Psychometric validation and interpretation of the Nocturia Impact Diary in a clinical trial setting

Purpose Psychometric evaluation of the Nocturia Impact (NI) Diary was conducted to support its use as a trial endpoint. Methods As part of a randomized, controlled Phase 2 clinical trial investigating a novel drug candidate for nocturnal polyuria, adult nocturia patients completed the NI Diary and a voiding diary for three nights preceding their clinic visit at Baseline and Weeks 1, 4, 8, and 12 (end of treatment). Exit interviews were conducted to obtain patient impressions of the NI Diary. Results A total of N = 302 participants were included. Confirmatory factor analysis (CFA) indicated that the 11-item measure is unidimensional with values of CFI, TLI, and RMSEA meeting relevant thresholds. Good internal consistency (Cronbach’s α 0.941) and test–retest reliability (intra-class correlation coefficients 0.730–0.880). Convergent validity with two reference measures was demonstrated with strong correlations of 0.573–0.730 were shown. Significant differences (P = 0.0018, standardized effect size = 0.372) between groups defined by number of night-time voids supported known-groups validity. Exit interviews in 66 patients indicated all participants experienced improvement in at least 1 NI Diary item and that a 1-point improvement on the item response scale and 1-void reduction per night (associated with an average best cut point on ROC analysis of − 11.6) constituted meaningful improvement. Anchor and distribution-based analyses identified a meaningful change threshold of − 15 to − 18 points on the NI Diary. Conclusion The NI Diary is a reliable and valid patient-reported psychometric instrument which is fit-for-purpose to evaluate the impact of nocturia on patient quality of life in the clinical trial setting. Trial registration number and registration date NCT03201419; June 28, 2017.

Methodological Standards for the Design, Implementation, and Analysis of Randomized Trials in Cardiac Surgery: A Scientific Statement From the American Heart Association

Cardiac surgery presents specific methodological challenges in the design, implementation, and analysis of randomized controlled trials. The purposes of this scientific statement are to review key standards in cardiac surgery randomized trial design and implementation, and to provide recommendations for conducting and interpreting cardiac surgery trials. Recommendations include a careful evaluation of the suitability of the research question for a clinical trial, assessment of clinical equipoise, feasibility of enrolling a representative patient cohort, impact of practice variations on the safety and efficacy of the study intervention, likelihood and impact of crossover, and duration of follow-up. Trial interventions and study end points should be predefined, and appropriate strategies must be used to ensure adequate deliverability of the trial interventions. Every effort must be made to ensure a high completeness of follow-up; trial design and analytic techniques must be tailored to the specific research question and trial setting.

To Compare Metformin Vs Insulin in Gestational Diabetes in Terms of Neonatal Hypoglycemia

Aim: To compare metformin vs insulin in Gestational Diabetes in terms of neonatal hypoglycemia. Methodology: Study design: Randomized controlled trial Setting: Obstetrics / Gynecology Unit-l, Holy Family Hospital, Rawalpindi. Duration of study: 6 months i.e. 10-11-2017 to 10-05-2018 Data collection procedure: 240 patients were randomly allotted into two groups; A & B. Group A received metformin and group B received regular insulin. Patient was admitted at 36 wks onwards. Neonatal hypoglycemia was measured and entered in structured Performa. All the data was entered and analyzed through SPSS version 22. Results: In this study, the mean ± sd ages of patients were 28.7±5.05 years in insulin group while 28.01±4.37years in metformin group. Mean neonatal blood sugar level was 51.58±11.77mg/dl in insulin group while 57.37±10.61mg/dl in metformin group. The difference was significant (p<0.05). In this study, neonatal hypoglycemia was noted in 28 (23.3%) cases with insulin while in 1 (0.8%) case with metformin. The difference was significant (p<0.05). Conclusion: Metformin has better outcome than insulin in terms of less number of neonatal hypoglycemia. Key words: Gestational Diabetes, Metformin, Insulin, Neonatal Hypoglycemia

Comparison of current and emerging strategies for treating hepatic encephalopathy.

