A Study to Evaluate the Safety and Efficacy of IPX203 in Parkinson's Disease Participants With Motor Fluctuations

Phase 3

Completed

Conditions: Parkinson's Disease (Disorder)

Interventions: Drug: IPX203 ER CD-LD
Drug: IR CD-LD
Other: Placebo Matching IR CD-LD
Other: Placebo Matching IPX203

Registration Number: NCT03670953

Lead Sponsor: Impax Laboratories, LLC

Brief Summary: To evaluate the safety and efficacy of IPX203 (carbidopa and levodopa) extended-release capsules (IPX203 ER CD-LD) in comparison to immediate release (IR) CD-LD in the treatment of CD-LD-experienced participants with Parkinson's disease (PD) who have motor fluctuations.

Detailed Description: This was a multicenter, randomized, double-blind, double-dummy, active-controlled, parallel-group study. The study consisted of a 3-week, open-label IR CD-LD dose adjustment period; a 4-week, open-label period for conversion to IPX203; followed by a 13-week double-blind treatment period with participants randomized in a 1:1 ratio, stratified by center, to receive either IPX203 (with matching IR CD-LD placebo) or IR CD-LD (with matching IPX203 placebo).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 630

Inclusion Criteria

Male or female participants diagnosed at age ≥ 40 years with PD, consistent with the United Kingdom Parkinson's Disease Society Brain Bank Diagnostic Criteria and who are being treated with stable regimens of CD-LD but experiencing motor fluctuations.
Able to provide written informed consent prior to the conduct of any study-specific procedures.
Female participants of childbearing potential must have a negative urine pregnancy test at Screening Visit.
Negative urine screen for drugs of abuse and negative alcohol breath test at Screening.
Hoehn and Yahr Stages 1, 2, 3, or 4 in the "On" state (part of Movement Disorders Society version of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS] Part III)
Agrees to use a medically acceptable method of contraception throughout the study and for 6 weeks after completing the study. Medically acceptable methods of contraception that may be used by the participant and/or partner include but are not limited to: abstinence, oral contraception, NuvaRing or transdermal systems, diaphragm with vaginal spermicide, intrauterine device, condom and partner using vaginal spermicide, surgical sterilization (6 months), progestin implant or injection, or postmenopausal female (no menstrual period for ˃ 2 years) or vasectomy (˃ 6 months).
Montreal Cognitive Assessment (MoCA) score ≥ 24 at Screening Visit in "On" state.
Able to differentiate "On" state from "Off" state as determined by at least 75% concordance with a trained rater in "On/Off" ratings for 8 ratings over a 4-hour training period. The concordance must include at least 1 "On" and 1 "Off" rating and must be achieved within two 4-hour training sessions.
Able and willing to comply with the protocol, including completion of diaries and availability for all study visits.
Responsive to CD-LD therapy and currently being treated on a stable regimen with CD-LD for at least 4 weeks prior to Visit 1.
At Screening, the participant has predictable "Off" periods.

