scholarly journals Use of the Estimand Framework to Manage the Disruptive Effects of COVID-19 on Stroke Clinical Trials

Stroke ◽  
2021 ◽  
Author(s):  
Nawaf Yassi ◽  
Kathryn S. Hayward ◽  
Bruce C.V. Campbell ◽  
Leonid Churilov
Keyword(s):  
Sensitivity Analysis ◽  
Clinical Trials ◽  
Intracerebral Hemorrhage ◽  
Stroke Care ◽  
Study Groups ◽  
Stroke Recovery ◽  
International Council ◽  
Statistical Strategy ◽  
Multiple Stages

The coronavirus disease 2019 (COVID-19) pandemic has presented unique challenges to stroke care and research internationally. In particular, clinical trials in stroke are vulnerable to the impacts of the pandemic at multiple stages, including design, recruitment, intervention, follow-up, and interpretation of outcomes. A carefully considered approach is required to ensure the appropriate conduct of stroke trials during the pandemic and to maintain patient and participant safety. This has been recently addressed by the International Council for Harmonisation which, in November 2019, released an addendum to the Statistical Principles for Clinical Trials guidelines entitled Estimands and Sensitivity Analysis in Clinical Trials. In this article, we present the International Council for Harmonisation estimand framework for the design and conduct of clinical trials, with a specific focus on its application to stroke clinical trials. This framework aims to align the clinical and scientific objectives of a trial with its design and end points. It also encourages the prospective consideration of potential postrandomization intercurrent events which may occur during a trial and either impact the ability to measure an end point or its interpretation. We describe the different categories of such events and the proposed strategies for dealing with them, specifically focusing on the COVID-19 pandemic as a source of intercurrent events. We also describe potential practical impacts posed by the COVID-19 pandemic on trials, health systems, study groups, and participants, all of which should be carefully reviewed by investigators to ensure an adequate practical and statistical strategy is in place to protect trial integrity. We provide examples of the implementation of the estimand framework within hypothetical stroke trials in intracerebral hemorrhage and stroke recovery. While the focus of this article is on COVID-19 impacts, the strategies and principles proposed are well suited for other potential events or issues, which may impact clinical trials in the field of stroke.

scholarly journals P431 Teduglutide use and nutritional outcomes in short bowel syndrome with intestinal failure: a real-world claims database analysis

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S433-S434
Author(s):  
D Micic ◽  
J Jiang ◽  
L Chen ◽  
T Fan ◽  
F Mu ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Clinical Trials ◽  
Short Bowel Syndrome ◽  
Real World ◽  
Index Date ◽  
Intestinal Failure ◽  
Sensitivity Analyses ◽  
Future Research ◽  
Short Bowel

Abstract Background Teduglutide (TED) is a glucagon-like peptide 2 analogue approved for the treatment of patients with short bowel syndrome (SBS) requiring parenteral support (PS). SBS is a rare condition resulting from a reduced absorptive surface area of the small intestine, most commonly due to inflammatory bowel disease (IBD). Patients with SBS with intestinal failure (SBS-IF) remain dependent on PS to maintain adequate calorie, fluid, electrolyte and micronutrient stability. In phase 3 clinical trials, TED reduced PS requirements in patients with SBS-IF. This study aimed to assess PS use and discontinuation rates among patients with SBS on TED using real-world data. Methods This retrospective cohort study of adults with SBS-IF (≥18 years) with ≥1 TED pharmacy claim(s) used the US-based administrative healthcare claims IBM MarketScan database (2009–2019). The first TED claim was defined as the index date. Patients required ≥6 months of continuous enrolment prior to index date (baseline period) and no history of malignancy. Primary analysis was conducted during the follow-up period (index date to earliest of continuous enrolment end or 2 years post-index). A sensitivity analysis was also conducted among the cohort during the TED utilization period (index date to the earliest of continuous enrolment end or TED discontinuation). Patients required PS use during both baseline and follow-up/TED utilization periods (primary and sensitivity analyses). PS discontinuation was defined as a PS utilization gap of ≥30 days. A generalized estimating equation linear regression model evaluated if PS use (days/week) changed significantly from baseline to selected time points post-index. Results Of 110 identified patients with SBS-IF, mean age was 53.4 (SD 13.2) years and 77 (70%) were women. Included were 51 (46%) patients with Crohn’s disease and 20 (18%) with ulcerative colitis. The main comorbidities were renal disease (23%) and liver disease (15%). PS frequency was 4.6 (2.5), 3.3 (2.9), 2.9 (3.0) and 3.6 (3.0) days/week at baseline and months 6 (p<0.0001), 12 (p<0.0001), and 24 (p=0.0267), respectively. PS discontinuation increased over time to 34.4%, 46.7% and 65.2% at 3, 6, and 12 months, respectively. The sensitivity analysis demonstrated similar rates of PS use and discontinuation. Conclusion In this real-world study of adults with SBS-IF, including >50% with IBD, TED was associated with PS reductions comparable to those achieved in clinical trials and higher PS discontinuation rates even when using a conservative analysis approach. Future research will be required to determine individual predictive factors of PS discontinuation.

