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Comparative Efficacy, Safety, and Tolerability of Rivastigmine 10 and 15 cm^2 Patch in Patients With Alzheimer's Disease (AD) Showing Cognitive Decline

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ClinicalTrials.gov Identifier: NCT00506415
Recruitment Status : Completed
First Posted : July 25, 2007
Results First Posted : September 19, 2012
Last Update Posted : September 19, 2012
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition: Alzheimer Disease
Interventions: Drug: Rivastigmine 5 cm^2
Drug: Rivastigmine 10 cm^2
Drug: Rivastigmine 15 cm^2
Drug: Placebo to 15 cm^2 patch
Drug: Placebo to 10 cm^2 patch

  Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
1,584 participants were enrolled, 1582 received study drug during the initial open label period; of these, 567 were qualified to enter a double blind randomized period.

Reporting Groups
  Description
Initial Open Label: Rivastigmine (5 cm^2 / 10 cm^2) Rivastigmine 5 cm^2 transdermal patch once a day during the first 4 weeks of open label treatment followed by rivastigmine 10 cm^2 transdermal patch once a day from week 4 to week 24, 36 or 48.
Double Blind: Rivastigmine (10 cm^2) Rivastigmine transdermal patch 10 cm^2 and placebo to rivastigmine 15 cm^2 once daily for 48 weeks during the double blind period.
Double Blind: Rivastigmine (15 cm^2) Rivastigmine transdermal patch 15 cm^2 and placebo to rivastigmine 10 cm^2 once daily for 48 weeks during double blind period.
Extended Open Label (10 cm^2) Rivastigmine 10 cm^2 transdermal patch once a day during 48 weeks (from week 48 to week 96) open label treatment.

Participant Flow for 3 periods

Period 1:   Initial Open Label (Maximum 48 Weeks)
    Initial Open Label: Rivastigmine (5 cm^2 / 10 cm^2)   Double Blind: Rivastigmine (10 cm^2)   Double Blind: Rivastigmine (15 cm^2)   Extended Open Label (10 cm^2)
STARTED   1584 [1]   0   0   0 
Exposed to Study Drug   1582   0   0   0 
COMPLETED   1085   0   0   0 
NOT COMPLETED   499   0   0   0 
Adverse Event                272                0                0                0 
Abnormal laboratory value                1                0                0                0 
Abnormal test procedure results                1                0                0                0 
Unsatisfactory therapeutic effect                58                0                0                0 
Withdrawal by Subject                88                0                0                0 
Lost to Follow-up                22                0                0                0 
Administrative problem                7                0                0                0 
Death                22                0                0                0 
Protocol Violation                28                0                0                0 
[1] Enrolled patients.

Period 2:   Double Blind (Maximum 48 Weeks )
    Initial Open Label: Rivastigmine (5 cm^2 / 10 cm^2)   Double Blind: Rivastigmine (10 cm^2)   Double Blind: Rivastigmine (15 cm^2)   Extended Open Label (10 cm^2)
STARTED   0   286 [1]   280   0 
COMPLETED   0   203   207   0 
NOT COMPLETED   0   83   73   0 
Adverse Event                0                33                28                0 
Death                0                5                3                0 
Unsatisfactory therapeutic effect                0                13                13                0 
Protocol Violation                0                5                3                0 
Lost to Follow-up                0                4                6                0 
Withdrawal by Subject                0                20                17                0 
Administrative problems                0                3                2                0 
Condition no longer requires study drug                0                0                1                0 
[1] 1 patient was randomized in error and did not receive study drug, hence excluded from this arm.

Period 3:   Extended Open Label (Maximum 48 Weeks)
    Initial Open Label: Rivastigmine (5 cm^2 / 10 cm^2)   Double Blind: Rivastigmine (10 cm^2)   Double Blind: Rivastigmine (15 cm^2)   Extended Open Label (10 cm^2)
STARTED   0   0   0   457 [1] 
COMPLETED   0   0   0   395 
NOT COMPLETED   0   0   0   62 
Administrative problems                0                0                0                4 
Adverse Event                0                0                0                18 
Lost to Follow-up                0                0                0                8 
Withdrawal by Subject                0                0                0                14 
Protocol Violation                0                0                0                5 
Unsatisfactory therapeutic effect                0                0                0                6 
Death                0                0                0                7 
[1] Two participants did not receive study drug, hence excluded from this arm.



  Baseline Characteristics

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
Total Patients Total number of patients enrolled in the initial open label period that may have been randomized in the double blind period or may have continued in the extended open label period.

