Withdrawal Criteria Research Articles

Prognostic significance of clinical seizures after cardiac arrest and target temperature management

AimClinical seizures are common after cardiac arrest and predictive of a poor neurological outcome. Seizures may be myoclonic, tonic-clonic or a combination of seizure types. This study reports the incidence and prognostic significance of clinical seizures in the target temperature management (TTM) after cardiac arrest trial. Our hypotheses were that seizures are associated with a poor prognosis and that the incidence of seizures is not affected by the target temperature. MethodsPost-hoc analysis of reported clinical seizures during day 1–7 in the TTM-trial including their treatment, EEG-findings, and long-term neurological outcome. The trial randomised 939 comatose survivors to TTM at 33°C or 36°C with strict criteria for withdrawal of life-sustaining therapies. Sensitivity, specificity and false positive rate for poor outcome were reported for different types of seizures. ResultsClinical seizures were registered in 268 patients (29%), similarly distributed in both intervention arms. Early and late seizures were equally predictive of poor outcome. Myoclonic seizures were the most common (240 patients, 26%) and the most predictive of a poor outcome (sensitivity 36.1%, false positive rate 4.3%). Two patients with status myoclonus regained consciousness, one with a good neurological outcome, generating a false positive rate of poor outcome of 0.2% (95%CI 0.0–1.0). ConclusionClinical seizures are common after cardiac arrest and indicate poor outcome with limited specificity. Prolonged seizures are a very grave sign but occasional patients may have a good outcome. The level of the target temperature does not affect the prevalence or prognostic significance of seizures.

Phase 1 study of new formulation of patritumab (U3-1287) Process 2, a fully human anti-HER3 monoclonal antibody in combination with erlotinib in Japanese patients with advanced non-small cell lung cancer

BackgroundThis phase 1 study evaluated the safety, tolerability, pharmacokinetics and efficacy of patritumab (U3-1287) Process 2, a new formulation of fully human anti-HER3 monoclonal antibody in combination with erlotinib, an epidermal growth factor receptortyrosine kinase inhibitor (EGFR-TKI) in prior chemotherapy treated Japanese patients with advanced non-small cell lung cancer (NSCLC).MethodsPatients received intravenous patritumab Process 2 formulation at 9 mg/kg every 3 weeks after initiation of 18 mg/kg loading dose combined with continuous daily dose of erlotinib (150 mg QD) until any of the withdrawal criteria are met. Adverse events (AEs) were assessed using CTCAE v4.0 and tumor response was assessed using RECIST v1.1. Full pharmacokinetic sampling and serum biomarker analyses were mainly performed during cycle 1 and 2.ResultsTotal of six EGFR-mutant NSCLC patients including one EGFR-TKI naïve patient received patritumab Process 2 formulation combined with erlotinib. No dose-limiting toxicities were observed. The most frequent AEs were gastrointestinal or skin toxicities, which were generally mild and manageable. One patient discontinued from study due to reversible grade 3 interstitial lung disease. The mean area under the curve (AUC) value was 2640 μg/day/mL; the Cmax value was 434 μg/mL, respectively. The median progression-free survival (95% confidence interval) was 220.0 (100.0–363.0) days. HER3 ligand heregulin was detected in serum from only a patient that maintained most durable stable disease.ConclusionsPatritumab Process 2 formulation in combination with erlotinib was well tolerated compatible with favorable PK profile in Japanese patients with advanced NSCLC.

Assessment of Adverse Events in Protocols, Clinical Study Reports, and Published Papers of Trials of Orlistat: A Document Analysis.

