Between-group Difference In Mean Change Research Articles

Is radial extracorporeal shock wave therapy (rESWT), sham-rESWT or a standardised exercise programme in combination with advice plus customised foot orthoses more effective than advice plus customised foot orthoses alone in the treatment of plantar fasciopathy? A double-blind, randomised, sham-controlled trial

ObjectivesTo assess whether radial extracorporeal shock wave therapy (rESWT), sham-rESWT or a standardised exercise programme in combination with advice plus customised foot orthoses is more effective than advice plus customised...

Ketamine Compared With Morphine for Out-of-Hospital Analgesia for Patients With Traumatic Pain

Pain is a common out-of-hospital symptom among patients, and opioids are often prescribed. Research suggests that overprescribing for acute traumatic pain is still prevalent, even when limits restricting opioid prescriptions have been implemented. Ketamine hydrochloride is an alternative to opioids in adults with out-of-hospital traumatic pain. To assess the noninferiority of intravenous ketamine compared with intravenous morphine sulfate to provide pain relief in adults with out-of-hospital traumatic pain. The Intravenous Subdissociative-Dose Ketamine Versus Morphine for Prehospital Analgesia (KETAMORPH) study was a multicenter, single-blind, noninferiority randomized clinical trial comparing ketamine hydrochloride (20 mg, followed by 10 mg every 5 minutes) with morphine sulfate (2 or 3 mg every 5 minutes) in adult patients with out-of-hospital trauma and a verbal pain score equal to or greater than 5. Enrollment occurred from November 23, 2017, to November 26, 2022, in 11 French out-of-hospital emergency medical units. Patients were randomly assigned to ketamine (n = 128) or morphine (n = 123). The primary outcome was the between-group difference in mean change in verbal rating scale pain scores measured from the time before administration of the study drug to 30 minutes later. A noninferiority margin of 1.3 was chosen. A total of 251 patients were randomized (median age, 51 [IQR, 34-69] years; 111 women [44.9%] and 140 men [55.1%] among the 247 with data available) and were included in the intention-to-treat population. The mean pain score change was -3.7 (95% CI, -4.2 to -3.2) in the ketamine group compared with -3.8 (95% CI, -4.2 to -3.4) in the morphine group. The difference in mean pain score change was 0.1 (95% CI, -0.7 to 0.9) points. There were no clinically meaningful differences for vital signs between the 2 groups. The intravenous morphine group had 19 of 113 (16.8% [95% CI, 10.4%-25.0%]) adverse effects reported (most commonly nausea [12 of 113 (10.6%)]) compared with 49 of 120 (40.8% [95% CI, 32.0%-49.6%]) in the ketamine group (most commonly emergence phenomenon [24 of 120 (20.0%)]). No adverse events required intervention. In the KETAMORPH study of patients with out-of-hospital traumatic pain, the use of intravenous ketamine compared with morphine showed noninferiority for pain reduction. In the ongoing opioid crisis, ketamine administered alone is an alternative to opioids in adults with out-of-hospital traumatic pain. ClinicalTrials.gov Identifier: NCT03236805.

The Effect of Family Nursing Conversations as an Add-on to Multidisciplinary Treatment in Patients with Chronic Non-Cancer Pain: A Quasi-Experimental Trial.

Chronic non-cancer pain (CNCP) is a lifelong condition with radical consequences, calling for management involving patients' families. Interventions based on the family systems nursing framework by Wright and Leahey have proved beneficial in other populations but require investigation in a CNCP population. This trial assumed that family nursing conversations (FNCs) based on the family systems nursing framework would increase patients' and family members' self-efficacy concerning CNCP management. To investigate whether an intervention with FNCs as an add-on to the usual multidisciplinary treatment of CNCP would have an effect on patients' and family members' self-efficacy. Additionally, to investigate any impact on family function, health-related quality of life, anxiety, and depression. The trial applied a prospective non-blinded quasi-experimental design with two comparable groups of patients and family members: a historical control group (HCG) and an intervention group (IG). The intervention was executed by nurses employed at a multidisciplinary pain center in the Capital Region of Denmark. HCG data were collected before the nurses' intervention training. The primary outcome was self-efficacy. Secondary outcomes were family function, health-related quality of life, anxiety, and depression. In total, 58 patients and 85 family members were included. The primary outcome, self-efficacy, detected no statistically significant between-group differences in mean change for patients, p = .990, or family members, p = .765. A statistically significant effect in favor of the IG was found in between-group differences in mean change in patients' behavioral family function, p = .034, and anxiety, p = .031. No statistically significant between-group differences were detected in family members' secondary outcomes. The intervention had no effect on patients' or family members' self-efficacy but a positive effect on patients' behavioral family function and anxiety. The intervention was deeply affected by the COVID-19 pandemic. Hence, any results should be interpreted with caution.

Evaluation of a Modified Mindfulness-Based Stress Reduction Intervention for Adults with Cerebral Palsy and Anxiety and/or Emotion Regulation Difficulties-A Randomised Control Trial.

