scholarly journals A Phase 3, double-blind, placebo-controlled efficacy and safety study of ADS-5102 (Amantadine) extended-release capsules in people with multiple sclerosis and walking impairment

2021 ◽  
pp. 135245852110353
Author(s):  
Jeffrey A Cohen ◽  
Michelle H Cameron ◽  
Myla D Goldman ◽  
Andrew D Goodman ◽  
Aaron E Miller ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Adverse Events ◽  
Extended Release ◽  
Walking Speed ◽  
Testing Procedure ◽  
Double Blind Study ◽  
Phase 3 ◽  
Timed Up And Go ◽  
Double Blind ◽  
Meaningful Improvement

Background: ADS-5102, a delayed-release, extended-release (DR/ER) amantadine, improved walking speed in MS in a Phase 2 trial. Objective: The aim of this study was to present primary results of a Phase 3, double-blind, ADS-5102 trial (INROADS) for walking speed. Methods: Adult participants with MS and walking impairment, not currently using amantadine or dalfampridine, underwent 4-week placebo run-in before randomization 1:1:1 to placebo, 137 or 274 mg/day ADS-5102 for 12 weeks. Primary outcome was the proportion of responders (20% increase in Timed 25-Foot Walk (T25FW) speed) for 274 mg ADS-5102 versus placebo at end of double-blind (Study Week 16). Additional measures included Timed Up and Go (TUG), 2-Minute Walk Test (2MWT), and 12-item Multiple Sclerosis Walking Scale (MSWS-12). Results: In total, 558 participants were randomized and received double-blind treatment. Significantly more participants responded with 274 mg ADS-5102 (21.1%) versus placebo (11.3%). Mean T25FW speed also significantly improved (0.19 ft/s) versus placebo (0.07 ft/s). Other measures were not significant using prespecified hierarchical testing procedure. Adverse events led to discontinuation for 3.8% (placebo), 6.4% (137 mg ADS-5102), and 20.5% (274 mg ADS-5102). Conclusion: INROADS met its primary endpoint, showing a significantly greater proportion of participants with meaningful improvement in walking speed for 274 mg ADS-5102 versus placebo. Numeric dose response was seen for some secondary efficacy outcomes and adverse events.

scholarly journals Safety and efficacy of ADS-5102 (amantadine) extended release capsules to improve walking in multiple sclerosis: A randomized, placebo-controlled, phase 2 trial

2018 ◽  
Vol 25 (4) ◽  
pp. 601-609 ◽  
Author(s):  
Jeffrey A Cohen ◽  
Samuel F Hunter ◽  
Theodore R Brown ◽  
Mark Gudesblatt ◽  
Ben W Thrower ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Extended Release ◽  
The United States ◽  
Timed Up And Go ◽  
Double Blind ◽  
Once Daily ◽  
Safety And Efficacy ◽  
Phase 2 Trial ◽  
Minute Walk

Background: Walking impairment causes disability and reduced quality of life in patients with multiple sclerosis (MS). Objective: Characterize the safety and efficacy of ADS-5102 (amantadine) extended release capsules, 274 mg administered once daily at bedtime in patients with MS with walking impairment. Methods: This randomized, double-blind, placebo-controlled, 4-week study was conducted at 14 trial sites in the United States. Study objectives included safety and tolerability of ADS-5102, and efficacy assessments (Timed 25-Foot Walk (T25FW), Timed Up and Go (TUG), 2-Minute Walk Test, and Multiple Sclerosis Walking Scale-12). Fatigue, depression, and cognition also were assessed. Results: A total of 60 patients were randomized (30 to ADS-5102 and 30 to placebo); 59 of whom were treated. The most frequent adverse events (AEs) were dry mouth, constipation, and insomnia. Five ADS-5102 patients and no placebo patients discontinued treatment due to AEs. One patient in the ADS-5102 group experienced a serious AE—suspected serotonin syndrome. A 16.6% placebo-adjusted improvement was seen in the T25FW test ( p < 0.05). A 10% placebo-adjusted improvement in TUG was also observed. No changes in fatigue, depression, or cognition were observed. Conclusion: ADS-5102 was generally well tolerated. These data demonstrate an effect of ADS-5102 on walking speed. Further studies are warranted to confirm these observations.

