Crossover Group Research Articles

Long-term denosumab treatment restores cortical bone loss and reduces fracture risk at the forearm and humerus: analyses from the FREEDOM Extension cross-over group

SummaryUpper limb fractures (including wrist, forearm, and humerus) represent a significant burden among postmenopausal women with osteoporosis. Up to 7 years of treatment with denosumab resulted in an increase in bone mineral density and decrease in fractures in upper limb sites.IntroductionUpper limb (wrist, forearm, and humerus) fractures are a significant burden in osteoporosis, associated with significant morbidity and mortality. Denosumab, a monoclonal antibody against RANK ligand, increases bone mineral density (BMD) and decreases vertebral, nonvertebral, and hip fractures. Here, we evaluated the long-term effect of denosumab treatment on upper limb fracture risk and BMD.MethodsIn the FREEDOM trial, subjects were randomized 1:1 to receive every-6-month denosumab 60 mg or placebo subcutaneously for 3 years, after which all subjects could receive denosumab for up to 7 years (Extension). Among placebo subjects who completed FREEDOM and enrolled in the Extension, wrist, forearm, humerus, and upper limb fracture rates and rate ratios between different time periods (FREEDOM years 1–3, Extension years 1–3, and Extension years 4–7) were computed. BMD at the ultradistal radius, 1/3 radius, and total radius was analyzed in a subset of subjects in a BMD substudy.ResultsThis analysis included 2207 subjects (116 in the BMD substudy). Fracture rates decreased over the 7-year Extension; fracture rate ratios between Extension years 4–7 (denosumab) and FREEDOM years 1–3 (placebo) reduced significantly for the wrist (0.57), forearm (0.57), humerus (0.42), and upper limb (0.52; p < 0.05 for all). Percentage increase in BMD from Extension baseline at the ultradistal radius, 1/3 radius, and total radius was significant by Extension year 7 (p < 0.05 for all).ConclusionsLong-term treatment with denosumab decreases upper limb fracture risk and increases forearm BMD, suggesting beneficial effects on both cortical and trabecular bone accruing over time.

Twelve-month analgesia and rescue, by cooled radiofrequency ablation treatment of osteoarthritic knee pain: results from a prospective, multicenter, randomized, cross-over trial

Background and objectivesAs a follow-up to the 6-month report,12 this study investigated the analgesic effect of cooled radiofrequency ablation (CRFA) in patients with knee osteoarthritis (OA) 12 months postintervention and...

Leucocyte-Rich Platelet-Rich Plasma Treatment of Gluteus Medius and Minimus Tendinopathy: A Double-Blind Randomized Controlled Trial With 2-Year Follow-up

Background: A previously published trial showed that patients with chronic gluteal tendinopathy achieved greater clinical improvement at 12 weeks when treated with a single platelet-rich plasma (PRP) injection than those treated with a single corticosteroid injection (CSI). Purpose: This follow-up study was conducted to determine whether there would be a sustained long-term difference in the modified Harris Hip Score (mHHS) at 2 years for a leucocyte-rich PRP (LR-PRP) injection in the treatment of chronic gluteal tendinopathy. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: This trial included 80 patients randomized 1:1 to receive LR-PRP or CSI intratendinously under ultrasound guidance. Patients had a mean age of 60 years, a 9:1 ratio of women to men, a mean body mass index of 27, and a mean length of symptoms >15 months. No patients had full-thickness tears of the gluteal tendons. An open-labeled extension allowed patients to receive crossover treatment after 3 months. The main outcome measure was the mHHS. Results: The mean mHHS improved significantly at 12 weeks in the PRP group (74.05; SD, 13.92) as compared with the CSI group (67.13; SD, 16.04) (P = .048). At 24 weeks, the LR-PRP group (77.60; SD, 11.88) improved further than the CSI group (65.72; SD, 15.28; P = .0003). Twenty-seven patients were deemed to have failed the CSI treatment at 16 to 24 weeks, with an exit score of 59.22 (SD, 11.54), and then had treatment with LR-PRP. The crossover group improved with the LR-PRP: from 59.22 (SD, 11.22) at baseline to 75.55 (SD, 16.05) at 12 weeks, 77.69 (SD, 15.30) at 24 weeks, and 77.53 (SD, 14.54) at 104 weeks. The LR-PRP group retained 38 of 39 patients to 52 weeks and continued to improve. Their baseline scores of 53.77 (SD, 12.08) improved to 82.59 (SD, 9.71) at 104 weeks (P < .0001). Conclusion: Among patients with chronic gluteal tendinopathy and a length of symptoms >15 months, a single intratendinous LR-PRP injection performed under ultrasound guidance results in greater improvement in pain and function than a single CSI. The improvement after LR-PRP injection is sustained at 2 years, whereas the improvement from a CSI is maximal at 6 weeks and not maintained beyond 24 weeks. Registration: ACTRN12613000677707 (Australian New Zealand Clinical Trials identifier).

