Pre-specified Secondary Outcomes Research Articles

Abstract 4134668: Title: Mandibular advancement device versus CPAP on cardiovascular health and quality of life in OSA a pre-specified 12 months follow up of outcomes

Background: Obstructive sleep apnoea (OSA) is a significant cause of hypertension. ACC/AHA Guidelines recommended screening and treatment of OSA in patients with hypertension; however, evidence comparing mandibular advancement devices (MAD) to continuous positive airway pressure (CPAP) on cardiovascular health is lacking. We present the complete 12 months follow-up data on the comparative effectiveness of MAD versus CPAP in ambulatory BP reduction, QoL, cardiac arrhythmia, and myocardial remodelling. Method: In a randomized, non-inferiority trial (margin 1.5 mmHg), 321 participants, aged over 40, with hypertension and high cardiovascular risk were recruited. Of these, 220 participants with OSA (apnoea–hypopnea index ≥15 events/h) were randomized to either MAD or CPAP (1:1). Pre-specified secondary outcomes include: ambulatory BP, quality of life (QoL) (sleep-specific: ESS, SAQLI, FOSQ; non-sleep-specific: SF-36, EQ-5D), ambulatory ECG monitoring, and cardiac MRI. Results: A total of 89 (80.9% of 110) participants from MAD, and 91 (82.7% of 110) participants from CPAP completed 12 months follow-up. The median daily usage was 5.5 hours for MAD and 4.9 hours for CPAP. The between-group difference in 24h mean BP from baseline to 12 months was - 0.57 mmHg (95% confidence interval: (-2.53 to 1.39, non-inferiority P < 0.001). Compared with the CPAP group, MAD group demonstrated a larger reduction in all the 24h with the most pronounced differences observed in the asleep BP parameters (Table 1). Both the MAD and CPAP improved QoL (Table 2). CPAP had greater improvement in FOSQ from sleep-specific questionnaires (P=0.038), and social QoL in SF-36 from non-sleep-specificl questionnaires (P=0.013). The ambulatory ECG monitoring (MAD: 2.8 ± 1.0 days, CPAP: 2.3 ± 1.1 days) showed no between-group differences in % atrial fibrillation(P=0.209), % ventricular ectopic isolated count (P=0.790) and % supraventricular ectopic isolated count (P= 0.333). The cardiac MRI sub-study (101 participants : MAD= 45, CPAP= 56) showed CPAP had greater improvement in right ventricular stroke volume (P=0.023) and MAD had greater improvement in circumferential strain favours the MAD group (P=0.015) (Table 3). Conclusion: At 12 months , MAD was non-inferior to CPAP for reducing 24h mean arterial BP. MAD showed greater reduction in 24h BPs, especially during asleep. While both the MAD and CPAP are effective in improving QoL, CPAP is more effective in improving FOSQ and social QoL (SF-36).

Randomized Crossover Clinical Trial of Nicotinamide Riboside and Coenzyme Q10 on Metabolic Health and Mitochondrial Bioenergetics in CKD.

Mitochondria-driven oxidative/redox stress and inflammation play a major role in chronic kidney disease (CKD) pathophysiology. Compounds targeting mitochondrial metabolism may improve mitochondrial function, inflammation, and redox stress; however, there is limited evidence of their efficacy in CKD. We conducted a randomized, double-blind, placebo-controlled crossover trial comparing the effects of 1200 mg/day of coenzyme Q10 (CoQ10) or 1000 mg/day of nicotinamide riboside (NR) supplementation to placebo in 25 people with moderate-to-severe CKD (eGFR <60mL/min/1.73 m2). We assessed changes in the blood transcriptome using 3'-Tag-Seq gene expression profiling and changes in pre-specified secondary outcomes of inflammatory and oxidative stress biomarkers. For a subsample of participants (n=14), we assessed lymphocyte and monocyte bioenergetics using an extracellular flux analyzer. The (mean±SD) age, eGFR, and BMI of the participants were 61±11 years, 37±9 mL/min/1.73m2, and 28±5 kg/m2 respectively. Of the participants, 16% had diabetes and 40% were female. Compared to placebo, NR-mediated transcriptomic changes were enriched in gene ontology (GO) terms associated with carbohydrate/lipid metabolism and immune signaling while, CoQ10 changes were enriched in immune/stress response and lipid metabolism GO terms. NR increased plasma IL-2 (estimated difference, 0.32, 95% CI of 0.14 to 0.49 pg/mL), and CoQ10 decreased both IL-13 (estimated difference, -0.12, 95% CI of -0.24 to -0.01 pg/mL) and CRP (estimated difference, -0.11, 95% CI of -0.22 to 0.00 mg/dL) compared to placebo. Both NR and CoQ10 reduced 5 series F2-Isoprostanes (estimated difference, -0.16 and -0.11 pg/mL, respectively; P<0.05 for both). NR, but not CoQ10, increased the bioenergetic health index (BHI) (estimated difference, 0.29, 95% CI of 0.06 to 0.53) and spare respiratory capacity (estimated difference, 3.52, 95% CI of 0.04 to 7 pmol/min/10,000 cells) in monocytes. Six weeks of NR and CoQ10 improved in oxidative stress, inflammation, and cell bioenergetics in persons with moderate to severe CKD.