Baseline Measures
   Total Patients 
Overall Participants Analyzed 
[Units: Participants]
 1584 
Age 
[Units: Years]
Mean (Standard Deviation)
 74.93  (7.131) 
Gender 
[Units: Participants]
 
Female   992 
Male   592 


  Outcome Measures

1.  Primary:   Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) Subscale at Week 48 of Double Blind Period   [ Time Frame: Baseline and week 48 of double blind period ]

Measure Type Primary
Measure Title Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) Subscale at Week 48 of Double Blind Period
Measure Description The Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog) subscale comprises 11 items summed to a total score ranging from 0 to 70, with lower scores indicating less severe impairment. A negative change indicates an improvement from baseline.
Time Frame Baseline and week 48 of double blind period  

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.
Intent to treat population double blind (ITT-DB): included all randomized patients who received at least 1 dose of double blind study drug, and had at least 1 post-randomization assessment for both co-primary efficacy variables: Alzheimer's Disease Assessment Scale-Cognitive and Disease Cooperative Study-Instrumental Activities of Daily Living.

Reporting Groups
  Description
Double Blind: Rivastigmine (10 cm^2) Rivastigmine transdermal patch 10 cm^2 and placebo to rivastigmine 15 cm^2 once daily for 48 weeks during the double blind period.
Double Blind: Rivastigmine (15 cm^2) Rivastigmine transdermal patch 15 cm^2 and placebo to rivastigmine 10 cm^2 once daily for 48 weeks during double blind period.

Measured Values
   Double Blind: Rivastigmine (10 cm^2)   Double Blind: Rivastigmine (15 cm^2) 
Participants Analyzed   268   264 
Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) Subscale at Week 48 of Double Blind Period 
[Units: Units on a scale]
Mean (Standard Deviation)
 4.9  (7.49)   4.1  (8.00) 

No statistical analysis provided for Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) Subscale at Week 48 of Double Blind Period



2.  Primary:   Change in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) Subscale Score From Baseline to Week 48 of Double Blind Period   [ Time Frame: Baseline and week 48 of double blind period ]

Measure Type Primary
Measure Title Change in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) Subscale Score From Baseline to Week 48 of Double Blind Period
Measure Description The Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) is a 16 item subscale of the caregiver-based ADCS-IADL scale, developed for the use in dementia studies. The ADCS-IADL total score ranges from 0 to 56, with higher scores indicating less severe impairment. A positive change indicates an improvement from baseline.
Time Frame Baseline and week 48 of double blind period  

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.
Intent to treat population double blind (ITT-DB): included all randomized patients who received at least 1 dose of double blind study drug, and had at least 1 post-randomization assessment for both co-primary efficacy variables: Alzheimer's Disease Assessment Scale-Cognitive and Disease Cooperative Study-Instrumental Activities of Daily Living.

Reporting Groups
  Description
Double Blind: Rivastigmine (10 cm^2) Rivastigmine transdermal patch 10 cm^2 and placebo to rivastigmine 15 cm^2 once daily for 48 weeks during the double blind period.
Double Blind: Rivastigmine (15 cm^2) Rivastigmine transdermal patch 15 cm^2 and placebo to rivastigmine 10 cm^2 once daily for 48 weeks during double blind period.

Measured Values
   Double Blind: Rivastigmine (10 cm^2)   Double Blind: Rivastigmine (15 cm^2) 
Participants Analyzed   271   265 
Change in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) Subscale Score From Baseline to Week 48 of Double Blind Period 
[Units: Units on a scale]
Mean (Standard Deviation)
 -6.2  (8.78)   -4.4  (8.21) 

No statistical analysis provided for Change in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) Subscale Score From Baseline to Week 48 of Double Blind Period



3.  Secondary:   Time to Functional Decline as Measured by Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) Subscale During the Double Blind Period   [ Time Frame: 390 days was the maximum ]

Measure Type Secondary
Measure Title Time to Functional Decline as Measured by Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) Subscale During the Double Blind Period
Measure Description Functional decline was defined by either an at least 1 point decrease in the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) subscale score in a visit and confirmed by the following visit/assessment or at least 2 points decrease from the double blind randomization baseline.
Time Frame 390 days was the maximum  

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.
Intent to treat population double blind (ITT-DB): included all randomized patients who received at least 1 dose of double blind study drug, and had at least 1 post-randomization assessment for both co-primary efficacy variables: Alzheimer's Disease Assessment Scale-Cognitive and Disease Cooperative Study-Instrumental Activities of Daily Living.

