COMPLETED CLINICAL TRIALS

BLIND-DATE The BLIND-DATE trial ("BLINDed Withdrawal of Deprenyl in the DATATOP Extension") examined the long-term effects of deprenyl on the course of levodopa-treated Parkinson's disease. (See DATATOP in the Completed Clinical Trials section for the background and details of BLIND-DATE).

CALM-PD The PSG, under the sponsorship of Pharmacia & Upjohn, Inc. (Kalamazoo, MI), led by Ira Shoulson, MD, and Stanley Fahn, MD, conducted the study, CALM-PD (Comparison of the Agonist Pramipexole versus Levodopa on Motor Complications of Parkinson's Disease). Enrollment of 301 subjects at 22 sites began in October 1996 and was completed August 1997. This parallel group, double-blind controlled trial is designed to compare the policies of initial treatment with pramipexole versus initial treatment with carbidopa/levodopa in Parkinson's disease patients. The development of dopaminergic motor complications was the primary outcome of interest. This study also included ß-CIT SPECT measurements, an economic outcome substudy, and a quality-of-life instrument customized for Parkinson's disease. Subjects were examined prospectively for at least 23.5 months, after which time they had the option of participating in the blinded extension of CALM-PD. Subjects concluded participation in CALM-PD and its extension in August, 2001. The results of the CALM-PD study were published in JAMA on October 18, 2000.

DARE DARE (Dyskinesias And Remacemide Effects), led by Anthony Lang, MD, Stanley Fahn, MD and Ira Shoulson, MD, and sponsored by Astra Pharmaceuticals, was a placebo-controlled study of subjects with Parkinson's disease who have severe dyskinesias despite optimized antiparkinsonian medications. Enrollment of 39 subjects at five sites began in December 1997 and was completed in May 1998. A report summarizing the preliminary data from RAMP, REAL and DARE entitled "The Glutamate Antagonist Remacemide Improves Motor Performance in Levodopa-Treated Parkinson's Disease" was presented at the 51st Annual Meeting of the American Academy of Neurology Scientific Session, April 21, 1999, in Toronto, Canada.

