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The Requip study has problems identical to the pramipexole study.

The abstract for the Requip study has been published in the American Academy
of Neurology Abstracts for the Denver meeting in 2002 (see below)

The Requip study was similar to the pramipexole study.  It showed delay in
the decay of radiolabeled DOPA uptake with ropinirole.

However, the study showed that the patients on levodopa did better than
those on ropinirole in terms of the clinical scale, the UPDRS.  The abstract
itself states:

"Although CGI indicated that both groups were adequately
controlled, changes in UPDRS motor score on medication favoured the L-dopa
group by six points"

So, these radioisotope studies have a problem...although they do suggest a
slowing down of the decay in isotope uptake, the efforts to link this to
clinically relevant delays in progression have failed twice - with
pramipexole and with ropinirole.  Indeed, with ropinirole, the UPDRS showed
that the patients on levodopa did better, despite the radioisotope findings.

How can they ignore this fact and still say that they have evidence that
ropinirole delays the progression of the disease?  It doesn't make sense.

This would suggest that the radioisotope studies are not as clean as the
investigators and the drug companies would like them to be.

The conclusion should be that the studies are very interesting, and need
further investigation.  They do not justify the line that they have fed the
media that these drugs delay the progression of the disease.

Jorge Romero

[S11.006] The REAL-PET Study: Slower progression in Early Parkinson's
Disease Treated with Ropinirole Compared with L-Dopa
Alan L. Whone, Philippe Remy, Margaret R. Davis, Michael Sabolek, Claude
Nahmias, A. Jon Stoessl, Ray L. Watts, David J. Brooks London, United
Kingdom; Orsay, France; Atlanta, GA; Ulm, Germany; Hamilton, ON, Canada;
Vancouver, BC, Canada

OBJECTIVE: To investigate the relative progression of early Parkinson's
disease (PD) patients treated with the dopamine agonist ropinirole versus
L-dopa as evidenced by brain 18F-dopa uptake.
BACKGROUND: Currently, there is no medication proven to have disease
modifying properties in PD. Preclinical studies have shown ropinirole to
have neuroprotective properties. Pilot 18F-dopa PET data from a cohort of 45
PD patients showed a trend towards 20% slower disease progression in
ropinirole versus L-dopa treated patients. The REAL-PET study was designed
to confirm this potential.
DESIGN/METHODS: This was a two year, double-blind, multinational study of
186 de novo PD patients treated with ropinirole (ReQuip®) or L-dopa
(Sinemet®); 1:1 randomisation. Patients with insufficient therapeutic
benefit could supplement medication with open adjunct L-dopa and continue in
the study. The primary endpoint was the change in putamen 18F-dopa uptake
measured with 3D PET. Scan data were transformed into standard stereotactic
space to normalise brain position and shape and analysed centrally with: 1.
Regions of interest (ROIs) placed on an MRI template. 2. Statistical
parametric mapping (SPM99) to localise and compare peak voxel changes
between groups. Local ROI analyses on non-spatially transformed data were
also performed by individual centres. Clinical progression scored with the
UPDRS and incidence of dyskinesias were secondary endpoints.
RESULTS: 93 PD patients were randomised to each treatment; 73% of the
ropinirole and 74% of the L-dopa patients completed the two year study. The
mean daily doses after 2 years were: 12.2(6.1)mg ropinirole and
558.7(180.8)mg L-dopa. Blinded review of baseline and follow-up PET
identified 11% of subjects as having normal caudate and putamen 18F-dopa
uptake so these were considered separately. 14% of ropinirole and 8% of
L-dopa patients required supplementary open L-dopa. Central ROI analysis of
putamen 18F-dopa uptake showed significantly slower progression with
ropinirole (-13% ropinirole versus -20% L-dopa; p=0.022). SPM detected
significantly slower progression in both putamen and nigra in the ropinirole
group (putamen: ropinirole -14% vs -20% L-dopa, p=0.034; nigra: ropinirole
+3% vs -8% L-dopa, p=0.035). Local ROI analysis of spatially non-normalised
putamen 18F-dopa uptake showed a trend in favour of ropinirole (-15%
ropinirole and -18% L-dopa; p=0.354).
The incidence of dyskinesia was 27% with L-dopa and 3% with ropinirole
(p<0.001; OR 0.09). Although CGI indicated that both groups were adequately
controlled, changes in UPDRS motor score on medication favoured the L-dopa
group by six points (95% CI 3.53, 9.14).
CONCLUSIONS: Both blinded central ROI analysis and SPM on spatially
normalised 18F-dopa PET data provide clear evidence of significantly slower
disease progression in PD patients taking ropinirole compared with L-dopa.
Furthermore, a significantly lower incidence of dyskinesias was seen in
patients taking ropinirole.
Supported By: GlaxoSmithKline
Category - Movement Disorders
SubCategory - Parkinson's Disease