Mindfulness-Based Stress Reduction (MBSR) has not yet been evaluated for people with cerebral palsy (CP). The aims of this randomised control trial were to investigate whether a modified telehealth MBSR program could improve mindfulness and reduce depression, anxiety, and emotion regulation difficulties among adults with CP with elevated anxiety and/or emotional regulation difficulties. Participants (n = 31) with elevated anxiety and/or emotion regulation difficulties and no/mild intellectual impairment were randomised to a modified telehealth MBSR program (90 min weekly, 9 weeks) group or a wait-list group. Measurements were collected prior to (T1), after (T2), and 8 weeks post-intervention (T3). The primary outcome was the mean between-group difference in the change in Cognitive and Affective Mindfulness Scale-R (CAMS-R) scores in T1-T2. The secondary outcomes included mean within-group differences over time for the CAMS-R total scores, Depression Anxiety and Stress Scale-21 subscales, and Difficulties in Emotion Regulation Scale (DERS) total t-score. We found no statistically significant between-group difference in mean change in mindfulness scores for T1-T2 (primary outcome). Secondary outcomes: The MBSR intervention group had improved CAMS-R scores with respect to T1-T2 and T1-T3; improved mean scores for Depression and Stress subscales for T1-T2; and improved DERS t-scores for T1-T2 and T1-T3. In conclusion, this study found no significant between-group difference for the primary outcome of mindfulness. The MBSR program was successfully modified for adults with CP and was effective in improving depression, stress, and emotion regulation. ACTRN12621000960853.

Advanced Hybrid Closed Loop in Adult Population With Type 1 Diabetes: A Substudy From the ADAPT Randomized Controlled Trial in Users of Real-Time Continuous Glucose Monitoring.

This analysis reports the findings from a predefined exploratory cohort (cohort B) from the ADAPT (ADvanced Hybrid Closed Loop Study in Adult Population with Type 1 Diabetes) study. Adults with type 1 diabetes (T1D) with suboptimal glucose control were randomly allocated to an advanced hybrid closed-loop (AHCL) system or multiple daily injections of insulin (MDI) plus real-time continuous glucose monitoring (RT-CGM). In this prospective, multicenter, exploratory, open-label, randomized controlled trial, 13 participants using MDI + RT-CGM and with HbA1c ≥8.0% were randomized to switch to AHCL (n = 8) or continue with MDI + RT-CGM (n = 5) for six months. Prespecified endpoints included the between-group difference in mean change from baseline in HbA1c, CGM-derived measures of glycemic control, and safety. The mean HbA1c level decreased by 1.70 percentage points in the AHCL group versus a 0.60 percentage point decrease in the MDI + RT-CGM group, with a model-based treatment effect of -1.08 percentage points (95% confidence interval [CI] = -2.17 to 0.00 percentage points; P = .0508) in favor of AHCL. The percentage of time spent with sensor glucose levels between 70 and 180 mg/dL in the study phase was 73.6% in the AHCL group and 46.4% in the MDI + RT-CGM group; model-based between-group difference of 28.8 percentage points (95% CI = 12.3 to 45.3 percentage points; P = .0035). No diabetic ketoacidosis or severe hypoglycemia occurred in either group. In people with T1D with HbA1c ≥8.0%, the use of AHCL resulted in improved glycemic control relative to MDI + RT-CGM. The scale of improvement suggests that AHCL should be considered as an option for people not achieving good glycemic control on MDI + RT-CGM.

Effect of Vitamin D Supplementation on Serum Hepcidin Levels in Non-Diabetic Chronic Kidney Disease Patients.

Vitamin D deficiency and anemia frequently coexist. Moreover, vitamin D deficiency is found to play a role in chronic kidney disease (CKD)-associated anemia. We investigated the effect of cholecalciferol on serum hepcidin levels in vitamin D-deficient, non-diabetic individuals with CKD in a randomized, double-blind, placebo-controlled trial. This study was performed on stored samples of our previously published randomized, double-blind, placebo-controlled trial of cholecalciferol supplementation in non-diabetic patients with stage III-IV CKD and vitamin D deficiency. Stable patients of either sex, aged 18-70 years, with non-diabetic stage III-IV CKD (estimated glomerular filtration rate between 15 and 60 ml/min/1.73 m2), and having serum 25-hydroxyvitamin D3 [25(OH) D] levels ≤20 ng/ml were included. Participants received either two directly observed oral doses of cholecalciferol (300,000 IU) or matching placebo at baseline and at eight weeks. Follow-up was done at 16 weeks. Serum hepcidin levels were analyzed at baseline and at 16 weeks. A total of 120 CKD patients were enrolled. Serum 25(OH) D levels were similar in the placebo and cholecalciferol groups at baseline (13.21 ± 4.78 ng/ml and 13.40 ± 4.42 ng/ml; P = 0.88). After 16 weeks, the serum 25(OH) D levels were found to be increased in the cholecalciferol group but not in the placebo group (between-group difference in mean change 23.40 ng/ml; 95% CI: 19.76 to 27.06; P < 0.001). Serum hepcidin levels were similar at baseline (median [IQR]: 33.6 [8.6-77.8] ng/ml vs. 24.6 [9.3-70.7] ng/ml, P = 0.903) and did not vary between groups at 16 weeks (median [IQR]: 41.5 [10.9-75.0] ng/ml vs. 34.8 [12.3-63.75] ng/ml, P = 0.703). Our study provides preliminary data based on which a larger adequately powered clinical trial can be conducted to conclusively assess the impact of vitamin D supplementation on hepcidin levels and anemia in patients with CKD and vitamin D deficiency.

