Hepatol Int. 2021 Feb 25. doi: 10.1007/s12072-021-10151-4. Online ahead of print.

ABSTRACT

BACKGROUND: Checkpoint inhibitor-induced hepatitis is an immune-related adverse event of programmed cell death protein 1 (PD-1) inhibition, cytotoxic T-lymphocyte associated 4 (CTLA-4) inhibition or the combination of both. Aim of this study was to assess whether checkpoint inhibitor-induced hepatitis is related to liver metastasis and outcome in a real-world nationwide cohort.

METHODS: Data from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR) was used to analyze incidence, risk factors of checkpoint inhibitor-induced grade 3-4 hepatitis and outcome.

RESULTS: 2561 advanced cutaneous melanoma patients received 3111 treatments with checkpoint inhibitors between May 2012 and January 2019. Severe hepatitis occurred in 30/1620 (1.8%) patients treated with PD-1 inhibitors, in 29/1105 (2.6%) patients treated with ipilimumab and in 80/386 (20.7%) patients treated with combination therapy. Patients with hepatitis had a similar prevalence of liver metastasis compared to patients without hepatitis (32% vs. 27%; p = 0.58 for PD-1 inhibitors; 42% vs. 29%; p = 0.16 for ipilimumab; 38% vs. 43%; p = 0.50 for combination therapy). There was no difference in median progression free and overall survival between patients with and without hepatitis (6.0 months vs. 5.4 months progression-free survival; p = 0.61; 17.0 vs. 16.2 months overall survival; p = 0.44).

CONCLUSION: Incidence of hepatitis in a real-world cohort is 1.8% for PD-1 inhibitor, 2.6% for ipilimumab and 20.7% for combination therapy. Checkpoint inhibitor-induced hepatitis had no relation with liver metastasis and had no negative effect on the outcome.

PMID:33634373 | DOI:10.1007/s12072-021-10151-4

J Neural Transm (Vienna). 2021 Feb 25. doi: 10.1007/s00702-021-02315-1. Online ahead of print.

ABSTRACT

The double-blind part of the COMFORT-PD (COMt-inhibitor Findings from Opicapone Repeated Treatment for Parkinson's Disease) study in Japanese levodopa-treated patients with Parkinson's disease and motor fluctuations found that both opicapone 25 and 50 mg were significantly more effective than placebo. This 52-week open-label extension study evaluated the long-term safety and efficacy of opicapone 50 mg tablets in patients who completed the double-blind part of the COMFORT-PD study. Safety was monitored via adverse events, laboratory testing, and physical, cardiovascular and neurological examinations. Efficacy was primarily assessed by change in OFF-time. Secondary efficacy measures included: ON-time, percentage of OFF/ON-time responders, other outcomes from the double-blind part. 391/437 patients were transferred to the open-label extension period and included in the safety analysis set (full analysis set, n = 387; open-label completers, n = 316). Adverse events were frequently reported (n = 338, 86.4%), but < 50% were considered drug-related (39.9%) and few were considered serious (2.6%) or led to discontinuation (2.8%). Decreased OFF-time was consistently observed over the open-label period regardless of initial randomization. Change [LSM (SE)] in OFF-time from the open-label baseline to the last visit showed a persistent effect in patients initially randomized to opicapone 25 mg [- 0.37 (0.20) h, P = 0.0689] and opicapone 50 mg [- 0.07 (0.21) h, P = 0.6913] whereas opicapone 50 mg led to a statistically significant reduction in the previous placebo group [- 1.26 (0.19) h, P < 0.05]. Once-daily opicapone 50 mg was generally well tolerated and consistently reduced OFF-time over 52 weeks in Japanese levodopa-treated patients with motor fluctuations.Trial registration JapicCTI-153112; date of registration: December 25, 2015.

PMID:33630140 | DOI:10.1007/s00702-021-02315-1

Dermatol Ther. 2021 Feb 24:e14912. doi: 10.1111/dth.14912. Online ahead of print.

ABSTRACT

BACKGROUND: The impact of intermittent circadian fasting (ICF) on skin disorders is far to be plenty deciphered. However, the circadian rhythm seems to exert a modulation on dermatoses severity, drug-response and drug-related side effects.

OBJECTIVES: To evaluate ICF effect in the daily management of dermatoses.

