12-week Treatment Research Articles

Efficacy of extension wrist hand orthosis on pain, grip strength and electromyographic activities in lateral epicondylitis: A randomized single-blind clinical trial

BackgroundLateral epicondylitis (LE) is one of the most common work-related complications characterized by pain, decreased grip strength and dysfunction of upper limb. Although conservative management such as physiotherapy and orthosis is reported as first line of treatment, sufficient evidence to decide their effectiveness is lacking and remains controversial. PurposeThe current study evaluated and compared the efficacy of a custom-made extension wrist hand orthosis adjunct to usual physiotherapy and therapeutics alone for subjects with LE. Study DesignProspective randomized single-blinded clinical trial. Methods62 subjects with LE were selected as samples using convenience method in this experimental study. They were randomly divided into two groups: usual physiotherapy only and its combination with orthosis. Pain and grip strength were measured using Visual Analog Scale and Jamar hydraulic digital hand dynamometer. Muscle activity of extensor carpi radialis brevis during hand gripping was measured using surface electro-myographic by PowerLab electromyography (AD Instruments, Castle Hill, Australia). Data analysis and comparison were performed for baseline and post-intervention (12weeks). ResultsAfter 12weeks of treatment, there were significant differences in mean scores of pain (1.22 ± 0.51, p = 0.001), maximum voluntary grip strength (5.82 ± 7.84, p = 0.04), and extensor carpi radialis brevis muscle activation (0.082 ± 0.094, p = 0.02) between the therapeutics alone group and the therapeutics plus orthosis group. Compared to therapeutics alone, those getting a combination of physiotherapy and orthosis had greater treatment efficacy (p < 0.05). ConclusionsBoth postintervention (12-week) treatments could affect pain scores, grip strength, and extensor muscle activation. Custom-made extension wrist hand orthosis adjunct to usual physiotherapy is more effective than therapeutics alone in subjects with LE. Therefore, the use of wrist orthosis adjunct to physiotherapy should be recommended in rehabilitation settings for LE.

Tafolecimab in Chinese Patients With Hypercholesterolemia (CREDIT-4): A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial

BackgroundTafolecimab is a novel fully human proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody, developed for the treatment of hypercholesterolemia. ObjectivesThe purpose of this study was to assess the efficacy and safety of tafolecimab in Chinese patients at high or very high cardiovascular risk with hypercholesterolemia. MethodsPatients with diagnoses of heterozygous familial hypercholesterolemia (HeFH) by the Simon Broome criteria or at high or very high cardiovascular risk with nonfamilial hypercholesterolemia, with screening low-density lipoprotein cholesterol (LDL-C) level ≥1.8 mmol/L, were randomized 2:1 to receive tafolecimab or placebo 450 mg every 4 weeks (Q4W) in the 12-week double-blind treatment period. The primary endpoint was the percent change from baseline to week 12 in LDL-C levels. ResultsA total of 303 patients were enrolled and received at least 1 dose of tafolecimab (n = 205) or placebo (n = 98). The least squares mean percent change in LDL-C level from baseline to week 12 was –68.9% (SE 1.4%) in the tafolecimab group and –5.8% (1.8%) in the placebo group (difference: –63.0%; [95% CI: –66.5% to –59.6%]; P < 0.0001). More patients treated with tafolecimab achieved ≥50% LDL-C reductions, LDL-C <1.8 mmol/L, and LDL-C <1.4 mmol/L at week 12 than did those in the placebo group (all P < 0.0001). Furthermore, tafolecimab markedly reduced non-HDL-C, apolipoprotein B, and lipoprotein(a) levels. During the double-blind treatment period, the most commonly reported adverse events included urinary tract infection (5.9% with tafolecimab vs 4.1% with placebo) and hyperuricemia (3.4% vs 4.1%). ConclusionsTafolecimab was safe and showed robust lipid-lowering efficacy in Chinese patients at high or very high cardiovascular risk with hypercholesterolemia. (A Study of IBI306 in Participants With Hypercholesterolemia; NCT04709536)

(314) MED3000, A CLINICALLY PROVEN, FAST-ACTING TOPICAL PRODUCT FOR ERECTILE DYSFUNCTION WITH THE PROSPECT OF BEING THE FIRST GLOBALLY AVAILABLE OTC TREATMENT FOR ED

Abstract Objectives To assess the effectiveness, onset of action and safety of MED3000 gel over a 24-week treatment period in male patients clinically diagnosed with ED. Methods 100 male patients clinically diagnosed with ED were randomised into two treatment groups, 50 to MED3000 and 50 to Tadalafil (5mg) in 11 Investigational sites in USA, Poland Georgia and Bulgaria. Results Both Co-Primary end points were achieved (P&amp;lt;0.001) (1) Mean IIEF-EF change from baseline at 24 weeks (2) Minimal clinically important difference (MCID) exceeded at 24 weeks). 61% of MED3000 users exceeded the MCID at 24 weeks The mean IIEF score at weeks 4, 8, 12, 16, 20, 24 was 4.59, 5.20, 5.12, 5.83, 5.57 5.73 Secondary Endpoint 10 minute onset of action FDA agreed standard for achieving a 10 minute onset of action was achieved. A key differentiator from PDEi's Effective in Mild, Moderate and Severe ED MED3000 also delivered a clinically meaningful outcome over 24 weeks in accordance with the Rosen 2, 5 and 7 criteria (Rosen et al 2011)1 in mild, moderate and severe ED subjects Adverse Events (&amp;lt;2 incidences) are detailed in figure 1. Reference 1 – Rosen RC et al “Minimal clinically important differences in the erectile function domain in the International Index of Erectile Function Scale Eur Urol 2011;60(5):1010-6 Conclusions MED3000 has been shown to deliver a clinically meaningful response and is fast-acting. It was also shown to be clinically effective in mild, moderate and severe ED. Results were generally consistent with a previously conducted clinical study used for European approval MED3000 was shown to have minimal adverse events. Its “drug-free” formula provides a further margin of safety with no propensity for adverse drug interactions. This profile makes it suitable for OTC use. FDA filing for marketing authorisation as a De Novo medical device occured in October 2022. Conflicts of Interest Professor David Ralph is a consultant to FMD Tim Holland and Ken James are employees of FMD The study was funded by FMD (Not for promotional purposes in the US).

