Tolerability of Rivastigmine Before and After Switching From Oral Formulation to Transdermal Patch in Alzheimer's Dementia
Study Details
Study Description
Brief Summary
This phase IIIb study is intended to implement a consistent treatment way for switching to Exelon transdermal patch from oral formulation of rivastigmine to stress the importance of (1) advantages of transdermal patch over conventional oral therapies: smooth drug delivery with reduced side effects;(2) encourage treatment compliance in the Alzheimer's dementia setting.
This study is a single-arm, treatment-switched design. Eligible patients, who are under Exelon capsule 3 mg b.i.d. treatment for 4 weeks before Visit 2, will be recruited, followed by treatment switch from oral capsule to patch for 48 weeks maintenance treatment. During the maintenance period, the treatment will be initiated with Exelon Patch 4.6 mg/24 hours (Exelon Patch 5 cm2) for the first 24 weeks and the dose will be escalated to Exelon Patch 9.5 mg/24 hours (Exelon Patch 10 cm2) for another 24 weeks if well tolerated. Visits to assess safety are scheduled at baseline, 3 days, 1 week and 2 weeks after the first treatment switch, every 4 weeks until Week 40, and at the end of study (Week 52). The assessment to address the primary objective will focus on the safety of treatment switching (Week 0~28); however the safety assessment will be performed during the whole study period.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 4 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Rivastigmine Eligible patients, who are under rivastigmine capsule 3 mg b.i.d. treatment for 4 weeks before Visit 2, will be recruited, followed by treatment switch from oral capsule to transdermal patch for 48 weeks maintenance treatment. |
Drug: ENA713
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Number of Patients With Adverse Events, Serious Adverse Events, and Death [Baseline through week 28]
The overall rate of adverse events reported from initiation through the first 28-week treatment period
Secondary Outcome Measures
- Change From Baseline in Mini-Mental Status Examination (MMSE) [Baselin, week 16, 28 and 52]
The changes in Mini-Mental Status Examination (MMSE) of patients with Alzheimer's disease treated with Exelon 5 cm^2 Patch at Week 28 and Exelon 10 cm2 Patch at Week 52 versus baseline, the treatment-switching day at Week 4. MMSE is a multi-item instrument that examines orientation, registration, attention, calculation, recall, visuospatial ability and language. The total score can range from 0 to 30, with a higher score indicating better function. A positive change score indicates improvement from baseline. The assessments will be conducted at Visit 1, 2, 8, 11 and 17 (screening, Week 4 (baseline), 16, 28 and 52).
- Change From Baseline in Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) [Baseline, week 16, 28 and 52]
The changes in Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) of patients with Alzheimer's disease treated with Exelon 5 cm^2 Patch at Week 28 and Exelon 10 cm^2 Patch at Week 52 versus baseline, the treatment-switching day at Week 4. ADAS-Cog has been used as the major cognitive measure of anti-dementia drugs. The total score range is 0 to 70 points, with higher scores indicating greater cognitive impairment. The assessments will be conducted at Visit, 2, 8, 11 and 17 (Week 4 (baseline), 16, 28 and 52).
- The Discontinuation Rate Due to the Treatment Switching From Oral Capsule to Rivastigmine Patch Treatment [Baseline through week 52]
The discontinuation rate due to the treatment switching from oral capsule to patch treatment. For patients who discontinue earlier due to intolerance of patch treatment, the proportion will be analyzed. Both the discontinuation rate of 5 cm2 and 10 cm^2 patch therapy will be presented.
- Percentage of Patients Successfully Titrated to Rivastigmine Patch 10 cm^2 [Baseline through week 52]
The percentage of patients successfully titrated to rivastigmine patch 10 cm2
Eligibility Criteria
Criteria
Inclusion Criteria:
-
With diagnosis of mild to moderate Alzheimer's disease.
-
Mini-Mental Status Examination score of 10-26 within 3 months before starting oral rivastigmine treatment.
-
A clinical diagnosis of probable AD according to NINCDS/ADRDA criteria. The brain scan (magnetic resonance imaging (MRI) or computed tomography (CT) used for establishing that these criteria are met must have been available on the source document within one year prior to study participation.
-
Patients who are currently taking or planned to receive Exelon 3 mg capsule twice-daily treatment.
-
Written informed consent must be obtained before any assessment is performed.
-
If female, must be surgically sterile or at least one year post-menopausal.
-
Sufficient education to read, write, and communicate effectively.
-
Capable of complying with the requirements of the study
Exclusion Criteria:
-
Any advanced, severe or unstable disease that could interfere with study evaluation or completion or put patient at special risk.
