Clinical trial NCT03100149: A Study to Evaluate the Efficacy of Prasinezumab (RO7046015/PRX002) in Participants With Early Parkinson's Disease
Official title: A Randomized, Double-Blind, Placebo-Controlled, 52-Week Phase II Study to Evaluate the Efficacy of Intravenous RO7046015/Prasinezumab (PRX002) in Participants With Early Parkinson's Disease With a 6-Year All-Participants-on-Treatment Extension
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Parkinson's Disease
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
Collaborators: name: Prothena Biosciences Limited
First posted: 2017-04-04
Enrollment: 316
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This multicenter, randomized, double-blind, placebo-controlled, Phase 2 study will evaluate the efficacy of intravenous prasinezumab (RO7046015/PRX002) versus placebo over 52 weeks in participants with early Parkinson's Disease (PD) who are untreated or treated with monoamine oxidase B (MAO-B) inhibitors since baseline. The study will consist of three parts: a 52-week, double-blind, placebo-controlled treatment period (Part 1) after which eligible participants will continue into an all-participants-on-treatment blinded dose extension for an additional 52 weeks (Part 2). Participants who complete Part 2 (including the 12-week treatment-free follow up visit assessing long term safety and efficacy of RO7046015) will be offered participation in Part 3 open-label extension (all-participants-on-RO7046015-treatment) for an additional 260 weeks.


Eligibility criteria: Inclusion Criteria:

* Idiopathic PD with bradykinesia plus one of the other cardinal signs of PD (resting tremor, rigidity) being present, without any other known or suspected cause of PD untreated or treated with MAO-B inhibitor
* Body weight range between: \>/=45 kg/ 99 pounds (lbs) and less than or equal to (\</=) 110 kg/242 lbs
* Body mass index (BMI) of 18 to 34 kilograms per meter-squared (kg/m\^2)
* A diagnosis of PD for 2 years or less at screening
* Hoehn and Yahr Stage I or II
* A screening brain DaT-SPECT consistent with PD (central reading)
* Clinical status does not require dopaminergic PD medication and is not expected to require dopaminergic treatment within 52 weeks from baseline
* If presently being treated for PD, a stable dose of MAO-B inhibitor (rasagiline or selegiline) for at least 90 days prior to baseline and not expected to change within 52 weeks
* For women of childbearing potential: use of highly effective contraceptive methods (that result in a failure rate of \<1 percent \[%\] per year) during the treatment period and for at least 30 days (or longer if required by local regulations) after the last dose of study drug
* For men with female partners of childbearing potential or pregnant female partners, must use a condom during the treatment period and for at least 30 days (or longer if required by local regulations) after the last dose of study drug to avoid exposing the embryo. Men must refrain from donating sperm during this same period. The female partners should use a contraception method with a failure rate of \<1% per year during the treatment period and for at least 30 days (or longer if required by local regulations) after the last dose of study drug. Use of contraceptive measures is not required for male participants enrolled in Part 3.

