Polyethylene glycol (PEG)-based bowel preparations are effective cleansers but many require high-volume intake. This phase 3, randomized, blinded, multicenter, parallel-group, central reader-assessed ...study assessed the 1 L PEG NER1006 bowel preparation vs. standard 2 L PEG with ascorbate (2LPEG).
Patients undergoing colonoscopy were randomized (1:1:1) to receive NER1006, as an evening/morning (N2D) or morning-only (N1D) regimen, or evening/morning 2LPEG. Cleansing was assessed using the Harefield Cleansing Scale (HCS) and the Boston Bowel Preparation Scale (BBPS). Primary end points were overall bowel cleansing success and high-quality cleansing in the right colon. Modified full analysis set (mFAS) and per protocol (PP) analyses were performed. Mean cleansing scores were analyzed post hoc
RESULTS: Of 849 randomized patients, efficacy was analyzed in the following patient numbers (mFAS/PP): total n = 822/670; N2D n = 275/220; N1D n = 275/218; 2LPEG n = 272/232. mFAS established noninferiority. PP showed superiority for N2D on overall success (97.3 % vs. 92.2 %;
= 0.014), and for N2D and N1D on right colon high-quality cleansing (N2D 32.3 % vs. 15.9 %,
< 0.001; N1D 34.4 % vs. 15.9 %,
< 0.001) vs. 2LPEG. Using HCS, N2D and N1D attained superior segmental high-quality cleansing (
≤ 0.003 per segment). N2D showed superior mean segmental HCS scores (
≤ 0.007 per segment). Both N2D and N1D achieved superior mean overall (
< 0.001 and
= 0.006) and right colon BBPS scores (
< 0.001 and
= 0.013). N2D demonstrated superior right colon polyp detection (
= 0.024). Adherence, tolerability, and safety were comparable between treatments.
NER1006 is the first low-volume preparation to demonstrate superior colon cleansing efficacy vs. standard 2LPEG with ascorbate, with comparable safety and tolerability. European Clinical Trials Database (EudraCT)2014-002185-78TRIAL REGISTRATION: Multicenter, randomized, parallel group, phase 3 trial 2014-002185-78 at https://eudract.ema.europa.eu/.
Polyethylene glycol (PEG) bowel preparations are widely used for precolonoscopy bowel cleansing. This phase 3 trial assessed the efficacy, safety, and tolerability of the novel 1 L PEG-based NER1006 ...vs. sodium picosulfate plus magnesium citrate (SP + MC) in day-before dosing.
Patients requiring colonoscopy were randomized (1 : 1) to receive NER1006 or SP + MC. Cleansing was assessed on the Harefield Cleansing Scale (HCS) and Boston Bowel Preparation Scale (BBPS) using central readers. Two primary end points were assessed: overall colon cleansing success and high-quality cleansing of the right colon. Intention-to-treat (modified full analysis set mFAS) and per protocol (PP) analyses were performed.
Of 515 patients, efficacy was analyzed in 501 (NER1006, n = 250; SP + MC, n = 251) and 379 patients (NER1006, n = 172; SP + MC, n = 207) in the mFAS and PP analyses, respectively. Non-inferiority of NER1006 vs. SP + MC was established in the mFAS for both overall cleansing (62.0 % vs. 53.8 %;
= 0.04) and high-quality cleansing in the right colon (4.4 % vs. 1.2 %;
= 0.03). Superiority of NER1006 was demonstrated using HCS in the PP set for overall cleansing success (68.0 % vs. 57.5 %;
= 0.02) and right colon high-quality cleansing (5.2 % vs. 1.0 %;
= 0.02) and using BBPS in the mFAS for overall cleansing success (58.4 % vs. 45.8 %;
= 0.003) and right colon high-quality cleansing (4.0 % vs. 0.8 %;
= 0.02). Mean segmental scores for 4/5 segments were higher with NER1006 (
≤ 0.04). Both treatments were well tolerated, with more mild adverse events for NER1006 (17.0 % vs. 10.0 %;
= 0.03).
Colon cleansing with NER1006 vs. SP + MC was non-inferior (mFAS) and superior (PP), with acceptable safety.European Clinical Trials Database (EudraCT)2014-002186-30TRIAL REGISTRATION: Multicenter, randomized, parallel group, phase 3 study 2014-002186-30 at https://eudract.ema.europa.eu/.