Exclusion Criteria

Received any investigational medications within 30 days or 5 times the half-life, whichever is longer, prior to Visit 1.
Female participants who are currently breastfeeding or lactating.
Had prior neurosurgical treatment for PD or if such procedure is planned or anticipated during the study period.
Allergic to any excipient in the study drugs.
History of medical conditions or of a prior surgical procedure that would interfere with LD absorption, such as gastrectomy, proximal small-bowel resection, or bariatric surgery.
History of upper gastrointestinal hemorrhage in participants with peptic ulcer disease within the past 5 years.
History of glaucoma with intraocular pressures that are elevated despite appropriate medical management.
History of seizure or epilepsy and experienced at least 1 seizure during the past 12 months or has not been compliant with medically recommended therapy or visits.
History of myocardial infarction with residual atrial, nodal, or ventricular arrhythmias that are not controlled with medical and/or surgical interventions. A recent (≤ 12 months) history of myocardial infarction with secondary arrhythmias is exclusionary regardless of the therapeutic control.
History of neuroleptic malignant syndrome or of nontraumatic rhabdomyolysis.
Liver enzyme values ≥ 2.5 times the upper limit of normal; or history of severe hepatic impairment.
Serum creatinine level ≥ 1.75 times the upper limit of normal; or requires dialysis at the time of Screening.
Participant with a history of malignant melanoma or with a suspicious undiagnosed skin lesion which in the opinion of the investigator could be melanoma.
History of drug or alcohol abuse within the 12 months prior to Screening.
Received within 4 weeks of Screening or planning to take during participation in the clinical study:
Any doses of a CR CD-LD apart from a single daily bedtime dose, any doses of Rytary, additional CD (eg, Lodosyn) or benserazide (eg, Serazide), or catechol-O-methyl transferase inhibitors (entacapone or tolcapone) or medications containing these inhibitors (Stalevo),
Nonselective monoamine oxidase inhibitors (MAOI), apomorphine, or antidopaminergic agents, including antiemetics.
Employees or family members of the investigator, study site, or sponsor.
Participants who have previously participated in an IPX203 study.
Participants who, in the opinion of the clinical investigator, should not participate in the study.
Based on clinical assessment, participant does not adequately comprehend the terminology needed to complete the PD diary.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
IPX203 - Double-Blind Maintenance	IPX203 ER CD-LD	Participants received IPX203 capsules orally, every 6 - 12 hours for 13 weeks at a stable dose established at the end of dose conversion period along with placebo matched to IR CD-LD.
IPX203 - Dose Conversion	IPX203 ER CD-LD	Participants received extended release (ER) CD-LD (IPX203) capsules orally, every 6 - 12 hours for a period of 4 weeks at a dose based on their most frequent stable dose of IR CD-LD in dose adjustment period. Participant with most frequent stable dose of 25-100 milligrams (mg) IR CD-LD received 70 - 280 mg IPX203 thrice daily (TID); \>25-100 - 37.5-150 mg IR CD-LD received 105-420 mg IPX203 TID; \>37.5-150 - 50-200 mg IR CD-LD received 140-560 mg IPX203 TID; \>50 - 200 mg IR CD-LD received 175-700 mg IPX203 TID. Participants who received a daily total dose of less than 125-500 mg IR CD-LD in dose adjustment received IPX203 every 12 hours. After initial dose conversion from IR CD-LD to IPX203 as per above mentioned dose conversion schedule, the dose of IPX203 could be further adjusted during the 4 week dose conversion period.
IR CD-LD - Double -Blind Maintenance	Placebo Matching IR CD-LD	Participants received IR CD-LD tablets daily orally, for 13 weeks at a stable dose established at the end of dose adjustment period along with placebo matched to IPX203.
IR CD-LD - Double -Blind Maintenance	IR CD-LD	Participants received IR CD-LD tablets daily orally, for 13 weeks at a stable dose established at the end of dose adjustment period along with placebo matched to IPX203.
IR CD-LD - Dose Adjustment	IR CD-LD	Participants started on the same dose as the pre-study dosing regimen of IR CD-LD and then received dose adjusted IR CD-LD tablets daily orally, for a period of 3 weeks. If the participant was taking controlled release carbidopa-levodopa (CR CD-LD), the CR CD-LD was discontinued and substituted with a 1:1 milligram-equivalent dose of IR CD-LD.
IPX203 - Double-Blind Maintenance	Placebo Matching IPX203	Participants received IPX203 capsules orally, every 6 - 12 hours for 13 weeks at a stable dose established at the end of dose conversion period along with placebo matched to IR CD-LD.

Primary Outcome Measures

Name	Time	Method
Mean Change From Baseline in "Good on" Time Per Day at Week 20/Early Termination (ET)	Baseline (Week 7) and Week 20/ET	"Good on" time was derived from the 3-day PD Diaries. For each day, "Good on" time was calculated by adding the number of half-hour intervals in which either an "On" without dyskinesia or "On" with nontroublesome dyskinesia was checked. Baseline was defined as data obtained from PD Diary collected over 3 days prior to Week 7/Randomization. Least square mean (LSM), standard error (SE), confidence interval (CI), Mixed model repeated measures (MMRM), Change from baseline (CFB).