Reporting Groups
  Description
Double Blind: Rivastigmine (10 cm^2) Rivastigmine transdermal patch 10 cm^2 and placebo to rivastigmine 15 cm^2 once daily for 48 weeks during the double blind period.
Double Blind: Rivastigmine (15 cm^2) Rivastigmine transdermal patch 15 cm^2 and placebo to rivastigmine 10 cm^2 once daily for 48 weeks during double blind period.

Measured Values
   Double Blind: Rivastigmine (10 cm^2)   Double Blind: Rivastigmine (15 cm^2) 
Participants Analyzed   271   265 
Time to Functional Decline as Measured by Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) Subscale During the Double Blind Period 
[Units: Time in days]
Median (95% Confidence Interval)
 90 
 (85 to 113) 
 91 
 (85 to 113) 

No statistical analysis provided for Time to Functional Decline as Measured by Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) Subscale During the Double Blind Period



4.  Secondary:   Change in Attention and Executive Function as Assessed by the Trail Making Test (Part A) at Week 48 of the Double Blind Period   [ Time Frame: Baseline and week 48 of double blind period ]

Measure Type Secondary
Measure Title Change in Attention and Executive Function as Assessed by the Trail Making Test (Part A) at Week 48 of the Double Blind Period
Measure Description Change from baseline to week 48 in total time to perform Trail Making Test (TMT) part A. This test provides information on visual search, scanning, speed of processing, mental flexibility, and executive functions. The TMT part A requires an individual to draw lines sequentially connecting 25 encircled numbers distributed on a sheet of paper. The score represents the amount of time required to complete the task. Total values for TMT part A range between 0 and 300 seconds. A negative change indicates an improvement from baseline.
Time Frame Baseline and week 48 of double blind period  

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.
Intent to treat population (ITT-DB): included all randomized patients with an assessment at baseline and week 48 who received at least 1 dose of double blind study drug, and had at least 1 post-randomization assessment for both co-primary efficacy variables (ADAS-cog and ADCS-IADL).

Reporting Groups
  Description
Double Blind: Rivastigmine (10 cm^2) Rivastigmine transdermal patch 10 cm^2 and placebo to rivastigmine 15 cm^2 once daily for 48 weeks during the double blind period.
Double Blind: Rivastigmine (15 cm^2) Rivastigmine transdermal patch 15 cm^2 and placebo to rivastigmine 10 cm^2 once daily for 48 weeks during double blind period.

Measured Values
   Double Blind: Rivastigmine (10 cm^2)   Double Blind: Rivastigmine (15 cm^2) 
Participants Analyzed   258   254 
Change in Attention and Executive Function as Assessed by the Trail Making Test (Part A) at Week 48 of the Double Blind Period 
[Units: Time in seconds]
Mean (Standard Deviation)
 18.2  (62.57)   16.3  (66.09) 

No statistical analysis provided for Change in Attention and Executive Function as Assessed by the Trail Making Test (Part A) at Week 48 of the Double Blind Period



5.  Secondary:   Change in Attention and Executive Function as Assessed by the Trail Making Test (Part B) at Week 48 of Double Blind Period   [ Time Frame: Baseline and week 48 of double blind period ]

Measure Type Secondary
Measure Title Change in Attention and Executive Function as Assessed by the Trail Making Test (Part B) at Week 48 of Double Blind Period
Measure Description Change from baseline to week 48 in total time to perform Trail Making Test (TMT) part B. This test provides information on visual search, scanning, speed of processing, mental flexibility, and executive functions. TMT has two parts: Part A requires an individual to draw lines sequentially connecting 25 encircled numbers distributed on a sheet of paper. Task requirements are similar for TMT-Part B except the person must alternate between numbers and letters. Total values for TMT part B range between 0 and 420 seconds. A negative change from baseline indicates an improvement in condition.
Time Frame Baseline and week 48 of double blind period  

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.
Intent to treat population (ITT-DB): included all randomized patients with an assessment at baseline and week 48 who received at least 1 dose of double blind study drug, and had at least 1 post-randomization assessment for both co-primary efficacy variables (ADAS-cog, ADCS-IADL).

Reporting Groups
  Description
Double Blind: Rivastigmine (15 cm^2) Rivastigmine transdermal patch 15 cm^2 and placebo to rivastigmine 10 cm^2 once daily for 48 weeks during the double blind period.
Double Blind: Rivastigmine (10 cm^2) Rivastigmine transdermal patch 10 cm^2 and placebo to rivastigmine 15 cm^2 once daily for 48 weeks during the double blind period.