Sustained-Release Fampridine for Symptomatic Treatment of Multiple Sclerosis

2008 ◽  
Vol 42 (10) ◽  
pp. 1458-1465 ◽  
Author(s):  
Anne R Korenke ◽  
Michael P Rivey ◽  
Douglas R Allington
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Adverse Events ◽  
Sustained Release ◽  
English Language ◽  
Walking Speed ◽  
Data Extraction ◽  
Walking Ability ◽  
Phase 3 ◽  
Safety And Efficacy

Objective: To review the pharmacology, pharmacokinetics, clinical trials, and adverse effects of sustained-release (SR) fampridine in patients with multiple sclerosis (MS). Data Sources: An English-language human data search was done using PubMed/MEDLINE (1966-August 2008) to retrieve relevant material using the search terms fampridine-SR, 4-aminopyridine. and multiple sclerosis. References of selected articles and information from the drug developer were used to further identify pertinent trials. Study Selection and Data Extraction: Article selection was based primarily on studies that evaluated the pharmacokinetics, safety, and efficacy of fampridine-SR in patients with MS. Relevant meeting abstracts were also included as part of the analysis. Data Synthesis: Fampridine-SR is a sustained-release, orally administered potassium-channel blocker acting in the central nervous system to enhance conduction in demyelinated axons Several small trials have evaluated the safety and efficacy of fampridine-SR in patients with MS to improve their walking ability. Data from a recent large Phase 3 trial indicated that walking speed improved in 42.9% of patients with MS who were treated with fampridine-SR compared with 9.3% of those who received placebo (p < 0.001), Treatment-related adverse events associated with the use of fampridine-SR include dizziness, insomnia, nausea, and paresthesia. More severe adverse events, such as seizure, have occurred in patients receiving doses higher than those currently recommended. Conclusions: Positive results from 2 Phase 3 clinical trials have put fampridine-SR on the path toward approval as a medication for improving walking speed and tower extremity strength in patients with MS.

scholarly journals Long-term safety and efficacy of dalfampridine for walking impairment in patients with multiple sclerosis: Results of open-label extensions of two Phase 3 clinical trials

2015 ◽  
Vol 21 (10) ◽  
pp. 1322-1331 ◽  
Author(s):  
Andrew D Goodman ◽  
Francois Bethoux ◽  
Theodore R Brown ◽  
Randall T Schapiro ◽  
Ron Cohen ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Walking Speed ◽  
Prolonged Release ◽  
Open Label ◽  
Phase 3 ◽  
Two Phase ◽  
Double Blind ◽  
Safety And Efficacy ◽  
Maximum Exposure

Background: In Phase 3 double-blind trials (MS-F203 and MS-F204), dalfampridine extended release tablets 10 mg twice daily (dalfampridine-ER; prolonged-release fampridine in Europe; fampridine modified or sustained release elsewhere) improved walking speed relative to placebo in patients with multiple sclerosis (MS). Objectives: Evaluation of long-term safety and efficacy of dalfampridine-ER in open-label extensions (MS-F203EXT, MS-F204EXT). Methods: Patients received dalfampridine-ER 10 mg twice daily; and had Timed 25-Foot Walk (T25FW) assessments at 2, 14 and 26 weeks, and then every 6 months. Subjects were categorized as dalfampridine-ER responders or non-responders, based on their treatment response in the double-blind parent trials that assessed T25FW. Results: We had 269 patients enter MS-F203EXT and 154 patients complete it; for a maximum exposure of 5 years. We had 214 patients enter MS-F204EXT and 146 complete it; for a maximum exposure of 3.3 years. No new safety signals emerged and dalfampridine-ER tolerability was consistent with the double-blind phase. Improvements in walking speed were lost after dalfampridine-ER was discontinued in the parent trial, but returned by the 2-week assessment after re-initiation of the drug. Throughout the extensions, mean improvement in walking speed declined, but remained improved, among the double-blind responders as compared with non-responders. Conclusions: The dalfamipridine-ER safety profile was consistent with the parent trials. Although walking speed decreased over time, dalfampridine-ER responders continued to show improved walking speed, which was sustained compared with non-responders.