Exclusion Criteria:

* Medical history indicating a Parkinson syndrome other than idiopathic PD, including but not limited to, progressive supranuclear gaze palsy, multiple system atrophy, drug-induced parkinsonism, essential tremor, primary dystonia
* Known carriers of certain familial PD genes (as specified in study protocol)
* History of PD related freezing episodes or falls
* A diagnosis of a significant CNS disease other than Parkinson's disease; history of repeated head injury; history of epilepsy or seizure disorder other than febrile seizures as a child
* Mini Mental State Examination (MMSE) \</=25
* Reside in a nursing home or assisted care facility
* History of or screening brain magnetic resonance imaging (MRI) scan indicative of clinically significant abnormality
* Concomitant disease or condition that could interfere with, or treatment of which might interfere with, the conduct of the study, or that would, in the opinion of the Investigator, pose an unacceptable risk to the participant in this study or interfere with the participant's ability to comply with study procedures or abide by study restrictions, or with the ability to interpret safety data
* Any significant cardiovascular condition
* Any significant laboratory abnormality
* Lactating women
* Prior treatment with dopaminergic medication (for example, levodopa or a dopaminergic agonist) with no clinical treatment response or a clinical treatment response inconsistent with PD (for example, absence of observable response to a sufficiently high-dose of levodopa \[i.e., ≥ 600 mg/day\])
* Use of any of the following: catechol-O-methyl transferase (COMT) inhibitors (entacapone, tolcapone), amantadine or anticholinergics, or dopaminergic medication (levodopa and both ergot and non-ergot \[pramipexole, ropinirole, rotigotine\] dopamine agonists) for more than a total of 60 days or within 60 days of baseline
* Anti-epileptic medication for non-seizure-related treatment which has not remained stable for at least 60 days prior to baseline
* Anti-depressant or anxiolytic use that has not remained stable for at least 90 days prior to baseline. The use of fluoxetine and fluvoxamine is not permitted. For patients treated with a MAO-B inhibitor and an antidepressant (except fluoxetine and fluvoxamine), a 6-month period of stable and tolerated dosing before baseline is required.
* Use of any of the following within 90 days prior to baseline: antipsychotics (including clozapine and olanzapine), metoclopramide, alpha methyldopa, clozapine, olanzapine, flunarizine, amoxapine, amphetamine derivatives, reserpine, bupropion, buspirone, cocaine, mazindol, methamphetamine, methylphenidate, norephedrine, phentermine, phenylpropanolamine, and modafinil
* Participated in an investigational drug, device, surgical , or stem cell study in PD
* Any prior treatment with an investigational PD-related vaccine (including active immunization or passive immunotherapy with monoclonal antibodies).
* Prior participation in any RO7046015 or PRX002 study
* Receipt of any non-PD investigational product or device, or participation in a non-PD drug research study within a period of 30 days (or 5 half-lives of the drug, whichever is longer) before baseline
* Receipt of any monoclonal antibody or an investigational immunomodulator within 180 days (or 5 half-lives, whichever is longer) before baseline
* Immunomodulating drugs within 30 days prior to baseline
* Allergy to any of the components of RO7046015 such as citrate, trehalose and polysorbate (Tween) 20 or a known hypersensitivity or an Infusion-related reaction (IRR) to the administration of any other monoclonal antibody
* Any contraindications to obtaining a brain MRI. Patients with a hypersensitivity to iodine may receive an alternative thyroid blocking agent.
* For participants consenting to provide optional cerebrospinal fluid (CSF) samples by lumbar puncture (LP): LP will only be performed if the participant does not have any contraindication to undergoing an LP
* Donation of blood over 500 milliliters (mL) within three months prior to screening

Primary outcomes:
measure: Change From Baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Total Score (Sum of Parts I, II, and III) at Week 52
