Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy

Background: Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods: ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings: Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation: Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding: UK Medical Research Council and Health Technology Assessment Programme

Adapting The Sniffin' Sticks Olfactory Test To Diagnose Parkinson's Disease In Estonia

The aim of the study was to develop a culturally adapted translation of the 12-item smell identification test from Sniffin' Sticks (SS-12) for the Estonian population in order to help diagnose Parkinson's disease (PD). Methods: A standard translation of the SS-12 was created and 150 healthy Estonians were questioned about the smells used as response options in the test. Unfamiliar smells were replaced by culturally familiar options. The adapted SS-12 was applied to 70 controls in all age groups, and thereafter to 50 PD patients and 50 age- and sex-matched controls. Results: 14 response options from 48 used in the SS-12 were replaced with familiar smells in an adapted version, in which the mean rate of correct response was 87% (range 73-99) compared to 83% with the literal translation (range 50-98). In PD patients, the average adapted SS-12 score (5.4/12) was significantly lower than in controls (average score 8.9/12), p<0.0001. A multiple linear regression using the score in the SS-12 as the outcome measure showed that diagnosis and age independently influenced the result of the SS-12. A logistic regression using the SS-12 and age as covariates showed that the SS-12 (but not age) correctly classified 79.0% of subjects into the PD and control category, using a cut-off of <7 gave a sensitivity of 76% and specificity of 86% for the diagnosis of PD. Conclusions: The developed SS-12 cultural adaption is appropriate for testing olfaction in Estonia for the purpose of PD diagnosis. © 2014 Elsevier Ltd.208830833Soudrya, Y., Lemogne, C., Malinvaud, D., Consoli, S.-M., Bonfils, P., Olfactory system and emotion: common substrates (2011) Eur Ann Otorhinolaryngol Head Neck Dis, 128, pp. 18-23Kovács, T., Mechanisms of olfactory dysfunction in aging and neurodegenerative disorders (2004) Ageing Res Rev, 3, pp. 215-232Chaudhuri, K.R., Odin, P., The challenge of non-motor symptoms in Parkinson's disease (2010) Prog Brain Res, 184, pp. 325-341Bohnen, N.I., Studenski, S.A., Constantine, G.M., Moore, R.Y., Diagnostic performance of clinical motor and non-motor tests of Parkinson disease: a matched case-control study (2008) Eur J Neurol, 15 (7), pp. 685-691Silveira-Moriyama, L., de Jesus Carvalho, M., Katzenschlager, R., Petrie, A., Ranvaud, R., Barbosa, E.R., The use of smell identification tests in the diagnosis of Parkinson's disease in Brazil (2008) Mov Disord, 23, pp. 2328-2334Silveira-Moriyama, L., Schwingenschuh, P., O'Donnell, A., Schneider, S.A., Mir, P., Carrillo, F., Olfaction in patients with suspected Parkinsonism and scans without evidence of dopaminergic deficit (SWEDDs) (2009) JNeurol Neurosurg Psychiatry, 80 (7), pp. 744-748Doty, R.L., Shaman, P., Kimmelman, C., Dann, M.S., University of Pennsylvania Smell Identification Test: a rapid quantitative olfactory function test for the clinic (1984) Laryngoscope, 94, pp. 176-178Doty, R.L., Marcus, A., Lee, W.W., Development of the 12-Item cross-cultural smell identification test (CC-SIT) (1996) Laryngoscope, 106, pp. 353-356Hummel, T., Konnerth, C.G., Rosenheim, K., Kobal, G., Screening of olfactory function using a 4 minute odor identification test: reliability, normative data, and investigations in patients with olfactory loss (2001) Ann Otol Rhinol Laryngol, 110, pp. 976-981Nordin, S., Bramerson, A., Liden, E., Bende, M., The Scandinavian odor-identification test: