OPTIMA
Study
design
OPTIMA Study design
• Functional decline*
• 2-point decline
9.5 mg/24 h
rivastigmine
patch (10 cm2)
on MMSE from
previous visit or
3-point decline
on MMSE from
baseline
Decline
No decline
Randomization
of decliners to
double-blind
phase
13.3 mg/24 h rivastigmine
patch (15 cm2)
9.5 mg/24 h rivastigmine
patch (10 cm2)
Extended open-label phase –
9.5 mg/24 h rivastigmine patch (10 cm2)
− 24–48 week open-label phase
− Decliners: 48-week double-blind phase
− Patients titrated up to study dose over a
four-week period
− Non-decliners: 48-week open-label phase
− Patients maintained on target study dose for a
maximum of 44 weeks
− Evaluation of decline at Weeks 24, 36, and 48
*Functional decline was assessed by the investigator.
Participants
• Main inclusion criteria:
– Males and females (not of child-bearing potential)
– Clinical diagnosis of dementia of the Alzheimer’s type (DSM-IV criteria) and probable AD
(NINCDS/ADRDA criteria; MRI/CT scan within 2 years prior to baseline visit)
– MMSE score of 10–24, inclusive
• Main exclusion criteria:
– Any medical or neurological condition other than AD that may cause dementia
– Current diagnosis of uncontrolled seizure disorder; severe/unstable cardiovascular
disease; bradycardia; sick-sinus syndrome, or conduction defects; acute, severe or
unstable asthmatic conditions; uncontrolled peptic ulceration/GI bleeding within last
3 months; clinically significant urinary obstruction
– Allergy to vitamin E containing products; sensitivity to cholinergic compounds; skin lesion/
disorder that would prevent transdermal patch use
– History (past 5 years) of malignancy of any organ system, unless stable; history or current
diagnosis of cerebrovascular disease
– Use of ChEIs (or other approved treatments for AD) 2 weeks prior to enrolment, with the
exception of stable memantine (at least 3 months)
ChEIs, cholinesterase inhibitors; CT, computed tomography; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders,
4th edition; MMSE, Mini-Mental State Examination; MRI, magnetic resonance imaging; NINCDS/ADRDA, National Institute of
Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria.
Primary outcomes
• Change from double-blind randomization to Week 48 of the double-blind
phase on the:
– Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily
Living (ADCS-IADL) scale
– Alzheimer’s Disease Assessment Scale–cognitive subscale
(ADAS-cog)
Patient disposition
Efficacy: superiority of 13.3 mg/24 h patch at Weeks 16–48 on
the ADCS-IADL (ITT[DB]-LOCF population)
Efficacy: superiority of 13.3 mg/24 h patch at Week 24
on the ADAS-cog (ITT[DB]-LOCF population)
Summary: efficacy data
• The 13.3 mg/24 h patch demonstrated superior efficacy compared with the
9.5 mg/24 h patch, with statistical significance reached at the co-primary
endpoint at Week 48 (p = 0.002) on the ADCS-IADL scale
– Significant differences in favour of 13.3 mg/24 h patch also observed on
the ADCS-IADL at Weeks 16, 24 and 32 (p = 0.025, 0.005
and < 0.001, respectively versus 9.5 mg/24 h patch)
• Less cognitive decline on the ADAS-cog was observed with the 13.3 mg/24 h
patch compared with the 9.5 mg/24 h patch, but this did not reach significance
at Week 48 (co-primary endpoint; p = 0.227)
– Statistically significant at Week 24 compared with 9.5 mg/24 h
patch (p = 0.027)
ADCS-IADL, Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living scale;
ADAS-cog, Alzheimer’s Disease Assessment Scale–cognitive subscale.
Deaths, SAE or discontinuation due to AE
(safety-DB population)
13.3 mg/24 h
rivastigmine
patch*
N = 280
n (%)
3 (1.1)
9.5 mg/24 h
rivastigmine
patch*
N = 283
n (%)
5 (1.8)
SAE†
44 (15.7)
44 (15.5)
Discontinued due to AE†
27 (9.6)
36 (12.7)
Discontinued due to SAE†
12 (4.3)
18 (6.4)
Deaths
*Safety
.
population; †Deaths were included AE, adverse event, SAE, serious adverse event.
Most common AEs, by preferred term
(DB phase; DB-safety population)
Preferred term
Total
13.3 mg/24 h 9.5 mg/24 h
Overall
patch*
patch*
N = 280
N = 283
N = 563
n (%)
n (%)
n (%)
210 (75.0)
193 (68.2) 403 (71.6)
Nausea
34 (12.1)
14 (4.9)
48 (8.5)
Vomiting
29 (10.4)
13 (4.6)
42 (7.5)
Fall
21 (7.5)
17 (6.0)
38 (6.7)
Weight decreased
19 (6.8)
8 (2.8)
27 (4.8)
Application site erythema
18 (6.4)
16 (5.7)
34 (6.0)
Decreased appetite
18 (6.4)
7 (2.5)
25 (4.4)
Diarrhoea
18 (6.4)
13 (4.6)
31 (5.5)
Urinary tract infection
15 (5.4)
12 (4.2)
27 (4.8)
Agitation
14 (5.0)
15 (5.3)
29 (5.2)
Depression
14 (5.0)
13 (4.6)
27 (4.8)
*Safety population. AE are sorted by descending frequency in the 13.3 mg/24 h patch group. A patient with multiple occurrences of an AE
within a preferred term was counted only once. Only AE shown occurring in > 3% of patients, in any treatment group.
Summary: safety data
• The profile for deaths and SAEs was similar between treatment groups.
• Higher incidence of AE in the 13.3 vs the 9.5 mg/24 h group (75.0% vs
68.2%). Between-group differences in the first 24 weeks on common AEs
tended to decrease with time.
• The incidence of application site erythema and pruritus was comparable
between groups, suggesting the 13.3 mg/24 h patch is not associated with
reduced skin tolerability
• No unexpected effects of long-term treatment with either dose
• Fewer discontinuations were seen in 13.3 vs the 9.5 mg/24 h group
– Discontinuations due to AE: 9.6% vs 12.7%, respectively
– Discontinuations due to SAE: 4.3% vs 6.4%, respectively