METHODS: In this multicenter, prospective observational study cohort study we enrolled patients willing to undergo the 2018 ICF (from May 16 to June 14). Patients' dermatoses severity were evaluated the at the beginning of ICF (T0) and at the end of ICF (T1) by two independent board-certified dermatologists.

RESULTS: Seventy-two patients suffering from different dermatoses volunteered to take part into the study. Mean age (standard deviation [SD]) was 40.38 ± 12.46 years (median 41.0 years), 25 subjects were males (34.7% of the entire sample). The median of change in weight was 0 kg. The overall effect size of the ICF was -0.58 ([95% CI -0.83 to -0.33], p < 0.0001, medium effect size). Since in the present investigation no body weight loss occurred, we could speculate that the impact of fasting in terms of improvements in the clinical symptoms could be rather due to the perturbation of the human biological clock.

CONCLUSIONS: Despite our data remain preliminary, a chronobiological approach should be incorporated in the dermatological clinical practice. This article is protected by copyright. All rights reserved.

PMID:33629451 | DOI:10.1111/dth.14912

Cureus. 2021 Jan 20;13(1):e12817. doi: 10.7759/cureus.12817.

ABSTRACT

BACKGROUND: Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the Western world. While it requires a diagnosis of exclusion, it is exceedingly prevalent in patients taking multiple hepatotoxic agents, the foremost of which are antibiotics, followed by herbal and dietary supplements. Below we will discuss a case of nafcillin-induced liver injury suggested by a thorough work-up and rule-out of other hepatic and biliary pathologies.

CASE PRESENTATION: We report the case of a 66-year-old white male who presented with painless jaundice. Clinical, laboratory and radiographic features demonstrated a cholestatic pattern of liver injury without significant abnormalities in the biliary tract. All workup for viral hepatitis and autoimmune diseases with liver involvement was negative. Liver biopsy showed acute necro-inflammatory changes suggestive of drug-induced liver injury. The patient had received 18 days of IV nafcillin for blood culture positive methicillin-susceptible Staphylococcus aureus (MSSA) four weeks prior to his presentation. He showed clinical and laboratory improvement of his liver functions with supportive care only.

CONCLUSION: Nafcillin is a safe and effective antibiotic for the treatment of methicillin-susceptible Staphylococcal infections. However, physicians and prescribing healthcare professionals should be aware of the rare, but serious side effects, especially one of drug-induced liver injury with emphasis on the need for early cessation of nafcillin if liver function abnormalities develop.

PMID:33628683 | PMC:PMC7894250 | DOI:10.7759/cureus.12817

Case Rep Rheumatol. 2021 Feb 5;2021:8876847. doi: 10.1155/2021/8876847. eCollection 2021.

ABSTRACT

Biological disease-modifying antirheumatic drugs (bDMARDs) are very effective for treating rheumatoid arthritis (RA). However, they sometimes induce adverse events such as psoriasis-like skin lesions. We describe psoriasis-like skin lesions that developed simultaneously with an RA flare in patient 1 during treatment with abatacept and in patient 2 soon after starting certolizumab pegol. The skin lesions persisted in patient 2 despite stopping certolizumab. Baricitinib was initiated because of RA flare and resulted in immediate beneficial effects on arthritis as well as skin lesions. The RA went into remission in both patients, and the psoriasis-like skin lesions disappeared within four weeks (patient 1) and three months (patient 2).

PMID:33628569 | PMC:PMC7884173 | DOI:10.1155/2021/8876847

Ther Adv Drug Saf. 2021 Feb 11;12:2042098621991280. doi: 10.1177/2042098621991280. eCollection 2021.

ABSTRACT

AIM: Accurate causality assessment (CA) of adverse events (AEs) is important in clinical research and routine clinical practice. The Naranjo scale (NS) used for CA lacks specificity, leading to a high rate of false positive causal associations. NS is a simple scale for CA; however, its limitations have reduced its popularity in favour of other scales. We therefore attempted to improvise the algorithm by addressing specific lacunae in NS.