Prostate-Specific Antigen Screening and 15-Year Prostate Cancer Mortality

The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) reported no effect of prostate-specific antigen (PSA) screening on prostate cancer mortality at a median 10-year follow-up (primary outcome), but the long-term effects of PSA screening on prostate cancer mortality remain unclear. To evaluate the effect of a single invitation for PSA screening on prostate cancer-specific mortality at a median 15-year follow-up compared with no invitation for screening. This secondary analysis of the CAP randomized clinical trial included men aged 50 to 69 years identified at 573 primary care practices in England and Wales. Primary care practices were randomized between September 25, 2001, and August 24, 2007, and men were enrolled between January 8, 2002, and January 20, 2009. Follow-up was completed on March 31, 2021. Men received a single invitation for a PSA screening test with subsequent diagnostic tests if the PSA level was 3.0 ng/mL or higher. The control group received standard practice (no invitation). The primary outcome was reported previously. Of 8 prespecified secondary outcomes, results of 4 were reported previously. The 4 remaining prespecified secondary outcomes at 15-year follow-up were prostate cancer-specific mortality, all-cause mortality, and prostate cancer stage and Gleason grade at diagnosis. Of 415 357 eligible men (mean [SD] age, 59.0 [5.6] years), 98% were included in these analyses. Overall, 12 013 and 12 958 men with a prostate cancer diagnosis were in the intervention and control groups, respectively (15-year cumulative risk, 7.08% [95% CI, 6.95%-7.21%] and 6.94% [95% CI, 6.82%-7.06%], respectively). At a median 15-year follow-up, 1199 men in the intervention group (0.69% [95% CI, 0.65%-0.73%]) and 1451 men in the control group (0.78% [95% CI, 0.73%-0.82%]) died of prostate cancer (rate ratio [RR], 0.92 [95% CI, 0.85-0.99]; P = .03). Compared with the control, the PSA screening intervention increased detection of low-grade (Gleason score [GS] ≤6: 2.2% vs 1.6%; P < .001) and localized (T1/T2: 3.6% vs 3.1%; P < .001) disease but not intermediate (GS of 7), high-grade (GS ≥8), locally advanced (T3), or distally advanced (T4/N1/M1) tumors. There were 45 084 all-cause deaths in the intervention group (23.2% [95% CI, 23.0%-23.4%]) and 50 336 deaths in the control group (23.3% [95% CI, 23.1%-23.5%]) (RR, 0.97 [95% CI, 0.94-1.01]; P = .11). Eight of the prostate cancer deaths in the intervention group (0.7%) and 7 deaths in the control group (0.5%) were related to a diagnostic biopsy or prostate cancer treatment. In this secondary analysis of a randomized clinical trial, a single invitation for PSA screening compared with standard practice without routine screening reduced prostate cancer deaths at a median follow-up of 15 years. However, the absolute reduction in deaths was small. isrctn.org Identifier: ISRCTN92187251.

Therapeutic high-dose vitamin D for vitamin D-deficient severe COVID-19 disease: randomized, double-blind, placebo-controlled study (SHADE-S).

efficacy of therapeutic cholecalciferol supplementation for severe COVID-19 is sparingly studied. effect of single high-dose cholecalciferol supplementation on sequential organ failure assessment (SOFA) score in moderate-to-severe COVID-19. participants with moderate to severe COVID-19 with PaO2/FiO2 ratio<200 were randomized to 0.6 million IU cholecalciferol oral (intervention) or placebo. primary outcome was change in Day 7 SOFA score and pre-specified secondary outcomes were SOFA and 28-day all-cause mortality. in all, 90 patients (45 each group) were included for intention-to-treat analysis. 25(OH)D3 levels were 12 (10-16) and 13 (12-18) ng/ml (P=0.06) at baseline; and 60 (55-65) ng/ml and 4 (1-7) ng/ml by Day 7 in vitamin D and placebo groups, respectively. The SOFA score on Day 7 was better in the vitamin D group [3 (95% CI, 2-5) versus 5 (95% CI, 3-7), P=0.01, intergroup difference-2 (95% CI, -4 to -0.01); r=0.4]. A lower all-cause 28-day mortality [24% compared to 44% (P=0.046)] was observed with vitamin D. single high-dose oral cholecalciferol supplementation on ICU admission can improve SOFA score at Day 7 and reduce in-hospital mortality in vitamin D-deficient COVID-19. ClinicalTrials.gov id: NCT04952857 registered dated 7 July 2021. What is already known on this topic-vitamin D has immunomodulatory role. Observational and isolated intervention studies show some benefit in COVID-19. Targeted therapeutic vitamin D supplementation improve outcomes in severe COVID-19 is not studied in RCTs. What this study adds-high-dose vitamin D supplementation (0.6 Million IU) to increase 25(OH)D>50ng/ml is safe and reduces sequential organ failure assessment score, in-hospital mortality in moderate to severe COVID-19. How this study might affect research, practice or policy-vitamin D supplementation in vitamin D-deficient patients with severe COVID-19 is useful may be practiced.

90. The Diagnosis of Ventilator-associated pneumonia (DIVA) trial: Results of a Clinical Trial of a Bundled VAP Diagnostic Stewardship Intervention