development, reliability, validity and normative data (1998) Acta Otolaryngol, 118, pp. 226-234Simmen, D., Briner, H.R., Hess, K., Screeningtest des Geruchssinnes mit Riechdiskette (1999) Laryngorhinootologie, 78, pp. 125-130Hummel, C., Zucco, G.M., Iannilli, E., Maboshe, W., Landis, B.N., Hummel, T., OLAF: standardization of international olfactory tests (2012) Eur Arch Otorhinolaryngol, 269 (3), pp. 871-880Cho, J.H., Jeong, Y.S., Lee, Y.J., Hong, S.C., Yoon, J.H., Kim, J.K., The Korean version of the Sniffin' stick (KVSS) test and its validity in comparison with the cross-cultural smell identification test (CC-SIT) (2009) Auris Nasus Larynx, 36, pp. 280-286Shu, C.H., Yuan, B.C., Lin, S.H., Lin, C.Z., Cross-cultural application of the "Sniffin' Sticks" odor identification test (2007) Am J Rhinol, 21 (5), pp. 570-573Silveira-Moriyama, L., Sirisena, D., Gamage, P., Ranjanie Gamage, R., Silva, R., Lees, A.J., Adapting the sniffin' sticks to diagnose PD in Sri Lanka (2009) Mov Disord, 24 (8), pp. 1229-1233Mackay-Sim, A., Grant, L., Owen, C., Chant, D., Silburn, P., Australian norms for a quantitative olfactory function test (2004) JClin Neurosci, 11, pp. 874-879Neumann, C., Tsioulos, K., Merkonidis, C., Salam, M., Clark, A., Philpott, C., Validation study of the "Sniffin' Sticks" olfactory test in a British population: a preliminary communication (2012) Clin Otolaryngol, 37 (1), pp. 23-27Eibenstein, A., Fioretti, A.B., Lena, C., Rosati, N., Ottaviano, I., Fusetti, M., Olfactory screening test: experience in 102 Italian subjects (2005) Acta Otorhinolaryngol Ital, 25 (1), pp. 18-22Boesveldt, S., Verbaan, D., Knol, D.L., Visser, M., van Rooden, S.M., van Hilten, J.J., Acomparative study of odor identification and odor discrimination deficits in Parkinson's disease (2008) Mov Disord, 23 (14), pp. 1984-1990Boesveldt, S., de Muinck Keizer, R.J., Knol, D.L., Wolters, E., Berendse, H.W., Extended testing across, not within, tasks raises diagnostic accuracy of smell testing in Parkinson's disease (2009) Mov Disord, 24 (1), pp. 85-90Hummel, T., Kobal, G., Gudziol, H., Mackay-Sim, A., Normative data for the "Sniffin' Sticks" including tests of odor identification, odor discrimination, and olfactory thresholds: an upgrade based on a group of more than 3,000 subjects (2007) Eur Arch Otorhinolaryngol, 264, pp. 237-243Doty, R.L., Olfactory dysfunction in Parkinson disease (2012) Nat Rev Neurol, 8 (6), pp. 329-339Brand, G., Millot, J.L., Sex differences in human olfaction: between evidence and enigma (2001) QJ Exp Psychol B, 54 (3), pp. 259-270Larsson, M., Nilsson, L.G., Olofsson, J.K., Nordin, S., Demographic and cognitive predictors of cued odor identification: evidence from a population-based study (2004) Chem Senses, 29 (6), pp. 547-554Doty, R.L., Cameron, E.L., Sex differences and reproductive hormone influences on human odor perception (2009) Physiol Behav, 97 (2), pp. 213-228Orhan, K.S., Karabulut, B., Keles, N., Deger, K., Evaluation of factors concerning the olfaction using the sniffin' sticks test (2012) Otolaryngol Head Neck Surg, 146 (2), pp. 240-246Frye, R.E., Schwartz, B.S., Doty, R.L., Dose-related effects of cigarette smoking on olfactory function (1990) JAMA, 263, pp. 1233-1236Katotomichelakis, M., Balatsouras, D., Tripsianis, G., Davris, S., Maroudias, N., Danielides, V., The effect of smoking on the olfactory function (2007) Rhinology, 45, pp. 273-280Bower, J.H., Maraganore, D.M., Peterson, B.J., Ahlskog, J.E., Rocca, W.A., Immunologic diseases, anti-inflammatory drugs, & Parkinson disease: a case-control study (2006) Neurology, 67 (3), pp. 494-496Sedig, L., Leibner, J., Ramjit, A.L., Wu, S.S., Dai, Y., Okun, M.S., Is rhinorrhea an under-recognized intrinsic symptom of Parkinson disease? A prospective pilot study (2010) Int J Neurosci, 120 (4), pp. 258-26