Objective: To compare the efficacy of rifaximin and metronidazole which are the most commonly used antibiotics used in treating this disorder. Study Design: Randomized Controlled Trial. Setting: Department of Medicine, Sharif Trust Hospital. Period: Jan 2018 to July 2018. Material & Methods: In this study cirrhotic patients irrespective of etiology were enrolled. West Haven Criteria (WHC) was utilized for grading the symptoms of HE at baseline and after 7 days of treatment. The study subjects were further subdivided into two groups: rifa group and metro group, and were given rifaximin and metronidazole respectively along with lactulose. The efficacy of the treatment and adverse effects in both the groups were estimated. Results: Total 180 subjects with HE (grade- III or IV) were selected, 90 subjects were subdivided into each group. Out of 90 subjects of Rifa group, efficacy of treatment was noted in 14 (15%) patients and out of 90 subjects of Metro Group, treatment was found effective in 45 (50%) patients with p value of 0.0001. Conclusion: The conclusion of this study is that metronidazole is superior to rifaximin in terms of efficacy in the management of an acute phase of hepatic encephalopathy due to chronic liver cirrhosis. Hence, due to its cheaper cost and a good safety margin its use is recommend in poor resource settings.

In Africa, a High Proportion of Adults with HbSC Meet American Society of Hematology's Eligibility Criteria for Severe Sickle Cell Disease and Starting Hydroxyurea Therapy in a Clinical Trial Setting

Introduction : Sickle cell disease (SCD), HbSC, is the second most frequent hemoglobinopathy after HbSS. Worldwide, an estimated 54,736 babies are delivered annually with HbSC disease, with the highest HbC gene frequency in West Africa (Piel et al.2013). A retrospective study at the Ghana Institute of Clinical Genetics [(GICG), a sickle cell clinic] reported that 40% of the 3,000 SCD patients attending the clinic yearly are HbSC (Asare et al.2018). HbSC disease usually results in a comparatively milder form of SCD. However, rates of maternal-fetal morbidity, retinopathy, avascular necrosis (AVN) of the hip, priapism, and chronic kidney disease are increased (Powars et al.2002; Oppong et al.2018). While microalbuminuria is lower in HbSC than HbSS, it still occurs in &gt;23% of adults (Drawz et al.2016). In addition, thrombosis, silent cerebral infarction, sensorineural hearing loss, and pulmonary hypertension may be higher than previously suspected (Sathi et al.2019). Unlike HbSS, hydroxyurea is not routinely recommended for HbSC patients because they are all perceived to have a milder phenotype, with improved life expectancy. Thus, HbSC individuals are often excluded from randomized controlled trials in children and adults with SCD (Luchtman-Jones et al.2016). Given the high proportion of adults with HbSC in Ghana, who may benefit from hydroxyurea therapy, we tested the hypothesis that at least 5% of adults with HbSC will meet the ASH criteria for severe disease and treatment. Data indicating that a significant proportion of adults with HbSC are eligible for hydroxyurea could potentially support pilot safety trials to determine the optimal hydroxyurea dose to ameliorate symptoms while limiting toxicity. Data can also facilitate government health policy decisions to subsidize hydroxyurea costs. Methodology : We conducted a medical chart review of all adults with HbSC disease (total: 639; 18-45years) who attended the SCD clinic, GICG (January 1, 2019, to December 31, 2019). We identified a comparison group of 639 adults with HbSS, age, and gender-matched to the HbSC patients from the same clinic. Severe complications were defined as a history of ≥3 sickle cell-associated moderate to severe pain episodes/year, a history of severe acute chest syndrome (ACS), and severe symptomatic chronic anemia that interferes with daily activities or quality of life (Hydroxyurea and Transfusion Therapy for the Treatment of Sickle Cell Disease.2014). We defined acute pain episode as new onset of pain that lasts at least 4 hours, for which there is no explanation other than vaso-occlusion, which requires therapy with parenteral opioids in a medical setting (Ballas et al.2010). Severe symptomatic chronic anemia was defined as a drop in hemoglobin by ≥2g/dL below the steady state. Data were analyzed using SPSS version 23 and summarized as simple descriptive statistics. Study endpoints were the proportion of individuals with SCD who met the definition of severe disease and were eligible for hydroxyurea. We also calculated the pain and ACS incidence rates. Results: The 639 HbSC participants had a mean age of 30.8years during the one-year study period, which was identical to that of the HbSS group. At least 8.5% of HbSC adults had ≥three acute pain episodes/ year, while 1.6% had ACS. No HbSC patient had severe symptomatic chronic anemia . In total, 10.0%(64/639) of patients with HbSC disease met the eligibility criteria for hydroxyurea therapy, compared to 24.1%(154/639) of patients with HbSS, p=&lt;0.001. The pain and ACS incidence rates for the HbSC and HbSS individuals were [74.6; 95% CI(67.9-81.3) and 2.3; 95% CI(1.2-3.5)] events per 100 patient-years vs. [123.0; 95% CI(114.4-131.6) and 5.6; 95% CI(3.8-7.5)] events per 100 patient-years respectively. Also, 1.1%(7/639), 7.7%(49/639), 0.5%(4/639), and 4.4%(11/252) of patients with HbSC had papillary necrosis, AVN, stroke, and priapism, respectively while 8.5%(54/639) of patients with HbSS had proteinuria, Table 1. Only 0.9%(HbSC) and 2.3%(HbSS) took hydroxyurea during the study period. Conclusion: Based on ASH's evidence-based guidelines, in a large SCD clinic at an academic medical center in Ghana, 10.0% of HbSC adults meet the criteria for shared decision-making to consider starting hydroxyurea therapy in a clinical trial setting. The optimal dose of hydroxyurea that maximizes benefit and minimizes toxicity in adults with HbSC is yet to be determined. Figure 1 Figure 1. Disclosures Asare: ASH Global Research Award: Research Funding.

