Rotigotine, transdermal patch, 4.5 mg (releasing approximately 2 mg per 24 hours), 9.0 mg (releasing approximately 4 mg per 24 hours), 13.5 mg (releasing approximately 6 mg per 24 hours), 18.0 mg (releasing approximately 8 mg per 24 hours), Neupro, March 2008
Public summary document. March 2008
Page last updated: 04 July 2008
Public Summary Document
Product: Rotigotine, transdermal patch, 4.5 mg (releasing approximately 2 mg per 24
hours), 9.0 mg (releasing approximately 4 mg per 24 hours), 13.5 mg (releasing approximately
6 mg per 24 hours), 18.0 mg (releasing approximately 8 mg per 24 hours), Neupro.
Sponsor: UCB Australia Pty Ltd
Date of PBAC Consideration: March 2008
1.Purpose of Application
The submission sought an unrestricted listing for use as monotherapy or in combination with levodopa for the treatment of idiopathic Parkinson’s disease (PD) from early stage to advanced disease.
2. Background
This was the first time rotigotine had been considered by the PBAC.
3. Registration Status
4. Listing Requested and PBAC’s View
The submission requested an unrestricted listing. However, the PBAC noted the sponsor had indicated a willingness to accept a ‘restricted benefit’ listing if rotigotine were recommended for listing.
5. Clinical Place for the Proposed Therapy
The rotigotine transdermal patch would provide access to a non-ergot dopamine agonist as a transdermal patch for patients with Parkinson’s disease.
6. Comparator
The submission nominated cabergoline as the appropriate main comparator.
The PBAC accepted this as an appropriate comparator, but considered a comparison with
levodopa in early Parkinson’s disease should also have been presented.
See Recommendation and Reasons for PBAC’s view.
7. Clinical Trials
The submission presented five randomised, double-blind, placebo controlled trials
comparing rotigotine in varying doses with placebo (three in early PD and two in PD
with motor fluctuations) and three randomised, double-blind, placebo controlled trials
comparing cabergoline with placebo in patients with PD with motor fluctuations.
Details of the trials published at the time of the submission are presented in the
table below.
|
Trial/First author |
Protocol title |
Publication citation |
|---|---|---|
|
Common reference: placebo |
||
|
Rotigotine |
||
|
SP506 |
A controlled trial of rotigotine monotherapy in early Parkinson's disease. |
Arch Neurol 2003; 60(12): 1721–1728 |
|
SP512 |
Transdermal rotigotine: Double-blind, placebo-controlled trial in Parkinson disease. |
|
|
SP513 |
Rotigotine transdermal patch in early Parkinson's disease: A randomized double-blind, controlled study versus placebo and ropinirole |
Movement Disorders. Available from: http://www3.interscience.wiley.com/journal/76507419/home |
|
SP515 |
Efficacy of pramipexole and transdermal rotigotine in advanced Parkinson's disease: a double-blind, double-dummy, randomised controlled trial. |
Lancet Neurol 2007; 6(6): 513–520 |
|
SP650 |
Advanced Parkinson’s disease treated with rotigotine transdermal system. |
Neurology 2007; 68:1262–1267 |
|
Cabergoline |
||
|
Ahlskog 1996 |
Adjunctive cabergoline therapy of Parkinson's disease: Comparison with placebo and assessment of dose responses and duration of effect. |
Clin Neuropharmacol 1996; 19(3): 202–212 |
|
Hutton 1996 |
Multicenter, placebo-controlled trial of cabergoline taken once daily in the treatment
of Parkinson's disease. |
Neurology 1996; 46(4): 1062–1065 |
|
Steiger 1996 |
Double-blind study of the activity and tolerability of cabergoline versus placebo in parkinsonians with motor fluctuations. |
J Neurol 1996; 243: 68–72 |
8. Results of Trials
Rotigotine trials – primary outcomes in Early PD
The primary outcome in the early PD rotigotine trials was the change in the sum of
the Unified Parkinson’s Disease Rating Scale (UPDRS) Activities of Daily Living (ADL)
and motor scores and the proportion of patients achieving at least a 20% of reduction
in sum of UPDRS ADL and motor subscales from baseline to end of maintenance phase.
The results demonstrate that patients with early PD, treated with rotigotine, have
a statistically significantly reduced sum of UPDRS ADL and motor subscales and a statistically
significantly greater proportion of patients treated with rotigotine achieved at least
a 20% reduction in sum of UPDRS ADL and motor subscales, from baseline to end of maintenance
phase, compared with those treated with placebo. Some heterogeneity between the trials
was noted. The results are presented in the tables below.
