Safety Of Triple Therapy Research Articles

Different regimens for eradication of Helicobacter pylori infection in children: a randomized controlled trial

Eradication of Helicobacter pylori (H. pylori) infection in children is challenging due to increased antibiotic resistance and decreased effectiveness of the current therapeutic choices, especially in developing countries. The purpose of this study is to compare the efficacy and safety of triple therapy (TT), sequential therapy (ST), hybrid therapy (HT), concomitant therapy (CT), and ciprofloxacin-based triple therapy (CTT) as an empirical therapy for H. pylori eradication in children. In this randomized controlled trial, 200 children (aged between 3 and 16 years) with both positive rapid urease test and histopathology for H. pylori infection were included. Patients were randomly assigned to receive either TT, ST, HT, CT, or CTT. The eradication status was evaluated using a stool antigen test (SAT) 4 weeks after stoppage of antibiotic therapy and 2 weeks after stoppage of proton pump inhibitors. SAT was performed using an ELISA monoclonal antibody-based kit. The most common presenting symptom was epigastric pain (79%). The most common endoscopic findings were gastric antral erythema (98%) and antral nodularity (54.5%). All gastric biopsies showed superficial lamina propria infiltration with plasma cells and lymphocytes. Active gastritis with neutrophils infiltration was seen in 75% of the cases. Gastric atrophy and intestinal metaplasia were uncommon histopathological findings (8.5% and 1%, respectively). The eradication rates for TT, ST, HT, CT, and CTT were 70%, 77.5%, 80%, 85%, and 90%, respectively, with the latter achieving a statistically significant difference when compared with TT (p = 0.025). The rate of occurrence of adverse effects among different regimens was not statistically different. Conclusion: As an empirical treatment for children with H. pylori infection, CTT is safe and provides the highest eradication rate. HT, ST, and CT might not be superior to TT.Trial registration: This study was registered at the Pan African Clinical Trials Registry, Cochrane South Africa, under the identifier PACTR202201686010590. Date of registration: 04 January 2022.What is Known:• Triple therapy has been the standard eradication regimen for pediatric H. pylori infection. The efficacy of triple therapy has decreased in many countries due to increased antibiotic resistance.What is New:• This randomized controlled trial is the first to compare triple therapy, sequential therapy, hybrid therapy, concomitant therapy, and ciprofloxacin-based triple therapy for the eradication of pediatric H. pylori infection. Triple therapy exhibited the lowest eradication rate among the studied regimens, suggesting it may not be an adequate therapeutic option for infected children. Ciprofloxacin-based triple therapy appears to be a safe and effective therapeutic choice for pediatric H. pylori infection. Additionally, this study provides the first reported eradication rate of hybrid therapy in pediatric H. pylori infection.

Triple Therapy and Clinical Control in B+ COPD Patients: A Pragmatic, Prospective, Randomized Trial

IntroductionTreatment with LABA/LAMA is recommended in GOLD B patients. We hypothesized that triple therapy (LABA/LAMA/ICS) will be superior to LABA/LAMA in achieving and maintaining clinical control (CC), a composite outcome that considers both impact and disease stability in a subgroup of GOLD B patients (here termed GOLD B+ patients) characterized by: (1) remaining symptomatic (CAT≥10) despite regular LABA/LAMA therapy; (2) having suffered one moderate exacerbation in the previous year; and (3) having blood eosinophil counts (BEC) ≥150cells/μL. MethodsThe ANTES B+ study is a prospective, multicenter, open label, randomized, pragmatic, controlled trial designed to test this hypothesis. It will randomize 1028 B+ patients to continue with their usual LABA/LAMA combination prescribed by their attending physician or to begin fluticasone furoate (FF) 92μg/umeclidinium (UMEC) 55μg/vilanterol (VI) 22μg in a single inhaler q.d. for 12 months. The primary efficacy outcome will be the level of CC achieved. Secondary outcomes include the clinical important deterioration index (CID), annual rate of exacerbations, and FEV1. Exploratory objectives include the interaction of BEC and smoking status, all-cause mortality and proportion of patients on LABA/LAMA arm that switch therapy arms. Safety analysis include adverse events and incidence of pneumonia. ResultsThe first patient was recruited on February 29, 2024; results are expected in the first quarter of 2026. ConclusionsThe ANTES B+ study is the first to: (1) explore the efficacy and safety of triple therapy in a population of B+ COPD patients and (2) use a composite index (CC) as the primary result of a COPD trial.