Describing Research Design

This article explains how the research design of a study can simultaneously be described in many different ways as nonempirical or empirical, case-based or sample-based, observational or interventional, retrospective or prospective, cross-sectional or longitudinal, uncontrolled or controlled, single arm or multiple arm, nonrandomized or randomized, crossover or parallel group, nonblind, single-blind, or double-blind, superiority or noninferiority, exploratory (hypothesis generating) or confirmatory (hypothesis driven), and many others. Some of these categories can be associated with special types of research design as well, such as cohort studies, case-control studies, nested case-control studies, wedge design studies, and so on. Readers should understand which descriptors are mutually exclusive and which are not.

Role of various small group teaching methods in enhancing learning among medical undergraduate students - A comparative study

Background: Small group teaching (SGT) has grown in popularity in medical education as it offers a dynamic setting for learning and it is also learner centered. Aim and Objectives: The aim of the study was (1) to compare the effectiveness of various SGT methods in enhancing students learning and (2) to assess the students perception on different small group learning methods. Materials and Methods: Sixty second year MBBS students who gave informed consent were divided randomly into five small groups of 12 each namely buzz groups, fishbowl structure, crossover group, circular group, and horseshoe group. The individual facilitator was priorly trained and assigned to each group to discuss the given clinical scenario and motivate them. Pre- and post-assessments were done based on multiple-choice questions. Students perception on different small group learning methods was evaluated based on five-point Likert scale. Data analyzed in SPSS software version 23 using paired t-test and ANOVA with Scheffe (post hoc). Results: There was a significant difference in pretest and post-test mean scores in each group (P < 0.01) and also in the mean gain between the groups (P < 0.01). Gain in performance in post-test was high in circular group (4.08) followed by fishbowl (3.50) and crossover (3.50). Small group tutorial teaching was agreed on by students and the faculties as more effective. About 88% in horseshoe, 85% in fishbowl reported that their technique improved their confidence level. About 93% of buzz group and 82% of horseshoe group students were able to identify their competency gaps. Conclusion: Case scenarios should be included in all teaching-learning sessions to help to generate interest. Future avenues for research analysis of different SGTs and student-teacher perceptions across the educational continuum including undergraduate, postgraduate, and continuing professional education can be initiated.

RANDOMIZED, PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY, SAFETY, AND TOLERABILITY OF BENZOCAINE WIPES IN SUBJECTS WITH PREMATURE EJACULATION