METHODS: We attempted to modify the existing NS by (a) changing the weightage given to certain responses, (b) achieving higher resolution to certain responses for delineating drug related and unrelated AEs and (c) modifying the slabs for classification of association as 'likely' and 'unlikely'. The new scale, named as the Sharma-Nookala-Gota (SNG) algorithm, was evaluated in a training set of 19 AEs in a tertiary care cancer hospital in western India, and further validated in a set of 104 AEs. Consensus of four physician opinion was taken as gold standard for comparison.

RESULTS: Of the 19 AEs in the training set, 6 were described by the treating physician as 'not related' and 13 as related to the drug. The SNG algorithm had 100% concordance with physician opinion, whereas the NS had only 73.7% concordance. NS showed a tendency to misclassify AEs as 'related' when they were indeed 'not related'. In the validation set of 104 AEs, NS and SNG algorithms misclassified 30 and 2 AEs, respectively, leading to a concordance of 70.2% and 98.1%, respectively, with physician opinion.

CONCLUSION: Decisive modifications of the NS resulted in the SNG scale, with superior specificity while retaining sensitivity against the gold standard.

PLAIN LANGUAGE SUMMARY: SNG algorithm - A novel tool for causality assessment of adverse drug reactions Adverse events (AEs) can cause increased morbidity, hospitalisation, and even death. Hence it is essential to recognise AEs and to establish their correct causal relationship to a drug. Many causality assessment methods, scales and algorithms are available to assess the relationship between an AE and a drug. The Naranjo algorithm is most commonly employed in spite of its many drawbacks as it is simple to use. Concerns have been raised regarding the performance of the scale, and researchers have tried to answer them, but none of them could address all issues satisfactorily. We too experienced many problems while using it in our routine clinical practice and in clinical trials. For instance, the Naranjo scale is non-specific and shows a bias toward implicating the drug as the causal factor for AEs. This improper assessment has often led to drug discontinuation, thereby compromising the efficacy of treatment. Hence, we modified the existing Naranjo scale to a new one (the Sharma-Nookala-Gota - SNG algorithm) to address these shortcomings. We piloted the SNG causality assessment algorithm in patients suffering from AEs due to various drugs. The SNG algorithm was found to have good concordance with the physicians' assessment of causality. As a next step, we validated the SNG algorithm in patients receiving a standard drug combination of pemetrexed and carboplatin for lung cancer combination. Out of the 104 AEs observed in 65 patients, the SNG causality assessment algorithm showed good concordance (except in two cases) with the physicians' decision of causality assessment, while the Naranjo algorithm was not so successful. Hence, the SNG algorithm can be a better guide for causality assessment of AEs.

PMID:33628419 | PMC:PMC7882752 | DOI:10.1177/2042098621991280

Eur J Hosp Pharm. 2021 Feb 24:ejhpharm-2020-002603. doi: 10.1136/ejhpharm-2020-002603. Online ahead of print.

ABSTRACT

BACKGROUND: Drug-related bradycardia (DRB) is a common clinical conundrum and can result in multiple hospital admissions as a result of the increased prescription of rate-limiting medications that can predispose to presyncopal or syncopal episodes.

AIM: To evaluate the incidence of DRB in elderly hospital inpatients.

METHODS: We conducted a retrospective analysis of all patients admitted to our acute medical unit between November 2018 and February 2019 and identified patients over the age of 70 with more than one diurnal bradycardic episode during their admission. We extracted patient demographics, presenting complaint, admission 12-lead ECG and medications from the hospital electronic database.

RESULTS: We screened 2312 adults and identified 100 patients over the age of 70 years with two or more episodes of diurnal bradycardia during their hospital admission. This constituted 4.32% of total admissions. Beta blockers were the most commonly prescribed rate-limiting medication (n=54, 87.1%), of which bisoprolol was the most frequently prescribed (n=41) and sinus bradycardia was the most commonly identified rhythm disturbance in our cohort of patients (n=41, 41%). Syncope was the most common presenting symptom and occurred in 23 patients, 14 (60.9%) of which were diagnosed with a DRB. Atrial fibrillation was more common in those with DRB compared with those with bradycardia not caused by medications (35.5% vs 10.5%, p=0.006), and atrial fibrillation was a significant predictor of DRB (OR=10.2, 95% CI 3.3 to 31.6, p<0.001).