Efficacy and safety of triple therapy (elexacaftor/tezacaftor/ ivacaftor) in children with cystic fibrosis: 12-month follow-up

The most effective drug for targeted therapy of cystic fibrosis (CF) today is the CFTR modulator elexacaftor/tezacaftor/ivacaftor. It is a combination of two CFTR correctors and a CFTR potentiator that correct the main genetic defect in patients with CF who carry at least one genetic variant specified in the instructions for use of the drug. In the Russian Federation, children with CF at the age of 6 years and older are provided with a targeted drug at the expense of the Circle of Kindness Charitable Foundation.The aim of the study was to investigate the efficacy and safety of therapy with the CFTR modulator elexacaftor/thezacaftor/ivacaftor in children with cystic fibrosis during 12 months of follow-up.Methods. The data of 48 patients aged 6 to 18 years who received targeted therapy with elexacaftor/tezacaftor/ivacaftor in 2021 and were included in the “Targeted therapy” section of the Register of Patients with Cystic Fibrosis in the Russian Federation, were analyzed. To study the effectiveness and safety of the therapy, the patients’ nutritional status, sweat test, respiratory function, blood chemistry, blood pressure, and lens condition were monitored during the therapy.Results. During therapy, an increase in body weight was noted from 44.1 (± 8.8) to 50.1 (± 7.8) kg (M ± SD) (p < 0.001); height, from 158.2 (± 9.1) to 161.9 (± 8.7) cm (p < 0.001); and BMI, from 17.5 (± 2.3) to 19 (± 1.9) kg / m2 (p < 0.001). The conductivity of sweat decreased from 114.8 (± 17.4) at the start of triple therapy to 73.9 (± 20.6) mmol/l NaCl (p < 0.001) after 12 months of treatment. In 28.5%, the sweat test results returned to normal (the sweat conductivity was equivalent to < 50 mmol / l NaCl). Statistically significant changes in the indices of respiratory function were obtained: the forced vital capacity increased from 72.8%pred. (± 21.7) to 86.6%pred. (± 24.4) (p < 0.001), FEV1 – from 67.2%pred. (± 21.7) to 84.9%pred. (± 28.9) (p < 0.001).Conclusion. Analysis of the tolerability showed a consistent safety profile of the triple therapy.

Pioglitazone as Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Dapagliflozin and Metformin: Double-Blind, Randomized, Placebo-Controlled Trial.

This study assessed the efficacy and safety of triple therapy with pioglitazone 15 mg add-on versus placebo in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and dapagliflozin. In this multicenter, double-blind, randomized, phase 3 study, patients with T2DM with an inadequate response to treatment with metformin (≥1,000 mg/day) plus dapagliflozin (10 mg/day) were randomized to receive additional pioglitazone 15 mg/day (n=125) or placebo (n=125) for 24 weeks. The primary endpoint was the change in glycosylated hemoglobin (HbA1c) levels from baseline to week 24 (ClinicalTrials.gov identifier: NCT05101135). At week 24, the adjusted mean change from baseline in HbA1c level compared with placebo was significantly greater with pioglitazone treatment (-0.47%; 95% confidence interval, -0.61 to -0.33; P<0.0001). A greater proportion of patients achieved HbA1c <7% or <6.5% at week 24 with pioglitazone compared to placebo as add-on to 10 mg dapagliflozin and metformin (56.8% vs. 28% for HbA1c <7%, and 23.2% vs. 9.6% for HbA1c <6.5%; P<0.0001 for all). The addition of pioglitazone also significantly improved triglyceride, highdensity lipoprotein cholesterol levels, and homeostatic model assessment of insulin resistance levels, while placebo did not. The incidence of treatment-emergent adverse events was similar between the groups, and the incidence of fluid retention-related side effects by pioglitazone was low (1.5%). Triple therapy with the addition of 15 mg/day of pioglitazone to dapagliflozin plus metformin was well tolerated and produced significant improvements in HbA1c in patients with T2DM inadequately controlled with dapagliflozin plus metformin.

Perioperative lenvatinib combined with tislelizumab plus transcatheter arterial chemoembolization in resectable hepatocellular carcinoma with high-risk of recurrence: A prospective, single-arm, phase 2 trial.

