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EASE LID 3

Randomized, placebo-controlled trial of ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson's disease (EASE LID 3)

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Year of Publication: 2017

Authors: Oertel W, Eggert K, Pahwa R, ..., Stempien MJ

Journal: Movement Disorders

Citation: Movement Disorders 2017;32(12):1701-1709

Link: https://doi.org/10.1002/mds.27131

PDF: https://onlinelibrary.wiley.com/doi/pdf/10.1002/mds.27131

Clinical Question

Does once-daily amantadine extended-release (ADS-5102) reduce levodopa-induced dyskinesia and OFF time in Parkinson's disease?

Bottom Line

Once-daily bedtime amantadine extended-release (ADS-5102, 274 mg) significantly reduced levodopa-induced dyskinesia (Unified Dyskinesia Rating Scale improved by 14.4 points more than placebo, p<0.0001) and decreased OFF time by 1.1 hours vs placebo (p=0.02) over 13 weeks in Parkinson's disease. This established ADS-5102 as the first approved therapy for levodopa-induced dyskinesia.

        Major Points
        Phase 3, multicenter, randomized, double-blind, placebo-controlled trial (EASE LID 3)
75 PD patients on stable levodopa with ≥1 hour of troublesome dyskinesia and ≥mild functional impact
Randomized 1:1 to ADS-5102 274 mg once daily at bedtime or matching placebo for 13 weeks
Primary endpoint: change in Unified Dyskinesia Rating Scale (UDysRS) total score from baseline to week 12
Key secondary: OFF time from 24-hour motor diary
UDysRS LSM change at week 12: −20.7 (ADS-5102) vs −6.3 (placebo); difference −14.4 (95% CI −20.4 to −8.3); p<0.0001
OFF time change: −0.5 h (ADS-5102, baseline 2.6 h) vs +0.6 h (placebo, baseline 2.0 h); difference −1.1 h (95% CI −2.0 to −0.2); p=0.02
Most common AEs: dry mouth (13.5%), nausea (13.5%), decreased appetite (10.8%), insomnia (10.8%), orthostatic hypotension (10.8%)
Discontinuation due to AEs: 19% with ADS-5102 vs 8% with placebo
No new or unexpected safety signals; all AEs consistent with known amantadine profile
Together with EASE LID 1/2, supported FDA approval of ADS-5102 (Gocovri) in 2017 as the FIRST approved therapy for levodopa-induced dyskinesia
2022 FDA approval expanded indication to adjunctive treatment for OFF episodes in PD

      

Design

Study Type: Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial

Randomization: 1

Blinding: Double-blind

Follow-up Duration: 13 weeks (double-blind treatment)

Centers: Multicenter, US and Europe

Sample Size: 75

Analyzed: 75

Analysis: Modified intention-to-treat; mixed model repeated measures

Inclusion Criteria

Adults with Parkinson's disease
Stable levodopa therapy ≥3 months
≥1 hour of troublesome levodopa-induced dyskinesia (diary)
≥mild functional impact of dyskinesia
Hoehn-Yahr 2-4

Exclusion Criteria

Surgical intervention for PD (DBS)
Other prior use of immediate-release amantadine
Severe cognitive impairment
Orthostatic hypotension (severe)
Psychosis

Baseline Characteristics

Characteristic	Control	Active
N	38	37
OFF time baseline	2.0 h	2.6 h
UDysRS baseline	Similar across arms	Similar across arms

Arms

Field	Control	ADS-5102 274 mg
N	38	37
Intervention	Matching placebo once daily at bedtime	Amantadine extended-release 274 mg once daily at bedtime (titrated over 1 week from 137 mg)
Duration	13 weeks	13 weeks

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Change in UDysRS total score from baseline to week 12	Primary	LSM change -6.3 (SE 2.1)	LSM change -20.7 (SE 2.2)		<0.0001
OFF time change (hours) at week 12	Secondary	+0.6 h (from baseline 2.0)	-0.5 h (from baseline 2.6)	Difference -1.1 h (95% CI -2.0 to -0.2)	p=0.02
ON time with troublesome dyskinesia	Secondary	Minimal change	Reduction with ADS-5102		Favorable
Clinical Global Impression of Change	Secondary	Minimal improvement	Greater improvement with ADS-5102		Favorable
Dry mouth	Adverse	2.6%	13.5%		Higher with ADS-5102
Nausea	Adverse	2.6%	13.5%		Higher with ADS-5102
Decreased appetite	Adverse	0%	10.8%		Higher with ADS-5102
Insomnia	Adverse	0%	10.8%		Higher with ADS-5102
Orthostatic hypotension	Adverse	0%	10.8%		Higher with ADS-5102
Constipation	Adverse	0%	8.1%		Higher with ADS-5102
Falls	Adverse	5.3%	8.1%		Similar
Visual hallucinations	Adverse	5.3%	8.1%		Similar; a concern with amantadine
Discontinuation due to AEs	Adverse	8%	19%		More with ADS-5102
Serious adverse events	Adverse	Uncommon	Uncommon		Similar rates

Subgroup Analysis

Efficacy on UDysRS was consistent across subgroups by age, sex, disease duration, and baseline dyskinesia severity. Anticholinergic AEs (dry mouth, constipation, visual hallucinations) particularly relevant in older PD patients — clinical use requires careful patient selection.