A note on the draft International Council for Harmonisation guidance on estimands and sensitivity analysis

2019 ◽  
Vol 16 (4) ◽  
pp. 339-344 ◽  
Author(s):  
Devan V Mehrotra
Keyword(s):  
Clinical Trial ◽  
Sensitivity Analysis ◽  
Clinical Trials ◽  
Working Group ◽  
Trial Design ◽  
Clinical Trial Design ◽  
Steering Committee ◽  
Therapeutic Area ◽  
International Council ◽  
Expert Working Group

In the second half of 2014, the Steering Committee of the International Council for Harmonisation endorsed the formation of an expert working group to develop an addendum to the International Council for Harmonisation E9 guideline ( Statistical Principles for Clinical Trials). The addendum was to focus on two clinical trial topics: estimands and sensitivity analysis. A draft of the addendum, referred to as E9/R1, was developed by the expert working group and made available for public comments across the International Council for Harmonisation regions in the second half of 2017. A structured framework for clinical trial design and analysis proposed in the draft addendum are briefly described, including four key inputs for developing objective-driven estimands and strategies for tackling one of the inputs (‘intercurrent events’). The proposed framework aligns each clinical trial objective with the corresponding statistical target of estimation (estimand), trial design and data to be collected, main method of estimation/inference, and sensitivity analysis to pressure test key analytic assumption(s) in the main analysis. A case study from the diabetes therapeutic area illustrates how the framework can be implemented in practice. International Council for Harmonisation E9/R1 is expected to enable better planning, conduct, analysis, and interpretation of randomised clinical trials. This will facilitate improvements in new drug applications and strengthen understanding of decision making by regulatory authorities and advisory committees.

scholarly journals A method to visualize a complete sensitivity analysis for loss to follow-up in clinical trials

2020 ◽  
Vol 19 ◽  
pp. 100586
Author(s):  
Enrique F. Schisterman ◽  
Elizabeth A. DeVilbiss ◽  
Neil J. Perkins
Keyword(s):  
Sensitivity Analysis ◽  
Clinical Trials ◽  
Loss To Follow Up

Intracerebral Hematoma, Perihemorrhagic Edema and Urinary Excreted Cysteinyl Leukotrienes Correlation Study

2014 ◽  
Vol 68 (2) ◽  
pp. 85-88
Author(s):  
Natalija Dolnenec-Baneva ◽  
Dijana Nikodijevic ◽  
Gordana Kiteva-Trenchevska ◽  
Igor Petrov ◽  
Dragana Petrovska-Cvetkovska ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Brain Edema ◽  
Correlation Study ◽  
Intracerebral Hematoma ◽  
Moderate Correlation ◽  
Hematoma Volume ◽  
Cysteinyl Leukotrienes ◽  
Edema Volume ◽  
Perihemorrhagic Edema

