Safety Of Combination Therapy Research Articles

Do testosterone supplements enhance response to phosphodiesterase 5 inhibitors in men with erectile dysfunction and hypogonadism: a systematic review and meta-analysis.

BackgroundCombining testosterone and phosphodiesterase 5 inhibitors (PDE5-Is) has become increasingly common in the treatment of men with erectile dysfunction (ED) and low testosterone levels, but combination therapy involving PDE5-Is and testosterone is highly debated, with strong reasons for and against argued by the various opinion leaders. PDE5-Is can be given prior to, alongside or after the commencement of any testosterone replacement therapy. Meanwhile, combination of PDE5-Is and testosterone is reported to better increase testosterone levels and thus improve International Index of Erectile Function (IIEF) score in hypogonadal men. The objective of this meta-analysis was to assess whether testosterone therapy (TTh) can possibly enhance the reaction to PDE5-Is in men with ED and hypogonadism.MethodsRelevant studies and available data were extensively collected form Medline, Embase, and Cochrane Library databases until June 2019. We calculated standard mean differences (SMDs) with their 95% confidence intervals (CIs) for IIEF including IIEF-5 and IIEF-EFD. Trial sequential analysis (TSA) was performed to explore whether the sample size of the accumulated evidence is sufficient.ResultsThere were 8 studies including 913 patients. The pooled SMD of erectile function (EF) component change was 0.663 [(0.299 to 1.027); P<0.0001], which concluded that combination therapy (TTh plus PDE5-Is) is superior to PDE5-Is monotherapy group. We also conducted a subgroup analysis according to trial follow-up, baseline serum total testosterone, baseline EF score and PDE5-Is type, which may explain for the underlying source of heterogeneity in part. The frequency of adverse events and change in PSA levels did not differ between the 2 groups. None of the patients experienced an increase in the prostate specific antigen (PSA) level above 4 ng/mL. Hematocrit increased significantly more in the testosterone group than in the placebo group but not greater than 0.54.ConclusionsIn summary, the present results confirm that combination therapy is effective and safe. TTh can enhance the reaction to PDE5-Is in men with ED and hypogonadism, but this effect also depends on the specific diagnosis and initial response to PDE5-Is. Most patients with adverse events during treatment are mild, and have a stable overall safety of combination therapy.

GLP1 Receptor Agonist and SGLT2 Inhibitor Combination: An Effective Approach in Real-world Clinical Practice

PurposeThe aim of this study was to evaluate the effectiveness and safety of combination therapy with a sodium-glucose cotransporter-2 (SGLT2) inhibitor and a glucagon-like peptide-1 receptor agonist (GLP1RA) in patients with inadequately controlled type 2 diabetes. MethodsA retrospective search of electronic prescriptions of patients undergoing GLP1RA and SGLT2 inhibitor combination therapy was conducted. Once the patients had been identified, demographic data, blood and urine analyses (glycosylated hemoglobin [HbA1c], glucose, renal function, albuminuria, lipid profile, liver enzymes, and uric acid), physical examination (weight, body mass index, and blood pressure), and adverse effects were obtained from their electronic clinical records according to each of the following 3 periods: before the initiation of the combination, the first visit after initiation, and the last available visit. The influence of the duration of diabetes and the drug combination sequence on the effectiveness of the treatment was also analyzed. Statistical analysis was performed with SPSS version 21.0 (IBM SPSS Statistics, IBM Corporation, Armonk, New York). Quantitative variables are presented as mean and SD and were compared by using the Student t test, one-way ANOVA, or repeated measures ANOVA with Bonferroni correction. Categorical variables are expressed as percentages and were compared by using the χ2 test. ResultsA total of 212 patients were included, with women accounting for 52.4%. The mean age (SD) of the population was 61.5 (9.6) years. A significant reduction in HbA1c (−12 mmol/mol [–1.1%]) was observed with combined therapy (P < 0.001). The target of HbA1c <53 mmol/mol (<7%) was achieved in 42% of the participants. Mean weight loss was −3.5 kg, and almost 40% of the patients attained the weight loss goal of ≥5% (P < 0.001 in all analyses). Transaminase levels and renal parameters also improved. These benefits persisted over time and bore no relation to the evolution of diabetes. Simultaneous initiation of a combination of a GLP1RA and SGLT2 inhibitor led to faster weight loss and a greater decrease in HbA1c than when they are used sequentially; however, the long-term benefits in terms of metabolic control were similar. Adverse events were rare, and a tendency for a reduced insulin dose was observed. ImplicationsThe findings of this study reveal the combined benefits of a GLP1RA and SGLT2 inhibitor in real-world clinical practice. In general, the combined treatment was well tolerated, and few adverse events were detected.

The efficacy and safety of combinations of SGLT2 inhibitors and GLP-1 receptor agonists in the treatment of type 2 diabetes or obese adults: a systematic review and meta-analysis.

