Analysis of autonomic outcomes in APOLLO, a phase III trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, debilitating disease often resulting in early-onset, life-impacting autonomic dysfunction. The effect of the RNAi therapeutic, patisiran, on autonomic neuropathy manifestations in patients with hATTR amyloidosis with polyneuropathy in the phase III APOLLO study is reported. Patients received patisiran 0.3 mg/kg intravenously (n = 148) or placebo (n = 77) once every 3 weeks for 18 months. Patisiran halted or reversed polyneuropathy and improved quality of life from baseline in the majority of patients. At baseline, patients in APOLLO had notable autonomic impairment, as demonstrated by the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire autonomic neuropathy domain. At 18 months, patisiran improved autonomic neuropathy symptoms compared with placebo [COMPASS-31, least squares (LS) mean difference, - 7.5; 95% CI: - 11.9, - 3.2; Norfolk QOL-DN autonomic neuropathy domain, LS mean difference, - 1.1; - 1.8, - 0.5], nutritional status (modified body mass index, LS mean difference, 115.7; - 82.4, 149.0), and vasomotor function (postural blood pressure, LS mean difference, - 0.3; - 0.5, - 0.1). Patisiran treatment also led to improvement from baseline at 18 months for COMPASS-31 (LS mean change from baseline, - 5.3; 95% CI: - 7.9, - 2.7) and individual domains, orthostatic intolerance (- 4.6; - 6.3, - 2.9) and gastrointestinal symptoms (- 0.8; - 1.5, - 0.2). Rapid worsening of all study measures was observed with placebo, while patisiran treatment resulted in stable or improved scores compared with baseline. Patisiran demonstrates benefit across a range of burdensome autonomic neuropathy manifestations that deteriorate rapidly without early and continued treatment.The study was funded by Alnylam Pharmaceuticals, Inc. Medical writing services provided by Kristen Brown (PhD) of Adelphi Communications Ltd, Macclesfeld, UK were funded by Alnylam Pharmaceuticals, Inc. in accordance with Good Publication Practice (GPP3) guidelines. We would like to thank Anastasia McManus (Alnylam Pharmaceuticals, Inc.) for her assistance during preparation of this manuscript.info:eu-repo/semantics/publishedVersio

A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS

To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength mega-score, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898)

What is the diagnostic accuracy of single nerve conduction studies and muscle ultrasound to identify critical illness polyneuromyopathy: a prospective cohort study

Abstract Background Critical illness polyneuromyopathy (CIPNM) is a major cause of weakness in intensive care unit (ICU) patients, but current diagnostic tests are limited. We evaluated the generalizability and validity of single nerve conduction studies (NCS) and muscle ultrasound testing to identify CIPNM, and we also assessed the ability of muscle ultrasound to prognosticate patient outcomes. Methods This was a prospective cohort study of mechanically ventilated medical, cardiac, surgical, and neurosurgical ICU patients. We performed weekly strength testing, NCS, electromyography (EMG), and muscle ultrasound. We calculated the sensitivity, specificity, and other test characteristics of single NCS and muscle ultrasound, and we used multivariable regression models to assess the prognostic ability of muscle ultrasound. Results Ninety-five patients were enrolled. The incidence of probable CIPNM was 18% and did not differ significantly by type of ICU (p = 0.49). For diagnosing probable CIPNM, the peroneal motor NCS had a sensitivity of 94% (95% confidence interval (CI) 71–100%) and specificity of 91% (95% CI 82–96%), the sural sensory NCS had a sensitivity of 100% (95% CI 80–100%) and specificity of 42% (95% CI 31–54%), and abnormal muscle ultrasound echogenicity had a sensitivity of 82% (95% CI 48–98%) and specificity of 57% (95% CI 43–70%). Abnormal echogenicity was associated with reduced likelihood of discharge to home (9% vs 50%, p = 0.0001), fewer ICU-free days (median 3 (interquartile range 0–15) days vs 16 (9.3–19.3) days, p = 0.0002), and increased ICU mortality (42% vs 12%, p = 0.004). Conclusions In a diverse cohort of critically ill patients, single NCS and muscle ultrasound achieved diagnostic accuracy for patients at risk for CIPNM. The routine utilization of these tests could be beneficial for all critically ill patients at risk for CIPNM