Age of transfused blood in critically ill adults Lacroix, Jacques; Hébert, Paul C; Fergusson, Dean A ...
New England journal of medicine/The New England journal of medicine,
04/2015, Volume:
372, Issue:
15
Journal Article
Peer reviewed
Open access
Fresh red cells may improve outcomes in critically ill patients by enhancing oxygen delivery while minimizing the risks of toxic effects from cellular changes and the accumulation of bioactive ...materials in blood components during prolonged storage.
In this multicenter, randomized, blinded trial, we assigned critically ill adults to receive either red cells that had been stored for less than 8 days or standard-issue red cells (the oldest compatible units available in the blood bank). The primary outcome measure was 90-day mortality.
Between March 2009 and May 2014, at 64 centers in Canada and Europe, 1211 patients were assigned to receive fresh red cells (fresh-blood group) and 1219 patients were assigned to receive standard-issue red cells (standard-blood group). Red cells were stored a mean (±SD) of 6.1±4.9 days in the fresh-blood group as compared with 22.0±8.4 days in the standard-blood group (P<0.001). At 90 days, 448 patients (37.0%) in the fresh-blood group and 430 patients (35.3%) in the standard-blood group had died (absolute risk difference, 1.7 percentage points; 95% confidence interval CI, -2.1 to 5.5). In the survival analysis, the hazard ratio for death in the fresh-blood group, as compared with the standard-blood group, was 1.1 (95% CI, 0.9 to 1.2; P=0.38). There were no significant between-group differences in any of the secondary outcomes (major illnesses; duration of respiratory, hemodynamic, or renal support; length of stay in the hospital; and transfusion reactions) or in the subgroup analyses.
Transfusion of fresh red cells, as compared with standard-issue red cells, did not decrease the 90-day mortality among critically ill adults. (Funded by the Canadian Institutes of Health Research and others; Current Controlled Trials number, ISRCTN44878718.).
NER1006 is the first 32 fluid ounce (1 L) polyethylene glycol-based bowel preparation. This randomized, multicenter, colonoscopist/central reader-blinded phase 3 non-inferiority trial assessed the ...efficacy, safety, and tolerability of NER1006 versus trisulfate for bowel cleansing.
Patients undergoing colonoscopy were randomized (1:1) to receive NER1006 or trisulfate, using evening/morning split-dosing administration. Blinded central readers used the validated Harefield Cleansing Scale to evaluate 2 alternative primary endpoints: overall bowel-cleansing success and high-quality cleansing of the ascending colon/cecum. Secondary endpoints included lesion detection, Boston Bowel Preparation Scale (BBPS) assessment, and adherence. The non-inferiority margin was 10% and the significance threshold was P < .025.
Of 621 patients randomized (NER1006, n=310; trisulfate, n=311), 556 were evaluated for efficacy (NER1006, n=276; trisulfate, n=280). NER1006 achieved non-inferiority versus trisulfate for both primary endpoints of overall bowel-cleansing success (85.1% vs 85.0%; difference, 0.14%; one-sided 97.5% lower confidence limit LCL, −8.15%; P = .528) and high-quality cleansing of the ascending colon/cecum (35.9% versus 29.3%; difference, 6.58%; LCL, −1.69%; P = .059). BBPS assessments supported overall bowel-cleansing success rates. Lesion detection rates were similar between the groups. The percentage of patients with treatment-related adverse events was 14.9% with NER1006 and 9.4% with trisulfate. Both bowel preparations showed similar overall tolerability and safety profiles. Adherence was very high in both arms.
With evening/morning split dosing, NER1006 was as effective as trisulfate for overall bowel and right-sided colon cleansing. Adverse event rates were slightly higher with NER1006 than trisulfate, but did not compromise tolerability, adherence, or efficacy. (Clinical trial registration number: NCT02254486.)
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Colonoscopy requires colon cleansing. For this, many polyethylene glycol (PEG)-based preparations still require a high preparation-volume intake. Using an increased osmotic load with ascorbate (Asc), ...five new low-volume PEG-based bowel preparations (LVPEG) were tested for clinical proof of concept.
