Trans Sodium Crocetinate (TSC) to Improve Oxygenation in COVID-19

Background: Trans Sodium Crocetinate (TSC) is a bipolar synthetic carotenoid under development as a drug to enhance oxygenation to hypoxic tissue in addition to standard of care. TSC acts via a novel mechanism of action, improving the diffusivity of oxygen in blood plasma. Thus, it is based on physical-chemical principles, unlike most drugs which are based on biochemistry-based mechanisms. We explored the use of escalating doses and multiple daily dosing of TSC as a potential therapeutic for patients suffering from hypoxemia due to SARS-CoV-2 infection. Methods: Individuals ≥18 years who were hospitalized with confirmed SARS-CoV-2 infection and hypoxemia, defined as SpO2 < 94% on room air or requiring supplemental oxygen, WHO ordinal scale 3 through 7 (exclusive of Extra Corporeal Membrane Oxygenation [ECMO]) were enrolled in cohorts of six subjects, each of whom received the same dose (0.25, 0.5, 1.0, or 1.5 mg/kg) of TSC via intravenous bolus every 6 hours in addition to standard of care (SOC). This report describes the safety and efficacy results from the lead-in phase of the study and the population pharmacokinetics (PK) analyses. Safety was assessed as the number of serious adverse events and dose-limiting toxicities (DLTs) observed with each dose. Several efficacy parameters were examined in the lead-in phase and descriptive statistics of efficacy parameters are provided. No formal statistical analyses were performed. The population PK analyses were based on previous analyses and examination of the concentration profiles, and two-compartment linear pharmacokinetic models were evaluated and validated. Covariates, including body size, age, sex, organ function, and dose level, were evaluated for inclusion into the model. Results: TSC was well tolerated. There were no treatment emergent adverse events (TEAEs) reported. There were 2 serious adverse events (SAEs) reported during the study, neither were considered treatment-related. A total of 24 (96%) subjects survived. One subject (4.0%) died during the study as a result of an SAE (respiratory failure), and that event was determined to be due to COVID-19 complications and not related to study drug. There was an observed reduction in the time to improvement in WHO Ordinal Scale with increasing dose. The median time to 1-point reduction in subjects receiving 0.25 mg/kg was 11.5 days versus 7.5 days in the 1.5 mg/kg treatment cohort. The overall range across all doses was 1 day to 28 days. A total of 36.0% of subjects had a 1-point improvement in WHO Ordinal Scale to Day 7. The 1.5 mg/kg dose resulted in observed superior outcomes for multiple secondary clinical outcomes: time to 1-point WHO Ordinal Score improvement through Day 29/discharge, 1-point improvement by Day 7, days to return to room air, and hospital length of stay. The PK results showed that the two-compartment model fit the data well. Clearance decreased with increasing dose level and there was no evidence that clearance was affected by covariates other than dose level. Conclusions: These findings suggest that TSC administration every 6 hours at doses up to 1.5 mg/kg for up to 15 days is safe and well tolerated with predictable pharmacokinetics and demonstrated an observed clinical benefit in the treatment of COVID-19-related hypoxemia.

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A phase I/Ib study of crenolanib with ramucirumab (RAM)/paclitaxel (PTX) as second-line therapy (2L tx) for advanced esophagogastric adenocarcinoma (EGA).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.116 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 116-116

Author(s):

Megan Greally ◽

Sujata Jha ◽

Sam S. Yoon ◽

Jia Li ◽

Avni Mukund Desai ◽

...

Keyword(s):

