A Phase 4 interventional study of Rivastigmine 4.6 mg/24 h (5 cm^2) and Rivastigmine 9.5 mg/24 h (10 cm^2) in Alzheimer's Disease, sponsored by Novartis. Completed at 95 sites in 2 countries. Open to participants aged 50 Years and older. Per ClinicalTrials.gov, last updated 2013-08-28.
Sponsored by Novartis · Phase 4, Interventional, and Treatment
The core study assessed the efficacy of a higher dose of rivastigmine 13.3 mg/24 h transdermally (15 cm\^2 patch) compared to a lower dose of the rivastigmine 4.6 mg/24 h transdermally (5 cm\^2 patch) in patients with Severe Dementia of the Alzheimer's Type in a 24-week study. The extension study obtained additional safety and efficacy data, as well as provided the higher dose rivastigmine patch to all patients who completed the core study for an additional 24 weeks.
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Core study
Inclusion Criteria:
Exclusion Criteria:
Extension study
Inclusion Criteria:
Exclusion Criteria:
Refer to the core study protocol for full details of the exclusion criteria.
Other protocol-defined inclusion/exclusion criteria applied to the study.
In the core study, patients were titrated to the rivastigmine 13.3 mg/24 h dose in 2 steps. For Weeks 1-4, patients received rivastigmine 4.6 mg/24 h. For Weeks 5-8, patients received rivastigmine 9.5 mg/24 h and placebo. For Weeks 9-24, patients received rivastigmine 13.3 mg/24 h and placebo. In the extension study, all patients were switched to rivastigmine 9.5 mg/24 h for a 4-week titration period and were then titrated up to 13.3 mg/24 h for a further 20 weeks of treatment.
Drug: Rivastigmine 4.6 mg/24 h (5 cm^2) · Drug: Rivastigmine 9.5 mg/24 h (10 cm^2) · Drug: Rivastigmine 13.3 mg/24 h (15 cm^2) · Drug: Placebo
In the core study, patients received rivastigmine 4.6 mg/24 h daily. For Weeks 1-4, patients received rivastigmine 4.6 mg/24 h. For Weeks 5-24, patients received rivastigmine 4.6 mg/24 h and placebo. No patients received this treatment in the extension study.
Drug: Rivastigmine 4.6 mg/24 h (5 cm^2) · Drug: Placebo
Rivastigmine was supplied in a 5 cm\^2 patch which released 4.6 mg/24 h. Patches were changed daily.
Also known as: ENA713D, Exelon, Exelon patch
Rivastigmine was supplied in a 10 cm\^2 patch which released 9.5 mg/24 h. Patches were changed daily.
Also known as: ENA713D, Exelon, Exelon path
Rivastigmine was supplied in a 15 cm\^2 patch which released 13.3 mg/24 h. Patches were changed daily.
Also known as: ENA713D, Exelon, Exelon patch
Placebo patches were identical in size and composition to the corresponding rivastigmine patches, except that they did not contain rivastigmine. Patches were changed daily.
Core Study: Change From Baseline in the Alzheimer's Disease Cooperative Study-Activities of Daily Living-Severe Impairment Version (ADCS-ADL-SIV) Score at Week 24
The ADCS-ADL-SIV is designed to assess the patient's performance of both basic and instrumental activities of daily living such as those necessary for personal care, communicating and interacting with other people, maintaining a household, conducting hobbies and interests, and making judgments and decisions. For each of the 19 questions in the ADCS-ADL-SIV, there was either a forced choice of best response or a "yes" or "no" question with additional sub-questions. Responses for each item were obtained from the caregiver through an interview. Higher numbered scores and answers of "yes" reflected a more self-sufficient individual. The total score was calculated as the sum of all items and sub-questions and ranged from 0 to 54. A higher total score represented a higher functioning patient. A positive change score indicates improvement.
