Challenges of clinical trial design when there is lack of clinical equipoise: use of a response-conditional crossover design

Clinical equipoise is widely accepted as the basis of ethics in clinical research and requires investigators to be uncertain of the relative therapeutic merits of trial comparators. When clinical equipoise is in question, innovative trial designs are needed to reduce ethical tension while satisfying regulators’ requirements. We report a novel response-conditional crossover study design used in a Phase 3, randomized, double-blind, placebo-controlled clinical trial of intravenous 10% caprylate-chromatography purified immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. During the initial 24-week period, patients crossed over to the alternative treatment at the first sign of deterioration or if they failed to improve or were unable to maintain improvement at any time after 6 weeks. This trial design addressed concerns about lack of equipoise raised by physicians interested in trial participation and proved acceptable to regulatory authorities. The trial design may be applicable to other studies where clinical equipoise is in question

Overview to the Hard X-ray Modulation Telescope (Insight-HXMT) Satellite

As China's first X-ray astronomical satellite, the Hard X-ray Modulation Telescope (HXMT), which was dubbed as Insight-HXMT after the launch on June 15, 2017, is a wide-band (1-250 keV) slat-collimator-based X-ray astronomy satellite with the capability of all-sky monitoring in 0.2-3 MeV. It was designed to perform pointing, scanning and gamma-ray burst (GRB) observations and, based on the Direct Demodulation Method (DDM), the image of the scanned sky region can be reconstructed. Here we give an overview of the mission and its progresses, including payload, core sciences, ground calibration/facility, ground segment, data archive, software, in-orbit performance, calibration, background model, observations and some preliminary results.Comment: 29 pages, 40 figures, 6 tables, to appear in Sci. China-Phys. Mech. Astron. arXiv admin note: text overlap with arXiv:1910.0443

Exploring the optimum approach to the use of CT densitometry in a randomised placebo-controlled study of augmentation therapy in alpha 1-antitrypsin deficiency

Background: Computed tomography (CT) lung densitometry has been demonstrated to be the most sensitive and specific outcome measure for the assessment of emphysema-modifying therapy, but the optimum densitometric index has yet to be determined and targeted sampling may be more sensitive than whole lung assessment. The EXAcerbations and CT scan as Lung Endpoints (EXACTLE) trial aimed to clarify the optimum approach to the use of CT densitometry data for the assessment of alpha 1-antitrypsin (AAT) augmentation therapy on the progression of emphysema in AAT deficiency (AATD). Methods: Patients with AATD (n = 77) were randomised to weekly infusions of 60 mg/kg human AAT (Prolastin (R)) or placebo over 2 to 2.5 years. Lung volume was included as a covariate in an endpoint analysis and a comparison was made of different CT densitometric indices (15th percentile lung density [PD15], mean lung density [MLD] and voxel index at a threshold of -910 [VI-910] and -950 [VI-950] Hounsfield Units) obtained from whole lung scans at baseline and at 24 to 30 months. Targeted regional sampling was compared with whole lung assessment. Results: Whole lung analysis of the total change (baseline to last CT scan) compared with placebo indicated a concordant trend that was suggestive of a treatment effect for all densitometric indices (MLD [1.402 g/L, p = 0.204]; VI-910 [-0.611, p = 0.389]; VI-950 [-0.432, p = 0.452]) and that was significant using PD15 (1.472 g/L, p = 0.049). Assessment of the progression of emphysema in the apical, middle and basal regions of the lung by measurement with PD15 showed that this treatment effect was more evident when the basal third was sampled (1.722 g/L, p = 0.040). A comparison between different densitometric indices indicated that the influence of inspiratory variability between scans was greatest for PD15, but when adjustment for lung volume was made this index was the most sensitive measure of emphysema progression. Conclusion: PD15 is the most sensitive index of emphysema progression and of treatment modification. Targeted sampling may be more sensitive than whole lung analysis. Trial registration: Registered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887

Detection of emphysema progression in alpha 1-antitrypsin deficiency using CT densitometry; Methodological advances-1

<p><b>Copyright information:</b></p><p>Taken from "Detection of emphysema progression in alpha 1-antitrypsin deficiency using CT densitometry; Methodological advances"</p><p>http://respiratory-research.com/content/9/1/21</p><p>Respiratory Research 2008;9(1):21-21.</p><p>Published online 13 Feb 2008</p><p>PMCID:PMC2287169.</p><p></p