Abstract Background Ventilator-associated pneumonia (VAP) is commonly overdiagnosed &amp; a primary driver of antibiotic overuse within intensive care units (ICUs). Antimicrobial stewardship programs have successfully leveraged diagnostic stewardship interventions (DSIs) to prevent overdiagnosis/overtreatment of diverse clinical syndromes, yet this approach has not been extended to VAP. In this trial, we aimed to evaluate the safety, feasibility &amp; efficacy of a novel DSI care bundle (DSI-CB) targeting VAP. Methods The DIVA trial (NCT05176353) was a pilot/feasibility trial conducted in 2 ICUs at Michigan Medicine from February 2022-February 2023. A DSI-CB targeting the respiratory culture testing pathway was implemented sequentially in study ICUs, using an interruptive electronic health record clinical decision support tool &amp; modifications to microbiology laboratory workflows (Table 1). Providers were counseled on DSI-CB use during bimonthly educational sessions during trial rollout &amp; via monthly email reminders thereafter. Rates of prespecified co-primary safety and secondary efficacy outcomes were compared between the postintervention study cohort &amp; 5-year preintervention historical controls using negative binomial regression. Interrupted time series analysis was used to evaluate ICU antibiotic utilization rates (ICU-AURs) to account for temporal trends. Results 1810 patients were admitted to study ICUs following DSI-CB implementation, 29% of whom were eligible for DSI-CB use. DSI-CB was utilized in 77% of eligible patients. Patient demographics, comorbidities &amp; measures of acute severity of illness were similar pre- &amp; post-intervention. DSI-CB implementation was not associated with increases in primary adverse safety outcomes (Table 2). DSI-CB implementation was associated with significant reductions in rates of total respiratory cultures ordered, rates of positive respiratory cultures &amp; reductions in both total &amp; broad-spectrum ICU-AURs (Table 2, Figure 1). Conclusion Implementation of a novel VAP DSI-CB was safe, feasible &amp; associated with significant reductions in rates of respiratory culture positivity and ICU-AURs. This represents the first trial of a DSI targeting VAP &amp; a novel avenue for ICU antimicrobial stewardship. Large-scale trials are warranted. Disclosures Owen Albin, MD, Biomeriux: Grant/Research Support|Charles River Laboratories: Advisor/Consultant|Shionogi: Advisor/Consultant Weirauch J. Andrew, RRT, Drager Medical: Equipment loaned for research purposes, but no monetary funds were provided.|Jones and Bartlett Learning: Honoraria Krishna Rao, MD, MS, Merck &amp; Co.: Grant/Research Support|Rebiotix: Advisor/Consultant|Seres Therapeutics: Advisor/Consultant|Summit Therapeutics: Advisor/Consultant Keith S. Kaye, MD, MPH, Entasis: Advisor/Consultant|Entasis: Honoraria|GSK: Advisor/Consultant|GSK: Honoraria|Merck: Advisor/Consultant|Merck: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria|VenatoRx: Advisor/Consultant|VenatoRx: Honoraria

Tight Blood-Glucose Control without Early Parenteral Nutrition in the ICU

BackgroundRandomized, controlled trials have shown both benefit and harm from tight blood-glucose control in patients in the intensive care unit (ICU). Variation in the use of early parenteral nutrition and in insulin-induced severe hypoglycemia might explain this inconsistency.MethodsWe randomly assigned patients, on ICU admission, to liberal glucose control (insulin initiated only when the blood-glucose level was >215 mg per deciliter [>11.9 mmol per liter]) or to tight glucose control (blood-glucose level targeted with the use of the LOGIC-Insulin algorithm at 80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]); parenteral nutrition was withheld in both groups for 1 week. Protocol adherence was determined according to glucose metrics. The primary outcome was the length of time that ICU care was needed, calculated on the basis of time to discharge alive from the ICU, with death accounted for as a competing risk; 90-day mortality was the safety outcome.ResultsOf 9230 patients who underwent randomization, 4622 were assigned to liberal glucose control and 4608 to tight glucose control. The median morning blood-glucose level was 140 mg per deciliter (interquartile range, 122 to 161) with liberal glucose control and 107 mg per deciliter (interquartile range, 98 to 117) with tight glucose control. Severe hypoglycemia occurred in 31 patients (0.7%) in the liberal-control group and 47 patients (1.0%) in the tight-control group. The length of time that ICU care was needed was similar in the two groups (hazard ratio for earlier discharge alive with tight glucose control, 1.00; 95% confidence interval, 0.96 to 1.04; P=0.94). Mortality at 90 days was also similar (10.1% with liberal glucose control and 10.5% with tight glucose control, P=0.51). Analyses of eight prespecified secondary outcomes suggested that the incidence of new infections, the duration of respiratory and hemodynamic support, the time to discharge alive from the hospital, and mortality in the ICU and hospital were similar in the two groups, whereas severe acute kidney injury and cholestatic liver dysfunction appeared less prevalent with tight glucose control.ConclusionsIn critically ill patients who were not receiving early parenteral nutrition, tight glucose control did not affect the length of time that ICU care was needed or mortality. (Funded by the Research Foundation–Flanders and others; TGC-Fast ClinicalTrials.gov number, NCT03665207.)

Protocol and statistical analysis plan for a randomized controlled trial of the effect of intravenous iron on anemia in Malawian pregnant women in their third trimester (REVAMP – TT)

Background: Anemia affects 40% of pregnant women globally, leading to maternal mortality, premature birth, low birth weight, and poor baby development. Iron deficiency causes over 40% of anemia cases in Africa. Oral iron supplementation is insufficient for Low-and-Middle-Income-Countries (LMICs) to meet current WHO targets. We hypothesized that a single intravenous dose of Ferric Carboxymaltose (FCM) may be more effective than oral iron treatment for anemia recovery, particularly in these settings where women present late for antenatal care. Methods: This is a two-arm parallel open-label individual-randomized controlled trial in third trimester, in malaria Rapid Diagnostic Test-negative pregnant women with moderate or severe anemia - capillary hemoglobin &lt;10 g/dL – who are randomized to receive either parenteral iron – with FCM – or standard-of-care oral iron for the remainder of pregnancy. This is the sister trial to the second-trimester REVAMP trial, funded by the Bill and Melinda Gates Foundation (trial registration ACTRN12618001268235, Gates Grant number INV-010612). In REVAMP-TT, recruitment and treatment are performed within primary health centers. The trial will recruit 590 women across Zomba district, Malawi. The primary outcome is the proportion of anemic women - venous hemoglobin &lt;11 g/dL - at 36 weeks’ gestation or delivery (whichever occurs first). Other pre-specified key secondary clinical and safety outcomes include maternal iron-status and hypophosphatemia, neonate birth weight, infant growth and infant iron and hematological parameters. Discussion: This study will determine whether FCM, delivered within primary health centers, is effective, safe and feasible for treating moderate to severe anemia in third-trimester pregnant Malawian women. This intervention could have long-term benefits for maternal and child health, resulting in improved survival and child development.