AimThis study investigated the efficacy and safety of benzocaine wipes (PREBOOST) applied to the penis prior to intercourse for the treatment of men with premature ejaculation.Materials and methodsThe study utilized the local anesthetic benzocaine, in the form of wipes, for topical application to the glans penis prior to sexual intercourse. The design included three phases: screening and baseline, blinded randomized controlled, and an open-label phase with crossover of the placebo group to open-label active treatment. The two co-primary efficacy measures were the intravaginal ejaculatory latency time (IELT) measured by stopwatch, and the patient-reported outcome measured by the Index of Premature Ejaculation (IPE). Additional efficacy evaluation included a responder analysis using a predetermined 120s improvement in IELT as a responder threshold. Safety evaluation included patient-reported events along with a physical examination. ResultsThe treatment phase showed a statistically significant increase from the baseline, in the treatment group (mean 165s) compared with the placebo group (mean 110s), P<0.007. After the second month of use, the treatment group had a mean IELT of 329.70s (±21.37 SE) in comparison to the placebo group which had a mean IELT of 110.10s (±9.90 SE) (P=0.001). The open-label phase showed further increase in IELT in the treatment group and a statistically significant increase in IELT in the placebo/ crossover group. Using the IPE, the men in the treatment group reported significantly higher sexual satisfaction (P=0.047) and greater improvement in distress (P=0.020) with a trend toward improve-ment in the ejaculatory control domain scores (P=0.093). The responder analysis showed a statisti-cally significant response to the use of benzocaine versus placebo, attesting an IELT increase that was clinically meaningful. Benzocaine wipes were well tolerated by subjects and partners.ConclusionThis randomized, placebo controlled clinical trial with crossover design showed that benzocaine wipes applied topically to the penis prior to sexual intercourse had a statistically significant prolongation of time to ejaculation, a clinically meaningful benefit, in the treatment of premature ejaculation. Furthermore, benzocaine wipes were well tolerated by the subjects and no evidence of transference to their female partners.

A specific protocol of autologous bone marrow concentrate and platelet products versus exercise therapy for symptomatic knee osteoarthritis: a randomized controlled trial with 2\xa0year follow-up

BackgroundCell-based therapies have shown promise for the treatment of knee osteoarthritis (OA). The current study compared exercise therapy to autologous bone marrow concentrate (BMC) and platelet products for knee OA treatment.MethodsPatients with symptomatic knee OA (N = 48) were randomized into either an exercise therapy control group or treatment group with injection of autologous BMC and platelet products. Patients in the control group could crossover to BMC treatment after 3 months. Clinical outcomes were documented at baseline and at 6-weeks, 3, 6, 12 and 24 months, including the Knee Society Score (KSS), Pain Visual Analogue Scale, Short Form-12 Scales (SF-12), and Lower Extremity Activity Scale (LEAS).ResultsAll patients in the exercise group crossed over to receive BMC treatment after 3 months (N = 22 crossover). At 3 months, KSS-knee, SF-12 Physical, and LEAS improved significantly in the crossover group compared to exercise, similar to significant improvements on KSS-knee and LEAS for the treatment group (N = 26) compared to exercise group at 3 months. After BMC treatment, patients’ clinical outcome scores (except SF-12 Mental Health), were significantly improved through the 2-year follow-up compared to baseline. No serious adverse events were reported.ConclusionThe use of image-guided percutaneous BMC with platelet products yielded better results than exercise therapy as an effective alternative therapy for patients with symptomatic moderate to moderate-severe osteoarthritis of the knee.Trial registration NCT02034032. https://clinicaltrials.gov/ct2/show/NCT02034032. Registered 13 January 2014

Electronic Version of the EQ-5D Quality-of-Life Questionnaire: Adaptation to a Brazilian Population Sample

ObjectivesTo assess the measurement equivalence of the original paper version of an adapted tablet version of the EuroQol five-dimensional questionnaire (EQ-5D). MethodsA randomly selected sample of 509 individuals aged 18 to 64 years from the general population responded to the EQ-5D at two time points separated by a minimum interval of 24 hours and were allocated to one of the following groups: test-retest group (tablet-tablet) or crossover group (paper-tablet and tablet-paper). Agreement between methods was determined using the intraclass correlation coefficient (ICC) and the κ coefficient. ResultsIn the crossover group, the following ICC values were obtained: 0.76 (confidence interval [CI] 0.58–0.89) for EQ-5D scores and 0.77 (CI 0.68–0.84) for visual analogue scale in subjects responding first to the tablet version; 0.83 (CI 0.75–0.89) for EQ-5D scores and 0.75 (CI 0.67–0.85) for visual analogue scale in subjects responding first to the paper version. In the test-retest group, the ICC was 0.85 (CI 0.73–0.91) for EQ-5D scores and 0.79 (CI 0.66–0.87) for visual analogue scale. The κ values were higher than 0.69 in this group. The internal consistencies of the paper and tablet methods were similar. ConclusionsThe paper and tablet versions of the EQ-5D are equivalent. Test-retest and crossover agreement was high and the acceptability of the methods was similar among individuals.

