Frequency Of Discontinuation Research Articles

A phase 3b safety study of fixed-dose durvalumab + tremelimumab or durvalumab monotherapy in advanced solid malignancies (STRONG): Urothelial and non-urothelial urinary tract carcinoma module A.

TPS538 Background: Despite initial high response rates to current SoC first-line chemotherapy, most patients with locally advanced or metastatic urothelial carcinoma (UC) eventually experience disease progression. With no defined SoC second-line therapies, prognosis remains poor. Durvalumab is a selective, high affinity, engineered human IgG1 mAb that blocks programmed cell death ligand-1 binding to programmed cell death-1 and CD80. Most current Phase 3 trials of durvalumab were initiated using weight-based dosing (mg/kg) regimens. STRONG (NCT03084471), a Phase 3b safety study of durvalumab alone or in combination with the anti-CTLA-4 agent tremelimumab is being conducted to expand understanding of the safety of fixed dosing in patients with advanced solid tumors. Module A of the study is enrolling patients with UC and non-urothelial carcinoma of the urinary tract (any histology) for treatment with durvalumab in the second-line setting post-chemotherapy. Other study modules will include durvalumab + tremelimumab combination arms. Methods: This is an open-label, multicenter study. Module A will enroll approximately 1200 patients to receive durvalumab monotherapy 1,500 mg i.v. q4w until disease progression or unacceptable toxicity. The study opened for enrolment on 17 April 2017 and is expected to be completed within 5 years. Patients must have histologically or cytologically confirmed disease that has progressed during or after nonplatinum or platinum-based chemotherapy either for metastatic disease or progressive disease less than 12 months after adjuvant or neo-adjuvant chemotherapy, and ECOG performance status 0–2. The primary objective is to assess the safety of durvalumab in terms of incidence, severity, nature, seriousness, intervention, outcome and causality (including immune-relatedness) of adverse events of special interest (AESIs). Secondary objectives include additional assessment of safety and tolerability, the frequency of treatment interruption and discontinuation, and overall survival. Clinical trial information: NCT03084471.

Influence of high-dose oral erythromycin on feeding intolerance in preterm neonates: A randomized controlled trial.

Background: Feeding intolerance is a common complication in preterm neonates and is responsible for prolonged hospitalization. This study aimed at assessing the effects of high-dose oral erythromycin on feeding intolerance in preterm infants. Methods: A randomized, double blinded, placebo-controlled trial was performed during 2014 and 2015 (Tehran-Iran). Preterm neonates aged >14 days, who met the feeding intolerance criteria were selected for the study and their medical records were randomly assigned into 2 groups by simple randomization. Infants in group A received 10 mg/kg oral erythromycin every 6 hours for 2 days, followed by 4 mg/kg oral erythromycin every 6 hours for 5 days; and infants in group B received placebo with the same route. The number of days until reaching complete oral feeding, day of discharge from NICU, and complications related to intervention were recorded and compared between the 2 groups. Independent samples t test, Mann-Whitney, Fischer exact test, and Chi square were used to analyze the relationships between variables. P-value less than 0.05 was considered statistically significant. Results: A total of 20 infants in group A received erythromycin and 20 infants in group B received placebo. Erythromycin could not alter the mean volume of feeding, duration of parental feeding, length of hospitalization, and frequency of feeding discontinuity (p>0.05); however, mean days to reach complete feeding in group A was significantly shorter than in group B (9.80 vs. 16.80 days; p=0.001). Conclusion: High-dose erythromycin as a rescue measure with no potential adverse effect is beneficial in reducing the time taken to achieve full enteral feeding. However, more extensive investigations are needed to determine the best administration dosage.

Optimising outcomes for patients with chronic lymphocytic leukaemia on ibrutinib therapy: European recommendations for clinical practice.