Randomized Double-Blind Placebo-Controlled Trial of the Corticosteroid-Sparing Effects of Immunoglobulin in Myasthenia Gravis

Background and objectivesMyasthenia gravis (MG) is an autoimmune disease characterized by dysfunction at the neuromuscular junction. Treatment frequently includes corticosteroids (CSs) and IV immunoglobulin (IVIG). This study was conducted to determine whether immune globulin (human), 10% caprylate/chromatography purified (IGIV-C) could facilitate CS dose reduction in CS-dependent patients with MG.MethodsIn this randomized double-blind placebo-controlled trial, CS-dependent patients with MG (Myasthenia Gravis Foundation of America Class II-Iva; AChR+) received a loading dose of 2 g/kg IGIV-C over 2 days (maximum 80 g/d) or placebo at week 0 (baseline). Maintenance doses (1 g/kg IGIV-C or placebo) were administered every 3 weeks through week 36. Tapering of CS was initiated at week 9 and continued through week 36 unless the patient worsened (quantitative MG score ≥4 points from baseline). CS doses were increased (based on the current CS dose) in patients who worsened. Patients were withdrawn if worsening failed to improve within 6 weeks or if a second CS increase was required. The primary efficacy end point (at week 39) was a ≥50% reduction in CS dose. Secondary and safety end points were assessed throughout the study and follow-up (weeks 42 and 45). The study results and full protocol are available at clinicaltrials.gov/ct2/show/NCT02473965.ResultsThe primary end point (≥50% reduction in CS dose) showed no significant difference between the IGIV-C treatment (60.0% of patients) and placebo (63.3%). There were no significant differences for secondary end points. Safety data indicated that IGIV-C was well tolerated.DiscussionIn this study, IGIV-C was not more effective than placebo in reducing daily CS dose. These results suggest that the effects of IGIV-C and CS are not synergistic and may be mechanistically different.Trial registration informationThe trial was registered on clinicaltrialsregister.eu (EudraCT #: 2013-005099-17) and clinicaltrials.gov (identifier NCT02473965).Classification of evidenceThis study provides Class II evidence that IVIG infusions in adult patients with MG do not increase the percentage of patients achieving a ≥50% reduction in corticosteroid dose compared with placebo

Restabilization treatment after intravenous immunoglobulin withdrawal in chronic inflammatory demyelinating polyneuropathy: Results from the pre-randomization phase of the Polyneuropathy And Treatment with Hizentra study

© 2019 CSL Behring. Journal of the Peripheral Nervous System published by Wiley Periodicals, Inc. on behalf of Peripheral Nerve Society. In patients with chronic inflammatory demyelinating polyneuropathy (CIDP), intravenous immunoglobulin (IVIG) is recommended to be periodically reduced to assess the need for ongoing therapy. However, little is known about the effectiveness of restabilization with IVIG in patients who worsen after IVIG withdrawal. In the Polyneuropathy And Treatment with Hizentra (PATH) study, the pre-randomization period included sudden stopping of IVIG followed by 12 weeks of observation. Those deteriorating were then restabilized with IVIG. Of 245 subjects who stopped IVIG, 28 did not show signs of clinical deterioration within 12 weeks. Two hundred and seven received IVIG restabilization with an induction dose of 2 g/kg bodyweight (bw) IgPro10 (Privigen, CSL Behring, King of Prussia, Pennsylvania) and maintenance doses of 1 g/kg bw every 3 weeks for up to 13 weeks. Signs of clinical improvement were seen in almost all (n = 188; 91%) subjects. During IVIG restabilization, 35 subjects either did not show CIDP stability (n = 21, analyzed as n = 22 as an additional subject was randomized in error) or withdrew for other reasons (n = 14). Of the 22 subjects who did not achieve clinical stability, follow-up information in 16 subjects after an additional 4 weeks was obtained. Nine subjects were reported to have improved, leaving a maximum of 27 subjects (13%) who either showed no signs of clinical improvement during the restabilization phase and 4 weeks post-study or withdrew for other reasons. In conclusion, sudden IVIG withdrawal was effective in detecting ongoing immunoglobulin G dependency with a small risk for subjects not returning to their baseline 17 weeks after withdrawal

Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (PATH): a randomised, double-blind, placebo-controlled, phase 3 trial

