Adv Ther (2021) 38:5286–5301

https://doi.org/10.1007/s12325-021-01893-6

ORIGINAL RESEARCH

Effectiveness of the 10 cm2 Rivastigmine Patch

in Taiwanese Patients with Mild-to-Moderate
Alzheimer’s Dementia: A 48-Week Real-World
Observational Study
Chiung-Chih Chang . Lung Chan . Hsi-Hsien Chou . Yu-Wan Yang .
Ta-Fu Chen . Ting-Bin Chen . Chin-I. Chen . Audrey Yang .
Chaur-Jong Hu

Received: May 27, 2021 / Accepted: August 11, 2021 / Published online: September 10, 2021
Ó The Author(s) 2021

ABSTRACT on physicians’ judgment and according to the

Taiwan reimbursement criteria of the drug. Data
Introduction: The current study aimed to pro- were prospectively collected at Week 0 (base-
vide data on the effectiveness of the 10 cm2 line), Week 24, and Week 48. The primary
rivastigmine patch in patients with Alzheimer’s endpoint was the change in the cognitive
disease (AD) in a real-world setting in Taiwan. assessment screening instrument (CASI) scores
Methods: This was a 48-week, single-arm, open- at Week 48 versus baseline. The changes from
label, observational, and post-marketing study baseline in clinical dementia rating (CDR),
conducted across seven centers in Taiwan mini-mental state examination (MMSE), and
between May 5, 2016 and July 10, 2017. Eligible neuropsychiatric inventory (NPI) scores were
patients (aged 55–95 years) treated with the evaluated, as were treatment persistence and
10 cm2rivastigmine patch were enrolled based the safety profile.
Results: Of the 285 eligible patients [full anal-
ysis set (FAS)], 216 (75.8%) completed the study
Supplementary Information The online version protocol while 180 (63.2%) persisted on the
contains supplementary material available at https://
doi.org/10.1007/s12325-021-01893-6. 10 cm2 rivastigmine patch for the full 48 weeks.

T.-F. Chen
C.-C. Chang
Department of Neurology, National Taiwan
Department of Neurology, Institute for
University Hospital, Taipei, Taiwan
Translational Research in Biomedicine, Kaohsiung
Chang Gung Memorial Hospital, Chang Gung T.-B. Chen
University College of Medicine, Kaohsiung, Taiwan Department of Neurology, Taichung Veterans
General Hospital, Taichung, Taiwan
L. Chan  C.-J. Hu (&)
Department of Neurology and Dementia Center, C.-I. Chen
Shung Ho Hospital, School of Medicine, College of Department of Neurology, Wan Fang Hospital,
Medicine, Taipei Medical University, New Taipei, Taipei, Taiwan
Taiwan
e-mail: [email protected] A. Yang
Novartis (Taiwan) Co., Ltd., Taipei, Taiwan
H.-H. Chou
Department of Neurology, Chung Shan Medical
University Hospital, Taichung, Taiwan

Y.-W. Yang
Department of Neurology, China Medical
University Hospital, Taichung, Taiwan
Adv Ther (2021) 38:5286–5301 5287