Ibrutinib is indicated in Europe for the treatment of several B-cell malignancies, including chronic lymphocytic leukaemia (CLL). However, despite the high efficacy and favourable toxicity profile of ibrutinib, recent data suggest that it is not always administered optimally in clinical practice, with an increased tendency for dose reduction and a higher frequency of discontinuation. An expert panel of European haematologists was convened to identify practical issues pertinent to physicians involved in the therapeutic management of ibrutinib-treated CLL patients and here we outline the findings. Practical management recommendations are given for treating patients with ibrutinib and clinical considerations for the management of adverse events (AEs) that can be associated with ibrutinib treatment are addressed. This article highlights that patients should be monitored for treatment emergent adverse events, most of which are mild, transient and generally occur early in therapy and that, even with more challenging AEs, patients can often be maintained on therapy with minimal disruption through careful management. The necessity to use the correct ibrutinib dose, along with increased awareness, vigilance, mitigation and management of AEs, are all recommended to maximise outcomes for CLL patients treated with ibrutinib.

Chronological Age and Risk of Chemotherapy Nonfeasibility: A Real-Life Cohort Study of 153 Stage II or III Colorectal Cancer Patients Given Adjuvant-modified FOLFOX6.

To assess nonfeasibility of adjuvant-modified FOLFOX6 chemotherapy in patients with stage II or III colorectal cancer. Consecutive patients managed between 2009 and 2013 in 2 teaching hospitals in the Paris urban area were included in the CORSAGE (COlorectal canceR, AGe, and chemotherapy fEasability study) cohort study. Nonfeasibility was defined by the frequencies of empirical first-cycle dose reduction (>15%), early discontinuation (<12 cycles), and low relative dose intensity (RDI) (<0.85). Risk factors for chemotherapy nonfeasibility were identified using multivariate logistic regression. Among 153 patients, 56.2% were male (median age, 65.6 y; 35.3%≥70 y; 7.3% with performance status [PS]≥2). For 5-fluorouracil (5-FU), 20.9% of patients had first-cycle dose reduction and 28.1% early discontinuation; RDI was 0.91 (25th to 75th percentiles, 0.68 to 0.99). Factors independently associated with first-cycle 5-FU dose reduction were aged 65 to 69 years versus those younger than 65 years (adjusted odds ratio [aOR], 5.5; 95% confidence interval [CI], 1.5-19.9) but not age 70 years and older, PS≥2 (aOR, 6.02; 95% CI, 1.15-31.4), higher Charlson Comorbidity Index (aOR1-point increase, 1.4; 95% CI, 1.05-1.82), or larger number of medications (aOR 1-medication increase, 1.19; 95% CI, 1.00-1.42). Oxaliplatin dose reduction occurred in 52.3% of patients and early discontinuation in 62.7%; the latter was more common in the 70 years and older group (92.6% vs. 74.6% in the <65-y group; P=0.01); RDI was 0.7 (95% CI, 0.55-0.88). In the real-world setting, compared with their younger and older counterparts, patients aged 65 to 69 years given modified FOLFOX6 for stage II or III colorectal cancer had higher frequencies of 5-FU nonfeasibility defined based on first-cycle dose reduction, early discontinuation, and RDI; and these differences were independent from PS, comorbidities, and number of medications.

Analysis of Adjuvant Endocrine Therapy in Practice From Electronic Health Record Data of Patients With Breast Cancer.

Adjuvant endocrine therapy is a long-term drug therapy prescribed to prevent recurrence of hormone receptor-positive breast cancer. Data on adjuvant endocrine therapy are reported though clinical trials, which may differ from treatment practice and outcomes in the general population of patients with breast cancer. With secondary use of electronic health record (EHR) data, we summarize adjuvant endocrine treatment practice and outcomes in real-world settings. We analyzed treatment data derived from EHR data on 1,587 patients with stage I to III breast cancer at a National Cancer Institute-designated comprehensive cancer center to learn the frequencies of real-world adjuvant endocrine drug switches and discontinuation and to explore the potential cause for drug switches and discontinuation from medical records. We measured rates of drug use, drug switches, early drug discontinuation, adverse events, recurrence, and death. We also measured adverse events and change in menopause status as potential causes for drug switch and discontinuation. Within the study population, approximately 49% of patients were lost to follow-up or did not complete adjuvant treatment through 5 years. Fifty-two percent of patients switched to a different endocrine therapy drug during their treatment. We found that age is correlated with drug switches and that adverse events are correlated with drug switches and discontinuation. We also found that patients who switched to an alternative endocrine therapy during treatment were more likely to complete 5 years of treatment. This study describes long-term adjuvant endocrine treatment in real-world settings and demonstrates the ability to leverage longitudinal EHR data to characterize oral medication treatment patterns in patients with cancer.