Adverse Events ◽

Phase I ◽

Objective Response ◽

Study Drug ◽

Standard Of Care ◽

Maximum Tolerated Dose ◽

Primary Objective ◽

Serious Adverse Events ◽

Ecog Ps ◽

Higher Doses

116 Background: PTX/RAM as 2L tx for patients (pts) with EGA is a standard-of-care based on the RAINBOW trial (Lancet Oncol 2014;15:1224). However, benefit is modest. Upregulation of the platelet-derived growth factor (PDGF)/PDGF receptor-β (PDGFR-β) pathway causes resistance to VEGF inhibition. Crenolanib is a selective inhibitor of PDGFR-β. We report initial results of the dose escalation phase of a study of crenolanib plus RAM/PTX in pts with previously treated advanced EGA. Methods: This phase I/Ib study is enrolling ECOG PS 0-1 EGA pts with progression on first-line chemo. PTX 80 mg/m2/ day on day 1, 8, 15 and RAM 8mg/kg q 14 days were administered with escalating doses of crenolanib (60, 80, 100 mg BID) after a 7 day “run-in” of crenolanib to assess crenolanib-related toxicities. The primary objective was to determine the maximum tolerated dose (MTD) of crenolanib plus RAM/PTX. Safety and preliminary efficacy were examined. Results: 15 pts were treated; 12 male, median age 58 (32-73), 66% were ECOG PS 1. Primary site was gastric in nine pts, GEJ in 4 pts and esophageal in two pts. Three pts each received crenolanib 60mg BID and 80mg BID, six pts received 100mg BID and three pts received higher doses. At data cutoff, eight pts continued on treatment. 12 pts have completed the DLT evaluation period across 3 dose levels (60 to 100 mg BID). Median treatment duration was 76 days (35-191). The combination was well tolerated, with no DLTs or serious adverse events (SAEs) attributed to study drug. Treatment related adverse events occurred in two pts (17%), all grade 1. These were fatigue, nausea, vomiting and hypertension. Disease progression was the most common reason for treatment discontinuation; no pt discontinued due to study drug related AEs. Nine pts were evaluable for response. One pt had objective response; the disease control rate was 78%. Median PFS and OS were 4.1 and 11.9 months respectively. Conclusions: Crenolanib plus RAM/PTX appears well tolerated at a dose level of 100mg BID. Further evaluation is needed to determine efficacy. Accrual is ongoing at higher doses. Once the MTD is defined, the dose expansion phase will enroll 25 pts. Updated data with pharmacokinetics and biomarkers will be presented. Clinical trial information: NCT03193918.

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ACTR-18. A PHASE IB/II CLINICAL TRIAL OF DODECAFLUOROPENTANE EMULSION (DDFPE) AS A RADIOSENSITIZER IN GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.061 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi16-vi16 ◽

Cited By ~ 1

Author(s):

Jason Lickliter ◽

Jeremy Ruben ◽

Ross Jennens ◽

Ganessan Kichenadasse ◽

Cecelia Gzell ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Adverse Events ◽

Tumor Hypoxia ◽

Standard Of Care ◽

Supplemental Oxygen ◽

Tumor Oxygenation ◽

Serious Adverse Events ◽

Before And After ◽

Mri Scans

Abstract BACKGROUND Tumor hypoxia decreases the response of glioblastoma multiforme (GBM) to radiotherapy (RT) and chemotherapy (temozolomide[TMZ]). The purpose of this study was to evaluate the safety and efficacy of a novel oxygen therapeutic, dodecafluoropentane emulsion (DDFPe), in chemoradiation treatment of GBM and stratify the results based on predicted TMZ response. METHODS With ethics approval and informed consent, 11 adult GBM patients were enrolled. Patients were administered DDFPe via IV infusion (2% w/vol at doses of 0.05, 0.1 or 0.17 mL/kg) within 5–30 minutes prior to each 2 Gy fraction of RT (30 fractions over 6-weeks) while breathing supplemental oxygen. Patients also received standard concurrent and adjuvant TMZ. To evaluate the reversal of tumor hypoxia, patients underwent oxygen-sensitive (TOLD) MRI before and after DDFPe administration. Patients were also studied with serial MRI scans per standard of care and followed for survival. RESULTS The non-serious adverse events considered by the investigator to be possibly, probably, or definitely related to DDFPe administration included fatigue (n=4), headache (n=2) and decrease in platelet count (n=2). Serious adverse events included two patients with symptomatic radiation necrosis: one patient at each of dose levels 0.1 and 0.17 mL/kg. Enrollment continued at the 0.1 mL/kg dose without additional significant DDFPe-related toxicity. Historically, the average overall survival for GBM patients is about 14.6 months. The median overall survival for the study was 591 days, or 19.4 months. According to independent review of the serial MR images, the median time to progression was 555 days, or 18 months, compared to a historical control of 6.9 months. TOLD MRI showed a trend in improved tumor oxygenation. CONCLUSION Although small, this trial shows that DDFPe used as a radiosensitizer appears to be safe and may provide some survival benefit. The FDA has allowed a Phase II clinical trial to assess its effectiveness.

