Evidence Table TxMN3What is the effectiveness of amantadine vs. placebo or levodopa in the treatment of functionally disabled early Parkinson’s disease?

Bibliographic referenceCrosby N, Deane KHO, Clarke CE. Amantadine in Parkinson’s disease (Cochrane Review). The Cochrane Library 2003.
Study typeCochrane review of 6 randomised, double-blind, placebo-controlled studies
Evidence level1++
Study objectiveTo compare the efficacy and safety of amantadine therapy (monotherapy or adjuvant therapy) versus placebo in treating people with Parkinson’s disease.
Number of patientsN=215 patients
 N=23 (Fahn)
 N=30 (Fehling)
 N=42 (Savery)
 N=50 (Silver)
 N=42 (Walker a)
 N=28 (Walker b)

Location: USA (all except one trial) and Sweden (Fehling)
sites: all one centre trials
Patient characteristicsThe mean ages of the patients in the 6 studies ranged from 61 to 66 years of age
Overall age of participants ranged from 29 to 82 years
Mean time since diagnosis (given in 4 trials) varied from 7.2 to 9.25 years (range 1–35 years)
Mean Hoehn and Yahr scores (given in 4 trials) ranged from 2.5 to 3.2
156/215 patients gender was reported in a ratio of 68%: 32% male: female
InterventionDose and frequency of amantadine varied
➢ 4 studies used 100mg 2x daily
➢ One study used 50mg/d and increased this to 100mg/d in first 2 weeks
➢ One study used 100mg/d for 3 weeks then increased to 200mg/d for second 3 weeks-then final 3 weeks patients chose which dosage they preferred
ComparisonTwo studies stated the mean daily levodopa dose of their subjects
➢ One study was 3.43 g (ranging from 2.0 to 6.0g)
➢ The other study was 3.58g
➢ Only one study used levodopa in combination with a decarboxylase inhibitor (carbidopa)
Length of follow-upNot stated
Outcome measuresParkinsonian severity scale, activity impairment scale, Simulated Activities of Daily Living, Clinical Quantitative Neurological Examination, adverse events
Effect size➢ 2 trials examined amantadine as an adjuvant to optimal levodopa therapy alone (Savery and Walker (b))
➢ One trial examined amantadine as an adjuvant to optimal levodopa therapy and anticholinergics (if patient had been on them prior to trial) (Fehling)
➢ 2 trials maintained their patients on previous medication during trial (these were stated to be anticholinergics but were not described) (Silver and Fahn)
➢ 1 study reduced patients anticholinergics medication to nil or the lowest dose the patients could tolerate (Walker (a))

➢ 3 trials were cross-over trials and did not present data from the end of the first arms (Fehling, Walker (b) and Fahn)
➢ Since there was a risk for carry-over effect the data from these trials was not analysed
➢ Fahn only presented data from the amantadine arms so no comparison could be made to the results of the placebo arm
➢ Silver compromised the randomisation by breaking the codes and did not analyse their data on an intention-to-treat basis and so their data was not analysed because of strong bias possibility

➢ Savery measured parkinsonian symptoms and impairments on an ad hoc assessment scale
➢ After 9 weeks of treatment the group treated with amantadine were on average 15.0 points better than the placebo group (average baseline score 21.4) in the parkinsonian severity scale
➢ And 28.1 points better (average baseline 38.3) on the activity impairment scale
➢ The statistical significance of this cannot be determined from the data provided by the authors
➢ Size of improvements does suggest they may have been clinically significant

➢ Wallker(a) measured 19 timed Simulated Activities of Daily Living such as putting on a shirt or using a fork
➢ Mean scores at the end of the first treatment arm are available but no standard deviations or baseline scores are provided
➢ Importance of these results to the patients and their clinical significance are unclear
➢ Also performed the Clinical Quantitative Neurological Examination (50 items)
➢ Only mean scores at the end of the first treatment are available but no standard deviations or baseline scores are provided
➢ Clinical significance of these results is unclear

Adverse events
➢ Walker (a) reports 16 different side-effects 10 of which are presented in patients on amantadine
➢ Including: weight-loss (4), constipation (3), unsteadiness, blurred vision, and urinary straining (2 each)
➢ 26 patients on amantadine reported no side-effects compared with 18 on placebo
➢ Walker (b) used the same patients as Walker (a) and reported no new side effects
➢ Savery reports that amantadine caused on trivial side effects-the total difference between in frequency of side effects was not significant between amantadine and placebo
➢ Fahn reported 6 different side effects caused by amantadine including: insomnia (4), anorexia (5), dizziness and nervousness (2 each)
➢ Fehling reported 14 different side-effects caused by amantadine including: dryness of mouth (14), tiredness (7), abdominal discomfort (4), blurred vision, and giddiness (3)
➢ Silver reported that side effects were encountered in 47% of patients receiving amantadine
➢ Most common was livido reticularis which occurred in 9/34 patients-oedema was seen in 4/9
➢ 12% of patients on placebo developed adverse events
Source of fundingNone stated
Additional commentsInclusion criteria for studies: all randomised controlled trials comparing monotherapy and adjuvant oral amantadine therapy with placebo were considered
➢ 6 trials were found that compared amantadine as either monotherapy or adjuvant therapy
➢ None of the 6 trials provided details on the method of randomisation
➢ Five trials failed to describe allocation concealment
Generalisability of results to female PD population limited by ratio of male: female participants
➢ Authors’ conclusions: “All six of the randomised controlled trials analysed in this review reported a positive effect of amantadine in Parkinson’s disease. However poor reporting of results and the small numbers in all of the trials prevents any firm conclusions regarding the efficacy and safety of amantadine in the treatment of Parkinson’s disease”.
➢ Trials included: Walker 1972 (a) (b), Savery 1977, Fahn 1975, Fehling 1973, and Silver 1971
NCC CC ID (Ref Man)51

From: Evidence Tables

Cover of Parkinson's Disease
Parkinson's Disease: National Clinical Guideline for Diagnosis and Management in Primary and Secondary Care.
NICE Clinical Guidelines, No. 35.
National Collaborating Centre for Chronic Conditions (UK).
Copyright © 2006, Royal College of Physicians of London.

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