BackgroundLittle is known about how adverse events are summarised and reported in trials, as detailed information is usually considered confidential. We have acquired clinical study reports (CSRs) from the European Medicines Agency through the Freedom of Information Act. The CSRs describe the results of studies conducted as part of the application for marketing authorisation for the slimming pill orlistat. The purpose of this study was to study how adverse events were summarised and reported in study protocols, CSRs, and published papers of orlistat trials.Methods and FindingsWe received the CSRs from seven randomised placebo controlled orlistat trials (4,225 participants) submitted by Roche. The CSRs consisted of 8,716 pages and included protocols. Two researchers independently extracted data on adverse events from protocols and CSRs. Corresponding published papers were identified on PubMed and adverse event data were extracted from this source as well. All three sources were compared. Individual adverse events from one trial were summed and compared to the totals in the summary report.None of the protocols or CSRs contained instructions for investigators on how to question participants about adverse events. In CSRs, gastrointestinal adverse events were only coded if the participant reported that they were “bothersome,” a condition that was not specified in the protocol for two of the trials. Serious adverse events were assessed for relationship to the drug by the sponsor, and all adverse events were coded by the sponsor using a glossary that could be updated by the sponsor. The criteria for withdrawal due to adverse events were in one case related to efficacy (high fasting glucose led to withdrawal), which meant that one trial had more withdrawals due to adverse events in the placebo group. Finally, only between 3% and 33% of the total number of investigator-reported adverse events from the trials were reported in the publications because of post hoc filters, though six of seven papers stated that “all adverse events were recorded.”For one trial, we identified an additional 1,318 adverse events that were not listed or mentioned in the CSR itself but could be identified through manually counting individual adverse events reported in an appendix. We discovered that the majority of patients had multiple episodes of the same adverse event that were only counted once, though this was not described in the CSRs. We also discovered that participants treated with orlistat experienced twice as many days with adverse events as participants treated with placebo (22.7 d versus 14.9 d, p-value < 0.0001, Student’s t test). Furthermore, compared with the placebo group, adverse events in the orlistat group were more severe. None of this was stated in the CSR or in the published paper.Our analysis was restricted to one drug tested in the mid-1990s; our results might therefore not be applicable for newer drugs.ConclusionsIn the orlistat trials, we identified important disparities in the reporting of adverse events between protocols, clinical study reports, and published papers. Reports of these trials seemed to have systematically understated adverse events. Based on these findings, systematic reviews of drugs might be improved by including protocols and CSRs in addition to published articles.

Abstract CT132: Safety of avelumab (MSB0010718C), an anti-PD-L1 antibody: updated analysis from the phase Ib JAVELIN Solid Tumor trial

Abstract Background: The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against multiple cancers. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody currently being investigated in clinical trials. The primary objective of this phase Ib, open-label expansion study (NCT01772004) was to assess the safety and tolerability of avelumab in patients (pts) with locally advanced or metastatic (LA/M) solid tumors. Methods: Pts from 16 different expansion cohorts (including NSCLC, gastric, ovarian, urothelial, and breast; ECOG performance status [PS] of 0-1 at trial entry) and unselected for PD-L1 expression were treated with avelumab at 10 mg/kg IV, Q2W until confirmed progression, unacceptable toxicity, or any criteria for withdrawal occurred. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Results: As of Aug 4, 2015, 900 pts were treated with avelumab and followed for ?4 wks. Median age was 62 years (range, 23-91), ECOG PS was 0 (39.1%), 1 (60.6%), or 2-3 (0.2%), and median number of prior lines of anticancer therapy was 2 (range, 1-13). Median duration of treatment with avelumab and number of administrations were 10.0 wks (range, 2-92) and 5 infusions (range, 1-43), respectively. Treatment-related (TR) AEs of any grade occurred in 585 pts (65.0%). Grade ?3 TRAEs occurred in 91 pts (10.1%). The most frequent (?0.5%) grade ?3 TRAEs were IRRs (n = 8, 0.9%), GGT elevation (n = 7, 0.8%), lipase elevation (n = 7, 0.8%), anemia (n = 7, 0.8%), and fatigue (n = 6, 0.7%). Seventy-five pts (8.3%) experienced potential immune-related (ir) TRAEs, with hypothyroidism (n = 34, 3.8%) and pneumonitis (n = 8, 0.9%) occurring most frequently (?0.5%). Grade ?3 potential irTRAEs were reported for 17 pts (1.9%); the most frequent (?0.3%) were autoimmune hepatitis (n = 4; 0.4%), colitis (n = 3; 0.3%), and pneumonitis (n = 3; 0.3%). TRAEs resulted in permanent treatment discontinuation for 64 pts (7.1%); 2.6% (n = 23) discontinued due to an IRR and 1.3% (n = 12) discontinued due to a potential irTRAE. TRAEs were considered the primary cause of death by the investigator for 4 pts (0.4%): radiation pneumonitis (1), autoimmune hepatitis (1), acute liver failure (1), and respiratory distress (1). Conclusion: Single-agent avelumab shows an acceptable safety profile in a heavily pretreated population of pts with LA/M malignancies. To date, &amp;gt;1,500 pts have been enrolled in the JAVELIN Solid Tumor clinical trial. Additional safety and efficacy analyses from this study are ongoing, and recruitment to several phase III trials is underway. *Proposed INN. Citation Format: Karen Kelly, Manish Patel, Jeffrey R. Infante, Nicholas Iannotti, Petros Nikolinakos, Joseph Leach, Ding Wang, Jason Chandler, Guy Jerusalem, Jayne Gurtler, Henrik-Tobias Arkenau, Marcis Bajars, Anja von Heydebreck, Isabell Speit, Christopher R. Heery, James L. Gulley. Safety of avelumab (MSB0010718C), an anti-PD-L1 antibody: updated analysis from the phase Ib JAVELIN Solid Tumor trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT132.