Varenicline and counseling for vaping cessation: a double-blind, randomized, parallel-group, placebo-controlled trial

BackgroundVaping cessation is virtually unexplored. The efficacy and safety of varenicline for vaping cessation has not been studied and rigorous research is required to advance best practice and outcomes for people who use electronic cigarettes (EC) and want to quit. The objective is to evaluate the efficacy and safety of varenicline (1 mg BID, administered for 12 weeks, with follow-up to week 24) combined with vaping cessation counseling in exclusive daily EC users intending to quit vaping.MethodsDesign: Double-blind, randomized, parallel-group, placebo-controlled trial.Setting: The study took place at a University-run smoking cessation center.Participants: People who exclusively use ECs daily and intend to quit vaping.Intervention: A total of 140 subjects were randomized to either varenicline (1 mg, administered twice daily for 12 weeks) plus counseling or placebo treatment (administered twice daily, for 12 weeks) plus counseling. The trial consisted of a 12-week treatment phase followed by a 12-week follow-up, nontreatment phase.Main outcomes and measures: The primary efficacy endpoint of the study was biochemically validated continuous abstinence rate (CAR) at weeks 4 to 12. Secondary efficacy end points were CAR at weeks 4 to 24 and 7-day point prevalence of vaping abstinence at weeks 12 and 24.ResultsCAR was significantly higher for varenicline vs placebo at each interval: weeks 4–12, 40.0% and 20.0%, respectively (OR = 2.67, 95% CI = [1.25–5.68], P = 0.011); weeks 4–24, 34.3% for varenicline with counseling and 17.2% for placebo with counseling (OR = 2.52, 95% CI = [1.14–5.58], P = 0.0224). The 7-day point prevalence of vaping abstinence was also higher for the varenicline than placebo at each time point. Serious adverse events were infrequent in both groups and not treatment-related.ConclusionsThe findings of the present RCT indicate that inclusion of varenicline in a vaping cessation program for people who use electronic cigarettes and intending to quit may result in prolonged abstinence. These positive findings establish a benchmark of intervention effectiveness, may support the use of varenicline combined with counseling in vaping cessation programs, and may also help guiding future recommendations by health authorities and healthcare providers.Trial registrationThe study has been registered in EUDRACT with Trial registration ID: 2016-000339-42.

Dynamic functional thalamocortical dysconnectivity in schizophrenia correlates to antipsychotics response

Although many studies have showed abnormal thalamocortical networks in patients with schizophrenia (SCZ), the dynamic functional thalamocortical connectivity of individuals with SCZ and the effect of antipsychotics on this connectivity have not been investigated. Drug-naïve first-episode individuals with SCZ and healthy controls were recruited. Patients were treated with risperidone for 12 weeks. Resting-state functional magnetic resonance imaging was acquired at baseline and week 12. We identified six functional thalamic subdivisions. The sliding window strategy was used to determine the dynamic functional connectivity (dFC) of each functional thalamic subdivision. Individuals with SCZ displayed decreased or increased dFC variance in different thalamic subdivisions. The baseline dFC between ventral posterior-lateral (VPL) portions and right dorsolateral superior frontal gyrus (rdSFG) correlated with psychotic symptoms. The dFC variance between VPL and right medial orbital superior frontal gyrus (rmoSFG) or rdSFG decreased after 12-week risperidone treatment. The decreased dFC variance between VPL and rmoSFG correlated with the reduction of PANSS scores. Interestingly, the dFC between VPL and rmoSFG or rdSFG decreased in responders. The dFC variance change of VPL and the averaged whole brain signal correlated with the risperidone efficacy. Our study demonstrates abnormal variability in thalamocortical dFC may be implicated in psychopathological symptoms and risperidone response in individuals with schizophrenia, suggesting that thalamocortical dFC variance may be correlated to the efficacy of antipsychotic treatment.Registration: ClinicalTrials.gov Identifier: NCT00435370. https://www.clinicaltrials.gov/ct2/show/NCT00435370?term=NCT00435370&draw=2&rank=1

Thirty-two cats with effusive or non-effusive feline infectious peritonitis treated with a combination of remdesivir and GS-441524.