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Management of pulmonary toxicity associated with immune checkpoint inhibitors

European Respiratory Review ◽

10.1183/16000617.0012-2019 ◽

2019 ◽

Vol 28 (154) ◽

pp. 190012 ◽

Cited By ~ 14

Author(s):

Myriam Delaunay ◽

Grégoire Prévot ◽

Samia Collot ◽

Laurent Guilleminault ◽

Alain Didier ◽

...

Keyword(s):

Adverse Events ◽

Immune Checkpoint ◽

Pulmonary Toxicity ◽

Immune Checkpoint Inhibitors ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Standard Of Care ◽

Serious Adverse Events ◽

Programmed Cell Death 1 ◽

Life Threatening

Immunotherapy has become a standard of care in oncology, following the recent approvals of cytotoxic T-lymphocyte-associated protein-4 and programmed cell death-1 inhibitors in lung cancer, melanoma, renal cell carcinoma, Hodgkin's lymphoma, bladder, head and neck cancers. Besides their efficacy, these agents also generate specific immune-related adverse events. Due to the increasing prescription of immune-checkpoint inhibitors, the incidence of immune toxicity will continue to rise. The awareness of immune-related adverse events is key to ensuring both diagnosis and management of the possible serious adverse events. Although severe immune-related adverse events remain rare, they can lead to discontinued treatment or to death if they are not forecasted and managed properly. Even if lung toxicity is not the most frequent adverse event, it remains critical as it can be life-threatening. Herein, the main aspects of pulmonary toxicity are reviewed and guidelines are also proposed in order to manage the possible side-effects.

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Effectiveness and Safety of Rizatriptan Benzoate 10 mg in the Treatment of Migraine Headaches

Clinical Medicine Insights Therapeutics ◽

10.4137/cmt.s4670 ◽

2010 ◽

Vol 2 ◽

pp. CMT.S4670

Author(s):

Michel Aubé ◽

Fridon Chouha ◽

Julie Vaillancourt ◽

John Sampalis

Keyword(s):

Adverse Events ◽

Real Life ◽

Study Drug ◽

Pain Severity ◽

Open Label ◽

Serious Adverse Events ◽

Over The Counter ◽

Rizatriptan Benzoate ◽

Migraine Headaches ◽

Real Life Setting

Background Patients that do not achieve therapeutic response with over the counter non-triptan medications may benefit from triptan-based treatments. Objective Phase I V, open-label, multi-center, prospective cohort study assessing the effectiveness of rizatriptan in the management of migraines for patients that have not responded to non-triptan treatment. Methods Patients were treated with one rizatriptan (MAXALT RPD®) 10 mg wafer at the onset of each migraine attack and were assessed after a minimum of one and a maximum of two consecutive headache episodes. Outcome measures included self-reported assessments (severity and duration of migraine headache) and the Migraine ACT questionnaire. Results A total of 369 patients were enrolled, of which 291 and 215 reported one and two attacks, respectively. For the first and second attacks, 47.2% and 53.9% of patients reported complete resolution of pain while 73.6% and 77.0% reported pain severity reduction within two hours of onset. Mean (SD) pain severity score (four-point Likert scale) during the 488 migraine episodes was reduced significantly ( P < 0.001) from 2.56 (0.49) at onset to 1.91 (0.85) at 30, 1.31 (1.00) at 60 and 0.84 (1.00) at 120 minutes. Similar improvements were observed for changes in Migraine ACT questionnaire scores. No treatment-related serious adverse events were reported. The most frequently reported non-serious adverse events that were attributed to the study drug were dizziness (2.2%), chest discomfort (1.1%), nausea (1.1%), and somnolence (0.8%). Conclusion In a real-life setting, rizatriptan benzoate 10 mg is effective and safe in the treatment of acute migraine headaches in patients who do not respond to non-triptan treatment.