Real-World Treatment of Patients with Large B-Cell Lymphoma in the United States with Chimeric Antigen Receptor T-Cell Therapy

Introduction: The advent of chimeric antigen receptor (CAR) T-cell therapy has represented one of the most innovative therapeutic advances in oncology in recent years. Impressive clinical responses to CAR T-cell therapy observed in patients in clinical trials have led to the Food and Drug Administration (FDA) approval of five CAR T-cell therapies in the US since 2017 to treat large B-cell, mantle cell, and follicular lymphomas, as well as acute lymphoblastic leukemia (ALL) and multiple myeloma. The first two CAR T-cell therapies approved by the FDA, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), have now been on the US market for the treatment of patients with large B-cell lymphoma (LBCL) since 2017 and 2018, respectively, allowing for assessment of their use in real-world clinical practice. Given the complex logistics of the manufacturing, distribution, administration and unique toxicity of CAR T-cell therapies, initial use was limited to larger centers with prior experience with CAR T-cell therapy clinical trials. With greater use and availability of multiple CAR T-cell therapies, real-world evaluation of the clinical profiles, treatment patterns, and outcomes of LBCL patients treated with CAR T-cell therapies may inform clinical, regulatory, and drug development decision making, ultimately helping to improve patient outcomes. This real-world claims-based study aimed to describe characteristics and treatment outcomes of patients with diffuse LBCL (DLBCL) treated with the CAR T-cell therapies axi-cel or tisa-cel in the non-trial setting. Methods: Patients with at least 1 claim for axi-cel or tisa-cel made prior to 03/31/21 and a diagnosis code of DLBCL were identified from the Symphony Integrated Dataverse (IDV), a large US claims database containing linked longitudinal prescription, medical, and hospital claims. The IDV contains claims for 280 million active unique patients representing over 63% of prescriptions with full lifecycle data, 62% of medical claims, and 25% of hospital claims volume in the US. Patients were excluded from analysis if axi-cel or tisa-cel was the first therapy identified for the patient since diagnosis of DLBCL within the claims database, if treatment was received as a part of a clinical trial, if there were no supporting claims around CAR T-cell therapy in the claims database, if next line of therapy was received within 30 days of a sole claim for axi-cel or tisa-cel, or if data supported a diagnosis of ALL. Patient characteristics and treatment patterns were summarized using descriptive statistics. Results: Among a total of 88 eligible patients with DLBCL identified in this study, 52% (n=46) received axi-cel and 48% (n=42) received tisa-cel. At the time of treatment with axi-cel or tisa-cel therapy, median patient age was 63 years (range, 20-78 years) and commercial insurance was the primary payer for 83% of patients (n=73). The majority (n=59, 67%) of patients were male. Patients with DLBCL treated with axi-cel or tisa-cel were distributed across each of the 4 US census regions, with 27% from the Northeast, 11% from the South, 32% from the Midwest, and 30% from the West. . Axi-cel or tisa-cel was received a median of 14 months following patients' initial diagnosis of DLBCL and for the majority (n=54, 61%) of patients, axi-cel or tisa-cel-related claims were associated with administration of CAR T-cell therapy in the outpatient setting (Table). Prior to axi-cel or tisa-cel, 57% of patients (n=50) received 2 or more lines of systemic therapy. Within a median follow-up period of 7.8 months, 17% of patients (n=15) received systemic therapy following axi-cel or tisa-cel treatment. Conclusions: In the first few years of US market availability, the CAR T-cell therapies axi-cel and tisa-cel have been used to treat patients with LBCL outside of the clinical trial setting. While the majority of patients in this real-world claims-based study received axi-cel or tisa-cel in an outpatient setting, hospital claims are underrepresented in the database utilized. Despite short follow-up (less than 8 months from initiation of these CAR T-cell therapies), approximately one in 6 patients appear to have relapsed disease, based on the need for subsequent systemic therapy. Further research is warranted to understand real-world clinical outcomes among patients treated with CAR T-cell therapy outside the trial setting. Figure 1 Figure 1. Disclosures Zimmerman Savill: Roche/Genentech: Ended employment in the past 24 months; Cardinal Health: Current Employment. Klink: Cardinal Health: Current Employment, Current holder of stock options in a privately-held company. Liassou: Cardinal Health: Current Employment. Chopra: Cardinal Health: Current Employment. Laney: Cardinal Health: Current Employment. Gajra: Cardinal Health: Current Employment, Current equity holder in publicly-traded company.