To evaluate the efficacy and safety of combination therapy with sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in the treatment of type 2 diabetes mellitus (T2DM) or obese adults. A meta-analysis was conducted of trials by searching in PubMed, Embase, CENTRAL, Web of Science, and Scopus. A total of five randomized controlled trials (RCTs) and six nonrandomized controlled trials (NCTs) enrolled 1604 participants were identified for meta-analysis. Compared with control/placebo, the combination therapy group had significantly reduced fasting plasma glucose level and 2 h postprandial glucose by 1.28 mmol/L (95% confidence interval [CI]: -1.39, -1.16; p < 0.001) and 1.34 mmol/L (95% CI: -1.47, -1.21; p < 0.001); glycosylated hemoglobin (HbA1c) by 1.32% (95% CI: -1.43, -1.20; p < 0.001); body weight by 0.93 kg (95% CI: -1.04, -0.83; p < 0.001), and systolic blood pressure (SBP) by 1.05 mmHg (95% CI: -1.17, -0.93; p < 0.001). The incidence of genital mycotic infections and urinary infections did not significantly differ from those in the control group, with relative risks (RRs) of 1.67 (95% CI: 0.85, 3.27; p = 0.651) and 1.25 (95% CI: 0.73, 2.15; p = 0.905), respectively. A decreased incidence of cardiovascular events was seen in the combination therapy group (RR = 0.19; 95% CI: 0.04, 0.96; p = 0.403), while an incidence of hypoglycemia was reported (RR = 2.22; 95% CI: 1.20, 4.10; p = 0.71). SGLT2 inhibitors and GLP-1 agonists combination treatment improved glycemic control, reduced body weight, and decreased SBP without an increase in total adverse events or genital and urinary infections in patients with T2DM or obesity.

Combination Therapy With Tofacitinib Plus Intensive Granulocyte and Monocyte Adsorptive Apheresis as Induction Therapy for Refractory Ulcerative Colitis.

BackgroundThe use of monotherapy with intensive granulocyte and monocyte adsorptive apheresis (GMA) or a Janus kinase (JAK) inhibitor has been limited to patients with refractory ulcerative colitis (UC). The efficacy and safety of combination therapy with tofacitinib (TOF) plus intensive GMA (two sessions per week) for refractory UC have not been evaluated.MethodsThis retrospective study evaluated the 10-week efficacy of combination therapy with TOF plus intensive GMA in patients with refractory UC.ResultsOf seven patients who received a combination therapy with TOF plus intensive GMA, 71.4% achieved clinical remission at 10 weeks. The percentages of patients with mucosal healing and complete mucosal healing at 10 weeks were 100% and 42.9%, respectively. The mean full Mayo score and endoscopic subscore at baseline were 8.71 ± 0.80 and 2.4 ± 0.2, respectively, and the corresponding values at 10 weeks were 1.57 ± 0.48 and 0.6 ± 0.2 (P < 0.01), respectively. Adverse events of an orolabial herpes and temporary increase in creatinine phosphokinase (CK) and triglyceride were observed in three patients.ConclusionsBased on these outcomes, combination therapy with TOF plus intensive GMA was well tolerated and may be useful for induction of clinical remission in patients with refractory UC.

BIG BANG study (EPOC1703): multicentre, proof-of-concept, phase II study evaluating the efficacy and safety of combination therapy with binimetinib, encorafenib and cetuximab in patients with BRAF non-V600E mutated metastatic colorectal cancer

BackgroundWhile the BRAF V600E mutation occurs in 5%–15% of metastatic colorectal cancer (mCRC), BRAF non-V600E mutations were recently reported to range from 1.6% to 5.1%. We have previously reported that BRAF non-V600E mutations could have a negative impact on efficacy outcomes as well as BRAF V600E mutation for antiepidermal growth factor receptor (EGFR) antibody treatment for pretreated patients with mCRC. Recently, simultaneous inhibitions of mitogen-activated protein kinase kinase (MEK), BRAF and EGFR exhibited relevant antitumour activities in patients with BRAF V600E mutant and also in BRAF non-V600E mutant but only in the preclinical model.Trial designThe BIG BANG (study is a multicentre, phase II study to assess the efficacy, safety and proof of concept of the combinations of binimetinib+encorafenib+cetuximab in patients with BRAF non-V600E mutated mCRC, identified by either tumour tissue (tumour tissue group) or blood samples (liquid biopsy group). Key eligibility criteria include Eastern Cooperative Oncology Group Performance Status of ≤1, mCRC with BRAF non-V600E mutant and RAS wild type, refractory or intolerant to at least one fluoropyrimidine-based regimen and no prior history of regorafenib, and no prior history of anti-EGFR antibody treatment (primary analysis cohort and liquid biopsy cohort) or refractory to prior anti-EGFR antibody treatment in patients with class 3 BRAF mutations (anti-EGFR antibody refractory class three cohort). Enrolled patients receive binimetinib (45 mg, two times per day), encorafenib (300 mg, once a day) and cetuximab (initially 400 mg/m2 and subsequently 250 mg/m2, once per week). The primary endpoint is the confirmed objective response rate in the primary analysis cohort.Trial registration numbersUMIN000031857 and 000031860.

