Rasagiline, tablet, 1 mg, Azilect® - July 2011
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Public Summary Document
Product: Rasagiline, tablet, 1 mg,
Azilect®
Sponsor: Lundbeck Australia Pty Ltd
Date of PBAC Consideration: July 2011
1. Purpose of Application
The submission sought an Authority required (Streamlined) listing
for the treatment of Parkinson disease as adjunctive therapy in
patients being treated with levodopa-decarboxylase inhibitor
combinations who are experiencing fluctuations in motor function
due to end-of-dose effect.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Rasagiline was TGA registered on 6 February 2012 for the
symptomatic treatment of idiopathic Parkinson’s disease (PD)
as monotherapy (without concomitant levodopa/decarboxylase
inhibitor therapy) or as adjunct therapy (with concomitant
levodopa/decarboxylase inhibitor therapy).
4. Listing Requested and PBAC’s View
Authority Required (STREAMLINED)
Parkinson disease as adjunctive therapy in patients being treated
with levodopa-decarboxylase inhibitor combinations who are
experiencing fluctuations in motor function due to end-of-dose
effect. The PBAC considered the requested restriction
appropriate.
5. Clinical Place for the Proposed Therapy
Parkinson disease is a chronic, progressive, neurodegenerative
disease which causes the neurons in the substantia nigra cells to
die, leading to a lack of dopamine in the brain, especially in the
basal ganglia. This results in loss of ability to control normal
body movements, with varying degrees of muscular control.
The submission proposed that the place in therapy of rasagiline is
as an alternative to entacapone as adjunctive therapy in patients
receiving levodopa-decarboxylase inhibitor combination therapy but
experiencing motor fluctuations due to end-of-dose effect.
6. Comparator
The submission nominated entacapone as the main comparator. The main arguments for the nomination are summarised below:
- rasagiline has the same proposed PBS indication as entacapone.
- rasagiline was tested in patients with similar characteristics to entacapone.
- the Australian treatment survey conducted by the submission suggested that entacapone is used frequently for motor fluctuations due to end dose effect of levodopa. PBS utilisation data also supports the contention that entacapone is the most widely used adjunctive therapy.
The PBAC did not agree that this was the appropriate comparator.
See Recommendation and Reasons.
7. Clinical Trials
The basis of the submission was one three-arm randomised trial
pre-specified to compare rasagiline with placebo, with additional
post-hoc analyses comparing rasagiline directly with the active
entacapone control arm (LARGO).
The submission also presented an indirect comparison of rasagiline
and entacapone using three randomised comparative trials (LARGO,
PRESTO and Rabey 2000) comparing rasagiline with placebo, and seven
randomised comparative trials comparing entacapone with placebo.
Each rasagiline trial included patients with PD and motor
fluctuations and assessed the use of 1 mg per day rasagiline in
addition to levodopa. The entacapone trials also included patients
with PD and motor fluctuations and assessed the use of, on average,
935 mg per day entacapone in addition to levodopa (entacapone 200mg
was taken with each levodopa dose).
Details of the trials published at the time of the submission are
in the table below.