Clinical Outcomes of the Oral Suspension vs Delayed-Release Tablet Formulations of Posaconazole for Prophylaxis of Invasive Fungal Infections

Background Posaconazole is effective prophylaxis for invasive fungal infections (IFIs). We compared incidence of breakthrough IFI (bIFI) and early posaconazole discontinuation between patients receiving delayed-release tablet and oral suspension formulations.Methods This was a retrospective cohort study of patients receiving posaconazole at Oregon Health & Science University Hospital between 1/1/2010 and 6/30/2016. Oral suspension was the preferred formulation until 2/2014; afterwards the tablet was preferred. We included all courses of primary prophylaxis for each patient during the study period. Data were extracted from an electronic health record repository and via chart review. Three independent reviewers identified bIFI using European Organization for Research and Treatment of Cancer criteria. We assessed rationale for early discontinuation of posaconazole for patients that were still indicated for antifungal prophylaxis based on National Comprehensive Cancer Network (NCCN) criteria.Results547 patients received 859 courses of posaconazole (53% oral suspension and 48% tablet). Prophylaxis was indicated according to NCCN criteria in 91% of courses. The primary indications for prophylaxis were acute myelogenous leukemia (68%), graft-vs-host disease (18%), and myelodysplastic syndrome (3%). There were no significant differences in demographics or indication between patients receiving the different formulations. The overall incidence rate of bIFI was 4.15/10,000 posaconazole-days (16 total bIFI events). Incidence of bIFI was not significantly different between patients receiving the different formulations (P = 0.92). Posaconazole was discontinued early in 147 (17%) courses; frequency of discontinuation was not significantly different between the tablet (20%) and oral suspension (15%) formulations (P = 0.10). The primary reasons for early discontinuation were elevated liver function tests or QT prolongation (25%), inability to take an oral formulation (17%), and drug cost (17%).Conclusion Among patients receiving posaconazole prophylaxis, incidence of bIFI was low and not significantly different between those receiving the tablet vs oral suspension formulations.Disclosures J. P. Furuno, Merck & Co.: Consultant and Grant Investigator, Consulting fee, Research grant and Speaker honorarium. J. S. Lewis II, Merck & Co.: Consultant, Consulting fee. J. C. McGregor, Merck & Co.: Grant Investigator, Research grant

Frequency of Symptoms and Treatment Discontinuation During Programmatic Use of the 12-Dose Isoniazid–Rifapentine Regimen for Treatment of Latent Tuberculosis Infection

Frequency of Symptoms and Treatment Discontinuation During Programmatic Use of the 12-Dose Isoniazid–Rifapentine Regimen for Treatment of Latent Tuberculosis Infection

Electrical, mineralogical, and geochemical properties of Um Gheig and Um Bogma Formations, Egypt

Dolostones of Um Bogma and Um Gheig Formations were studied using mineralogical and geochemical characterizations. The present work has tried to identify the origin, environment, pollution, and their electrical properties for the two formations. Also, the environmental geochemistry that resulted from the trace element concentration is examined here and we will try to differentiate between them. The study samples are fissile and highly fossiliferous dolomites. The two formations are classified as dolostones and nearly ordered. The mineralogy and geochemistry studies indicated that the two formations were formed under mixing zone at the near-surface oxidizing environment. The diagenetic features of both formations demonstrate many processes with clear effects. Dolostones of both formations may be precipitated from two different solutions. Meteoric water is the main supply, while the other solution may be resulted from the deep hydrothermal solutions that come up from deep faults. The distribution of Sr and Y content of dolostones at Um Bogma Formation indicated that they are precipitated at 110–150 °C, while those in Um Gheig are deposited at <150 °C. Electrical properties were measured at ~21 °C and humidity ~55% in a frequency range of 42 Hz–5 MHz. Slight changes were seen to be the result of changes in texture between grains and mineral composition for the two formations. The most effective factor in the changes of electrical properties is the distribution of grains (texture). The dielectric constant, generally, decreases with the decrease of discontinuous paths and frequency. Electrical conduction, usually, increases with the increase of conductor continuous paths and frequency.

Adverse events of raltegravir and dolutegravir.