503 Background: Early recurrence is common after surgery for hepatocellular carcinoma (HCC) and associated with poor prognosis. There is no standard of care neoadjuvant therapy. The combinations of lenvatinib, anti-PD-1 antibodies and transcatheter arterial chemoembolization (TACE) (triple therapy) has shown better trend in tumor response and survival outcomes on unresectable HCC. This study aims to explore the efficacy and safety of triple therapy in the neoadjuvant therapy of resectable HCC patients with high-risk of recurrence. Methods: This prospective, single-arm, phase 2 trial (ChiCTR2100048249) enrolled patients with primary resectable HCC who had not received prior anti-tumor therapy. TACE will be performed once on Day 1. Tislelizumab (an anti-PD-1 antibody, 200 mg) intravenously once every 3 weeks and lenvatinib (bodyweight ≥ 60 kg, 12 mg; &lt; 60 kg, 8 mg) orally daily was initiated within 7-10 days after TACE treatment. Surgery was performed 8 weeks after treatment. After 4-8 weeks of surgery, patients continued to receive tislelizumab and lenvatinib for 6 months. Primary endpoint was relapse-free survival (RFS). Secondary endpoints were objective response rate (ORR) by mRECIST, major pathological reactions, R0 resection rates, overall survival, and adverse events (AE). Results: From April 2022 to June 2023, 29 patients (median age, 54 years) from ten Chinese hospitals were enrolled, all Child-Pugh A and ECOG PS 0, mostly males (79.3%) and HBV infection (93.1%). According to mRECIST, the ORR was 89.7% (26/29, CR 4, PR 22), and the DCR was 96.7% (28/29). No grade 3 or above AE were observed. The most common AE were rash (4/29, 13.8%), thrombocytopenia (3/29, 10.3%), fatigue (3/29, 10.3%), elevated aspartate aminotransferase (2/29, 6.9%), elevated alanine aminotransferase (2/29, 6.9%), and hypertension (2/29, 6.9%). In 29 patients, 26 patients had received surgical treatment (R0 resection rates were 100%), 20 patients (20/26, 76.9%) achieved major pathological reaction (necrosis &gt; 90%), and 4 patients (4/26, 15.4%) achieved complete pathological response. 2 patient (6.9%) refused surgery. 1 patient (3.4%) developed disease progression and lost the chance of surgery. After a median follow-up of 8.0 months (interquartile range 4.6-12.3 months), one patient died of severe pneumonia caused by COVID-19 infection 9.9 months after operation. Tumor recurrence was detected in 3 patients. The 6- and 12-month RFS rates were 90% and 82.5%, respectively. Median RFS and overall survival were not reached. Conclusions: Lenvatinib, tislelizumab, and TACE were safe and showed promising efficacy as a neoadjuvant therapy for resectable HCC with high risk of recurrence. Clinical trial information: ChiCTR2100048249.

Treatment of Helicobacter pylori infection 14-day concomitant quadruple therapy versus triple therapy: A parallel double-blind randomized controlled trial.

Successful Helicobacter pylori (Hp) eradication with the traditional 7-day course of proton pump inhibitor triple therapy is declining. Prolonging therapy to 14 days is associated with better eradication rates. Most learned societies recommend concomitant quadruple therapy (QC) as a first-line alternative therapy for this bacterial infection. The aim of this study is to compare the efficacy and safety of triple therapy (TT) and QC for the eradication of Hp infection. A parallel double-blind randomized controlled trial was conducted. The diagnosis of Hp infection was made by pathological examination of gastric biopsies. Patients were randomly assigned to two treatment groups: either QC (esomeprazole 80 mg, amoxicillin 2000 mg, clarithromycin 1000 mg, and metronidazole 1000 mg daily) or triple therapy (esomeprazole 80 mg, amoxicillin 2000 mg, and clarithromycin 1000 mg daily in divided doses) for 14 days. The efficacy of the treatment is defined by Hp eradication attested by a negative breath test performed 6 weeks after the completion of treatment. Treatment outcomes were compared using the chi-square test, while binary logistic regression identified predictors of treatment failure. Ninety-two patients were included. Forty-two patients belonged to the QC group and 50 to the TT group. No significant difference was noted between the two groups concerning the rate of Hp eradication either by intention to treat (81% vs. 72% respectively, p = 0.31) or per protocol (81.6% vs. 76.1% respectively, p = 0.54). Likewise, there was no difference between the two groups in terms of tolerance to treatment (59.5% for QC vs. 58% for TT, p = 0.88). No factor has been associated with treatment failure. There was no significant difference in the rate of HP eradication between the QC and the 14-day triple therapy. Neither regimen should be used topically because of their low eradication rates.

Donafenib combined with anti-PD-1 antibodies plus transarterial therapy for initially unresectable hepatocellular carcinoma.