ANCOVA results for change in sum of UPDRS ADL and motor subscales from baseline to
the end of the maintenance phase in the early PD rotigotine trials
|
Trial |
Rotigotine |
Placebo |
Weighted Mean Difference |
||
|---|---|---|---|---|---|
|
n (%) |
Mean (SD) |
n (%) |
Mean (SD) |
||
|
SP512 |
177 (97.8) |
–3.98 (9.41) |
96 (100) |
1.31(9.37) |
–5.29 (–7.62, –2.96) |
|
SP513 |
213 (99.1) |
–6.83 (9.62) |
117 (98.3) |
–2.33 (9.54) |
–4.50 (–6.66, –2.34) |
|
Meta-analysis: Rotigotine-Early PD |
-4.86 (-6.45, -3.28) |
||||
CI=confidence interval; SD=standard deviation; n=number of participants reporting
data;
Bolded typography indicates statistically significant differences between treatment
groups;
UPDRS ADL – Unified Parkinson’s Disease Rating Scale Activities Daily Living;
ANCOVA- Analysis of Covariance model.
Number of patients achieving at least a 20% reduction in sum of UPDRS ADL and motor
subscales from baseline to end of maintenance phase (dichotomous data) comparing trial
medication with placebo in the early PD rotigotine trials
|
Trial |
Rotigotine |
Placebo |
Relative risk (95% CI) |
||
|---|---|---|---|---|---|
|
n (%) |
Number of responders |
n (%) |
Number of responders |
||
|
SP506 |
254 (95.8) |
123 |
62 (96.9) |
18 |
1.67 (1.11, 2.51) |
|
SP512a |
177 (97.8) |
84 |
96 (100) |
18 |
2.53 (1.62, 3.95) |
|
SP513a |
213 (99.1) |
110 |
117 (98.3) |
35 |
1.73 (1.27, 2.35) |
|
Meta-analysis: Rotigotine-Early PD |
1.88 (1.48, 2.38) |
||||
CI=confidence interval; SD=standard deviation; n=number of participants reporting
data;
Bolded typography indicates statistically significant differences between treatment
groups;
aprimary outcome
Rotigotine trials – primary outcomes in Advanced PDThe primary outcome in the advanced PD rotigotine
trials was the change in absolute time “off” in hours and the proportion of patients
achieving at least a 30% reduction in absolute time ‘off’ in hours, from baseline
to end of maintenance phase. The results for these outcomes are presented in the following
tables.
ANCOVA results for change in absolute time ‘off’ in hours from baseline to end of
maintenance phase (continuous data) in the advanced PD rotigotine trials
|
Trial |
Rotigotine |
Placebo |
Weighted Mean Difference (95% CI) |
||
|---|---|---|---|---|---|
|
n (%) |
Change from baseline |
n (%) |
Change from baseline |
||
|
SP515 |
201 (100) |
-2.46 (2.89) |
100 (100) |
-0.88 (2.9) |
-1.58 (-2.27, -0.89) |
|
SP650 |
222 (96.1) |
-2.41 (3.37) |
119 (99.2) |
-0.90 (3.27) |
-1.51 (-2.05, -0.77) |
|
Meta-analysis: Rotigotine – Advanced PD |
-1.55 (-2.05, -1.04) |
||||
CI=confidence interval; SD=standard deviation; n=number of participants reporting
data;
Bolded typography indicates statistically significant differences between treatment
groups.
Number of patients achieving at least a 30% reduction in absolute time ‘off’ in hours
from baseline to the end of the maintenance phase (dichotomous data) comparing trial
medication with placebo in the advanced PD rotigotine trials
|
Trial |
Rotigotine |
Placebo |
Relative risk (95% CI) |
||
|---|---|---|---|---|---|
|
n (%) |
Number of responders |
n (%) |
Number of responders |
||
|
SP515 |
201 (100) |
120 |
100 (100) |
35 |
1.71 (1.28, 2.28) |
|
SP650 |
222 (96.1) |
124 |
119 (99.2) |
41 |
1.62 (1.29, 2.13) |
|
Meta-analysis: Rotigotine – Advanced PD |
1.66 (1.36, 2.03) |
||||
CI=confidence interval; SD=standard deviation; n=number of participants reporting
data;
Bolded typography indicates statistically significant differences between treatment
groups.
The results demonstrated that patients with advanced PD, treated with rotigotine,
have a statistically significant reduction in absolute time ‘off’ in hours and a statistically
significantly greater proportion of patients treated with rotigotine achieved at least
a 30% reduction in absolute time ‘off’ in hours, from baseline to end of maintenance
phase, compared with those treated with placebo.
Indirect comparison of rotigotine with cabergoline
The results of all the indirect comparisons (all rotigotine trials, only the advanced
PD rotigotine trials and only rotigotine trial SP515) demonstrated that there was
no significant difference in UPDRS ADL subscale scores at the end of the maintenance
phase between rotigotine and cabergoline with a weighted mean difference (WMD) (95%
CI) of 0.60 (-1.86, 3.06); 0.11 (-2.54, 2.76) and -0.1 (-2.98, 2.78), respectively.