DATATOP AND ITS FOLLOW-ON PROTOCOLS DATATOP (Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism), led by Ira Shoulson, MD, and Stanley Fahn, MD, and sponsored by NINDS, is the largest and longest prospective controlled study of therapeutic interventions in Parkinson's disease conducted in the world. It was the first of PSG's multi-center trials. The original cohort of 800 subjects in DATATOP represents the largest group of early Parkinson's disease patients to be followed prospectively and systematically. In-person evaluations of this cohort began in 1987 and continued under several government and industry-sponsored protocols (described below) until 1995. Organized follow-up concluded in 1997 after two additional years of telephone ascertainment of vital status. Thus, the term "DATATOP" refers specifically to the initial NIH-sponsored trial and generically to the decade of follow-up of the initial cohort throughout the subsequent trials. DATATOP. The NIH-sponsored DATATOP trial was carried out to determine whether long-term therapy with deprenyl (selegiline) and/or tocopherol would extend the time before advancing disability required the initiation of levodopa therapy in patients with early, untreated Parkinson's disease. Deprenyl, 10 mg/day, was found to significantly delay the initiation of levodopa. Tocopherol, 2000 IU/day, produced no benefits and there was no interaction of the two drugs. PEP. The DATATOP study was designed to follow subjects for up to 24 months from the time of enrollment into the study. Subjects who reached endpoint (need for levodopa treatment) prior to completion of 24 months were given the opportunity to be re-started in blinded fashion on their previously assigned study drugs for the balance of their 24-month enrollment period. The purpose of this study, called PEP (Preliminary Endpoint Protocol), was to investigate the effectiveness of deprenyl and/or tocopherol, used in combination with levodopa (Sinemet), in delaying the onset and reducing the severity of levodopa-related adverse effects (wearing-off, on-off, toxicity). Of the original 800 DATATOP subjects, 191 subjects were followed in PEP beginning in May 1988. DATX & PEPX. When a preliminary analysis indicated the significant benefit of deprenyl in postponing the need for levodopa in otherwise untreated patients with early PD, the DATATOP and PEP protocols were modified to allow all subjects to cross over in blinded fashion to active deprenyl while remaining on their blinded assignment for tocopherol/placebo. Beginning in August 1989, 367 DATATOP subjects not requiring levodopa were enrolled in DATX and 240 subjects who had required levodopa were enrolled in PEPX. The results of DATX and PEPX were published in Annals of Neurology in 1996, indicating that the initial advantage of deprenyl in delaying the need for levodopa treatment was not sustained and that prior treatment with deprenyl or tocopherol did not reduce the occurrence of subsequent levodopa-associated adverse effects. DATE. At the completion of the NIH-funded DATATOP/PEP/DATX/PEPX studies, an open-label observational study of the long-term effects of deprenyl in early Parkinson's disease continued under the leadership of Ira Shoulson and Stanley Fahn. DATE (DATATOP EXTENSION) was designed to evaluate the long-term effects of deprenyl prior to and following the need for levodopa or dopamine agonists. In 1991, consenting subjects who were still active in DATX (214) or PEPX (347) continued with open-label administration of deprenyl. Open-label tocopherol was prescribed at the investigator's discretion. Subjects who developed the need for an agonist during the study were randomly assigned to either bromocriptine (Parlodel) or pergolide (Permax). Additional financial support for DATE was provided by Somerset Pharmaceuticals. BLIND-DATE. By 1993 the vast majority of the DATATOP subjects were being treated with levodopa. In order to examine in a controlled fashion the long-term effects of deprenyl on the course of levodopa-treated Parkinson's disease, DATE subjects, beginning in April 1993, consented to enroll in BLIND-DATE ("BLINDed Withdrawal of Deprenyl in the DATATOP Extension"). In this trial, supported primarily by Somerset Pharmaceuticals, 368 subjects were randomized to continue or withdraw from deprenyl (selegiline) treatment while remaining on levodopa. After two years of prospective follow up, sustained deprenyl therapy was found to accelerate the occurrence of dyskinesias but postpone on-off motor fluctuations and freezing of gait. A full report is in preparation. Vital Status. At the conclusion of BLIND-DATE in 1995, active subjects and original DATATOP subjects who were no longer trial participants, were invited to return for a final in-person evaluation and consent to contribute a blood DNA sample. Four hundred sixty-eight of the original 800 subjects provided this valuable data. In both 1996 and 1997 investigators and coordinators mounted a telephone ascertainment of the status of the 800 DATATOP subjects. Neither deprenyl nor tocopheral significantly affected mortality; however, the DATATOP cohort as a whole had a remarkably low mortality rate, about the same as age-matched persons without Parkinson's disease (March 1998 issue of Annals of Neurology). A summary of the collective findings of the DATATOP protocols was published in 1998 in Annals of Neurology. PSG Investigators are continuing to explore the wealth of clinical, biological, and genetic data collected over the years of DATATOP and its follow-on protocols.

DATE-MATE DATE-MATE, led by Julie Carter, RN, ANP, Barbara Stewart, RN, PhD, and Pat Archbold, RN, DNSc, FAAN, and sponsored by the Parkinson Study Group, Medical Research Foundation of Oregon, American Parkinson's Disease Association, and the Oregon Chapter of American Parkinson's Disease Association, was a longitudinal study of spouse caregivers of patients participating in the DATATOP trial. The purpose of this study of 321 spouses was to examine how the consequences and outcomes of caregiving in the healthy spouse are affected by the progression of PD. The PSG report (Carter JH, primary author), "Living with a Person with Parkinson's Disease: The Spouse's Perspective by Stage of Disease", was published in the January 1998 issue of Movement Disorders. Data analysis is continuing and a second report is being prepared for publication.

Evaluation of DOPASCAN™ in Parkinson's Disease and Related Disorders PSG, under the leadership of Kenneth Marek, MD, and John Seibyl, MD, and the sponsorship of Guilford Pharmaceuticals, Inc. (Baltimore, MD), conducted a five-center trial to examine DOPASCAN™, a SPECT imaging ligand, as a diagnostic marker for Parkinson's disease. DOPASCAN™ is a radiotracer that binds to the dopamine transporter and provides a measure of the integrity of dopamine terminals. Enrollment and follow-up of 96 subjects at five sites was completed in December 1996. Data were published in abstract form in Movement Disorders and Journal of Nuclear Medicine and a full report is under review.