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Ceftazidime–Avibactam versus Meropenem for the Treatment of Complicated Intra-Abdominal Infections

Antibiotics ◽

10.3390/antibiotics8040255 ◽

2019 ◽

Vol 8 (4) ◽

pp. 255 ◽

Cited By ~ 3

Author(s):

Che-Kim Tan ◽

Chih-Cheng Lai ◽

Chien-Ming Chao

Keyword(s):

Adverse Events ◽

Clinical Cure ◽

Clinical Cure Rate ◽

Study Drug ◽

Comparable Efficacy ◽

Integrated Analysis ◽

Cure Rate ◽

Serious Adverse Events ◽

Mitt Population ◽

Abdominal Infections

This study reports an integrated analysis of three randomized controlled trials to compare the clinical efficacies and safety of the ceftazidime–avibactam (CAZ–AVI) combination and meropenem in the treatment of adult patients with complicated intra-abdominal infections (cIAIs). Overall, a total of 1677 patients (CAZ–AVI: 835 patients; meropenem: 842 patients) were included in this analysis. CAZ–AVI had a clinical cure rate at test of cure in the clinically evaluable (CE) population similar to that of meropenem (OR, 0.88; 95% CI, 0.58–1.32; I2 = 0%). Similar trends were also observed in the modified intent-to-treat (MITT) population (OR, 0.80; 95% CI, 0.59–1.09; I2 = 0%) and microbiological evaluable (ME) population (OR, 0.73; 95% CI, 0.32–1.68; I2 = 0%). In terms of clinical cure rate at the end of treatment, the efficacy of CAZ–AVI was comparable to that of meropenem in the CE population (OR, 0.77; 95% CI, 0.47–1.25; I2 = 0%), MITT population (OR, 0.70; 95% CI, 0.47–1.06; I2 = 5%), and ME population (OR, 1.26; 95% CI, 0.39–4.08; I2 = 0%). CAZ–AVI had a similar risk of (i) treatment emergent adverse events (TEAEs) (OR, 1.03; 95% CI, 0.79–1.36; I2 = 38%), (ii) any serious adverse events (OR, 0.97; 95% CI, 0.67–1.40; I2 = 0%), (iii) discontinuation of study drug due to TEAE (OR, 2.14; 95% CI, 1.00–4.57), and iv) all-cause mortality (OR, 1.66; 95% CI, 0.78–3.53; I2 = 0%) when compared with meropenem. In conclusion, CAZ–AVI had comparable efficacy and safety profile to those of meropenem in the treatment of cIAI.

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Phase I trial of ADI-peg 20 plus docetaxel (DOC) in patients (pts) with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.2569 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 2569-2569

Author(s):

