SWITCH:Restless Legs Patients Switched to Ropinirole From Pramipexole

BACKGROUND Dopamine agonists such as ropinirole (Requip) and pramipexole (Mirapex) are
effective treatments for Restless Legs Syndrome and Parkinson Disease. However, although
the safety and efficacy may be established, it is common for clinicians to switch between
therapies in order to seek optimal symptomatic relief for their patients. The best strategy
for switching from other dopamine agonists to Requip is currently undetermined. Currently,
ropinirole is the only medication indicated for the treatment of moderate to severe RLS.

Every patient will have an individual response to each dopamine agonist. Usually patients
are switched from one dopamine agonist to another due to the following factors:

- Lack of response or loss of efficacy

- Predictable and dose-related side effects

- Ergot-associated adverse events (pulmonary fibrosis, cardiac valvulopathy, etc.)

- Sleep events (sudden onset of sleep)

- Peripheral edema

- Patient co-morbidities

The lack of clinical data makes it difficult to recommend switching guidelines that are
suitable for all patients. It is therefore recommended that the switching regimen be based
on clinical judgment with individualization for each patient. Switching from one dopamine
agonist to another is dependent upon a number of factors including:

1. The currently prescribed dopamine agonist

2. The dose of the current dopamine agonist

3. Whether dopamine agonist is being administered as monotherapy or as adjunct therapy to
L-dopa

4. Individual patient response to both the current agonist and to the other dopamine
agonist (efficacy and tolerability)

5. Stage of the disease

In placebo-controlled, clinical trials for Requip, a protocol for switching patients to
Requip was not utilized. Patients were generally required to discontinue previous dopamine
agonist medications at least two weeks prior to baseline evaluation. Patients already on
dopamine agonists were discontinued according to the practices of the investigators.

Methods of switching that have been studied previously include:

1. Withdrawal of the current dopamine agonist according to the manufacturer's
recommendations followed by initiation of the other dopamine agonist based upon the
manufacturer's recommendations

2. An overnight switch with abrupt cessation of the current dopamine agonist followed by
initiation of an estimated equivalent dose of the other dopamine agonist

3. Gradual withdrawal of the current dopamine agonist with simultaneous upward titration
of the other dopamine agonist

STUDY DESIGN

SWITCH is a principal investigator-initiated, open-label study that is being conducted
at two sites, to include the Medical College of Georgia and the VA Medical Center
(VAMC). A total of 20 subjects will be enrolled at MCG/VAMC. Individuals who choose to
participate will have approximately three to four study visits over a four week time
period. Patients with moderate to severe primary Restless Legs Syndrome will be
included in the study. All RLS medications will be at a stable dose for at least 4
weeks prior to enrollment. Patients will be switched overnight at the Baseline Visit
at a ratio of either 1:4 or 1:6 Mirapex (pramipexole) to Requip (ropinirole) per
Conversion Table 1 below:

Table 1: Conversion Table

Pramipexole Dose Requip Dose (tablets)

1:4 conversion

0.25mg------------------ 1mg (1X1mg)

0.5mg ------------------ 2mg(1X2mg)

0.75mg-------------------3mg (1X 3mg)

1:6 Conversion

0.25mg------------------1.5mg (3X0.5mg)

0.5mg ------------------3mg (1X 3mg)

0.75mg------------------4mg (1X4mg)

At the baseline study visit, a signed and dated consent will first be obtained from the
subject. In addition, inclusion/exclusion criteria will be reviewed before the start
of any study procedures.

During the course of the study, some or all of the following procedures will be
performed, when patients come to the clinic for their study visit (Table 2):

- Health and Medication Review: Ask patients to answer questions about their
health, medical history, and their medications. (All visits)

- Mini-Mental State Examination: Patients will be asked a series of questions to
determine their mental status. (Visit 1)

- CGI-S/CGI-I: (Visits 1, 2, and 4)

- IRLS: (Visits 1, 2, and 4)

- Epworth Sleepiness Scale: (Visits 1, 2, and 4)

- ECG: An "ECG" or "electrocardiogram" is a test that measures the electrical
activity of the heart. (Visits 1, 2, and 4)

- Blood Tests: The study staff will draw about 3 tablespoons. The study doctor will
use this blood for Hematology and Chemistry panel laboratory tests. (Visit 1)