timeFrame: From baseline to Week 52
Secondary outcomes:
measure: Change From Baseline in the MDS-UPDRS Part IA, Part IB, Part I Total, Part II Total, Part III Total and Part III Subscores
timeFrame: From baseline to Week 52
measure: Change From Baseline in Dopamine Transporter Imaging With Single Photon Emission Computed Tomography (DaT-SPECT) Striatal Binding Ratio (SBR) in the Putamen Ipsilateral to the Clinically Most Affected Side
timeFrame: From baseline to Week 52
measure: Change From Baseline in Montreal Cognition Assessment (MoCA) Total Score
timeFrame: From baseline to Week 52
measure: Change From Baseline in Clinical Global Impression of Improvement (CGI-I) Score
timeFrame: From baseline to Week 52
measure: Change From Baseline in Patient Global Impression of Change (PGIC) Score
timeFrame: From baseline to Week 52
measure: Change From Baseline in Schwab and England Activity of Daily Living (SE-ADL) Score
timeFrame: From baseline to Week 52
measure: Time to Worsening in Motor or Non-Motor Symptoms
timeFrame: From baseline to Week 52
measure: Time to Start of Dopaminergic Parkinson's Disease Treatment
timeFrame: From baseline to Week 52
measure: Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs)
timeFrame: From baseline to Week 52
measure: Percentage of Participants With Anti-Drug Antibodies (ADAs) Against RO7046015
timeFrame: Baseline, Pre-dose (0 hours) on Weeks 4, 20, 36, 52, 56, 68, 80, and 104; at early termination (up to Week 104), and follow-up (12 weeks after last dose up to Week 116)
measure: Systemic Clearance (CL) of RO7046015
timeFrame: Predose (0 hours) and end of infusion (infusion length=2 hours or less) on Baseline, Weeks 4, 20, 36, 52, 56, 68, 80, and 104; at Day 7, Day 14, early termination (up to Week 104), and follow-up (12 weeks after last dose up to Week 116)
measure: Apparent Volume of Distribution (Vz/F) of RO7046015
timeFrame: Predose (0 hours) and end of infusion (infusion length=2 hours or less) on Baseline, Weeks 4, 20, 36, 52, 56, 68, 80, and 104; at Day 7, Day 14, early termination (up to Week 104), and follow-up (12 weeks after last dose up to Week 116)
measure: Area Under the Serum Concentration-Time Curve (AUC) of RO7046015 Over the Dosing Interval
timeFrame: Baseline over the duration of the study
measure: Maximum Observed Serum Concentration (Cmax) of RO7046015 at Steady-state
timeFrame: Baseline over the duration of the study
measure: Minimum Observed Serum Concentration (Ctrough) of RO7046015 at Steady-state
timeFrame: Baseline over the duration of the study
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Uab Medicine
state: Alabama
city: Phoenix
country: United States
facility: Barrow Neurology Clinics
state: Arizona
city: Fullerton
country: United States
facility: Neurology Center of North Orange County
state: California
city: Los Angeles
country: United States
facility: USC Keck Medical Center of USC
state: California
city: San Francisco
country: United States
facility: University of California at San Francisco
state: California
city: Englewood
country: United States
facility: CenExel Rocky Mountain Clinical Research, LLC
state: Colorado
city: Fairfield
country: United States
facility: Associated Neurologists of Southern CT PC
state: Connecticut
city: New Haven
country: United States
facility: Molecular Neurolmaging
state: Connecticut
city: Aventura
country: United States
facility: Aventura Neurologic Associates
state: Florida
city: Orlando
country: United States
facility: Compass Research East, LLC
state: Florida
city: Tampa
country: United States
facility: USF Parkinsons Disease and Movement Disorders Center
state: Florida
city: Evanston
country: United States
facility: Northwestern University
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Farmington Hills
country: United States
facility: Quest Research Institute
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health Medical Group
state: Michigan
city: West Bloomfield
country: United States
facility: Henry Ford Health System
state: Michigan
city: New York
country: United States
facility: Columbia University
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Tulsa
country: United States
facility: The Movement Disorder Clinic of Oklahoma