Analysis of energy management strategies for hybrid electric vehicles in urban driving conditions

The pursuit of fuel consumption reduction by vehicles leads to a sudden increase in the share of hybrid and electric drives in the vehicle market. Replacing hybrid vehicles with electric vehicles requires long-term technological solutions, both for the infrastructure and the vehicles themselves. Therefore, one of the leading types of passenger car drives is currently the hybrid drive. The generated work share of electric drives used to power hybrid vehicles is a determinant of the viability of using electric drives. The article estimates the operating time share of electric and hybrid modes operation in real driving conditions (RDC) based on the latest Toyota hybrid model. The research object was a vehicle from the crossover group equipped with a fourth generation hybrid drive. Analysis of the drives operation allowed to determine the conditions of energy flow and determine the work share of the electric drive in the total driving time.

Rehabilitation of stroke patients with plegic hands: Randomized controlled trial of expanded Constraint-Induced Movement therapy.

To evaluate the efficacy of an expanded form of Constraint-Induced Movement Therapy (eCIMT) that renders CIMT, originally designed for treating mild-to-moderate upper-extremity hemiparesis, suitable for treating severe hemiparesis. Twenty-one adults ≥1 year after stroke with severe upper-extremity hemiparesis (with little or no capacity to make movements with the more-affected hand) were randomly assigned to eCIMT (n = 10), a placebo-control procedure (n = 4), or usual care (n = 7). The participants who received usual care were crossed over to eCIMT four months after enrollment. The CIMT protocol was altered to include fitting of orthotics and adaptive equipment, selected neurodevelopmental techniques, and electromyography-triggered functional electrical stimulation. Treatment was given for 15 consecutive weekdays with 6 hours of therapy scheduled daily for the immediate eCIMT group and 3.5 hours daily for the cross-over eCIMT group. At post-treatment, the immediate eCIMT group showed significant gains relative to the combination of the control groups on the Grade-4/5 Motor Activity Log (MAL; mean = 1.5 points, P < 0.001, f = 4.2) and a convergent measure, the Canadian Occupational Performance Measure (COPM; mean = 2.3, P = 0.014, f = 1.1; f values ≥0.4 are considered large, on the COPM changes ≥2 are considered clinically meaningful). At 1-year follow-up, the MAL gains in the immediate eCIMT group were only 13% less than at post-treatment. The short and long-term outcomes of the crossover eCIMT group were similar to those of the immediate eCIMT group. This small, randomized controlled trial (RCT) suggests that eCIMT produces a large, meaningful, and persistent improvement in everyday use of the more-affected arm in adults with severe upper-extremity hemiparesis long after stroke. These promising findings warrant confirmation by a large RCT.

Fexapotide triflutate: results of long-term safety and efficacy trials of a novel injectable therapy for symptomatic prostate enlargement