Background Approximately two-thirds of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) need long-term intravenous immunoglobulin. Subcutaneous immunoglobulin (SCIg) is an alternative option for immunoglobulin delivery, but has not previously been investigated in a large trial of CIDP. The PATH study compared relapse rates in patients given SCIg versus placebo. Methods Between March 12, 2012, and Sept 20, 2016, we studied patients from 69 neuromuscular centres in North America, Europe, Israel, Australia, and Japan. Adults with definite or probable CIDP who responded to intravenous immunoglobulin treatment were eligible. We randomly allocated participants to 0·2 g/kg or 0·4 g/kg of a 20% SCIg solution (IgPro20) weekly versus placebo (2% human albumin solution) for maintenance treatment for 24 weeks. We did randomisation in a 1:1:1 ratio with an interactive voice and web response system with a block size of six, stratified by region (Japan or non-Japan). The primary outcome was the proportion of patients with a CIDP relapse or who were withdrawn for any other reason during 24 weeks of treatment. Patients, caregivers, and study personnel, including those assessing outcomes, were masked to treatment assignment. Analyses were done in the intention-to-treat and per-protocol sets. This trial is registered with ClinicalTrials.gov, number NCT01545076. Findings In this randomised, double-blind, placebo-controlled trial, we randomly allocated 172 patients: 57 (33%) to the placebo group, 57 (33%) to the low-dose group, and 58 (34%) to the high-dose group. In the intention-to-treat set, 36 (63% [95% CI 50–74]) patients on placebo, 22 (39% [27–52]) on low-dose SCIg, and 19 (33% [22–46]) on high-dose SCIg had a relapse or were withdrawn from the study for other reasons (p=0·0007). Absolute risk reductions were 25% (95% CI 6–41) for low-dose versus placebo (p=0·007), 30% (12–46) for high-dose versus placebo (p=0·001), and 6% (−11 to 23) for high-dose versus low-dose (p=0·32). Causally related adverse events occurred in 47 (27%) patients (ten [18%] in the placebo group, 17 [30%] in the low-dose group, and 20 [34%] in the high-dose group). Six (3%) patients had 11 serious adverse events: one (2%) patient in the placebo group, three (5%) in the low-dose group, and two (3%) in the high-dose group; only one (an acute allergic skin reaction in the low-dose group) was assessed to be causally related. Interpretation This study, which is to our knowledge, the largest trial of CIDP to date and the first to study two administrations of immunoglobulins and two doses, showed that both doses of SCIg IgPro20 were efficacious and well tolerated, suggesting that SCIg can be used as a maintenance treatment for CIDP. Funding CSL Behring

Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (PATH): a randomised, double-blind, placebo-controlled, phase 3 trial

© 2018 Elsevier Ltd Background Approximately two-thirds of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) need long-term intravenous immunoglobulin. Subcutaneous immunoglobulin (SCIg) is an alternative option for immunoglobulin delivery, but has not previously been investigated in a large trial of CIDP. The PATH study compared relapse rates in patients given SCIg versus placebo. Methods Between March 12, 2012, and Sept 20, 2016, we studied patients from 69 neuromuscular centres in North America, Europe, Israel, Australia, and Japan. Adults with definite or probable CIDP who responded to intravenous immunoglobulin treatment were eligible. We randomly allocated participants to 0·2 g/kg or 0·4 g/kg of a 20% SCIg solution (IgPro20) weekly versus placebo (2% human albumin solution) for maintenance treatment for 24 weeks. We did randomisation in a 1:1:1 ratio with an interactive voice and web response system with a block size of six, stratified by region (Japan or non-Japan). The primary outcome was the proportion of patients with a CIDP relapse or who were withdrawn for any other reason during 24 weeks of treatment. Patients, caregivers, and study personnel, including those assessing outcomes, were masked to treatment assignment. Analyses were done in the intention-to-treat and per-protocol sets. This trial is registered with ClinicalTrials.gov, number NCT01545076. Findings In this randomised, double-blind, placebo-controlled trial, we randomly allocated 172 patients: 57 (33%) to the placebo group, 57 (33%) to the low-dose group, and 58 (34%) to the high-dose group. In the intention-to-treat set, 36 (63% [95% CI 50–74]) patients on placebo, 22 (39% [27–52]) on low-dose SCIg, and 19 (33% [22–46]) on high-dose SCIg had a relapse or were withdrawn from the study for other reasons (p=0·0007). Absolute risk reductions were 25% (95% CI 6–41) for low-dose versus placebo (p=0·007), 30% (12–46) for high-dose versus placebo (p=0·001), and 6% (−11 to 23) for high-dose versus low-dose (p=0·32). Causally related adverse events occurred in 47 (27%) patients (ten [18%] in the placebo group, 17 [30%] in the low-dose group, and 20 [34%] in the high-dose group). Six (3%) patients had 11 serious adverse events: one (2%) patient in the placebo group, three (5%) in the low-dose group, and two (3%) in the high-dose group; only one (an acute allergic skin reaction in the low-dose group) was assessed to be causally related. Interpretation This study, which is to our knowledge, the largest trial of CIDP to date and the first to study two administrations of immunoglobulins and two doses, showed that both doses of SCIg IgPro20 were efficacious and well tolerated, suggesting that SCIg can be used as a maintenance treatment for CIDP. Funding CSL Behring

Placebo effect in chronic inflammatory demyelinating polyneuropathy: The PATH study and a systematic review