CONCLUSION: Bradycardia is a significant cause of hospital admissions in older adults and can be avoided with pharmacovigilance. Caution should be exercised when initiating or changing the dose of rate-limiting agents in these patients; while those with atrial fibrillation should undergo regular review of their heart rate followed by appropriate medication dose adjustments.

PMID:33627477 | DOI:10.1136/ejhpharm-2020-002603

Drug Ther Bull. 2021 Mar;59(3):39-42. doi: 10.1136/dtb.2020.000036.

ABSTRACT

Topics for DTB review articles are selected by DTB's editorial board to provide concise overviews of medicines and other treatments to help patients get the best care. Articles include a summary of key points and a brief overview for patients. Articles may also have a series of multiple choice CME questions.

PMID:33627351 | DOI:10.1136/dtb.2020.000036

Drug Ther Bull. 2021 Mar;59(3):35-36. doi: 10.1136/dtb.2020.000057.

NO ABSTRACT

PMID:33627350 | DOI:10.1136/dtb.2020.000057

Rev Med Suisse. 2021 Feb 24;17(727):399-404.

ABSTRACT

Along with the arrival of the first vasopressin-receptor V2R inhibitor, the indications for its use have increased. We review here and focus on polycystic kidney disease (PKD) and hyponatremia. Tolvaptan is the first drug available to slow down the progression of PKD in patients with rapid progressing disease. However, the benefits are moderate and the side effects are important, making important to share the decision of treatment together with the patient. Hyponatremia with preserved extra-cellular volume or associated with edema may be reversed by tolvaptan. Patients with SIADH or hyponatremia and edema might benefit from this treatment under strict monitoring. Overall, vaptans are helpful in several conditions, but remain tools that must be used under close control.

PMID:33625806

Rev Med Suisse. 2021 Feb 24;17(727):383-388.

ABSTRACT

In the last few years, there has been a growing interest in the study of complement, fueleld mainly by the design of complement modulators, especially the C5-blocker eculizumab. The latter has significantly improved the prognosis of some nephropathies, such as the atypical hemolytic uremic syndrome. This breakthrough is a perfect example of fundamental translational research leading to clinical applications for patients. Currently, new molecules are being developed and some of them have already demonstrated clinical efficacy, such as avacopan (C5aR blocker) in ANCA vasculitis. As for kidney transplantation, complement modulators may lead to a new perspective in the treatment of some complications, such as humoral rejection. However, complement modulators carry the side effects, especially the infectious, and high costs.

PMID:33625803

Pharmacoepidemiol Drug Saf. 2021 Feb 24. doi: 10.1002/pds.5212. Online ahead of print.

ABSTRACT

PURPOSE: We used data from two public health surveillance systems for national estimates and detailed descriptions of insulin mix-up errors resulting in emergency department (ED) visits and other serious adverse events to help inform prevention efforts.

METHODS: ED visits involving patients seeking care for insulin medication errors collected by the NEISS-CADES project in 2012-2017 and voluntary reports of serious insulin medication errors submitted to the U.S. Food and Drug Administration (FDA) in 2016-2017 were analyzed. National estimates of insulin product prescriptions dispensed from retail pharmacies were obtained from IQVIA National Prescription Audit.

RESULTS: Between 2012 and 2017, based on 514 NEISS-CADES cases, there were an estimated 5,636 (95% CI, 4,143-7,128) ED visits annually for insulin mix-up errors; overall, over three-quarters (77.5%; 95% CI, 71.6%-83.3%) involved taking rapid-acting instead of long-acting insulin. Between 2012 and 2017, the proportion of mix-up errors among all estimated ED visits for all insulin errors decreased by 60%; concurrently, the proportion of pens among all insulin package types dispensed increased by 50%. Among 58 voluntary reports submitted to FAERS, over one-half (56.9%) of cases involved taking rapid- instead of long-acting insulin. Among 27 cases with documented contributing factors, approximatley one-half involved patients having difficulty differentiating products.

CONCLUSIONS: Among all ED visits for insulin errors collected by NEISS-CADES in 2012-2017, the proportion involving mix-up errors has declined. Continued reductions may require additional prevention strategies, including improving insulin distinctiveness, particularly for rapid- vs. long-acting insulins. Ongoing national surveillance is important for identifying the impact of interventions. This article is protected by copyright. All rights reserved.