Treatment Rationale and Study Design for the RELAY Study: A Multicenter, Randomized, Double-Blind Study of Erlotinib With Ramucirumab or Placebo in Patients With Epidermal Growth Factor Receptor Mutation-Positive Metastatic Non–Small-Cell Lung Cancer

IntroductionWe present the treatment rationale and study design for the RELAY study (NCT02411448 ). This phase Ib/III study will assess safety, tolerability, and efficacy of the combination of ramucirumab with erlotinib in previously untreated stage IV non–small-cell lung cancer patients with an activating epidermal growth factor receptor (EGFR) mutation. Patients and MethodsThe study is being conducted in approximately 120 sites in North America, Europe, and Asia and is currently open for enrollment. In part A (phase Ib), approximately 12 patients will receive ramucirumab (10 mg/kg) every 2 weeks with erlotinib (150 mg) every day. Dose-limiting toxicity will be assessed during 2 cycles (4 weeks) of treatment. In part B (phase III), approximately 450 patients will be randomized in a 1:1 ratio to receive ramucirumab or placebo every 2 weeks with erlotinib daily until disease progression, unacceptable toxicity, or other withdrawal criteria are met. The primary end point is progression-free survival, on the basis of investigator assessment. Secondary end points include overall survival, objective response rate, disease control rate, duration of response, safety, and quality of life. ConclusionErlotinib with ramucirumab combination was chosen because the addition of an antiangiogenic agent, such as ramucirumab, would further improve the efficacy of erlotinib, which is a standard of care in the first-line treatment of patients with activating EGFR mutations.

Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial

Ponatinib has shown potent activity against chronic myeloid leukaemia that is resistant to available treatment, although it is associated with arterial occlusion. We investigated whether this activity and safety profile would result in superior outcomes compared with imatinib in previously untreated patients with chronic myeloid leukaemia. The Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia (EPIC) study was a randomised, open-label, phase 3 trial designed to assess the efficacy and safety of ponatinib, compared with imatinib, in newly diagnosed patients with chronic-phase chronic myeloid leukaemia. Patients from 106 centres in 21 countries were randomly assigned (1:1, with stratification by Sokal score at diagnosis) using an interactive voice and web response system to receive oral ponatinib (45 mg) or imatinib (400 mg) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met. Eligible patients were at least 18 years of age, within 6 months of diagnosis, and Philadelphia chromosome-positive by cytogenetic assessment, with Eastern Cooperative Oncology Group performance status of 0-2, and had not previously been treated with tyrosine kinase inhibitors. The primary endpoint was major molecular response at 12 months. Patients who remained on study and had molecular assessments at specified timepoints were studied at those timepoints. Safety analyses included all treated patients, as per study protocol. This trial is registered with ClinicalTrials.gov, number NCT01650805. Between Aug 14, 2012, and Oct 9, 2013, 307 patients were randomly assigned to receive ponatinib (n=155) or imatinib (n=152). The trial was terminated early, on Oct 17, 2013, following concerns about vascular adverse events observed in patients given ponatinib in other trials. Trial termination limited assessment of the primary endpoint of major molecular response at 12 months, as only 13 patients in the imatinib group and ten patients in the ponatinib group could be assessed at this timepoint; the proportion of patients achieving a major molecular response at 12 months did not differ significantly between the two groups (eight [80%] of ten patients given ponatinib and five [38%] of 13 patients given imatinib; p=0·074). 11 (7%) of 154 patients given ponatinib and three (2%) of 152 patients given imatinib had arterial occlusive events (p=0·052); arterial occlusive events were designated serious in ten (6%) of 154 patients given ponatinib and in one (1%) of 152 patients given imatinib (p=0·010). The data monitoring committee criterion for risk assessment (significant difference in serious grade 3 or 4 ischaemic events between groups) was not met (five [3%] of 154 vs one [1%] of 152; p=0·21). Grade 3 or 4 adverse events observed in more than 5% of patients in the ponatinib group were increased lipase (22 [14%] of 154 vs three [2%] of 152 with imatinib), thrombocytopenia (19 [12%] of 154 vs ten [7%] of 152 with imatinib), rash (ten [6%] of 154 vs two [1%] of 152 with imatinib). In the imatinib group, grade 3 or 4 adverse events observed in more than 5% of patients were neutropenia (12 [8%] of 152 vs five [3%] of 154 with ponatinib) and thrombocytopenia (ten [7%] of 152 vs 19 [12%] of 154 with ponatinib). Serious adverse events that occurred in three or more patients given ponatinib were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). No serious adverse event occurred in three or more patients given imatinib. The efficacy of ponatinib treatment of newly diagnosed chronic-phase chronic myeloid leukaemia compared with imatinib could not be assessed due to trial termination, but preliminary data suggest there might be benefit, although with more arterial occlusive events than with imatinib at the doses studied. Because the EPIC trial was terminated early, efficacy of ponatinib in this setting remains to be established. ARIAD Pharmaceuticals.