PurposeThese studies were undertaken to determine if fexapotide triflutate 2.5 mg transrectal injectable (FT) has significant long-term (LT) safety and efficacy for the treatment of benign prostatic hyperplasia (BPH).MethodsTwo placebo controlled double-blind randomized parallel group trials with 995 BPH patients at 72 sites treated 3:2 FT:placebo, with open-label FT crossover (CO) re-injection in 2 trials n = 344 and long-term follow-up (LF) 2–6.75 years (mean 3.58 years, median 3.67 years; FT re-injection CO mean 4.27 years, median 4.42 years) were evaluated. 12 months post-treatment patients elected no further treatment, approved oral medications, FT, or interventional treatment. Primary endpoint variable was change in Symptom Score (IPSS) at 12 months and at LF. CO primary co-endpoints were 3-year incidence of (1) surgery for BPH in FT treated CO patients versus patients crossed over to oral BPH medications and (2) surgery or acute urinary retention in FT-treated CO placebo patients versus placebo patients crossed over to oral BPH medications. 28 CO secondary endpoints assessed surgical and symptomatic outcomes in FT reinjected patients versus conventional BPH medication CO and control subgroups at 2 and 3 years.ResultsFT injection had no significant safety differences from placebo. LF IPSS change from baseline was higher in FT treated patients compared to placebo (median FT group improvement − 5.2 versus placebo − 3.0, p < 0.0001). LF incidence of AUR (1.08% p = 0.0058) and prostate cancer (PCa) (1.1% p = 0.0116) were both reduced in FT treated patients. LF incidence of intervention for BPH was reduced in the FT group versus oral BPH medications (8.08% versus 27.85% at 3 years, p < 0.0001). LF incidence of intervention or AUR in placebo CO group with FT versus placebo CO group with oral medications was reduced (6.07% versus 33.3% at 3 years, p < 0.0001). 28/28 secondary efficacy endpoints were reached in LF CO re-injection studies.ConclusionsFT 2.5 mg is a safe and effective transrectal injectable for LT treatment of BPH. FT treated patients also had reduced need for BPH intervention, and reduced incidence of PCa and AUR.

The effects of yoga on stress and psychological health among employees: an 8- and 16-week intervention study

ABSTRACTBackground: The stresses of modern work life necessitate effective coping strategies that are accessible and affordable to the general public. Yoga has been found to reduce stress in clinical samples, but studies are needed to examine standard gym yoga classes among functional individuals.Objectives: This study investigated the effects of 8- and 16-week gym yoga on stress and psychological health.Design and Method: Ninety individuals reporting moderate-to-high stress were randomly assigned to 16 consecutive weeks of yoga, or to a waitlist crossover group who did not practice yoga for 8 weeks then practiced yoga for 8 weeks. Stress and psychological health variables were assessed at baseline, 8 weeks, and 16 weeks.Results: Significant reductions in stress and all psychological health measures were found within the Yoga group over 16 weeks. When compared to the control group, yoga practitioners showed significant decreases in stress, anxiety, and general psychological health, and significant increases in well-being. The group who did not practice yoga showed significant decreases in stress, anxiety, depression, and insomnia after they crossed over and practiced yoga for 8 weeks.Conclusions: Gym yoga appears to be effective for stress amelioration and promotion of psychological health among workers experiencing stress.

Predictive Factors for Patients Undergoing ASD Device Occlusion Who "Crossover" to Surgery.

The aim of this study was to define characteristics of those patients who are referred for device closure of an Atrial septal defect (ASD), but identified to "crossover" surgery. All patients who underwent surgical and device (Amplatzer or Helex occluder) closures of secundum ASDs from 2001 to 2010 were reviewed and organized into three groups: surgical closure, device closure, and "crossover" group. 369 patients underwent ASD closure (265 device, 104 surgical). 42 of the 265 patients referred for device closure "crossed over" to the surgical group at various stages of the catheterization procedure. The device group had defect size measuring 14.2mm (mean) and an ASD index (Defect Size (mm)/BSA) of 14.0 compared to the corresponding values in the surgical group (20.1mm, ASD index 25.9) (P<0.001) and in the "crossover" group (20.7mm, 22.6 ASD index) (P<0.001). 79 patients in the device group had a deficient rim, and 86% were located in the retroaortic region. 33 patients in the "crossover" group had deficient rims with 70% deficiency in the posterior/inferior rim. The device group with deficient rims had an ASD index of 14.7 compared with the crossover group ASD index of 23.8 (P<0.001). Comparing the device and "crossover" groups, an ASD index greater than 23.7 had a 90% specificity in "crossing over" to surgery. The crossover and surgical groups had statistically larger ASD defect size indexes compared with the device group. Deficient rim in the posterior/inferior rim is associated with a large ASD size index which is a predictive factor for crossing over to surgery. Catheterization did not negatively impact surgical results in the "crossover" group.