e16135 Background: Given its clear efficacy and high safety demonstrated in the phase 3 ZGDH3 study, donafenib has been recommended by the Chinese guidelines for the first-line treatment of unresectable hepatocellular carcinoma (uHCC). Recently, combination therapies have shown favorable results. However, triple therapy with donafenib, anti-PD-1 antibodies, and transarterial therapy has not yet been investigated. Thus, we aimed to investigate the efficacy and safety of triple therapy with donafenib, anti-PD-1 antibodies, and transarterial therapy in patients with uHCC. Methods: A single-center, retrospective study was performed based on the medical records of consecutive patients diagnosed with HCC who were not suitable for curative surgery or local ablation at Zhujiang Hospital of Southern Medical University from June 2021 to October 2022. Patients with ≥18 years, Child-Pugh score ≤7, ECOG PS ≤1, no prior systemic therapy, having at least one measurable lesion (per mRECIST) were enrolled. Patients were treated with donafenib 200 mg orally twice daily, anti-PD-1 antibodies intravenously every three weeks, and transarterial therapy until disease progression or unacceptable toxicity. Endpoints include objective response rate (ORR, the proportion of patients with partial or complete response according to mRECIST and RECIST v1.1), surgical conversion rate (the proportion of patients who successfully underwent resection), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Results: A total of 27 patients were enrolled (median age 52 years [range, 29–74], 81% males, 85% with HBV infection, 41% with cirrhosis, 48% with AFP level ≥400 ng/mL, and 67% in BCLC C). All patients received donafenib and anti-PD-1 antibodies with hepatic arterial infusion chemotherapy (HAIC, n = 10), transarterial chemoembolization (TACE, n = 8), or both (n = 9). By the cutoff date of January 6, 2023, the median follow-up duration was 6.8 months (95% confidence interval [CI], 5.9–7.7), and 17 (63.0%) patients were still undergoing treatment. The ORR and DCR were 59.3% and 92.6% by mRECIST, and 18.5% and 88.9% by RECIST v1.1, respectively. The surgical conversion rate was 22.2%, and the median surgical conversion time was 3.4 months (range, 2.2–4.6). The median PFS was 8.3 months (95% CI, 6.8–9.8), and median OS was not reached. The 6-month PFS rate and 12-month OS rate were 74.7% and 72.9%, respectively. Grade 3 treatment-related adverse events (TRAEs) were observed in 5 patients (18.5%), the most common of which was increased total bilirubin (11.1%). No grade 4/5 TRAEs occurred. Conclusions: Donafenib combined with anti-PD-1 antibodies plus transarterial therapy shows promising efficacy and manageable toxicity in patients with initially uHCC. Clinical trial information: NCT05638438 .

PROMETHEUS: Long-Term Exacerbation and Mortality Benefits of Implementing Single-Inhaler Triple Therapy in the US COPD Population.

Background: The US population includes 24 million to 29 million people with diagnosed and undiagnosed chronic obstructive pulmonary disease (COPD). Studies have demonstrated the safety and efficacy of single-inhaler triple therapy (SITT) in reducing COPD exacerbations. Long-term population implications of SITT use have not been quantified. Objectives: This simulation-based projection aimed to estimate the potential impact of widespread SITT use on the US COPD population. Methods: Exacerbation and all-cause mortality reductions reported in the Efficacy and Safety of Triple Therapy in Obstructive Lung Disease trial (ETHOS; NCT02465567) were used to project clinical outcomes in US patients meeting ETHOS trial eligibility criteria (ETHOS-Eligible) and patients meeting a practical definition of SITT eligibility (Expanded ETHOS-Eligible). The US COPD population was modeled with 1000 simulations of patient progression over 10 years. Agent characteristics were based on literature and claims analysis of the 2016-2018 Medicare 100% fee-for-service and IBM MarketScan® databases. Agent annual characteristics reflected incident cases, changes in COPD severity, treatment, mortality, and exacerbations under status quo treatment patterns and scenarios for the adoption of SITT. The scenarios assumed the reduced exacerbation and mortality rates associated with SITT according to ETHOS trial outcomes mean values. Results: Higher than current SITT adoption over 10 years would be expected to substantially reduce COPD exacerbation-associated hospitalizations by 2 million. Applying mean improvements reported in ETHOS for SITT would extend average patient life expectancy 2.2 years for ETHOS-Eligible patients and 1.7 years for Expanded ETHOS-Eligible patients. The number needed to treat to extend the average patient life by 1 year was 8 for the ETHOS-Eligible population and 10 for the Expanded ETHOS-Eligible population. Discussion: Widespread SITT adoption may be impeded by competitive pressures from generic treatments and nonadherence, and efficacy observed in clinical trials may not occur in real-world populations. Conclusions: Assuming ETHOS treatment effects and adherence translate to clinical practice, higher than current use of SITT can substantially reduce COPD exacerbations and hospitalizations and extend survival. These results should be viewed cautiously, because the improved outcomes for SITT in the ETHOS final retrieved vital statistics data were not statistically significant for all comparator therapy groups.

