Advances in Therapy

Correction to: Cerebrolysin for the Treatment of Aneurysmal Subarachnoid Hemorrhage in Adults: A Retrospective Chart Review Unfortunately the funding information is incorrect in the published article.

A Rigorous Evaluation of Methoxyflurane is Needed: Comment on “Methoxyflurane Versus Standard of Care for Acute Trauma-Related Pain in the Emergency Setting: Protocol for a Randomised, Controlled Study in Italy (MEDITA)”

Response to “A Rigorous Evaluation of Methoxyflurane is Needed: Comment on ‘Methoxyflurane Versus Standard of Care for Acute Trauma-Related Pain in the Emergency Setting: Protocol for a Randomised, Controlled Study in Italy (MEDITA)’”

Anti-MEK and Anti-EGFR mAbs in RAS-Mutant Metastatic Colorectal Cancer: Case Series and Rationale Abstract KRAS (Kirsten rat sarcoma viral oncogene) or BRAF (v-raf murine sarcoma viral oncogene homolog B1) constitutive activation leads to anti-EGFR (epidermal growth factor receptor) therapy resistance of metastatic colorectal cancer patients. In this article we investigate the effects of anti-MEK (mitogen-activated protein kinase) antibody (trametinib) combined with anti-EGFR (cetuximab) on colon cancer cell lines with different RAS statuses. Even though cetuximab has no effect on RAS cell viability and ERK (extracellular-signal-regulated kinase) phosphorylation (one of the last kinases of the EGFR pathway), trametinib can induce cell death and inhibit the activation of ERK alone or in combination with cetuximab. In a more pathologic context, we observed that KRAS colon cancer patient biopsies treated ex vivo with trametinib and cetuximab also present less ERK phosphorylation. Finally, nine ovarian, endometrial and colon cancer patients with different KRAS statuses were treated with anti-EGFR/anti-MEK combination off label after molecular tumor board decision. KRAS exon 2 patients have significantly longer PFS (progression-free survival) than with previous lines of treatments. We believe that such observations provide a rationale for designing a clinical trial to test this association in RAS exon 2 mutated cancers.

Indirect Comparison of Ropinirole and Pramipexole as Levodopa Adjunctive Therapy in Advanced Parkinson’s Disease: A Systematic Review and Network Meta-Analysis Abstract Introduction To evaluate the comparative efficacy and safety of ropinirole and pramipexole as adjunctive therapies to levodopa (l-dopa) for the management of advanced Parkinson’s disease (PD), via a systematic review and network meta-analysis. Methods Twenty-one double-blind randomised controlled trials of patients with advanced PD with motor fluctuations receiving l-dopa comparing ropinirole or pramipexole with comparators were identified from 2550 publications. Bayesian indirect comparison methods were applied to independently review efficacy outcomes including off-time reduction, Unified Parkinson's Disease Rating Scale-Activity of Daily Living (UPDRS-ADL) and UPDRS-motor scores, and safety outcomes including adverse events (AE) and patient withdrawals, to determine indirect treatment comparison mean differences (MD) or hazard ratios (HR) with 95% confidence intervals (CI). Results The indirect efficacy comparison resulted in a statistically nonsignificant off-time reduction difference (hours) of ropinirole-sustained release (SR) versus pramipexole-immediate release (MD − 0.25; 95% CI − 0.71, 0.21) and ropinirole-SR versus pramipexole-extended release (ER) (MD 0.18; 95% CI − 0.40, 0.76). Ropinirole-SR adjunctive treatment showed a tendency towards more improvement in UPDRS-ADL score (MD 1.24; 95% CI 0.23, 2.24) than adjunctive treatment of pramipexole-ER. Pramipexole-ER may be less likely to induce somnolence as an AE compared with ropinirole-SR (HR 0.46; 95% CI 0.23, 0.89). However, there were no statistically significant differences in UPDRS-motor score reduction, incidence of dyskinesia, hallucination, hypotension, insomnia and nausea, or withdrawals due to AE, for any reason. Conclusion Adjunctive therapy with ropinirole-SR or pramipexole appears to offer similar efficacy and tolerability in patients with advanced PD on the basis of this indirect comparison. Funding GSK