PMID:33625786 | DOI:10.1002/pds.5212

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Epilepsy Res. 2021 Feb 4;172:106570. doi: 10.1016/j.eplepsyres.2021.106570. Online ahead of print.

ABSTRACT

BACKGROUND: Perampanel (PER) is an effective adjunctive therapy for controlling focal-onset seizures (FOS), but few studies have examined its effects as an early add-on for the treatment of FOS in daily clinical practice.

METHODS: Our retrospective, multicenter, observational study evaluated the effectiveness and safety of PER as an early add-on in 77 patients with FOS, with and without focal to bilateral tonic-clonic seizures (FBTCS) after 3, 6 and 12 months in a real-world setting.

RESULTS: After 12 months of treatment (median dose 6 [4,8] mg/day), the retention rate was 79.2 % and 60 % of patients (39/65) experienced a ≥50 % reduction in seizure frequency relative to baseline. The seizure-free rate was 38.5 % for all seizures (25/65) and 60 % for FBTCS (12/20). The responder rate at 12 months was significantly higher when PER was given with one concomitant AED (72.2 %) compared to when PER was given with two concomitant AEDs (44.8 %). Drug-related adverse events (AEs) were reported in 40.3 % of patients, most of them being mild (64.2 %). Twelve patients (15.6 %) discontinued treatment because of AEs.

CONCLUSIONS: PER is an effective and safe early add-on for patients with refractory FOS, especially for those with FBTCS.

PMID:33621770 | DOI:10.1016/j.eplepsyres.2021.106570

Clin Gastroenterol Hepatol. 2021 Feb 20:S1542-3565(21)00209-3. doi: 10.1016/j.cgh.2021.02.031. Online ahead of print.

NO ABSTRACT

PMID:33621669 | DOI:10.1016/j.cgh.2021.02.031

Mult Scler. 2021 Feb 23:1352458521996698. doi: 10.1177/1352458521996698. Online ahead of print.

ABSTRACT

Severe prolonged lymphopenia as rare side-effect of dimethyl fumarate is mostly reversible. Caldito et al. report a case of persistent severe lymphopenia over 5 years after discontinuation of dimethyl fumarate. We discuss several clinical implications. Safe withdrawal of disease modifying therapies in terms of reoccurrence of disease activity and drug related adverse events need further attention as our treatment armamentarium continues to grow.

PMID:33620267 | DOI:10.1177/1352458521996698

Eur J Nucl Med Mol Imaging. 2021 Feb 23. doi: 10.1007/s00259-021-05229-y. Online ahead of print.

ABSTRACT

PURPOSE: This is the first prospective trial evaluating the efficacy of alpha emitter Radium-223 in patients with bone metastases from radioactive iodine (RAI) refractory (RAIR) differentiated thyroid cancer.

METHODS: RADTHYR is a multicenter, single-arm prospective Simon two-stage phase II trial (NCT02390934). The primary objective was to establish the efficacy of three administrations of 55 kBq/kg of Radium-223 by 18F-FDG PET/CT according to PERCIST criteria. Secondary objectives were to establish the efficacy of six administrations of Radium-223 by 18F-FDG PET/CT, 99mTc-HMDP bone scan and 18FNa PET/CT, clinical benefits, changes in serum bone markers, thyroglobulin levels, and safety.

RESULTS: Ten patients were enrolled between July 2015 and December 2017 (4 M; median age 74 years). Prior to Radium-223 administration, patients received a median RAI cumulative activity of 15 GBq (7.4-35.6), external radiation therapy (n = 9), bone surgery (n = 8), cimentoplasty (n = 5), and cryoablation (n = 2). 18F-FDG PET/CT showed stable disease (SD) in 4/10 and progressive disease (PD) in 6/10 cases after three administrations and SD in 4/10, PD in 5/10 cases, and 1/10 non-evaluable (NE) case after six administrations. After six injections, 99mTc-HMDP bone scan showed SD in 9 cases and was NE in 1 case; 18FNa PET/CT showed SD in 8 cases, partial response (PR) in 1 case, and was NE in 1 case. No significant clinical benefits were reported during the study. A skeletal event occurred in 6 patients (median time without skeletal event of 12.1 months). Seventy-seven adverse events were reported during treatment (7 of grade 3-4). Three patients developed an acute myeloid, a promyelocytic, and a chronic myeloid leukemia after the last Radium-223 administration considered as drug-related.