AbstractIntroduction.Several mechanisms in formation of perihemorrhagic edema are activated after contact of brain tissue-extravasated blood in intracerebral hemorrhage. Cysteinyl leukotrienes (cysLT) (C4, D4, E4) are included in this process as significant edema factors and they determine the neurological deficit and outcome. The study aim was a 5-day follow-up (admission/3 day/5 day) of urinary cysLT, hematoma volume, edema volume values and their correlation in patients after spontaneous, primary supratentorial intracerebral hemorrhage.Methods.An enzyme immunoassay was used for urinary cysLT measured in 62 patients and 80 healthy controls. Hematoma and edema volumes were visualized and measured by computed tomography and mathematically calculated with a special spheroid shape formula (V=AxBxC/2).Results.CysLT of hemorrhagic patients (1842.20±1413.2, 1181.54±906.2, 982.30±774.2pg/ml/mg creatinine) were significantly excreted (p<0.01). Brain edema (12.86±13.5, 22.38±21.1, 28.45±29.4cm3) was significantly increased (p<0.01). Hematoma volume values (13.05±14.5, 13.13±14.7, 12.99±14.7cm3) were not significant (p>0.05). A high correlation (multiple regression) between cysLT, hematoma and edema was found on the 3rdday (R=0.6) and a moderate correlation at admission (R=0.3) and on the 5thday (R=0.3).Conclusion.In our 5-day follow-up study a significant cysLT brain synthesis and significant brain edema progression versus constant hematoma volume values in hemorrhagic patients was found. A high correlation between cysLT, hematoma and edema volume was found on the 3rdday, a moderate correlation on admission and on the 5thday, which means that high cysLT and hematoma values were associated with high/moderate edema values.

The Significance of Renal Function in Response to Cardiac Resynchronisation Therapy – The Piece of a Much Larger Puzzle

2020 ◽  
Vol 18 ◽  
Author(s):  
Agnieszka Dębska-Kozłowska ◽  
Izabela Warchoł ◽  
Marcin Książczyk ◽  
Andrzej Lubiński
Keyword(s):  
Renal Function ◽  
Nyha Class ◽  
Heart Association ◽  
Cardiac Resynchronisation Therapy ◽  
Study Groups ◽  
Creatinine Concentration ◽  
Significant Difference ◽  
Cardiac Resynchronisation ◽  
Resynchronisation Therapy

Background: Although cardiac resynchronisation therapy (CRT) is an important player in the treatment of heart failure (HF) patients, the proportion of CRT patients with no improvement in either echocardiographic or clinical parameters remains consistently high and accounts for about 30% despite meeting CRT implantation criteria. Furthermore, in patients suffering from HF, renal dysfunction accounts for as many as 30-60%. Accordingly, CRT may improve renal function inducing a systemic haemodynamic benefit leading to increased renal blood flow. Objectives: The aim of the present study was to evaluate the importance of renal function in response to resynchronisation therapy during a 12-month follow-up period. Materials and methods: The study consisted of 46 HF patients qualified for implantation of cardiac resynchronisation therapy defibrillator (CRT-D). A CRT responder is defined as a person without chronic HF exacerbations during observation whose physical efficiency has improved owing to New York Heart Association (NYHA) class improvement ≥1. Results: A statistically significant difference was noted between responders and non-responders regarding creatinine level at the 3rd month (p=0.04) and, particularly, at the 12th month (p=0.02) of follow-up (100±23 vs 139±78 μmol/l). Moreover, there was a remarkable difference between both study groups with regard to GFR CKD-EPI (glomerular filtration rate (GFR) assessed using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula) at the 6th (p=0.03) and 12th month (p=0.01) of follow-up. The reference values for initial creatinine concentrations (101 μmol/l) as well as GFR CKD-EPI (63 ml/min/1.73m2 ) were empirically evaluated to predict favourable therapeutic CRT response. Conclusions: Predictive value of GFR CKD-EPI and creatinine concentration for a positive response to CRT were found relevant.