Melatonin, vitamins and minerals supplements for the treatment of Covid-19 and Covid-like illness: A prospective, randomized, double-blind multicenter study

BackgroundMelatonin, zinc, and multivitamins are among most recommended supplements in the fight against coronavirus disease 2019 (COVID-19). We aimed to examine the efficacy and safety of this association in the treatment of COVID-19 and COVID-like illnesses. MethodsWe conducted a multicenter prospective, randomized, double-blind, controlled trial. Patients with no medical history consulting the emergency department for covid and covid-like illness and who were not hospitalized were included. Patients were assigned in a 1:1 ratio to the treatment or the placebo group. The primary outcome was studying the effectiveness of zinc multivitamin supplement and melatonin in the treatment of COVID and -like illnesses symptoms’ according to the time from randomization to clinical improvement. The pre-specified secondary outcomes were date of disappearance of symptoms present on admission, appearance of an adverse effect due to the administration of the treatment, number of patients developing complications, requiring hospitalization, requiring respiratory support. ResultsOne hundred sixty four patients were eligible for the study and were randomized to either the treatment group or the placebo group. Overall, 128 of the 164 patients had a PCR for SARS-CoV-2, yielding a positive PCR result in 49.1% of them. Regarding the disappearance of all initial presenting symptoms: on the 5th day of the follow-up, there was a significant difference between the two groups with a p value 0.04;On the 10th day, there was a significant difference too with p value of 0.038. There were no significant differences between the two groups in recovery during the 15th day of follow-up p>0.5. Finally, 100% of patients fully recovered in the treatment group vs 98.8% in the placebo group. No severe adverse events were reported throughout the trial. ConclusionsOur results showed that daily doses of Melatonin, zinc and vitamins did significantly reduce the duration of symptoms accelerating its disappearance among patients consulting with COVID-19 or COVID-19 like illness.

Hemodynamic Changes with Umbilical Cord Milking in Nonvigorous Newborns: A Randomized Cluster Cross-over Trial

To assess the hemodynamic safety and efficacy of umbilical cord milking (UCM) compared with early cord clamping (ECC) in nonvigorous newborn infants enrolled in a large multicenter randomized cluster-crossover trial. Two hundred twenty-seven nonvigorous term or near-term infants who were enrolled in the parent UCM vs ECC trial consented for this substudy. An echocardiogram was performed at 12±6hours of age by ultrasound technicians blinded to randomization. The primary outcome was left ventricular output (LVO). Prespecified secondary outcomes included measured superior vena cava (SVC) flow, right ventricular output (RVO), peak systolic strain, and peak systolic velocity by tissue Doppler examination of the RV lateral wall and the interventricular septum. Nonvigorous infants receiving UCM had increased hemodynamic echocardiographic parameters as measured by higher LVO (225±64 vs 187±52mL/kg/min; P<.001), RVO (284±88 vs 222±96mL/kg/min; P<.001), and SVC flow (100±36 vs 86±40mL/kg/min; P<.001) compared with the ECC group. Peak systolic strain was lower (-17±3 vs -22±3%; P<.001), but there was no difference in peak tissue Doppler flow (0.06 m/s [IQR, 0.05-0.07 m/s] vs 0.06 m/s [IQR, 0.05-0.08 m/s]). UCM increased cardiac output (as measured by LVO) compared with ECC in nonvigorous newborns. Overall increases in measures of cerebral and pulmonary blood flow (as measured by SVC and RVO flow, respectively) may explain improved outcomes associated with UCM (less cardiorespiratory support at birth and fewer cases of moderate-to-severe hypoxic ischemic encephalopathy) among nonvigorous newborn infants.

Kidney and Cardiovascular Effects of Canagliflozin According to Age and Sex: A Post Hoc Analysis of the CREDENCE Randomized Clinical Trial

It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the CREDENCE study. Secondary analysis of a randomized controlled trial. Participants in the CREDENCE trial. Participants were randomly assigned to canagliflozin 100 mg daily or placebo. Primary composite outcome of kidney failure, doubling of serum creatinine, or death due to kidney or cardiovascular disease. Pre-specified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (<60, 60-69, and ≥70 years) and sex in the intention-to-treat population using Cox regression models. The mean age of the cohort was 63.0±9.2 years and 34% were female. Older age and female sex were independently associated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of the serum creatinine, or death from kidney or cardiovascular causes) differed between age groups (HR 0.67, 95% CI 0.52 to 0.87; HR 0.63, 95% CI 0.48 to 0.82; and HR 0.89, 95% CI 0.61 to 1.29; for the <60, 60-69, and ≥70 year groups, respectively; Pinteraction=0.3); or among females and males (HR 0.71, 95% CI 0.54 to 0.95; and HR 0.69, 95% CI 0.56 to 0.84, respectively; Pinteraction=0.8). No differences in safety outcomes by age group or sex were observed. This was a post hoc analysis with multiple comparisons. Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. Owing to higher background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants.

The CONFIDENT study protocol: a randomized controlled trial comparing two methods to increase long-term care worker confidence in the COVID-19 vaccines