CONCLUSION: The trial was stopped after interim analysis for lack of response of bone metastases from RAIR thyroid cancer to Radium-223. Severe hematological toxicity was observed in patients heavily pretreated with RAI and external radiation.

TRIAL REGISTRATION NUMBER: NCT02390934. Registration date 18.03.2015.

PMID:33619600 | DOI:10.1007/s00259-021-05229-y

Neurooncol Adv. 2021 Feb 15;3(1):vdab006. doi: 10.1093/noajnl/vdab006. eCollection 2021 Jan-Dec.

ABSTRACT

BACKGROUND: Dexanabinol is a synthetic analogue of tetrahydrocannabinol identified as a potential anti-cancer therapeutic by e-Therapeutics PLC. Dexanabinol was selected for further investigation based on its preclinical tumoricidal activity. This phase I dose-escalation trial examined the safety, drug penetration into the central nervous system (CNS), preliminary antitumor activity, and recommended phase II dose.

METHODS: Dexanabinol formulated in cremophor/ethanol was administered once weekly via 3-hour intravenous infusion to patients with brain cancer.

RESULTS: A total of 26 patients were dosed once weekly at 2, 4, 8, 16, 24, 28, and 36 mg/kg. Two patients at 36 mg/kg were nonevaluable for dose level confirmation, having withdrawn early for reasons unrelated to study treatment. A recommended phase II dose of dexanabinol was established at 28 mg/kg due to related, reversible adverse events at higher dose levels that required medications for symptomatic relief. The most common drug-related toxicities were the depressed level of consciousness and lightheadedness, diarrhea, itching, fatigue, chest discomfort, and tingling in the mouth. Systemic exposure to dexanabinol (AUC0-t and C max) increased from 2 to 36 mg/kg, with dose nonproportionality apparent at the highest dose; dexanabinol was present in appreciable levels in the cerebrospinal fluid (CSF), which implies the possibility of exposure of intracranial tumors to drug. Five of 24 efficacy-evaluable patients (21%) experienced stable disease with a median duration of 2 cycles (28-day cycle) as the best response.

CONCLUSIONS: Dexanabinol administered weekly by intravenous infusion was safe and well-tolerated up to 28 mg/kg in brain cancer patients, but has limited antitumor activity in patients with brain cancer.

PMID:33615223 | PMC:PMC7883766 | DOI:10.1093/noajnl/vdab006

Indian Pediatr. 2021 Feb 19:S097475591600287. Online ahead of print.

ABSTRACT

OBJECTIVE: To compare the efficacy of Epinephrine plus Vasopressin versus Epinephrine plus Placebo in the pediatric intensive care unit (PICU) cardiopulmonary resuscitation (CPR).

DESIGN: Randomized, double-blind controlled clinical trial.

SETTING: PICU in a tertiary care institute from February 2019 to May 2020.

PARTICIPANTS: Children aged one month to 13 years who required CPR during PICU stay. Patients in whom vascular access was not available or return of spontaneous circulation (ROSC) was achieved by defibrillation without Epinephrine were excluded.

INTERVENTION: Patients were randomized to receive Vasopressin 0.1 mL per kg (=0.8 Unit per kg) or Placebo (0.1 mL per kg normal saline) in addition to Epinephrine (1:10000) 0.1 mL per kg. The drugs were given as bolus doses every three minutes until the ROSC or up to a maximum of five doses, whichever was earlier.

OUTCOME MEASURE: The primary outcome was the proportion of patients who achieved ROSC. The secondary outcomes were survival rate and functional status (at 24-hour, PICU, hospital, and 90-day post-discharge), need for organ supports, length of stay (PICU and hospital), and adverse effect(s) of the study drugs.

RESULT: Ninety patients (Epinephrine plus Vasopressin group n=45 and Epinephrine plus Placebo group n=45) were analyzed on the "intention to treat" basis. There was no significant difference in the primary outcome between Epinephrine plus Vasopressin (n=25, 55.5%) and Epinephrine plus Placebo groups (n=24, 53.3%) (Relative risk 1.04, 95% CI 0.71 to 1.52). There was no significant difference in survival rate at 24-hour (n=7, 15.6% vs. n=8, 17.8%), at PICU, hospital, and 90-day post-discharge (n=1, 2.2% vs. n=1, 2.2%). There was no difference in other secondary outcomes. No trial drug-related serious adverse events were observed.

