Phase 2 trial design of BMS-986278, a lysophosphatidic acid receptor 1 (LPA1) antagonist, in patients with idiopathic pulmonary fibrosis (IPF) or progressive fibrotic interstitial lung disease (PF-ILD)

IntroductionIdiopathic pulmonary fibrosis (IPF) and non-IPF, progressive fibrotic interstitial lung diseases (PF-ILD), are associated with a progressive loss of lung function and a poor prognosis. Treatment with antifibrotic agents can slow, but not halt, disease progression, and treatment discontinuation because of adverse events is common. Fibrotic diseases such as these can be mediated by lysophosphatidic acid (LPA), which signals via six LPA receptors (LPA1–6). Signalling via LPA1 appears to be fundamental in the pathogenesis of fibrotic diseases. BMS-986278, a second-generation LPA1 antagonist, is currently in phase 2 development as a therapy for IPF and PF-ILD.Methods and analysisThis phase 2, randomised, double-blind, placebo-controlled, parallel-group, international trial will include adults with IPF or PF-ILD. The trial will consist of a 42-day screening period, a 26-week placebo-controlled treatment period, an optional 26-week active-treatment extension period, and a 28-day post-treatment follow-up. Patients in both the IPF (n=240) and PF-ILD (n=120) cohorts will be randomised 1:1:1 to receive 30 mg or 60 mg BMS-986278, or placebo, administered orally two times per day for 26 weeks in the placebo-controlled treatment period. The primary endpoint is rate of change in per cent predicted forced vital capacity from baseline to week 26 in the IPF cohort.Ethics and disseminationThis study will be conducted in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles, and local ethical and legal requirements. Results will be reported in a peer-reviewed publication.Trial registration numberNCT04308681.

A Systematic Review of Unexplained Early Regression in Adolescents and Adults with Down Syndrome

A proportion of young people with Down syndrome (DS) experience unexplained regression that severely impacts on their daily lives. While this condition has been recognised by clinicians, there is a limited understanding of causation and an inconsistent approach to diagnosis and treatment. Varied symptomology and little knowledge of the cause of this regression have impacted on clinician’s ability to prevent or manage this condition. The purpose of this review was to examine the current evidence surrounding unexplained regression in adolescents and young adults, and to establish patterns that may be of use to clinicians, as well as raising awareness of this condition. Four areas were specifically reviewed, (1) terminology used to refer to this condition, (2) the symptoms reported, (3) potential trigger events and, (4) treatments and prognosis. A variety of terminology is used for this condition, which has constrained past attempts to identify patterns. An extensive number of symptoms were reported, however sleep impairment, loss of language and distinct changes in personality and behaviour, such as disinterest and withdrawal, were among the most frequently seen. Life events that were tentatively associated with the onset of a regressive period included a significant change in environmental circumstances or a transition, such as moving home or leaving school. Prognosis for this condition is relatively positive with the majority of individuals making at least a partial recovery. However, few patients were found to make a full recovery to their previous level of functioning and serious adverse effects could persist in those who have made a partial recovery. This is an under-researched condition with significant impacts on people with DS and their families. There are no established treatments for this condition and there is relatively little recognition in the research community. Further studies that focus on the prevention and treatment of this condition with controlled treatment trials are needed.

Protocol and statistical analysis plan for the phase 3 randomised controlled Treatment of Invasively Ventilated Adults with Early Activity and Mobilisation (TEAM III) trial