At baseline, 89.8% of patients had a CDR score of INTRODUCTION

0.5 or 1, while the change in CDR score at
Week 48 was not significant. In the FAS, both the
Alzheimer’s disease (AD) is a progressive neu-
CASI and MMSE scores had numerical improve-
rodegenerative disease characterized by a steady
ment at Week 24 but declined by 2.1 and 0.4
decline in the patient’s cognition, function, and
points, respectively, at Week 48 (p = 0.005 and
behavior. The World Alzheimer’s Report in
p = 0.022). The increment in NPI scores was not
2019 estimated that there are over 50 million
significant. The most common drug-related
people living with dementia, and that this is set
adverse events (AEs) were pruritus (11.2%),
to increase to 152 million by 2050 [1]. Taiwan
nausea (3.5%), rash (3.2%), and vomiting (2.8%).
has one of the fastest growing aging popula-
Conclusions: The use of the 10 cm2 rivastig-
tions in the world, and the percentage of people
mine patch in the mild stage of AD maintained
aged C 65 years increased from 4.1% in 1980 to
cognitive function at Week 24 and neuropsy-
10.7% in 2010 [2]. In a nationwide survey con-
chiatric function at Week 48. The treatment
ducted from 2011 to 2012 in Taiwan, the
persistency and safety profile support the clinical
prevalence of all-cause dementia in patients
tolerability of the rivastigmine patch in the
aged C 65 years was 8.04% [3], and the number
management of mild-to-moderate AD in Taiwan.
of people with dementia was projected to
increase to up to 210,000 by 2020 [4].
Keywords: Alzheimer’s disease; Cognitive Rivastigmine is a reversible cholinesterase
function; Rivastigmine patch inhibitor (ChEI), originally developed as an oral
capsule and liquid formulation. In the United
Key Summary Points States, rivastigmine is indicated for the treat-
ment of all stages of AD and mild-to-moderate
Taiwan has one of the fastest growing Parkinson’s disease.
aging populations in the world, and the In a large, 24-week, randomized, multicen-
number of people with dementia was ter, placebo-controlled, double-blind study
projected to increase to up to 210,000 by (IDEAL; Investigation of transDermal Exelon in
2020. ALzheimer’s disease), the 10 cm2 rivastigmine
patch was shown to have comparable efficacy
The 10 cm2 rivastigmine patch was and improved tolerability than the 12 mg/day
approved in 2013 in Taiwan, yet its real- rivastigmine capsules. The patch also had fewer
world treatment efficacy in Alzheimer’s withdrawals due to gastrointestinal adverse
disease (AD) patients from Taiwan is still events (AEs) and three-fold lower incidences of
limited. nausea and vomiting, allowing most patients to
The current study aimed to provide achieve the optimal dose compared to the
additional efficacy and safety data of the 12 mg/day rivastigmine capsules (95.9% vs.
10 cm2 rivastigmine patch in a real-world 64.4%, respectively). The IDEAL study therefore
setting by primarily assessing cognitive established the 10 cm2 rivastigmine patch as the
assessment screening instrument score. currently recommended target maintenance
dose in the treatment of patients with mild-to-
Treatment with the 10 cm2 rivastigmine moderate AD [5, 6]. This patch, containing
patch was well tolerated and improved 18 mg of rivastigmine in line with a dosage of
cognitive functioning, neuropsychiatric 9.5 mg/24 h, was approved in Taiwan in 2013.
functioning, and treatment persistence in Various structured neuropsychological tools
patients with mild-to-moderate AD. have been used in AD clinical trials for different
purposes [7, 8]. In Taiwan, annual cognitive
The prospective study suggests that the
changes are generally measured simultaneously
10 cm2 rivastigmine patch is a convenient
by the mini-mental state examination (MMSE),
treatment option in the management of
cognitive assessment screening instrument
mild-to-moderate AD in Taiwan.
5288 Adv Ther (2021) 38:5286–5301

(CASI) [9], and clinical dementia rating (CDR) The Independent Ethics Committee or Institu-
[10]. tional Review Board reviewed the study proto-
Oral acetylcholinesterase inhibitors (AchEIs) col for each center (information provided
have demonstrated efficacy in treating patients within the supplementary material). All
with AD [11]; however, many patients adhere to patients provided written informed consent
their treatment for a relatively short duration before enrollment.
[12]. A number of factors may contribute to the
non-adherence in AD. Decline in cognitive or Study Workflow
functional abilities is inevitable in AD, and the
non-adherence may be related to dissatisfaction Patients initiating treatment with the 10 cm2
of the treatment outcome. However, a greater rivastigmine patch were enrolled based on the
proportion of non-adherence is related to AEs of physicians’ judgment and the Taiwan reim-
AchEIs or forgetfulness about medication. Non- bursement criteria of rivastigmine.
compliance with oral agents has been a com- The assignment of the patient to the
mon problem for the treatment of AD, mostly rivastigmine patch was decided within the cur-
due to the gastrointestinal side effects associ- rent practice and the medical indication.
ated with large fluctuations in acetylcholine Patients were followed-up at outpatient clinics
levels [12]. The patch formulation allows for 48 weeks to observe usage of the rivastig-
smooth and continuous drug delivery. In addi- mine patch.
tion, its favorable tolerability, efficacy, and After informed consent, the study included
convenience of use may increase treatment one screening phase (Week 0) and two follow-
compliance. up phases (Weeks 24 and 48). In the screening
The overall persistence and adherence to phase at baseline (Week 0), the inclusion and
rivastigmine (oral and the 5 cm2 patch) versus exclusion criteria were checked and the demo-
donepezil in the Taiwanese population was graphics data were collected. We also collected
recently reported using the national health the neurobehavioral assessment data at base-
dataset [13]. The real-world treatment efficacy line. At Week 24, there was a follow-up neu-
of the 10 cm2 rivastigmine patch in patients robehavioral assessment, which included
with AD has still not been extensively reported. collection of CASI, MMSE, CDR, and neuropsy-
To our knowledge, the present study is the first chiatric inventory (NPI) scores. AEs were also
prospective large-scale observational study of recorded and treatment persistency was calcu-
this patch in Taiwan. Here, we report the effi- lated. At the second follow-up at Week 48, all
cacy and safety results of a 48-week, observa- effectiveness and safety assessments were per-
tional study of the 10 cm2 rivastigmine patch. formed and the persistency data were collected.
The study also evaluated the results of adher-
ence to this patch and the most commonly
Eligibility Criteria
accepted dosing regimen in Taiwan.