Real World Experience on the Use of Ibrutinib Monotherapy in Waldenström Macroglobulinemia

BACKGROUND Ibrutinib is approved as a second line treatment option for Waldenström Macroglobulinemia (WM) patients in the United Kingdom and for patients unsuitable for chemo-immunotherapy. In a clinical trial setting, Ibrutinib monotherapy produced a major response rate (MRR) of 79.4% and a predicted five-year overall survival (OS) rate of 87%1. Valuable insights can be gained on the response and tolerability outcomes of Ibrutinib monotherapy in WM outside of the clinical trial setting. This study aimed to evaluate these outcomes in a large specialist centre which receives referrals from across the UK. METHODS A retrospective analysis was performed on consecutive patients with WM who commenced Ibrutinib between December 2014 and February 2021; all included patients were treated for at least 3 months. Data were collated from the WMUK Rory Morrison Registry. The primary outcomes were depth of response, event free survival (EFS, defined as time from commencement to permanent ibrutinib discontinuation due to toxicity, disease progression or death), duration of response (time from best response to progressive disease, PD), progression free survival (PFS) and overall survival (OS). Response was determined in accordance with the Sixth International Workshop on WM (IWWM) response criteria 2. Baseline characteristics and toxicity data were also collated. RESULTS Of the 84 patients who had commenced ibrutinib, sufficient data was available for 62 patients; median age was 69 years (range 44 - 85) and 40 (64.5%) were male. Among the 50 patients for whom International Prognostic Scoring System for WM (IPSSWM) data were available, the IPSSWM risk score at the time of ibrutinib initiation was low (n=8, 16%), intermediate (n=25, 50%) and high (n=17, 34%). The median number of prior therapy lines was 2 (range 1 - 7). The median time from diagnosis to commencement of ibrutinib was 70 months (Range 2 - 243). The median follow-up was 29 months (Range 3 - 71). Objective response rate (≥MR) was 79% (n=49) and MRR was 62.9% (n=39). Best response achieved was CR in 12.9%, VGPR in 24.2%, PR in 25.8%, MR in 16.1% and SD in 11.2%; 9.7% of patients experienced PD. The median time to best response was 5 months (Figure 1A) and the median EFS was 37 months (Range 3 - 71). Of the 49 patients who achieved an objective response, the median PFS was not reached and the two-year predicted PFS rate was 73.5%. At the time of analysis, 15 patients (24.2%) had discontinued ibrutinib due to disease progression, 5 (8.1%) due to adverse effects and 4 (6.5%) due to death. The median OS was not reached, and the predicted two-year OS rate was 87.8% (Figure 1B). The most common adverse effects were diarrhoea (14.5%), atrial fibrillation (AF, 9.7%) and rash (9.7%). Six of the seven patients who developed treatment-emergent AF continued ibrutinib with concurrent anticoagulants and either rate or rhythm control. Ibrutinib was permanently discontinued due to heart failure/AF (n=1), intracranial haemorrhage whilst taking ibrutinib and warfarin concurrently for brittle antiphospholipid syndrome and WM (n=1), significant liver function derangement (n=2) and intractable diarrhoea (n=1). Ibrutinib dose was reduced to 280 mg daily (n=13) and 140 mg daily (n=4) due to adverse reactions. CONCLUSION In a real-world setting, ibrutinib produces clinically meaningful objective responses in patients with relapsed WM; these response rates are comparable to those achieved in a clinical trial setting. Ibrutinib can produce durable disease control with long remission intervals. The toxicity profile is acceptable. REFERENCES 1. Treon, S., Meid, K., Gustine, J., Yang, G., Xu, L., & Liu, X. et al. (2021). Long-Term Follow-Up of Ibrutinib Monotherapy in Symptomatic, Previously Treated Patients With Waldenström Macroglobulinemia. Journal Of Clinical Oncology, 39(6), 565-575. doi: 10.1200/jco.20.00555 2. Owen, S., Kyle, R., Stone, M., Rawstron, A., Leblond, V., Merlini, G. et al. (2013). Response assessment in Waldenström Macroglobulinemia: updated from the VIth International Workshop. British Journal of Haematology, 60, 171-176. doi: 10.1111/bjh.12102 Figure 1 Figure 1. Disclosures D'Sa: Sanofi: Honoraria; BeiGene: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding.