OBJECTIVE: To describe the protocol and statistical analysis plan for the Treatment of Invasively Ventilated Adults with Early Activity and Mobilisation (TEAM III) trial. DESIGN: An international, multicentre, parallel-group, randomised controlled phase 3 trial. SETTING: Intensive care units (ICUs) in Australia, New Zealand, Germany, Ireland, the United Kingdom and Brazil. PATIENTS: 750 adult patients expected to receive mechanical ventilation for more than 48 hours. INTERVENTIONS: Early activity and mobilisation delivered to critically ill patients in an ICU for up to 28 days compared with standard care. MAIN OUTCOME MEASURES: The primary outcome is the number of days alive and out of hospital at 180 days after randomisation. Secondary outcomes include ICU-free days, ventilator-free days, delirium-free days, all-cause mortality at 28 and 180 days after randomisation, and functional outcome at 180 days after randomisation. RESULTS: Recruitment at 46 research sites passed 576 patients in March 2021. Final collection of all 180-day outcome data for the target of 750 patients is anticipated by May 2022. CONCLUSIONS: Consistent with international guidelines, a detailed protocol and prospective analysis plan has been developed for the TEAM III trial. This plan specifies the statistical models for evaluating primary and secondary outcomes, defines covariates for adjusted analyses, and defines methods for exploratory analyses. Application of this protocol and statistical analysis plan to the forthcoming TEAM III trial will facilitate unbiased analyses of the clinical data collected. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03133377.

Safety of Ocrelizumab in Patients With Relapsing and Primary Progressive Multiple Sclerosis

ObjectiveTo report safety of ocrelizumab (OCR) up to 7 years in patients with relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS) enrolled in clinical trials or treated in real-world postmarketing settings.MethodsSafety analyses are based on integrated clinical and laboratory data for all patients who received OCR in 11 clinical trials, including the controlled treatment and open-label extension (OLE) periods of the phase 2 and 3 trials, plus the phase 3b trials VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, CONSONANCE, and LIBERTO. For selected adverse events (AEs), additional postmarketing data were used. Incidence rates of serious infections (SIs) and malignancies were contextualized using multiple epidemiologic sources.ResultsAt data cut-off (January 2020), 5,680 patients with multiple sclerosis (MS) received OCR (18,218 patient years [PY] of exposure) in clinical trials. Rates per 100 PY (95% CI) of AEs (248; 246–251), serious AEs (7.3; 7.0–7.7), infusion-related reactions (25.9; 25.1–26.6), and infections (76.2; 74.9–77.4) were similar to those within the controlled treatment period of the phase 3 trials. Rates of the most common serious AEs, including SIs (2.01; 1.81–2.23) and malignancies (0.46; 0.37–0.57), were consistent with the ranges reported in epidemiologic data.ConclusionContinuous administration of OCR for up to 7 years in clinical trials, as well as its broader use for more than 3 years in the real-world setting, are associated with a favorable and manageable safety profile, without emerging safety concerns in a heterogeneous MS population.Classification of evidenceThis analysis provides Class III evidence that long-term, continuous treatment with OCR has a consistent and favorable safety profile in patients with RMS and PPMS. This study is rated Class III because of the use of OLE data and historical controls.

Fullers Earth Treatment for Esters Liquids used in Power Apparatuses: Inferences and Arguments

Insulating Liquids are widely used for their electrical and thermal properties in power apparatuses, particularly at the level of liquid-filled transformers. With the shift in engineering aspects towards sustainable development, it is important to find a sustainable solution with ecofriendly nature. Therefore, alternative (biodegradable) liquids are of high importance in the global transformer communities. In the present study, the alternative dielectric fluids (ester-based) feasibility for potential regeneration with Fuller’s earth is investigated. The experimental results are confined to the reclamation temperature as well as the ratio of Fuller's earth (the sorbent) and the liquid. A suitable laboratory treatment apparatus is designed and is adopted in this study. Promising measurements to comment on the effectiveness of the treatment have been performed at controlled treatment temperature and sorbent-liquid ratio with the ASTM 7150-13 as a reference norm.The results of this study allowed 80°C and 1 g/30 ml as affirmative conditions for the present experimental conditions. Diagnostic measurements include turbidity, particle counter, and UV spectrophotometry before and after treatments. It is inferred that fuller’s earth is not a promising sorbent for the reclamation of ester liquids.