| Trial | Protocol title/ Publication title | Publication citation |
|---|---|---|
| Direct comparison | ||
| Rasagiline vs entacapone | ||
| Indirect comparison (Placebo as common reference) | ||
| Rasagiline | ||
| Entacapone | ||
| LARGO (post-hoc analysis) Rascol O, et al | Rasagiline as an adjunct to levodopa in patients with Parkinson's disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. | The Lancet 2005; 365(9463): 947-54, |
| LARGO (pre-specified analysis) | As above | As above |
| PRESTO Parkinson Study Group | A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. | Arch Neurol 2005; 62(2):241-8. |
| Rabey 2000 | Rasagiline Mesylate, a New Mao-B Inhibitor for the Treatment of Parkinson’s Disease: A Double-Blind Study as Adjunctive Therapy to Levodopa. | Clinical Neuropharmacology 2000; 23 (6):324–330. |
| Poewe 2002 | Efficacy and safety of entacapone in Parkinson's disease patients with suboptimal Levodopa response: a 6-month randomized placebo-controlled double-blind study in Germany and Austria (Celomen study). | Acta Neurol Scand 2002; 105: 245-255. |
| Reichmann 2005 | Efficacy of combining levodopa with entacapone on quality of life and activities of daily living in patients experiencing wearing-OFF type fluctuations. | Acta Neurol Scand 2005: 111: 21–28. |
| Myllyla 2001 | Twelve-month safety of entacapone in patients with Parkinson’s Disease. | European Journal of Neurology 2001; 8:53-60. |
| Fenelon 2003 | Efficacy and tolerability of entacapone in patients with Parkinson’s disease treated with levodopa plus a dopamine agonist and experiencing wearing-OFF motor fluctuations. A randomized, double-blind, multicentre study. | J Neural Transm 2003; 110: 239–251. |
| Rinne 1998 | Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations. | Neurology 1998; 5 1: 1309-1314. |
| PSG 1997 | Parkinson Study Group. Entacapone Improves Motor Fluctuations in Levodopa-Treated Parkinson’s Disease Patients. | Ann Neurol 1997; 42:747-755. |
| Brooks 2003 | Entacapone is beneficial in both fluctuating and non-fluctuating patients with Parkinson’s Disease: a randomised, placebo controlled, double blind, six month study. | J Neurol Neurosurg Psychiatry 2003; 74: 1071-1079. |
8. Results of Trials
The table below summarises the results of the primary outcome of
the LARGO trial. As stated above, the comparison of rasagiline and
entacapone was conducted post-hoc, thus the trial may not have been
powered to detect a difference between treatments. The power
calculations for the LARGO trial were based on the primary
endpoint, the change from baseline in the mean total daily
“OFF” time, as measured through subject daily
‘24-hour’ diaries at baseline and during treatment. A
difference between changes of the placebo-treated arm and the
active treatment arm of 45 minutes or more was considered as a
change of clinical importance.
Main results from the LARGO trial for the mITT populations
| Outcomes | PBO N=218 | ENT N=218 | RAS N=222 |
|---|---|---|---|
| Primary Outcome: Change from baseline in mean daily ‘OFF’ time (hours) | |||
| Difference v PBO (95% CI, p value) | -0.80 (-1.20, -0.41) p<0.0001 | -0.78 (-1.18, -0.39) p=0.0001 | |
| Baseline | 5.50 | 5.60 | 5.60 |
| Endpoint | 5.10 | 4.40 | 4.42 |
| Change (95%CI) | -0.40 (-0.69, -0.10) | -1.20 (-1.49, -0.90) | -1.18 (-1.47, -0.88) |
| Difference RAS v ENT (95% CI, p value) Post-hoc | 0.02 (-0.37, 0.42) P=0.92 | ||
Abbreviations: RAS = rasagiline, ENT = entacapone, PBO= placebo;
mITT = modified intention-to-treat (primary endpoint analysis
undertaken on all patients with at least one post-randomisation
measurement (or diary) for that endpoint)
Bolded typography indicates statistically significant differences
between groups
For the primary outcome of the LARGO trial, rasagiline treatment
was associated with statistically significant reductions in mean
daily “OFF” time versus placebo, a difference of -0.78
hours (95% CI: -1.18, -0.39; p=0.0001). Forty-five minutes is
considered a clinically important difference between rasagiline and
placebo. The reduction in OFF time as expressed in minutes is
(-46.8; 95% CI: -70.8, -23.4), thus although statistically
significantly different, the results may not indicate a clinically
significant difference between rasagiline and placebo as the
reduction in OFF time could be as little as 23 minutes. The
reduction in OFF time was of similar magnitude to that observed for
entacapone versus placebo (difference (95% CI): -0.80 hours (-1.20,
-0.41); p<0.0001). This expressed in minutes is (-48.0; 95% CI:
-72.0, -24.6). When comparing rasagiline to entacapone, in post-hoc
analyses, there was no statistically significant difference between
the two treatment groups (difference (95% CI): 0.02 (-0.37, 0.42),
however the trial may not have been powered to detect any
differences. This difference expressed in minutes is (1.2; 95% CI:
-22.2, 25.2). The upper limit of 0.42 translates into a reduction
in OFF time of approximately 25 min per day less for rasagiline
versus entacapone. The results for the reported secondary outcomes
similarly did not demonstrate any differences between
treatments.