Abstract S1-04: Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: A phase Ib JAVELIN solid tumor trial

Abstract Background: The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against cancer. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody being investigated in clinical trials. We report clinical activity of avelumab in a cohort of patients (pts) with locally advanced (LA) or metastatic breast cancer (MBC) refractory to or progressing after standard-of-care therapy (NCT01772004). Methods: Pts received avelumab at 10 mg/kg Q2W until confirmed progression, unacceptable toxicity, or any criterion for withdrawal occurred. Tumors were assessed every 6 wks (RECIST 1.1). Unconfirmed best overall response was evaluated. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Biopsy or surgical specimens were collected within 90 days prior to 1st dose of avelumab for biomarker analyses. Tumor PD-L1 expression was assessed by immunohistochemistry using various cutoff criteria. Results: As of 27 Feb 2015, 168 pts (167 female, 1 male) with MBC, including ductal (56.5%), carcinoma NOS (9.5%), lobular (3.6%), or other (30.4%), were treated with avelumab and followed for a median of 10 mo (range 6-15). Median age was 55y (range 31-81), ECOG performance status was 0 (49.4%) or 1 (50.6%), and pts had received a median of 3 prior therapies for LA/M disease (range 0-10; pts must have received prior treatment with taxane and anthracycline, unless contraindicated). Pts were HER2–/ER+ or PR+ (69 [41.1%]), triple negative (TNBC = HER2–/ER–/PR–; 57 [33.9%]), HER2+ (26 [15.5%]), or had unknown biomarker status (16 [9.5%]). Median duration of treatment was 8 wks (range 2-50), and 9 pts (5.4%) remained on avelumab. Any grade treatment-related treatment-emergent AEs (TEAEs) occurred in 120 pts (71.4%); the most common (&amp;gt;10%) were fatigue (33 [19.6%]), nausea (24 [14.3%]), and infusion-related reactions (20 [11.9%]). Treatment-related grade ≥3 TEAEs occurred in 24 pts (14.3%) and included (≥1%) fatigue, anemia, increased GGT, and autoimmune hepatitis (each 3 [1.8%]), and arthralgia (2 [1.2%]). There were 2 treatment-related deaths (acute liver failure, respiratory distress). Unconfirmed objective response rate (ORR) in the entire cohort was 5.4% (9 pts; 95% CI: 2.5, 9.9), with 1 CR and 8 PRs. Five of 9 responses were ongoing at time of cutoff. Stable disease was observed in additional 40 pts (23.8%), for an overall disease control rate of 29.2%. Evidence of tumor reduction by ≥30% was seen in 15 pts (8.9%). There were responders in all biomarker subgroups, including 5 PRs in TNBC (n=57 [8.8%; 95% CI: 2.9, 19.3]). PD-L1 expression was evaluable in 136 pts. Among all pts with PD-L1 expressing immune cells within the tumor, 33.3% (4 of 12) had PRs. In pts with TNBC who had PD-L1+ immune cells within the tumor, 44.4% (4 of 9) had PRs, compared with 2.6% (1 of 39) for TNBC and PD-L1– immune cells. Conclusions: Avelumab showed an acceptable safety profile and had clinical activity in a subset of pts with MBC. In pts with TNBC, presence of PD-L1 expressing immune cells within the tumor may be associated with clinical responses to avelumab. Further analyses of PD-L1 expression and clinical activity of avelumab in MBC are ongoing. *Proposed INN. Citation Format: Dirix LY, Takacs I, Nikolinakos P, Jerusalem G, Arkenau H-T, Hamilton EP, von Heydebreck A, Grote H-J, Chin K, Lippman ME. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: A phase Ib JAVELIN solid tumor trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S1-04.

A randomized, double-blind, placebo-controlled phase III study of cisplatin plus a fluoropyrimidine with or without ramucirumab as first-line therapy in patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma (RAINFALL, NCT02314117).