Time frame: Baseline of the core study to Week 24 of the core study
Core Study: Change From Baseline in the Severity Impairment Battery (SIB) Score at Week 24
The SIB is a 40-item scale developed for the evaluation of the severity of cognitive dysfunction in more advanced Alzheimer Disease patients. The domains assessed included social interaction, memory, language, attention, orientation, praxis, visuo-spatial ability, construction, and orienting to name. The items of the SIB were developed as simple 1-step commands which are presented by a trained rater with gestural cues and repeated if necessary. The SIB was scored from 0 to 100, with higher scores reflecting higher levels of cognitive ability. A positive change score indicates improvement.
Time frame: Baseline of the core study to Week 24 of the core study
Core Study: Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) Score at Week 24
The ADCS-CGIC assesses the clinical meaningfulness of a treatment based on the clinician's rating of change. The rating is provided by a trained clinician or psychometrician blinded to the patient's treatment. The rater interviewed the patient and caregiver separately at Baseline using a worksheet that provided space for notes and comments. At baseline, raters had access to all of the patient's available records and evaluations. The rater used a similar worksheet at follow-up visits, and referred to the baseline worksheet prior to making a rating of change. The worksheets were divided into 3 domains: mental/cognitive state, behavior, and functioning. Change ratings were based on a 7-point scale: Marked (1), moderate (2), and minimal improvement (3), no change (4), and marked (5), moderate (6), and minimal worsening (7). The percentage of patients in each of the 7 categories is reported.
Time frame: Baseline of the core study to Week 24 of the core study
Core Study: Change From Baseline in the Neuropsychiatric Inventory (NPI-12) Score at Week 24
The NPI-12 assesses a wide range of behaviors encountered in patients with dementia to provide a means of distinguishing the frequency and severity of behavioral changes over time. Ten behavioral and 2 neurovegetative domains were evaluated in an interview with the caregiver given by a mental health professional. The scale included both frequency and severity ratings of each domain as well as a composite domain score (frequency x severity). The sum of the composite scores for the 12 domains yielded the NPI-12 total score. The NPI-12 was scored from 0 to 144, with lower scores reflecting improvement in psychiatric behavior. A negative change score indicates improvement.
Time frame: Baseline of the core study to Week 24 of the core study
Extension Study: Change From Baseline in the Alzheimer's Disease Cooperative Study-Activities of Daily Living-Severe Impairment Version (ADCS-ADL-SIV) Score at Week 24
The ADCS-ADL-SIV is designed to assess the patient's performance of both basic and instrumental activities of daily living such as those necessary for personal care, communicating and interacting with other people, maintaining a household, conducting hobbies and interests, and making judgments and decisions. For each of the 19 questions in the ADCS-ADL-SIV, there was either a forced choice of best response or a "yes" or "no" question with additional sub-questions. Responses for each item were obtained from the caregiver through an interview. Higher numbered scores and answers of "yes" reflected a more self-sufficient individual. The total score was calculated as the sum of all items and sub-questions and ranged from 0 to 54. A higher total score represented a higher functioning patient. A positive change score indicates improvement.
Time frame: Baseline of the core study to Week 24 of the extension study
Extension Study: Change From Baseline in the Severity Impairment Battery (SIB) Score at Week 24
The SIB is a 40-item scale developed for the evaluation of the severity of cognitive dysfunction in more advanced Alzheimer Disease patients. The domains assessed included social interaction, memory, language, attention, orientation, praxis, visuo-spatial ability, construction, and orienting to name. The items of the SIB were developed as simple 1-step commands which are presented by a trained rater with gestural cues and repeated if necessary. The SIB was scored from 0 to 100, with higher scores reflecting higher levels of cognitive ability. A positive change score indicates improvement.
Time frame: Baseline of the core study to Week 24 of the extension study
Extension Study: Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) Score at Week 24
The ADCS-CGIC assesses the clinical meaningfulness of a treatment based on the clinician's rating of change. The rating is provided by a trained clinician or psychometrician blinded to the patient's treatment. The rater interviewed the patient and caregiver separately at Baseline using a worksheet that provided space for notes and comments. At baseline, raters had access to all of the patient's available records and evaluations. The rater used a similar worksheet at follow-up visits, and referred to the baseline worksheet prior to making a rating of change. The worksheets were divided into 3 domains: mental/cognitive state, behavior, and functioning. Change ratings were based on a 7-point scale: Marked (1), moderate (2), and minimal improvement (3), no change (4), and marked (5), moderate (6), and minimal worsening (7). The percentage of patients in each of the 7 categories is reported.