GS-441524 has been successfully used to treat feline infectious peritonitis (FIP) in cats. However, the use of its prodrug, remdesivir, in combination with a PO GS-441524 containing product for the treatment of FIP has not yet been described. Describe treatment protocols, response to treatment and outcomes in cats with FIP treated with a combination of PO GS-441524 and injectable remdesivir. Thirty-two client-owned cats diagnosed with effusive or non-effusive FIP including those with ocular and neurological involvement. Cats diagnosed with FIP at a single university hospital between August 2021 and July 2022 were included. Variables were recorded from time of diagnosis, and subsequent follow-up information was obtained from the records of referring veterinarians. All surviving cats were observed for the entire 12-week treatment period. Cats received treatment with different combinations of IV remdesivir, SC remdesivir, and PO GS-441524 at a median (range) dosage of 15 (10-20) mg/kg. Clinical response to treatment was observed in 28 of 32 cats (87.5%) in a median (range) of 2 (1-5) days. Twenty-six of 32 cats (81.3%) were alive and in clinical and biochemical remission at the end of the 12-week treatment period. Six of 32 cats (18.8%) died or were euthanized during treatment with 4 of the 6 cats (66%) dying within 3 days of starting treatment. We describe the effective use of injectable remdesivir and PO GS-441524 for the treatment of FIP in cats. Success occurred using different treatment protocols and with different presentations of FIP including cats with ocular and neurological involvement.

Oral Semaglutide Induces Loss of Body Fat Mass Without Affecting Muscle Mass in Patients With Type 2 Diabetes.

Excessive body fat may be a major cause of insulin resistance and diabetes. But body weight reduction by energy restriction may simultaneously reduce both fat and muscle. Skeletal muscle is an important organ for glucose metabolism regulation, and loss of muscle may deteriorate glucose metabolism. Therefore, it is preferable to predominantly reduce fat without significant loss of muscle with weight loss in patients with type 2 diabetes. Previously, the anti-diabetic agent glucagon-like peptide-1 receptor agonists (GLP-1RAs) liraglutide and semaglutide given by injection were reported to decrease fat with less effect on muscle in diabetic patients. Recently oral semaglutide was developed and was reported to decrease body weight, but the effect on muscle has not been fully evaluated. This was a non-interventional retrospective longitudinal study. We evaluated the effect of 24-week treatment with oral semaglutide on body fat and muscle mass in 25 Japanese patients with type 2 diabetes. Laboratory examination and body composition test by bioelectrical impedance analysis (BIA) were performed at baseline, 12 weeks, and 24 weeks, and the effects on glycemic control and body composition were assessed. Hemoglobin A1c significantly decreased at 12 weeks and further ameliorated at 24 weeks (8.7±0.87% at baseline; 7.6±1.00% at 12 weeks; 7.0±0.80% at 24 weeks; mean ± standard error (SE)). While body fat significantly decreased (28.3 ± 1.52 kg at baseline; 26.8 ± 1.59 kg at 12 weeks; 25.5 ± 1.57 kg at 24 weeks; mean ± SE), whole-body lean mass was not significantly changed (48.1 ± 1.92 kg at baseline; 47.7 ± 1.93 kg at 12 weeks; 47.6 ± 1.89 kg at 24 weeks; mean ± SE). Furthermore, the appendicular skeletal muscle index (SMI) defined as appendicular skeletal muscle mass (ASM)/height squared (units; kg/m2) was also unchanged. The 24-week treatment with oral semaglutide ameliorated glycemic control with reduction of body fat but not muscle mass in Japanese patients with type 2 diabetes.

The contribution of the cingulate cortex: treating depressive symptoms in first-episode drug naïve schizophrenia.

Our previous study has shown the cingulate cortex abnormalities in first-episode drug naïve (FEDN) schizophrenia patients with comorbid depressive symptoms. However, it remains largely unknown whether antipsychotics may induce morphometric change in cingulate cortex and its relationship with depressive symptoms. The purpose of this study was to further clarify the important role of cingulate cortex in the treatment on depressive symptoms in FEDN schizophrenia patients. In this study, 42 FEDN schizophrenia patients were assigned into depressed patients group (DP, n=24) and non-depressed patients group (NDP, n=18) measured by the 24-item Hamilton Depression Rating Scale (HAMD). Clinical assessments and anatomical images were obtained from all patients before and after 12-week treatment with risperidone. Although risperidone alleviated psychotic symptoms in all patients, depressive symptoms were decreased only in DP. Significant group by time interaction effects were found in the right rostral anterior cingulate cortex (rACC) and other subcortical regions in the left hemisphere. After risperidone treatment, the right rACC were increased in DP. Further, the increasing volume of right rACC was negatively associated with improvement in depressive symptoms. These findings suggested that the abnormality of the rACC is the typical characteristics in schizophrenia with depressive symptoms. It's likely key region contributing to the neural mechanisms underlying the effects of risperidone treatment on depressive symptoms in schizophrenia.

Dupilumab for patients with photoaggravated dermatoses with skin nodules as main manifestations: A case series

Photoaggravated dermatoses (PD) are diseases that occur without ultraviolet (UV) radiation but are sometimes or frequently exacerbated by UV radiation. The clinical manifestations of PD are varied, some patients may present with pruritic nodular lesions at the site of light exposure, which possibly through a light-induced type 2 inflammatory response. Some cases may be difficult to treat, safe and effective treatment methods are constantly being explored. Here, we reported five patients with moderate to severe PD with skin nodules as main manifestations successfully treated with dupilumab, who were previously resistant to conventional treatment. After the 16-week treatment period, dupilumab showed good efficacy and safety in PD mainly characterized by nodules.

Serum CDC42 is increased during tumor necrosis factor inhibitor treatment, and its elevation correlates with satisfactory treatment response in rheumatoid arthritis patients.