Addition of Cabergoline to Oral Octreotide Capsules May Improve Biochemical Control in Patients With Acromegaly Who Are Inadequately Controlled With Monotherapy

Background: Oral octreotide capsules (OOC; MYCAPSSA®) are approved in the US for individuals with acromegaly who responded to and tolerated treatment with injectable somatostatin receptor ligands (iSRLs). Add-on cabergoline therapy has shown effectiveness in patients previously inadequately controlled with iSRLS.1 The phase 3 MPOWERED trial assessed maintenance of response with OOC compared to iSRLs. Patients receiving OOC and ineligible for randomized controlled treatment (RCT) phase were eligible for a sub-study evaluating combination therapy with cabergoline, a dopamine agonist. Methods: Patients who fail to respond to 80 mg/d OOC for ≥2 weeks during the 26-week Run-in phase, or ineligible to enter the RCT on 80 mg/d OOC, due to inadequate biochemical control (insulin-like growth factor I [IGF-I] ≥1.3 × upper limit of normal [ULN] to <2 × ULN or IGF-I <1.3 × ULN and mean integrated growth hormone [GH] ≥2.5 ng/mL) were eligible for sub-study combination OOC 80 mg/d and cabergoline ≤3.5 mg/wk (fixed algorithm) for 36 weeks. End points included categorical changes in IGF-I and mean GH levels at sub-study end and adverse event (AE) incidence and severity. Echocardiogram was performed at sub-study start and every 12 weeks after. Results: Of 146 patients enrolled in MPOWERED, 14 entered the combination sub-study, 9 having IGF-I ≥1.3 × ULN at sub-study start. Final cabergoline doses were 1 (n=5), 2 (n=3), 3 (n=1), and 3.5 mg (n=5) with 25.4-week (SD, 14.1) mean treatment duration. Week 36 IGF-I improved in most patients (n=12; 85.7%). Of 9 patients with IGF-I ≥1.3 × ULN at sub-study start, 5 (55.6%; 95% CI, 21.2%-86.3%) exhibited IGF-I decreased to predefined responder range (<1.3 × ULN) by week 36. AE incidence and nature with combined treatment were similar to known octreotide safety profile and acromegaly disease burden. There were no serious AEs or AEs leading to discontinuation of either sub-study drug. Conclusion: We have shown for the first time the benefit of an all-oral combination treatment for acromegaly and avoidance of injection-related burdens. Addition of cabergoline to OOC yielded biochemical control improvement (IGF-I reduction) in patients inadequately controlled with OOC monotherapy. As both combination and OOC monotherapy safety profiles were similar, adjunctive cabergoline may be helpful in patients with acromegaly who do not achieve adequate biochemical control on OOC alone. 1Giustina A, et al. Nat Rev Endocrinol. 2014;10(4):243-248.

Stone Localization Is Pivotal for the Success of Percutaneous Nephrolithotomy

<b><i>Objective:</i></b> The objective of this study was to predict computed tomography (CT)-controlled treatment success after minimally invasive percutaneous nephrolithotomy (Mini-PCNL). <b><i>Patients and Methods:</i></b> We relied on retrospective single institutional data from 92 kidney stone patients treated with Mini-PCNL. Residual stones after treatment were evaluated by post-Mini-PCNL CT scans. Stone-free status was defined as clinically insignificant residual stones ≤3 mm after surgery. Multivariable logistic regression analyses predicted stone-free status after Mini-PCNL. <b><i>Results:</i></b> Overall, 53 (57.6%) patients achieved stone-free status after Mini-PCNL treatment. In multivariable logistic regression analyses, stone localization was the strongest predictor for stone-free status after Mini-PCNL. Specifically, patients with exclusively pelvic stones were 7.1-fold more likely to achieve stone-free status than those patients with stones at multiple localizations (OR: 7.1; <i>p</i> = 0.005). Additionally, stone size represented a barrier for stone-free status (OR: 0.9; <i>p</i> = 0.03). <b><i>Conclusions:</i></b> Stone localization revealed the highest impact on treatment success after Mini-PCNL. Especially, those patients with exclusively pelvic stones were most likely to achieve stone-free status. Conversely, patients with multiple stone localizations were less likely to achieve stone-free status and need to be informed about higher risk of additional interventions after initial Mini-PCNL.