Intravenous acetaminophen with morphine versus intravenous morphine alone for acute pain in the emergency room: protocol for a multicenter, randomized, placebo-controlled, double-blinded study (ADAMOPA)

BackgroundIn emergency medicine, pain is a frequent reason for consultation. However, there is a great variation in its management which is often insufficient. The use intravenous morphine alone or multimodal analgesia with paracetamol is recommended for severe pain. But robust data are lacking to justify the association of paracetamol with morphine versus morphine alone for pain management in the emergency room (ER). The aim of our study is therefore to assess if in patients with acute pain of moderate to severe intensity with a numerical verbal scale (NVS) ≥5 in the ER, the intravenous administration of morphine alone is not inferior to the administration of intravenous morphine combined with paracetamol at 30 min from the first administration of the study drug.MethodsADAMOPA is a prospective, non-inferiority, multicenter, placebo-controlled, parallel-group, randomized (1:1), double-blind trial. Subjects will be enrolled in the ER if they experience moderate to severe, acute, non-traumatic, and traumatic pain, defined as an NVS ≥5. The primary endpoint will be the between-group difference in mean change in NVS pain scores among patients receiving the combination of intravenous morphine plus paracetamol or intravenous morphine given alone, measured from the time before administration of the study medication to 30 min later.DiscussionThis trial will determine the clinical utility of the association of paracetamol with morphine for pain management in the emergency room. The ADAMOPA trial will be conducted in accordance with the International Council on Harmonization Good Clinical Practices.Trial registrationEudraCT number: 2019-002149-39. ClinicalTrials.gov identifier: NCT04148495. Date of trial registration: November 1, 2019.

Evaluating the Safety and Efficacy of Crenezumab vs Placebo in Adults With Early Alzheimer Disease

Alzheimer disease (AD), a neurodegenerative disease characterized by β-amyloid plaques and τ tangles in the brain, represents an unmet medical need with no fully approved therapeutics to modify disease progression. To investigate the safety and efficacy of crenezumab, a humanized monoclonal immunoglobulin G4 antibody targeting β-amyloid oligomers, in participants with prodromal to mild (early) AD. Two phase 3 multicenter randomized double-blind placebo-controlled parallel-group efficacy and safety studies of crenezumab in participants with early AD, CREAD and CREAD2, were initiated in 2016 and 2017, respectively, and were designed to evaluate the efficacy and safety of crenezumab in participants with early AD. CREAD (194 sites in 30 countries) and CREAD2 (209 sites in 27 countries) were global multicenter studies. A total of 3736 and 3664 participants were screened in CREAD and CREAD2, respectively. A total of 3736 and 3664 participants were screened in CREAD and CREAD2, respectively. Both trials enrolled individuals aged 50 to 85 years with early AD. Participants with some comorbidities and evidence of cerebral infarction or more than 4 microbleeds or areas of leptomeningeal hemosiderosis on magnetic resonance imaging were excluded. After 2923 and 2858 were excluded, respectively, 813 participants in CREAD and 806 in CREAD2 were randomly assigned in a 1:1 ratio to either placebo or crenezumab. In the final analysis, there were 409 participants in the placebo group and 404 in the crenezumab group in CREAD and 399 in the placebo group and 407 in the crenezumab group in CREAD2. Data were analyzed up until January 2019 and August 2019, respectively. Participants received placebo or 60 mg/kg crenezumab intravenously every 4 weeks for up to 100 weeks. The primary outcome was change from baseline to week 105 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score. There were 813 participants in CREAD (mean [SD] age, 70.7 [8.2] years; 483 female and 330 male) and 806 in CREAD2 (mean [SD] age, 70.9 [7.7] years; 456 female and 350 male). Baseline characteristics were balanced between both groups. The between-group difference in mean change from baseline in CDR-SB score (placebo minus crenezumab) was -0.17 (95% CI, -0.86 to 0.53; P = .63) at week 105 in the CREAD study (88 placebo; 86 crenezumab). Compared with previous trials, no new safety signals were identified, and amyloid-related imaging abnormalities with edema were rare, mild, and transient. No meaningful changes in AD biomarkers were observed. Both studies were discontinued following a preplanned interim analysis indicating that CREAD was unlikely to meet the primary end point. Crenezumab was well tolerated but did not reduce clinical decline in participants with early AD. ClinicalTrials.gov Identifiers: CREAD, NCT02670083; CREAD2, NCT03114657.

Single-dose intravenous ferric carboxymaltose infusion versus multiple fractionated doses of intravenous iron sucrose in the treatment of post-operative anaemia in colorectal cancer patients: a randomised controlled trial.

Recent clinical guidelines suggest that treatment of postoperative anaemia in colorectal cancer surgery with intravenous iron reduces transfusion requirements and improves outcomes. The study aimed at comparing two intravenous iron regimens in anaemic patients after colorectal cancer surgery. This was a single-centre, open-label, randomised, controlled trial in patients undergoing elective colorectal cancer surgery. Patients with moderate to severe anaemia (haemoglobin [Hb] <11 g/dL) after surgery were randomly assigned 1:1 to receive ferric carboxymaltose (FC; 1,000 mg, single dose) or iron sucrose (IS; 200 mg every 48 hours until covering the total iron deficit or discharge). Randomisation was stratified by Hb level: <10 g/dL (Group A) or ≥10-10.9 (Group B). The primary endpoint was the change in Hb concentration at postoperative day 30. Secondary endpoints included iron status parameters, transfusion requirements, complications, and length of hospital stay. From September 2015 to May 2018, 104 patients were randomised (FC 50, IS 54). The median intravenous iron dose was 1,000 mg and 600 mg in the FC and IS groups, respectively. There were no between-group differences in mean change in Hb from postoperative day 1 to postoperative day 30 (FC: 2.5 g/dL, 95% CI: 2.1-2.9; IS: 2.4 g/dL, 95% CI: 2.0-2.8; p=0.52), in transfusion requirements or length of stay. The infection rate was lower in the FC group compared with the IS group (9.8% vs 37.2%, respectively). The administration of approximately 500 mg of IS resulted in an increase in Hb at postoperative day 30 similar to that of 1,000 mg of FC, but it was associated with a higher infection rate. Future research will be needed to confirm the results, and to choose the best regime in terms of effectiveness and side effects to treat postoperative anaemia in colorectal cancer patients.