TPS178 Background: Ramucirumab, a human IgG1 monoclonal antibody directed to the ectodomain of VEGFR-2, prevents ligand binding to the receptor, blocking activation of downstream receptor-mediated pathways. Ramucirumab has demonstrated significant improvement in overall survival (OS) and progression-free survival (PFS) in 2 phase III registration studies (REGARD, RAINBOW) in patients in second-line treatment of gastric cancer. This global phase III trial will compare PFS in patients with HER2-negative, metastatic gastric or GEJ adenocarcinoma receiving ramucirumab with cisplatin/capecitabine (or 5-FU) versus placebo with cisplatin/capecitabine (or 5-FU) as first-line treatment. The trial is conducted in 137 sites in the Americas, Europe and Japan and is currently open to enrollment. Methods: Eligible patients will be randomized to receive ramucirumab (8mg/kg on days 1 and 8, based upon population pharmacokinetic modelling) or placebo with cisplatin/capecitabine every 21-day cycle until disease progression, unacceptable toxicity, or other withdrawal criteria are met. The primary endpoint is PFS; OS is the key secondary endpoint. Efficacy will be considered at 3 analysis points: futility analysis for PFS, primary analysis of PFS &amp; final analysis of OS. A gatekeeping strategy will be used to assess PFS and OS. The OS endpoint will only be tested if the PFS test is significant to control Type I error at 5% across both endpoints. An exposure/safety analysis will be done after 60 patients have started the 3rd cycle. The study has 90% power to demonstrate a PFS advantage assuming HR = 0.70 and 80% power to demonstrate an OS advantage assuming HR = 0.77. Other secondary endpoints include PFS2 (the time from randomization to disease progression after the start of additional systemic anticancer treatment, or death from any cause, whichever occurs first), objective response rate, safety and quality of life. As of 9/11/2015, 128 patients have been enrolled in 19 countries. The 1st exposure/safety analysis is underway. Clinical trial information: NCT02314117.

Avelumab (MSB0010718C), an anti-PD-L1 antibody, as a third-line treatment in patients with advanced gastric or gastroesophageal junction cancer: A phase Ib JAVELIN Solid Tumor trial.

TPS188 Background: The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against cancer. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody being investigated in clinical trials. The phase Ib study (NCT01772004) is an open-label, parallel-group expansion trial in patients (pts) with locally advanced or metastatic (LA/M) solid tumors that includes a heavily pretreated cohort of pts with advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJ) to evaluate safety and efficacy of avelumab in the 3rd-line setting. Prior to adding this 3rd-line cohort, this trial had enrolled a separate cohort with advanced GC/GEJ who had received prior 1st-line chemotherapy (Chung et al, ECC 2015). Methods: This trial cohort is enrolling pts with histologically confirmed unresectable LA/M GC/GEJ who have been previously treated with 1st-line combination chemotherapy and 2nd-line ramucirumab, alone or in combination, and whose disease has progressed during or after ramucirumab treatment. Pts who have received prior treatment with trastuzumab and pts with HER2+ status are allowed. Eligible pts also must have tumor archival material or fresh biopsy, an ECOG performance status of 0 or 1 at the time of trial entry, and disease with ≥ 1 measurable lesion according to RECIST 1.1. Exclusions include prior therapy with immune checkpoint drugs or history of autoimmune disease. Up to 150 eligible pts will receive avelumab at 10 mg/kg as an IV infusion Q2W. Treatment will continue until disease progression, unacceptable toxicity, or any criterion for withdrawal occurs. Primary endpoint is confirmed best overall response (RECIST 1.1) as adjudicated by an IERC. Secondary objectives include assessment of progression-free survival, overall survival, and immune-related efficacy assessments. Association between tumor PD-L1 expression and efficacy will be evaluated. Adverse events will be assessed and graded according to NCI-CTCAE v4.0. Tumor evaluation will be performed every 6 wks until progression. Enrollment in this cohort began in June 2015. *Proposed INN Clinical trial information: NCT01772004.

Safety, clinical activity, and PD-L1 expression of avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with metastatic urothelial carcinoma from the JAVELIN Solid Tumor phase Ib trial.

367 Background: Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody being investigated in multiple clinical trials. We report safety and clinical activity of avelumab as a second-line therapy in patients (pts) with metastatic urothelial carcinoma (mUC) based on level of PD-L1 expression (NCT01772004). Methods: Pts with mUC unselected for PD-L1 expression received avelumab at 10 mg/kg Q2W by IV infusion until confirmed progression, unacceptable toxicity, or any criterion for withdrawal occurred. Tumors were assessed every 6 wks (RECIST 1.1). Best overall response rate (ORR) and progression-free survival (PFS) were evaluated. Adverse events (AEs) were graded by NCI-CTCAE v4.0. PD-L1 expression was assessed by immunohistochemistry. Results: As of 19 Mar 2015, 44 pts (30 men, 14 women) with mUC were treated with avelumab (median 13 wks [range 2-28]) and followed for a median of 3.5 mo (range 3.0-5.0). Median age was 68y (range 30-84), ECOG performance status was 0 (43.2%) or 1 (56.8%), and pts had received a median of 2 prior therapies (range 1- ≥ 4). Treatment-related treatment-emergent AEs (TR-TEAEs) of any grade occurred in 26 pts (59.1%); those occurring ≥ 10% were grade 1/2 infusion-related reactions (8 [18.2%]) and fatigue (7 [15.9%]). One pt had grade 3 asthenia. There were no treatment-related deaths. ORR was 15.9% (7 pts; 95% CI: 6.6, 30.1) with 1 CR and 6 PRs; 6 responses were ongoing at data cutoff. Stable disease (SD) was observed in 19 pts (42.3%) and disease-control rate (CR+PR+SD) was 59.1%. PD-L1 expression was evaluable in 32 pts. Using a ≥ 5% cutoff (10/32 [31.3%] were PD-L1+), ORR was 40.0% in PD-L1+ pts (4/10) vs 9.1% in PD-L1– pts (2/22; p= 0.060). PFS rate at 12 wks was 70.0% (95% CI: 32.9, 89.2) in PD-L1+ pts vs 45.5% (95% CI 22.7, 65.8) in PD-L1− pts. Conclusions: Avelumabshowed an acceptable safety profile and had clinical activity in pts with mUC. There was a trend towards higher ORR and prolonged PFS rate at 12 wks in pts with PD-L1+ mUC. Further analyses of PD-L1 expression and clinical activity of avelumab in UC are ongoing. *Proposed INN. Clinical trial information: NCT01772004.