scholarly journals Real-World Experience with Bezlotoxumab for Prevention of Recurrence of Clostridioides difficile Infection

2020 ◽  
Vol 10 (1) ◽  
pp. 2
Author(s):  
Rosa Escudero-Sánchez ◽  
María Ruíz-Ruizgómez ◽  
Jorge Fernández-Fradejas ◽  
Sergio García Fernández ◽  
María Olmedo Samperio ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Real World ◽  
Recurrence Rates ◽  
Factors Associated ◽  
Clostridioides Difficile ◽  
Multicentre Cohort Study ◽  
Clostridioides Difficile Infection ◽  
Prevention Of Recurrence ◽  
Multicentre Cohort

Bezlotoxumab is marketed for the prevention of recurrent Clostridioides difficile infection (rCDI). Its high cost could be determining its prescription to a different population than that represented in clinical trials. The objective of the study was to verify the effectiveness and safety of bezlotoxumab in preventing rCDI and to investigate factors related to bezlotoxumab failure in the real world. A retrospective, multicentre cohort study of patients treated with bezlotoxumab in Spain was conducted. We compared the characteristics of cohort patients with those of patients treated with bezlotoxumab in the pivotal MODIFY trials. We assessed recurrence rates 12 weeks after completion of treatment against C. difficile, and we analysed the factors associated with bezlotoxumab failure. Ninety-one patients were included in the study. The cohort presented with more risk factors for rCDI than the patients included in the MODIFY trials. Thirteen (14.2%) developed rCDI at 12 weeks of follow-up, and rCDI rates were numerically higher in patients with two or more previous episodes (25%) than in those who had fewer than two previous episodes of C. difficile infection (CDI) (10.4%); p = 0.09. There were no adverse effects attributable to bezlotoxumab. Despite being used in a more compromised population than that represented in clinical trials, we confirm the effectiveness of bezlotoxumab for the prevention of rCDI.

scholarly journals Moderate Consumption of Beer (with and without Ethanol) and Menopausal Symptoms: Results from a Parallel Clinical Trial in Postmenopausal Women

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2278
Author(s):  
Marta Trius-Soler ◽  
María Marhuenda-Muñoz ◽  
Emily P. Laveriano-Santos ◽  
Miriam Martínez-Huélamo ◽  
Gemma Sasot ◽  
...  
Keyword(s):  
Postmenopausal Women ◽  
Study Groups ◽  
Menopausal Symptoms ◽  
Control Group ◽  
P Value ◽  
Intervention Trial ◽  
Hormone Profile ◽  
Perimenopausal Symptoms ◽  
Main Food Source

The menopausal transition can be a challenging period for women’s health and a trigger of uncomfortable symptoms. Beer is the main food source of isoxanthohumol, a precursor of 8-prenylnaringenin, the strongest phytoestrogen identified to date. As phytoestrogens are reported to reduce perimenopausal symptoms, we evaluated if a daily moderate consumption of beer with (AB) and without alcohol (NAB) could improve menopausal symptoms and modify cardiovascular risk factors. A total of 37 postmenopausal women were enrolled in a parallel controlled intervention trial and assigned to three study groups: 16 were administered AB (330 mL/day), 7 NAB (660 mL/day), and 14 were in the control group. After a 6-month follow-up of the 34 participants who finished the trial, both interventions (AB and NAB) significantly reduced the severity of the menopause-related symptoms (p-value AB vs. Control: 0.009; p-value NAB vs. Control: 0.033). Moreover, AB had a beneficial net effect on psychological menopausal discomforts compared to the control group. As the sex hormone profile did not differ significantly between the study groups, the effects of both types of beers (AB and NAB) are attributed to the non-alcoholic fraction of beer. Furthermore, moderate NAB consumption improved the lipid profile and decreased blood pressure in postmenopausal women.