Pathology Case Study: Leg Weakness and Numbness

The University of Pittsburgh School of Medicine's Department of Pathology has compiled a series of case studies to help both students and instructors. In this particular study, a 48 year-old man is admitted to the hospital with âa three week history of back pain, progressive right leg weakness and bilateral lower leg numbness.â A detailed patient history and account of the attending doctorâs examination is provided in the âPatient Historyâ section. MRI and CT images of the patient, as well as gross and microscopic descriptions of the condition are included as well. Clicking on the âFinal Diagnosisâ provides a thorough explanation of the diagnosis and treatment

Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations (PAIN-CONTRoLS): Bayesian Adaptive Comparative Effectiveness Randomized Trial

© 2020 American Medical Association. All rights reserved. Importance: Cryptogenic sensory polyneuropathy (CSPN) is a common generalized slowly progressive neuropathy, second in prevalence only to diabetic neuropathy. Most patients with CSPN have significant pain. Many medications have been tried for pain reduction in CSPN, including antiepileptics, antidepressants, and sodium channel blockers. There are no comparative studies that identify the most effective medication for pain reduction in CSPN. Objective: To determine which medication (pregabalin, duloxetine, nortriptyline, or mexiletine) is most effective for reducing neuropathic pain and best tolerated in patients with CSPN. Design, Setting, and Participants: From December 1, 2014, through October 20, 2017, a bayesian adaptive, open-label randomized clinical comparative effectiveness study of pain in 402 participants with CSPN was conducted at 40 neurology care clinics. The trial included response adaptive randomization. Participants were patients with CSPN who were 30 years or older, with a pain score of 4 or greater on a numerical rating scale (range, 0-10, with higher scores indicating a higher level of pain). Participant allocation to 1 of 4 drug groups used the utility function and treatment\u27s sample size for response adaptation randomization. At each interim analysis, a decision was made to continue enrolling (up to 400 participants) or stop the whole trial for success (80% power). Patient engagement was maintained throughout the trial, which helped guide the study and identify ways to communicate and disseminate information. Analysis was performed from December 11, 2015, to January 19, 2018. Interventions: Participants were randomized to receive nortriptyline (n = 134), duloxetine (n = 126), pregabalin (n = 73), or mexiletine (n = 69). Main Outcomes and Measures: The primary outcome was a utility function that was a composite of the efficacy (participant reported pain reduction of ≥50% from baseline to week 12) and quit (participants who discontinued medication) rates. Results: Among the 402 participants (213 men [53.0%]; mean [SD] age, 60.1 [13.4] years; 343 White [85.3%]), the utility function of nortriptyline was 0.81 (95% bayesian credible interval [CrI], 0.69-0.93; 34 of 134 [25.4%] efficacious; and 51 of 134 [38.1%] quit), of duloxetine was 0.80 (95% CrI, 0.68-0.92; 29 of 126 [23.0%] efficacious; and 47 of 126 [37.3%] quit), pregabalin was 0.69 (95% CrI, 0.55-0.84; 11 of 73 [15.1%] efficacious; and 31 of 73 [42.5%] quit), and mexiletine was 0.58 (95% CrI, 0.42-0.75; 14 of 69 [20.3%] efficacious; and 40 of 69 [58.0%] quit). The probability each medication yielded the highest utility was 0.52 for nortriptyline, 0.43 for duloxetine, 0.05 for pregabalin, and 0.00 for mexiletine. Conclusions and Relevance: This study found that, although there was no clearly superior medication, nortriptyline and duloxetine outperformed pregabalin and mexiletine when pain reduction and undesirable adverse effects are combined to a single end point. Trial Registration: ClinicalTrials.gov Identifier: NCT02260388

Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study

Background Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy

Phase 2 Trial of Rituximab in Acetylcholine Receptor Antibody-Positive Generalized Myasthenia Gravis The BeatMG Study