Our previous study discovered that cell division control protein 42 (CDC42) correlated with decreased disease activity and risk of developing rheumatoid arthritis (RA), along with repressed T helper type 17 cell differentiation. This study aimed to further estimate the longitudinal change of serum CDC42 and its association with treatment outcomes to tumor necrosis factor inhibitor (TNFi) in RA. CDC42 was detected in serum by ELISA at week (W)0, W6, W12, and W24 in 88 RA patients undergoing TNFi treatment, and after enrollment in 20 disease controls (DCs) and 20 healthy controls (HCs). CDC42 was lower in RA patients compared with DCs and HCs (both p < .001); meanwhile, it negatively related to C-reactive protein (p = .011) and DAS28 score (p = .006). Regarding TNFi type, 40.9%, 33.0%, 17.0%, and 9.1% of patients received adalimumab, etanercept, golimumab, and infliximab, respectively. Notably, CDC42 was increased from W0 to W24 in RA patients receiving TNFi treatment (p < .001), also in patients receiving adalimumab (p < .001), etanercept (p < .001), golimumab (p < .001), and infliximab (p = .001). Furthermore, CDC42 at W24 was higher in patients with a clinical response to TNFi treatment compared with those without (p = .023); CDC42 at W12 (p = .027) and W24 (p = .002) was elevated in patients with clinical low disease activity in response to TNFi treatment versus those without; whereas CDC42 at W12 (p = .074) and W24 (p = .068) only showed an increasing trend in patients with clinical remission with TNFi treatment, but did not achieve statistical significance. Circulating CDC42 is elevated during TNFi administration; its increase reflects good 24-week TNFi treatment responses in RA patients.

Should Nicotine Replacement Therapy be Provided Free of Charge? A Cost-Utility Analysis in Sweden.

Treatment with nicotine replacement therapy (NRT) during an attempt to quit smoking increases the likelihood of success by about 55%. However, out-of-pocket payment for NRT can hinder its use. This study aims therefore to assess the cost-effectiveness of subsidizing NRT in Sweden. A homogeneous cohort-based Markov model was used to assess the lifetime costs and effects of subsidized NRT from a payer and societal perspective. Data to populate the model were retrieved from the literature, and selected parameters were varied in deterministic and probabilistic sensitivity analyses to assess robustness of model outputs. Costs are presented in USD, year 2021. A 12-week treatment with NRT was estimated to cost USD 632 (474-790) per person. From a societal perspective, subsidized NRT was a cost-saving alternative in 98.5% of the simulations. NRT is cost-saving across all ages, but the health and economic gains are somewhat larger among younger smokers from a societal perspective. When a payer perspective was used, the incremental cost-effectiveness ratio was estimated at 14 480 (11 721-18 515) USD per QALY which was cost-effective at a willingness to pay of 50 000 USD per QALY in 100 % of the simulations. Results were robust with realistic changes in the inputs during scenario and sensitivity analyses. Subsidizing NRT is potentially a cost-saving smoking cessation strategy from a societal perspective and cost-effective from a payer perspective. This study found that subsidizing NRT is potentially a cost-saving smoking cessation policy alternative compared to current practice from a societal perspective. From a healthcare payer perspective, subsidizing NRT is estimated to cost USD 14 480 to gain an extra QALY. NRT is cost-saving across all ages, but the health and economic gains are somewhat larger among younger smokers from a societal perspective. Moreover, subsidizing NRT removes the financial barriers that are mostly faced by socioeconomically disadvantaged smokers which might reduce health inequalities. Thus, future economic evaluations should further investigate the health inequality impacts with methods that are more suitable for this.

Effect of Shi-Zhen-An-Shen herbal formula granule in the treatment of young people at ultra-high risk for psychosis: a pilot study.

To date, there is no conclusive evidence for early interventions on ultra-high risk (UHR) for psychosis. The Chinese herbal medicine is confirmed to be beneficial in improving psychiatric symptoms and cognitive impairments for schizophrenia patients. However, the effect of Chinese herbal medicine on treating UHR patients remains unknown. Eighty UHR patients were recruited from the outpatient department. They were randomly assigned to receive either Shi-Zhen-An-Shen herbal formula granule (SZAS-HFG) combined with aripiprazole placebo or aripiprazole combined with SZAS-HFG placebo for a 12-week treatment. The psychiatric symptoms were assessed using the Structured Interview for Prodromal Syndromes (SIPS). The Trail Making Test part A (TMT-A), Brief Visuospatial Memory Test (BVMT), Hopkins Verbal Learning Test (HVLT), and Continuous Performance Test (CPT) were used to assess cognitive functions. we also employed the Global Assessment of Functioning (GAF) to evaluate social functioning. The linear mixed-effects models were performed to detect the difference in effectiveness between the two groups. After 12-week treatment, both groups showed significant effects of time on SIPS, TMT-A, HVLT, BVMT, and GAF. There was a significant effect of group only on CPT. Moreover, we also found a significant interaction effect on GAF. SZAS-HFG can effectively alleviate psychosis symptoms, and improve cognitive impairments and overall functioning as well as aripiprazole.Clinical trial registration: Chinese Clinical Trial Registry, ChiCTR-IOR-17013513.

Ameliorative effects of Kyung-Ok-Ko and its mixture with Pueraria lobata Ohwi on postmenopausal osteoporosis by promoting phytoestrogenic activity in rats.