BackgroundClinical and real-world effectiveness data for the COVID-19 vaccines have shown that they are the best defense in preventing severe illness and death throughout the pandemic. However, in the US, some groups remain more hesitant than others about receiving COVID-19 vaccines. One important group is long-term care workers (LTCWs), especially because they risk infecting the vulnerable and clinically complex populations they serve. There is a lack of research about how best to increase vaccine confidence, especially in frontline LTCWs and healthcare staff. Our aims are to: (1) compare the impact of two interventions delivered online to enhanced usual practice on LTCW COVID-19 vaccine confidence and other pre-specified secondary outcomes, (2) determine if LTCWs’ characteristics and other factors mediate and moderate the interventions’ effect on study outcomes, and (3) explore the implementation characteristics, contexts, and processes needed to sustain a wider use of the interventions.MethodsWe will conduct a three-arm randomized controlled effectiveness-implementation hybrid (type 2) trial, with randomization at the participant level. Arm 1 is a dialogue-based webinar intervention facilitated by a LTCW and a medical expert and guided by an evidence-based COVID-19 vaccine decision tool. Arm 2 is a curated social media web application intervention featuring interactive, dynamic content about COVID-19 and relevant vaccines. Arm 3 is enhanced usual practice, which directs participants to online public health information about COVID-19 vaccines. Participants will be recruited via online posts and advertisements, email invitations, and in-person visits to care settings. Trial data will be collected at four time points using online surveys. The primary outcome is COVID-19 vaccine confidence. Secondary outcomes include vaccine uptake, vaccine and booster intent for those unvaccinated, likelihood of recommending vaccination (both initial series and booster), feeling informed about the vaccines, identification of vaccine information and misinformation, and trust in COVID-19 vaccine information provided by different people and organizations. Exploration of intervention implementation will involve interviews with study participants and other stakeholders, an in-depth process evaluation, and testing during a subsequent sustainability phase.DiscussionStudy findings will contribute new knowledge about how to increase COVID-19 vaccine confidence and effective informational modalities for LTCWs.Trial registrationNCT05168800 at ClinicalTrials.gov, registered December 23, 2021.

Levels of immunoglobulin isotypes in serum and respiratory samples of patients with chronic obstructive pulmonary disease: protocol for a systematic review and meta-analysis

IntroductionChronic obstructive pulmonary disease (COPD) is an inflammatory respiratory disorder characterised by the progressive worsening of lung function. Acute exacerbation of COPD (AECOPD) is a leading contributor to patient morbidity,...

Effect of switching from intermittently scanned to real-time continuous glucose monitoring in adults with type 1 diabetes: 24-month results from the randomised ALERTT1 trial

Comparing Continuous With Flash Glucose Monitoring In Adults With Type 1 Diabetes (ALERTT1) examined whether switching from first-generation intermittently scanned continuous glucose monitoring (isCGM) without alerts to real-time continuous glucose monitoring (rtCGM) with alert functionality offers additional benefits to adults with type 1 diabetes. The extension of the randomised ALERTT1 trial assessed the effect of switching from isCGM to rtCGM up to 24 months. In this 6-month, double-arm, parallel-group, non-masked, randomised, controlled trial, done across six hospitals in Belgium, 254 adults aged 18 years or older with type 1 diabetes previously using isCGM were randomly assigned (1:1) to rtCGM with alerts (intervention; n=127) or isCGM without alerts (control; n=127). Upon completion of the 6-month trial, the control group switched to rtCGM (is-rtCGM group), and the intervention group continued rtCGM (rt-rtCGM group). The extension focused on within-group changes in time in range (TIR; 3·9-10·0 mmol/L; primary outcome), HbA1c, time in clinically significant hypoglycaemia (<3·0 mmol/L), and Hypoglycaemia Fear Survey worry (HFS-worry) score (all prespecified key secondary outcomes). Mean within-group change versus the start of rtCGM is reported, with a positive value referring to a lower value at start of rtCGM. This trial is registered at ClinicalTrials.gov (NCT03772600). 119 participants were assigned to the is-rtCGM group of whom 112 (94%) completed the 24-month trial, and 123 participants were assigned to the rt-rtCGM group of whom 117 (95%) completed the 24-month trial. TIR increased from 51·8% (95% CI 49·1-54·5) at start of rtCGM (month 6) to 63·5% (60·7-66·3) at month 12 in the is-rtCGM group, and remained stable up to month 24 (change 11·7 percentage points [pp] [9·4-14·0; p<0·0001). In the rt-rtCGM group, TIR increased from 52·5% (95% CI 49·8-55·1) at start of rtCGM (month 0) to 63·0% (60·3-65·8) at month 12, also remaining stable up to month 24 (change 10·5 pp [8·2-12·8]; p<0·0001). HbA1c decreased from 7·4% (57 mmol/mol; month 6) to 6·9% (52 mmol/mol) at month 24 (change -0·54 pp [95% CI -0·64 to -0·44]; -5 mmol/mol [95% CI -6 to -4]; p<0·0001) in the is-rtCGM group, and from 7·4% (57 mmol/mol; month 0) to 7·0% (53 mmol/mol) at month 24 (change -0·43 pp [95% CI -0·53 to -0·33]; -4 mmol/mol [95% CI -5 to -3]; p<0·0001) in the rt-rtCGM group. The change in HFS-worry score was -2·67 (month 24 vs month 6; p=0·0008) in the is-rtCGM group and -5·17 points (month 24 vs month 0; p<0·0001) in the rt-rtCGM group. Time in clinically significant hypoglycaemia was unchanged in both groups after month 12. Severe hypoglycaemia decreased from 31·0 to 3·3 per 100 patient-years after switching to rtCGM. Glycaemic control and hypoglycaemia worry improved significantly up to 24 months after switching from isCGM without alerts to rtCGM with alerts, supporting the use of rtCGM in the care of adults with type 1 diabetes. Dexcom.

Restoring Study PRGF: a randomized clinical trial on plasma rich in growth factors for knee osteoarthritis