Efficacy of Repetitive Trans-spinal Magnetic Stimulation for Patients with Parkinson's Disease: a Randomised Controlled Trial.

We evaluated the effect of repetitive trans-spinal magnetic stimulation (rTSMS) in patients with Parkinson's disease (PD) in a randomised, single-blind study. Participants were hospitalised and administered a single trial of rTSMS or sham treatment 2days a week for 4weeks. In addition, all participants underwent rehabilitation 5days a week for 4weeks. The primary outcome was the difference between the two groups in the mean change from baseline to post-training in the total score on the Unified Parkinson's Disease Rating Scale (UPDRS). Secondary endpoints included the differences between the two groups in the mean change on the UPDRS part III (motor) score and the Timed Up and Go (TUG) score. Eligible participants were randomly assigned to either the rTSMS group (n = 50) or sham group (n = 50). The between-group difference in mean change in the total UPDRS score was 10.28 (95% confidence interval (CI), 4.42 to 16.13; P = 0.014) immediately after intervention from baseline, 5.04 (95% CI, - 5.41 to 15.50; P = 0.024) 3months after intervention from baseline and 2.38 (95% CI, 7.18 to 11.85; P = 0.045) 6months after intervention from baseline. Significant differences between groups in UPDRS part III and TUG scores were maintained more strictly than those in the UPDRS total score. These results strongly indicate that rTSMS promotes the effect of rehabilitation on motor function in patients with PD.

Cholecalciferol supplementation and angiogenic markers in chronic kidney disease.

Vitamin D plays an important role in proliferation and differentiation of cells and deficiency of vitamin D disturbs angiogenic balance. Previous studies in animal models have reported an association between serum levels of vitamin D and balance between pro- and anti-angiogenic factors. There is insufficient evidence about the effect of vitamin D on mediators of angiogenesis in patients with CKD. We investigated the effect of cholecalciferol supplementation on serum levels of angiogenic markers in non-diabetic patients with CKD stage 3–4. In this secondary analysis on stored samples of our previously published randomized, double-blind, placebo-controlled trial, stable patients of either sex, aged 18–70 years, with non-diabetic CKD stage 3–4 and vitamin D deficiency (serum 25-hydroxyvitamin D ≤20 ng/ml) were randomized to receive either two directly observed oral doses of cholecalciferol (300,000 IU) or matching placebo at baseline and 8 weeks. The primary outcome was change in brachial artery flow-mediated dilatation at 16 weeks. Changes in levels of serum angiogenesis markers (angiopoietin-1, angiopoietin-2, VEGF-A, VEGEF-R, and Tie-2) between groups over 16 weeks were compared. A total 120 patients were enrolled. Supplementation with cholecalciferol led to significant improvement in FMD. Serum 25(OH)D levels were similar in both groups at baseline (13.21±4.78 ng/ml and 13.40±4.42 ng/ml; p = 0.888). At 16 weeks, the serum 25(OH)D levels increased in the cholecalciferol group but not in the placebo group (between-group difference in mean change:23.40 ng/ml; 95% CI, 19.76 to 27.06; p<0.001). Serum levels of angiogenic markers were similar at baseline. At 16 weeks, angiopoietin-2 level decreased in cholecalciferol group (mean difference:-0.73 ng/ml, 95%CI, -1.25 to -0.20, p = 0.002) but not in placebo group (mean difference -0.46 ng/ml, 95%CI, -1.09 to 0.17, p = 0.154), however there was no between-group difference at 16 weeks (between-group difference in mean change: -0.27 ng/ml, 95%CI, -1.09 to 0.55, p = 0.624). Serum angiopoietin-1 level increased [mean change: 5.63 (0.51 to 10.75), p = 0.018] and VEGF-R level decreased [mean change: -87.16 (-131.89 to -42.44), p<0.001] in placebo group but did not show any change in cholecalciferol group. Our data shows the changes in Ang-1, Ang-2 and Ang-1/Ang-2 ratio after high dose oral cholecalciferol supplementation in patients with non-diabetic G3-4 CKD. The data suggests changes in circulating levels of angiogenic markers which needs to be confirmed through an adequately powered study.

The diabetes community exercise programme plus usual care versus usual care in patients with type 2 diabetes: A randomised, two-arm, parallel, open-label trial