scholarly journals Disability improvement as a clinically relevant outcome in clinical trials of relapsing forms of multiple sclerosis

2021 ◽  
pp. 135245852110002
Author(s):  
Bruce AC Cree ◽  
Jeffrey A Cohen ◽  
Anthony T Reder ◽  
Davorka Tomic ◽  
Diego Silva ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Therapeutic Benefit ◽  
Disease Modifying Therapies ◽  
Long Term Follow Up ◽  
Post Hoc ◽  
Switch Group ◽  
Relevant Outcome

Background: Disease-modifying therapies (DMTs) can reduce the risk of disability worsening in patients with relapsing forms of multiple sclerosis (RMS). High-efficacy DMTs can lead to confirmed or sustained disability improvement (CDI and SDI). Objective and Methods: Post hoc analyses of data from the TRANSFORMS, FREEDOMS, and FREEDOMS II trials and their extensions assessed the effects of fingolimod (0.5–1.25 mg/day) on stabilizing or improving disability over ⩽8 years in participants with RMS. CDI and SDI rates were compared between participants initially randomized to fingolimod, interferon (IFNβ-1a), or placebo. Results: At 8 years’ follow-up in TRANSFORMS, 35.1% (95% confidence interval [CI], 28.2%–43.1%) of assessed participants in the IFNβ-1a–fingolimod switch group and 41.9% (36.6%–47.6%) on continuous fingolimod experienced CDI; disability did not worsen in approximately 70%. Similar results were seen in the combined FREEDOMS population. Proportionally fewer TRANSFORMS participants achieved SDI in the IFNβ-1a–fingolimod switch group than on continuous fingolimod (5.4% [3.0%–9.5%] vs 14.2% [10.8%–18.4%], p = 0.01). Conclusion: CDI and SDI are outcomes of interest for clinical trials and for long-term follow-up of participants with RMS. Monitoring CDI and SDI in addition to disability worsening may facilitate understanding of the therapeutic benefit of RMS treatments.

Patients with shoulder pain referred to specialist care; treatment, predictors of pain and disability, emotional distress, main symptoms and sick-leave: a cohort study with a six-months follow-up

2020 ◽  
Vol 20 (4) ◽  
pp. 775-783
Author(s):  
Kaia B. Engebretsen ◽  
Jens Ivar Brox ◽  
Niels Gunnar Juel
Keyword(s):  
Clinical Trials ◽  
Cohort Study ◽  
Sick Leave ◽  
Shoulder Pain ◽  
Emotional Distress ◽  
Outpatient Clinic ◽  
Treatment Duration ◽  
Specialist Care ◽  
Yellow Flags