Fampridine-SR in multiple sclerosis: a randomized, double-blind, placebo-controlled, dose-ranging study

2007 ◽  
Vol 13 (3) ◽  
pp. 357-368 ◽  
Author(s):  
A.D. Goodman ◽  
J.A. Cohen ◽  
A. Cross ◽  
T. Vollmer ◽  
M. Rizzo ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Adverse Events ◽  
Lower Extremity ◽  
Walking Speed ◽  
Manual Muscle Testing ◽  
Controlled Study ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Muscle Testing ◽  
Lower Extremity Muscle

Objective To determine the safety of sustained-release 4-aminopyridine in subjects with mutiple sclerosis (MS) and to examine dose-related efficacy up to 40 mg twice daily. Method Multicenter, randomized, double-blind, placebo-controlled, study. Following a 4-week baseline peroid, subjects were randomly assigned to receive Fampridine-SR (n=25, doses from 10 to 40 mg twice daily, increasing in 5 mg increments weekly) or placebo (n=11). A battery of assessments was performed weekly, including the MS Functional Composite (MSFC), fatigue questionnaires, and lower extremity manual muscle testing. Results The most common adverse events were dizziness, insomnia, paresthesia, asthenia, nausea, headache, and tremor. Five subjects were discontinued from Fampridine-SR because of adverse events at doses greater than 25 mg, and these included convulsions in two subjects at doses of 30 and 35 mg twice daily. Improvement were seen in lower extremity muscle strength (prospective analysis) and walking speed (post-hoc analysis) in the Fampridine-SR group compared to placebo (unadjusted p-values of 0.01 and 0.03, respectively). There were no significant differences in other MSFC measure or fatigue scores. Conclusions Future studies should employ doses up to 20 mg twice daily with lower extremity strength and walking speed as potential outcome measures. Multiple Sclerosis 2007; 13: 357-368. http://msj.sagepub.com

scholarly journals P097 Incidence of abnormal dreams and nightmares with lemborexant in adults with insomnia: results from two Phase 3 studies

2021 ◽  
Vol 2 (Supplement_1) ◽  
pp. A52-A52
Author(s):  
T Roth ◽  
J Yardley ◽  
K Pinner ◽  
D Kumar ◽  
J Cheng ◽  
...  
Keyword(s):  
Adverse Events ◽  
Extended Release ◽  
Treatment Initiation ◽  
Phase 3 ◽  
Two Phase ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Insomnia Disorder ◽  
Before And After ◽  
Sedative Hypnotics

Abstract Introduction Abnormal dreams and nightmares have been reported by insomnia patients before and after treatment with sedative-hypnotics. Since dual-orexin-receptor-antagonists such as lemborexant (LEM; approved in multiple countries for adult insomnia) increase REM sleep, during which dream content is more likely to be recalled, we assessed the frequency of nightmares/abnormal dreams in Phase 3 studies. Methods Study 303 (SUNRISE-2) was a 12mo, randomized, double-blind, placebo (PBO)-controlled (first 6mo [Period 1]), phase 3 study that enrolled subjects ≥18y with insomnia disorder and ISI scores ≥15. During Period 1, the safety analysis set (SAS) included: PBO, n=319; LEM 5mg, (LEM5), n=314; LEM 10mg (LEM10), n=314. Study 304 (SUNRISE-1) was a 1mo, randomized, double-blind, PBO- and active-controlled (zolpidem tartrate extended-release 6.25mg [ZOL-ER]) study of LEM5 and LEM10. The SAS included: PBO, n=209; ZOL-ER, n=263; LEM5, n=266; LEM10, n=268. Results In Study 303, Period 1, 28/947 subjects (3.0%) reported nightmares (n=12; PBO-1; LEM5-4; LEM10-7) or abnormal dreams (n=17; PBO-6; LEM5-7; LEM10-4) as treatment-emergent adverse events (TEAEs). In Study 304, 12/1006 subjects (1.2%) reported nightmares (n=4; PBO-1; ZOL-ER-0; LEM5-2; LEM10-1) or abnormal dreams (n=8; PBO-1; ZOL-ER-3; LEM5-0; LEM10-4). 32/40 subjects (80.0%) reporting these events were female (% females in the studies: 303=67.9%; 304=86.4%). In the LEM groups, 11/28 subjects (39.3%) reported the TEAE within 3 days of treatment initiation. There were 2 TEAEs of nightmare/abnormal dreams during the PBO run-in prior to randomization. Conclusion Abnormal dreams/nightmares were not common events in either study. Incidence was slightly higher with LEM10 and proportional to enrollment based on sex.