PROMETHEUS: Long-Term Exacerbation and Mortality Benefits of Implementing Single-Inhaler Triple Therapy in the US COPD Population

Background: The US population includes 24 million to 29 million people with diagnosed and undiagnosed chronic obstructive pulmonary disease (COPD). Studies have demonstrated the safety and efficacy of single-inhaler triple therapy (SITT) in reducing COPD exacerbations. Long-term population implications of SITT use have not been quantified. Objectives: This simulation-based projection aimed to estimate the potential impact of widespread SITT use on the US COPD population. Methods: Exacerbation and all-cause mortality reductions reported in the Efficacy and Safety of Triple Therapy in Obstructive Lung Disease trial (ETHOS; NCT02465567) were used to project clinical outcomes in US patients meeting ETHOS trial eligibility criteria (ETHOS-Eligible) and patients meeting a practical definition of SITT eligibility (Expanded ETHOS-Eligible). The US COPD population was modeled with 1000 simulations of patient progression over 10 years. Agent characteristics were based on literature and claims analysis of the 2016-2018 Medicare 100% fee-for-service and IBM MarketScan® databases. Agent annual characteristics reflected incident cases, changes in COPD severity, treatment, mortality, and exacerbations under status quo treatment patterns and scenarios for the adoption of SITT. The scenarios assumed the reduced exacerbation and mortality rates associated with SITT according to ETHOS trial outcomes mean values. Results: Higher than current SITT adoption over 10 years would be expected to substantially reduce COPD exacerbation-associated hospitalizations by 2 million. Applying mean improvements reported in ETHOS for SITT would extend average patient life expectancy 2.2 years for ETHOS-Eligible patients and 1.7 years for Expanded ETHOS-Eligible patients. The number needed to treat to extend the average patient life by 1 year was 8 for the ETHOS-Eligible population and 10 for the Expanded ETHOS-Eligible population. Discussion: Widespread SITT adoption may be impeded by competitive pressures from generic treatments and nonadherence, and efficacy observed in clinical trials may not occur in real-world populations. Conclusions: Assuming ETHOS treatment effects and adherence translate to clinical practice, higher than current use of SITT can substantially reduce COPD exacerbations and hospitalizations and extend survival. These results should be viewed cautiously, because the improved outcomes for SITT in the ETHOS final retrieved vital statistics data were not statistically significant for all comparator therapy groups.

Efficacy and safety of triple therapy containing berberine hydrochloride, amoxicillin, and rabeprazole in the eradication of Helicobacter pylori.

To estimate the effectiveness and safety of triple therapy containing berberine, amoxicillin, and rabeprazole in the eradication of Helicobacter pylori (H. pylori). This prospective, randomized controlled, open-label, noninferiority trial included treatment-naive patients with H. pylori infection who were randomly allocated at a ratio of 1:1 into the berberine triple therapy group (berberine hydrochloride 300 mg thrice daily, amoxicillin 1 g twice daily, and rabeprazole 10 mg twice daily) or standard bismuth-containing quadruple therapy group (amoxicillin 1 g twice daily, rabeprazole 10 mg twice daily, clarithromycin 500 mg twice daily, and bismuth tartrate 200 mg twice daily) for 14 days. Negative 13 C/14 C-urea breath test at 4 weeks after completion of the therapy was regarded as successful eradication. Altogether 262 and 262 patients received berberine triple therapy and bismuth-containing quadruple therapy, respectively. Both intention-to-treat (79.8% vs 80.9%, P=0.742) and per-protocol analyses (83.6% and 85.1%, P=0.636) showed comparable eradication rate between the two groups, indicating a noninferior eradication rate (the lower limit of the 95% confidence interval over -10% [-7.9% and -7.87%, respectively]). Adverse events more commonly occurred in the bismuth-containing quadruple-therapy group (8.8% vs 16.0%, P=0.012), while patient compliance and symptom improvement of the two regimens were comparable. Triple therapy containing berberine, amoxicillin and rabeprazole is noninferior to bismuth-containing quadruple therapy in the initial treatment for H. pylori eradication.

Different inhaled corticosteroid doses in triple therapy for chronic obstructive pulmonary disease: systematic review and Bayesian network meta-analysis

A systematic review and Bayesian network meta-analysis is necessary to evaluate the efficacy and safety of triple therapy with different doses of inhaled corticosteroids (ICS) in stable chronic obstructive pulmonary disease (COPD). We selected 26 parallel randomized controlled trials (41,366 patients) comparing triple therapy with ICS/long-acting beta-agonist (LABA), LABA/long-acting muscarinic antagonist (LAMA), and LAMA in patients with stable COPD for ≥ 12 weeks from PubMed, EMBASE, the Cochrane Library, and clinical trial registries (search from inception to June 30, 2022). Triple therapy with high dose (HD)-ICS exhibited a lower risk of total exacerbation in pre-specified subgroups treated for ≥ 48 weeks than that with low dose (LD)-ICS (odds ratio [OR] = 0.66, 95% credible interval [CrI] = 0.52–0.94, low certainty of evidence) or medium dose (MD)-ICS (OR = 0.66, 95% CrI = 0.51–0.94, low certainty of evidence). Triple therapy with HD-ICS exhibited a lower risk of moderate-to-severe exacerbation in pre-specified subgroups with forced expiratory volume in 1 s < 65% (OR = 0.6, 95% CrI = 0.37–0.98, low certainty of evidence) or previous exacerbation history (OR = 0.6, 95% CrI = 0.36–0.999, very low certainty of evidence) than triple therapy with MD-ICS. Triple therapy with HD-ICS may reduce acute exacerbation in patients with COPD treated with other drug classes including triple therapy with LD- or MD-ICS or dual therapies.