-
Any medical or neurological condition other than AD that could explain the patient's dementia (e.g., abnormal thyroid function tests, Vitamin B12 or folate deficiency, posttraumatic conditions, Huntington's disease, Parkinson's disease, syphilis).
-
Active uncontrolled peptic ulceration, or gastrointestinal bleeding, within the previous 3 months prior to visit 1.
-
A current diagnosis of active, uncontrolled seizure disorder.
-
A history within the past year or current diagnosis of cerebrovascular disease (e.g., stroke, transient ischemic attacks, aneurysms).
-
Bradycardia (< 50 beats per minute), sick sinus syndrome, conduction deficits (S-A block, second or third degree A-V block)
-
Severe or unstable cardiovascular disease.
-
Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer.
-
History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes, or other components of the formulation.
-
Current diagnosis of a systemic active skin disorder or lesion that would prevent accurate assessment of the adhesion and skin irritation potential of the patch.
-
Previous lack of efficacy with cholinesterase inhibitors.
-
History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases. Patients with history of malignancy yet have been treated and defined as complete remission for more than 5 years are not excluded from study participation.
-
Pregnant or nursing (lactating) women.
-
Concurrently treated with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol 2 weeks before the start of study drug and during the treatment period.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Novartis Investigative Site | Taichung | Taiwan ROC | Taiwan | |
| 2 | Novartis Investigative Site | Taipei | Taiwan, ROC | Taiwan | 112 |
| 3 | Novartis Investigative Site | Taichung | Taiwan | 40447 | |
| 4 | Novartis Investigative Site | Taipei | Taiwan | 10002 |
Sponsors and Collaborators
- Novartis Pharmaceuticals
Investigators
- Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CENA713DTW04
Study Results
Participant Flow
| Recruitment Details | Patients receiving Exelon patch 5 cm^2 were more than those receiving Exelon capsule for 4 weeks as least, because some patients had interrupted Exelon capsule for few days in the middle of 4-week Exelon capsule treatment, but still switched to Exelon patch 5 cm2 |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Rivastigmine |
|---|---|
| Arm/Group Description | Eligible patients, who are under rivastigmine capsule 3 mg b.i.d. treatment for 4 weeks before Visit 2, will be recruited, followed by treatment switch from oral capsule to transdermal patch for 48 weeks maintenance treatment. |
| Period Title: Overall Study | |
| STARTED | 121 |
| Safety Set | 102 |
| Exelon Patch 5 cm2 | 114 |
| Exelon Patch 10 cm2 | 96 |
| COMPLETED | 82 |
| NOT COMPLETED | 39 |
Baseline Characteristics
| Arm/Group Title | Rivastigmine |
|---|---|
| Arm/Group Description | Eligible patients, who are under rivastigmine capsule 3 mg b.i.d. treatment for 4 weeks before Visit 2, will be recruited, followed by treatment switch from oral capsule to transdermal patch for 48 weeks maintenance treatment. |
| Overall Participants | 102 |
| Age (Years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [Years] |
74.8
(7.93)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
52
51%
|
| Male |
50
49%
|
Outcome Measures
| Title | Number of Patients With Adverse Events, Serious Adverse Events, and Death |
|---|---|
| Description | The overall rate of adverse events reported from initiation through the first 28-week treatment period |
| Time Frame | Baseline through week 28 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population: All enrolled subjects who received 3 mg b.i.d Exelon capsule for more than 4 weeks and used at least one dose of Exelon patch therapy. |
| Arm/Group Title | Rivastigmine |
|---|---|
| Arm/Group Description | Eligible patients, who are under rivastigmine capsule 3 mg b.i.d. treatment for 4 weeks before Visit 2, will be recruited, followed by treatment switch from oral capsule to transdermal patch for 48 weeks maintenance treatment. |
| Measure Participants | 102 |
| Patients with at least one SAEs |
16
15.7%
|
| Patients with at least one AE |
94
92.2%
|
| Death |
0
0%
|
| Title | Change From Baseline in Mini-Mental Status Examination (MMSE) |
|---|---|