Enteric-coated mycophenolate sodium in the treatment of non-infectious intermediate uveitis: results of a prospective, controlled, randomised, open-label, early terminated multicentre trial

Background/aimsTo evaluate the efficacy, safety and tolerability of enteric-coated mycophenolate sodium (EC-MPS) in combination with low-dose corticosteroids compared with a monotherapy with low-dose corticosteroids in subjects with non-infectious intermediate uveitis...

The Impact of Treatment Preferences in Second-Line Chemotherapy on the Prognosis of HER2-Negative Metastatic Breast Cancer

Objective: We assessed the impact of treatment preferences in second-line chemotherapy on breast cancer prognosis using the SELECT BC study. Methods: The SELECT BC study was performed in patients with HER2-negative metastatic breast cancer treated with initial chemotherapy. From these patients, 618 were assigned to 2 groups (S-1 group, 309; taxane group, 309). The S-1 and taxane groups were each subdivided into 3 groups: crossover group, protocol-recommended group, and other group, and the analysis of overall survival (OS) was performed using Cox regression with inverse probability weighting, to adjust for postrandomization confounding. Results: In the taxane group, the OS of the crossover group (39.6 months) was better than that of the protocol-recommended group (35.7 months) and the other chemotherapy group (36.9 months) (vs. the protocol-recommended group, HR 0.72 [95% CI 0.52-0.98], p = 0.037; vs. the other chemotherapy group, HR 0.71 [95% CI 0.43-1.18], p = 0.183). In the S-1 group, there was no statistically significant difference in OS between the 3 groups. Conclusion: The study of the combination of first-line chemotherapy and second-line chemotherapy showed that S-1 might be recommended as a second-line chemotherapy in patients in whom taxane was the primary chemotherapy.

Clinical outcomes of left main crossover stenting for ostial left anterior descending artery acute myocardial infarction.

Percutaneous coronary interventions to ostial left anterior descending artery (LAD)-acute myocardial infarction (AMI) were challenging, especially in crossover stenting from left main trunk (LMT) to LAD. The clinical outcomes of ostial LAD-AMI that needed crossover stenting were not well investigated. The objective of this study was to compare the clinical outcomes of LMT crossover stenting with those of ostial LAD just proximal (jp) stenting. Between January 2009 and March 2016, 1499 patients were diagnosed as AMI in our institution. Among them, 76 ostial LAD-AMIs were included in this study, and divided into 30 LMT crossover stenting (the crossover group) and 46 jp stenting (the jp stenting group). The primary endpoint was major cardiovascular events (MACE) defined as the composite of cardiac death, acute myocardial infarction (AMI), stent thrombosis (ST), target lesion revascularization (TLR) and target vessel revascularization (TVR). The frequency of MACE was comparable between the 2 groups (16.7% in the crossover group and 21.7% in the jp stenting group, P=0.587). Similarly, the frequency of cardiac death was comparable between the 2 groups (6.7% in the crossover group and 13.0% in the jp stenting group, P=0.376). The frequencies of TLR (6.7% in the crossover group and 6.5% in the jp stenting group, P=0.980) and TVR (10.0% in the crossover group and 8.7% in the jp stenting group, P=0.848) were not significantly different between the 2 groups. In conclusion, the clinical outcomes of the crossover stenting were comparable to the jp stenting in the stenting strategy for ostial LAD-AMI. LMT-LAD crossover stenting would be the acceptable strategy for ostial LAD-AMI.

Effect of catheter size and injection rate of contrast agent on enhancement and image quality for triple-phase helical computed tomography of the liver in small dogs.