Comparative study of midline versus paramedian approach of spinal block in elderly.

Objective: To compare the efficacy of paramedian and midline approach for spinal block in elderly, in terms of success rate and number of attempts required by either approach. Study Design: Randomized Controlled Trial. Setting: Department of Anaesthesia, Madina Teaching Hospital Faisalabad. Period: January 2018 to December 2019. Material & Method: 120 elderly ASA I-III patients scheduled to undergo lower abdominal or limbs; general or orthopaedic surgery were randomly divided into two equal groups A and B of sixty patients. Patients were assigned into groups by lottery method. Group A patients were supposed to receive spinal block by midline approach while group B patients were planned to receive spinal block by paramedian approach. Results: It was observed that success rate was significantly high in group B, 98.3% as compared to group A, 80%, (p value 0.001). The number of attempts were significantly less in group B in comparison to group A (p-value 0.0001). Conclusion: The paramedian approach for spinal block in elderly patient’s offers ease of administration and a higher success rate as compared to midline approach.

Comparison of Salbutamol and Salbutamol with ipratropium bromide in children with exacerbation of Asthma in terms of peak expiratory flow rate (PEFR).

Objective: To compare the Salbutamol alone and Ipratropium Bromide supplemented Salbutamol in children with exacerbation of asthma in terms of PEFR. Study Design: Randomized Controlled Trial. Setting: Pediatrics Emergency, KRL Hospital Islamabad. Period: 1st August 2016 to 31 January 2017. Material & Methods: Group A patients were given only Salbutamol (0.15mg/kg per dose with minimum 2.5 mg, maximum 5 mg/dose). Group B was given Ipratropium Bromide supplemented Salbutamol (250 mcg/dose for <20 kg while 500 mcg/dose for >20kg of Ipratropium Bromide with same dose of Salbutamol as prescribed for Group A). Baseline spirometry was performed on each patient and after measurement of baseline peak expiratory flow. The outcome was measured by Peak flow meter and reassessed at 60 minutes. Results: Comparison of salbutamol alone and ipratropium bromide supplemented salbutamol in children with exacerbation of asthma in terms of PEFR shows that 40.5 + 4.28 in Group-A and 59.5 +4.75 in Group-B, P-value was calculated as 0.0001, showing a significant difference between the two groups while the difference in increase was recorded as 19%. Conclusion: We concluded that salbutamol alone is significantly less effective when compared with Ipratropium Bromide supplemented Salbutamol in children with exacerbation of asthma in terms of PEFR.

Rapid 500 mL albumin bolus versus rapid 200 mL bolus followed by slower continuous infusion in post-cardiac surgery patients: a pilot before-and-after study

OBJECTIVE: To evaluate the haemodynamic effects of rapid fluid bolus therapy (FBT) (500 mL of 4% albumin over several minutes) versus combined FBT (rapid 200 mL FBT followed by a 300 mL infusion over 30 minutes). DESIGN: Single centre, prospective, before-and-after trial. SETTING: A tertiary intensive care unit in Australia. PARTICIPANTS: Fifty mechanically ventilated post-cardiac surgery patients. INTERVENTIONS: Rapid 4% albumin FBT versus combined FBT. MAIN OUTCOME MEASURES: We recorded haemodynamic parameters from before FBT to 30 minutes after FBT. A mean arterial pressure (MAP) response was defined by a MAP increase > 10%, and a cardiac index (CI) response was defined by a CI increase > 15%. RESULTS: Immediately after rapid FBT versus combined FBT, there was a CI response in 13 patients (52%) compared with five patients (20%) respectively (P = 0.038), and a MAP response in 11 patients (44%) in each group. However, from FBT administration to 30 minutes, there was a time and group interaction such that MAP was higher in the rapid FBT group (P = 0.003), as was the case for central venous pressure (P = 0.002) and mean pulmonary artery pressure (P < 0.001). Body temperature fell immediately and was lower with rapid FBT but became warmer than with combined FBT later (P < 0.001). At 30 minutes, a MAP response was seen in ten patients (40%) compared with nine patients (36%) (P < 0.99) and a CI response was present in eight patients (32%) compared with 11 patients (44%) (P = 0.56) in the rapid versus combined FBT groups respectively. CONCLUSION: Rapid FBT was superior to combined FBT in terms of mean MAP levels and immediate CI response. However, the number of MAP responders or CI responders was similar at 30 minutes.