CONCLUSION: A combination of Epinephrine plus Vasopressin did not improve the rate of return of spontaneous circulation in the pediatric intensive care unit cardiopulmonary resuscitation as compared with Epinephrine plus Placebo.

PMID:33612485

Safety and efficacy of tilavonemab in progressive supranuclear palsy: a phase 2, randomised, placebo-controlled trial.

Lancet Neurol. 2021 Mar;20(3):182-192

Authors: Höglinger GU, Litvan I, Mendonca N, Wang D, Zheng H, Rendenbach-Mueller B, Lon HK, Jin Z, Fisseha N, Budur K, Gold M, Ryman D, Florian H, Arise Investigators

Abstract
BACKGROUND: Progressive supranuclear palsy is a neurodegenerative disorder associated with tau protein aggregation. Tilavonemab (ABBV-8E12) is a monoclonal antibody that binds to the N-terminus of human tau. We assessed the safety and efficacy of tilavonemab for the treatment of progressive supranuclear palsy.
METHODS: We did a phase 2, multicentre, randomised, placebo-controlled, double-blind study at 66 hospitals and clinics in Australia, Canada, France, Germany, Italy, Japan, Spain, and the USA. Participants (aged ≥40 years) diagnosed with possible or probable progressive supranuclear palsy who were symptomatic for less than 5 years, had a reliable study partner, and were able to walk five steps with minimal assistance, were randomly assigned (1:1:1) by interactive response technology to tilavonemab 2000 mg, tilavonemab 4000 mg, or matching placebo administered intravenously on days 1, 15, and 29, then every 28 days through to the end of the 52-week treatment period. Randomisation was done by the randomisation specialist of the study sponsor, who did not otherwise participate in the study. The sponsor, investigators, and participants were unaware of treatment allocations. The primary endpoint was the change from baseline to week 52 in the Progressive Supranuclear Palsy Rating Scale (PSPRS) total score in the intention-to-treat population. Adverse events were monitored in participants who received at least one dose of study drug. Prespecified interim futility criteria were based on a model-based effect size of 0 or lower when 60 participants had completed the 52-week treatment period and 0·12 or lower when 120 participants had completed the 52-week treatment period. This study is registered at ClinicalTrials.gov, number NCT02985879.
FINDINGS: Between Dec 12, 2016, and Dec 31, 2018, 466 participants were screened, 378 were randomised. The study was terminated on July 3, 2019, after prespecified futility criteria were met at the second interim analysis. A total of 377 participants received at least one dose of study drug and were included in the efficacy and safety analyses (2000 mg, n=126; 4000 mg, n=125; placebo, n=126). Least squares mean change from baseline to week 52 in PSPRS was similar in all groups (between-group difference vs placebo: 2000 mg, 0·0 [95% CI -2·6 to 2·6], effect size 0·000, p>0·99; 4000 mg, 1·0 [-1·6 to 3·6], -0·105, p=0·46). Most participants reported at least one adverse event (2000 mg, 111 [88%]; 4000 mg, 111 [89%]; placebo, 108 [86%]). Fall was the most common adverse event (2000 mg, 42 [33%]; 4000 mg, 54 [43%]; placebo, 49 [39%]). Proportions of patients with serious adverse events were similar among groups (2000 mg, 29 [23%]; 4000 mg, 34 [27%]; placebo, 33 [26%]). Fall was the most common treatment-emergent serious adverse event (2000 mg, five [4%]; 4000 mg, six [5%]; placebo, six [5%]). 26 deaths occurred during the study (2000 mg, nine [7%]; 4000 mg, nine [7%]; placebo, eight [6%]) but none was drug related.
INTERPRETATION: A similar safety profile was seen in all treatment groups. No beneficial treatment effects were recorded. Although this study did not provide evidence of efficacy in progressive supranuclear palsy, the findings provide potentially useful information for future investigations of passive immunisation using tau antibodies for progressive supranuclear palsy.
FUNDING: AbbVie Inc.

PMID: 33609476 [PubMed - as supplied by publisher]