Relationship between risk, cumulative burden of exacerbations and mortality in patients with COPD: modelling analysis using data from the ETHOS study

BackgroundThe major drivers of cost-effectiveness for chronic obstructive pulmonary disease (COPD) therapies are the occurrence of exacerbations and deaths. Exacerbations, including acute and long-term events, can cause worsening of COPD and lead to an increased risk of further exacerbations, and ultimately may elevate the risk of death. In contrast to this, health economic models are based on COPD severity progression. In this post hoc analysis of the ETHOS study, we focus on the progression of COPD due to exacerbations and deaths.MethodsWe fitted semi-parametric and fully parametric multi-state Markov models with the following five progressive states: State 1, no exacerbation; State 2, 1 moderate exacerbation; State 3, ≥ 2 moderate exacerbations; State 4, ≥ 1 severe exacerbations; State 5, death. The models only allowed a patient to transition to a worsened health state, and transitions did not necessarily have to be to the next adjacent state. We used the multi-state models to analyse data from ETHOS, a phase III, 52-week study assessing the efficacy and safety of triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate in moderate-to-very severe COPD.ResultsThe Weibull multi-state Markov model showed good fit of the data. In line with clinical evidence, we found a higher mortality risk after a severe exacerbation (11.4-fold relative ratio increase [95% CI, 7.7–17.0], 6.4-fold increase [95% CI, 3.8–10.8] and 5.4-fold increase [95% CI, 2.9–10.3] relative to no exacerbations, 1 moderate exacerbation or ≥ 2 moderate exacerbations, respectively). One moderate exacerbation increased mortality risk 1.8-fold (95% CI, 1.1–2.9) vs no exacerbations. We also found a higher risk of severe exacerbation and mortality following ≥ 2 moderate exacerbations.ConclusionMulti-state modelling of patients with COPD in ETHOS found an acute and chronic effect of severe exacerbations on mortality risk. Risk was also increased after a moderate exacerbation. Clinical management with effective pharmacotherapies should be optimised to avoid even moderate exacerbations. Modelling with exacerbations could be an alternative to current COPD models focused on disease progression.Trial registrationNCT02465567

Evaluation of the Efficacy and Safety of Triple Therapy Combined with Rebamipide in the Treatment of Senile Peptic Gastric Ulcer

Evaluation of the Efficacy and Safety of Triple Therapy Combined with Rebamipide in the Treatment of Senile Peptic Gastric Ulcer

Budesonide/Glycopyrrolate/Formoterol Fumarate Co-suspension Metered Dose Inhaler: A Triple Therapy for the Treatment of Chronic Obstructive Pulmonary Disease.

To review current evidence on the use of a fixed-dose combination (FDC) of budesonide/glycopyrrolate/formoterol fumarate (BGFF) triple therapy delivered via metered dose inhaler (MDI) in patients with chronic obstructive pulmonary disease (COPD) and offer clinical practice insights. We used PubMed to conduct the literature search from 1946 through June 30, 2021, using budesonide, glycopyrrolate or glycopyrronium, and formoterol. We included clinical trials in patients with COPD along with pharmacokinetic or pharmacodynamic studies. In all, 19 citations were included. BGFF MDI reduces the risk of exacerbations regardless of exacerbation history compared with dual bronchodilators or inhaled corticosteroid/long-acting β-agonist. Rescue inhaler use decreased, and patient-reported outcomes of symptoms and well-being improved with triple therapy. Mortality was decreased with the higher-dose BGFF MDI in comparison to dual bronchodilator therapy. Dysphonia and candidiasis were more common with BGFF MDI compared with dual bronchodilators, as was pneumonia. BGFF MDI is the second FDC triple therapy approved for COPD treatment. BGFF MDI improves important patient outcomes in COPD, including exacerbation risk. The unique co-suspension technology allows delivery of 3 active ingredients in 1 inhaler, a potential benefit to overcome adherence and technique-related barriers. These benefits must be gently weighed against the increased risk of pneumonia. The findings from phase 3 trials support the efficacy and safety of triple therapy in COPD. Future studies are needed to confirm potential mortality benefit and the role of triple therapy in patients without an exacerbation history.

Phase 2 Study of Nivolumab Plus Bevacizumab Plus Paclitaxel in Patients with HER2-Negative Metastatic Breast Cancer

Phase 2 Study of Nivolumab Plus Bevacizumab Plus Paclitaxel in Patients with HER2-Negative Metastatic Breast Cancer

Reduced All-Cause Mortality in the ETHOS Trial of Budesonide/Glycopyrrolate/Formoterol for Chronic Obstructive Pulmonary Disease. A Randomized, Double-Blind, Multicenter, Parallel-Group Study.