This two-part, open-label study examined preparation-volumes of 1-1.25 L and total required fluid volumes of 2-3 L. Part 1, in healthy volunteers, used mean cumulative 24-h stool weight (target > 2750 g) to identify a lead candidate. Part 2 was endoscopist-blinded: patients undergoing screening colonoscopy were randomized before treatment with the selected lead, one of two variants of it, or the control 2 L PEG + Asc. Two primary endpoints were used for proof of concept demonstration: mean 24-h stool weight and bowel cleansing success (Harefield Cleansing Scale).
A total of 120 subjects (30 per group) were enrolled/randomized 1:1:1:1 (max 40:60 gender ratio) per completed Part. In Part 1, LVPEG-3 achieved the largest mean stool weight (3399 g: P < 0.0001 vs target) and was selected for Part 2. In Part 2, stool weights exceeded the target, notably for LVPEG-4 (3215 g: P < 0.001), which achieved 100% cleansing success after a total required fluid intake of 2 L. The control achieved 90% cleansing success. Adverse events were few, gastrointestinal in nature and similar between groups.
LVPEG-4 achieved a clinically useful combination of cleansing, safety/tolerability and low consumption volume: 1 L preparation + 1 L required additional fluid. Named NER1006, LVPEG-4 demonstrated clinical proof of concept and warrants further investigation.
October 2012. Identifier: NCT01714466 . EudraCT: 2012-003052-37 The trial was prospectively registered.
Delays in treating anaesthesia-induced malignant hyperthermia increase risks of complications and death. NPJ5008 is a novel formulation of the indicated treatment, dantrolene sodium, developed to ...shorten preparation and administration times compared with the reference formulation Dantrium®. The two formulations have been compared preclinically.
Assess bioequivalence of overall dantrolene (free acid) exposure of NPJ5008 versus Dantrium® and ascertain similarities in their pharmacokinetics and safety/tolerability profiles. Evaluate preparation/administration time savings for the new formulation.
Part 1 of this open-label trial in humans was a 1 : 1 randomised crossover study; part 2 was a single-arm study. Trial pharmacy data and laboratory simulations assessed preparation/administration step timings.
Single clinical centre in the UK, April to July 2021.
Twenty-one healthy male and female individuals.
Part 1: single intravenous 60 mg dose of NPJ5008 or Dantrium®, sequentially. Part 2: single intravenous 120 mg dose of NPJ5008. Simulation: five vials per formulation using paediatric and adult cannulas.
Overall drug exposure to last measurable concentration (AUC 0 to last ) and extrapolated to infinity (AUC 0 to ∞ ) were primary endpoints. Other pharmacokinetic, clinical and muscle-function parameters, and adverse events, were monitored.
Adjusted geometric mean ratios of NPJ5008 versus Dantrium® were 90.24 and 90.44% for AUC 0 to last and AUC 0 to ∞ , respectively, with the 90% confidence intervals (CI) within the 80 to 125% acceptance interval, establishing bioequivalence. No new safety issues emerged: any adverse events were of a similar magnitude across treatments and related to pharmacological properties of dantrolene. Pharmacy and simulation data revealed that every step in preparation and administration was 26 to 69% faster for NPJ5008 than Dantrium®.
NPJ5008 showed comparable pharmacokinetic and safety profiles to Dantrium®, while reducing dantrolene dose preparation/administration times, potentially reducing patient complications/healthcare resourcing in malignant hyperthermia.
EudraCT Number: 2020-005719-35, MHRA approval.
Background
Development of bowel preparation products has been based upon colon cleansing rating by a local endoscopist. It is unclear how bowel preparation scales perform when centrally evaluated.
...Aims
To evaluate the reliability of bowel preparation quality scales when assessed by central readers.
Methods
Four central readers evaluated 52 videos in triplicate, 2 weeks apart, during the entire endoscopic procedure (insertion/withdrawal of the colonoscope) and exclusively on colonoscope withdrawal using the Boston Bowel Preparation Scale (BBPS), Chicago Bowel Preparation scale, Harefield Cleansing Scale, Ottawa Bowel Preparation Quality Scale (OBPQS), Aronchick score, a visual analogue scale, and additional items proposed in a modified Research and Development/University of California Los Angeles appropriateness process. Reliability was assessed with intraclass correlation coefficients.