Two-Year Outcomes After Aquablation Compared to TURP: Efficacy and Ejaculatory Improvements Sustained Abstract Introduction To compare 2-year safety and efficacy outcomes after Aquablation or transurethral resection of the prostate (TURP) for the treatment of lower urinary tract symptoms related to benign prostate hyperplasia (BPH). Methods One hundred eighty-one patients with BPH were assigned at random (2:1 ratio) to either Aquablation or TURP. Patients and follow-up assessors were blinded to treatment. Assessments included the International Prostate Symptom Score (IPSS), Male Sexual Health Questionnaire (MSHQ), International Index of Erectile Function and uroflow. The focus of analysis was 2-year outcomes. Results At 2 years, IPSS scores improved by 14.7 points in the Aquablation group and 14.9 points in TURP (p = .8304, 95% CI for difference − 2.1 to 2.6 points). Two-year improvements in maximum flow rate (Qmax) were large in both groups at 11.2 and 8.6 cc/s for Aquablation and TURP, respectively (p = 0.1880, 95% CI for difference − 1.3 to 6.4). Sexual function as assessed by MSHQ was stable in the Aquablation group and decreased slightly in the TURP group. At 2 years, PSA was reduced significantly in both groups by 0.7 and 1.2 points, respectively; the reduction was similar across groups (p = 0.1816). Surgical retreatment rates after 12 months for Aquablation were 1.7% and 0% for TURP. Over 2 years, surgical BPH retreatment rates were 4.3% and 1.5% (p = 0.4219), respectively. Conclusion Two-year efficacy outcomes after TURP and Aquablation were similar, and the rate of surgical retreatment was low and similar to TURP. Trial Registration ClinicalTrials.gov no. NCT02505919. Funding PROCEPT BioRobotics.

Impact of a Community Pharmacist-Delivered Information Program on the Follow-up of Type-2 Diabetic Patients: A Cluster Randomized Controlled Study Abstract Introduction Low-quality communication between patients and care providers and limited patient knowledge of the disease and the therapy are important factors associated with poor glycemic control in patients with type 2 diabetes. We conducted a multicenter study to determine whether structured and tailored information delivered by pharmacists to type 2 diabetic patients could improve patient treatment adherence, hemoglobin A1c (HbA1c) levels and knowledge about diabetes. Methods One hundred seventy-four pharmacies were randomized to deliver an educational program on diet, drug treatment, disease and complications during three 30-min interviews over a 6-month period, or to provide no intervention, to type 2 diabetic patients treated with oral antidiabetic agents. Medication adherence was assessed by measuring the medication possession ratio and diabetes control by collecting HbA1c values. Levels of patient treatment self-management and disease knowledge were assessed using self-questionnaires. Results Three hundred seventy-seven patients were analyzed. The medication possession ratio, already very high at baseline in the intervention (94.8%) and control (92.3%) groups, did not vary significantly after 6 months with no difference between the two groups. Significant decreases in HbA1c were observed in both groups at 6 months (p < 0.001) and 12 months (p < 0.01), with significantly greater changes from baseline in the intervention group than in the control group at 6 months (− 0.5% vs. − 0.2%, p = 0.0047) and 12 months (− 0.6% vs. − 0.2%, p = 0.0057). Patients in the intervention group showed greater improvement in their ability to self-manage treatment (+ 4.86 vs. + 1.58, p = 0.0014) and in the extent of their knowledge about diabetes (+ 0.6 vs. + 0.2, p < 0.01) at 6 months versus baseline compared with the control group. Conclusion Tailored information provided by the pharmacist to patients with type 2 diabetes did not significantly improve the already high adherence rates, but was associated with a significant decrease in HbA1c and an improvement of patient knowledge about diabetes. Trial Registration ISRCTN33776525. Funding MSD France.

Integrating Osimertinib in Clinical Practice for Non-Small Cell Lung Cancer Treatment Abstract Treatment of non-small cell lung cancer (NSCLC) is evolving with the use of precision medicine for patients with sensitizing epidermal growth factor receptor (EGFR) mutation. First- and second-generation EGFR tyrosine kinase inhibitors (TKIs) remained the standard of care for patients with EGFR-mutated advanced NSCLC for about a decade. However, treatment resistance eventually develops for most patients who experience initial response to these agents. The most commonly acquired resistance mechanism is the T790M gatekeeper mutation. Poor drug penetration leading to central nervous system (CNS) relapse and dose-limiting toxicities are other concerns. The third-generation EGFR-TKI osimertinib, initially approved as the second-line treatment for patients with T790-mutant NSCLC, demonstrated survival benefits in TKI-naïve EGFR-mutated patients, especially in patients with CNS metastasis. The FLAURA study has shown statistically significant progression-free survival benefit and prolongation of all post-progression outcome endpoints, time to first subsequent therapy, second subsequent therapy, and second progression on subsequent treatment, along with acceptable toxicity and better quality of life outcomes. These data favor osimertinib in the first-line setting for EGFR-mutated NSCLC. This is an important milestone since sequencing the TKI therapy based on accurate prediction of T790M is clinically challenging. In countries like India, T790M testing is not routinely conducted and two-thirds of patients with NSCLC do not receive any second-line therapy. Osimertinib can be administered pragmatically as a first-line therapy. Mature overall survival data from the FLAURA study will be important and could help define the optimal personalized treatment for patients with advanced NSCLC. Funding: AstraZeneca Pharma India Ltd.