Rationale: In the phase III, 52-week ETHOS (Efficacy and Safety of Triple Therapy in Obstructive Lung Disease) trial in chronic obstructive pulmonary disease (COPD) (NCT02465567), triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF) significantly reduced all-cause mortality compared with glycopyrrolate/formoterol fumarate (GFF). However, 384 of 8,509 patients were missing vital status at Week 52 in the original analyses.Objectives: To assess the robustness of the ETHOS mortality findings after additional data retrieval for patients missing Week 52 vital status in the original analyses.Methods: Patients with moderate to very severe COPD and prior history of exacerbation received twice-daily dosing with 320/18/9.6 μg of BGF (BGF 320), 160/18/9.6 μg of BGF (BGF 160), 18/9.6 μg of GFF, or 320/9.6 μg of budesonide/formoterol fumarate (BFF) (all delivered via a single metered-dose Aerosphere inhaler). Time to death (all-cause) was a prespecified secondary endpoint.Measurements and Main Results: In the final retrieved dataset, which included Week 52 vital status for 99.6% of the intent-to-treat population, risk of death with BGF 320 was significantly lower than GFF (hazard ratio, 0.51; 95% confidence interval, 0.33–0.80; unadjusted P = 0.0035). There were no significant differences in mortality when comparing BGF 320 with BFF (hazard ratio, 0.72; 95% confidence interval, 0.44–1.16; P = 0.1721), nor were significant differences observed when comparing BGF 160 against either dual comparator. Results were similar when the first 30, 60, or 90 days of treatment were excluded from the analysis. Deaths from cardiovascular causes occurred in 0.5%, 0.8%, 1.4%, and 0.5% of patients in the BGF 320, BGF 160, GFF, and BFF groups, respectively.Conclusions: Using final retrieved vital status data, triple therapy with BGF 320 reduced the risk of death compared with GFF, but was not shown to significantly reduce the risk of death compared with BFF, in patients with COPD. Triple therapy containing a lower dose of inhaled corticosteroid (BGF 160) was not shown to significantly reduce the risk of death compared with the dual therapy comparators.

Additive beneficial effects of Fibrates combined with Obeticholic acid in the treatment of patients with Primary Biliary Cholangitis and inadequate response to second-line therapy: data from the Italian PBC Study Group

Obeticholic acid (OCA) and fibrates are the only therapies, which have shown biochemical benefit in PBC patients with inadequate response to ursodeoxycholic acid (UDCA). However, the efficacy of their combination is unknown. Aim of our study was to investigate the efficacy of a combined therapy with OCA and fibrateson the liver biochemistry in high-risk PBC patients, i.e. those with inadequate response to UDCA. This is a proof-of-concept retrospective cohort study. Patients with PBC treated with at least 12 weeks with combination therapy of UDCA (13-15 mg/kg/day), OCA (5-10 mg/daily) and fibrates (bezafibrate 400 mg/daily or fenofibrate 200 mg/daily) were included. Demographical, clinical and biochemical data were collected and analysed before starting the second line therapy, before starting the third line therapy and after 3-6 months of triple therapy. Eleven PBC patients from three liver centres in Italy were included. Median ALP level at the start of the second line therapy was 273U/L (interquartile range, IQR 203,311) with a median reduction of 22%[-0.9,35]. The median ALP level at the start of the third line therapy was 232U/L[199,293] with a median reduction of 29%[22,48] (Figure 1). Eight patients experienced any reduction in ALP levels during triple therapy.The median bilirubin level at the start of the second line therapy was of 0.72 mg/dL[0.6,1] with a median reduction of 13%[-36,20]. The median bilirubin level at the start of the third line therapy was 0.80 mg/dL[0.7,0.9] with a median reduction of 3%[-5,18]. One patient dropped out for persistently abnormal transaminases secondary to introduction of bezafibrates. Triple therapy with UDCA, OCA and fibrates improves liver biochemistry and increases the rate of ALP normalization in patients with PBC and an inadequate response to OCA/UDCA or fibrates/UDCA dual therapy. A randomized clinical trial to assess the efficacy and safety of triple therapy in high-risk PBC patients is warranted.