Time frame: Baseline of the core study to Week 24 of the extension study
| Milestone | Rivastigmine 13.3 mg/24 h Transdermal Patch | Rivastigmine 4.6 mg/24 h Transdermal Patch |
|---|---|---|
| Started | 356 | 360 |
| Exposed to study medication | 355 | 359 |
| Completed | 229 | 234 |
| Not completed | 127 | 126 |
| Withdrew: Adverse event | 73 | 51 |
| Withdrew: Unsatisfactory therapeutic effect | 13 | 14 |
| Withdrew: Patient withdrew consent | 27 | 46 |
| Withdrew: Lost to follow-up | 3 | 2 |
| Withdrew: Administrative problems | 2 | 2 |
| Withdrew: Death | 1 | 1 |
| Withdrew: Protocol deviation | 8 | 10 |
| Milestone | Rivastigmine 13.3 mg/24 h Transdermal Patch | Rivastigmine 4.6 mg/24 h Transdermal Patch |
|---|---|---|
| Started | 397 | 0 |
| Exposed to study medication | 396 | 0 |
| Completed | 306 | 0 |
| Not completed | 91 | 0 |
| Withdrew: Adverse event | 43 | 0 |
| Withdrew: Unsatisfactory therapeutic effect | 2 | 0 |
| Withdrew: Study drug no longer required | 1 | 0 |
| Withdrew: Patient withdrew consent | 32 | 0 |
| Withdrew: Lost to follow-up | 8 | 0 |
| Withdrew: Administrative problems | 1 | 0 |
| Withdrew: Death | 4 | 0 |
The ADCS-ADL-SIV is designed to assess the patient's performance of both basic and instrumental activities of daily living such as those necessary for personal care, communicating and interacting with other people, maintaining a household, conducting hobbies and interests, and making judgments and decisions. For each of the 19 questions in the ADCS-ADL-SIV, there was either a forced choice of best response or a "yes" or "no" question with additional sub-questions. Responses for each item were obtained from the caregiver through an interview. Higher numbered scores and answers of "yes" reflected a more self-sufficient individual. The total score was calculated as the sum of all items and sub-questions and ranged from 0 to 54. A higher total score represented a higher functioning patient. A positive change score indicates improvement.
| Units on a scale | Rivastigmine 13.3 mg/24 h Transdermal Patch | Rivastigmine 4.6 mg/24 h Transdermal Patch |
|---|---|---|
| Core Study: Change From Baseline in the Alzheimer's Disease Cooperative Study-Activities of Daily Living-Severe Impairment Version (ADCS-ADL-SIV) Score at Week 24 | -2.6 ± 6.82 | -3.6 ± 7.68 |
The SIB is a 40-item scale developed for the evaluation of the severity of cognitive dysfunction in more advanced Alzheimer Disease patients. The domains assessed included social interaction, memory, language, attention, orientation, praxis, visuo-spatial ability, construction, and orienting to name. The items of the SIB were developed as simple 1-step commands which are presented by a trained rater with gestural cues and repeated if necessary. The SIB was scored from 0 to 100, with higher scores reflecting higher levels of cognitive ability. A positive change score indicates improvement.
| Units on a scale | Rivastigmine 13.3 mg/24 h Transdermal Patch | Rivastigmine 4.6 mg/24 h Transdermal Patch |
|---|---|---|
| Core Study: Change From Baseline in the Severity Impairment Battery (SIB) Score at Week 24 | -1.6 ± 13.54 | -6.4 ± 14.01 |
The ADCS-CGIC assesses the clinical meaningfulness of a treatment based on the clinician's rating of change. The rating is provided by a trained clinician or psychometrician blinded to the patient's treatment. The rater interviewed the patient and caregiver separately at Baseline using a worksheet that provided space for notes and comments. At baseline, raters had access to all of the patient's available records and evaluations. The rater used a similar worksheet at follow-up visits, and referred to the baseline worksheet prior to making a rating of change. The worksheets were divided into 3 domains: mental/cognitive state, behavior, and functioning. Change ratings were based on a 7-point scale: Marked (1), moderate (2), and minimal improvement (3), no change (4), and marked (5), moderate (6), and minimal worsening (7). The percentage of patients in each of the 7 categories is reported.