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health & Science Uni
state: Oregon
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: Baylor College
state: Texas
city: Round Rock
country: United States
facility: Central Texas Neurology Consultants
state: Texas
city: Burlington
country: United States
facility: University of Vermont Medical Center
state: Vermont
city: Innsbruck
country: Austria
facility: Medizinische Universität Innsbruck
city: Bordeaux
country: France
facility: Groupe Hospitalier Pellegrin
city: Clermont-ferrand
country: France
facility: Hopital Gabriel Montpied
city: Creteil
country: France
facility: Hopital Henri Mondor
city: Grenoble
country: France
facility: Hôpital Michallon - Centre d'Investigation Clinique
city: Marseille
country: France
facility: hopital de la Timone
city: Nice
country: France
facility: CHU de Nice Hopital Pasteur
city: Paris
country: France
facility: Hopital Pitie-Salpetriere APHP
city: Poitiers
country: France
facility: CHU Poitiers
city: Rouen cedex
country: France
facility: CHU Rouen Charles Nicolle
city: St Herblain
country: France
facility: CHU de Nantes - Hopital Laennec
city: Toulouse
country: France
facility: CIC - Hôpital Purpan
city: Düsseldorf
country: Germany
facility: Heinrich-Heine Universitätsklinik Düsseldorf
city: Kassel
country: Germany
facility: Paracelsus Elena Klinik Kassel
city: Leipzig
country: Germany
facility: Klinik und Poliklinik für Neurologie Universitätsklinikum
city: Marburg
country: Germany
facility: Philipps Universität Marburg
city: München
country: Germany
facility: DZNE Clinical Trial Unit
city: Tübingen
country: Germany
facility: Universitaettsklinikum Tübingen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Sant Cugat del Valles
country: Spain
facility: Hospital General de Catalunya
state: Barcelona
city: Donostia
country: Spain
facility: Policlínica Guipuzcoa
state: Guipuzcoa
city: Pamplona/iruña
country: Spain
facility: Clinica Universidad de Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario de la Princesa
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
Study officials:
References:
citation: Pagano G, Taylor KI, Anzures-Cabrera J, Marchesi M, Simuni T, Marek K, Postuma RB, Pavese N, Stocchi F, Azulay JP, Mollenhauer B, Lopez-Manzanares L, Russell DS, Boyd JT, Nicholas AP, Luquin MR, Hauser RA, Gasser T, Poewe W, Ricci B, Boulay A, Vogt A, Boess FG, Dukart J, D'Urso G, Finch R, Zanigni S, Monnet A, Pross N, Hahn A, Svoboda H, Britschgi M, Lipsmeier F, Volkova-Volkmar E, Lindemann M, Dziadek S, Holiga S, Rukina D, Kustermann T, Kerchner GA, Fontoura P, Umbricht D, Doody R, Nikolcheva T, Bonni A; PASADENA Investigators; Prasinezumab Study Group. Trial of Prasinezumab in Early-Stage Parkinson's Disease. N Engl J Med. 2022 Aug 4;387(5):421-432. doi: 10.1056/NEJMoa2202867.
citation: Lipsmeier F, Taylor KI, Postuma RB, Volkova-Volkmar E, Kilchenmann T, Mollenhauer B, Bamdadian A, Popp WL, Cheng WY, Zhang YP, Wolf D, Schjodt-Eriksen J, Boulay A, Svoboda H, Zago W, Pagano G, Lindemann M. Reliability and validity of the Roche PD Mobile Application for remote monitoring of early Parkinson's disease. Sci Rep. 2022 Jul 15;12(1):12081. doi: 10.1038/s41598-022-15874-4.
citation: Pagano G, Boess FG, Taylor KI, Ricci B, Mollenhauer B, Poewe W, Boulay A, Anzures-Cabrera J, Vogt A, Marchesi M, Post A, Nikolcheva T, Kinney GG, Zago WM, Ness DK, Svoboda H, Britschgi M, Ostrowitzki S, Simuni T, Marek K, Koller M, Sevigny J, Doody R, Fontoura P, Umbricht D, Bonni A; PASADENA Investigators; Prasinezumab Study Group. A Phase II Study to Evaluate the Safety and Efficacy of Prasinezumab in Early Parkinson's Disease (PASADENA): Rationale, Design, and Baseline Data. Front Neurol. 2021 Oct 1;12:705407. doi: 10.3389/fneur.2021.705407. eCollection 2021.
citation: Jankovic J, Goodman I, Safirstein B, Marmon TK, Schenk DB, Koller M, Zago W, Ness DK, Griffith SG, Grundman M, Soto J, Ostrowitzki S, Boess FG, Martin-Facklam M, Quinn JF, Isaacson SH, Omidvar O, Ellenbogen A, Kinney GG. Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti-alpha-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease: A Randomized Clinical Trial. JAMA Neurol. 2018 Oct 1;75(10):1206-1214. doi: 10.1001/jamaneurol.2018.1487.