Cannabis Withdrawal, Posttreatment Abstinence, and Days to First Cannabis Use Among Emerging Adults in Substance Use Treatment: A Prospective Study.

Very little prospective research investigates how cannabis withdrawal is associated with treatment outcomes, and this work has not used the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) thresholds for cannabis withdrawal. The sample included 110 emerging adults entering outpatient substance use treatment who were heavy cannabis users with no other drug use and limited alcohol use. We used survival analyses to predict days to first use of cannabis and logistic regression to predict whether participants were abstinent and living in the community at 3 months. Those meeting criteria for cannabis withdrawal were more likely to return to use sooner than those not meeting criteria for cannabis withdrawal. However, the presence of cannabis withdrawal was not a significant predictor of 3-month abstinence. Emerging adults with DSM-5 cannabis withdrawal may have difficulty initiating abstinence in the days following their intake assessment, implying the need for strategies to mitigate their more rapid return to cannabis use.

A Randomized Trial of Phototherapy with Filtered Sunlight in African Neonates

BackgroundSequelae of severe neonatal hyperbilirubinemia constitute a substantial disease burden in areas where effective conventional phototherapy is unavailable. We previously found that the use of filtered sunlight for the purpose of phototherapy is a safe and efficacious method for reducing total bilirubin. However, its relative safety and efficacy as compared with conventional phototherapy are unknown.MethodsWe conducted a randomized, controlled noninferiority trial in which filtered sunlight was compared with conventional phototherapy for the treatment of hyperbilirubinemia in term and late-preterm neonates in a large, urban Nigerian maternity hospital. The primary end point was efficacy, which was defined as a rate of increase in total serum bilirubin of less than 0.2 mg per deciliter per hour for infants up to 72 hours of age or a decrease in total serum bilirubin for infants older than 72 hours of age who received at least 5 hours of phototherapy; we prespecified a noninferiority margin of 10% for the difference in efficacy rates between groups. The need for an exchange transfusion was a secondary end point. We also assessed safety, which was defined as the absence of the need to withdraw therapy because of hyperthermia, hypothermia, dehydration, or sunburn.ResultsWe enrolled 447 infants and randomly assigned 224 to filtered sunlight and 223 to conventional phototherapy. Filtered sunlight was efficacious on 93% of treatment days that could be evaluated, as compared with 90% for conventional phototherapy, and had a higher mean level of irradiance (40 vs. 17 μW per square centimeter per nanometer, P<0.001). Temperatures higher than 38.0°C occurred in 5% of the infants receiving filtered sunlight and in 1% of those receiving conventional phototherapy (P<0.001), but no infant met the criteria for withdrawal from the study for reasons of safety or required an exchange transfusion.ConclusionsFiltered sunlight was noninferior to conventional phototherapy for the treatment of neonatal hyperbilirubinemia and did not result in any study withdrawals for reasons of safety. (Funded by the Thrasher Research Fund, Salt Lake City, and the National Center for Advancing Translational Sciences of the National Institutes of Health; Clinical Trials.gov number, NCT01434810.)

The physiological and thermal responses of military personnel undertaking a military exercise in Kenya

Undertaking operational patrolling activity in hot environments, carrying heavy loads and wearing personal protective equipment (PPE) presents a significant physiological challenge to Service personnel. Planned research trials involving volunteers exercising in the heat observe an important volunteer withdrawal criterion of attainment of a core body temperature of 39.5 °C. However, trained populations (marathon runners) have been shown to sustain exercise with core temperatures in excess of 40 °C with no recognised adverse health effects [1]. Thus, it could be hypothesised that military personnel with a good level of physical fitness might similarly sustain higher than usual core temperatures, albeit while wearing impermeable PPE. The aim of the present study was to measure the actual thermal response of military personnel while performing operationally specific exercises in the most arduous phase of a military exercise in a hot-dry environment.