BackgroundA randomized clinical trial assessing plasma rich in growth factors (PRGF) versus hyaluronic acid for knee osteoarthritis was published in 2012 (sponsor trial ID BTI-01-EC/07/ART). Evidence of misreporting was discovered following access to unpublished materials. In accordance with the principles of the Restoring Invisible and Abandoned Trials (RIAT) initiative, we sought to re-analyse Study PRGF based on the unpublished trial materials.MethodsReanalysis was made possible primarily based on two unpublished study documents (original trial protocol and final report) obtained from the authors of the original publication. A call to action, calling on the authors to correct the original publication, was publicly issued. The involved ethics committee was repeatedly approached and extensive discussion with the authors ensued. After no agreement to correct the paper was reached, we embarked on this restoration. Reanalysis was focused on providing updated analyses for efficacy and safety.ResultsThe efficacy of PRGF was not statistically different from hyaluronic acid for any prespecified primary or secondary efficacy outcomes. For the primary endpoint, the percent of patients on PRGF compared to hyaluronic acid with a decrease >40% in WOMAC pain subscale score was 5.4% higher; 95% confidence interval (CI) −10.4% to 21.3%; p = 0.505. This differs from the original publication that reported a non-prespecified primary endpoint (decrease >50% in WOMAC pain subscale score) which was 14.1% higher; 95% CI 0.5 to 27.6%; p=0.044. Furthermore, in contrast to the article statement that all the adverse events disappeared in 48 h, at least two patients in the hyaluronic arm and five patients in the PRGF arm reported persistent adverse events. Inadequate disclosure of conflicts of interest in the original publication was also noted.ConclusionsThis reanalysis of Study PRGF found no clinically or statistically significant benefit from PRGF compared to hyaluronic acid. The restoration of Study PRGF shows the urgency of important changes to trial reporting and oversight practices. In the future, timely access to all clinical trial documents is needed to minimize the risk of reporting bias. Similarly, ethics committees should be ready to intervene whenever a case of potential misconduct arises.Trial registrationThis is a RIAT project, whose original trial was approved and registered on 19 December 2007 by the Ethics Committee of the Basque Country, Spain, as BTI-01-EC/07/ART.

Inconsistent Outcome Reporting in Heart Failure Randomized Controlled Trials

Randomized controlled trials (RCTs) may report outcomes different from those prespecified on trial-registration websites, protocols and statistical analysis plans (SAPs). This study sought to investigate the prevalence and characteristics of heart failure (HF) RCTs that report outcomes different from those prespecified. MEDLINE via PubMed was searched to include phase II-IV HF RCTs in 9 high-impact journals from 2010 to 2020. Outcomes reported in trial publications were compared with prespecified outcomes in protocols, registration websites and SAPs. We used the χ2 or Fisher exact test to analyze correlations between trial characteristics and inconsistencies. Among 216 trials, 32 inconsistencies were observed in 28 trials (13.0%). Among 32 inconsistencies, 2 (6.3%) pertained to omission of prespecified primary outcomes, 4 (12.5%) to omission of prespecified secondary outcomes, 2 (6.3%) to changing prespecified primary outcomes to secondary outcomes, and 2 (6.3%) to changing prespecified secondary outcomes to primary outcomes. Of the inconsistencies, 3 (9.4%) pertained to addition of new primary outcomes, 17 (53.1%) to addition of new secondary outcomes, and 2 (6.3%,) to changes in the timing of assessment of primary outcomes. The majority of the inconsistencies favored statistically significant findings; 78 (36.1%) were registered retrospectively. Single-center recruitment was associated with outcome inconsistencies (β = -0.14; 95% CI, -0.22 - -0.01; P = 0.035). More than 1 in 10 trials reported outcomes inconsistent with those specified in trial registration websites, SAPs and protocols. An action plan is warranted to minimize selective reporting and improve transparency.

β3 adrenergic agonist treatment in chronic pulmonary hypertension associated with heart failure (SPHERE-HF): a double blind, placebo-controlled, randomized clinical trial.

Pulmonary hypertension (PH) associated with left heart disease is an increasingly prevalent problem, orphan of targeted therapies, and related to a poor prognosis, particularly when pre- and post-capillary PH combine. The current study aimed to determine whether treatment with the selective β3 adrenoreceptor agonist mirabegron improves outcomes in patients with combined pre- and post-capillary PH (CpcPH). The β3 Adrenergic Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure (SPHERE-HF) trial is a multicentre, randomized, parallel, placebo-controlled clinical trial that enrolled stable patients with CpcPH associated with symptomatic heart failure. A total of 80 patients were assigned to receive mirabegron (50 mg daily, titrated till 200 mg daily, n=39) or placebo (n=41) for 16 weeks. Of them, 66 patients successfully completed the study protocol and were valid for the main analysis. The primary endpoint was the change in pulmonary vascular resistance (PVR) on right heart catheterization. Secondary outcomes included the change in right ventricular (RV) ejection fraction by cardiac magnetic resonance or computed tomography, other haemodynamic variables, functional class, and quality of life. The trial was negative for the primary outcome (placebo-corrected mean difference of 0.62 Wood units, 95% confidence interval [CI] -0.38, 1.61, p=0.218). Patients receiving mirabegron presented a significant improvement in RV ejection fraction as compared to placebo (placebo-corrected mean difference of 3.0%, 95% CI 0.4, 5.7%, p=0.026), without significant differences in other pre-specified secondary outcomes. SPHERE-HF is the first clinical trial to assess the potential benefit of β3 adrenergic agonists in PH. The trial was negative since mirabegron did not reduce PVR, the primary endpoint, in patients with CpcPH. On pre-specified secondary outcomes, a significant improvement in RV ejection fraction assessed by advanced cardiac imaging was found, without differences in functional class or quality of life.