Objective:To compare the frequency and risk factors of toxicity-related treatment discontinuations between raltegravir and dolutegravir.Design:Prospective cohort study.Methods:All antiretroviral therapy (ART)-naïve and ART-experienced HIV-infected individuals from the Swiss HIV Cohort Study who initiated raltegravir or dolutegravir between 2006 and 2015 were investigated concerning treatment modification within the first year.Results:Of 4041 patients initiating ART containing raltegravir (n = 2091) or dolutegravir (n = 1950), 568 patients discontinued ART during the first year, corresponding to a rate of 15.5 [95% confidence interval (CI) 14.5–16.9] discontinuations per 100 patient-years. Only 10 patients on raltegravir (0.5%) and two patients on dolutegravir (0.1%) demonstrated virologic failure. The main reason for ART discontinuation was convenience expressed as patient's wish, physician's decision, or treatment simplification (n = 302). Toxicity occurred in 4.3% of patients treated with raltegravir and 3.6% with dolutegravir, respectively. In multivariable analysis, the only independent risk factor for discontinuing ART because of toxicity was female sex (hazard ratio 1.98, 95% CI 1.45–2.71, P < 0.001).Neuropsychiatric complaints were the most commonly reported toxic adverse events and more frequent in the dolutegravir (n = 33, 1.7%) compared with the raltegravir group (n = 13, 0.6%). Risk of discontinuation for neurotoxicity was lower for raltegravir than for dolutegravir in multivariable analysis (hazard ratio 0.46, 95% CI 0.22–0.96, P = 0.037).Conclusion:In this, large cohort raltegravir and dolutegravir-containing regimen demonstrated a high virologic efficacy. Drug toxicity was infrequent and discontinuation because of neuropsychiatric events within the first year of treatment was only marginal higher with dolutegravir compared with raltegravir. However, monitoring of neurotoxic side-effects of dolutegravir is important.

Efficacy and safety in elderly patient subsets across studies investigating endocrine monotherapy versus combination therapy in patients with HR+/HER2−advanced breast cancer.

1045 Background: Combination of endocrine therapy and targeted agents in 1st and 2nd-line therapy prolong progression-free survival (PFS) in patients with hormone receptor–positive (HR+), HER2 − advanced breast cancer (ABC). However, a greater risk of adverse events (AEs) and a greater possibility of drug-drug interaction, associated with combination therapy, present challenges in older patients. Methods: This study reviewed PFS and safety data in age-stratified subsets from Phase II or III clinical trials comparing endocrine monotherapy vs combinations of endocrine or targeted therapy in patients with HR+, HER2−ABC. Results: Among 9 identified studies, combination therapy that included ribociclib, palbociclib, and everolimus significantly reduced risk of disease progression vs monotherapy in older and younger patient subsets (Table). For combination therapy that included ribociclib or palbociclib, frequency of discontinuations due to AEs was similar between the subsets; more frequent discontinuations due to AEs were noted in the ≥70-year subset with everolimus. Conclusions: Combination endocrine therapies involving CDK4/6 or mTOR inhibitors have similar efficacy but vary in tolerability among older and younger patients with HR+, HER2− ABC. [Table: see text]

Vasomotor symptoms resulting from natural menopause: a systematic review and network meta-analysis of treatment effects from the National Institute for Health and Care Excellence guideline on menopause.

Vasomotor symptoms (VMSs) are the hallmarks of menopause, occurring in approximately 75% of postmenopausal women in the UK, and are severe in 25%. To identify which treatments are most clinically effective for the relief of VMSs for women in natural menopause without hysterectomy. English publications in MEDLINE, Embase, and The Cochrane Library up to 13 January 2015 were searched. Randomised controlled trials (RCTs) of treatments for women with a uterus for the outcomes of frequency of VMSs (up to 26 weeks), vaginal bleeding, and discontinuation. Bayesian network meta-analysis (NMA) using mean ratios (MRs) and odd ratios (ORs). Across the three networks, 47 RCTs of 16 treatment classes (n = 8326 women) were included. When compared with placebo, transdermal estradiol and progestogen (O+P) had the highest probability of being the most effective treatment for VMS relief (69.8%; MR 0.23; 95% credible interval, 95% CrI 0.09-0.57), whereas oral O+P was ranked lower than transdermal O+P, although oral and transdermal O+P were no different for this outcome (MR 2.23; 95% CrI 0.7-7.1). Isoflavones and black cohosh were more effective than placebo, although not significantly better than O+P. Not only were selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) found to be ineffective in relieving VMSs, but they also had significantly higher odds of discontinuation than placebo. Limited data were available for bleeding, therefore no conclusions could be made. For women who have not undergone hysterectomy, transdermal O+P was the most effective treatment for VMS relief. Which treatment best relieves menopause flushes? Results from the #NICE guideline network meta-analysis.