Possibility of combined therapy with an oral phosphodiesterase-4 inhibitor (apremilast) and dihydrofolatereductase inhibitor (methotrexate) in patients with psoriatic arthritis plaque psoriasis

Background: Data on the possible combinations of apremilast with other types of psoriasis therapy is limited.&#x0D; Description of clinical cases: We present the data on the efficacy and safety of combination therapy of the selective phosphodiesterase 4 inhibitor and dihydrofolatereductase inhibitor (methotrexate) for the treatment of psoriasis and psoriatic arthritis in patients with moderate-to-severe plaque psoriasis and active psoriatic arthritis with lack of efficacy of methotrexate in the anamnesis. The selective phosphodiesterase 4 inhibitor (apremilast) was administered according to the prescription. The severity psoriatic arthritis of was estimated by PASI. The effectiveness of therapy was evaluated at week 14. Due to the lack of effect, methotrexate was added subcutaneously at week 14. The effectiveness of combination therapy was assessed at week 26. In both cases, the significant clinical improvement was reached (patients reached PASI 75 and PASI 90), a decrease of the psoriatic arthritis activity according to the DAS28 and DAPSA.&#x0D; Conclusion: These clinical cases demonstrate the efficacy and safety of combined therapy with methotrexate and apremilast inpatients with active psoriatic arthritis and moderate to severe plaque psoriasis.

The Efficacy and Safety of Fluticasone/Salmeterol Compared to Fluticasone in Children Younger Than Four Years of Age

The combination of inhaled corticosteroid (ICS) and long-acting β-2 agonist (LABA) is widely used as maintenance therapy for children with asthma. However, use in young children has not been well studied. This study investigates the efficacy and safety of combination therapy with fluticasone propionate 50 µg and salmeterol xinafoate 25 µg in children up to 4 years of age.Study participants were children aged 6 months to 4 years with asthma diagnosed according to the Japanese Pediatric Guideline for the Treatment and Management of Asthma 2012 and in whom ICS and LABA was considered necessary by their physician.This 27-week double-blind, randomized controlled trial was conducted from May 2014 to October 2016 in 70 Japanese pediatric centers. The study consisted of 4 time intervals: (1) a 2-week run-in period, during which all children received inhaled fluticasone propionate twice daily; (2) an 8-week randomized treatment period, during which fluticasone only or fluticasone and salmeterol was administered twice daily; (3) a 16-week open-label period, during which all children received fluticasone and salmeterol twice daily; and (4) a 1-week follow-up period, during which children received care that the investigator felt was appropriate. Children <2 years received 1 inhalation per dose, whereas children 2 years or older received 1 to 2 inhalations per dose, according to the investigator’s judgment. The number of inhalations remained consistent during the run-in and treatment phases but could be adjusted during the open-label phase, if appropriate. As needed, salbutamol 100 µg was allowed as a rescue inhaler. Study endpoints and compliance were assessed via twice-daily recordings in a patient diary by the parent or legal guardian.A total of 300 patients were randomized 1:1 to the double-blind period, of whom 148 completed treatment with ICS and LABA, and 142 completed treatment with ICS only. The study was completed by 268 patients. In both treatment groups, boys predominated, and the majority (≥90%) of patients had moderate or severe persistent asthma. Both groups showed reduction in total asthma symptom scores; however, the primary end point of mean change in total asthma symptom scores from baseline to the last 7 days of the treatment period was not significantly different between the 2 groups (−3.97 for ICS and LABA versus −3.01 for ICS only, P = .21). Secondary outcome analysis showed fewer exacerbations in the ICS and LABA group (3% vs 5% in the ICS group) and statistically greater mean change from baseline in Japanese Pediatric Asthma Control scores in the ICS and LABA group (0.4 points vs −0.3 points for ICS only, P = .04). Little change from baseline in daily rescue medication use or percentage of rescue-free days was seen, with no statistically significant differences between the groups. Incidence of adverse effects was virtually identical between the ICS and LABA (74%) and ICS only (73%) groups and was not associated with age or number of inhalations. No new safety concerns were identified during the open-label period. Decreased plasma cortisol was reported in 6 children during the open-label and follow-up periods, although most values normalized on recheck. No serious adverse effects were considered by the investigators to be drug related.Combination therapy with ICS and LABA showed similar safety profiles to ICS alone in children with asthma up to 4 years of age. Although combination therapy improved total asthma symptom scores, it did not show superior efficacy to ICS alone.Asthma management in young children is challenging because of inability to perform pulmonary function tests and the intermittent nature of symptoms, with many children being clinically well in between exacerbations. Importantly, this study provides new evidence regarding the safety of ICS and LABA use in young children. Regarding efficacy, statistically significant differences were seen for some secondary outcomes, which may suggest better symptom control with ICS and LABA, although it is unclear if these differences warrant the use of ICA and LABA over ICS only in this age group. Further studies are needed to make this determination and support the findings in this study.

Systematic Review with Network Meta-Analysis: Comparative Efficacy and Safety of Combination Therapy with Angiotensin II Receptor Blockers and Amlodipine in Asian Hypertensive Patients.