Clinical Application of LC–MS/MS in the Follow-Up for Treatment of Children with Methylmalonic Aciduria Abstract Introduction To explore the value of high-performance liquid chromatography–tandem mass spectrometry (LC–MS/MS) in the follow-up for treatment of children with methylmalonic aciduria (MMA). Methods Methylmalonic acid (MMA), 2-methylcitric acid (MCA) and homocysteine (Hcy) were detected by LC–MS/MS in a total of 1016 samples whose estimated 0.5th and 99.5th percentiles was taken as the reference value. The samples of children with MMA and propionic aciduria (PA) who were followed up in our hospital from January 2017 to August 2018 were collected. Samples of dried blood spots, serum, and urine were taken from each patient on the same day. The concentration of the C3 indicator in the dried blood spots was tested by MS/MS. MMA, MCA, and Hcy in the dried blood spots were quantitatively determined by LC–MS/MS, the concentrations of MMA and MCA in urine filter papers were determined by gas chromatography–mass spectrometry (GC/MS), and the concentration of homocysteine in serum was determined by enzymatic cycling assay. Results Reference values of MMA, MCA and HCY by LC–MS/MS in the newborn population were determined. The samples from a total of 50 patients were collected, 48 were from children with MMA, and 2 were from children with PA. The first-order equation regression coefficient of MMA in the blood spots and MMA in urine was significant (P < 0.05), r2 = 0.736; the first-order equation regression coefficient of MCA in bthe lood spots and MCA in urine was significant (P < 0.05), r2 = 0.946; the first-order equation regression coefficient of tHcy in bthe lood spots and Hcy in serum was significant (P < 0.05), r2 = 0.771. Conclusion LC–MS/MS can be used for the follow-up of children with MMA after treatment, but it is necessary to establish a reference interval suitable for the local population.

Roxadustat Treatment of Chronic Kidney Disease-Associated Anemia in Japanese Patients Not on Dialysis: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial Abstract Introduction This study evaluated efficacy and safety/tolerability of roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, in Japanese anemic non-dialysis-dependent chronic kidney disease (NDD-CKD) patients. Methods In this phase 2, double-blind, 24-week study, NDD-CKD patients were randomized to oral placebo or roxadustat (50, 70, or 100 mg) three times weekly (TIW) for 6 weeks followed by dose adjustments to maintain hemoglobin (Hb) at 10–12 g/dL for 18 weeks; patients meeting pre-defined criteria were re-randomized to TIW or once-weekly dosing. The primary end point was rate of rise of Hb (g/dL/week) during the first 6 weeks; secondary end points included response rate (Hb ≥ 10.0 g/dL and increase in Hb from baseline ≥ 1 g/dL) and mean Hb and change from baseline in Hb at weeks 18–24. The main safety outcomes were vital signs, laboratory test results, electrocardiograms, and frequency of treatment-emergent adverse events. Results Of 107 patients randomized, 83 completed the study. The mean (SD) rate of rise of Hb during the first 6 weeks was − 0.052 (0.142) for placebo and + 0.200 (0.160), + 0.453 (0.256), and + 0.570 (0.240) for roxadustat 50-, 70-, and 100-mg TIW groups, respectively (p < 0.001). Response rate was 14.8% for placebo and 81.5%, 100%, and 100% for roxadustat TIW groups (p < 0.001). Change in Hb from baseline at weeks 18–24 was − 0.17 (0.61) for placebo and + 1.10 (0.71), + 1.33 (0.82), and + 1.55 (0.88) g/dL for roxadustat TIW groups (p < 0.001). No deaths or major adverse cardiac events occurred with roxadustat. Conclusion Roxadustat was well tolerated and effective in correcting Hb levels within 6 weeks in Japanese anemic NDD-CKD patients. Trial registration ClinicalTrials.gov: NCT01964196. Registered 15 October 2013 (retrospectively registered). Funding Astellas Pharma Inc.