ELLDOPA One of the most lingering and important questions in the therapeutics of PD is whether levodopa, the mainstay of treatment, has long-term beneficial or harmful effects on the progression of disease. A survey on treating patterns was conducted during the PSG/MDS Symposia in October 1995 and reported in October 1996 in Movement Disorders. An application was submitted to the National Institute of Health (NIH) in June 1996 for the ELLDOPA (Earlier versus Later LevoDOPA) placebo-controlled trial, which was reviewed favorably and awarded by the National Institute of Neurological Disorders and Stroke (NINDS-NIH) in January 1998. The ELLDOPA trial, under the direction of Stanley Fahn, MD, and Ira Shoulson, MD, began enrollment of 360 patients with early Parkinson's disease at 35 PSG sites in October 1998. Subjects were followed for 40 weeks prior to a 17-day washout and final evaluation of the progression of disease. A ß-CIT SPECT study, funded by a grant to Kenneth Marek, MD, by the Department of Defense, was carried out in a sub-set of ELLDOPA subjects to assess a biological marker of the progression of Parkinson's disease (loss of dopamine transporter binding sites). As of September 2001, enrollment was closed for the study with 361 subjects completing enrollment. The final subject visit is expected in June 2002 with analysis to follow. For additional information on the scientific rationale for this study, please see the 1999 publication in Archives of Neurology.

PATCH I PATCH I (PArkinson's Disease Transdermal Clinical Trial Helping to Assess SPM-962 Transdermal System (TDS) in Patients Not Receiving DopaminergicTherapy), led by Ira Shoulson, MD, and under the sponsorship of Schwarz Pharma Inc. (Meguon, WI and Monheim, Germany) conducted a Phase IIb efficacy, safety and tolerability study of the experimental dopamine agonist SPM-962, delivered as a transdermal patch system in patients with Parkinson's disease who are not receiving dopaminergic therapy. Enrollment of 242 subjects at 28 sites began on November 15, 1999 and was completed in July, 2000.

POETRY The POETRY study, Parkinson's Disease on Estrogen Replacement Therapy in the Menopause Years, under the direction of Dr. Lisa Shulman, was a study in postmenopausal women with PD to measure the safety and tolerability of estrogen replacement therapy (ERT). The study also measured how ERT affects thinking and behavior, movement and activities of daily living, as well as motor fluctuations and dyskinesias. Approximately thirty participants were enrolled at 6 US sites. Enrollment began in late spring/early summer 2003, and ended in December 2005.

PRECEPT The Parkinson Study Group (PSG), in collaboration with two pharmaceutical companies, Cephalon, Inc. (West Chester, PA) and H. Lundbeck A/S (Valby-Copenhagen, Denmark), conducted a study for patients with early Parkinson's disease called PRECEPT (Parkinson Research Examination of CEP1348 Trial). The goal of PRECEPT was to determine if the investigational drug CEP-1347 could slow the clinical progression of early Parkinson's disease. The study assessed the safety and tolerability of different doses of CEP-1347 and also examined the long-term effects of CEP-1347 on the areas of the brain affected by Parkinson's disease. The study recruited approximately 800 participants at 65 sites across the United States and Canada. Enrollment began in April 2002 and was completed in March 2004.

PRESTO   The Parkinson Study Group (PSG), in collaboration with Teva Clinical Research, Inc., conducted a study for patients with moderate to advanced Parkinson’s Disease called PRESTO (Parkinson's Resagiline: Efficacy & Safety in the Treatment of "Off"). This 26-week study examined the safety, effectiveness and tolerability of an investigational drug in patients who do not experience full benefit from their L-dopa dosage. T he study recruited about 450 subjects at 44 sites across the United States and Canada. Enrollment began in September 2000 and was completed in June 2002. For additional information, please visit PRESTO.

PRIME The PRIME (PRamipexole In Minority Persons with Parkinson's Disease: Efficacy) study led by Caroline Tanner, MD, and Cynthia Comella, MD, and sponsored by Pharmacia & Upjohn, Inc. (Kalamazoo, MI) was a placebo-controlled, safety, efficacy and pharmacokinetic study of pramipexole in minority persons with moderate to advanced Parkinson's disease who are receiving concomitant carbidopa/levodopa therapy. Enrollment of 144 subjects at 17 sites began in January 1997 and the final subject visit was completed in October 1998. This is the first trial in Parkinson's disease designed to evaluate the influence of ethnicity on the safety, efficacy and pharmacokinetics of a therapeutic agent.

PSYCLOPS The PSYCLOPS (PSYchosis and CLOzapine in Parkinson'S Disease) study led by Joseph Friedman, MD, and Christopher Goetz, MD, which examined the effects of the non-neuroleptic, antipsychotic clozapine on dopaminergic-induced psychosis in PD patients, was supported primarily by the FDA Orphan Drug Division. Enrollment of 60 subjects at six PSG sites began in April of 1995 and the final subject visit was completed in January 1997. This randomized, controlled clinical trial supported the findings of multiple open-label studies that low dose clozapine ameliorates psychosis without worsening parkinsonism. The results have been published in abstract form and a full report was in the March 1999 issue of the New England Journal of Medicine, volume 340, pg 757-763.