The results of the indirect comparison of rasagiline and
entacapone, using placebo as the common reference were generally
consistent with those of the post-hoc analysis of the LARGO trial.
The placebo response rates across the trials varied substantially.
As for the LARGO trial, these analyses were all conducted
post-hoc.
The submission provided no data assessing the comparative
effectiveness and safety of rasagiline versus selegiline.
The incidence of adverse events between rasagiline and entacapone
treated patients in the LARGO trial were similar and did not
significantly differ between the two groups, with the exception of
cardiovascular system adverse events that were slightly higher for
rasagiline versus entacapone treatment (RD (95%CI): 0.06 (0.01,
0.12)). There were no statistically significant differences between
rasagiline and entacapone treatment from the indirect comparison of
the included trials. A summary of the periodic safety update report
(PSUR) covering 3 Jan 2009 to 2 Jan 2010 was provided with the
submission. No new signals of concern or changes to the company
core data sheets (and thus the draft Product Information) were
deemed necessary.
For PBAC’s comments on these results, see Recommendation
and Reasons.
9. Clinical Claim
The submission described rasagiline as non-inferior in terms of
comparative effectiveness and comparative safety over
entacapone.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a cost minimisation analysis. The
equi-effective doses were estimated as rasagiline 1 mg and
entacapone 953 mg, based on the doses in the LARGO trial.
11. Estimated PBS Usage and Financial Implications
The submission estimated a net cost to the PBS of less than $10
million in year 5 of listing.
12. Recommendation and Reasons
The PBAC agreed that the requested restriction is appropriate and
is consistent with the trial evidence.
The PBAC considered that the submission’s nomination of
entacapone as the sole main comparator was inappropriate as
selegiline is a pharmacological analogue of rasagiline.
The PBAC noted the sponsor’s argument that selegiline is used
in a different population than rasagiline. However, the PBAC
considered that it remains unclear whether ‘motor
fluctuations’ were a symptom associated with late stage
Parkinson disease, and therefore there may be some overlap in
patients with motor fluctuations and those classified as having
late stage disease. Therefore this argument was not considered to
provide sufficient justification for the exclusion of selegiline
from consideration as a comparator. Therefore the PBAC considered
that a comparison with selegiline would be necessary.
The PBAC acknowledged that entacapone appears to be more widely
used than selegiline, and that rasagiline is likely to substitute
to some extent for entacapone, and therefore considered that a
mixed comparator, comprising both entacapone and selegiline might
be appropriate.
The PBAC noted that there had previously been concerns around
increased risk of melanoma with rasagiline, but considered that
these concerns had been appropriately resolved, and that at this
time this issue is not relevant.
The submission presented one three-arm randomised trial, LARGO,
pre-specified to compare rasagiline with placebo, with additional
post-hoc analyses comparing rasagiline directly with the active
entacapone control arm. The results of LARGO showed no difference
in off time for patients treated with rasagiline compared to
entacapone. The PBAC considered that based on the LARGO study the
claim of non-inferiority to entacapone was reasonable, however, as
noted above, this comparison was not considered the only evidence
that was relevant in the absence of any comparison with
selegiline.
The PBAC rejected the application to list rasagiline on the PBS on
the basis that the comparator was not appropriate because it did
not include the pharmacological analogue, selegiline. Further, the
cost-minimisation basis of the submission that flows on from the
clinical data is an insufficient basis on which to make a judgement
on the cost effectiveness of rasagiline.
The PBAC noted the consumer comments received in its consideration
of rasagiline.
Recommendation:
Reject
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.
14. Sponsor’s Comment
The sponsor has no comment.