Criticisms

Small sample size (N=75)
Short 13-week follow-up does not assess durability of dyskinesia benefit
No active comparator (immediate-release amantadine)
Higher discontinuation rate (19% vs 8%) may limit real-world utility
Visual hallucinations and orthostatic hypotension carry clinical significance in elderly PD
Bedtime dosing may not address morning-dose dyskinesia in all patients

Funding

Adamas Pharmaceuticals, Inc. (manufacturer of ADS-5102/Gocovri)

Based on: EASE LID 3 (Movement Disorders, 2017)

Authors: Oertel W, Eggert K, Pahwa R, ..., Stempien MJ

Citation: Movement Disorders 2017;32(12):1701-1709

Content summarized and formatted by NeuroTrials.ai.

EASE LID 3

(2017)

Objective

ADS-5102 (amantadine extended-release) 274 mg at bedtime — to evaluate efficacy and safety for treatment of levodopa-induced dyskinesia in patients with Parkinson's disease.

Study Summary

• Amantadine ER 274 mg at bedtime (ADS-5102) reduced levodopa-induced dyskinesia by 14.4 points more than placebo on the Unified Dyskinesia Rating Scale at 12 weeks (LSM change −20.7 vs −6.3; p<0.0001) in Parkinson's disease.
• OFF time improved by 1.1 hours more with ADS-5102 than placebo (LSM change −0.5 vs +0.6 h; p=0.02) — meaningful because most dyskinesia-targeted therapies risk worsening OFF time.
• Established ADS-5102 as the first FDA-approved therapy specifically indicated for levodopa-induced dyskinesia in PD (approved in 2017 as Gocovri).

Intervention

ADS-5102 (amantadine extended-release) 274 mg once daily at bedtime vs matching placebo for 13 weeks.

Inclusion Criteria

Adults with Parkinson's disease on stable levodopa therapy with ≥1 hour of troublesome levodopa-induced dyskinesia during a 24-hour motor diary and at least mild functional impact.

Study Design

Arms: ADS-5102 274 mg vs Placebo

Patients per Arm: ADS-5102: 37; Placebo: 38

Outcome

• Primary: UDysRS total score change at week 12: LSM −20.7 (ADS-5102) vs −6.3 (placebo); difference −14.4 (95% CI −20.4 to −8.3); p<0.0001
• OFF time: LSM change −0.5 h (ADS-5102, baseline 2.6 h) vs +0.6 h (placebo, baseline 2.0 h); difference −1.1 h (95% CI −2.0 to −0.2); p=0.02
• Most common AEs (ADS-5102 vs placebo): dry mouth 13.5% vs 2.6%, nausea 13.5% vs 2.6%, decreased appetite 10.8% vs 0%, insomnia 10.8% vs 0%, orthostatic hypotension 10.8% vs 0%
• Treatment discontinuation from AEs: 19% (ADS-5102) vs 8% (placebo)

Clinical Question

Does ADS-5102 (amantadine extended-release) reduce levodopa-induced dyskinesia and OFF time in Parkinson's disease?

Bottom Line

Major Points

Phase 3, multicenter, randomized, double-blind, placebo-controlled trial (EASE LID 3)
75 PD patients on stable levodopa with ≥1 hour of troublesome dyskinesia and ≥mild functional impact
Randomized 1:1 to ADS-5102 274 mg once daily at bedtime or matching placebo for 13 weeks
Primary endpoint: change in Unified Dyskinesia Rating Scale (UDysRS) total score from baseline to week 12
Key secondary: OFF time from 24-hour motor diary
UDysRS LSM change at week 12: −20.7 (ADS-5102) vs −6.3 (placebo); difference −14.4 (95% CI −20.4 to −8.3); p<0.0001
OFF time change: −0.5 h (ADS-5102, baseline 2.6 h) vs +0.6 h (placebo, baseline 2.0 h); difference −1.1 h (95% CI −2.0 to −0.2); p=0.02
Most common AEs: dry mouth (13.5%), nausea (13.5%), decreased appetite (10.8%), insomnia (10.8%), orthostatic hypotension (10.8%)
Discontinuation due to AEs: 19% with ADS-5102 vs 8% with placebo
No new or unexpected safety signals; all AEs consistent with known amantadine profile
Together with EASE LID 1/2, supported FDA approval of ADS-5102 (Gocovri) in 2017 as the FIRST approved therapy for levodopa-induced dyskinesia
2022 FDA approval expanded indication to adjunctive treatment for OFF episodes in PD

Study Design

Study Type: Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial
Randomization: Yes
Blinding: Double-blind
Sample Size: 75
Follow-up: 13 weeks (double-blind treatment)
Centers: Multicenter, US and Europe

Primary Outcome

Definition: Change in UDysRS total score from baseline to week 12

Control	Intervention	HR/OR	P-value
LSM change -6.3 (SE 2.1)	LSM change -20.7 (SE 2.2)	- (-20.4 to -8.3)	<0.0001

Limitations & Criticisms

Small sample size (N=75)
Short 13-week follow-up does not assess durability of dyskinesia benefit
No active comparator (immediate-release amantadine)
Higher discontinuation rate (19% vs 8%) may limit real-world utility
Visual hallucinations and orthostatic hypotension carry clinical significance in elderly PD
Bedtime dosing may not address morning-dose dyskinesia in all patients

Citation

Movement Disorders 2017;32(12):1701-1709

View Original Publication →

EASE LID 3

Randomized, placebo-controlled trial of ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson's disease (EASE LID 3)

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

Ask about EASE LID 3