Background Hypertension (HTN) is the leading risk factor for cardiovascular mortality globally. The WHO estimates a 60% increase in Asian HTN patients between 2000 and 2025. Numerous studies have compared safety and efficacy between antihypertensive classes, but in-class comparisons of angiotensin II receptor blockers (ARBs) in combination therapy (CT) (fixed-dose combination or dual combination) with a calcium channel blocker (CCB) are lacking in Asia. Objective To compare the efficacy and safety of the various ARB-amlodipine CTs and amlodipine (AML) monotherapy for treatment of HTN in Asian population. Methods A systematic literature review sourced Asian randomized controlled trials (RCTs) from PubMed and Cochrane Libraries to inform a network meta-analysis (NMA). We considered the ARB-AML CT. The primary efficacy and safety endpoints were short-term (8–12 weeks) treatment response and treatment-emergent adverse events (TEAEs), respectively. AML monotherapy was used as a comparator to allow for indirect treatment effect estimation in the absence of direct RCTs evidence comparing the different ARB-AML CTs. Results The analysis included 1198 Asian HTN patients from seven studies involving six ARB-AML CTs: azilsartan (AZL), candesartan (CAN), fimasartan (FIM), losartan (LOS), olmesartan (OLM), and telmisartan (TEL). Compared to AML monotherapy, CT of AZL-AML had five times greater odds of prompting a treatment response (OR 5.2, 95% CI: 2.5, 11.2), while CAN-AML had 3.9 (95% CI: 2.5, 6.4), FIM-AML had 3.4 (95% CI: 1.4, 8.5), TEL-AML had 3.3 (95% CI: 1.6, 7.1), OLM-AML had 2.7 (95% CI: 1.6, 5.0), and LOS-AML had 2.0 (95% CI: 0.6, 7.3). All ARB-AML CTs had safety profiles comparable to AML monotherapy except TEL-AML, which had significantly lower odds of TEAEs (0.26 (95% CI: 0.087, 0.70)). Conclusion This study suggests that all ARB-AML CTs compared favorably to AML monotherapy regarding short-term treatment response in uncomplicated HTN patients of Asian origin. AZL-AML prompted the most favorable treatment response. Safety profiles among the ARB-AML CTs were largely comparable. Due to the limited study size and small number of trials (direct evidence), our findings should best be interpreted as an exploratory effort importance to inform future research direction.

Efficacy and safety of combined therapy with synthetic disease-modifying antirheumatic drugs in rheumatoid arthritis: Systematic literature review

Objective(1) To systematically and critically review the evidence of combined therapy with synthetic disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) and (2) to design practical recommendations on their use. MethodsA systematic literature review (SLR) was performed with a sensitive bibliographic search strategy in Medline, EMBASE and Cochrane Library. We selected randomised clinical trials that analysed the efficacy and/or safety of (1) combined therapy of synthetic compared with sequential therapy of synthetic DMARD in early RA and (2) combination of methotrexate+leflunomide or triple therapy with synthetic DMARD in established RA refractory to synthetic DMARD. Two reviewers made the first selection by title and abstract and 11 performed the selection after detailed review of the articles and data collection. The quality of the studies was evaluated with the Jadad scale. Based on the results, related recommendations were agreed upon in a nominal group meeting. ResultsUltimately, no articles were included in the SLR. The analysis of the reviewed articles demonstrated the effectiveness of the treatment with synthetic DMARD following a “treat to target” strategy in early RA patients, and of combination therapy of synthetic DMARD in established RA refractory to synthetic DMARD. This resulted in 6 recommendations concerning combination therapy with synthetic DMARD. ConclusionsThese recommendations aim to facilitate decision-making with the use of combined therapy with DMARD in RA.

Combination of Sclerotherapy and Dual-Wavelength Laser in the Management of Infantile Hemangiomas in Chinese Infants.

To evaluate the efficacy and safety of combination therapy with sclerotherapy and dual-wavelength pulsed dye laser (PDL) & Nd:YAG for infantile hemangiomas (IHs). Fifty-nine patients with IH received treatment with sclerotherapy and dual-wavelength PDL & Nd:YAG treatment at 4-week intervals. Observers assessed the size and color of IH using a size rating scale and color rating scale before and after treatments. The study showed that IH improved significantly after several sessions of treatment. Sclerotherapy reduced the size of IH, whereas dual-wavelength laser lightened the color of IH. No serious adverse effects occurred. Combined sclerotherapy and dual-wavelength laser treatment is an effective and safe option for IH.