Effect of School Integrated Pest Management or Classroom Air Filter Purifiers on Asthma Symptoms in Students With Active Asthma: A Randomized Clinical Study

To determine if environmental control measures (1) school-wide integrated pest management (IPM) program and/or (2) use of high-efficiency particulate air (HEPA) filter purifiers in inner city elementary school classrooms would reduce asthma morbidity in students with active asthma.Forty-one inner city elementary schools in the Northeastern United States were recruited for this study. There were 236 students with active, physician-diagnosed asthma randomized to IPM (by school) and/or HEPA filter purifiers (by classroom). Physician-diagnosed asthma was defined as the child having had unscheduled doctor visits, hospitalization, corticosteroid bursts, symptoms, or controller medication use in the past year. Fifty seven percent of the children were Hispanic and 24% were Black. Mean age was 8.1 years, 48% female, mean FEV1 97% to 99.7% predicted at randomization. Forty-fifty percent of the children were using short acting β agonists alone and the rest were on inhaled corticosteroids and/or leukotriene modifiers. The study was conducted during the school years 2015 to 2020.All students with active physician-diagnosed asthma had a screening visit with questionnaires, skin testing, and spirometry as well as 2 follow-up visits with the same assessments during the year. Baseline environmental assessment for a panel of allergens (mouse, rat, dust mite, cockroach, cat, dog, Alternaria alternate, and Aspergillus fumigatus) were conducted at the schools by collecting a 1-week air sample, immediately followed by vacuum–settled dust samples from each students’ primary classroom and in the participants homes. The allergens were analyzed using a multiplex assay (MARIA, Indoor Biotechnologies). Follow-up environmental assessment after randomization took place once each winter and spring during the school year.The allocation to free standing classroom HEPA filter purifiers, active or sham, was blinded to the participants and those assessing the outcomes. The IPM program consisted of application of rodenticide, sealing entry points, trap placement, targeted cleaning, and brief educational handouts for the school staff. Infestation was assessed every 3 months and IPM reapplied as needed. Trained pest management specialists providing the school-wide IPM program were unblinded, but the student participants and trial investigators remained blinded throughout the trial.Four groups of 59 students each were randomized using a factorial design to either intervention alone, both interventions together, or neither for the entire school year. Classroom and home allergen and particle levels at randomization were balanced between the 4 groups.The asthma-related health outcomes of the students were assessed by parent survey at baseline and every 2 months until the end of the school year. The primary outcome was the number of symptom-days with asthma during a 2-week period assessed over the 10 months of randomization. Prespecified secondary outcomes were school absences, Composite Asthma Severity Index score, healthcare utilization, and spirometry measurements.Ninety eight percent of the classrooms had detectable levels of mouse allergen and 26% of the participants were sensitized to mouse allergen. More than 90% of baseline classroom allergen levels for cockroach, rat, Alternaria, Aspergillus and dust mite were undetectable.Use of the school-wide IPM program resulted in a mean of 1.5 symptom-days with asthma during a 2-week period versus 1.9 symptom-days for no IPM; use of HEPA filter purifiers resulted in a mean of 1.6 symptom-days with asthma versus 1.8 symptom-days for sham HEPA filter purifiers; neither comparison was statistically significant. Other prespecified secondary outcomes, including healthcare utilization or missed school days because of asthma also did not differ significantly between the intervention groups. The HEPA filter purifiers significantly reduced mouse and dog allergens in the classrooms. The IPM program did not significantly reduce concentrations of any of the allergens or particles measured. A post hoc exploratory analysis found a statistically significant association of reduction in asthma symptoms with the school wide IPM program but only for a limited time (mid-November to February).In an inner-city population of elementary school students with active asthma, use of a school-wide IPM program or HEPA filter purifiers in the classrooms did not significantly reduce symptom-days with asthma.It is possible that these children had asthma that was too mild to see a significant difference in these environmental interventions. Also unclear is whether resources to perform environmental control measures are best used at the school level or at home. As an accompanying editorial notes, “as allergen sensitization is related to the pathogenesis and pathophysiology of childhood asthma,” allergen avoidance should still be a basic tenet of treatment and worth continued investigation.URL: www.pediatrics.org/cgi/doi/10.1542/peds.10.1001/jama.2021.11559

Impact of universal testing and treatment on sexual risk behaviour and herpes simplex virus type 2: a prespecified secondary outcomes analysis of the HPTN 071 (PopART) community-randomised trial

Comprehensive HIV prevention strategies have raised concerns that knowledge of interventions to reduce risk of HIV infection might mitigate an individual's perception of risk, resulting in riskier sexual behaviour. We investigated the prespecified secondary outcomes of the HPTN 071 (PopART) trial to determine whether a combination HIV prevention strategy, including universal HIV testing and treatment, changed sexual behaviour; specifically, we investigated whether there was evidence of sexual risk compensation. HPTN 071 (PopART) was a cluster-randomised trial conducted during 2013-18, in which we randomly assigned 21 communities with high HIV prevalence in Zambia and South Africa (total population, approximately 1 million) to combination prevention intervention with universal antiretroviral therapy (ART; arm A), prevention intervention with ART provided according to local guidelines (universal since 2016; arm B), or standard of care (arm C). The trial included a population cohort of approximately 2000 randomly selected adults (aged 18-44 years) in each community (N=38 474 at baseline) who were followed up for 36 months. A prespecified secondary objective was to evaluate the impact of the PopART intervention compared with standard of care on herpes simplex virus type 2 (HSV-2) and sexual behaviour (N=20 422 completed final visit). Secondary endpoints included differences in sexual risk behaviour measures at 36 months and were assessed using a two-stage method for matched cluster-randomised trials. This trial is registered with ClinicalTrials. gov, number NCT01900977. The PopART intervention did not substantially change probability of self-reported multiple sex partners, sexual debut, or pregnancy in women at 36 months. Adjusted for baseline community prevalence, reported condomless sex was significantly lower in arm A versus arm C (adjusted prevalence ratio 0·80 [95% CI 0·64-0·99]; p=0·04) but not in arm B versus arm C (0·94 [0·76-1·17]; p=0·55). 3-year HSV-2 incidence was reduced in arm B versus arm C (adjusted risk ratio 0·76 [95% CI 0·63-0·92]; p=0·010); no significant change was shown between arm A versus arm C (0·89 [0·73-1·08]; p=0·199). We found little evidence of any change in sexual behaviour owing to the PopART interventions, and reassuringly for public health, we saw no evidence of sexual risk compensation. The findings do not help to explain the differences between the two intervention groups of the HPTN 071 (PopART) trial. National Institute of Allergy and Infectious Diseases, the National Institutes of Health, the International Initiative for Impact Evaluation (3ie), the Bill &amp; Melinda Gates Foundation, the US President's Emergency Plan for AIDS Relief, and the Medical Research Council UK.