SummaryBackgroundExercise is important in type 2 diabetes (T2D) management. Focussing on Māori and Pacific people and those from deprived circumstances, the Diabetes Community Exercise Programme (DCEP) was developed to engage people with T2D in exercise. We report the evaluation of whether being offered DCEP (plus usual care) was more effective than usual care in improving glycaemic control at 1-year.MethodsA randomised, two-arm, parallel, open-label trial with blinding of outcome assessor and data analyst. Adults (age ≥35 years) with T2D recruited from two New Zealand (NZ) communities were randomised, using opaque sealed envelopes and stratified by centre with random block lengths, to DCEP or usual care. DCEP comprises twice-weekly, two-hour sessions of exercise and education over 12-weeks, followed by a twice-weekly maintenance exercise class. The primary outcome was between-group differences in mean changes of glycated haemoglobin (HbA1c) from baseline to 1-year follow-up with intention-to treat analysis. This trial is registered with the Australian NZ Clinical Trials Registry (ANZCTR): ACTRN12617001624370p and is closed to new participants.FindingsFrom 2018 – 2019, of 294 people screened, 165 (mean age 63·8, SD16·2 years, 56% female, 78·5% European, 14% Māori, 6% Pacific, 27% most deprived) were baseline evaluated, randomised, and analysed at study end (DCEP = 83, control = 82). Multimorbidity (≥2) and polypharmacy (>5 medications) were high (82%, 69%). We found no statistically significant between-groups differences in HbA1c (mmol/mol) change at 15 months (mean 3% higher in DCEP, 95% CI 2% lower to 8% higher, p = 0·23). Twelve-week intervention adherence was good (41% attended >80% available sessions). No adverse events were reported.InterpretationDCEP was not effective in improving glycaemic control, possibly due to insufficient exercise intensity. Our attendance demonstrated DCEP's cultural accessibility. DCEP might be good to engage in exercise marginalised people with high Hb1Ac levels, multimorbidity, and high polypharmacy.FundingHealth Research Council of New Zealand.

Abstract P4-10-04: Health-related quality of life (HRQoL) in hormone receptor-positive, HER2-negative, luminal B breast cancer patients treated with ribociclib plus letrozole or chemotherapy

Abstract Background: Neoadjuvant ribociclib plus letrozole (R+L), was evaluated in the phase II Coralleen study (NCT03248427) in comparison with poli-chemotherapy (CT) in women with hormone receptor-positive (HR+), HER2-negative, luminal B breast cancer. In the primary efficacy analysis, both groups showed a similar proportion of pts with PAM50 low-risk risk of recurrence at surgery (46.9% vs 46.1%) (Prat. Lancet Oncol. 2020). Now we present patients (pts)-reported HRQoL results. Methods: In the CORALLEEN study, 106 postmenopausal women with stage I-IIIA HR+/HER2-negative Luminal B breast cancer by PAM50 were randomized 1:1 to receive six 28-days cycles of R+L (n=52) or four cycles of doxorubicin and cyclophosphamide followed by weekly paclitaxel (n=54). The primary efficacy endpoint was the proportion of patients with PAM50 Risk of Recurrence (ROR) low disease at surgery in each arm. Pts-reported HRQoL was evaluated at baseline (bl), day 1 of each subsequent cycle and before surgery, using i) the European Organization for Research and Treatment of Cancer (EORTC QLQ-C30) and ii) the breast cancer-specific EORTC QLQ-BR23 questionnaires. On-treatment comparison of mean change from bl in global health status (GHS), functioning and symptom scales was performed. Longitudinal linear mixed-effect models using a random intercept and random slope were fitted to estimated least squares (LS) mean change. The proportion of patients with clinically meaningful (10-point thereshold) deterioration was estimated in each group. Results: Completion and compliance rates of HRQoL questionaries at bl was 100% for R+L group and 98% for CT group, at week 12 completion rate was 92% and 87% and before surgery 80% in both groups. At bl, EORTC QLQ-C30 GHS scores were similar between R+L and CT groups (median 80.4 and 79.4, respectively). Before surgery, GHS scores presented a slight decrease in the R+L group while it considerably decreased in the CL group (mean change -5.2 vs. -23.6). The between-group difference in mean change from bl was 18.4 points (95% CI 9.8 - 26.9) showing a worsening in patients receiving CT. Overall, at the end of treatment 38% of patients in the R+L and 68% of patients in the CT group reported a clinically meaningful deterioration. R+L group presented better results in the mean change from bl in all functioning and symptom scales, specially in terms of fatigue and appetite loss (28.7 and 24 points difference between groups, respectively) (Table). Conclusions: R+L provided better outcomes in GHS HRQoL, functioning and symptoms in comparison with CT for the treatment of patient with high-risk breast cancer in the pre-operative setting. Together with the similar clinical efficacy and manageable safety profile, these results provide additional support for the development of clinical trials evaluating R+L in this patient population. Estimated mean change from baseline to before surgery (95% CI)Estimated mean change from baseline to before surgery (95% CI)Difference in the mean change in R+L vs. CTR+LCTGlobal health status 1-5.2 (-11.3 ; 0.9)-23.6 (-29.6 ; -17.6)18.4 (9.8 ; 26.9)Functional scales• Physical1-4.3 ( -9.5 ; 0.8)-20.3 (-25.5 ; -15.1)16 (8.7 ; 23.2)• Social1-6.3 (-13 ; 0.4)-19.7 (-26.1 ; -13.4)13.4 (4.2 ; 22.6)• Emotional1-0.7 (-7.4 ; 6.0)-6.8 (-13.3 ; -0.2)6.1 (-3.3 ; 15.4)• Role1-4.8 (-11.8 ; 2.2)-26.7 (-33.7 ; -19.7)21.9 (12 ; 31.8)• Body imagine2-3.2 (-8.9 ; 2.5)-12.9 (-18.5 ; -7.3)9.7 (1.7 ; 17.7)• Sexual enjoymnet2-5.3 (-20.4 ; 9.9)-36.1 (-54.4 ; -17.8)30.8 (7.2 ; 54.5)Symptom scales• Fatigue15.7 (0.7 ; 10.9)35.1 (26.6 ; 43.7)-28.7 (-38.2 ; -19.1)• Pain15.5 (-1.2 ; 12.1)15.5 (9 ; 22.1)-10.1 (-19.4 ; -0.8)• Insomnia14.8 (-2.7 ; 12.4)10.6 (3.2 ; 18.0)-5.8 (-16.2 ; 4.6)• Appetite loss12.5 (-5.8 ; 10.8)26.5 (18.2 ; 34.9)-24 (-35.8 ; -12.3)• Upset by hair loss28.8 (-10.4 ; 27.9)27.7 (8.3 ; 47.2)-18.9 (-45.6 ; 7.7)• Breast symptoms2-2.6 (-6.3 ; 1.2)0.7 (-3.0 ; 4.3)-3.3 (-8.5 ; 1.9)Positive values favour R+L except for symptom scale where negative values favour R+L. Changes from baseline were estimated using a repeated-measures mixed-effect model. CI, confidence interval. 1 EORTC QLQ-C30, 2EORTC QLQ-BR23 questionnaires. Citation Format: Guillermo Villacampa, Laia Paré, Cristina Hernando, Miriam Arumí, Montserrat Muñoz, Miguel Gil-Gil, Yann Izarzugaza, Neus Ferrer, Alvaro Montaño, Eva Ciruelos, Santiago González-Santiago, Claudette Falato, Patricia Villagrasa, Joaquín Gavilá, Aleix Prat, Tomás Pascual. Health-related quality of life (HRQoL) in hormone receptor-positive, HER2-negative, luminal B breast cancer patients treated with ribociclib plus letrozole or chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-10-04.