Kyung-Ok-Ko (KOK) is a popular traditional medicine used as a natural alternative to hormone replacement therapy for treating postmenopausal symptoms in Asia. Pueraria lobata Ohwi (P. lobata) is rich in isoflavones and has been traditionally used in combination with other herbs to produce synergistic and pharmaceutical effects via a multi-target approach for disease treatment. We aimed to investigate the phytoestrogenic effects of KOK extract against postmenopausal symptoms in ovariectomized (OVX) rats and confirm its efficacy by mixing KOK and P. lobata extracts. OVX rats were daily oral administrated with KOK and KOK + P. lobata mixture extracts (300-400 mg/kg) and their body weight and tail temperature were monitored for 12 weeks. The biochemical parameters, estradiol levels, and bone turnover markers were measured in the serum samples. Moreover, the estrogen receptor, ER-α and ER-β expression in the uterus and the uterus morphology were evaluated. AMPK, ATG1/ULK1, and mTOR protein expression in the liver were assessed. The 12-week treatment with KOK and KOK + P. lobata mixture extracts did not cause liver damage or hormonal changes in the OVX rats. The treatments reduced the high lipid accumulation-related body weight gain and the tail temperature increase that was induced by ovariectomy. Further, it exhibited protective effects against hyperlipidemia and osteoporosis. No significant difference was observed in uterine weight compared to the OVX-treated group, while endometrial thickness reduction inhibition was observed due to ovariectomy. Bone mineral density (BMD) and serum osteocalcin levels, which decreased in OVX rats, increased with both treatments. Western blotting analysis showed that ER-α and ER-β were not expressed in the treated rats, whereas these proteins were expressed in Sham-operated rats. No significant differences in the phosphorylation of AMPK were observed; however, the ATG1/ULK1 and mTOR protein phosphorylation levels were upregulated and downregulated in the treated rats compared to those of OVX rats, respectively. This is the first in vivo study observing the efficacy and synergistic effects of the mixture of KOK and P. lobata. Our results suggest the potential of KOK and KOK + P. lobata mixture as an alternative therapy for alleviating menopausal symptoms.

Effectiveness of Timely Implementation of Palliative Care on the Well-Being of Patients With Chronic Heart Failure: A Randomized Case-Control Study.

Objectives: To date, there is a lack of consensus on the timely implementation of palliative care (PC) in patients with chronic heart failure (HF). We aimed to investigate the impact of primary PC intervention on chronic HF patients with different classes of cardiac function, and to determine a proper time point for the implementation of primary PC intervention. Methods: A consecutive series of 180 chronic HF patients with the New York Heart Association (NYHA) Cardiac function ranging from I to III were enrolled in this study. Patients with the same cardiac function class, they were randomized and equally assigned to the usual care (UC) group or to the PC intervention group. At the end of 24-week treatment, quality-of-life (QoL) measurements were evaluated. Left ventricular ejection fraction and N-terminal pro-B-type natriuretic peptide were measured for each group at baseline and the final follow-up, respectively. Results: Through the 6-month follow-up, patients randomized to the PC intervention group presented significantly better QoL and cardiac function as compared with patients randomized to the UC group alone. Subgroup analysis showed that for patients with NYHA class II or III, significantly improved cardiac function and QoL were observed in the PC intervention group as compared with the control group. As for patients with class I, no significant difference was found between the 2 groups. Conclusions: Palliative program can effectively improve the QoL and cardiac function of patients with chronic HF. Moreover, we provided evidence on timely referral of patients to PC intervention, which could be beneficial for patients with NYHA class II.

101-LB: Phase 3 Trial to Evaluate Efficacy and Safety of Gemigliptin and Dapagliflozin Dual Add-on Therapy to Metformin—SOLUTION 2 Study

Background: Type 2 diabetes mellitus (T2DM) patients inadequately controlled with metformin alone require an addition of other medications with complementary mechanism of action. Gemigliptin, a dipeptidyl peptidase-4 inhibitor, and Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, can be considered as additional options. In this clinical trial, efficacy and safety of treatment of gemigliptin and dapagliflozin were evaluated in T2DM patients inadequately controlled with metformin monotherapy. Method: Total 469 T2DM patients receiving treatment with stable metformin for ≥ 8 weeks before screening were randomized to gemigliptin and dapagliflozin (n=157) or gemigliptin (n =156) or dapagliflozin (n =156), respectively. The primary endpoint was the change in HbA1c at 24 weeks from baseline. Results: At 24-week treatment, the HbA1c change from baseline in dual add-on of gemigliptin and dapagliflozin showed a significant reduction (LS Mean -1.34%) compared to gemigliptin add on (-0.90%; difference -0.44% [95% CI -0.58% to -0.31%]) and dapagliflozin add on (-0.78%; difference -0.56% [95% CI -0.69% to -0.42%]). Most of the reported adverse events were mild with no episodes of severe hypoglycemia. Conclusion: This study demonstrated that triple therapy of gemigliptin and dapagliflozin dual add-on to metformin was effective and well tolerated in T2DM patients. Disclosure K. Park: None. K. Han: None. Y. Hwang: None. S. Moon: None. H. Cho: None. H. Yoo: None. S. Choi: None. S. Chon: None. K. Kim: None. T. Kim: None. J. Kang: None. C. Park: None. J. Won: None. S. Lee: Advisory Panel; LG Chem. Speaker's Bureau; Dong-A Pharm. Advisory Panel; CKD Pharm. Speaker's Bureau; Novo Nordisk, Lilly. Advisory Panel; Daiichi Sankyo. Speaker's Bureau; Boehringer Ingelheim Inc. N. Kim: None. E. Kang: None. D. Kim: None. S. Kim: None.