Comparative Effects of LAMA-LABA-ICS vs LAMA-LABA for COPD: Cohort Study in Real-World Clinical Practice

Triple therapy combinations of a long-acting muscarinic antagonist (LAMA), a long-acting beta2-agonist (LABA), and an inhaled corticosteroid (ICS) for COPD were studied in randomized trials and observational studies, with variable results. We compared the effectiveness and safety of triple therapy with a LAMA-LABA combination in a real-world clinical practice setting. We identified a cohort of patients with COPD during 2002 through 2015,≥ 55 years of age, from the UK's Clinical Practice Research Datalink. Patients initiating LAMA-LABA-ICS were matched 4:1 on time-conditional propensity scores with patients initiating LAMA-LABA, and followed for 1 year for the occurrence of a moderate or severe COPD exacerbation and severe pneumonia. The cohort included 6,921 initiators of LAMA-LABA-ICS matched to 1,932 initiators of LAMA-LABA. The adjusted hazard ratio (HR) of a COPD exacerbation associated with LAMA-LABA-ICS initiation compared with LAMA-LABA initiation was 0.97 (95%CI, 0.87-1.08). For patients with blood eosinophil counts > 6%, the HR was 0.66 (95%CI, 0.46-0.94). For patients with two or more prior exacerbations, it was 0.83 (95%CI, 0.70-0.98). The incidence of severe pneumonia requiring hospitalization was increased with LAMA-LABA-ICS initiation (HR, 1.46; 95%CI, 1.03-2.06). In a real-world setting of COPD treatment, the triple combination of LAMA, LABA, and ICS inhalers is generally as effective as combining LAMA and LABA inhalers in preventing COPD exacerbations. However, with the possible exception of patients with significant eosinophilia or frequent exacerbators, a LAMA-LABA combination without ICS may be preferable because it is associated with fewer severe cases of pneumonia.

More about the combination of rituximab, cyclosporine and dexamethasone in the treatment of chronic ITP. A useful option on an environment with limited resources

Treatment of chronic primary immune thrombocytopenia (ITP) is challenging especially with limited resources and therapy-related complications. This prospective interventional study assessed the efficacy and safety of triple therapy(TT4); a combination treatment of oral dexamethasone 40 mg for days1-4, oral cyclosporine A 2–3 mg/kg daily for 28 consecutive days and intravenous rituximab 100 mg for days7,14,21 and 28 among 40 patients with ITP who failed previous 2 or more treatment options. Our aim was to maintain platelet count ≥ 30 X 109/L without any obvious bleeding at any point in the study. Platelet counts were assessed weekly for a month then monthly for 2 years to evaluate the long-term response. TT4 was well tolerated and induced a good response with a significant increase in the mean platelet count after the 1st, 2nd, 3rd, and 4thweek compared to the baseline. Patients with mean platelet count ≥ 30 X 109/L at the 6th month were 75% (30/40 patients). Treatment free survivals (TFS) at 12 and 24 months were 93.3% (28/30 patients) and 80% (24/30 patients) respectively. TT4 is an effective treatment option that maintained platelet count in the desired level and induced a higher sustained response, especially in an environment with limited resources.

Triple therapy with low-dose dapagliflozin plus saxagliptin versus dual therapy with each monocomponent, all added to metformin, in uncontrolled type 2 diabetes.

AimTo evaluate the efficacy and safety of triple therapy with low‐dose dapagliflozin plus saxagliptin added to metformin in uncontrolled type 2 diabetes.Materials and methodsThis 24‐week, double‐blind trial (NCT02681094) randomized 883 patients (glycated haemoglobin [HbA1c] 7.5‐10.0%) on metformin ≥1500 mg/d to add‐on dapagliflozin 5 mg/d plus saxagliptin 5 mg/d or to add‐on of either monocomponent. The primary endpoint was change in HbA1c from baseline.ResultsBaseline mean ± SD patient characteristics were: age 56.7 ± 10.5 years; HbA1c 8.2 ± 0.9%; and diabetes duration 7.6 ± 6.1 years. Triple therapy significantly decreased HbA1c versus dual therapy (−1.03% vs. −0.63% [dapagliflozin] vs. −0.69% [saxagliptin]; P < .0001). More patients achieved HbA1c <7.0% with triple versus dual therapy (41.6% vs. 21.8% [dapagliflozin; P < .0001] vs. 29.8% [saxagliptin; P = .0018]). Triple therapy significantly decreased fasting plasma glucose (−1.5 mmol/L vs. −1.1 mmol/L [dapagliflozin; P = .0135] vs. −0.7 mmol/L [saxagliptin; P < .0001]) and body weight (−2.0 kg vs. −0.4 kg [saxagliptin; P < .0001]), and β‐hydroxybutyrate levels were lower than with dapagliflozin plus metformin (mean difference −0.51; P = .0009). Urinary tract/genital infections and hypoglycaemia occurred in <5.0% and 5.8% of patients, respectively, with triple therapy.ConclusionsTriple therapy with once‐daily dapagliflozin 5 mg, saxagliptin 5 mg and metformin significantly improved glycaemic control versus dual therapy with either agent added to metformin in uncontrolled type 2 diabetes, and was generally well tolerated.