Effect of Praliciguat on Peak Rate of Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is often characterized by nitric oxide deficiency. To evaluate the efficacy and adverse effects of praliciguat, an oral soluble guanylate cyclase stimulator, in patients with HFpEF. CAPACITY HFpEF was a randomized, double-blind, placebo-controlled, phase 2 trial. Fifty-nine sites enrolled 196 patients with heart failure and an ejection fraction of at least 40%, impaired peak rate of oxygen consumption (peak V̇o2), and at least 2 conditions associated with nitric oxide deficiency (diabetes, hypertension, obesity, or advanced age). The trial randomized patients to 1 of 3 praliciguat dose groups or a placebo group, but was refocused early to a comparison of the 40-mg praliciguat dose vs placebo. Participants were enrolled from November 15, 2017, to April 30, 2019, with final follow-up on August 19, 2019. Patients were randomized to receive 12 weeks of treatment with 40 mg of praliciguat daily (n = 91) or placebo (n = 90). The primary efficacy end point was the change from baseline in peak V̇o2 in patients who completed at least 8 weeks of assigned dosing. Secondary end points included the change from baseline in 6-minute walk test distance and in ventilatory efficiency (ventilation/carbon dioxide production slope). The primary adverse event end point was the incidence of treatment-emergent adverse events (TEAEs). Among 181 patients (mean [SD] age, 70 [9] years; 75 [41%] women), 155 (86%) completed the trial. In the placebo (n = 78) and praliciguat (n = 65) groups, changes in peak V̇o2 were 0.04 mL/kg/min (95% CI, -0.49 to 0.56) and -0.26 mL/kg/min (95% CI, -0.83 to 0.31), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was -0.30 mL/kg/min ([95% CI, -0.95 to 0.35]; P = .37). None of the 3 prespecified secondary end points were statistically significant. In the placebo and praliciguat groups, changes in 6-minute walk test distance were 58.1 m (95% CI, 26.1-90.1) and 41.4 m (95% CI, 8.2-74.5), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was -16.7 m (95% CI, -47.4 to 13.9). In the placebo and praliciguat groups, the placebo-adjusted least-squares between-group difference in mean change in ventilation/carbon dioxide production slope was -0.3 (95% CI, -1.6 to 1.0). There were more dizziness (9.9% vs 1.1%), hypotension (8.8% vs 0%), and headache (11% vs 6.7%) TEAEs with praliciguat compared with placebo. The frequency of serious TEAEs was similar between the groups (10% in the praliciguat group and 11% in the placebo group). Among patients with HFpEF, the soluble guanylate cyclase stimulator praliciguat, compared with placebo, did not significantly improve peak V̇o2 from baseline to week 12. These findings do not support the use of praliciguat in patients with HFpEF. ClinicalTrials.gov Identifier: NCT03254485.