Patients aged 55–95 years with a diagnosis of

METHODS mild-to-moderate AD based on the core clinical
criteria proposed by the National Institute on
Study Design Aging/Alzheimer’s Association workgroup were
included in the study [14]. Eligible patients had
This was a 48-week, single-arm, open-label, to have received a new prescription of the
multicenter, prospective, non-interventional, 10 cm2 rivastigmine patch at the screening
observational, and post-marketing study of the phase and had to provide a written informed
10 cm2 rivastigmine patch conducted in Taiwan consent. The prior treatments of eligible
between May 5, 2016 and July 10, 2017. The patients were the 5 cm2 rivastigmine patch, and
study was conducted in accordance with the oral rivastigmine 9 mg/day and oral rivastig-
ethical principles of the Declaration of Helsinki. mine 3 mg/day.
Adv Ther (2021) 38:5286–5301 5289

Patients were excluded if they had previously patients who met the eligibility criteria of the
exhibited contraindications to rivastigmine or protocol. The PP population included patients
had contraindications to the rivastigmine as who completed the 10 cm2 rivastigmine patch
described on the drug label. treatment for 48 weeks. Data collection from
the patients was missed at certain time points.
Study Endpoints and Assessments Hence, there was a difference in the number of
patients analyzed from week to week.
The primary endpoint of the study was the The primary and secondary endpoints were
change in the CASI scores [9] between baseline presented as descriptive statistics for both
and Week 48. The CASI is used as a screening absolute values and the change from baseline. A
instrument for dementia, to monitor disease paired t test or a Wilcoxon signed rank test was
progression, and to provide a profile of impair- performed, as appropriate, in calculating longi-
ment among various cognitive domains [9]. The tudinal changes. Summary statistics for contin-
maximum score of the CASI is 100, with higher uous variables included number, mean,
scores indicating better cognitive ability. standard deviation (SD), minimum, median,
Secondary endpoints were the changes in maximum, and the 95% confidence interval.
MMSE, CDR, and NPI scores from baseline to For discrete variables, summary statistics were
Week 48. The NPI is a questionnaire adminis- presented in contingency tables with absolute
trated to caregivers of AD patients to assess the and relative frequencies. If not otherwise spec-
12 subdomains of neuropsychiatric behavioral ified, p values were presented as two-sided and
symptoms in AD (including delusions, halluci- the significance level was set at 0.05. AEs were
nations, depression, anxiety, euphoria, and coded using the Medical Dictionary for Regula-
anomalous behavior) over the previous months tory Activities (v.21.1). The occurrence of each
by rating the frequency of the symptoms on a AE was counted and reported as a relative
4-point scale and their severity on a 3-point percentage.
scale. NPI is quantified by calculation of the
product of frequency (0–4 points) and severity RESULTS
(0–3 points) of each subdomain. A maximum
score of 12 is given to each symptom, with an Between May 5, 2016 and July 10, 2017, 285
overall scale of 0–144 points; a higher score patients were enrolled across seven sites. Of the
indicates more serious neuropsychiatric behav- 285 patients (FAS), 181 (63.5%) were titrated
ioral symptoms. The safety profile of rivastig- from the 5 cm2 rivastigmine patch, and the rest
mine patch was also assessed in this study. were switched/titrated from various doses of the
We also calculated treatment persistency, rivastigmine capsule. In total, 216 (75.8%)
which was the proportion of patients who patients completed the study (patients were not
continued using the 10 cm2 rivastigmine patch considered as dropped out if they switched to
to the end of the study. The calculation was another form/dose of rivastigmine after the
based on the following equation: 10 cm2 rivastigmine patch) and 180 (63.2%)
patients remained on the patch for 48 weeks.
Treatment persistency ð%Þ ¼
The mean (SD) duration of the patch treatment
ðfull analysis set ½FAS  number of withdrawalsÞ= was 284.3 (143.3) days (range 1.0–1161.0).
ðFAS  100Þ: Sixty-nine patients (24.2%) discontinued the
study, due to AEs (26.1%, 18/69), withdrawal of
Statistical Analysis consent (27.5%, 19/69), lost to follow-up
(15.9%, 11/69), and death (15.9%, 11/69)
(Fig. 1). None of the deaths were considered
In this study, there were two analysis sets: the
related to usage of the rivastigmine patch.
full analysis set (FAS) and the per-protocol (PP)
Baseline demographics and disease charac-
population. The FAS included all enrolled
teristics are summarized in Table 1. Female
5290 Adv Ther (2021) 38:5286–5301