| Description | The changes in Mini-Mental Status Examination (MMSE) of patients with Alzheimer's disease treated with Exelon 5 cm^2 Patch at Week 28 and Exelon 10 cm2 Patch at Week 52 versus baseline, the treatment-switching day at Week 4. MMSE is a multi-item instrument that examines orientation, registration, attention, calculation, recall, visuospatial ability and language. The total score can range from 0 to 30, with a higher score indicating better function. A positive change score indicates improvement from baseline. The assessments will be conducted at Visit 1, 2, 8, 11 and 17 (screening, Week 4 (baseline), 16, 28 and 52). |
| Time Frame | Baselin, week 16, 28 and 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population: All enrolled subjects who received 3 mg b.i.d Exelon capsule orally for 4 weeks and at least one dose of Exelon patch therapy |
| Arm/Group Title | Rivastigmine |
|---|---|
| Arm/Group Description | Eligible patients, who are under rivastigmine capsule 3 mg b.i.d. treatment for 4 weeks before Visit 2, will be recruited, followed by treatment switch from oral capsule to transdermal patch for 48 weeks maintenance treatment. |
| Measure Participants | 102 |
| Week 16 (n=90) |
-0.1
(2.62)
|
| Week 28 (n=82) |
0.1
(2.62)
|
| Week 52 (n=93) |
-1.0
(3.48)
|
| Title | Change From Baseline in Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) |
|---|---|
| Description | The changes in Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) of patients with Alzheimer's disease treated with Exelon 5 cm^2 Patch at Week 28 and Exelon 10 cm^2 Patch at Week 52 versus baseline, the treatment-switching day at Week 4. ADAS-Cog has been used as the major cognitive measure of anti-dementia drugs. The total score range is 0 to 70 points, with higher scores indicating greater cognitive impairment. The assessments will be conducted at Visit, 2, 8, 11 and 17 (Week 4 (baseline), 16, 28 and 52). |
| Time Frame | Baseline, week 16, 28 and 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| ITT population: All enrolled subjects who received 3 mg b.i.d Exelon capsule orally for 4 weeks and at least one dose of Exelon patch therapy. |
| Arm/Group Title | Rivastigmine |
|---|---|
| Arm/Group Description | Eligible patients, who are under rivastigmine capsule 3 mg b.i.d. treatment for 4 weeks before Visit 2, will be recruited, followed by treatment switch from oral capsule to transdermal patch for 48 weeks maintenance treatment. |
| Measure Participants | 102 |
| Week 16 (n=90) |
0.0
(4.92)
|
| Week 28 (n=82) |
0.4
(5.20)
|
| Week 52 (n=93) |
0.8
(7.37)
|
| Title | The Discontinuation Rate Due to the Treatment Switching From Oral Capsule to Rivastigmine Patch Treatment |
|---|---|
| Description | The discontinuation rate due to the treatment switching from oral capsule to patch treatment. For patients who discontinue earlier due to intolerance of patch treatment, the proportion will be analyzed. Both the discontinuation rate of 5 cm2 and 10 cm^2 patch therapy will be presented. |
| Time Frame | Baseline through week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Of the patients treated, N=121, number of patients analyzied were those who received 5cm patch (n=114) and those who received 10cm patch (n=96) |
| Arm/Group Title | Rivastigmine |
|---|---|
| Arm/Group Description | Eligible patients, who are under rivastigmine capsule 3 mg b.i.d. treatment for 4 weeks before Visit 2, will be recruited, followed by treatment switch from oral capsule to transdermal patch for 48 weeks maintenance treatment. |
| Measure Participants | 114 |
| Exelon patch 5 cm 2:Week 4 - Week 28 |
18
17.6%
|
| Exelon patch 10 cm 2: Week 28 - Week 52 |
14
13.7%
|
| Title | Percentage of Patients Successfully Titrated to Rivastigmine Patch 10 cm^2 |
|---|---|
| Description | The percentage of patients successfully titrated to rivastigmine patch 10 cm2 |
| Time Frame | Baseline through week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety population: All enrolled subjects who received 3 mg b.i.d Exelon capsule for more than 4 weeks and used at least one dose of Exelon patch therapy. |
| Arm/Group Title | Rivastigmine |
|---|---|
| Arm/Group Description | Eligible patients, who are under rivastigmine capsule 3 mg b.i.d. treatment for 4 weeks before Visit 2, will be recruited, followed by treatment switch from oral capsule to transdermal patch for 48 weeks maintenance treatment. |