SUN-086 EFFECT OF VITAMIN D SUPPLEMENTATION ON SERUM HEPCIDIN LEVELS IN CKD

Vitamin D has been shown to be a regulator of hepcidin-ferroportin axis. Vitamin D deficiency is common in CKD. Whether native vitamin D supplementation favorably affects serum hepcidin in CKD is not known. We investigated the effect of cholecalciferol supplementation on serum hepcidin levels in non-diabetic patients with CKD stage 3-4. In this secondary analysis of our previously published randomized, double-blind, placebo-controlled trial(https://jasn.asnjournals.org/content/28/10/3100), stable patients of either sex, aged 18-70 years, with non-diabetic CKD stage 3-4 and vitamin D deficiency (serum 25-hydroxyvitamin D ≤20 ng/ml) were randomized to receive either two directly observed oral doses of cholecalciferol (300,000 IU) or matching placebo at baseline and 8 weeks. The primary outcome was change in FMD at 16 weeks. Serum level of Hepcidin was analyzed by ELISA (Quantikine®ELISA kit, R&D, Minneapolis, MN, USA). Intra-assay and inter-assay coefficient of variation of this kit was 3.2-4.3% and 6.2-11%, respectively. Changes in serum hepcidin levels between groups over 16 weeks were compared using paired t test. 120 patients were enrolled. Baseline characteristics showed no differences between groups with respect to demographic details and causes of CKD. Supplementation with cholecalciferol led to significant improvement in FMD. Serum 25(OH)D levels were similar in both groups at baseline (13.21±4.78 ng/ml and13.40±4.42ng/ml; P=0.88). At16 weeks, the serum 25(OH)D levels increased in the cholecalciferol group but not in the placebo group(between-group difference in mean change:23.40 ng/ml; 95% CI, 19.76 to27.06; P<0.001). Blood levels of hemoglobin were similar at baseline (12.02±1.94 mg/dl vs 11.97±1.69mg/dl, p=0.947) and there were no significant changes at 16 weeks in either group [between group difference; 0.21 (-0.22 to 0.63), p=0.34]. Serum hepcidin levels were similar at baseline [median (IQR): 33.6 (8.6-77.8) ng/ml vs 24.6 (9.3-70.7) ng/ml, p=0.903] and did not vary between groups at 16 week [median (IQR): 41.5 (10.9-75.0) ng/ml vs34.8(12.3-63.75) ng/ml, p=0.703]. High dose oral cholecalciferol supplementation has no effect on serum hepcidin levels in subjects with non-diabetic CKD stage 3-4.

Abstract P1-11-01: Effect of aerobic and resistance exercise on Reynolds risk score in overweight or obese breast cancer survivors

Abstract Background Breast cancer survivors have approximately double the risk of mortality from cardiovascular disease than age-matched women without a cancer history. Reynolds risk score is a validated algorithm for the assessment of cardiovascular disease, which incorporates high sensitivity C-Reactive Protein (hsCRP), hemoglobin A1c (HbA1c), and parental history of myocardial infarction with traditional biomarkers including cholesterol, systolic blood pressure (SBP), and presence of diabetes. We previously demonstrated that exercise improves Framingham risk score (12.0±2.0 to 2.0±1.5), calculated by traditional risk factors of cardiovascular disease, SBP (132.9±13.0 to 120.7±9.5 mmHg), high-density lipoprotein cholesterol (HDL-C; 43.1±6.6 to 64.7±7.8 mg/dL), and total cholesterol (TC; 196.5 ± 53.4 to 157.5 ± 37.1 mg/dL), in breast cancer survivors. This secondary analysis sought to examine the effects of a 16-week aerobic and resistance exercise intervention on Reynolds risk score in breast cancer survivors. Methods One hundred overweight or obese (BMI&amp;gt;25kg/m2) sedentary breast cancer survivors (stage I-III) who completed cancer treatment within 6 months prior to enrollment were randomized to the Exercise group (EX; n=50) or the Control (CON; n=50). The EX underwent supervised moderate-to-vigorous intensity aerobic and resistance exercise sessions 3 times/week for 16 weeks. The CON was asked to maintain their current level of activity. Reynolds risk score was calculated for each participant by assigning values for each of the following eight categories: age, SBP, TC, HDL-C, presence of diabetes; HbA1c, smoking status, hsCRP; and parental history of myocardial infarction. Within-group and between-group differences in mean change for individual outcomes measured at 16 weeks were evaluated using general linear models repeated-measures analyses of variance and mixed model repeated-measures analysis, respectively. Results Following the 16-week study period, Reynolds risk score was significantly reduced (8.3% to 0.9%), with improvements in hsCRP (3.4±0.6 to 2.3±0.3 mg/L), presence of diabetes (40 to 20%), and HbA1c (7.5±0.9 to 2.9±0.2%) in EX compared to CON (P&amp;lt;0.01). There were no significant changes in TC (194.4±48.9 to 210.4±52.2), HDL-C (41.0±4.3to 39.9±4.0), SBP (133.7±9.7to 135.9±9.8), hsCRP (3.7±0.3 to 4.2±0.4), presence of diabetes (22 to 24%), HbA1c (7.5±0.8 to 7.9±0.8) and Reynolds risk score in CON (P&amp;gt;0.05). Conclusion A 16-week supervised aerobic and resistance exercise intervention is an effective approach to reduce the risk of developing cardiovascular disease by reducing hsCRP, cholesterol, diabetes status, and SBP in breast cancer survivors. Participation in supervised exercise training during cancer survivorship should be considered to reduce the risk for cardiovascular disease mortality in breast cancer survivors. Citation Format: Kyuwan Lee, Debu Tripathy, Wendy Demark-Wahnefried, Kerry Courneya, Joanne Mortimer, Christina Dieli-Conwright. Effect of aerobic and resistance exercise on Reynolds risk score in overweight or obese breast cancer survivors [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-11-01.

Health-Related Quality of Life (HRQoL) in Patients with Myelofibrosis Treated with Fedratinib, an Oral, Selective Inhibitor of Janus Kinase 2 (JAK2), in the Randomized, Placebo-Controlled, Phase III JAKARTA Study

Health-Related Quality of Life (HRQoL) in Patients with Myelofibrosis Treated with Fedratinib, an Oral, Selective Inhibitor of Janus Kinase 2 (JAK2), in the Randomized, Placebo-Controlled, Phase III JAKARTA Study

Patient-reported outcomes in individuals with hepatitis C virus infection treated with elbasvir/grazoprevir.