Ben Kent Tomlinson ◽

John S. Bomalaski ◽

Monica Diaz ◽

Taiwo Akande ◽

Nichole Mahaffey ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Level ◽

Phase I Trial ◽

Tongue Cancer ◽

Performance Status ◽

Study Drug ◽

Serum Levels ◽

Serious Adverse Events ◽

Combination Methods

2569 Background: ADI-PEG20 is an enzyme that degrades arginine (Arg), an amino acid relevant to biosynthetic pathways of normal and malignant cells. It has shown tolerability and activity in several solid tumors. Preclinical studies have shown that Arg deprivation by ADI-PEG 20 in cancer cells induces autophagy, caspase-independent apoptosis, and potentiates DOC-induced cytotoxicity in prostate cancer (PC) models. A phase I trial (standard 3+3 design) of ADI-PEG20 (IM weekly) plus DOC (IV on day 1 q 3 weeks) was conducted to assess feasibility and safety of the combination. Methods: Eligible pts were >18 years of age, had advanced malignant solid tumors, adequate end organ function, and performance status (PS) 0-2. ADI-PEG 20 was escalated over 4 dose levels (4.5, 9, 18, 36 mg/m2). DOC dose was 75 mg/m2. Dose limiting toxicity (DLT) was defined as any of the following in cycle 1: thrombocytopenia [grade (Gr) 3 with bleeding/transfusion, or Gr 4]; neutropenia with fever or documented infection attributable to ADI PEG20; or any ≥ Gr 3 non-heme toxicity related to study drug except alopecia. Allergic reaction associated with DOC was not considered a DLT. Serum levels of Arg were serially measured. Results: 18 pts were accrued: median age, 64.5 yrs; male, 83%; PS 0, 72%. Most common tumors were NSCLC (8), PC (3), and tongue cancer (TC) (2). Median number of prior systemic therapies was 3. One DLT was seen in dose level 1 (urticarial rash) requiring expansion of that dose level to 6 pts. No additional DLTs attributable to ADI PEG20 were seen. Serious adverse events (all expected and attributed to DOC) were recorded in 11/18 pts, including Gr IV neutropenia (6, 33%) and Gr IV anemia (2, 11%). There were 2 on-study deaths unrelated to protocol therapy. In 11 pts with evaluable disease, 1 with TC had a partial response (PR), 6 had stable disease (SD) (3 NSCLC, 2 PC, 1 TC). Arg levels decreased in the 1st cycle for 6/11 pts with available data, including 2 with SD, and 1 with PR. Conclusions: The combination of ADI PEG20 and DOC is feasible with reasonable tolerability in this heavily pre-treated cohort. Full doses of both agents were achievable: ADI-PEG 20 at 36mg/m2 with DOC 75 mg/m2. An expansion cohort of castration resistant PC pts is now accruing at this recommended dose. Clinical trial information: NCT01497925.

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Trabectedin for recurrent WHO grade II or III meningioma: A randomized phase II study of the EORTC Brain Tumor Group (EORTC-1320-BTG).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.2007 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 2007-2007 ◽

Cited By ~ 5

Author(s):

Matthias Preusser ◽

Antonio Silvani ◽

Emilie Le Rhun ◽

Riccardo Soffietti ◽

Giuseppe Lombardi ◽

...

Keyword(s):

Adverse Events ◽

Progression Free Survival ◽

Standard Of Care ◽

Somatostatin Analogue ◽

Synthesis Methods ◽

Serious Adverse Events ◽

Who Grade ◽

Sea Squirt ◽

Grade Ii ◽

Grade 3

2007 Background: EORTC-1320-BTG investigated the activity, safety and quality of life of therapy with the tetrahydroisoquinoline alkaloid trabectedin (Yondelis) in patients with recurrent higher-grade meningiomas. Trabectedin was originally derived from the Caribbean sea squirt, Ecteinascidia turbinata, and currently is manufactured by total synthesis. Methods: Adult patients with histological diagnosis of WHO grade II or III meningioma and radiologically documented progression after maximal feasible surgery and radiotherapy were randomly assigned in a 2:1 ratio to receive intravenous trabectedin (1.5 mg/m2every three weeks) or local standard of care (LOC). The primary endpoint was progression-free survival (PFS). Results: Within 22.1 months, we randomized a total of 90 patients (n=29 in LOC arm, n=61 in trabectedin arm) in 35 institutions and nine countries. In the LOC arm, the following treatments were administered: hydroxyurea (n=11), bevacizumab (n=9), none (n=4), chemotherapy (n=3), somatostatin analogue (n=1), combined chemotherapy and somatostatin analogue (n=1). With 71 PFS events, median PFS was 4.17 months in the LOC and 2.43 months in the trabectedin arm (hazard ratio [HR] for progression, 1.42; 80% CI, 1.00-2.03; p=0.204) with a PFS-6 rate of 29.1% (95% CI, 11.9%-48.8%) in the LOC and 21.1% (95% CI, 11.3%-32.9%) in the trabectedin arm. Median OS was 10.61 months in the LOC and 11.37 months in the trabectedin arm (HR for death, 0.98; 95% CI, 0.54-1.76; p=0.94).Grade 3 to 5 adverse events occurred in 44.4% (18.5% related, 4 serious adverse events, 0 lethal events) of the patients in the LOC and 59% (32.8% related, 57 serious adverse events and 2 toxic deaths) of patient in the trabectedin arm. Conclusions: In this first prospective randomized trial performed in recurrent grade II or III meningioma, trabectedin did not improve PFS and OS and was associated with significantly higher toxicity as compared to LOC treatment. The data collected in this study may serve as benchmark for future clinical trials in this setting. Clinical trial information: NCT02234050.

