Nebulized Recombinant Tissue Plasminogen Activator (rt-PA) for Acute COVID-19-Induced Respiratory Failure: An Exploratory Proof-of-Concept Trial.

Acute lung injury in COVID-19 results in diffuse alveolar damage with disruption of the alveolar-capillary barrier, coagulation activation, alveolar fibrin deposition and pulmonary capillary thrombi. Nebulized recombinant tissue plasminogen activator (rt-PA) has the potential to facilitate localized thrombolysis in the alveolar compartment and improve oxygenation. In this proof-of-concept safety study, adults with COVID-19-induced respiratory failure and a <300 mmHg PaO2/FiO2 (P/F) ratio requiring invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS) received nebulized rt-PA in two cohorts (C1 and C2), alongside standard of care, between 23 April-30 July 2020 and 21 January-19 February 2021, respectively. Matched historical controls (MHC; n = 18) were used in C1 to explore efficacy. Safety co-primary endpoints were treatment-related bleeds and <1.0-1.5 g/L fibrinogen reduction. A variable dosing strategy with clinical efficacy endpoint and minimal safety concerns was determined in C1 for use in C2; patients were stratified by ventilation type to receive 40-60 mg rt-PA daily for ≤14 days. Nine patients in C1 (IMV, 6/9; NIRS, 3/9) and 26 in C2 (IMV, 12/26; NIRS, 14/26) received nebulized rt-PA for a mean (SD) of 6.7 (4.6) and 9.1(4.6) days, respectively. Four bleeds (one severe, three mild) in three patients were considered treatment related. There were no significant fibrinogen reductions. Greater improvements in mean P/F ratio from baseline to study end were observed in C1 compared with MHC (C1; 154 to 299 vs. MHC; 154 to 212). In C2, there was no difference in the baseline P/F ratio of NIRS and IMV patients. However, a larger improvement in the P/F ratio occurred in NIRS patients (NIRS; 126 to 240 vs. IMV; 120 to 188) and fewer treatment days were required (NIRS; 7.86 vs. IMV; 10.5). Nebulized rt-PA appears to be well-tolerated, with a trend towards improved oxygenation, particularly in the NIRS group. Randomized clinical trials are required to demonstrate the clinical effect significance and magnitude.

Phase 1-2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B.

BACKGROUND: FLT180a (verbrinacogene setparvovec) is a liver-directed adeno-associated virus (AAV) gene therapy that uses a synthetic capsid and a gain-of-function protein to normalize factor IX levels in patients with hemophilia B. METHODS: In this multicenter, open-label, phase 1-2 trial, we assessed the safety and efficacy of varying doses of FLT180a in patients with severe or moderately severe hemophilia B (factor IX level, ≤2% of normal value). All the patients received glucocorticoids with or without tacrolimus for immunosuppression to decrease the risk of vector-related immune responses. After 26 weeks, patients were enrolled in a long-term follow-up study. The primary end points were safety and efficacy, as assessed by factor IX levels at week 26. RESULTS: Ten patients received one of four FLT180a doses of vector genomes (vg) per kilogram of body weight: 3.84×1011 vg, 6.40×1011 vg, 8.32×1011 vg, or 1.28×1012 vg. After receiving the infusion, all the patients had dose-dependent increases in factor IX levels. At a median follow-up of 27.2 months (range, 19.1 to 42.4), sustained factor IX activity was observed in all the patients except one, who resumed factor IX prophylaxis. As of the data-cutoff date (September 20, 2021), five patients had normal factor IX levels (range, 51 to 78%), three patients had levels from 23 to 43%, and one had a level of 260%. Of the reported adverse events, approximately 10% were related to FLT180a and 24% to immunosuppression. Increases in liver aminotransferase levels were the most common FLT180a-related adverse events. Late increases in aminotransferase levels occurred in patients who had received prolonged tacrolimus beyond the glucocorticoid taper. A serious adverse event of arteriovenous fistula thrombosis occurred in the patient with high factor IX levels. CONCLUSIONS: Sustained factor IX levels in the normal range were observed with low doses of FLT180a but necessitated immunosuppression with glucocorticoids with or without tacrolimus. (Funded by Freeline Therapeutics; ClinicalTrials.gov numbers, NCT03369444 and NCT03641703; EudraCT numbers, 2017-000852-24 and 2017-005080-40.).