PurposePeople chronically infected with hepatitis C virus (HCV) have diminished patient-reported outcomes (PROs). This study aimed to compare the impact of elbasvir/grazoprevir (EBR/GZR) treatment versus sofosbuvir with pegylated interferon and ribavirin (SOF/PR) on changes in PROs: 1) during the treatment period and 2) at posttreatment follow-up.Patients and methodsPRO data collected during the Phase III C-EDGE Head-2-Head (H2H) open-label study was analyzed. In this trial, patients infected with HCV were randomized 1:1 to receive either EBR/GZR or SOF/PR for 12 weeks. Patients self-administered the Short Form-36 version 2 (SF-36v2®) Health Survey Acute (1-week recall) Form and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale at baseline, during treatment, and posttreatment. Between-group differences in mean change of PRO scores from baseline were estimated during the treatment period and also at the posttreatment follow-up. Effect sizes were calculated to evaluate if the detected change in mean PRO scores is clinically meaningful between groups.ResultsThere were 255 patients (99.2% White, 54.1% female, 74.9% treatment naïve) included in the analysis. During the treatment period, significant declines in SF-36v2 scores were observed across all domains for the SOF/PR group. Compared to the SOF/PR group, the EBR/GZR group reported more improvement in scores across all SF-36v2 domain scores at the end of the treatment period. At treatment week 12, the between-group differences for 6 out of the 8 domain scores for these patients reflected at least moderate effects (effect sizes >0.5). No significant between-group differences in change in SF-36v2 scores from baseline were detected posttreatment. The decline in SF-36v2 scores observed during the treatment period for the SOF/PR group returned to near baseline scores or above posttreatment. Treatment with EBR/GZR did not impact fatigue scores, but treatment with SOF/PR led to increased fatigue scores during treatment which resolved by posttreatment follow-up week 12.ConclusionThis study demonstrated that HCV treatment with EBR/GZR resulted in a significantly better PRO profile as compared to SOF/PR. PROs are an important consideration as worsening PROs experienced during treatment may negatively influence adherence and ultimately contribute to an unfavorable clinical outcome.Clinicaltrials.gov IdentifierNCT02358044

Change in Fitness and the Relation to Change in Cognition and Neuropsychiatric Symptoms After Aerobic Exercise in Patients with Mild Alzheimer's Disease.

Background:Physical activity has the potential to improve physical function in patients with Alzheimer’s disease (AD) and may contribute to modify disease processes and cognitive function.Objective:The aim of this study was to investigate 1) the effect of moderate-high-intensity aerobic exercise on cardiorespiratory fitness, i.e., peak oxygen uptake (VO2peak) determined by direct breath-by-breath cardiopulmonary exercise test, and 2) the association between changes in VO2peak and changes in cognition and neuropsychiatric symptoms in patients with mild AD.Methods:The study is based on secondary outcome analyses from the large single-blinded multi-center study ADEX (Preserving Cognition, Quality of Life, Physical Health and Functional Ability in Alzheimer’s Disease: The Effect of Physical Exercise). A preselected sub-group of 55 participants (age 52–83 years), 29 from the intervention group (IG) and 26 from the control group (CG), was included. IG performed 16 weeks of supervised moderate-to-high intensity aerobic exercise. Assessments of VO2peak, mental speed and attention (Symbol Digit Modalities Test, SDMT), and neuropsychiatric symptoms (Neuropsychiatric Inventory, NPI) were performed at baseline and at 16 weeks.Result:VO2peak increased 13% in the IG and a between-group difference in mean change (3.92 ml/kg/min, 95% CI 6.34–1.51, p = 0.003) was present in favor of the IG. Combined data from IG and CG showed positive associations between changes in VO2peak and changes in NPI (Rho = – 0.41, p = 0.042) and changes in SDMT (Rho = 0.36, p = 0.010), respectively.Conclusion:Aerobic exercise improves VO2peak in community-dwelling patients with mild AD. Furthermore, changes in VO2peak appear to be associated to changes in cognition and neuropsychiatric symptoms.

Is intravenously administered, subdissociative-dose KETAmine non-inferior to MORPHine for prehospital analgesia (the KETAMORPH study): study protocol for a randomized controlled trial

BackgroundAcute pain is a common condition among prehospital patients and prompt management is pivotal. Opioids are the most frequently analgesics used in the prehospital setting. However, opioids are highly addictive, and some patients may develop opioid dependence, even when they are exposed to brief opioid treatments. Therefore, alternative non-opioid analgesia should be developed to manage pain in the prehospital setting. Used at subdissociative doses, ketamine, a noncompetitive N-methyl-D-aspartate and glutamate receptor antagonist, provides analgesic effects accompanied by preservation of protective airway reflexes. In this context, we will carry out a randomized controlled, open-label, multicenter trial to compare a subdissociative dose of ketamine to morphine to provide pain relief in the prehospital setting, in patients with traumatic and non-traumatic pain.Methods/designThis will be a multicenter, single-blind, randomized controlled trial. Consecutive adults will be enrolled in the prehospital setting if they experience moderate to severe, acute, non-traumatic and traumatic pain, defined as a numeric rating scale score greater or equal to 5. Patients will be randomized to receive ketamine or morphine by intravenous push. The primary outcome will be the between-group difference in mean change in numeric rating scale pain scores measured from the time before administration of the study medication to 30 min later.DiscussionThis upcoming randomized clinical trial was design to assess the efficacy and safety of ketamine, an alternative non-opiate analgesia, to manage non-traumatic and traumatic pain in the prehospital setting. We aim to provide evidence to change prescribing practices to reduce exposition to opioids and the subsequent risk of addiction.Trial registrationClinicalTrials.gov, ID: NCT03236805. Registered on 2 August 2017.