Rapid contrast injection is recommended for triple-phase helical computed tomography (CT) of the liver. However, a large-gauge catheter is needed for faster contrast injection and this is not practical for small breed dogs or cats. The purpose of this crossover group study was to evaluate applicability of a lower injection rate with a small-gauge (G) catheter for triple-phase hepatic CT in small dogs. Triple-phase CT images were acquired for six beagle dogs using three protocols: an injection rate of 1.5 ml/s with a 24 G catheter, 3.0 ml/s with a 22 G catheter, and 4.5 ml/s with a 20 G catheter. Enhancement of the aorta, portal vein, and hepatic parenchyma was measured in each phase (arterial, portal, and delayed) and image quality was scored subjectively by two observers. Injection duration, time to scan delay, and time to peak enhancement were also recorded. Contrast injection duration decreased with a higher injection rate (n = 6, P ≤ 0.01), but time to peak enhancement and time to scan delay were not significantly affected by injection rates and catheter sizes. Contrast injection rate did not significantly affect aortic, portal, and hepatic enhancement. In addition, separation between each phase and quality of images was subjectively scored as good regardless of injection rate. Findings from the current study supported using an injection rate of 1.5 ml/s with a catheter size of 24 G for triple-phase hepatic CT in small dogs (weight < 12 kg).

Long-term vagal stimulation for heart failure: Eighteen month results from the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) trial

BackgroundThe NECTAR-HF study evaluated safety and feasibility of vagal nerve stimulation (VNS) for the treatment of heart failure patients. The first six-month randomized phase of the study did not show improvement in left ventricular remodelling in response to VNS. This study reports the 18-month results and provides novel findings aiming to understand the lack of efficacy of VNS, including a new technique assessing the effects of VNS. MethodsNinety-six patients were randomized 2:1 to active or inactive VNS for 6months, thereafter VNS was activated for all patients. The primary safety endpoint was 18-month all-cause mortality. ResultsNinety-one patients continued in the long-term evaluation with active VNS. The on-therapy survival estimate at 18months was 95% with a 95% one-sided lower confidence limit of 91%, (better than the predefined criterion).Left ventricular systolic volume decreased in the crossover group (VNS OFF→ON; 144±37 to 139±40, p<0.05) after VNS activation; LVESD (5.02±0.77 to 4.96±0.82, p>0.05) and LVEF (33.2±4.9 to 33.3±6.5, p>0.05) did not change.A new technique to detect subtle heart rate changes during Holter recordings, i.e. “heat maps”, revealed that VNS evoked heart rate response in only 13/106 studies (12%) at 6 and 12months with active VNS. ConclusionsAlthough a favourable long-term safety profile was found, improvements in the efficacy endpoints were not seen with VNS. A new technique for detecting acute heart rate responses to VNS suggests that the recruitment of nerve fibres responsible for heart rate changes were substantially lower in NECTAR-HF than in pre-clinical models.