| Percentage of patients | Rivastigmine 13.3 mg/24 h Transdermal Patch | Rivastigmine 4.6 mg/24 h Transdermal Patch |
|---|---|---|
| Marked improvement | 1.0 | 1.3 |
| Moderate improvement | 3.5 | 3.5 |
| Minimal improvement | 20.1 | 11.4 |
| No change | 34.2 | 29.2 |
| Minimal worsening | 24.3 | 31.4 |
| Moderate worsening | 14.1 | 19.0 |
| Marked worsening | 2.9 | 4.1 |
The NPI-12 assesses a wide range of behaviors encountered in patients with dementia to provide a means of distinguishing the frequency and severity of behavioral changes over time. Ten behavioral and 2 neurovegetative domains were evaluated in an interview with the caregiver given by a mental health professional. The scale included both frequency and severity ratings of each domain as well as a composite domain score (frequency x severity). The sum of the composite scores for the 12 domains yielded the NPI-12 total score. The NPI-12 was scored from 0 to 144, with lower scores reflecting improvement in psychiatric behavior. A negative change score indicates improvement.
| Units on a scale | Rivastigmine 13.3 mg/24 h Transdermal Patch | Rivastigmine 4.6 mg/24 h Transdermal Patch |
|---|---|---|
| Core Study: Change From Baseline in the Neuropsychiatric Inventory (NPI-12) Score at Week 24 | -0.4 ± 14.01 | 1.2 ± 16.79 |
The ADCS-ADL-SIV is designed to assess the patient's performance of both basic and instrumental activities of daily living such as those necessary for personal care, communicating and interacting with other people, maintaining a household, conducting hobbies and interests, and making judgments and decisions. For each of the 19 questions in the ADCS-ADL-SIV, there was either a forced choice of best response or a "yes" or "no" question with additional sub-questions. Responses for each item were obtained from the caregiver through an interview. Higher numbered scores and answers of "yes" reflected a more self-sufficient individual. The total score was calculated as the sum of all items and sub-questions and ranged from 0 to 54. A higher total score represented a higher functioning patient. A positive change score indicates improvement.
| Units on a scale | Rivastigmine 13.3 mg/24 h Transdermal Patch |
|---|---|
| Extension Study: Change From Baseline in the Alzheimer's Disease Cooperative Study-Activities of Daily Living-Severe Impairment Version (ADCS-ADL-SIV) Score at Week 24 | -4.3 ± 8.37 |
The SIB is a 40-item scale developed for the evaluation of the severity of cognitive dysfunction in more advanced Alzheimer Disease patients. The domains assessed included social interaction, memory, language, attention, orientation, praxis, visuo-spatial ability, construction, and orienting to name. The items of the SIB were developed as simple 1-step commands which are presented by a trained rater with gestural cues and repeated if necessary. The SIB was scored from 0 to 100, with higher scores reflecting higher levels of cognitive ability. A positive change score indicates improvement.
| Units on a scale | Rivastigmine 13.3 mg/24 h Transdermal Patch |
|---|---|
| Extension Study: Change From Baseline in the Severity Impairment Battery (SIB) Score at Week 24 | -5.9 ± 16.72 |
The ADCS-CGIC assesses the clinical meaningfulness of a treatment based on the clinician's rating of change. The rating is provided by a trained clinician or psychometrician blinded to the patient's treatment. The rater interviewed the patient and caregiver separately at Baseline using a worksheet that provided space for notes and comments. At baseline, raters had access to all of the patient's available records and evaluations. The rater used a similar worksheet at follow-up visits, and referred to the baseline worksheet prior to making a rating of change. The worksheets were divided into 3 domains: mental/cognitive state, behavior, and functioning. Change ratings were based on a 7-point scale: Marked (1), moderate (2), and minimal improvement (3), no change (4), and marked (5), moderate (6), and minimal worsening (7). The percentage of patients in each of the 7 categories is reported.