The impact of the extent of gastric resection on advanced gastric cancer treated with systemic chemotherapy.

194 Background: In previous clinical trials of adjuvant chemotherapy for gastric cancer, severe toxicity and discontinuation of chemotherapy was more common in patients receiving total gastrectomy (TG) than in those with distal gastrectomy (DG). However, data on the significance of the extent of gastric resection for stage IV gastric cancer treated with systemic chemotherapy are not available. Methods: This is a retrospective review of patients who were received chemotherapy with S-1 and cisplatin for stage IV gastric cancer at our institution between June 2009 and August 2015. The patients were classified into three groups according to the extent of gastrectomy (TG, DG and no gastric resection (NG)) before chemotherapy. Patient characteristics, survival and toxicities of chemotherapy were compared between three groups. Results: Among the 83 patients, 24 underwent TG, 19 DG, and 40 NG. Patient characteristics were well balanced between three groups. There was no significant difference in the requirement for dose reduction between TG, DG and NG patients (29% vs 11% vs 20%, respectively, p= 0.32). However, the rate of discontinuation because of toxicity was significantly higher in TG than in DG or NG patients (46% vs 16% vs 25%, respectively, p= 0.04). The main reasons of discontinuation were anorexia (43%), myelosuppression (23%), nausea (18%) and diarrhea (16%). The median progression-free survival was 8.9, 6.1 and 5.3 months ( p= 0.25), and the median overall survival was 16.0, 16.0 and 9.8 months ( p= 0.40) in the patients with TG, DG and NG, respectively. Conclusions: There was a high frequency of discontinuation of systemic chemotherapy in the advanced gastric cancer patients who underwent TG, but it was not associated with prognosis.

Frequency of discontinuation of injectable osteoporosis therapies in US patients over 2years.

This study was designed to assess the frequency of treatment discontinuation over time among patients who initiate injectable osteoporosis therapies. This retrospective observational study utilized an administrative claims database to measure discontinuation of injectable osteoporosis therapy, reported at 6-month intervals over 2years. Eligible patients were aged ≥55years, had newly initiated injectable osteoporosis therapy between January 2008 and June 2012, and were continuously enrolled in the health plan for ≥1year prior to and ≥1.5years after the date the first injectable medication was received (the index date). Follow-up time ranged from 18 to 24months. Injectable osteoporosis treatments included in the analysis were denosumab, ibandronate, teriparatide, and zoledronic acid. Discontinuation was assessed using Kaplan-Meier survival analysis and was defined at each time point as the percentage of patients who did not receive the dose scheduled for that time point. A 90-day grace period was allowed to accommodate flexibility in the scheduling of post-index re-administrations. Sensitivity analyses assessed discontinuation using grace periods of 60 and 30days. A total of 4756 patients met the inclusion criteria for the study, with 617 utilizing denosumab, 233 ibandronate, 778 teriparatide, and 3128 zoledronic acid. At 12months, discontinuation was highest among patients using ibandronate (69.1%), followed by teriparatide (67.1%), zoledronic acid (59.2%), and denosumab (48.8%). By 24months, discontinuation was higher for each treatment: 87.5% for ibandronate, 87.9% for teriparatide, 79.8% for zoledronic acid, and 64.3% for denosumab. The majority of US patients discontinue injectable osteoporosis treatment by the end of the first year following initiation.