Efficacy and Safety of Combination Therapy of Moderate-intensity Statin and Ezetimibe Compared to High-intensity Statin

Efficacy and Safety of Combination Therapy of Moderate-intensity Statin and Ezetimibe Compared to High-intensity Statin

Use of low-dose \u03b21-blocker for sinus tachycardia in patients with catecholamine support following cardiovascular surgery: a retrospective study

BackgroundSinus tachycardia coupled with high-dose catecholamine is common after cardiopulmonary bypass (CPB). The present study assessed the hemodynamic efficacy and safety of combination therapy using low-dose β1-selective adrenergic blocker (landiolol) and inotropes.MethodsThis was a retrospective, single center, self-comparison study at post-anesthesia care unit within a tertiary care center. The study included adults who underwent cardiac surgery with CPB and received landiolol between April 2007 and November 2011. We assessed hemodynamic data prior to and 1 h after initiation of landiolol therapy.ResultsWe evaluated 11 patients who were administered 2.6 ± 1.3 μg/kg/min (mean ± SD) landiolol with sinus tachycardia and received catecholamine therapy after on-pump cardiovascular surgery. Landiolol administration led to a significant reduction in heart rate (HR; 112.4 ± 5.8 vs 126.0 ± 7.6 beats/min, p < 0.001), and a significant increase in stroke volume index (SVI) assessed by pulmonary artery catheterization (22.4 ± 5.4 vs. 18.9 ± 4.2 mL/m2, p = 0.04). Only one patient showed no HR reduction, whereas seven patients showed decreased HR and increased SVI (64, 95% confidence interval: 30–98%). Moreover, all five patients who received high-dose catecholamine support showed improved hemodynamics. In terms of safety, no patients required cessation of landiolol therapy.ConclusionsLow-dose landiolol therapy may safely decrease HR and improve hemodynamics among patients with sinus tachycardia receiving catecholamine treatment after cardiovascular surgery.Trial registrationThis study is retrospective. Registration number: 11. Duration of registration: April 2007~November 2011.

Gemcitabine and docetaxel combination chemotherapy for advanced bone and soft tissue sarcomas: protocol for an open-label, non-randomised, Phase 2 study

BackgroundThe prognosis of patients with metastatic or advanced sarcomas is poor and there are few options for treatment. Several studies have shown that gemcitabine and docetaxel (GD) combination chemotherapy has antitumor activity against various subtypes of sarcoma. Recently, some studies have shown a favourable outcome for GD combination chemotherapy for relapsed high-grade osteosarcoma and spindle cell sarcoma of bone. If the effectiveness of GD is proven, this will result in new treatment options for advanced bone and soft tissue sarcomas (STS). The aim of this prospective Phase 2 study is to evaluate the efficacy and toxicity of the GD combination in patients with advanced bone sarcomas and STS.MethodsThis is a Phase 2, single-arm, open-label study to investigate the efficacy and safety of combination chemotherapy with GD for advanced bone sarcomas and STS and will enrol 20 patients. The patients will receive gemcitabine 900 mg/m2 on Days 1 and 8, and docetaxel 70 mg/m2 on Day 8 in 3-week cycles until disease progression or other evidence of treatment failure. The primary aim of this study is to analyse GD’s effect on progression-free survival (PFS). The secondary objectives are to analyse treatment efficacy and safety in terms of response rate, tumour control rate, overall survival, and adverse event rate. The length of follow-up will be 5 years.DiscussionThis study will evaluate the efficacy and safety of combination therapy with gemcitabine and docetaxel for bone sarcomas and STS. If this combination proves to be acceptable, it could be used for as second, third, or later line therapy for patients with sarcomas (especially bone sarcomas). In the future, the role of various treatments, including GD therapy, will be clarified for specific subtypes of sarcoma.Trial registrationThis study was registered as UMIN000031004 (University Hospital Medical Information Network-Clinical Trial Registry: UMIN-CTR) on 1 March 1 2018 and with the Japan Registry of Clinical Trials (jRCT) as jRCTs051180042 on 30 January 2019. The posted information will be updated as needed to reflect protocol amendments and study progress.

Treatment of chronic extensive alopecia areata by diphenylcyclopropenone alone versus in combination with anthralin.

Alopecia areata (AA) is a chronic inflammatory, recurrent, tissue-specific autoimmune disease, mediated by autoreactive CD8+ T cells, occurring in genetically predisposed individuals. Targeting intrabulbar and peribulbar lymphocytic infiltrate by using squaric acid dibutyl ester and diphenylcyclopropenone (DPCP) in contact immunotherapy is by far the best chemotherapy for AA. The aim of this work was to evaluate the efficacy and safety of combination therapy with DPCP and anthralin in chronic extensive AA. A total of 24 patients (12 were treated only with DPCP and 12 with DPCP and anthralin for at least 24 weeks) were evaluated. Complete hair regrowth was observed in 62.5 and 18.2% of the patients who received DPCP and combination therapy, respectively (p = .04). Hair regrowth duration was different in both groups. The DPCP therapy is superior to the combination therapy with DPCP and anthralin in terms of efficacy, the time of onset of hair regrowth, and the time of completion of hair regrowth, Moreover, combination therapy has more side effects in combination therapy group have been discussed in this work.

Retrospective investigation of tacrolimus combined with an anti-tumor necrosis factorα antibody as remission induction therapy for refractory ulcerative colitis: Efficacy, safety, and relapse rate.