QE2 QE2 (Coenzyme Q10 Evaluation-2) was a randomized, double-blind, parallel group 16-month study, designed to compare three dosages of coenzyme Q10 (ubiquinone) and placebo in patients who have early PD. Ten PSG sites were selected to enroll 80 subjects. The goals of the study were to: (1) assess a clinical trial design devised to efficiently evaluate the maximally tolerated dose and efficacy of potential protective therapies for PD; (2) extend our previous studies of the safety and tolerability of high doses of coenzyme Q10; and (3) evaluate the ability of coenzyme Q10 to affect the clinical progression of PD and platelet mitochondrial function. Enrollment of 80 subjects was completed in February of 2000.

Quality-of-Life Instrument/Economic Outcomes Parkinson's Disease QUAlity of LIFe (PDQUALIF) was a multi-center study to develop and test a quality-of-life instrument specific for Parkinson's disease. Under the direction of Mickie Welsh, RN, DNS, this study employed a cross-sectional design of individuals in all stages of Parkinson's disease in an effort to establish the reliability and validity of the PDQUALIF. There were a total of 233 patients enrolled at the participating 13 PSG sites. Analysis compared the PDQUALIF to the SF36 and SIP quality-of-life instruments. An abstract of the preliminary results from Phase II testing was presented at the 1997 PSG/Movement Disorders Society (MDS) Symposia and published in Movement Disorders. In the CALM-PD and TEMPO trials, a modified PDQUALIF scale was used.

RAMP The RAMP (Remacemide As Monotherapy in Parkinson's Disease) study, led by Ira Shoulson, MD, and J. Timothy Greenamyre, MD, PhD, and sponsored by Astra Pharmaceuticals was the first placebo-controlled study to evaluate the safety, tolerability and efficacy of dosages of remacemide as monotherapy in patients with early Parkinson's disease. Enrollment of 200 subjects at 21 PSG sites began in March 1997 and was completed in April 1998.

RAPID The Parkinson Study Group (PSG), under the sponsorship of Teva Clinical Research, conduced a study for advanced Parkinson's disease patients with motor complications ("on-off" effects) called RAPID (Rapid-Acting ParkInson's Drug). This 20-24 week study of TV-1203/Carbidopa dispersible tablets, a novel investigational variation of levodopa, examined the efficacy, safety, and tolerability of TV-1203/Carbidopa dispersible tablets in treating advanced Parkinson disease patients who have motor fluctuations while being treated with chronic levodopa/carbidopa therapy. Teva Clinical Research, based in North Wales, PA is the U.S. affiliate of Teva Pharmaceutical Industries, LTD, Israel, an international pharmaceutical company headquartered in Israel. This study enrolled approximately 300 patients at 41 sites across the United States and Canada and completed enrollment in June 2002. For additional information, please visit RAPID.

REAL REAL (REmacemide as an Adjunct to Levodopa), led by Ira Shoulson, MD, and John Penney, MD, and sponsored by Astra Pharmaceuticals, was the first placebo-controlled study to evaluate the safety, tolerability and efficacy of remacemide in levodopa-treated patients with Parkinson's disease who have motor fluctuations. Enrollment of 279 subjects at 29 PSG sites began in August 1997 and was completed in June 1998.

ROADS Follow-up of the 320 subjects in the ROADS (RO 19-6327 Assessment and Dose Finding Study) controlled trial of the MAO-B inhibitor lazabemide, led by Ira Shoulson, MD, and Karl Kieburtz, MD, was completed in 1994 and analysis was completed in 1995. Like deprenyl, lazabemide extended the time before emerging disability required the initiation of levodopa therapy in patients with early Parkinson's disease. An abstract of the preliminary results of this 18-site investigation of lazabemide in untreated PD patients was presented in May 1995 at the annual meeting of the American Academy of Neurology. A full report was published in Annals of Neurology.

SEESAW The SEESAW (Safety and Efficacy of Entacapone Study Assessing Wearing-off) controlled trial, led by Ira Shoulson, MD, and Stanley Fahn, MD, and sponsored by Orion-Farmos, Inc. (Espoo, Finland), was initiated in March 1994 to examine the impact of entacapone, a COMT inhibitor, in levodopa-treated PD patients with motor fluctuations. Enrollment of 205 subjects at 18 PSG sites was completed in December 1994, and follow-up was completed in June 1995. A summary of the results of the study was presented at the Fourth International Congress of Movement Disorders meeting in Vienna, Austria, June 1996 (published in Movement Disorders) and the 10th PSG/MDS Symposia in Miami, October 1996 (published in Movement Disorders). A full report of the SEESAW trial was published in Annals of Neurology.