789-P: Real-Life Effectiveness of iGlarLixi (Insulin Glargine 100 U/ml and Lixisenatide) in People with Type 2 Diabetes (T2D) according to Prior Insulin Use

Little is known in real life clinical practice about the effectiveness and safety of iGlarLixi in insulin naïve compared to insulin treated people with T2D. In the European REALI pooled database, we analyzed patient-level data of 1317 people with T2D initiating a 24-week iGlarLixi treatment: 718 were insulin naïve (55%) and 598 insulin treated (45%), with a median treatment duration of 2.5 years. Demographics were similar among groups with an overall mean±SD age of 61±9 years and BMI 32.2±5.5 kg/m². Median T2D duration was 8 years in the naïve group and 10 years in the treated group. At Baseline, mean HbA1c was 9.39% in the naïve and 8.76% in the treated (p&amp;lt;0.001). The least square (LS) mean HbA1c change from Baseline to Week 24 (using MMRM) was -1.57% in the naïve and -1.29% in the treated (Fig 1); the LS mean [95% CI] fasting plasma glucose change was -52.5 [-54.9; -50.1] and -50.4 [-53.4; -47.5] mg/dL, respectively. Mean±SD body weight decreased by 1.8±4.6 kg at Week 24, with no difference between groups. Mean iGlarLixi daily dose at Baseline was 14.3U in the naïve and 24.4U in the treated, and reached 30.7U and 36.4U, respectively, at Week 24. Symptomatic hypoglycemia reports and gastrointestinal side effects were low in both groups. This analysis demonstrated effectiveness and safety of iGlarLixi in both insulin naïve and insulin treated people with T2D in clinical practice. Disclosure J.Seufert: Advisory Panel; Abbott Diabetes, Boehringer Ingelheim Pharma GmbH&amp;Co.KG, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Abbott Diabetes, Bayer Inc., Boehringer Ingelheim Pharma GmbH&amp;Co.KG, Merck Sharp &amp; Dohme Corp., Sanofi-Aventis Deutschland GmbH, Novartis, Novo Nordisk. N.Freemantle: Advisory Panel; AstraZeneca, Research Support; Galderma, ALK-Abelló A/S, Ipsen Biopharmaceuticals, Inc., Vertex Pharmaceuticals Incorporated, Thea, Speaker's Bureau; Abbott Singapore, ALK Shanghai. C.Guja: Advisory Panel; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Speaker's Bureau; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi, Servier Laboratories, Viatris Inc. M.Haluzik: Advisory Panel; Novo Nordisk, Lilly Diabetes, Boehringer-Ingelheim, Research Support; Sanofi, Speaker's Bureau; Abbott, AstraZeneca. G.Bigot: None. M.Tournay: None. M.Bonnemaire: Employee; Sanofi, Stock/Shareholder; Sanofi. J.T.Kis: None. Funding Sanofi

384 Ruxolitinib 1.5% cream efficacy data for moderate-to-severe chronic hand dermatitis: open-label trial 4-weeks interim analysis

Abstract Chronic hand dermatitis (CHD) is a common condition with a profound negative effect on patients’ quality of life (QoL) presenting with a wide range of clinical manifestations often involving a combination of erythema, edema, scaling, vesicles and fissuring with intense pruritus and pain. (i) The clinical heterogeneity reflects the complex, multifactorial pathophysiology, with irritant/allergic contact dermatitis and atopic dermatitis as predominant etiological subtypes. (ii) Treatment of CHD remains challenging with no FDA-approved medications; routine treatment options include avoidance of relevant allergens/irritants, emollients, topical corticosteroids, calcineurin inhibitors, phototherapy and systemic immunosuppressive medications. (iii) Providers and patients are often frustrated with unsatisfactory treatment options for CHD. (iv) Topical ruxolitinib, currently FDA-approved for vitiligo and AD, is a Jak1/Jak2 inhibitor that blocks the signaling pathway of several cytokines with a potential to block critical inflammation in CHD. An investigator-initiated, open-label, single-site study (NCT05293717) is currently ongoing to assess the clinical efficacy of 12-weeks treatment with ruxolitinib cream 1.5% in recalcitrant CHD. Here we report the results of an interim analysis after 4 weeks of treatment. This is the first study evaluating the efficacy of ruxolitinib on CHD. This study aims to investigate clinical efficacy and impact on quality of life after 4 weeks of treatment with ruxolitinib 1.5% in moderate-severe CHD. This is an open-label investigator-initiated trial in subjects with recalcitrant CHD. After a washout period, subjects (n = 15, age 18–75) applied ruxolitinib twice daily to the entire hands. Moisturizers were allowed if consistently used before and during the study. Subjects with positive PATCH test that could not avoid the antigen and subjects that reported prolonged contact with water were excluded. Subjects were not permitted to treat skin lesions outside of the hands with prohibited medications or the study drug. Clinical assessments include Investigator Global Assessment (IGA, 5-point scale: clear, almost clear, mild, moderate and severe), Hand Eczema Severity Index (HECSI, a validated scoring system that incorporates both the severity and extent of the disease across fingers, palms, dorsal hands and wrists [5]), Itch Numerical Rating Scale (NRS, average itch over the past 24 h) and change in QoL were assessed with Dermatology Life Quality Index (DLQI). The study drug diary, a prepopulated calendar for each month, records AM/PM drug application and average and worst itch on a scale of 0–10 over the past 24 h. Fourteen subjects (eight female; mean age 50 years) completed the first 4 weeks of treatment. Notably, all the subjects had previously failed topicals (corticosteroid and/or calcineurin inhibitors) and in some cases systemic (e.g. oral steroids, methotrexate and phototherapy) treatments. At baseline, all subjects had an IGA score ≥2 and moderate to severe HECSI score (mean ± SD: 55.7 ± 23.2). The average itch at baseline was moderate (NRS, mean ± SD: 5.5 ± 3.39). After 4 weeks of treatment, 79% of subjects had a ≥2-point reduction in IGA. One hundred percent subjects reached HECSI-50%, and 64% reached a HECSI-75 with a mean reduction in HECSI of 44 (P &amp;lt; 0.01). Seventy-one percent of subjects had a ≥2-point reduction and 57% of subjects had a ≥4-point improvement in average itch (NRS; P &amp;lt; 0.01). Interestingly, 75% of the subjects had a ≥2-point reduction in reported worst daily itch within the first week as noted in their study drug diary. The DLQI was significantly reduced (P &amp;lt; 0.01) in the first month. No treatment-related adverse events were reported, and no rescue medication was needed. Data from 4 weeks interim analysis are encouraging and suggest that ruxolitinib 1.5% may be an effective and well-tolerated treatment for moderate-severe CHD with significant impact on subject’s quality of life. Trial is ongoing to evaluate clinical outcomes at 12 weeks.