Background and AimCombined therapy with tacrolimus (TAC) and an anti‐tumor necrosis factorα (TNFα) antibody is used to induce remission in ulcerative colitis (UC) patients who have not responded to monotherapy with either drug. We evaluated the efficacy and safety of combined therapy, as well as the relapse rate.MethodsCombined therapy was performed to induce remission in UC patients showing an inadequate response to monotherapy with TAC or an anti‐TNFα antibody. The following items were assessed retrospectively: (i) clinical characteristics, (ii) the remission induction rate, (iii) the relapse rate, and (iv) adverse events.ResultsCombined therapy induced remission in 7 of the 12 patients (58.3%). There were no significant differences in clinical characteristics between the patients with and without the successful induction of remission. However, the number of female patients tended to be higher in the remission group than in the nonremission group. The remission group also showed trends of a lower clinical activity index (Lichtiger index; CAI) on admission and before combined therapy and a lower total dose of prednisolone during hospitalization. The 1‐year relapse rate was 33.3%. Adverse events due to combined therapy included renal impairment (n = 2), tremors (n = 2), influenza (n = 1), and a positive cytomegalovirus antibody test (n = 3). None of these events were serious.ConclusionsCombined therapy was effective in more than half of the patients with refractory UC who had not responded to monotherapy. Our findings suggest that combination therapy may be a new, third option for the treatment of refractory UC.

Randomised Phase II Study of Palbociclib Plus Exemestane with GnRH Agonist Versus Capecitabine in Premenopausal Women with Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer

Background: Endocrine treatment is preferred recommendation by clinical guidelines in premenopausal as well as postmenopausal women with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC). In real-world clinical practice, however, substantial numbers of patients are treated with chemotherapy in earlier lines The purpose of this phase II study was to compare the clinical antitumor activity and safety of combined therapy with exemestane plus gonadotropin-releasing hormone (GnRH) agonist plus palbociclib with that of capecitabine in premenopausal women with HR-positive, HER2-negative MBC. Methods: This was a prospective, two-arm, randomized, multicenter open-label phase II study. Participants were premenopausal women with breast cancer that had relapsed or progressed during prior tamoxifen. One line of previous chemotherapy for metastatic setting was allowed. Patients were randomized to chemotherapy (capecitabine 1250 mg/m2 twice daily for 2 weeks every 3 weeks) or combination endocrine therapy (exemestane 25 mg/day for 28 days and palbociclib 125 mg/day for 21 days every 4 weeks plus leuprolide). Primary end point was progression-free survival (PFS). Findings: Of 189 patients enrolled between 2015 and 2018 from 14 centers, 184 were randomly assigned to chemotherapy (n=92) or endocrine therapy with palbociclib (n=92). Median age was 44 years (range 28–58). Approximately half the patients (51%) were treatment naive for MBC. During a median 17 months of followup, median PFS was superior for endocrine therapy plus palbociclib than for capecitabine [20·1 vs. 14·4 months, p=0·0469 by log-rank test; hazard ratio 0·659 (95 CI 0·437–0·994)]. Hematological toxicities of ≥ grade 3 were significantly more common with palbociclib than with capecitabine (75·0% vs. 16·3%). Diarrhea (12·0% vs. 38·4%) and hand–foot syndrome (1% vs. 77%) were more common with capecitabine. Interpretation: Exemestane plus palbociclib with ovarian suppression showed clinical benefit in terms of PFS compared with capecitabine in premenopausal patients with HR-positive, HER2-negative MBC. Trial Registration: The ClinicalTrials.gov identifier number was NCT02592746. Funding Statement: This study was supported by Pfizer (exemestane, palbociclib), Shinpoong (capecitabine), Daewoong Korea and Takeda (leuprolide) for study drugs. This work was partly funded by a grant from the Ministry of Health and Welfare, Republic of Korea (HA17C0055) and by the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1720150). Declaration of Interests: Dr. PARK reports grants and non-financial support from Pfizer, grants and non-financial support from AstraZeneca, grants and non-financial support from Novartis, grants and non-financial support from Merck, grants from Eisai, grants and non-financial support from Roche, outside the submitted work. Dr. Im reports grants from Pfizer, drug supply from Pfizer, Shinpoong, Daewoong, and Dakeda, during the conduct of the study; grants from AstraZeneca and Pfizer, travel expenses for advisory board participation and advisory role for Novartis, advisory role for Hanmi, Pfizer, Eisai, Amgen, Lilly, MediPacto, Roche, outside the submitted work. Dr. Jung reports personal fees from AstraZeneca Korea, personal fees from Roche Korea, outside the submitted work. Dr. Kim reports grants from Ono Pharma Korea Co., Ltd., outside the submitted work. Dr. Ahn reports personal fees and non-financial support from Astrazeneca, Roche, Beringer Ingelheim, Menarini, Pfizer, BMS, ONO, Boryung, grants from Samyang, outside the submitted work. Dr. Lee reports personal fees from AstraZeneca, personal fees from Bayer, personal fees from Eisai, personal fees from Novartis, personal fees from Ono, personal fees from Roche, personal fees from Samsung Bioepis, outside the submitted work. Dr. Kim reports grants from Novarts, grants from Sanofi Genzyme, non-financial support from Dongkook Pharma Co Ltd., outside the submitted work. Dr. Ahn reports personal fees from Amgen, personal fees from Pfizer, personal fees from AstraZeneca, personal fees from Menarini, personal fees from Roche, personal fees from Eisai, personal fees from Boehringer-Ingelheim, personal fees from BMS-Ono, personal fees from MSD, personal fees from Janssen, personal fees from Samsung Bioepis, personal fees from Takeda, outside the submitted work. All other authors declare they have no conflicts of interest. Ethics Approval Statement: The study was conducted in full accordance with the guidelines for Good Clinical Practice and the Declaration of Helsinki, and was approved by the institutional ethics committees of each hospital and the KCSG institutional review board. Written informed consent was obtained from each participant.