- Pregnancy Tests: If the patient is female and can have children, their blood
(about one extra tablespoon will be needed to perform this test) will be tested to
see if they are pregnant. Patients will be told if the test results are positive.
The results of the test must be negative in order for the patient to be in the
study. (Visit 1)

- Neurological and Physical Exam: The study doctor will perform both a neurological
and a physical exam. (Visit 1)

- Brief Physical Exam (Visits 2 and 4)

- Concomitant Medication Review (All visits)

- Blood Pressure, Pulse (Visits 1, 2, and 4)

- Height (Visit 1)

- Weight (Visit 1)

- Study Drug: Give patients a supply of study drug and tell them how to take it.
Patients will be asked to bring back all unused study drug to each visit. (Visits
1, 2, and 4)

- Drug Compliance (Visits 2, 3, and 4)

- Adverse Event Review (Visits 2, 3, and 4)

- Telephone Contact: The study doctor or study staff will call the patient to check
on his/her health and see how he/she is handling the study drug. If the study
doctor decides that the patient is doing well on the medication, Visit 3 could
only consist of a telephone contact to include a review of concomitant
medications, adverse events, and drug compliance. If the patient is experiencing
breakthrough symptoms, a clinic visit will be required for Visit 3.

All study visits will take approximately two (2) hours and the telephone contact should
take no longer than thirty (30) minutes.

Study Patients will see both the study coordinator and an investigator at every visit.

At the end of study treatment, subjects will be given treatment options; subjects will
have the option of continuing on ropinirole or returning to the use of pramipexole.
Subjects will then return to the care of their primary care physician/neurologist.

USE OF HUMAN SUBJECTS and/or HUMAN DERIVED MATERIALS

SUBJECT CHARACTERISTICS Patients with moderate to severe Restless Legs Syndrome that
are currently taking a stable dose of Pramipexole will be approached during their visit
to the MCG Movement Disorders Clinic and the VA Neurology Clinic and asked to
participate in SWITCH. If it becomes necessary to recruit from outside of MCG/VAMC,
all advertisement materials will be submitted to the HAC for approval prior to use.
SWITCH is a double site study. We plan to enroll a total of 25-30 individuals between
the two sites. Approximately 20 patients will be enrolled at MCG/VAMC.

MANAGING SIDE EFFECTS As with all drugs, the possibility of unforeseeable risks and
side effects exist. The patients will be told of any important new information that
might affect their decision to continue in the study in a timely manner. Their Restless
Legs Syndrome may not improve or may worsen, despite participation. In previous
studies, patients taking ropinirole reported the following side effects to include:
nausea, headache, dizziness, drowsiness, or sleepiness. Individuals taking ropinirole
may experience dizziness, nausea, sweaty or faintness when first standing up from lying
down. Hallucinations (unreal visions, sounds, or sensations) have also been reported
in patients taking ropinirole, especially in elderly patients, patients taking
ropinirole with L-dopa, or patients taking higher amounts of ropinirole. If a patient
is taking L-dopa for Parkinson's disease, ropinirole may worsen some of the side
effects of L-dopa.

Additionally, ropinirole has been associated with sedating effects, including
somnolence and the possibility of falling asleep while engaged in activities of daily
living, including operation of a motor vehicle.

Syncope or symptomatic hypertension may also occur, particularly during initial
treatment or dose titration. Patients should be cautioned against rising rapidly after
sitting or lying down. Because of possible additive effects, it is recommended that
caution be exercised with patients who have sleep disorders or are taking sedating
medications, alcohol, CNS depressants, or medications that increase ropinirole plasma
levels.

Patients should get medical help and contact the study doctor or study staff, if they
have any of these or any other side effects during the study.

If the study doctor considers that it is in the patient's best interest to discontinue
a current medication so that they can enter the study, the patient may experience some
withdrawal symptoms.

The risks and discomforts of blood drawing from a vein include the possibility of pain
or bruising at the site of the blood draw; occasional feelings of lightheadedness; and,
rarely, infection at the site of the blood draw.

Currently, Ropinirole is an FDA approved drug for the treatment of RLS. There are
currently other medications used for the treatment of Restless Legs Syndrome such as
Pramipexole, gabapentin, Sinemet, clonazepam, opiods (pain medications),
benzodiazepines (sleep medications), anticonvulsants (medications to prevent seizures),
and iron therapy. The study doctor will discuss the benefits and risks associated with
these alternatives with each patient.

If a research related event arises, the study team will manage the patient's care. In
the event of an emergency, the research team is available any time, day or night, via
the MCG paging operator.