Fig. 1 Patient flow chart. *180 patients persisted on the 10 cm2 rivastigmine patch for 48 weeks. AE adverse events, BID
twice a day, QD once a day, SAE serious AE

patients accounted for 57.2% of the FAS popu- After 48 weeks of treatment, the CASI score
lation. At baseline, the mean (SD) age of the FAS (mean [SD]) was significantly reduced by 2.1
population was 78.1 (7.7) years and the mean (9.3) points (p = 0.005) in the FAS population
(SD) body weight was 58.3 (10.8) kg. The (Fig. 2). The reduction was from a baseline score
majority of patients (n = 254; 89.8%) were of 64.1 (17.2) to a score of 62.5 (18.8) at Week
diagnosed with mild AD with a CDR score of 0.5 48 (Fig. 2).
or 1 at baseline. Most of the patients (n = 276; The FAS population showed stable MMSE
96.8%) lived with family or caregivers. scores with small mean (SD) changes from
The primary endpoint was the change in baseline of 0.2 (2.7) at Week 24 and - 0.4 (2.8)
CASI score after the 48-week treatment period. at Week 48 (Fig. 3). CDR scores were well
Adv Ther (2021) 38:5286–5301 5291

Table 1 Baseline demographics and disease characteristics of the FAS population

Particulars 10 cm2rivastigmine patch
n 5 285
Age Mean ± SD 78.1 (7.7)
Female n (%) 163 (57.2)
Body weight (kg) Mean ± SD 58.3 (10.8)
Diagnosed with mild AD n (%) 254 (89.8)
Patients living with family or a caregiver n (%) 276 (96.8)
Baseline MMSE score Number of patients 284
Mean ± SD 18.9 ± 5.4
95% CI 18.3, 19.6
Baseline CDR score, n (%) Patient number 283
0.5 145 (51.2)
1 (mild) 109 (38.5)
2 (moderate) 29 (10.2)
Baseline CASI score Patient number 268
Mean ± SD 64.1 ± 17.2
95% CI 62.1, 66.2
Baseline NPI score Patient number 167
Mean ± SD 7.7 ± 11.9
95% CI 5.9, 9.5
AD Alzheimer’s disease, CASI cognitive assessment screening instrument, CDR clinical dementia rating, CI confidence
interval, FAS full analysis set, MMSE mini-mental state examination, NPI neuropsychiatric inventory, SD standard
deviation

sustained over the 48-week treatment period The overall treatment persistency was 63.2%.
(Table 2). The proportion of patients from the Treatment persistency was also calculated for
FAS population with CDR score B 1 at baseline patients based on their prior treatment. It was
dropped from 89.7 to 84.6% at Week 48. Most observed that the majority of patients in the
patients (78.6%) had no change or improve- study had used either oral rivastigmine
ment in CDR score at Week 48. The FAS showed 3 mg/day (n = 21, 7.4%), oral rivastigmine
numerically stable NPI scores with small mean 9 mg/day (n = 55, 19.3%) or the 5 cm2 rivastig-
(SD) changes of 0.9 (12.4) at Week 24 and 0.4 mine patch (n = 181, 63.5%) as the prior treat-
(11.0) at Week 48 for the total score. Changes ment. Treatment persistency over a 1-year
from baseline in scores of single NPI domains, period was similar in patients irrespective of
including delusions, hallucinations, apathy, prior treatment (oral rivastigmine 3 mg vs. oral
and depression, were also limited to rivastigmine 9 mg vs. 5 cm2 rivastigmine patch:
between - 0.2 and 0.5 points at Week 48 66.7% vs. 65.5% vs. 66.3%). Effects of persis-
(Table 2). tency on CASI, MMSE, and CDR scores were also
investigated. We observed that CASI score
5292 Adv Ther (2021) 38:5286–5301

Fig. 2 Change in the CASI score. *Significant p value. CASI cognitive assessment screening instrument. n number of
patients analyzed

[mean (SD)] was reduced by 2.0 (9.3) (p = 0.010) CDR scores were well sustained over the
in patients who persisted on the 10 cm2 48-week treatment period. Most patients
rivastigmine patch treatment for 48 weeks (79.2%) had no change or an improvement in
(Table 3). The reduction was from a baseline CDR score at Week 48 (Table 3). Over the study
score of 64.4 (16.3) to a score of 63.1 (17.9) at period, 523 AEs were reported by 158 (55.4%)
Week 48. MMSE scores were stable with small patients; among these, 102 were serious AEs
mean (SD) changes from baseline of 0.1 (2.6) at (SAEs) occurring in 46 (16.1%) patients. The
Week 24 and - 0.3 (2.7) at Week 48 (Table 3). most common drug-related AEs were pruritus
Adv Ther (2021) 38:5286–5301 5293

Fig. 3 Change in the MMSE score. *Significant p value. MMSE mini-mental state examination