10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension

Long-term safety and efficacy of osteoporosis treatment are important because of the chronic nature of the disease. We aimed to assess the long-term safety and efficacy of denosumab, which is widely used for the treatment of postmenopausal women with osteoporosis. In the multicentre, randomised, double-blind, placebo-controlled, phase 3 FREEDOM trial, postmenopausal women aged 60-90 years with osteoporosis were enrolled in 214 centres in North America, Europe, Latin America, and Australasia and were randomly assigned (1:1) to receive 60 mg subcutaneous denosumab or placebo every 6 months for 3 years. All participants who completed the FREEDOM trial without discontinuing treatment or missing more than one dose of investigational product were eligible to enrol in the open-label, 7-year extension, in which all participants received denosumab. The data represent up to 10 years of denosumab exposure for women who received 3 years of denosumab in FREEDOM and continued in the extension (long-term group), and up to 7 years for women who received 3 years of placebo and transitioned to denosumab in the extension (crossover group). The primary outcome was safety monitoring, comprising assessments of adverse event incidence and serious adverse event incidence, changes in safety laboratory analytes (ie, serum chemistry and haematology), and participant incidence of denosumab antibody formation. Secondary outcomes included new vertebral, hip, and non-vertebral fractures as well as bone mineral density (BMD) at the lumbar spine, total hip, femoral neck, and one-third radius. Analyses were done according to the randomised FREEDOM treatment assignments. All participants who received at least one dose of investigational product in FREEDOM or the extension were included in the combined safety analyses. All participants who enrolled in the extension with observed data were included in the efficacy analyses. The FREEDOM trial (NCT00089791) and its extension (NCT00523341) are both registered with ClinicalTrials.gov. Between Aug 3, 2004, and June 1, 2005, 7808 women were enrolled in the FREEDOM study. 5928 (76%) women were eligible for enrolment in the extension, and of these, 4550 (77%) were enrolled (2343 long-term, 2207 crossover) between Aug 7, 2007, and June 20, 2008. 2626 women (1343 long-term; 1283 crossover) completed the extension. The yearly exposure-adjusted participant incidence of adverse events for all individuals receiving denosumab decreased from 165·3 to 95·9 per 100 participant-years over the course of 10 years. Serious adverse event rates were generally stable over time, varying between 11·5 and 14·4 per 100 participant-years. One atypical femoral fracture occurred in each group during the extension. Seven cases of osteonecrosis of the jaw were reported in the long-term group and six cases in the crossover group. The yearly incidence of new vertebral fractures (ranging from 0·90% to 1·86%) and non-vertebral fractures (ranging from 0·84% to 2·55%) remained low during the extension, similar to rates observed in the denosumab group during the first three years of the FREEDOM study, and lower than rates projected for a virtual long-term placebo cohort. In the long-term group, BMD increased from FREEDOM baseline by 21·7% at the lumbar spine, 9·2% at total hip, 9·0% at femoral neck, and 2·7% at the one-third radius. In the crossover group, BMD increased from extension baseline by 16·5% at the lumbar spine, 7·4% at total hip, 7·1% at femoral neck, and 2·3% at one-third radius. Denosumab treatment for up to 10 years was associated with low rates of adverse events, low fracture incidence compared with that observed during the original trial, and continued increases in BMD without plateau. Amgen.

Influence of subject discontinuation on long-term nonvertebral fracture rate in the denosumab FREEDOM Extension study

BackgroundDenosumab treatment for up to 8 years in the FREEDOM study and Extension was associated with low fracture incidence. It was not clear whether subjects who discontinued during the study conduct had a higher risk of fracture than those who remained enrolled, thereby underestimating the true fracture risk for the entire trial cohort. Thus, we explored the influence of early withdrawals on nonvertebral fracture incidence during the Extension study.MethodsTo understand the potential effect of depletion of susceptible subjects on fracture incidence, we first evaluated subject characteristics in patients who were enrolled in the Extension vs those who were not. We subsequently employed a Kaplan-Meier multiple imputation (KMMI) approach to consider subjects who discontinued as if they remained enrolled with a 0%, 20%, 50%, and 100% increase in fracture risk compared with participants remaining on study.ResultsExtension enrollees were generally similar to nonparticipants in median age (71.9 and 73.1 years, respectively), mean total hip bone mineral density T-score (–1.9 and –2.0, respectively), and probability of fracture risk by Fracture Risk Assessment Tool (FRAX®) at FREEDOM baseline (16.9% and 17.7% for major osteoporotic fracture and 6.7% and 7.4% for hip fracture, respectively). When we assumed a doubled fracture risk (100% increase) after discontinuation in KMMI analyses, nonvertebral fracture rate estimates were only marginally higher than the observed rates for both the crossover group (10.32% vs 9.16%, respectively) and the long-term group (7.63% vs 6.63%, respectively).ConclusionThe observation of continued denosumab efficacy over 8 years of treatment was robust and does not seem to be explained by depletion of susceptible subjects.Trial registrationClincalTrials.gov registration number NCT00523341; registered August 30, 2007