A Study of the Safety and Efficacy of Memantine in Moderate to Severe Alzheimer's Disease

This study has been completed.
Sponsor:
Information provided by:
Forest Laboratories
ClinicalTrials.gov Identifier:
NCT00322153
First received: May 3, 2006
Last updated: August 25, 2010
Last verified: August 2010
Results First Received: July 20, 2010  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Dementia of the Alzheimer's Type
Interventions: Drug: memantine ER
Drug: Placebo

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
The recruitment period was from May 20, 2005 to April 18th, 2007 at 83 study centers in four countries (23 in Argentina, 11 in Chile, 11 in Mexico, and 38 in the US)

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Study consisted of 1-2 weeks single-blind placebo treatment followed by 24 weeks double-blind treatment. At the end of single-blind placebo treatment, patients meeting entry criteria were randomized (1:1) to 1 of 2 double-blind treatment groups receiving memantine or placebo.

Reporting Groups
  Description
Placebo Matching placebo oral administration once daily for 24 weeks.
Memantine ER 28mg once daily oral administration for 24 weeks.

Participant Flow:   Overall Study
    Placebo     Memantine ER  
STARTED     335 [1]   342 [2]
SAFETY POPULATION     335 [3]   341 [4]
COMPLETED     272     273  
NOT COMPLETED     63     69  
Adverse Event                 21                 34  
Protocol Violation                 6                 14  
Withdrawal by Subject                 18                 10  
Lack of Efficacy                 8                 3  
Lost to Follow-up                 5                 4  
Withdrawn for other reasons                 5                 4  
[1] Randomized to placebo
[2] Randomized to Memantine ER
[3] Safety population defined as all patients who took at least one dose of double-blind study drug.
[4] Safety population: one patient was randomized but did not receive double-blind study drug.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Placebo Matching placebo oral administration once daily for 24 weeks.
Memantine ER 28mg once daily oral administration for 24 weeks.
Total Total of all reporting groups

Baseline Measures
    Placebo     Memantine ER     Total  
Number of Participants  
[units: participants]
  335     341     676  
Age, Customized  
[units: participants]
     
<= 64 years     26     34     60  
65-74 years     79     85     164  
75-84 years     179     176     355  
>= 85 years     51     46     97  
Age  
[units: years]
Mean ± Standard Deviation
  76.8  ± 7.76     76.2  ± 8.35     76.5  ± 8.07  
Gender  
[units: participants]
     
Female     243     244     487  
Male     92     97     189  
Region of Enrollment  
[units: participants]
     
United States     85     93     178  
Argentina     158     153     311  
Chile     44     46     90  
Mexico     48     49     97  



  Outcome Measures
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1.  Primary:   Change From Baseline in Severe Impairment Battery (SIB) at Week 24 (LOCF)   [ Time Frame: Baseline to week 24 ]

Measure Type Primary
Measure Title Change From Baseline in Severe Impairment Battery (SIB) at Week 24 (LOCF)
Measure Description The SIB was developed for the evaluation of cognitive function in patients with more advanced dementia, and evaluates the areas of memory, language, praxis, orientation, and attention. The SIB test items consist of simple, one-step commands presented with gestural cues that are repeated if necessary. The test contains 51 items, and the range of possible scores is 0 to 100 (with 0 being the worst result). The SIB has been shown to be a valid and reliable instrument sensitive to longitudinal change.
Time Frame Baseline to week 24  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Primary efficacy analysis was based on the Intent-to-Treat (ITT) Population. The ITT Population was consisted of all patients in the Safety Population who completed at least one post-Baseline efficacy assessment in SIB or CIBIC-Plus. The last-observation-carried-forward approach was used to impute missing post-Baseline values.

Reporting Groups
  Description
Placebo Matching placebo oral administration once daily for 24 weeks.
Memantine ER 28mg once daily oral administration for 24 weeks.

Measured Values
    Placebo     Memantine ER  
Number of Participants Analyzed  
[units: participants]
  327     332  
Change From Baseline in Severe Impairment Battery (SIB) at Week 24 (LOCF)  
[units: Units on a scale]
Least Squares Mean ± Standard Error
  -0.4  ± 0.65     2.2  ± 0.65  


Statistical Analysis 1 for Change From Baseline in Severe Impairment Battery (SIB) at Week 24 (LOCF)
Groups [1] All groups
Method [2] ANCOVA
P Value [3] 0.001
Mean Difference (Final Values) [4] 2.6
95% Confidence Interval ( 1.0 to 4.2 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The co-primary efficacy parameter was change from Baseline to Week 24 in SIB total score. Missing SIB total scores at Week 24 were imputed using the last-observation-carried-forward (LOCF) approach.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Least-squares mean (-0.4 in placebo and 2.2 in memantine ER) are controlled for center and adjusted for SIB baseline value.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