AbstractObjectivesRecommendations for referral of patients with shoulder pain from primary to specialist care are mainly clinical. Several patients are referred without meeting these criteria for referral, whereas some are referred for a second opinion although surgery is not recommended. The aims of this study were to describe a shoulder pain cohort in specialist healthcare according to demographic data, clinical, and psychological factors; evaluate changes in pain and disability, distress and main symptoms from baseline to six-month follow-up; and to assess predictors of pain and disability, changes in the main symptoms and sick-leave at six-months. Results were compared to previous randomised trials conducted at the same clinic in patients with subacromial shoulder pain.MethodsThis prospective study included 167 patients from an outpatient clinic in specialist healthcare with shoulder pain for more than 6 weeks. Clinical (pain duration, intensity, pain sites), sociodemographic (age, gender, educational level, work status) and psychological variables (emotional distress (HSCL-10), fear of pain, screening of “yellow flags”, health-related quality of life) were collected. Shoulder pain and disability (SPADI-score) were assessed and the patients were asked about their outcome expectation and to predict their status of their shoulder problem the next month. They underwent a clinical interview, a clinical assessment of shoulder function and orthopaedic tests for diagnostic purposes. After six months they received a questionnaire with main variables.ResultsOf the 167 patients (55% women), 50% had symptoms for more than 12 months and 37 (22%) were on sick-leave. Characteristics were in general comparable to patients previously included in clinical trials at the same department. The SPADI-score was 46 (23) points. Mean emotional distress was within the normal range (1.7 (SD 0.6)). More than 80% had received treatment before, mainly physiotherapy in addition to the GPs treatment. One hundred and thirty-seven patients (82%) were re-referred to physiotherapy, 74 (44%) in the outpatient clinic specialist healthcare, and 63 (38%) in primary care. One hundred and eighteen (71%) answered the follow-up questionnaire. Mean change in SPADI-score was 10.5 points (95% CI (6.5–14.5)), and 29% of the patients improved more than the smallest detectable difference (SDD). The percentage sick-listed was 19.5%, and mean change in main symptoms (−9 to +9) was 3.4 (SD 3.9). The subgroup of patients receiving physiotherapy in outpatient specialist care did not show any significant change in the main variables. The prediction models suggested that a lower level of education, more fear of pain and a high baseline SPADI-score, predicted a higher SPADI-score at follow-up. A high baseline HSCL-10 score was the only significant predictor for a high HSCL-10 score. At follow-up, less pain at rest predicted more change in main symptoms and more yellow flags (a higher score on the Örebro screening test) predicted sick-leave.ConclusionsWithin the limitations of a cohort study, patients with persistent shoulder pain referred to an outpatient specialist clinic had similar baseline characteristics but shorter treatment duration, inferior clinical results and predictors somewhat different compared with previous clinical trials conducted at the same clinic. The study raises some questions about the effectiveness of the routines in daily clinical practice, the selection of patients, the treatment duration and content.

scholarly journals Conservative oxygen therapy for critically ill patients: a meta-analysis of randomized controlled trials

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Xiao-Li Chen ◽  
Bei-Lei Zhang ◽  
Chang Meng ◽  
Hui-Bin Huang ◽  
Bin Du
Keyword(s):  
Sensitivity Analysis ◽  
Randomized Controlled Trials ◽  
Critically Ill Patients ◽  
Oxygen Therapy ◽  
Primary Outcome ◽  
Meta Analysis ◽  
Controlled Trials ◽  
Icu Patients ◽  
Randomized Controlled

Abstract Objective Conservative oxygen strategy is recommended in acute illness while its benefit in ICU patients remains controversial. Therefore, we sought to conduct a systematic review and meta-analysis to examine such oxygen strategies’ effect and safety in ICU patients. Methods We searched PubMed, Embase, and the Cochrane database from inception to Feb 15, 2021. Randomized controlled trials (RCTs) that compared a conservative oxygen strategy to a conventional strategy in critically ill patients were included. Results were expressed as mean difference (MD) and risk ratio (RR) with a 95% confidence interval (CI). The primary outcome was the longest follow-up mortality. Heterogeneity, sensitivity analysis, and publication bias were also investigated to test the robustness of the primary outcome. Results We included seven trials with a total of 5265 patients. In general, the conventional group had significantly higher SpO2 or PaO2 than that in the conservative group. No statistically significant differences were found in the longest follow-up mortality (RR, 1.03; 95% CI, 0.97–1.10; I2=18%; P=0.34) between the two oxygen strategies when pooling studies enrolling subjects with various degrees of hypoxemia. Further sensitivity analysis showed that ICU patients with mild-to-moderate hypoxemia (PaO2/FiO2 >100 mmHg) had significantly lower mortality (RR, 1.24; 95% CI, 1.05–1.46; I2=0%; P=0.01) when receiving conservative oxygen therapy. These findings were also confirmed in other study periods. Additional, secondary outcomes of the duration of mechanical ventilation, the length of stay in the ICU and hospital, change in sequential organ failure assessment score, and adverse events were comparable between the two strategies. Conclusions Our findings indicate that conservative oxygen therapy strategy did not improve the prognosis of the overall ICU patients. The subgroup of ICU patients with mild to moderate hypoxemia might obtain prognosis benefit from such a strategy without affecting other critical clinical results.

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