A randomized, double-blind, placebo-controlled, 104-week proof-of-concept study to evaluate the efficacy of intravenous prasinezumab in participants with Parkinson's disease carrying a severe mutation in the GBA gene (prevent cognitive decline in GBA-associated PD)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Tuebingen AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Decision date (initial)

2026-06-22

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

F. Hoffmann-La Roche Ltd · Michael J. Fox Foundation for Parkinson’s Research

External identifiers

EU CT number

2024-513496-40-00

ClinicalTrials.gov

NCT07055087

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To assess the efficacy of prasinezumab compared with placebo on cognitive function measured at week 104.

Secondary objectives 1

1. The secondary objective of this study is to assess the efficacy of prasinezumab compared with placebo on motor function at week 104.

Conditions and MedDRA coding

PARKINSON’S DISEASE

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Diagnosis of PD according to MDS-Criteria.
2. Known heterozygous severe GBA mutation (based on PD-related pathogenicity, Supplemental Table 1). This includes inclusion of patients carrying the GBA risk variant E326K.
3. MoCA ≥ 21.
4. HY in dopaminergic ON ≤3.
5. 35 to 80 years of age at the time of signing the Informed Consent.
6. Able and willing to provide written informed consent and to comply with the study protocol according to the International Council for Harmonization (ICH) and local regulations.