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Reversal of SARS-CoV2 Induced Hypoxia by Nebulized Sodium-Ibuprofen in a Compassionate Use Program

10.21203/rs.3.rs-390980/v1 ◽

2021 ◽

Author(s):

Oscar Salva ◽

Pablo Alexis Doreski ◽

Celia Sara Giler ◽

Dario Conrado Quinodoz ◽

Lucia Guadalupe Guzman ◽

...

Keyword(s):

Adverse Events ◽

Average Length ◽

Vital Signs ◽

Standard Of Care ◽

Ambient Air ◽

Outcome Data ◽

Compassionate Use ◽

Rapid Improvement ◽

Serious Adverse Events ◽

Average Length Of Stay

Abstract BackgroundSodium-ibuprofenate in hypertonic saline (NaIHS) administered directly to the lungs by nebulization and inhalation has antibacterial and anti-inflammatory effects with the potential to deliver these benefits to hypoxic patients. We describe a compassionate use program that offered this therapy to hospitalized COVID-19 patients.MethodsNaIHS (50 mg ibuprofen, tid) was provided in addition to standard of care to hospitalized Covid-19 patients until oxygen saturation levels of >94% were achieved on ambient air. Patients wore a containment hood to diminish aerosolization. Outcome data from participating patients treated at multiple hospitals in Argentina between April 04, 2020, through October 31, 2020 are summarized.Results383 patients were treated, including 327 not on mechanical ventilation at baseline (MV) and 56 ICU patients receiving MV. For those not on baseline MV (59±0.8 years), 64% were male, most with at least one recognized risk factor for disease severity, and mean NEWS2 score prior to treatment initiation of 7.0±0.1. The average length of stay (ALOS) was 11.5±0.3 days and length of treatment (LOT) 9.0±0.2 days. In patients on baseline MV (60.6±2.2 years), 69.9% were male, baseline mean NEWS2 Score was 8.8±0.4, ALOS 15.5±1.4 days and LOT 10.5±0.7 days. Reversal of deterioration in oxygenation and NEWS2 scores was observed acutely following initiation of therapy. Overall in-hospital mortality was 10.7% among patients not on MV at baseline, and 19.6% among patients receiving MV at baseline. No serious adverse events were considered related to ibuprofen therapy.ConclusionsTreatment of COVID-19 pneumonitis with inhalational nebulized NaIHS was associated with rapid improvement in hypoxia and vital signs, with no serious adverse events attributed to therapy. Nebulized NaIHS is worthy of further study in randomized, placebo-controlled trials.(ClinicalTrials.gov:NCT04382768).

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Safety findings from CENTURION, a phase 3 consistency study of lasmiditan for the acute treatment of migraine

The Journal of Headache and Pain ◽

10.1186/s10194-021-01343-2 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

C Tassorelli ◽

S Bragg ◽

JH Krege ◽

EG Doty ◽

PA Ardayfio ◽

...

Keyword(s):