(11.2%), nausea (3.5%), rash (3.2%), and vom- which pneumonia [11 (3.9%)] and urinary tract
iting (2.8%) (Table 4). Forty-eight (16.8%) infection [7 (2.5%)] occurred in C 2% patients.
patients discontinued the 10 cm2 rivastigmine Although 58 of the 102 SAEs were graded as
patch due to AEs, and these were most com- severe [occurring in 29 (10.2%) patients], eight
monly pruritus (4.9%) or rash (2.1%). Most AEs as life threatening [3 (1.1%) patients], and seven
were managed by symptomatic treatments as fatal in severity [7 (2.5%) patients], none were
(39.3%). The most common SAE (C 5.0%) was suspected to be related to the 10 cm2 rivastig-
infection and infestations [n (%); 21 (7.4%)], of mine patch. Of these SAEs, 53 were resolved in
5294 Adv Ther (2021) 38:5286–5301

Table 2 Secondary endpoints in the FAS population

10 cm2rivastigmine patch
n 5 285
Summary of changes in the CDR scorea
Week 24, n (%) - 1 stage 5 (5.3)
No change 78 (82.1)
? 1 stage 12 (12.6)
? 2 stages 0
Week 48, n (%) - 1 stage 6 (3.2)
No change 147 (78.6)
? 1 stage 32 (17.1)
? 2 stages 2 (1.1)
Changes in NPI score
Total score
Week 24 (n = 39) Mean ± SD 8.6 ± 10.3
Change from baseline 0.9 ± 12.4
p value 0.671
Week 48 (n = 115) Mean ± SD 6.5 ± 10.7
Change from baseline 0.4 ± 11.0
p value 0.994
Delusions
Week 24 (n = 38) Mean ± SD 0.6 ± 1.5
Change from baseline 0.3 ± 1.5
p value 0.211
Week 48 (n = 115) Mean ± SD 0.7 ± 2.1
Change from baseline 0.3 ± 2.0
p value 0.236
Hallucinations
Week 24 (n = 38) Mean ± SD 0.5 ± 2.0
Change from baseline - 0.4 ± 1.5
p value 0.188
Week 48 (n = 115) Mean ± SD 0.1 ± 0.4
Change from baseline - 0.2 ± 1.3
p value 0.073
Adv Ther (2021) 38:5286–5301 5295

Table 2 continued
10 cm2rivastigmine
patchn 5 285

Apathy
Week 24 (n = 38) Mean ± SD 1.4 ± 2.4
Change from baseline 0.6 ± 2.5
p value 0.159
Week 48 (n = 115) Mean ± SD 1.0 ± 2.2
Change from baseline 0.3 ± 2.6
p value 0.176
Depression
Week 24 (n = 38) Mean ± SD 0.7 ± 1.7
Change from baseline 0.0 ± 2.1
p value 0.951
Week 48 (n = 115) Mean ± SD 0.7 ± 2.0
Change from baseline 0.0 ± 2.2
p value 0.978
CDR clinical dementia rating, FAS full analysis set, NPI neuropsychiatric inventory, SD standard deviation
a
A decrease in the stage suggests improvement of the status, and vice versa

30 (10.5%) patients. However, 11 SAEs caused patients with mild-to-moderate AD. Over 80%
7 (2.5%) patients to discontinue the rivastig- of patients maintained a CDR score B 1 in the
mine patch and 22 SAEs caused the death of 11 48 weeks of treatment with the patch. We
(3.9%) patients. However, none of the deaths observed a decrease of\3 points in the CASI
were related to use of the rivastigmine patch. score, especially in patients with mild-to-mod-
The cause of death included metastases to erate dementia at baseline, which was lower
lung/colon cancer, septic shock, cardiac failure, than that in previous research [9].
metastases to liver, necrosis, renal failure, res- To the best of our knowledge, this is the first
piratory failure, colon cancer stage IV/hepatic study to evaluate CASI outcomes after treat-
cirrhosis, acute kidney injury, pneumonia, ment with the 10 cm2 rivastigmine patch in a
hemophagocytic lymphohistiocytosis, multiple real-world setting. Our study demonstrated an
organ dysfunction syndrome, cardiac arrest, increase of 0.5 points in CASI score at Week 24
sepsis, urinary tract infection, fall, and compared with baseline, which compares
myocardial infraction. favorably with the decrease of 1.5 points in
CASI score in the 6-month pilot study of
rivastigmine 4.5 mg capsules [15]. The disparity
DISCUSSION in this result could be due to varying disease
severity and the distinct dose and drug formu-
Our results demonstrated that the 10 cm2 lation. Patients in the pilot study had a lower
rivastigmine patch provides clinical benefit in mean CASI score at baseline (47.5 vs. 64.1 in the
5296 Adv Ther (2021) 38:5286–5301