SPIRAL The PSG study, led by Karl Kieburtz, MD, and John Nutt, MD, and sponsored by Astra Pharmaceuticals, conducted the study SPIRAL (Study of Pharmacokinetic Interactions Between Remacemide And Levodopa), which was the first study to evaluate whether remacemide, a glutamate receptor antagonist, exerts an effect on circulating plasma levodopa concentrations in patients with Parkinson's disease. Enrollment of 16 subjects at four sites began in February 1997 and was completed in April 1997. A report has been submitted for publication.

START-LE START-LE (Short Term Assessment of RO 19-6327 Tolerability in Levodopa Exposed Patients) was the second of the PSG's trials investigating lazabemide. In this trial, sponsored by Hoffmann-La Roche and led by Ira Shoulson, MD, and Stanley Fahn, MD, 137 subjects being treated with levodopa for their Parkinson's disease were enrolled at 14 sites from March 1991 to January 1992. This eight-week study demonstrated the overall safety and tolerability of lazabemide in subjects taking levodopa. The primary report of this study was published in Archives of Neurology.

START-UP Lazabemide (RO 19-6327) is a short-acting, reversible, highly selective inhibitor of monoamine oxidase type B which, unlike deprenyl, is not metabolized to active compounds. The PSG, under the sponsorship of Hoffmann-La Roche, Inc. (Nutley, NJ), and led by Ira Shoulson, MD, and Stanley Fahn, MD, undertook the first of its three trials of lazabemide in the study START-UP (Short Term Assessment of RO 19-6327 Tolerability in Untreated Parkinson's Disease) from November 1990 to September 1991; 201 subjects with early, untreated PD were enrolled at 14 sites. The overall safety and benefits of lazabemide observed in this eight-week trial justified further long-term investigation of the drug. The primary report of the study was published in Annals of Neurology.

STEP-UP The STEP-UP (Safety, Tolerability and Efficacy of Pramipexole in Untreated Parkinsonism) controlled trial, led by Ira Shoulson, MD, and Stanley Fahn, MD, and sponsored by Pharmacia & Upjohn, Inc., was initiated in March 1994 to examine multiple dosages of the dopamine agonist pramipexole in early PD. Active follow-up of the 264 enrolled subjects at 20 PSG sites was completed in December 1994. An abstract summarizing the preliminary results of this trial was presented at the PSG/MDS Symposia in Washington, DC, October 1995, and published in Movement Disorders. A full report of the STEP-UP trial was published in the July 9, 1997 issue of the Journal of the American Medical Association.

TEMPO TEMPO (Rasagiline Mesylate [TVP-1012] in Early Monotherapy for PD Outpatients), led by Ira Shoulson, MD, and Stanley Fahn, MD, is a placebo-controlled multi-center trial, sponsored by Teva Pharmaceutical Industries, Ltd. - Israel and Teva Pharmaceuticals, USA, examining the effects of two dosages of rasagiline in patients with early Parkinson's disease. Rasagiline is a novel MAO-B inhibitor. Enrollment of approximately 400 patients at 27 PSG sites began in November 1997 and was completed in April of 1999. The results of the TEMPO study were published in Archives of Neurology on December 18, 2002. Please see the TEMPO press release for more information.

TEST-PD/RETEST-PD The TEST-PD/RETEST-PD (Tolerability and Efficacy of SIB-1508Y Therapy in PD), led by Ira Shoulson, MD and John Growdon, MD, and sponsored by SIBIA Neurosciences, Inc. (La Jolla, CA), is the first placebo-controlled study to evaluate the safety, tolerability and efficacy of dosages of SIB-1508Y in patients with Parkinson's disease who are requiring, but not receiving, dopaminergic therapy. SIB-1508Y is a nicotinic acetylcholine receptor agonist which produces motor and cognitive benefits in animal models of Parkinson's disease. Enrollment of 32 subjects at ten sites for the initial phase of the study (TEST-PD, higher dosage groups) began in January 1998 and was completed in May, 1998. Enrollment of 45 subjects for the second phase (RETEST-PD, lower dosage groups) began in July 1998 and was completed in April 1999. The data are currently being analyzed.

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