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in "Off" Time Per Day at Week 20/ET	Baseline (Week 7) and Week 20/ET	"Off" time was derived from the 3-day PD Diaries. For each day, "Off" time was calculated by adding the number of half-hour intervals in which the Status "Off" was checked. Baseline was defined as data obtained from PD Diary collected over 3 days prior to Week 7/Randomization.
Change From Baseline in The Sum of MDS-UPDRS Part II and Part III at Week 20/ET	Baseline (Week 7) and Week 20/ET	MDS-UPDRS is a multimodal scale assessing impairment and disability consisting of 4 parts. (Part I; 13 items) non-motor experiences of daily living, (Part II; 13 items) motor experiences of daily living completed by the participants, (Part III; 34 items) motor examination of PD and was administered by the rater, and (Part IV; 6 items) motor complication integrates participant-derived information with the rater's clinical observations and judgements and is completed by the rater. For each question a numeric score was assigned between 0-4, where 0 = Normal, 1 = Slight, 2 = Mild, 3 = Moderate, 4 = Severe. MDS-UPDRS Total Score equals the sum of Parts I, II, and III and IV (Range 0-234). The scale range for Part II+III score is 0-188. A higher score indicated more severe symptoms of PD. Baseline was defined as data obtained from PD Diary collected over 3 days prior to Week 7/Randomization.
Percentage of Participants With Either "Much Improved" or "Very Much Improved" in Patient Global Impression of Change (PGI-C) Scores at Week 20/ET	Week 20/ET	The Patient Global Impression of Change (PGIC) is self assessment questionnaire which was used by participants to compare his/her condition on a 7-point scale ranging from 1-Very Much Worse, 2-Much Worse, 3-Minimally Worse, 4-No Change, 5-Minimally Improved, 6-Much Improved, 7-Very Much Improved. Percentage of participants with either "Much Improved" or "Very Much Improved" was reported.
Change From Baseline in The Movement Disorders Society Version of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III at Week 20/ET	Baseline (Week 7) and Week 20/ET	MDS-UPDRS is a multimodal scale assessing impairment and disability consisting of 4 parts. (Part I; 13 items) non-motor experiences of daily living, (Part II; 13 items) motor experiences of daily living completed by the participants, (Part III; 34 items) motor examination of PD and was administered by the rater, and (Part IV; 6 items) motor complication integrates participant-derived information with the rater's clinical observations and judgements and is completed by the rater. For each question a numeric score was assigned between 0-4, where 0 = Normal, 1 = Slight, 2 = Mild, 3 = Moderate, 4 = Severe. MDS-UPDRS Total Score equals the sum of Parts I, II, and III and IV (Range 0-234). Part III score ranges from 0 to 136. A higher score indicated more severe symptoms of PD. Baseline was defined as data obtained from PD Diary collected over 3 days prior to Week 7/Randomization.

