SWITCH:Restless Legs Patients Switched to Ropinirole From Pramipexole
Condition: Restless Legs Syndrome
MeSH terms: Psychomotor Agitation; Restless Legs Syndrome
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to determine the equipotent dose of ropinirole and pramipexole
      for patients switched from pramipexole to ropinirole in patients with moderate to severe
      primary Restless Legs Syndrome (RLS). The rationale behind Switch is that patients with
      Restless Legs Syndrome can maintain stable efficacy and tolerability if correctly switched
      from one dopamine agonist to an equipotent dose of another.
    

Detailed description: 
      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.
    

Intervention name(s): pramipexole
Intervention type(s): Drug
Intervention description(s): PO, 0.25mg, 0.50mg, or 0.75mg QHS
Intervention MeSH terms: Pramipexole
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Restless Legs Syndrome; Mirapex (pramipexole); Requip(Ropinirole); Dopamine Agonist