| Measure Participants | 102 |
| Number [Percentage of participants] |
85.3
83.6%
|
Adverse Events
| Time Frame | 52 weeks | |
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Rivastigmine | |
| Arm/Group Description | Eligible patients, who are under rivastigmine capsule 3 mg b.i.d. treatment for 4 weeks before Visit 2, will be recruited, followed by treatment switch from oral capsule to transdermal patch for 48 weeks maintenance treatment. | |
All Cause Mortality |
||
| Rivastigmine | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Rivastigmine | ||
| Affected / at Risk (%) | # Events | |
| Total | 16/102 (15.7%) | |
| Cardiac disorders | ||
| Cardiac failure chronic | 1/102 (1%) | |
| Supraventricular tachycardia | 1/102 (1%) | |
| Gastrointestinal disorders | ||
| Inguinal hernia | 1/102 (1%) | |
| Vomiting | 1/102 (1%) | |
| Hepatobiliary disorders | ||
| Cholecystitis | 1/102 (1%) | |
| Cholelithiasis | 1/102 (1%) | |
| Infections and infestations | ||
| Arthritis infective | 1/102 (1%) | |
| Cellulitis | 1/102 (1%) | |
| Escherichia sepsis | 1/102 (1%) | |
| Pneumonia | 3/102 (2.9%) | |
| Pyuria | 1/102 (1%) | |
| Tertiary syphilis | 1/102 (1%) | |
| Urinary tract infection | 2/102 (2%) | |
| Injury, poisoning and procedural complications | ||
| Open fracture | 1/102 (1%) | |
| Pelvic fracture | 1/102 (1%) | |
| Wrist fracture | 1/102 (1%) | |
| Metabolism and nutrition disorders | ||
| Hyponatraemia | 1/102 (1%) | |
| Musculoskeletal and connective tissue disorders | ||
| Neck mass | 1/102 (1%) | |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||
| Benign neoplasm of prostate | 1/102 (1%) | |
| Lung adenocarcinoma | 1/102 (1%) | |
| Nervous system disorders | ||
| Headache | 1/102 (1%) | |
| Renal and urinary disorders | ||
| Nephrolithiasis | 1/102 (1%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Acute respiratory failure | 1/102 (1%) | |
| Idiopathic pulmonary fibrosis | 1/102 (1%) | |
| Pleural effusion | 1/102 (1%) | |
| Surgical and medical procedures | ||
| Knee arthroplasty | 1/102 (1%) | |
| Vascular disorders | ||
| Venous thrombosis limb | 1/102 (1%) | |
Other (Not Including Serious) Adverse Events |
||
| Rivastigmine | ||
| Affected / at Risk (%) | # Events | |
| Total | 83/102 (81.4%) | |
| Eye disorders | ||
| Cataract | 3/102 (2.9%) | |
| Dry eye | 3/102 (2.9%) | |
| Gastrointestinal disorders | ||
| Abdominal discomfort | 4/102 (3.9%) | |
| Constipation | 4/102 (3.9%) | |
| Diarrhoea | 6/102 (5.9%) | |
| Mouth ulceration | 3/102 (2.9%) | |
| Nausea | 12/102 (11.8%) | |
| Vomiting | 11/102 (10.8%) | |
| General disorders | ||
| Application site erosion | 3/102 (2.9%) | |
| Application site erythema | 18/102 (17.6%) | |
| Application site pruritus | 34/102 (33.3%) | |
| Application site rash | 14/102 (13.7%) | |
| Chest discomfort | 3/102 (2.9%) | |
| Pyrexia | 3/102 (2.9%) | |
| Infections and infestations | ||
| Bronchitis | 3/102 (2.9%) | |
| Conjunctivitis | 3/102 (2.9%) | |
| Nasopharyngitis | 6/102 (5.9%) | |
| Periodontitis | 3/102 (2.9%) | |
| Upper respiratory tract infection | 7/102 (6.9%) | |
| Urinary tract infection | 3/102 (2.9%) | |
| Injury, poisoning and procedural complications | ||
| Fall | 5/102 (4.9%) | |
| Investigations | ||
| Weight decreased | 28/102 (27.5%) | |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 12/102 (11.8%) | |
| Musculoskeletal and connective tissue disorders | ||
| Myofascial pain syndrome | 3/102 (2.9%) | |
| Pain in extremity | 3/102 (2.9%) | |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||
| Benign neoplasm of prostate | 3/102 (2.9%) | |
| Nervous system disorders | ||
| Dizziness | 24/102 (23.5%) | |
| Headache | 3/102 (2.9%) | |
| Psychiatric disorders | ||
| Agitation | 5/102 (4.9%) | |
| Insomnia | 4/102 (3.9%) | |
| Irritability | 3/102 (2.9%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | 5/102 (4.9%) | |
| Skin and subcutaneous tissue disorders | ||
| Eczema | 3/102 (2.9%) | |
| Papule | 3/102 (2.9%) | |
| Vascular disorders | ||
| Hypertension | 3/102 (2.9%) | |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
Results Point of Contact
| Name/Title | Study Director |
|---|---|
| Organization | Novartis Pharmaceutical |
| Phone | 862-778-8300 |
- CENA713DTW04