The results of all the indirect comparisons (all rotigotine trials, only the advanced
PD rotigotine trials and only rotigotine trial SP515) demonstrated that there was
no significant difference in UPDRS motor subscale scores at the end of the maintenance
phase between rotigotine and cabergoline.
Analysis of change in UPDRS ADL subscale scores from baseline to the end of the maintenance
phase demonstrated that patients treated with rotigotine in the early and advanced
stages of PD and those treated with cabergoline in the advanced PD have statistically
significantly greater reductions in UPDRS ADL scores from baseline to the end of the
maintenance phase, compared with those treated with placebo.
Based on trial data rotigotine and cabergoline have similar adverse event profiles
in terms of dopaminergic effects including nausea, dizziness, somnolence and hallucinations.
Rotigotine is associated with increased application site reactions compared with placebo.
Cabergoline is associated with fibrotic serosal reactions including valvulopathy.
9. Clinical Claim
The submission claimed that based on the clinical evidence presented rotigotine is
therapeutically non-inferior to cabergoline, but has fewer serious safety issues.
For the PBAC’s views see Recommendation and Reasons.
10. Economic Analysis
The equi-effective doses of rotigotine 7.6 mg daily and cabergoline 3.42 mg daily
used in the cost-minimisation analysis were considered a likely underestimate favouring
rotigotine. The mean daily dose (8.8 mg) using only the optimal dose trials which
correspond with the dosage regimens proposed in the submission, trials SP513 and SP515,
was considered more appropriate.
For the PBAC’s views see Recommendation and Reasons.
11. Estimated PBS Usage and Financial Implications
12. Recommendation and Reasons
The PBAC noted the sponsor had indicated its willingness to accept a restricted benefit
listing if rotigotine were recommended for listing.
The PBAC accepted that cabergoline, as a dopamine receptor agonist, is an appropriate
comparator in advanced Parkinson’s disease (PD), noting also that cabergoline has
a small but valuable place as first line treatment in early PD. However, the PBAC
considered a comparison versus levodopa in early PD should also have been presented.
The Pre-PBAC response had reiterated the opinion that there is a growing international
trend towards using dopamine agonists as first line therapy for PD, however, other
comments made to the PBAC, coupled with the high PBS usage of levodopa, indicated
this was not current Australian clinical practice.
The PBAC considered that although no significant differences between rotigotine and
cabergoline were observed in any of the indirect comparisons presented, the dose of
cabergoline used in the trials may have represented sub-therapeutic doses of cabergoline
(up to 5 mg per day was used in the trials, however the TGA-approved PI recommends
use of up to 6 mg). The PBAC noted studies of the relative bioavailability of rotigotine
found differences in bioavailability varying from <1% (abdomen versus hip) to 41%
(shoulder versus thigh) depending on the application site. Therefore, the dose of
rotigotine delivered (and the subsequently effectiveness of rotigotine) may vary from
day to day depending on the application site.
With respect to safety, the claim that rotigotine has fewer serious safety issues
compared to cabergoline was not considered to be demonstrated to the extent claimed
in the submission. The therapeutic claims are based on an indirect comparison of five
rotigotine and three cabergoline randomised controlled trials using placebo as a common
comparator. No direct comparison was provided. Therefore, although there are probably
fewer serious safety issues with rotigotine than with cabergoline, the absolute magnitude
of this benefit is unclear. The data presented were considered equivocal and incomplete,
as important adverse effects about which only incomplete information is currently
available include the relative incidence of sleep attacks, ophthalmological adverse
reactions and fibrosis.
The equi-effective doses of rotigotine 7.6 mg daily and cabergoline 3.42 mg daily
used in the cost-minimisation analysis were considered a likely underestimate favouring
rotigotine. The mean daily dose (8.8 mg) using only the optimal dose trials which
correspond with the dosage regimens proposed in the submission, trials SP513 and SP515,
was considered more appropriate.
The monitoring costs for cabergoline were also considered to be an over-estimate as
there is a discrepancy between the monitoring recommended by the Movement Disorder
Society of Australia (MDSA) and the PI, and some assessments would be performed by
the treating neurologist incurring few, if any, extra consultations.
The PBAC also noted advice that the estimation of likely numbers of patients eligible
for rotigotine treatment should have taken into account the substitution of levodopa
with rotigotine. The submission should have also taken into account the likely numbers
of patients who are not currently receiving dopamine agonists that may be eligible
for rotigotine treatment.
The PBAC rejected the application on the grounds that a comparison should also have
been made against levodopa and a decarboxylase inhibitor in early Parkinson’s disease,
the claim of superior safety profile over cabergoline had not been substantiated,
and because the claimed cost offsets for monitoring the safety of cabergoline were
unacceptable.
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia. It considers submissions in this context. A PBAC decision not to recommend listing or not to recommend changing a listing does not represent a final PBAC view about the merits of the medicine. A company can resubmit to the PBAC or seek independent review of the PBAC decision.