436 Nemolizumab monotherapy was associated with significant improvements in prurigo activity score in adult patients with moderate-to-severe prurigo nodularis: results from a phase 3 trial (OLYMPIA 2)

Abstract Prurigo nodularis (PN) or chronic nodular prurigo is a debilitating, and severely pruritic neuroimmune skin disease, predominantly characterized by the presence of multiple pruriginous nodules symmetrically distributed in large areas of the trunk and extremities. Other pruriginous lesions such as papules, plaques and umbilicated lesions can also be present. Prurigo nodularis dramatically reduces quality of life among patients, including disruption of physical, emotional and psychosocial domains. Therapeutic goals are primarily to reduce pruritus and improve lesion healing. Interleukin-31 (IL-31) is a neuroimmune cytokine highly expressed in PN lesional skin that bridges the immune and nervous systems, functioning as a central mediator of main pathophysiological processes in PN. Prurigo nodularis has a unique immunophenotype, with recent studies revealing activation of Type-2-inflammation, and also induction of Th17 and Th22 pathways. Nemolizumab, an IL-31 receptor alpha antagonist, was shown to downregulate these pathways and was associated with significant improvements in pruritus and lesion healing in patients with PN in a phase-2-trial. Here, the authors report additional outcomes on excoriations and healing of pruriginous lesions from the OLYMPIA 2 phase-3-study after 16 weeks of treatment with nemolizumab. This study aims to assess the safety and efficacy of nemolizumab compared with placebo in ≥18-year-old patients with moderate-to-severe PN after a 16-week treatment period. OLYMPIA 2 (NCT04501679) was a phase 3, global, multicenter, double-blind study in adults with PN presenting ≥20 nodules, Investigator’s Global Assessment (IGA) score ≥3 (range 0–4) and Peak Pruritus Numerical Rating Scale (PP-NRS) score ≥7.0 (range: 0–10). Patients were randomized (2 : 1) to receive nemolizumab (n = 183) or matching placebo (n = 91). Following an initial 60 mg loading dose, patients weighing &amp;lt;90 kg received 30 mg every 4 weeks (q4w) and those weighing ≥90 kg received 60 mg q4w, for a period of 16 weeks, during which, treatment with topical corticosteroids (TCS) or topical calcineurin inhibitors (TCI)was not allowed. The primary endpoints were proportion of patients with a ≥4-point improvement in weekly average PP-NRS and proportion of patients with IGA Success for nodule healing [score of 0 (clear) or 1 (almost clear) and a ≥2-grade improvement] at Week (W) 16. Key secondary endpoints included proportion of patients with ≥4-point improvement in PP-NRS at W4 and Sleep Disturbance NRS (SD-NRS) at W4 and W16. Other secondary endpoints included percentage of patients with pruriginous lesions with excoriations/crusts [Prurigo activity score (PAS) item 5a], healed pruriginous lesions (PAS item 5b) and &amp;lt;20 pruriginous lesions (PAS item 2) at each visit through W16. The baseline demographic and clinical characteristics were balanced between the groups. At W16, both primary endpoints, were met (P &amp;lt; 0.0001). A significantly higher proportion of patients in the nemolizumab-treated group vs. placebo-treated group achieved a ≥4-point improvement in weekly average PP-NRS score (56.3% vs. 20.9%) and IGA success (37.7% vs. 11.0%) at W16. The study also met all key secondary endpoints on pruritus and sleep disturbance (P &amp;lt; 0.0001). Among other secondary endpoints, a significantly higher proportion of patients in the nemolizumab-treated group vs. placebo-treated group achieved mild disease activity with ≤25% excoriations/crusts (PAS item 5a) (56.8% vs. 23.1%; P &amp;lt; 0.0001 at W16), &amp;gt;75% healed lesions (PAS item 5b) (55.2% vs. 16.5%; P &amp;lt; 0.0001 at W16) and &amp;lt;20 pruriginous lesions (PAS item 2) (54.6% vs. 22.0%; P &amp;lt; 0.0001 at W16) at each visit, from baseline through W16. Treatment-emergent adverse events (AEs) were reported in 61.2% of nemolizumab-treated patients and 52.7% of placebo-treated patients, while serious AEs were reported in 2.2% of nemolizumab-treated patients and 5.5% of placebo-treated patients. Nemolizumab monotherapy (without TCS or TCI) demonstrated a significant reduction of pruritus as well as excoriations and number of pruriginous lesions after 16 weeks of treatment in patients with moderate-to-severe PN. The safety profile was consistent with that previously observed.