Safety and Tolerability of Immune Globulin Intravenous in Chronic S Inflammatory Demyelinating Polyradiculoneuropathy

Background: Chronic inflammatory demyelinating poly-radiculoneuropathy (CIDP) is a common inflammatory neuropathy that can be progressive, stepwise progressive, or relapsing and remitting. Objectives: To further evaluate the long-term safety and tolerability of immune globulin intravenous, 10% caprylate chromatography purified immune globulin intravenous in CIDP. Design: Randomized multicenter trial. Setting: Hospitals and outpatient clinics. Patients: Adults with CIDP (n = 113). Interventions: Immune globulin intravenous, 10% caprylate chromatography purified (2 g/kg of body weight) or placebo was infused as a baseline loading dose, followed by a maintenance dose (1 g/kg) every 3 weeks for up to 24 weeks. Patients who responded were rerandomized into a double-blind extension phase of immune globulin intravenous, 10% caprylate chromatography purified (1 g/kg) or placebo every 3 weeks for up to 24 weeks. Patients who relapsed during the extension phase were withdrawn from the study. Main Outcome Measures: Additional analyses of safety and tolerability. Results: Overall, 113 patients and 95 patients were exposed to immune globulin intravenous, 10% caprylate chromatography purified and placebo, respectively. Exposure to immune globulin intravenous, 10% caprylate chromatography purified was approximately twice that of placebo (1096 vs 575 infusions). Most maintenance dose courses were administered over 1 day in the immune globulin intravenous, 10% caprylate chromatography purified (89.1% of 783 dose courses) and placebo (91.1% of 359 dose courses) groups. The most common drug-related adverse events (AEs) with immune globulin intravenous, 10% caprylate chromatography purified were headache (4.0 per 100 infusions) and pyrexia (2.4 per 100 infusions). Five drug-related serious AEs (pulmonary embolism, pyrexia, vomiting, and 2 headache events) were reported in 3 patients (2.7%) exposed to immune globulin intravenous, 10% caprylate chromatography purified. The incidence of drug-elated serious AEs was higher after loading dose infusions than after maintenance dose infusions (4 AEs vs 1 AE). Age, weight, CIDP severity, and previous immune globulin intravenous exposure had no substantial effect on the percentage of patients with AEs, including serious AEs. Conclusion: Data support a favorable safety and tolerability profile for administration of immune globulin intravenous, 10% caprylate chromatography purified as CIDP maintenance therapy

Contemporary risk scores predict clinical worsening in pulmonary arterial hypertension - An analysis of FREEDOM-EV

BACKGROUND: Risk scores integrate clinical variables emphasizing symptoms, exercise capacity, and measures of cardiac strain to predict clinical outcome better than any single value in pulmonary arterial hypertension (PAH). Risk scores have demonstrated prognostic utility for outcomes in registries, and recent studies have suggested that they are also therapy-responsive in controlled trials. METHODS: FREEDOM-EV, a global, placebo-controlled, event-driven study, randomized 690 PAH participants 1:1 to oral treprostinil (TRE) or placebo. Clinical assessments were performed every 12 weeks to calculate the non-invasive French risk assessment (FRA), 4-strata COMPERA, REVEAL 2.0, and REVEAL Lite 2; median follow-up was 58 weeks. The Week 12 risk scores were used to predict time to clinical worsening (from Week 12) with Kaplan-Meier product-limit estimates. Log-rank test was used to calculate the statistical difference among risk categories, and mediation analysis tested the hypothesis that improvements in risk score contributed to reduced likelihood for clinical worsening. We assessed the previously proposed net clinical benefit (achievement of FRA low-risk status and absence of clinical worsening). RESULTS: Both REVEAL scores, COMPERA, and FRA at Week 12 predicted subsequent clinical worsening better than baseline risk. Mediation analysis demonstrated that Week 12 risk score reduction explained part of TRE\u27s effect on clinical worsening, especially for those with higher baseline risk. TRE assigned participants were more likely to achieve the previously proposed net clinical benefit at Weeks 24 and beyond. Few participants who achieved \u27net clinical benefit\u27 had subsequent clinical worsening. CONCLUSIONS: Contemporary risk scores were therapy responsive in FREEDOM-EV and early improvements predicted subsequent outcomes. This post hoc analysis suggests that risk scores may be a surrogate for clinical worsening