Treatment of Chronic Progressive Multiple Sclerosis with Intravenous Immunoglobulins - interim Results on Drug Safety of an Ongoing Study

2000 ◽  
Vol 6 (2_suppl) ◽  
pp. S21-S23 ◽  
Author(s):  
D Poehlau ◽  
Keyword(s):  
Multiple Sclerosis ◽  
Adverse Events ◽  
Drug Safety ◽  
Intravenous Immunoglobulins ◽  
Progressive Multiple Sclerosis ◽  
Ivig Treatment ◽  
Double Blind Study ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Multiple Sclerosis Patients

In a blinded administrative look we analyzed the safety profile of intravenous immunoglobulin (IVIG) treatment in an ongoing randomized, placebo controlled double blind study on the treatment of multiple sclerosis (MS) patients with primary or secondary chronic progressive MS. Up to October 1999 131 patients were included in the study. Collectively, these patients received approximately 1200 infusions either with IVIG (400 mg/kg bodyweight every 4 weeks) or with placebo; approximately 600 IVIG infusions were administered. All reported serious adverse events (SAE), including reports on adverse events submitted directly to the drug safety department of the sponsor, were closely analyzed. A total of 25 SAE's (in 25 patients) have been reported up until 15th October 1999, whereby the main criterion for ‘serious’ in all of these cases was hospitalization. None of these 25 SAE were regarded as drug related. No side effects relating to liver functions, kidney functions or rheological problems have been reported. Since the mean score on the EDSS-scale of the patients at the point of inclusion in the study was 5.6 (median EDSS: 6.0) we conclude that IVIG treatment, at a dose of 400 mg/kg bodyweight every 4 weeks, is a relatively safe therapy even for severely disabled multiple sclerosis patients.

scholarly journals 9 Phase 3 Randomized, Double-blind, Placebo-Controlled Studies Evaluating Efficacy and Safety of Extended-Release Viloxazine for Pediatric ADHD

CNS Spectrums ◽  
2019 ◽  
Vol 24 (1) ◽  
pp. 177-178
Author(s):  
Azmi Nasser ◽  
Janet K. Johnson ◽  
Toyin Adewole ◽  
Tesfaye Liranso ◽  
Ronald Marcus
Keyword(s):  
Adverse Events ◽  
Children And Adolescents ◽  
Extended Release ◽  
Rating Scale ◽  
Stress Index ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Double Blind ◽  
Double Blind Placebo