Commentary on: Are we overpathologizing everyday life? A tenable blueprint for behavioral addiction research. Excessive behaviors are not necessarily addictive behaviors.

Background and AimsThe commentary aims to provide clarity to the article “Are we overpathologizing everyday life? A tenable blueprint for behavioral addiction research.”MethodsWe provide another viewpoint for the important issues of behavior addiction.ResultThe course of behavior addiction should be further studied. The criteria of withdrawal and tolerance of behavior addiction are ill-defined and need to be further evaluated.ConclusionsThe etiology, course, presentation, and functional impairment of behavior addiction should be validated by evidencebased data before being defined as a disorder.

The effects of adding epinephrine to ropivacaine for popliteal nerve block on the duration of postoperative analgesia: a randomized controlled trial.

BackgroundDuration of peripheral nerve blocks depends on multiple factors. Both technique and type of local anesthetic used, either with or without adjuncts, may result in different duration times of the block. The purpose of the present study was to compare the duration of postoperative analgesia of 30 mL ropivacaine 0.75 % with or without epinephrine for popliteal sciatic nerve block.MethodsThirty-eight patients were included to receive ultrasound guided continuous popliteal nerve block with ropivacaine 0.75 % either without (ROPI) or with epinephrine 5 μg/mL (ROPI-EPI) for ankle fusion, subtalar fusion, or a combination of both. The primary outcome parameter was the duration of postoperative analgesia as reflected by the time to first request for postoperative analgesia (TTFR) through the popliteal nerve catheter. Secondary outcome measures included the onset of sensory and motor block and NRS score for pain at rest and during movement.ResultsThirty patients, 15 in each group, were studied. Eight patients were withdrawn because of specific withdrawal criteria described in the protocol and replaced according to their group allocation. Median [interquartile range] TTFR was 463 [300–1197] min and 830 [397–1128] min for the ROPI vs ROPI-EPI group respectively. Hodges Lehman median difference between groups was 71 min (95 % CI −415 – 473 min). There was no difference in any clinical outcome measure between the groups.ConclusionThe results of this study did not show any significant increase in the duration of postoperative analgesia by adding epinephrine to ropivacaine for popliteal nerve block. This may be due to the intrinsic vasoconstrictive properties of ropivacaine. The absence of a significant difference can also be the result of a type II error caused by a large variation in the individual TTFR.Trial registrationTrial register.nl identifier: NTR3330, keyword TTFR

Preliminary experience using milnacipran in patients with juvenile fibromyalgia: lessons from a clinical trial program.

BackgroundThere are no approved medications for juvenile fibromyalgia (JFM), a disorder that is often under-diagnosed. The effects of milnacipran, a drug approved for the management of fibromyalgia (FM) in adults, was assessed in a clinical trial program for JFM.MethodsPatients, ages 13–17 years who met the Yunus and Masi criteria for JFM and/or 1990 American College of Rheumatology criteria for FM, were enrolled in a responder-enriched, randomized withdrawal trial. After receiving open-label milnacipran (8 weeks), patients with ≥50 % improvement in pain underwent double-blind randomization (1:2) to either placebo or continuing treatment with milnacipran (8 weeks). All patients, including those who did not meet the randomization criteria for double-blind withdrawal, were allowed to enter an extension study with open-label milnacipran (up to 52 weeks). The primary endpoint was loss of therapeutic response (LTR) during the double-blind period. Additional outcome measures included the Patient Global Impression of Severity (PGIS), Pediatric Quality of Life Inventory (PedsQL: Generic Core Scales, Multidimensional Fatigue Scale), and Multidimensional Anxiety Scale for Children (MASC). Safety assessments included adverse events (AEs), vital signs, electrocardiograms, and laboratory tests.ResultsThe milnacipran program was terminated early due to low enrollment. Because only 20 patients were randomized into the double-blind withdrawal period, statistical analyses were not conducted for the LTR endpoint. However, 116 patients entered the open-label period of the initial study and 57 participated in the open-label extension study. Their experience provides preliminary information about the use of milnacipran in JFM patients. During both open-label periods, there were mean improvements in pain severity, PGIC, PedsQL, and MASC scores. No unexpected safety issues were detected. The most commonly reported treatment-emergent AEs were nausea, headache, vomiting, and dizziness. Mean increases in heart rate and blood pressure were observed, and were consistent with the AE profile in adults with FM.ConclusionsThe open-label findings provide preliminary evidence that milnacipran may improve symptoms of JFM, with a safety and tolerability profile that is consistent with the experience in adult FM patients. Future trial designs for JFM should consider the relatively low recognition of this condition compared to adult FM and the difficulties with enrollment.Trial registrationNCT01328002; NCT01331109Electronic supplementary materialThe online version of this article (doi:10.1186/s12969-015-0025-9) contains supplementary material, which is available to authorized users.