Peripheral Neuropathy (PN) with Immunomodulatory Drugs in Patients with Multiple Myeloma (MM)

Background: PN is a recognized adverse event (AE) with thalidomide (THAL). Despite similarities between THAL and its analogues (lenalidomide [LEN] and pomalidomide [POM]) that include structural, binding target, and common drug-induced substrates, the result of unshared downstream molecular, cellular, and microenvironment effects among the compounds is a diverse array of biological responses and different efficacy and safety outcomes (Bjorklund CC, et al. Blood Cancer J. 2015;5:e354). This underscores the mechanistic diversity of a family of agents rather than the mechanistic uniformity of a therapeutic class. In untreated patients with MM, low incidence (3%-13%) of symptomatic PN has been reported, while the estimated rate was much higher (40%-60%) for subclinical PN (Kwan JY. Neurol Clin. 2007;25:47-69).Objective: To describe the frequency, severity, and tolerability of PN in patients with MM treated with THAL-, LEN-, and POM-based therapy from Celgene-sponsored pivotal and other registrational studies.Methods: AEs of new and worsening PN were analyzed for THAL-, LEN-, and POM-based therapy in 9 randomized clinical trials in 3518 patients with MM. Eight of the 9 clinical trials included patients with baseline grade 1 PN, while 1 clinical trial excluded all patients with PN. The search for PN used narrow-scope Standardised MedDRA Query "peripheral neuropathy." The AEs were rated per NCI-CTCAE.Results: PN was reported more frequently in patients in the THAL-based pool (36.2%; 460/1272) compared with the LEN-based pool (23.2%; 400/1727) and POM-based pool (12.3%; 64/519). Generally, PN was grade 1/2: 27.2% in the THAL-, 19.9% in the LEN-, and 11.4% in the POM-based pool. The frequency of patients with grade 3/4 PN events was 9.0% in the THAL-, 3.2% in the LEN-, and 1.0% in the POM-based pool. The frequencies of patients with serious AEs (SAEs) of PN were low (≤ 1%) for both THAL- and LEN-based pools; no patient had an SAE of PN in the POM-based pool. PN led to THAL-based therapy discontinuation in 7.0% and dose adjustments (reduction, modification, or interruption) in 16.7% of the patients. PN led to LEN-based therapy discontinuation in 0.6%, dose reduction in 2.5%, and interruption in 1.5% of the patients. PN led to POM-based therapy discontinuation in 0.4%, dose reduction in 0.6%, and interruption/reduction in 0.2% of the patients.Conclusions: The frequency and severity of PN and therapy discontinuation or modification is highest in THAL-treated patients with MM compared with LEN- and POM-treated patients. LEN and POM demonstrate improved safety for PN compared with THAL. DisclosuresMezo:Celgene: Employment, Equity Ownership. Castaneda:Celgene: Employment. Weiss:Celgene: Consultancy, Employment, Equity Ownership. Minton:Celgene: Employment, Equity Ownership. Hirsch:Celgene: Employment, Equity Ownership. Renz:Celgene: Employment. Arunagiri:Celgene: Employment. Brown:Celgene: Employment, Equity Ownership. Gambini:Celgene: Employment, Equity Ownership. Peng:Celgene: Employment. Yu:Celgene: Employment, Equity Ownership. Yu:Celgene: Employment. Freeman:Celgene: Employment.

Therapy discontinuation or substitution in patients with cardiovascular disease, switching among different products of the same off-patent active substance: a ‘real-world’ retrospective cohort study

ObjectiveThe present study investigated the effects of switching to different products of the same off-patent active substance (brand name or generic) on therapy discontinuation or substitution with another molecule of...

Short-term open-label chamomile (Matricaria chamomilla L.) therapy of moderate to severe generalized anxiety disorder