Adverse Events ◽

Acute Treatment ◽

Motor Vehicle ◽

Specific Treatment ◽

Study Drug ◽

Control Group ◽

Phase 3 ◽

Serious Adverse Events ◽

Double Blind ◽

Vehicle Accidents

Abstract Background Lasmiditan (LTN) is a selective 5-HT1F receptor agonist for the acute treatment of migraine in adults. We present detailed safety findings from the placebo-controlled, double-blind Phase 3 study, of LTN treatment across 4 attacks (CENTURION). Methods Patients were randomized 1:1:1 to LTN 200 mg (LTN200), LTN100, or a control group that received placebo for 3 attacks and LTN50 for either the 3rd or 4th attack (1:1). Safety analyses were conducted for patients who took ≥1 dose of study drug and, in some cases, those who took all 4 doses. Results Overall, 1471 patients treated 4494 attacks. The incidences of treatment-emergent serious adverse events (SAEs) were - placebo, n=2 (0.4 %); LTN100, n=1 (0.2 %); LTN200, n=2 (0.4 %); no specific treatment-emergent SAE was reported in more than one patient. The most common treatment emergent adverse events (TEAEs) with lasmiditan were dizziness, paresthesia, fatigue, nausea, vertigo, and somnolence; the vast majority were mild or moderate in severity. The incidences of these TEAEs were highest during the first attack and decreased during subsequent attacks. For patients who experienced a common TEAE with the first attack, less than 45 % experienced the same event in subsequent attacks. Patients who did not experience an event in the 1st attack infrequently experienced the same event in subsequent attacks. The time of onset of the common TEAE ranged from ~40 min to 1 h (dependent upon TEAE) and, for individual TEAE, the onset was similar across attacks. Duration was dependent upon TEAE and attack. It was shortest for paresthesia (< 2 h for all attacks); it ranged from 1.8 to 5.5 h for other common TEAEs and was generally similar across attacks. Serotonin syndrome was reported for 2 patients post LTN dosing; there were no meaningful differences across treatment groups in suicidality; there was no evidence of an increase in motor vehicle accidents. Conclusion In this blinded, controlled, multiple-attack study, LTN was associated with generally mild or moderate CNS-related TEAEs of short duration. TEAEs tended to decrease in frequency across the 4 attacks. Trial registration NCT03670810

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Efficacy and harms of convalescent plasma for treatment of hospitalized COVID-19 patients: a systematic review and meta-analysis

Archives of Medical Science ◽

10.5114/aoms/132492 ◽

2021 ◽

Author(s):

Alejandro Piscoya ◽

Luis Ng-Sueng ◽

Angela Parra del Riego ◽

Renato Cerna-Viacava ◽

Vinay Pasupuleti ◽

...

Keyword(s):

Adverse Events ◽

Clinical Improvement ◽

Meta Analysis ◽

Random Effect ◽

Standard Of Care ◽

Serious Adverse Events ◽

Quality Of Evidence ◽

All Cause Mortality ◽

Grade Methodology

IntroductionWe systematically reviewed benefits and harms of convalescent plasma (CP) in hospitalized COVID-19 patients.Material and methodsRandomized controlled trials (RCTs) and observational studies assessing CP effects on hospitalized, adult COVID-19 patients were searched until November 24, 2020. We assessed risk of bias (RoB) using Cochrane RoB 2.0 and ROBINS-I tools. Inverse variance random effect meta-analyses were performed. Quality of evidence was evaluated using GRADE methodology. Primary outcomes were all-cause mortality, clinical improvement, and adverse events.ResultsFive RCTs (n = 1067) and 6 cohorts (n = 881) were included. Three and 1 RCTs had some concerns and high RoB, respectively; and there was serious RoB in all cohorts. Convalescent plasma did not reduce all-cause mortality in RCTs of severe (RR = 0.60, 95% CI: 0.33–1.10) or moderate (RR = 0.60, 95% CI: 0.09–3.86) COVID-19 vs. standard of care (SOC); CP reduced all-cause mortality vs. SOC in cohorts (RR = 0.66, 95% CI: 0.49–0.91). Convalescent plasma did not reduce invasive ventilation vs. SOC in moderate disease (RR = 0.85, 95% CI: 0.47–1.55). In comparison to placebo + SOC, CP did not affect all-cause mortality (RR = 0.75, 95% CI: 0.48–1.16) or clinical improvement (HR = 1.07, 95% CI: 0.82–1.40) in severe patients. Adverse and serious adverse events were scarce, similar between CP and controls. Quality of evidence was low or very low for most outcomes.ConclusionsIn comparison to SOC or placebo + SOC, CP did not reduce all-cause mortality in RCTs of hospitalized COVID-19 patients. Convalescent plasma did not have an effect on other clinical or safety outcomes. Until now there is no good quality evidence to recommend CP for hospitalized COVID-19 patients.

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