“Correct Use of Inhaled Corticosteroids in Chronic Obstructive Pulmonary Disease”: A Consensus Document

IntroductionIndications for inhaled corticosteroids (IC) in combination with long-acting bronchodilators (LABD) are well defined in clinical practice guidelines. However, there are some doubts about their efficacy and safety. The aim of this document is to establish an expert consensus to clarify these issues. MethodA coordinator group was formed, which systematically reviewed the scientific evidence with the aim of identifying areas of uncertainty about the efficacy of ICs, the adverse effects associated with their use and criteria for withdrawal. Their proposals were submitted to a panel of experts and the Delphi technique was used to test the level of consensus. ResultsTwenty-five experts participated in the panel, and consensus was reached on the use of IC in the mixed chronic obstructive pulmonary disease (COPD)-asthma phenotype and in frequent exacerbators, and on not using IC in association with LABD for improving lung function in COPD. There was no general consensus on restricting the use of IC to prevent adverse effects. The panel did agree that IC withdrawal is feasible but should be undertaken gradually, and patients who have discontinued must be evaluated in the short term. ConclusionsConsensus was reached regarding the indication of IC in mixed COPD-asthma and frequent exacerbator phenotypes. The potential for adverse effects must be taken into consideration, but there is no consensus on whether limiting use is justified. The withdrawal of ICs was uniformly agreed to be feasible.

Criteria of withdrawal of first-line DMT and substitution for second-line drugs (treatment escalation) basing on MRI results

Criteria of withdrawal of first-line DMT and substitution for second-line drugs (treatment escalation) basing on MRI results

Documento de consenso «Uso adecuado de los corticoides inhalados en la enfermedad pulmonar obstructiva crónica»

IntroductionIndications for inhaled corticosteroids (IC) in combination with long-acting bronchodilators (LABD) are well defined in clinical practice guidelines. However, there are some doubts about their efficacy and safety. The aim of this document is to establish an expert consensus to clarify these issues. MethodA coordinator group was formed, which systematically reviewed the scientific evidence with the aim of identifying areas of uncertainty about the efficacy of ICs, the adverse effects associated with their use and criteria for withdrawal. Their proposals were submitted to a panel of experts and the Delphi technique was used to test the level of consensus. ResultsTwenty-five experts participated in the panel, and consensus was reached on the use of IC in the mixed chronic obstructive pulmonary disease (COPD)-asthma phenotype and in frequent exacerbators, and on not using IC in association with LABD for improving lung function in COPD. There was no general consensus on restricting the use of IC to prevent adverse effects. The panel did agree that IC withdrawal is feasible but should be undertaken gradually, and patients who have discontinued must be evaluated in the short term. ConclusionsConsensus was reached regarding the indication of IC in mixed COPD-asthma and frequent exacerbator phenotypes. The potential for adverse effects must be taken into consideration, but there is no consensus on whether limiting use is justified. The withdrawal of ICs was uniformly agreed to be feasible.

¿Están los grandes repetidores adictos a los comportamientos suicidas?

The literature provides support for the hypothesis that some major repeaters (individuals with >=5 lifetime suicide attempts) are addicted to suicidal behavior (SB). This study explores whether major repeaters are addicted to SB or not using 7 criteria: tolerance (Criterion 1), withdrawal (Criterion 2), loss of control (Criterion 3), problems in quitting/cutting down (Criterion 4), much time spent using (Criterion 5), substantial reduction in activities (Criterion 6), and adverse physiological/physical consequences (Criterion 7). Total dependence on SB was indicated by the presence of 3 or more of the 7 criteria in the last 12 months. This cross-sectional study at Puerta de Hierro University Hospital (Madrid, Spain) recruited 118 suicide attempters including 8 major repeaters (7%, 8/118), who were all females. The association between each SB addiction criterion, physiological dependence and total dependence with major repeater status was tested for significance and for effect size with odds ratios (ORs) and their 95% confidence intervals. As hypothesized, major repeaters met significantly higher frequency of criteria for total dependence on SB, OR=62.9 (6.4-615). A backward stepwise logistic regression model was used to provide an OR between major repeater status and total dependence status corrected by confounding variables. Age, panic disorder without agoraphobia, borderline personality disorder, history of psychiatric inpatient admission, and total dependence on SB were introduced as independent variables with major repeater status as the dependent variable. The model selected total dependence and age as the remaining significant variables in the last step. Accordingly, major repeaters appear to be addicted to SB.