----- Original Message -----
From: "Hans van der Genugten" <[log in to unmask]>
To: <[log in to unmask]>
Sent: Saturday, April 06, 2002 8:58 PM
Subject: Fw: Requip Slows Progression of PD


> (abstract was modified by Dr. Lieberman to make it more readable for lay
> people.)
>
> The REAL-PET Study:
> Slower progression in Early Parkinson's Disease
> Treated with Ropinirole Compared with L-Dopa
> Presented American Academy of Neurology, April 2002 Denver Colorado
>
> Authors
> Alan L. Whone, Philippe Remy, Margaret R. Davis, Michael Sabolek, Claude
> Nahmias, A. Jon Stoessl, Ray L. Watts, David J. Brooks
>
> Countries
> London, United Kingdom, Orsay, France, Atlanta, GA, Ulm, Germany,
> Hamilton, Ontario, Vancouver, British Columbia
>
> OBJECTIVE:
> To investigate the relative progression of early PD patients treated with
> the dopamine agonist ropinirole (Requip) versus L-dopa as evidenced by
brain
> 18F-dopa uptake.
>
> BACKGROUND:
> Currently, there is no medication proven to have disease modifying
> properties in PD. Preclinical studies have shown ropinirole (Requip) to
have
> neuro-protective properties. Pilot 18F-dopa PET data from a cohort of 45
PD
> patients showed a trend towards 20% slower disease progression in
ropinirole
> (Requip) versus L-dopa treated patients. The REAL-PET study was designed
to
> confirm this potential.
>
> DESIGN/METHODS:
> This was a 2 year, double-blind, multinational study of 186 de novo
> (untreated) PD patients subsequently treated with ropinirole (Requip) or
> L-dopa (Sinemet). The randomization was 1:1 half were treated with
> ropinirole, half with L-dopa. .
>
> Patients with insufficient therapeutic benefit could supplement medication
> with additional L-dopa and continue in the study. The primary endpoint was
> the change in putamen 18F-dopa uptake measured with 3D PET.
>
> Scan data were transformed into standard stereo-tactic space to normalize
> brain position and shape and analyzed by:
> 1. Placing regions of interest on an MRI template.
> 2. Using statistical parametric mapping to localize and compare peak
> changes between groups.
>
> Local regions of interest analyses were also performed by individual
> centers.
>
> Clinical progression scored with the Unified Parkinson Disease Rating
> Scale and incidence of dyskinesias were secondary endpoints.
>
> RESULTS:
> 93 PD patients were randomized to each treatment
> 73% of the ropinirole and 74% of the L-dopa patients completed the 2 year
> study.
>
> The mean daily doses after 2 years were:
> 12.2 mg of ropinirole ( +/- 6.1 mg)
> 558.7 mg of L-dopa (+/- 180.8 mg)
>
> Blinded review of baseline and follow-up PET identified 11% of subjects as
> having normal caudate and putamen 18F-dopa uptake. These were considered
> separately.
>
> 14% of ropinirole and 8% of L-dopa patients required additional L-dopa.
>
> Central region of interest analysis of putamen 18F-dopa uptake showed
> significantly slower progression with ropinirole:
> -13% progression with ropinirole versus
> -20% progression with L-dopa (p value of significance=0.022).
>
> Statistical parametric mapping detected significantly slower progression
> in two regions with ropinirole (Requip).
>
> In the putamen there was
> -14% progression with ropinirole versus
> -20% progression with L-dopa (p value of significance =0.034)
>
> In the substantia nigra there was: +3% progression with ropinirole
> versus -8% progression with L-dopa ( p = 0.035).
>
> Local region of interest analysis of 18F-dopa uptake showed a trend in
> favor of ropinirole
> -15% progression with ropinirole versus
> -18% progression with L-dopa (p =0.354).
> The incidence of dyskinesia was: 3% with ropinerole 27% with L-dopa (p
less
> than 0.001)
>
> Although overall the PD symptoms of both groups were adequately
controlled,
> changes in the Unified Parkinson Disease Rating Scale favored the L-dopa
> group by 6 points.
>
> CONCLUSIONS:
> Both blinded central region of interest analysis and spacial parametric
> mapping on spatially normalized 18F-dopa PET data provide clear evidence
> of significantly slower disease progression in PD patients taking
> ropinirole (Requip) compared with L-dopa.
>
> Furthermore, a significantly lower incidence of dyskinesias was seen in
> patients taking ropinirole(Requip) compared with L-dopa.
>
> Supported By: Glaxo SmithKline
>

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