AbstractStudy ObjectivesAlthough stimulants are commonly used for attention-deficit/hyperactivity disorder (ADHD), 10–30% of patients have an inadequate response, adverse events, or comorbidities preventing use. Thus, there is a need for safe, effective nonstimulant options. Extended-release viloxazine (SPN-812), a nonstimulant, is currently in development for the treatment of ADHD in children and adolescents. SPN-812 is a structurally distinct, bicyclic norepinephrine reuptake inhibitor with selective serotonergic activity. Results of the Phase 2 program demonstrated efficacy (improved mean ADHD Rating Scale-IV total score) and safety of SPN-812 in children (6–12 years), as well as an onset of action within 1–2 weeks.MethodFour ongoing Phase 3 randomized, double-blind, placebo-controlled, outpatient, US studies are investigating the efficacy and safety of once-daily SPN-812 for ADHD in children (ages 6–11; 100–400mg) and adolescents (ages 12–17; 200–600mg). Two studies are enrolling children and two are enrolling adolescents. Eligible subjects are required to have minimum baseline scores of ≥28 for ADHD-RS-5 and ≥4 for Clinical Global Impression-Severity scale (CGI-S). These studies will randomize ∼1200 subjects, with ∼800 subjects receiving SPN-812 over a 1–3-week titration and 5-week maintenance period. The primary endpoint in all studies is mean change from baseline to end of study (EOS) in ADHD-RS-5 total score for SPN-812 vs. placebo. Secondary endpoints include change from baseline to EOS in 30% responder rate (% change: ADHD RS 5); Hyperactivity/Impulsivity and Inattention ADHD-RS-5 subscale scores; Conners 3 Rating Scale (parent and self-report); CGI-S/CGI-I (Improvement); Weiss Functional Impairment Rating Scale (parent report); Parenting Stress Index (children); and Stress Index for Parents of Adolescents (adolescents) after 6–8 weeks of treatment. Safety is assessed via adverse events, clinical laboratory tests, vital signs, electrocardiograms, physical examinations, and the Columbia-Suicide Severity Rating Scale. Phase 3 completers are offered the option of enrolling in an open-label extension study (OLE; up to 3 years) with a starting dose of 100/200mg (children/adolescents). Data will be summarized with descriptive statistics and analyzed using appropriate statistical methods.ResultsAs of August 2018, enrollment in 1 child study is complete, and the other 3 trials are at ∼89%; rollover into the OLE is ∼90%.ConclusionsThere is an unmet need for nonstimulant ADHD treatment for children and adolescents that is effective, long-acting, and well tolerated. SPN-812 is being investigated in four Phase 3 randomized, placebo-controlled studies for the treatment of children and adolescents with ADHD, based on demonstrated efficacy and safety in the Phase 2 program.This study is an encore of a poster presentation at the 2018 Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP).Funding Acknowledgements: Supernus Pharmaceuticals, Inc.

scholarly journals Evaluation of Dalfampridine Extended Release 5 and 10 mg in Multiple Sclerosis

2015 ◽  
Vol 17 (3) ◽  
pp. 138-145 ◽  
Author(s):  
Robert Yapundich ◽  
Angela Applebee ◽  
Francois Bethoux ◽  
Myla D. Goldman ◽  
George J. Hutton ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Extended Release ◽  
Walking Speed ◽  
Walking Distance ◽  
Walk Distance ◽  
Double Blind ◽  
Post Hoc ◽  
6 Minute Walk Test ◽  
Minute Walk Distance ◽  
Minute Walk

Background: Dalfampridine extended-release (ER) tablets, 10 mg twice daily, have been shown to improve walking in people with multiple sclerosis. We evaluated the safety and efficacy of dalfampridine-ER 5 mg compared with 10 mg. Methods: Patients were randomized to double-blind treatment with twice-daily dalfampridine-ER tablets, 5 mg (n = 144) or 10 mg (n = 143), or placebo (n = 143) for 4 weeks. Primary efficacy endpoint was change from baseline walking speed by the Timed 25-Foot Walk 3 to 4 hours after the last dose. At 40% of sites, 2-week change from baseline walking distance was measured by the 6-Minute Walk test. Results: At 4 weeks, walking speed changes from baseline were 0.363, 0.423, and 0.478 ft/s (placebo, dalfampridine-ER 5 mg, and dalfampridine-ER 10 mg, respectively [P = NS]). Post hoc analysis of average changes between pretreatment and on-treatment showed that relative to placebo, only dalfampridine-ER 10 mg demonstrated a significant increase in walking speed (mean ± SE): 0.443 ± 0.042 ft/s versus 0.303 ± 0.038 ft/s (P = .014). Improvement in 6-Minute Walk distance was significantly greater with dalfampridine-ER 10 mg (128.6 ft, P = .014) but not with 5 mg (76.8 ft, P = .308) relative to placebo (41.7 ft). Adverse events were consistent with previous studies. No seizures were reported. Conclusions: Dalfampridine-ER 5 and 10 mg twice daily did not demonstrate efficacy on the planned endpoint. Post hoc analyses demonstrated significant increases in walking speed relative to placebo with dalfampridine-ER 10 mg. No new safety signals were observed.

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