Trial Locations

Locations (108): University of Miami-UHealth at Boca Raton (152)
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Boca Raton, Florida, United States
Parkinson's Disease and Movement Disorders Center of Boca Raton (121)
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Boca Raton, Florida, United States
Keck School of Medicine of USC/University of Southern California (106)
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Los Angeles, California, United States
Emory Brain Health Center (110)
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Atlanta, Georgia, United States
Houston Methodist Neurological Institute/Movement Disorders Clinic (135)
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Houston, Texas, United States
Neurohk, s.r.o (701)
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Choceň, Czechia
Fakultni nemocnice u sv. Anny v Brne, I. neurologicka klinika (704)
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Brno, Czechia
Medical Professional Clinical Research Center, INC (163)
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Miami, Florida, United States
NZOZ Neuro-Kard Ilkowski i Partnerzy Spolka Partnerska Lekarzy (801)
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Poznań, Poland
Cleveland Clinic Lou Ruvo Center for Brain Health (142)
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Las Vegas, Nevada, United States
Roseman Medical Research Institute/Roseman Medical Group (154)
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Las Vegas, Nevada, United States
Ucgni (133)
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Cincinnati, Ohio, United States
Curiositas ad sanum, Studien und Beratungs GmbH(311)
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München, Bavaria, Germany
University of Kansas Medical Center (118)
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Kansas City, Kansas, United States
St. Josef-Hospital, Universitatsklinik fur Neurologie, Klinisches Forschungszentrum fur Neurodegeneration (301)
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Bochum, North Rhine-Westphalia, Germany
Xenoscience, Inc. (102)
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Phoenix, Arizona, United States
St. Joseph's Hospital & Medical Center/ Barrow Neurological Institute (156)
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Phoenix, Arizona, United States
Centro Ricerca Parkinson San Raffaele Cassino (601)
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Cassino, Italy/Frosinone/Lazio, Italy
Fondazione lstituto Neurologico Nazionale "C. Mondino" (606)
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Pavia, Italy/Pavia/Lombardia, Italy
Azienda Ospedaliero-Universitaria Pisana (602)
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Pisa, Italy/Pisa/Toscana, Italy
Department of Neuroscience, Mental Health and Sensory System (NeSMOS), Sapienza University (603)
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Roma, Italy/Roma/Lazio, Italy
INSERM, Centre d'investigation Clinique 1402, CHU de Poitiers (402)
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Poitiers Cedex, France
Klinikum rechts der lsar der TUM, Klinik und Poliklinik fur Neurologie (303)
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München, Bavaria, Germany
University of Arkansas for Medical Sciences (117)
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Little Rock, Arkansas, United States
Loma Linda University Health Care, Department of Neurology (137)
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Loma Linda, California, United States
Clinical Trials, Inc. (113)
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Little Rock, Arkansas, United States
SC3 Research - Pasadena (148)
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Pasadena, California, United States
Hoag Memorial Hospital Presbyterian (134)
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Newport Beach, California, United States
SC3 Research - Reseda (146)
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Reseda, California, United States
Christiana Care Neurology Specialists (153)
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Newark, Delaware, United States
JEM Research Institute (136)
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Atlantis, Florida, United States
MD Clinical (111)
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Hallandale Beach, Florida, United States
Infinity Clinical Research (104)
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Hollywood, Florida, United States
University of Florida Health Science Center(129)
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Jacksonville, Florida, United States
Neurology Associates, P.A. (125)
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Maitland, Florida, United States
Infinity Clinical Research, LLC (105)
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Sunrise, Florida, United States
University of Miami (149)
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Miami, Florida, United States
Parkinsons's Disease Treatment Center of Southwest Florida (131)
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Port Charlotte, Florida, United States
Charter Research (166)
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Winter Park, Florida, United States
Premiere Research Institute at Palm Beach Neurology (174)
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West Palm Beach, Florida, United States
NeuroStudies.net, LLC (155)
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Decatur, Georgia, United States
Northwestern Medical Group Neurology Clinic(145)
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Chicago, Illinois, United States
Central DuPage Hospital (151)
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Winfield, Illinois, United States
Indiana University Health Neuroscience Center (164)
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Indianapolis, Indiana, United States
Struthers Parkinson's Center (130)
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Golden Valley, Minnesota, United States
Henry Ford West Bloomfield Hospital (100)
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West Bloomfield, Michigan, United States
Quest Research Institute (103)
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Farmington Hills, Michigan, United States
Washington University (109)
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Saint Louis, Missouri, United States
Albany Medical College (139)
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Albany, New York, United States
University Hospitals Cleveland Medical Center (123)
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Cleveland, Ohio, United States
Mount Sinai West-Department of Neurology(172)
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New York, New York, United States
Cleveland Clinic (144)
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Cleveland, Ohio, United States
University of Toledo, Gardner-McMaster Parkinson Center (122)
