data are presented. Tildrakizumab was efficacious for the treatment of scalp psoriasis with no new safety signals.