BackgroundConventional drug treatments for Generalized Anxiety Disorder (GAD) are often accompanied by substantial side effects, dependence, and/or withdrawal syndrome. A prior controlled study of oral chamomile (Matricaria chamomilla L.) extract showed significant efficacy versus placebo, and suggested that chamomile may have anxiolytic activity for individuals with GAD. HypothesisWe hypothesized that treatment with chamomile extract would result in a significant reduction in GAD severity ratings, and would be associated with a favorable adverse event and tolerability profile. Study designWe report on the open-label phase of a two-phase randomized controlled trial of chamomile versus placebo for relapse-prevention of recurrent GAD. MethodsSubjects with moderate to severe GAD received open-label treatment with pharmaceutical-grade chamomile extract 1500mg/day for up to 8 weeks. Primary outcomes were the frequency of clinical response and change in GAD-7 symptom scores by week 8. Secondary outcomes included the change over time on the Hamilton Rating Scale for Anxiety, the Beck Anxiety Inventory, and the Psychological General Well Being Index. Frequency of treatment-emergent adverse events and premature treatment discontinuation were also examined. ResultsOf 179 subjects, 58.1% (95% CI: 50.9% to 65.5%) met criteria for response, while 15.6% prematurely discontinued treatment. Significant improvement over time was also observed on the GAD-7 rating (β=−8.4 [95% CI=−9.1 to −7.7]). A similar proportion of subjects demonstrated statistically significant and clinically meaningful reductions in secondary outcome ratings of anxiety and well-being. Adverse events occurred in 11.7% of subjects, although no serious adverse events occurred. ConclusionChamomile extract produced a clinically meaningful reduction in GAD symptoms over 8 weeks, with a response rate comparable to those observed during conventional anxiolytic drug therapy and a favorable adverse event profile. Future comparative effectiveness trials between chamomile and conventional drugs may help determine the optimal risk/benefit of these therapies for patients suffering from GAD.

Long-Term Durability of Tenofovir-Based Antiretroviral Therapy in Relation to the Co-Administration of Other Drug Classes in Routine Clinical Practice.

BackgroundIn clinical trials, toxicity leading to tenofovir disoproxil fumarate (TDF) discontinuation is rare (3% by 2 years); however in clinical practice it seems to be higher, particularly when TDF is co-administered with ritonavir-boosted protease inhibitors (PI/r). Aims of this study were to assess the rate of TDF discontinuations in clinical practice and to identify factors associated with the risk of stopping TDF.MethodsAll antiretroviral treatment (ART)-naive patients initiating a TDF-based regimen were selected from the ICONA Foundation Study cohort. The primary outcome was TDF discontinuation regardless of the reason; secondary outcome measures were TDF discontinuation due to toxicity and selective TDF discontinuation (that is, TDF discontinuation or substitution, maintaining unchanged the remaining antiretroviral treatment).Results3,618 ART-naïve patients were included: 54% started a PI/r-based and 46% a NNRTI-based based regimen. Two-hundred-seventy-seven patients discontinued TDF and reintroduced ART within 30 days without TDF. The probability of TDF discontinuation regardless of the reason was of 7.4% (95%CI:6.4–8.5) by 2 years and 14.1% (95%CI:12.2–16.1) by 5 years. The 5-year KM estimates in the PI/r vs. NNRTI group were 20.4% vs. 7.6%, respectively (log-rank p = 0.0001), for the outcome of stopping regardless of the reason, and 10.7% vs. 4.7% (p = 0.0001) for discontinuation due to toxicity. PI/r use and lower eGFR were associated with an increased risk of discontinuing TDF.ConclusionIn our cohort, the frequency of TDF discontinuations was higher than that observed in clinical trials. Co-administration of TDF with PI/r was associated with an increased rate of TDF discontinuations. Further studies are needed to clarify the mechanisms that might have led to this outcome.

Evaluation of Pump Discontinuation and Associated Factors in the T1D Exchange Clinic Registry.

The objectives of this study were to examine factors associated with insulin pump discontinuation among children and adults followed longitudinally for 1 year in the multicenter T1D Exchange clinic registry, and to provide participant-reported reasons for stopping pump therapy. We longitudinally followed 8935 participants of all ages using an insulin pump at the time of registry enrollment. Logistic regressions were used to identify demographic and clinical factors associated with pump discontinuation. Pump discontinuation was self-reported by participants on a first annual follow-up survey. The overall frequency of pump discontinuation was 3%. Discontinuation was higher in adolescents (4%) and young adults (4%) than in younger children (3%) or older adults (1%). In multivariate analysis of children between 6 and <13 and 13 and <18 years, participants who discontinued pump use were more likely to have higher HbA1c levels at baseline (adjusted P < .001 for both). The top participant-reported reasons for discontinuing the pump included problems with wearability (57%), disliking the pump or feeling anxious (44%), and problems with glycemic control (30%). In T1D Exchange registry participants, insulin pump discontinuation is uncommon, but more prevalent among adolescents and young adults, and youth with poor glycemic control. Given the known benefits of pump therapy, these populations should be targeted for support and education on troubleshooting pump use. Common reasons for discontinuation should also be considered in future device design and technological improvement.