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Toledo, Ohio, United States
Movement Disorder Clinic of Oklahoma (115)
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Tulsa, Oklahoma, United States
The Vanderbilt Clinic(158)
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Nashville, Tennessee, United States
University of Texas Southwestern Medical Center (143)
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Dallas, Texas, United States
Neurology Consultants of Dallas, PA (108)
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Dallas, Texas, United States
Inova Medical Group-Neurology I (147)
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Alexandria, Virginia, United States
VCU Health - Neuroscience, Orthopaedic and Wellness Center (124)
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Henrico, Virginia, United States
Inland Northwest Research (119)
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Spokane, Washington, United States
Booth Gardner Parkinson's Care Center (112)
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Kirkland, Washington, United States
AXON Clinical, s.r.o. (700)
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Praha 5, Czechia
Clintrial s.r.o. (703)
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Praha 10, Czechia
Nemocnice Pardubickeho kraje, a.s., Pardubicka nemocnice, Neurologicka klinika (702)
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Pardubice, Czechia
CHU de Clermont-Ferrand - Hopital Gabriel Montpied (404)
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Clermont-Ferrand Cedex 1, France
Neurologicka ordinace FORBELI s.r.o.(706)
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Praha 6, Czechia
Centre Hospitalier Universitaire de Nice (400)
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Nice, France
CHU de Montpellier, Hopital Gui de Chauliac(405)
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Montpellier Cedex 5, France
Kliniken Beelitz GmbH, Neurologisches Fachkrankenhaus fUr Bewegungsstorungen/Parkinson (300)
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Beelitz-Heilstatten, Brandenburg, Germany
Universitatsklinikum Carl Gustav Carus, Klinik und Poliklinik fur Neurologie (307)
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Dresden, Saxony, Germany
Centre d'Investigation Clinique 1436-CHU Purpan-Hopital Pierre Paul Riquet (403)
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Toulouse Cedex 9, France
Klinik Haag i. OB, Geriatric Hospital (305)
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Haag In Oberbayern, Oberbayern (Upper Bavaria), Germany
Gemeinschaftspraxis Dr. med. Joachim Springub/ Wolfgang Schwarz, Studienzentrum Nord-West (306)
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Westerstede, Lower Saxony, Germany
Dr. med. REINHARDT Ehret Neurologie Berlin Schlobstr. 29 (309)
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Berlin, Germany
Department "G.F. Ingrassia" Section of neuroscience-Policlinico "Vittorio Emanuele" (608)
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Catania, Italy/Catania/Sicily, Italy
Universita G. D'annunzio CeSi Met (604)
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Chieti, Italy/Chieti/Abbruzzo, Italy
Szpital Sw. Rozy (805)
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Kraków, Poland
University of Rome Tor Vergata/Hospital Tor Vergata (605)
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Roma, Italy/Roma/Lazio, Italy
IRCCS San Raffaele Pisana (600)
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Roma, Italy/Roma/Lazio, Italy
Centrum Medyczne Neuromed (803)
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Bydgoszcz, Poland
Krakowska Akademia Neurologii Sp. z o.o.(802)
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Kraków, Poland
NZOZ Neuromed M. i M Nastaj Spolka Partnerska(800)
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Lublin, Poland
Neuro-Care Sp. z o.o. sp. k.(804)
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Siemianowice Śląskie, Poland
Hospital Genral Universitario de Elche (509)
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Elche, Alicante, Spain
Centrum Medyczne NeuroProtect (806)
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Warszawa, Poland
Hospital Universitari Mutua Terrassa (506)
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Terrassa, Barcelona, Spain
Re:Cognition Health Ltd (202)
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London, United Kingdom
Hospital Universitari General de Catalunya (504)
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Sant Cugat Del Vallès, Barcelona, Spain
Policlinica Gipuzkoa, S.A.,(511)
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San Sebastian, Gipuzkoa, Spain
Clinica Universidad de Navarra (512)
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Pamplona, Navarra, Spain
Hospital Universitario Quiron Dexeus (501)
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Barcelona, Spain
Hospitalaries Del Sagrat Cor De Jesus Hospital Sant Rafael (516)
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Barcelona, Spain
Hospital Clinic de Barcelona (507)
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Barcelona, Spain
Hospital Universitario Vall d' Hebron (505)
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Barcelona, Spain
Hospital De La Santa Creu i Sant Pau (502)
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Barcelona, Spain
Hospital Universitario Ramon y Cajal (500)
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Madrid, Spain
Hospital Universitario Infanta Sofia (513)
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Madrid, Spain
Re: Cognition Health Ltd(205)
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Plymouth, Devon, United Kingdom
Hospital Universitario y politecnico La Fe (515)
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Valencia, Spain
Imperial College Healthcare NHS Trust (200)
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London, United Kingdom
Hospital Universitario Virgen del Rocio (503)
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Sevilla, Spain
Hospital Universitario de la Princesa (508)
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Madrid, Spain
Visionary Investigators Network (168)
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Aventura, Florida, United States
Rocky Mountain Movement Disorders Center (116)
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Englewood, Colorado, United States
University of Colorado Hospital Anschutz Outpatient Pavilion (120)
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Aurora, Colorado, United States
University of South Florida (114)
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Tampa, Florida, United States
Wake Forest Baptist Health Sciences (127)
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Winston-Salem, North Carolina, United States
Medical University of South Carolina (150)
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Charleston, South Carolina, United States