Measured Values
   Double Blind: Rivastigmine (15 cm^2)   Double Blind: Rivastigmine (10 cm^2) 
Participants Analyzed   235   236 
Change in Attention and Executive Function as Assessed by the Trail Making Test (Part B) at Week 48 of Double Blind Period 
[Units: Time in seconds]
Mean (Standard Deviation)
 9.3  (68.80)   5.8  (65.38) 

No statistical analysis provided for Change in Attention and Executive Function as Assessed by the Trail Making Test (Part B) at Week 48 of Double Blind Period



6.  Secondary:   Change From Baseline in Neuropsychiatric Inventory (NPI)-10 Score at Week 48 of Double Blind Period   [ Time Frame: Baseline and week 48 of double blind period ]

Measure Type Secondary
Measure Title Change From Baseline in Neuropsychiatric Inventory (NPI)-10 Score at Week 48 of Double Blind Period
Measure Description Change from baseline to week 48 as assessed by the Neuropsychiatric Inventory (NPI)-10 total score. The scale consists of 10 domains that are rated for both frequency (range 1-4) and severity (range 1-3). A composite score for each domain is calculated (frequency x severity) which ranges from 1 to 12. There is a leading question for each item. If the symptom is not present then the frequency, severity and distress scores are not completed. In this case the score is 0 for the item. The sum of the composite scores yields the NPI-10 total score (range 0-120). A negative change in score indicates an improvement from baseline (symptom reduction).
Time Frame Baseline and week 48 of double blind period  

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.
Intent to treat population double blind (ITT-DB): included all randomized patients with an assessment at baseline and week 48, who received at least 1 dose of double blind study drug, and had at least 1 post-randomization assessment for both co-primary efficacy variables (ADAS-cog, ADCS-IADL).

Reporting Groups
  Description
Double Blind: Rivastigmine (10 cm^2) Rivastigmine transdermal patch 10 cm^2 and placebo to rivastigmine 15 cm^2 once daily for 48 weeks during the double blind period.
Double Blind: Rivastigmine (15 cm^2) Rivastigmine transdermal patch 15 cm^2 and placebo to rivastigmine 10 cm^2 once daily for 48 weeks during double blind period.

Measured Values
   Double Blind: Rivastigmine (10 cm^2)   Double Blind: Rivastigmine (15 cm^2) 
Participants Analyzed   271   265 
Change From Baseline in Neuropsychiatric Inventory (NPI)-10 Score at Week 48 of Double Blind Period 
[Units: Units on a scale]
Mean (Standard Deviation)
 0.9  (10.98)   1.4  (11.51) 

No statistical analysis provided for Change From Baseline in Neuropsychiatric Inventory (NPI)-10 Score at Week 48 of Double Blind Period



7.  Secondary:   Number of Patients With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events   [ Time Frame: 30 days after a maximum of 96 weeks treatment ]

Measure Type Secondary
Measure Title Number of Patients With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events
Measure Description No text entered.
Time Frame 30 days after a maximum of 96 weeks treatment  

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 safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.

Reporting Groups
  Description
Initial Open Label: Rivastigmine (5 cm^2 / 10 cm^2) Rivastigmine 5 cm^2 transdermal patch once a day during the first 4 weeks of open label treatment followed by rivastigmine 10 cm^2 transdermal patch once a day from week 4 to week 24, 36 or 48.
Double Blind: Rivastigmine (10 cm^2) Rivastigmine transdermal patch 10 cm^2 and placebo to rivastigmine 15 cm^2 once daily for 48 weeks during the double blind period.
Double Blind: Rivastigmine (15 cm^2) Rivastigmine transdermal patch 15c m^2 and placebo to rivastigmine 10 cm^2 once daily for 48 weeks during double blind period.
Extended Open Label (10 cm^2) Rivastigmine 10 cm^2 transdermal patch once a day during 48 weeks open label treatment running in parallel to the double blind period.

Measured Values
   Initial Open Label: Rivastigmine (5 cm^2 / 10 cm^2)   Double Blind: Rivastigmine (10 cm^2)   Double Blind: Rivastigmine (15 cm^2)   Extended Open Label (10 cm^2) 
Participants Analyzed   1582   283   280   457 
Number of Patients With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events 
[Units: Participants]
 1135   193   210   263 

No statistical analysis provided for Number of Patients With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats

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
No text entered.


  More Information

Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Study Director
Organization: Novartis
phone: 862 778 8300


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00506415     History of Changes
Other Study ID Numbers: CENA713D2340
First Submitted: July 20, 2007
First Posted: July 25, 2007
Results First Submitted: May 1, 2012
Results First Posted: September 19, 2012
Last Update Posted: September 19, 2012