Table 3 Effect of persistency on CASI, MMSE, and CDR Table 3 continued

scores
Score Persistency
Score Persistency
Yesn 5 180 Non 5 105
Yes No
n 5 180 n 5 105 ? 2 stages 0 (0.0) 2 (5.3)
Change from baseline in CASI score CASI cognitive assessment screening instrument, CDR
Week 24 clinical dementia rating, MMSE mini-mental state exam-
ination, SD standard deviation
Number 67 15 *Statistical significance
Mean ± SD 0.7 ± 7.93 - 0.2 ± 7.92
p value 0.333 0.911
Week 48
Number 143 25 present study), representing a population with a
more advanced disease stage. Again, the 10 cm2
Mean ± SD - 2.0 ± 9.33 - 2.3 ± 8.98 rivastigmine patch provides similar exposure to
p value 0.010* 0.210 rivastigmine as the capsule, although the dose
of rivastigmine in the capsule formulation is
Change from baseline in MMSE score slightly higher (12 mg/day vs. 9.5 mg/day) than
Week 24 that in the patch [16]. Finally, unlike capsules,
the patch formulation allows continuous and
Number 76 20
steady delivery of rivastigmine through the
Mean ± SD 0.1 ± 2.63 0.6 ± 3.08 skin, thus avoiding the first-pass effects after
oral administration [17]. This could mean that
p value 0.855 0.395
titrating to a higher dose earlier may allow
Week 48 patients to achieve an optimal therapeutic dose
Number 159 38 and also benefit from a longer duration of
treatment. However, findings suggest that fur-
Mean ± SD - 0.3 ± 2.66 - 1.1 ± 3.06 ther research is required to determine which
p value 0.124 0.041* population of patients may benefit from titrat-
ing to a high dose [16, 17]. Clinical adherence of
Summary of changes in the CDR score the 5 cm2 rivastigmine patch has been explored
Week 24, n (%) and the results have shown a significant nega-
tive correlation between subscapular skin fold
- 1 stage 3 (4.0) 2 (10.0)
thickness and serum metabolite levels [18].
No change 63 (84.0) 15 (75.0) A decline of 2.3 points per year in MMSE
scores has been observed in those who pro-
? 1 stage 9 (12.0) 3 (15.0)
gressed to dementia without treatment [19]. Per
? 2 stages 0 (0.0) 0 (0.0) the National Health Insurance regulations in
Week 48, n (%) Taiwan, patients with AD using reimbursed
rivastigmine should switch to another treat-
- 1 stage 6 (4.0) 0 (0.0) ment if the MMSE score decreases by more than
No change 118 (79.2) 29 (76.3) two points [13]. During the follow-up period,
patients treated with the 10 cm2 rivastigmine
? 1 stage 25 (16.8) 7 (18.4) patch maintained cognitive performance, and
only one patient had to withdraw from the
study due to a failure in re-submission for
health insurance reimbursement; however, the
Adv Ther (2021) 38:5286–5301 5297