2300-PUB: The Efficacy and Safety of Combinations of SGLT2 Inhibitors and GLP-1 Receptor Agonists in the Treatment of Type 2 Diabetes: A Systematic Review and Meta-analysis

Objective: The aim of this study was to evaluate the efficacy and safety of combination therapy with sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in the treatment of type 2 diabetes mellitus (T2DM). Methods: We searched clinical trials indexed in PubMed, Embase, CENTRAL, Web of Science, and Scopus from inception through December 3, 2018. A meta-analysis was conducted of trials involving patients receiving SGLT2 inhibitors and GLP-1 agonists using Stata 12.0 software. Results: A total of 9 clinical trials, including 5 randomized controlled trials (RCTs), that enrolled 1369 participants were identified for meta-analysis. Compared with the control/placebo group, the combination therapy group had significantly reduced fasting plasma glucose level by 0.78 mmol/L (95% confidence interval [CI]: -1.36, -0.2), 2-h postprandial glucose level by 0.47mmol/L (95% CI: -0.69, -0.24), glycosylated hemoglobin (HbA1c) by 0.73% (95% CI: -1.45, 0); body weight that was lower by 0.39 kg (95% CI: -0.59, -0.18) (4 non-randomized controlled trials indicated a larger reduction in body weight of 3.53 kg), and systolic blood pressure (SBP) that was lower by 0.26 mmHg (95% CI: -0.40, -0.11). The total incidence of adverse events (AEs) and genital and urinary infections in the therapy group did not significantly differ from those in the control group, with relative risks (RRs) of 1.06 (95% CI: 0.96, 1.17) and 1.19 (95% CI: 0.69, 2.07), respectively. An increased incidence of hypoglycemia was seen in the combination therapy group (RR=2.49; 95% CI: 1.40, 4.45). Conclusions: SGLT2 inhibitor and GLP-1 agonist combination treatment improved glycemic control, reduced body weight, and decreased SBP without an increase in total AEs or genital and urinary infections in patients with T2DM. However, the risk of hypoglycemia should be carefully monitored in future clinical trials. Disclosure M. Guo: None. J. Gu: None. J. Li: None. Y. Xu: None. Funding National Natural Science Foundation of China (81800741)

Efficacy and safety of etanercept combined plus methotrexate and comparison of expression of pro-inflammatory factors expression for the treatment of moderate-to-severe plaque psoriasis

Etanercept has greatly improved management considerably. However, the efficacy and safety of combination therapy with methotrexate and the mechanism of action are not known. We aimed to describe the use of combined therapy of etanercept and methotrexate against moderate-to-severe plaque psoriasis in a Chinese population. We also wished to study the changes in expression of pro-inflammatory factors in peripheral blood mononuclear cells (PBMCs) and serum after the treatment to ascertain the mechanism of action. Thirty patients with moderate-to-severe plaque psoriasis were assigned into a monotherapy group and combination group randomly and equally. All patients received etanercept (50 mg, s.c., weekly), whereas patients in the combination group also received oral methotrexate (7.5–15 mg, p.o., weekly). Serum levels of interleukin (IL)-17A, IL-23, tumor necrosis factor (TNF)-α and their mRNA expressions in PBMCs were measured by ELISA and qRT-PCR. In the monotherapy group, Psoriasis Area and Severity Index (PASI) 50/75/90 responses were achieved by 86.7/66.7/40% after 24 weeks of treatment whereas, in the combination group, they were achieved by 93.3/80/60%, respectively. Although the overall prevalence of adverse effects (AEs) was higher in the combination group (60%) than in the monotherapy group (33.3%), the AEs were mild to moderate. The serum levels of IL-17A, IL-23, TNF-α, IL-33 and their mRNA expression in the PBMCs of the two groups were significantly higher than those of healthy controls (P < 0.05). Compared with the monotherapy group, serum levels of IL-17A, IL-23, TNF-α and their mRNA expression in PBMCs were decreased significantly in the combination group (P < 0.05). These data suggest that the efficacy of etanercept could be improved upon combination with methotrexate in the treatment of moderate-to-severe plaque psoriasis without increasing the risk of serious AEs. The mechanism of action might be associated with down-regulation of IL-17A, IL-23, and TNF-α.