Effect of Selective Decontamination of the Digestive Tract on Hospital Mortality in Critically Ill Patients Receiving Mechanical Ventilation

Whether selective decontamination of the digestive tract (SDD) reduces mortality in critically ill patients remains uncertain. To determine whether SDD reduces in-hospital mortality in critically ill adults. A cluster, crossover, randomized clinical trial that recruited 5982 mechanically ventilated adults from 19 intensive care units (ICUs) in Australia between April 2018 and May 2021 (final follow-up, August 2021). A contemporaneous ecological assessment recruited 8599 patients from participating ICUs between May 2017 and August 2021. ICUs were randomly assigned to adopt or not adopt a SDD strategy for 2 alternating 12-month periods, separated by a 3-month interperiod gap. Patients in the SDD group (n = 2791) received a 6-hourly application of an oral paste and administration of a gastric suspension containing colistin, tobramycin, and nystatin for the duration of mechanical ventilation, plus a 4-day course of an intravenous antibiotic with a suitable antimicrobial spectrum. Patients in the control group (n = 3191) received standard care. The primary outcome was in-hospital mortality within 90 days. There were 8 secondary outcomes, including the proportion of patients with new positive blood cultures, antibiotic-resistant organisms (AROs), and Clostridioides difficile infections. For the ecological assessment, a noninferiority margin of 2% was prespecified for 3 outcomes including new cultures of AROs. Of 5982 patients (mean age, 58.3 years; 36.8% women) enrolled from 19 ICUs, all patients completed the trial. There were 753/2791 (27.0%) and 928/3191 (29.1%) in-hospital deaths in the SDD and standard care groups, respectively (mean difference, -1.7% [95% CI, -4.8% to 1.3%]; odds ratio, 0.91 [95% CI, 0.82-1.02]; P = .12). Of 8 prespecified secondary outcomes, 6 showed no significant differences. In the SDD vs standard care groups, 23.1% vs 34.6% had new ARO cultures (absolute difference, -11.0%; 95% CI, -14.7% to -7.3%), 5.6% vs 8.1% had new positive blood cultures (absolute difference, -1.95%; 95% CI, -3.5% to -0.4%), and 0.5% vs 0.9% had new C difficile infections (absolute difference, -0.24%; 95% CI, -0.6% to 0.1%). In 8599 patients enrolled in the ecological assessment, use of SDD was not shown to be noninferior with regard to the change in the proportion of patients who developed new AROs (-3.3% vs -1.59%; mean difference, -1.71% [1-sided 97.5% CI, -∞ to 4.31%] and 0.88% vs 0.55%; mean difference, -0.32% [1-sided 97.5% CI, -∞ to 5.47%]) in the first and second periods, respectively. Among critically ill patients receiving mechanical ventilation, SDD, compared with standard care without SDD, did not significantly reduce in-hospital mortality. However, the confidence interval around the effect estimate includes a clinically important benefit. ClinicalTrials.gov Identifier: NCT02389036.

Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis

SummaryBackgroundTestosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyse subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD.MethodsWe did a systematic review and meta-analysis of randomised controlled trials including IPD. We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Epub Ahead of Print, Embase, Science Citation Index, the Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and Database of s of Review of Effects for literature from 1992 onwards (date of search, Aug 27, 2018). The following inclusion criteria were applied: (1) men aged 18 years and older with a screening testosterone concentration of 12 nmol/L (350 ng/dL) or less; (2) the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of 3 months; (3) a comparator of placebo treatment; and (4) studies assessing the pre-specified primary or secondary outcomes of interest. Details of study design, interventions, participants, and outcome measures were extracted from published articles and anonymised IPD was requested from investigators of all identified trials. Primary outcomes were mortality, cardiovascular, and cerebrovascular events at any time during follow-up. The risk of bias was assessed using the Cochrane Risk of Bias tool. We did a one-stage meta-analysis using IPD, and a two-stage meta-analysis integrating IPD with data from studies not providing IPD. The study is registered with PROSPERO, CRD42018111005.Findings9871 citations were identified through database searches and after exclusion of duplicates and of irrelevant citations, 225 study reports were retrieved for full-text screening. 116 studies were subsequently excluded for not meeting the inclusion criteria in terms of study design and characteristics of intervention, and 35 primary studies (5601 participants, mean age 65 years, [SD 11]) reported in 109 peer-reviewed publications were deemed suitable for inclusion. Of these, 17 studies (49%) provided IPD (3431 participants, mean duration 9·5 months) from nine different countries while 18 did not provide IPD data. Risk of bias was judged to be low in most IPD studies (71%). Fewer deaths occurred with testosterone treatment (six [0·4%] of 1621) than placebo (12 [0·8%] of 1537) without significant differences between groups (odds ratio [OR] 0·46 [95% CI 0·17–1·24]; p=0·13). Cardiovascular risk was similar during testosterone treatment (120 [7·5%] of 1601 events) and placebo treatment (110 [7·2%] of 1519 events; OR 1·07 [95% CI 0·81–1·42]; p=0·62). Frequently occurring cardiovascular events included arrhythmia (52 of 166 vs 47 of 176), coronary heart disease (33 of 166 vs 33 of 176), heart failure (22 of 166 vs 28 of 176), and myocardial infarction (10 of 166 vs 16 of 176). Overall, patient age (interaction 0·97 [99% CI 0·92–1·03]; p=0·17), baseline testosterone (interaction 0·97 [0·82–1·15]; p=0·69), smoking status (interaction 1·68 [0·41–6·88]; p=0.35), or diabetes status (interaction 2·08 [0·89–4·82; p=0·025) were not associated with cardiovascular risk.InterpretationWe found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone.FundingNational Institute for Health Research Health Technology Assessment Programme.