Table 4 Drug-related adverse events et al., the change in the MMSE score was 0.11 at
6 months and - 0.62 at 12 months [21]. A
Adverse event, n (%) 10
6-month, observational study of switching from
cm2rivastigmine
patch donepezil or rivastigmine capsules to the 5 or
n 5 285 10 cm2 rivastigmine transdermal patches also
reported a stable MMSE outcome, with a mini-
Skin and subcutaneous tissue 53 (18.6) mal change of - 0.5 [22].
disorders There are a number of AchEIs used in real-
world practice for AD patients. From a statistical
Pruritus 32 (11.2)
perspective, oral rivastigmine 3 mg/day, oral
Rash 9 (3.2) rivastigmine 9 mg/day, and the 5 cm2 rivastig-
Erythema 5 (1.8) mine patch are comparable in bridging to the
10 cm2 rivastigmine patch when the persistency
Gastrointestinal disorders 17 (6.0) rate for the 10 cm2 rivastigmine patch serves as
Nausea 10 (3.5) the major clinical outcome. These results may
indicate the relatively applicable usage of either
Vomiting 8 (2.8) 3-transformation formula, i.e., switching from
Nervous system disorders 8 (2.8) either of the three doses of rivastigmine (oral
rivastigmine 3 mg or 9 mg and the 5 cm2
General disorders and administration 5 (1.8)
rivastigmine patch) to the 10 cm2 rivastigmine
site conditions patch is feasible. Of particular note is that the
Decreased appetite 5 (1.8) shift from oral rivastigmine 3 mg/day to the
5 cm2 rivastigmine patch is tolerable in the
Ear and labyrinth disorders 3 (1.1)
Taiwanese population [23].
Cardiac disorders 2 (0.7) In our study, the majority of AEs were mild,
Psychiatric disorders 2 (0.7) local skin tolerability was good, discontinua-
tions due to drug-related AEs occurred in less
Weight decreased 1 (0.4) than a fifth of the patients, and no unexpected
Renal and urinary disorders 1 (0.4) safety issues arose. The IDEAL study [5]
demonstrated that the 10 cm2 rivastigmine
patch provided similar efficacy as the rivastig-
reason for the failure was not specified. The mine capsule (12 mg/day), but with a superior
results were as expected, supporting the bene- tolerability profile due to lower incidences of
ficial role of the 10 cm2 rivastigmine patch in vomiting (6.2%) and nausea (7.2%) over
the maintenance of global cognition and dis- 6 months; however, in our study, such inci-
ease severity. Based on the results for the CASI dences occurred in only 1.4% patients, each
total score, MMSE scores, and CDR scores, we over a longer observational period of 48 weeks.
observed that a higher persistency rate with the In the current study, 63.2% of patients contin-
10 cm2 rivastigmine patch is associated with ued on the 10 cm2 rivastigmine patch treatment
numerically better clinical outcomes. Moreover, at Week 48, which was in line with the 55–65%
even though the overall treatment persistency of patients observed with earlier studies at Week
was 63.2%, the remaining * 37% of patients 24 with an equivalent oral dose (obtained with
still adhered to the treatment for 274 days. Our 12 mg/day rivastigmine capsules) [21, 24, 25].
effectiveness data were also comparable to prior These findings were comparable to those in an
observational studies. An 18-month observa- open-label study, which reported a study com-
tional Canadian study comprising of patients pletion rate of 74.5% after 24 weeks of treat-
treated with the 5 or 10 cm2 rivastigmine pat- ment with the 10 cm2 rivastigmine patch, and
ches showed a mean change in MMSE score of the 6-month IDEAL study where 83.8% of par-
0.5 at 6 months and 0.2 at 12 months [20]. In an ticipants stayed on the 10 cm2 rivastigmine
observational study conducted by Minthon patch for at least 8 weeks [25]. The results from
5298 Adv Ther (2021) 38:5286–5301

the Real-world Evaluation of Compliance And memantine, or discontinuing the AchEI alto-
Preference in Alzheimer’s disease treatment gether [26, 30].
(RECAP) [23] and Exploring and Managing The efficacy and safety of the rivastigmine
Dementia in Black African and Caribbean Elders patch has been validated in patients with AD
(EMBRACE) [20] studies also showed that 82.4% who failed to benefit from treatment with
and 88.2% of caregivers of patients with AD donepezil [31], and the switch from donepezil
preferred the rivastigmine transdermal patch to the (5 cm2) rivastigmine patch and the
over oral medication. Therefore, the 10 cm2 gradual switch or a cross-tapering strategy both
rivastigmine patch may allow patients easier showed a high rate of adherence and low inci-
access to higher doses compared with the dences of side effects [22, 32, 33]. The favorable
12 mg/day rivastigmine capsule, thereby safety and tolerability profile reported with the
enabling patients to stay on and benefit from 10 cm2 rivastigmine patch and increased ease of
long-term effective treatment. use than an oral formulation may increase
The safety data in our study were also com- adherence to a higher dose therapy. This could
parable to prior observational studies. In a encourage patients with AD to stay on treat-
Canadian study with the 5 or 10 cm2 rivastig- ment for a longer period, offering the possibility
mine patches, 18.3% of patients discontinued of enhanced outcomes in clinical practice.
due to an AE, with pruritus (4.0%), erythema Although the transdermal patch may cause skin
(2.9%), nausea (2.5%), rash (1.9%), skin reac- reactions, these events were manageable. In line
tion (1.7%), application site erythema (1.6%), with prior studies [5], erythema/rash and pru-
vomiting (1.3%), decreased appetite (1.1%), and ritus were the most commonly reported reac-
dizziness (1.0%) being the most common [20]. tions in our study; however, importantly, no
Similarly, in a 6-month observational study of patient experienced a skin reaction that was
switching from donepezil or rivastigmine cap- reported as an SAE. Our data support a favorable
sules to the 5 or 10 cm2 rivastigmine patches, skin tolerability profile for the 10 cm2 rivastig-
discontinuation due to AEs occurred in 18% of mine patch and therefore further reinforce the
patients, with skin reactions and gastrointesti- fact that its benefits should not be dismissed
nal disorders causing 9% and 3% of patients, due to skin irritation problems.
respectively, to stop the treatment [22].
All AchEIs require titration from a low dose Limitations
and the complex dosing regimen [26] may
affect drug adherence and, therefore, the out- The open-label and real-life observational
come. Rivastigmine is administered in four oral design of our study has some limitations. As
formulations (doses of 1.5 mg, 3 mg, 4.5 mg, there was no placebo or parallel control group,
and 6 mg) and two transdermal patch formula- outcomes in the absence of the 10 cm2
tions (5 cm2 and 10 cm2) [27, 28]. Conse- rivastigmine patch are unknown. It is suggested
quently, the dosing regimen may vary widely that researchers in this field should consider
among practicing physicians as observed in this including a control group in future studies.
study and hence might interfere with compli- Physicians were not blinded to study treatment
ance. The other two approved AchEIs in Taiwan and were able to adjust the dosage freely as
are galantamine and donepezil, which are needed within the study, such as temporarily
administered in two oral doses, and the dosing switching to the other formulation (i.e.,
regimens are titrated if an AE occurs. In clinical rivastigmine capsule) or a lower dose (i.e., the
practice, AD patients also fail to adhere to AchEI 5 cm2 rivastigmine patch). These adjustments
treatment due to a lack of efficacy. When one could be influential to treatment response.
AchEI may fail to reach the therapeutic expec- Therefore, the clinical outcome might not
tation and the dosing strategy may not improve entirely represent the effects of the continuous
efficacy, the physician may consider switching 10 cm2 rivastigmine patch treatment. Also, it is
to another AchEI [29], using an add-on of important to note that randomized controlled
Adv Ther (2021) 38:5286–5301 5299