Hibiscus sabdariffa, a Treatment for Uncontrolled Hypertension. Pilot Comparative Intervention.

In Iraq, in 2019, there were about 1.4 million Internally Displaced Persons (IDP); medical treatments were often interrupted. The feasibility of using Hibiscus sabdariffa (HS) decoction to curb hypertension was evaluated. A multicentric comparative pilot intervention for 121 participants with high blood pressure (BP) (≥140/90 mmHg) was conducted. Participants of the intervention group (with or without conventional medication) received HS decoction on a dose regimen starting from 10 grams per day. BP was measured five times over six weeks. The major active substances were chemically quantified. Results: After 6 weeks, 61.8% of participants from the intervention group (n = 76) reached the target BP < 140/90 mmHg, compared to 6.7% in the control group (n = 45). In the intervention group, a mean (±SD) reduction of 23.1 (±11.8) mmHg and 12.0 (±11.2) for systolic and diastolic BP, respectively, was observed, while in the control group the reduction was 4.4 (±10.2)/3.6 (±8.7). The chemical analysis of the starting dose indicated a content of 36 mg of total anthocyanins and 2.13 g of hibiscus acid. The study shows the feasibility of using HS decoction in IDP's problematic framework, as hibiscus is a safe, local, affordable, and culturally accepted food product.

Psychiatric and neurological symptoms in patients with Niemann-Pick disease type C (NP-C): Findings from the International NPC Registry.

Objectives: Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease that should be recognised by psychiatrists as a possible underlying cause of psychiatric abnormalities. This study describes NP-C patients who had psychiatric manifestations at enrolment in the international NPC Registry, a unique multicentre, prospective, observational disease registry. Methods: Treating physicians' data entries describing psychiatric manifestations in NPC patients were coded and grouped by expert psychiatrists. Results: Out of 386 NP-C patients included in the registry as of October 2015, psychiatric abnormalities were reported to be present in 34% (94/280) of those with available data. Forty-four patients were confirmed to have identifiable psychiatric manifestations, with text describing these psychiatric manifestations. In these 44 patients, the median (range) age at onset of psychiatric manifestations was 17.9 years (2.5-67.9; n = 15), while the median (range) age at NP-C diagnosis was 23.7 years (0.2-69.8; n = 34). Almost all patients (43/44; 98%) had an occurrence of ≥1 neurological manifestation at enrolment. Conclusions: These data show that substantial delays in diagnosis of NP-C are long among patients with psychiatric symptoms and, moreover, patients presenting with psychiatric features and at least one of cognitive impairment, neurological manifestations, and/or visceral symptoms should be screened for NP-C.

Use of a post-sleep questionnaire-interactive voice response system (PSQ-IVRS) to evaluate the subjective sleep effects of ramelteon in adults with chronic insomnia.

OBJECTIVE: Ramelteon is an MT(1)/MT(2) melatonin receptor agonist approved in the US and Japan for the treatment of sleep-onset insomnia. This study evaluated the effects of ramelteon 8mg on patient reported sleep parameters in adults with chronic insomnia in an at-home setting using a post-sleep questionnaire-interactive voice response system (PSQ-IVRS). METHODS: Adults aged 18-64 years with chronic insomnia were randomized to receive ramelteon 8 mg or placebo nightly for 3weeks. Sleep parameters were assessed via PSQ-IVRS within 60 min of awakening each morning. Adverse effects were collected throughout the study. RESULTS: A total of 552 subjects (mean age 43.2 years) received treatment (274 ramelteon, 278 placebo). There was a reduction in mean sleep latency at weeks 1, 2, and 3 compared with placebo but none reached statistical significance (-4.1 min, p=0.088 week 1; -2.8 min, p=0.258 week 2; -4.9 min, p=0.060 week 3). There were no significant differences between placebo and ramelteon in other PSQ-IVRS sleep parameters. Only headache (18 [6.5%] placebo, 18 [6.6%] ramelteon) and somnolence (5 [1.8%], 12 [4.4%] ramelteon) occurred in>3% of subjects. CONCLUSIONS: Use of ramelteon 8 mg in an at-home setting did not demonstrate statistically significant improvements in subjective sleep latency compared with placebo, when measured by PSQ-IVRS.