© 2020 CSL Behring. Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society. The Polyneuropathy And Treatment with Hizentra (PATH) study required subjects with chronic inflammatory demyelinating polyneuropathy (CIDP) to show dependency on immunoglobulin G (IgG) and then be restabilized on IgG before being randomized to placebo or one of two doses of subcutaneous immunoglobulin (SCIG). Nineteen of the 51 subjects (37%) randomized to placebo did not relapse over the next 24 weeks. This article explores the reasons for this effect. A post-hoc analysis of the PATH placebo group was undertaken. A literature search identified other placebo-controlled CIDP trials for review and comparison. In PATH, subjects randomized to placebo who did not relapse were significantly older, had more severe disease, and took longer to deteriorate in the IgG dependency period compared with those who relapsed. Published trials in CIDP, whose primary endpoint was stability or deterioration, had a mean non-deterioration (placebo effect) of 43%, while trials with a primary endpoint of improvement had a placebo response of only 11%. Placebo is an important variable in the design of CIDP trials. Trials designed to show clinical improvement will have a significantly lower effect of this phenomenon than those designed to show stability or deterioration

Restabilization treatment after intravenous immunoglobulin withdrawal in chronic inflammatory demyelinating polyneuropathy: Results from the pre-randomization phase of the Polyneuropathy And Treatment with Hizentra study

In patients with chronic inflammatory demyelinating polyneuropathy (CIDP), intravenous immunoglobulin (IVIG) is recommended to be periodically reduced to assess the need for ongoing therapy. However, little is known about the effectiveness of restabilization with IVIG in patients who worsen after IVIG withdrawal. In the Polyneuropathy And Treatment with Hizentra (PATH) study, the pre-randomization period included sudden stopping of IVIG followed by 12 weeks of observation. Those deteriorating were then restabilized with IVIG. Of 245 subjects who stopped IVIG, 28 did not show signs of clinical deterioration within 12 weeks. Two hundred and seven received IVIG restabilization with an induction dose of 2 g/kg bodyweight (bw) IgPro10 (Privigen, CSL Behring, King of Prussia, Pennsylvania) and maintenance doses of 1 g/kg bw every 3 weeks for up to 13 weeks. Signs of clinical improvement were seen in almost all (n = 188; 91%) subjects. During IVIG restabilization, 35 subjects either did not show CIDP stability (n = 21, analyzed as n = 22 as an additional subject was randomized in error) or withdrew for other reasons (n = 14). Of the 22 subjects who did not achieve clinical stability, follow-up information in 16 subjects after an additional 4 weeks was obtained. Nine subjects were reported to have improved, leaving a maximum of 27 subjects (13%) who either showed no signs of clinical improvement during the restabilization phase and 4 weeks post-study or withdrew for other reasons. In conclusion, sudden IVIG withdrawal was effective in detecting ongoing immunoglobulin G dependency with a small risk for subjects not returning to their baseline 17 weeks after withdrawal

Restabilization treatment after intravenous immunoglobulin withdrawal in chronic inflammatory demyelinating polyneuropathy: Results from the pre-randomization phase of the Polyneuropathy And Treatment with Hizentra study

In patients with chronic inflammatory demyelinating polyneuropathy (CIDP), intravenous immunoglobulin (IVIG) is recommended to be periodically reduced to assess the need for ongoing therapy. However, little is known about the effectiveness of restabilization with IVIG in patients who worsen after IVIG withdrawal. In the Polyneuropathy And Treatment with Hizentra (PATH) study, the pre-randomization period included sudden stopping of IVIG followed by 12 weeks of observation. Those deteriorating were then restabilized with IVIG. Of 245 subjects who stopped IVIG, 28 did not show signs of clinical deterioration within 12 weeks. Two hundred and seven received IVIG restabilization with an induction dose of 2 g/kg bodyweight (bw) IgPro10 (Privigen, CSL Behring, King of Prussia, Pennsylvania) and maintenance doses of 1 g/kg bw every 3 weeks for up to 13 weeks. Signs of clinical improvement were seen in almost all (n = 188; 91%) subjects. During IVIG restabilization, 35 subjects either did not show CIDP stability (n = 21, analyzed as n = 22 as an additional subject was randomized in error) or withdrew for other reasons (n = 14). Of the 22 subjects who did not achieve clinical stability, follow-up information in 16 subjects after an additional 4 weeks was obtained. Nine subjects were reported to have improved, leaving a maximum of 27 subjects (13%) who either showed no signs of clinical improvement during the restabilization phase and 4 weeks post-study or withdrew for other reasons. In conclusion, sudden IVIG withdrawal was effective in detecting ongoing immunoglobulin G dependency with a small risk for subjects not returning to their baseline 17 weeks after withdrawal