Results
Intraclass correlation coefficients (95% confidence interval) for inter-rater reliability of the quality scales ranged from 0.51 to 0.65 (consistent with moderate to substantial inter-rater reliability) during the entire procedure. Corresponding intraclass correlation coefficients for intra-rater reliability ranged from 0.69 to 0.77 (consistent with substantial intra-rater reliability). Reliability was highest in the right colon and lowest in the left colon. No differences were observed in reliability when assessed for the procedure overall (insertion/withdrawal) relative to assessment on withdrawal alone.
Conclusion
All five bowel preparation quality scales had moderate to substantial inter-rater reliability. Panelists considered the Aronchick score too simplistic for clinical trials and recognized that assessment of residual fluid in the Ottawa Bowel Preparation Quality Scale was not amenable to central assessment.
IntroductionTraumatic brain injury (TBI) is the leading cause of mortality and long-term disability in young adults. Despite the high prevalence of anaemia and red blood cell transfusion in patients ...with TBI, the optimal haemoglobin (Hb) transfusion threshold is unknown. We undertook a randomised trial to evaluate whether a liberal transfusion strategy improves clinical outcomes compared with a restrictive strategy.Methods and analysisHEMOglobin Transfusion Threshold in Traumatic Brain Injury OptimizatiON is an international pragmatic randomised open label blinded-endpoint clinical trial. We will include 742 adult patients admitted to an intensive care unit (ICU) with an acute moderate or severe blunt TBI (Glasgow Coma Scale ≤12) and a Hb level ≤100 g/L. Patients are randomly allocated using a 1:1 ratio, stratified by site, to a liberal (triggered by Hb ≤100 g/L) or a restrictive (triggered by Hb ≤70 g/L) transfusion strategy applied from the time of randomisation to the decision to withdraw life-sustaining therapies, ICU discharge or death. Primary and secondary outcomes are assessed centrally by trained research personnel blinded to the intervention. The primary outcome is the Glasgow Outcome Scale extended at 6 months. Secondary outcomes include overall functional independence measure, overall quality of life (EuroQoL 5-Dimension 5-Level; EQ-5D-5L), TBI-specific quality of life (Quality of Life after Brain Injury; QOLIBRI), depression (Patient Health Questionnaire; PHQ-9) and mortality.Ethics and disseminationThis trial is approved by the CHU de Québec—Université Laval research ethics board (MP-20-2018-3706) and ethic boards at all participating sites. Our results will be published and shared with relevant organisations and healthcare professionals.Trial registration numberNCT03260478.
The "Age of Blood in Children in Pediatric Intensive Care Unit" (ABC PICU) study is a randomized controlled trial (RCT) that aims to determine if red blood cell (RBC) unit storage age affects ...outcomes in critically ill children. While RBCs can be stored for up to 42 days in additive solutions, their efficacy and safety after long-term storage have been challenged. Preclinical and clinical observational evidence suggests loss of efficacy and lack of safety of older RBC units, especially in more vulnerable populations such as critically ill children. Because there is a belief that shorter storage will improve outcomes, some physicians and institutions systematically transfuse fresh RBCs to children. Conversely, the standard practice of blood banks is to deliver the oldest available RBC unit (first-in, first-out policy) in order to decrease wastage.
The ABC PICU study, is a double-blind superiority trial comparing the development of "New or Progressive Multiple Organ Dysfunction Syndrome" (NPMODS) in 1538 critically ill children randomized to either transfusion with RBCs stored for ≤ 7 days or to standard-issue RBCs (oldest in inventory). Patients are being recruited from 52 centers in the US, Canada, France, Italy, and Israel.
The ABC PICU study should have significant implications for blood procurement services. A relative risk reduction of 33% is postulated in the short-storage arm. If a difference is found, this will indicate that fresher RBCs do improve outcomes in the pediatric intensive care unit population and would justify that use in critically ill children. If no difference is found, this will reassure clinicians and transfusion medicine specialists regarding the safety of the current system of allocating the oldest RBC unit in inventory and will discourage clinicians from preferentially requesting fresher blood for critically ill children.
ClinicalTrials.gov, ID: NCT01977547 . Registered on 6 November 2013.
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