2.  Primary:   Clinician’s Interview-Based Impression of Change With Caregiver Input (CIBIC-plus) at Week 24 (LOCF)   [ Time Frame: Week 24 ]

Measure Type Primary
Measure Title Clinician’s Interview-Based Impression of Change With Caregiver Input (CIBIC-plus) at Week 24 (LOCF)
Measure Description The CIBIC-Plus is a measure of an overall clinical effect and is based on a comprehensive evaluation at Baseline and later visits of four domains: general (overall clinical status), functional (including activities of daily living), cognitive, and behavioral. A skilled clinician interviews the patient, and includes information supplied by a knowledgeable caregiver. The CIBIC-Plus is a rating of the patient’s global status relative to Baseline, ranging from a score of 1, indicating “marked improvement” to a score of 4, indicating “no change” to a score of 7, indicating “marked worsening.”
Time Frame Week 24  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Primary efficacy analysis was based on the Intent-to-Treat (ITT) Population. The ITT Population was consisted of all patients in the Safety Population who completed at least one post-Baseline efficacy assessment in SIB or CIBIC-Plus. The last-observation-carried-forward approach was used to impute missing post-Baseline values.

Reporting Groups
  Description
Placebo Matching placebo oral administration once daily for 24 weeks.
Memantine ER 28mg once daily oral administration for 24 weeks.

Measured Values
    Placebo     Memantine ER  
Number of Participants Analyzed  
[units: participants]
  328     333  
Clinician’s Interview-Based Impression of Change With Caregiver Input (CIBIC-plus) at Week 24 (LOCF)  
[units: Units on a scale]
Mean ± Standard Error
  4.1  ± 0.07     3.8  ± 0.07  


Statistical Analysis 1 for Clinician’s Interview-Based Impression of Change With Caregiver Input (CIBIC-plus) at Week 24 (LOCF)
Groups [1] All groups
Method [2] Cochran-Mantel-Haenszel
P Value [3] 0.008
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The co-primary efficacy parameter was CIBIC-Plus total score at week 24. Missing CIBIC-Plus total scores at Week 24 were imputed using the last-observation-carried-forward (LOCF) approach.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.



3.  Secondary:   Change From Baseline in the 19-Item Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL19) Scale at Week 24 (LOCF)   [ Time Frame: Baseline to week 24 ]

Measure Type Secondary
Measure Title Change From Baseline in the 19-Item Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL19) Scale at Week 24 (LOCF)
Measure Description The ADCS-ADL19 modified inventory consists of 19 items used to measure the functional capabilities of patients with moderate to severe dementia. Each activity-of-daily-living (ADL) item comprises a series of hierarchical subquestions ranging from the highest level of independent performance to complete loss of ability to perform the ADL Inventory. The inventory is performed by interviewing a person in close contact with the patient and covers the most usual and consistent performance of the patient over the preceding 4 weeks. Response range is 0 (total disability) to 54 (total independence).
Time Frame Baseline to week 24  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The secondary efficacy analysis was based on the ITT Population. The last-observation-carried-forward approach was used to impute missing post-Baseline values.

Reporting Groups
  Description
Placebo Matching placebo oral administration once daily for 24 weeks.
Memantine ER 28mg once daily oral administration for 24 weeks.

Measured Values
    Placebo     Memantine ER  
Number of Participants Analyzed  
[units: participants]
  328     331  
Change From Baseline in the 19-Item Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL19) Scale at Week 24 (LOCF)  
[units: Units on a scale]
Least Squares Mean ± Standard Error
  -1.7  ± 0.44     -1.0  ± 0.44  


Statistical Analysis 1 for Change From Baseline in the 19-Item Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL19) Scale at Week 24 (LOCF)
Groups [1] All groups
Method [2] ANCOVA
P Value [3] 0.177
Mean Difference (Final Values) [4] 0.7
95% Confidence Interval ( -0.3 to 1.8 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The secondary efficacy parameter was change from Baseline at Week 24 in the total score of the 19-Item Alzheimer’s Disease Cooperative Study—Activities of Daily Living Inventory (ADCS-ADL19). Missing scores at week 24 were imputed using the last-observation-carried-forward (LOCF) approach.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Least-squares mean (-1.7 in placebo and -1.0 in memantine ER) are controlled for center and adjusted for ADCS-ADL19 baseline value.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information