A phase II Salvage Trial of AR Inhibition with ADT and Apalutamide with Radiation therapy followed by docetaxel in men with PSA recurrent prostate cancer (PC) after radical prostatectomy (STARTAR).

TPS5097 Background: Androgen deprivation combined with salvage external beam radiation therapy (RT) have improved survival for patients (pts) with non-metastatic hormone naïve PC and PSA recurrence after radical prostatectomy (RP). Our recent STREAM trial showed addition of enzalutamide to RT and ADT had a 3-year progression free survival (PFS) of 53%. Adding effective PC treatments in this setting may further improve 3-year PFS. Methods: STARTAR is an investigator-initiated phase 2 trial for salvage treatment of biochemically recurrent PC following prostatectomy. Key inclusion criteria include histologic prostate adenocarcinoma, either Gleason 7 with T3/positive margin/1-4 positive lymph nodes or Gleason 8-10 disease, PSA relapse within 4 years of prostatectomy (minimum PSA 0.2 ng/mL to maximum PSA 4 ng/mL). Treatment involves ADT with apalutamide for 9 months, continue with with prostate bed +/- nodal RT at month 3, followed by 6 cycles of docetaxel 75mg/m2 IV every 3 weeks for 6 cycles. The primary endpoint of the study is 3-year PFS. With a one-sided alpha of 0.05 to improve 3-year PFS from 50% to 75%, we will have 92% power by enrolling 42 pts (including 10% dropout rate) based on the binomial test. Key secondary endpoints include 1, 2, and 3-year PSA recurrence rates with testosterone recovery, PSA PFS, PSA nadir, time to testosterone recovery, and safety of combination therapy. Quality of life will be assessed by EPIC questionnaire. As of February 2019, we have enrolled and treated 12 pts in this PCCTC trial. Accrual to the STARTAR trial is ongoing (NCT03311555). Clinical trial information: NCT03311555.

Efficacy and Safety of Triple Therapy With Telmisartan, Amlodipine, and Rosuvastatin in Patients With Dyslipidemia and Hypertension: The Jeil Telmisartan, Amlodipine, and Rosuvastatin Randomized Clinical Trial

PurposeFixed-dose combination therapy with telmisartan, amlodipine, and rosuvastatin is needed in patients with hypertension and dyslipidemia for better adherence and cost-effectiveness than free–equivalent combination therapies. This study aimed to compare the efficacy and safety of combination therapy with telmisartan, amlodipine, and rosuvastatin versus telmisartan plus amlodipine or telmisartan plus rosuvastatin in patients with hypertension and dyslipidemia. MethodsThe Jeil Telmisartan, Amlodipine, and Rosuvastatin Randomized Clinical Trial (J-TAROS-RCT) was an 8-week, multicenter, randomized, double-blind, parallel, Phase III clinical trial conducted at 9 hospitals in Korea. After a run-in period of >4 weeks, patients who fulfilled the criteria of the National Cholesterol Education Program Adult Treatment Panel III guidelines were eligible for randomization to receive 1 of 3 treatments for 8 weeks: (1) telmisartan/amlodipine 80 mg/10 mg plus rosuvastatin 20 mg, (2) telmisartan/amlodipine 80 mg/10 mg, or (3) telmisartan 80 mg plus rosuvastatin 20 mg. The primary end point was efficacy evaluation of combination therapy with telmisartan/amlodipine/rosuvastatin by comparing the change in mean sitting systolic blood pressure (msSBP) and mean percentage change in LDL-C from baseline after 8 weeks of treatment. Adverse events (AEs), clinical laboratory data, and vital signs were assessed in all patients. FindingsAmong 148 patients, the changes in msSBP from baseline after 8 weeks of treatment were a mean (SD) of −24.41 (2.38) versus −9.31 (2.36) mm Hg in the telmisartan/amlodipine/rosuvastatin and telmisartan/rosuvastatin groups, respectively. Significantly more participants achieved the target BP at week 8 in the telmisartan/amlodipine/rosuvastatin group (41 patients [87.2%]) than in the telmisartan/rosuvastatin group (24 [50.0%], P < 0.001). The changes in mean (SD) LDL-C at 8 weeks compared with baseline values were −57.59% (11.59%) versus 6.08% (20.98%) in the telmisartan/amlodipine/rosuvastatin and telmisartan/amlodipine groups, respectively. The percentages of patients who achieved the target LDL-C according to their risk factors after 8 weeks of treatment were 97.87% vs 6.12% in the telmisartan/amlodipine/rosuvastatin and the telmisartan/amlodipine groups (P < 0.0001), respectively. No significant differences were found in the incidence of overall AEs and adverse drug reactions, and serious AEs were comparable among 3 groups. ImplicationsFixed-dose combinations of telmisartan, amlodipine, and rosuvastatin decreased BP and LDL-C in patients with hypertension and dyslipidemia. The safety and tolerability profiles of fixed-dose telmisartan, amlodipine, and rosuvastatin combination therapy were comparable with those of telmisartan plus amlodipine or telmisartan plus rosuvastatin. ClinicalTrials.gov identifier: NCT03088254.