trials, despite being conducted in a controlled (Taiwan) Co., Ltd., in accordance with Good
setting, are associated with several limitations Publication Practice (GPP3) guidelines (http://
including incomplete understanding of AD www.ismpp.org/gpp3).
pathophysiology that might have led to selec-
tion of the wrong targets, inappropriate patient Authorship. All the authors meet the Inter-
selection, variable rates of progression, subop- national Committee of Medical Journal Editors
timal dosing, drug exposure and/or target (ICMJE) criteria for authorship for this article,
engagement, inappropriate time of interven- take responsibility for the integrity of the work
tion, inappropriate outcome measures, and low as a whole, and have given their approval for
sensitivity of clinical scales. These variables are this version to be published.
even more difficult to control in a real-world
study. Authors’ Contributions. All authors had full
The results may not be generalized to the access to the data and were responsible for the
entire Taiwan population because, in the real final decision to submit the manuscript. C-CC,
world, patients face the issue of failing the re- AY, and C-JH were involved in study concep-
application of drug reimbursement and the tion and design. C-CC, AY, and C-JH carried out
effect of this situation is not captured in our formal analysis and interpretation. C-JH was
study. However, the present study offers real- involved in funding acquisition. All authors
world insights into the persistency, treatment were involved in study investigation (except for
outcomes and unique treatment pattern in AY), methodology, data curation, and valida-
Taiwan. tion of study results. C-CC was involved in
writing the manuscript. All authors approved of
the manuscript and were accountable for all
CONCLUSIONS aspects of the work.

The use of the 10 cm2 rivastigmine patch in a Prior Presentation. Some of these data were
real-life setting was efficacious for patients with previously presented at the CTAD 2019, Dec
mild-to-moderate AD and was not associated 4–7, San Diego, California, USA.
with any significant safety concerns. Thus, the
10 cm2 rivastigmine patch represents an effica- Disclosures. Chiung-Chih Chang, Lung
cious, tolerable, and convenient treatment Chan, Hsi-Hsien Chou, Yu-Wan Yang, Ta-Fu
option in the management of mild-to-moderate Chen, Ting-Bin Chen, Chin-I Chen, and Chaur-
AD in Taiwan. Jong Hu have no competing interests. Audrey
Yang is an employee of Novartis (Taiwan) Co.,
Ltd.
ACKNOWLEDGEMENTS Compliance with Ethical Guidelines. Par-
ticipants provided written informed consent
We thank the study investigators and patients prior to participation. The Independent Ethics
for their participation and commitment to this Committee or Institutional Review Board
work. reviewed the study protocol for each study
center (information provided within supple-
Funding. This study was funded by Novartis mentary material). The study was conducted
(Taiwan) Co., Ltd. The study sponsor is also according to the Guidelines for Good Clinical
funding the journal’s Rapid Service and Open Practice that have their origin in the Declara-
Access fees. tion of Helsinki.

Medical Writing Assistance. Medical writ- Data Availability. The datasets used and/or
ing support was provided by Nisha Narayanan analyzed during the study are available from the
and Preethi Bheereddy (Novartis Healthcare Pvt. corresponding author on reasonable request.
Ltd, India), which was funded by Novartis
5300 Adv Ther (2021) 38:5286–5301

Open Access. This article is licensed under a Companion CNS Disord. 2014. https://doi.org/10.
Creative Commons Attribution-NonCommer- 4088/PCC.14r01654.
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any non-commercial use, sharing, adaptation, and on behalf of the EXPLORE investigators. Effects
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