Physiotherapy combined with dry needling among patients with chronic low back pain: Study protocol for a randomized controlled clinical trial

BackgroundChronic low back pain (CLBP) is an extremely common public health concern responsible for pain-related disability. CLBP is challenging to manage despite having a plethora of treatment options. Physiotherapy is a guideline-recommended treatment for CLBP. Furthermore, some forms of complementary medicines, such as dry needling, spinal manipulation, Tai Chi, and yoga are also recommended for CLBP treatment. We hypothesized that the combined treatment would be more effective when managing CLBP. Therefore, this randomized clinical trial aims to examine the impact of combined therapy of dry needling and physiotherapy compared to the treatment effect of only physiotherapy among patients with CLBP. MethodsThe study is a two-armed single-center, randomized controlled clinical superiority trial where participants are randomized to combined therapy of usual care physiotherapy and dry needling or only usual care physiotherapy (1:1). Individuals who are 18 years or older and experiencing LBP with or without leg pain for a minimum of three months will be considered eligible for the study. Pain severity, pain affective and physical interference, activity limitation, and insomnia symptoms of patients with CLBP will be measured at the baseline after four, 12 and 24-week treatment started. ConclusionFinding a better management strategy for managing CLBP is an ongoing challenge. Most of the novel techniques that try to manage CLBP are limitedly tested. This study will allow testing of the combined effect of usual care physiotherapy and dry needling when managing CLBP in terms of clinical efficacy. If the combined therapy is proven significantly effective, compared to usual care physiotherapy alone will provide plausible evidence of an effective treatment option to manage CLBP. Trial registrationClinical Trial Registry-India; trial registration number- CTRI/2022/09/045625.

#5413 FRONTIER-1: A PHASE 2B STUDY OF IL-33 BLOCKADE IN DIABETIC KIDNEY DISEASE

Abstract Background and Aims Several biomarkers of inflammation have been correlated with poor renal outcomes and mortality in DKD. However, an effective, well-tolerated treatment of progressive renal disease driven by inflammation has remained elusive. Inhibition of IL-33 may provide a novel opportunity to address this unmet medical need in high-risk patients. Here, we: 1) show that tozorakimab, a high-affinity IL-33-neutralizing mAb, promotes glomerular health in inflammation; 2) describe the clinical study to test tozorakimab in patients with DKD; 3) present participant baseline characteristics; and 4) evaluate inflammation-associated biomarker in FRONTIER-1 and four external validation cohorts. Method FRONTIER-1 (NCT04170543) is a phase 2b, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy, safety, pharmacokinetics (PK), and immunogenicity of tozorakimab in patients with DKD; defined as T2DM with an eGFR of 25-75 mL/min/1.73 m2 and a UACR in the range of 100-3,000 mg/g. All participants are expected to receive an ACEi/ARB for &amp;gt; 6 weeks before the treatment period. Approximately 565 patients from multiple countries will be randomized to four dose levels of tozorakimab, or volume-matched placebo dosed subcutaneously every 28 days over a 24-week treatment period. All participants will receive 10 mg dapagliflozin Day 85-168. The primary objective of the study is to evaluate the effect of tozorakimab on albuminuria. Secondary objectives are to assess the safety and tolerability of tozorakimab with and without SGLT2i, evaluate the effect of tozorakimab in combination with ACEi or ARB with and without SGLT2i on albuminuria, and describe the PK and immunogenicity of tozorakimab. Key exploratory objective is to assess baseline and treatment-response for urine and/or circulating biomarkers of inflammation, including hsCRP, IL-33/sIL1RL1, CCL2, and TNFR-1/2. Biomarker response was, furthermore, evaluated in pre-clinical models of DKD, and respective distributions and risk were assessed in four independent DKD cohorts (N &amp;gt; 200). Results Transcriptomic profiling of kidney biopsies from patients with DKD indicated a significant glomerular up-regulation of IL-33. Inhibition of IL-33 signalling reduced glomerular damage and albuminuria in the uninephrectomized db/db mouse model of DKD. This was associated with improved glomerular endothelial health as indicated by decreased cellular inflammation and reduced release of pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, TNFR-1, and CCL2. Hence, FRONTIER-1 was started in 2019. So far, all trial groups are well-balanced and in line with our expectations for this patient population (N = 574). At baseline, &amp;gt; 95% were receiving ACEi/ARBs and approximately 25% were receiving SGLT2i. The mean eGFR was 47.8 ml/min/1,73 m2 (+/- 14.7) and mean UACR was 765 mg/g (+/- 775). The inflammatory state of participants at baseline was assessed in circulation and urine by hsCRP, TNFR-1 and CCL2 (N &amp;gt; 146). Comparison to independent reference cohorts (N &amp;gt; 200) confirmed elevated risk in DKD patients with high urinary TNFR-1 and CCL2 and showed that 6-week treatment of dapagliflozin did not alter these biomarkers significantly. Conclusion Taken together, inhibition of IL-33 may be beneficial in patients with DKD on standard of care, who have elevated biomarkers of inflammation such as TNFR-1 and/or CCL2. This hypothesis is currently being tested in the FRONTIER-1 phase 2b clinical study. To identify the patients most likely to benefit from immunomodulatory treatment with tozorakimab, the study will conduct a retrospective analysis of albuminuria and inflammatory biomarkers. The primary analysis of the study is planned for the second half of 2023.