Safety and tolerability of long-acting injectable versus oral antipsychotics: A meta-analysis of randomized controlled studies comparing the same antipsychotics

ObjectiveWe aimed to assess whether long-acting injectable antipsychotics (LAIs), which are initiated in a loading strategy or overlapping with oral antipsychotics (OAPs) and which cannot be stopped immediately, are associated with greater safety/tolerability issues than OAPs. MethodSystematic review and meta-analysis of randomized controlled trials (RCTs) comparing LAIs and OAPs, including only LAI-OAP pairs of the same OAP (allowing oral risperidone and paliperidone as comparators for either risperidone or paliperidone LAI). Primary outcome was treatment discontinuation due to adverse events. Secondary outcomes included serious adverse events, death, ≥1 adverse event and individual adverse event rates. ResultsAcross 16 RCTs (n=4902, mean age=36.4years, males=65.8%, schizophrenia=99.1%) reporting on 119 adverse event outcomes, 55 (46.2%) adverse events were reported by ≥2 studies allowing a formal meta-analysis. Out of all 119 reported adverse events, LAIs and OAPs did not differ significantly regarding 115 (96.6%). LAIs were similar to OAPs regarding the frequency of treatment discontinuation due to adverse events, serious adverse events, all-cause death and death for reasons excluding accident or suicide. Compared to OAPs, LAIs were associated with significantly more akinesia, low-density lipoprotein cholesterol change and anxiety. Conversely, LAIs were associated with significantly lower prolactin change. ConclusionLAIs and OAPs did not differ on all serious and >90% of individual adverse events. However, more studies focusing on adverse event frequencies, severity and time course associated with LAI vs OAP formulations of the same antipsychotic are needed. Additionally, adverse events data for LAIs after stopping overlapping oral antipsychotic treatment are needed.

Efficacy and safety of boceprevir based triple therapy in Hungarian patients with hepatitis C genotype 1 infection, advanced stage fibrosis and prior treatment failure

During 2011 and 2013, 155 Hungarian hepatitis C genotype 1 infected patients, mostly with advanced liver fibrosis, who did not respond to prior peginterferon + ribavirin dual therapy, started boceprevir based triple therapy in an early access program. Efficacy and safety of the therapy was retrospectively assessed based on sustained virologic responses, as well as on frequency and type of serious adverse events and of those leading to therapy discontinuation. In an intent-to-treat analysis 39.4% patients (61/155) reached sustained virologic response. Amongst pervious relapsers, partial responders and null-responders 59.5%, 41.4 % and 22.9% (p<0.05 compared to the other two categories) reached sustained virologic response, respectively, while amongst non-cirrhotics and cirrhotics 52.5% and 31.3% (p<0.05 compared to the non-cirrhotics) achieved sutained virologic response, respectively. Six out of the 33 most difficult to cure patients (previous null responder and cirrhotic) have reached sustained virologic response (18.2%). Frequency of early discontinuations due to insufficient virologic response was 31.1%, while due to adverse event 10.3%. Reported frequency of serious adverse event was 9.8%. These events represented anemia, diarrhoea, depression, agranulocytosis, elevated aminotransferases, generalized dermatitis and severe gingivitis with loss of teeth, prolonged QT interval on ECG, generalized oedema and severe dyspnoea, uroinfection, exacerbation of Crohn's disease, Campylobacter pylori infection and unacceptable weakness and fatigue. Eight patients received transfusion, 4 patients erythropoietin and 1 granulocyte colony stimulating factor during therapy. No death has been reported. With boceprevir based triple therapy, one of the bests available in 2011-2013 in Hungary, a relevant proportion of hepatitis C infected patients with advanced liver fibrosis achieved sustained viral response. In this cohort, side-effects resembled those reported in registration studies, and resulted in therapy discontinuation with consequent treatment failure in a relevant number of patients. Efficacy and tolerability of boceprevir-based triple therapy are suboptimal, particularly in the most difficult to cure patient population. Orv. Hetil., 2016, 157(34), 1366-1374.