| Percentage of patients | Rivastigmine 13.3 mg/24 h Transdermal Patch |
|---|---|
| Marked improvement | 1.8 |
| Moderate improvement | 5.0 |
| Minimal improvement | 9.7 |
| No change | 26.2 |
| Minimal worsening | 31.5 |
| Moderate worsening | 21.5 |
| Marked worsening | 4.2 |
Collected over Adverse events were reported from randomization in the core study through the end of the extension study (48 weeks).. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Core Study: Rivastigmine 13.3 mg/24 h Transdermal Patch | — | 82/355 (23.1%) | 216/355 (60.8%) |
| Core Study: Rivastigmine 4.6 mg/24 h Transdermal Patch | — | 74/359 (20.6%) | 210/359 (58.5%) |
| Extension Study: Rivastigmine 13.3 mg/24 h Transdermal Patch | — | 79/396 (19.9%) | 248/396 (62.6%) |
| Event | Core Study: Rivastigmine 13.3 mg/24 h Transdermal Patch | Core Study: Rivastigmine 4.6 mg/24 h Transdermal Patch | Extension Study: Rivastigmine 13.3 mg/24 h Transdermal Patch |
|---|---|---|---|
| Urinary tract infectionInfections and infestations | 5/355 | 7/359 | 8/396 |
| FallInjury, poisoning and procedural complications | 7/355 | 7/359 | 5/396 |
| SyncopeNervous system disorders | 7/355 | 6/359 | 7/396 |
| DehydrationMetabolism and nutrition disorders | 6/355 | 4/359 | 6/396 |
| AgitationPsychiatric disorders | 2/355 | 6/359 | 1/396 |
| Mental status changesPsychiatric disorders | 3/355 | 6/359 | 5/396 |
| PneumoniaInfections and infestations | 4/355 | 5/359 | 5/396 |
| Chest painGeneral disorders | 2/355 | 4/359 | 5/396 |
| VomitingGastrointestinal disorders | 4/355 | 1/359 | 2/396 |
| Hip fractureInjury, poisoning and procedural complications | 4/355 | 1/359 | 2/396 |
| Event | Core Study: Rivastigmine 13.3 mg/24 h Transdermal Patch | Core Study: Rivastigmine 4.6 mg/24 h Transdermal Patch | Extension Study: Rivastigmine 13.3 mg/24 h Transdermal Patch |
|---|---|---|---|
| AgitationPsychiatric disorders | 47/355 | 55/359 | 58/396 |
| Urinary tract infectionInfections and infestations | 42/355 | 43/359 | 58/396 |
| Application site erythemaGeneral disorders | 48/355 | 44/359 | 52/396 |
| Weight decreasedInvestigations | 37/355 | 26/359 | 47/396 |
| Application site dermatitisGeneral disorders | 30/355 | 36/359 | 43/396 |
| FallInjury, poisoning and procedural complications | 30/355 | 26/359 | 42/396 |
| DiarrhoeaGastrointestinal disorders | 25/355 | 27/359 | 36/396 |
| VomitingGastrointestinal disorders | 27/355 | 24/359 | 30/396 |
| InsomniaPsychiatric disorders | 27/355 | 24/359 | 30/396 |
| NauseaGastrointestinal disorders | 23/355 | 17/359 | 19/396 |
| Age Continuous(years) | Core Study: Rivastigmine 13.3 mg/24 h Transdermal Patch | Core Study: Rivastigmine 4.6 mg/24 h Transdermal Patch | Total |
|---|---|---|---|
| Mean | 77.6 ± 8.69 | 76.5 ± 9.35 | 77.0 ± 9.04 |
| Sex: Female, Male(Participants) | Core Study: Rivastigmine 13.3 mg/24 h Transdermal Patch | Core Study: Rivastigmine 4.6 mg/24 h Transdermal Patch | Total |
|---|---|---|---|
| Female | 227 | 234 | 461 |
| Male | 129 | 126 | 255 |
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