Background and Objective To determine whether rituximab is safe and potentially beneficial, warranting further investigation in an efficacy trial for acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR-Ab+ gMG). Methods The B-Cell Targeted Treatment in MG (BeatMG) study was a randomized, double-blind, placebo-controlled, multicenter phase 2 trial that utilized a futility design. Individuals 21-90 years of age, with AChR-Ab+ gMG (MG Foundation of America Class II-IV) and receiving prednisone >= 15 mg/d were eligible. The primary outcome was a measure of steroid-sparing effect, defined as the proportion achieving >= 75% reduction in mean daily prednisone dose in the 4-weeks prior to week 52 and with clinical improvement or no significant worsening as compared to the 4-week period prior to randomization. The coprimary outcome was safety. Secondary outcomes included MG-specific clinical assessments. Fifty-two individuals were randomized (1:1) to a 2-cycle rituximab/placebo regimen, with follow-up through 52 weeks. Results Of the 52 participants included, mean +/- SD age at enrollment was 55.1 +/- 17.1 years; 23 (44.2%) were women and 31 (59.6%) were Myasthenia Gravis Foundation of America Class II. The mean +/- SD baseline prednisone dose was 22.1 +/- 9.7 mg/d. The primary steroid-sparing outcome was achieved in 60% of those on rituximab vs 56% on placebo. The study reached its futility endpoint (p = 0.03), suggesting that the predefined clinically meaningful improvement of 30% due to rituximab over placebo was unlikely to be achieved in a subsequent, larger trial. No safety issues were identified. Discussion Although rituximab was safe and well-tolerated, these results suggest that there is a low probability of observing the defined clinically meaningful steroid-sparing effect over a 12-month period in a phase 3 trial of mild to moderately symptomatic AChR-Ab+ gMG. Classification of Evidence This study provides Class I evidence that for mild to moderate AChR-Ab+ gMG, compared with placebo, rituximab is safe but unlikely to reduce steroid use by an absolute difference of at least 30% at 1 year

Phase 2 Trial of Rituximab in Acetylcholine Receptor Antibody-Positive Generalized Myasthenia Gravis: The BeatMG Study

ObjectiveTo determine whether rituximab is safe and potentially beneficial, warranting further investigation in an efficacy trial for acetylcholine receptor antibody-positive generalized MG (AChR-Ab+ gMG).MethodsThe B-Cell Targeted Treatment in MG (BeatMG) study was a randomized, double-blind, placebo-controlled, multicenter phase-2 trial that utilized a futility design. Individuals 21-90 years of age, with AChR-Ab+ gMG (MG Foundation of America Class II-IV) and receiving prednisone ≥15 mg/day were eligible. The primary outcome was a measure of steroid-sparing effect, defined as the proportion achieving ≥75% reduction in mean daily prednisone dose in the 4-weeks prior to week 52 and with clinical improvement or no significant worsening as compared to the 4-week period prior to randomization. The co-primary outcome was safety. Secondary outcomes included MG-specific clinical assessments. Fifty-two individuals were randomized (1:1) to either a two-cycle rituximab/placebo regimen, with follow-up through 52-weeks.ResultsOf the 52 participants included, mean (±SD) age at enrollment was 55.1 (±17.1) years; 23 (44.2%) were female, and 31 (59.6%) were MGFA Class II. The mean (±SD) baseline prednisone dose was 22.1 (±9.7) mg/day. The primary steroid-sparing outcome was achieved in 60% of those on rituximab vs. 56% on placebo. The study reached its futility endpoint (p=0.03) suggesting that the pre-defined clinically meaningful improvement of 30% due to rituximab over placebo was unlikely to be achieved in a subsequent, larger trial. No safety issues identified.ConclusionsWhile rituximab was safe and well-tolerated, these results suggest that there is a low probability of observing the defined clinically meaningful steroid-sparing effect over a 12-month period in a phase-3 trial of mild-moderately symptomatic AChR-Ab+ gMG.Classification of evidenceThis study provides Class I evidence that for mild-to-moderate AChR-Ab+ gMG, compared with placebo, rituximab is safe but unlikely to reduce steroid use by an absolute difference of at least 30% at 1 year.Trial registrationClinicalTrials.gov Identifier: NCT02110706

Duplication within the SEPT9 gene associated with a founder effect in North American families with hereditary neuralgic amyotrophy

Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant disorder associated with recurrent episodes of focal neuropathy primarily affecting the brachial plexus. Point mutations in the SEPT9 gene have been previously identified as the molecular basis of HNA in some pedigrees. However in many families, including those from North America demonstrating a genetic founder haplotype, no sequence mutations have been detected. We report an intragenic 38 Kb SEPT9 duplication that is linked to HNA in 12 North American families that share the common founder haplotype. Analysis of the breakpoints showed that the duplication is identical in all pedigrees, and molecular analysis revealed that the duplication includes the 645 bp exon in which previous HNA mutations were found. The SEPT9 transcript variants that span this duplication contain two in-frame repeats of this exon, and immunoblotting demonstrates larger molecular weight SEPT9 protein isoforms. This exon also encodes for a majority of the SEPT9 N-terminal proline rich region suggesting that this region plays a role in the pathogenesis of HNA