Exclusion criteria 31

1. Known pathogenic mutation carriers of the following familial PD genes: PRKN, PINK1, DJ1, LRRK2.
2. Lactating or pregnant female participants. Female participants of childbearing potential must have a negative serum pregnancy test result during screening prior to initiation of study drug.
3. If on treatment with symptomatic therapy: no stable dosage for at least 90 days before Baseline of following drugs/drug classes: a. dopamine agonists, b. MAO-B inhibitors, c. COMT inhibitors, d. amantadine, and/or e. levodopa. Note: pumps for continuous levodopa treatment are acceptable if on stable dosage for at least 90 days before Baseline
4. Manifest Gaucher’s Disease and treatment for Gaucher’s Disease: a. enzyme replacement therapy (ERT), b. substrate reduction therapy (SRT). Note: A second PD-associated risk variant in the GBA gene, namely E326K and T396M is allowed
5. Anti-epileptic medication for non-seizure-related treatment which has not remained on a stable dosage for at least 90 days prior to baseline and not planned to remain stable during the study.
6. Anti-depressant or anxiolytic use that has not remained on a stable dosage for at least 90 days prior to baseline and not planned to remain stable during the study.
7. Use of any of the following medications within 90 days prior to baseline: typical neuroleptics, metoclopramide, flunarizine, amoxapine, amphetamine derivatives, reserpine, mazindol, methamphetamine, methylphenidate, norephedrine, phentermine, phenylpropanolamine, modafinil, alpha methyldopa, cocaine. Note: Amantadine, quetiapine, and clozapine are allowed but should be on a stable dose for at least 90 days prior to baseline.
8. Prior and concomitant participation in a putative disease-modifying investigational trial with surgical, or stem cell intervention in PD.
9. Prior and concomitant participation in an investigational clinical trial with symptomatic or disease modifying PD treatment within 90 days (or 5 half-lives of the drug, whichever is longer) before baseline.
10. Any prior treatment with an investigational PD-related vaccine (including active immunization or passive immunotherapy with monoclonal antibodies).
11. Prior participation in any prasinezumab study or study with other compounds targeting alpha-synuclein.
12. Medical history indicating a Parkinsonian syndrome other than sporadic PD (progressive supranuclear palsy, multiple system atrophy, drug-induced parkinsonism, essential tremor, primary dystonia).
13. Receipt of any non-PD investigational product or device, or participation in a non-PD drug research study within a period of 90 days (or 5 half-lives of the drug, whichever is longer) before baseline.
14. Receipt of any monoclonal antibody or investigational immunomodulator within 180 days (or 5 half-lives, whichever is longer) before baseline (e.g., monoclonal antibodies, intravenous immunoglobulin [IVIG], interleukin 2 [IL-2], interleukin 12 [IL-12], interferon or immunosuppressive drugs).
15. Immunomodulating drugs including oral corticosteroids within 90 days prior to baseline.
16. Allergy to any of the components of prasinezumab such as citrate, trehalose and polysorbate (Tween) 20 or a known hypersensitivity or an IRR to the administration of any other monoclonal antibody.
17. Any contraindications to obtaining a brain MRI (if brain MRI was not already performed within 2 years before of Screening) (e.g., claustrophobia unresponsive to reassurance or low dose of an anxiolytic agent, tooth implants).
18. Donation of blood over 500 mL within three months prior to Screening.
19. For participants consenting to provide optional CSF samples by lumbar puncture (LP): participant does have one or more contraindication to undergoing an LP including: INR > 1.4 or other coagulopathy, platelet cell count of < 120,000/μL, infection at the desired LP site, taking anticoagulant medication within 10 days of baseline (Note: low dose aspirin [acetylsalicylic acid and clopidogrel is permitted], severe degenerative arthritis of the lumbar spine, suspected non-communicating hydrocephalus or intracranial mass, prior history of spinal mass or trauma is/are identified. Participants failing to meet these criteria can still participate in the study and all other study assessments (with the exception of LP) as appropriate.
20. Patients under legal supervision or guardianship.
21. Participants who are not fluent in the national language.
22. Residing in a nursing home or assisted care facility.
23. A diagnosis of a significant CNS disease other than PD.
24. Participating in any other interventional clinical trial. Note: Enrollment in a non-interventional study may be allowed if approved in advance by the Sponsor.
25. Previous, current or planned (within next 2 years) treatment with Deep Brain Stimulation (DBS) or ablation with high-intensity focused ultrasound or planned treatment with these within the next 2 years.
26. History of brain MRI scan indicative of clinically significant abnormality of prior hemorrhage or ischemic infarction > 1 cm3, > 3 lacunar infarctions, vascular encephalopathy with white matter lesions according to Fazekas grade III. Clinical routine brain MRI scan must be available within 2 years before Screening.
27. Concomitant disease or condition, or treatment thereof that could 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, including: a. Autoimmune disease (however, well controlled conditions such as quiescent rheumatoid arthritis [RAS], controlled type I diabetes, or mild-to-moderate psoriasis not requiring systemic medications may be acceptable after discussion with Sponsor). b. History of malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, non-metastatic prostate cancer, or Stage I uterine cancer. c. Any active infectious disease at Screening. d. Current, or history of, alcohol or drug abuse or other dependence (except nicotine dependence) within one year before Screening. Drug and/or alcohol abuse within 12 months prior to screening, in the investigator's judgment (except nicotine dependence, Marijuana use is not allowed [this includes all forms of cannabidiol and tetrahydrocannabinol even if given for therapeutic use]). e. Any febrile illness within one week prior to first dose administration. f. Any current psychiatric diagnosis according to Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5), International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) or equivalent, that may interfere with the participant’s ability to perform the study and all assessments (e.g., major depression (BDI-II >28, mental retardation, schizophrenia, bipolar disorder, etc.). Note: Mild depression, depressive mood or mild anxiety arising in the context of PD, are not exclusionary. g. Acute suicidality, as evidenced by a) Question 5 (“Lifetime”/”Since last visit”) on the Columbia- Suicide Severity Rating Scale (C-SSRS), indicating active suicidal ideation with any intent to act, at Screening or baseline (Day 1), or answering “yes” for Question 3 (“In the Past Month”/”Since last visit”) on the C-SSRS, indicating active suicidal ideation with any methods (not plan) without intent to act, at Screening or baseline (Day 1)
28. The following cardiovascular conditions: a. Myocardial infarction in the last 12 months prior to baseline. b. Known history or documentation of uncontrolled bradycardia on more than one occasion within three months prior to baseline. c. Resting pulse rate (PR) greater than 110. d. Known history or documentation of uncontrolled hypertension on more than one occasion within three months prior to baseline. e. Clinically significant cardiovascular disease including any of the following: unstable angina, decompensated congestive heart failure, clinically significant arrhythmias.
29. Clinically significant abnormalities in laboratory test results at the Screening visit, including hepatic and renal panels, complete blood count, and urinalysis, including: a. Total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 times the upper limit of normal (ULN). b. Serum creatinine > 1.5 times the ULN. c. Hematocrit (Hct) less than 35% for males and less than 32% for females, or absolute neutrophil cell count of < 1500/μL (with the exception of a documented history of a chronic benign neutropenia), or platelet cell count of < 100,000/μL; international normalized ratio (INR) > 1.4 d. A clinically significant abnormal thyroid-stimulating hormone (TSH) test. e. A positive urine drug screen for a drug of abuse. For participants treated with selegiline, the amphetamine drug abuse test should be based on the results from a urine assay by liquid chromatography-mass spectrometry which is able to differentiate false positives from true positives for methamphetamine. For participants treated with benzodiazepines: A positive urine drug screen for benzodiazepines is allowed, provided that the prescription has been on a stable dosage for 90 days prior to baseline. f. Positive result for acute or chronic infectious hepatitis B virus (HBV; [i.e., hepatitis B surface antigen (HBsAg positive test)]), for hepatitis C virus (HCV), or HIV 1 or 2. Successfully treated patients with HCV (undetectable HCV RNA) are eligible for enrollment. Participants who are immune due to HBV natural infection or HBV vaccination are eligible.
30. Female participants of childbearing potential without highly effective contraceptive methods (that result in a failure rate of < 1% per year) during the treatment period and for at least 90 days (or longer if required by local regulations) after the last dose of study drug. a. A female participant is considered to be of childbearing potential if she is post-menarchal, has not reached a post-menopausal state (> 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (i.e. removal of ovaries, fallopian tubes, and/or uterus). b. Examples of highly effective contraceptive methods (with a failure rate of < 1% per year) include bilateral tubal ligation, vasectomized partner, established, proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. c. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation or post ovulation methods) and withdrawal are not acceptable methods of contraception. d. Female participants must agree to adhere to the contraceptive requirements
31. Participants who are not able to write or read for any reason.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. PDCCS

Secondary endpoints 8

1. Cognitive function measured by MoCA_z.
2. Percentage of participants with diagnosis of PD-MCI defined by MDS Level II criteria.
3. Percentage of participants with diagnosis of PDD.
4. Cognitive function per cognitive domain (at least 2 tests per domain) measured by comprehensive neuropsychological test battery: • Attention and working Memory: TMT A + WAIS IV (LNS) • Executive: Verbal Fluency (animal fluency) + Stroop interference + TMT B • Memory: Hopkins verbal learning test HVLT Delayed Recall + WMS (logical memory) • Visuospatial: Benton’s Judgment of Line Orientation + Hooper Visual Organization Test • Language: Boston naming + WAIS IV (similarities)
5. MDS-UPDRS I-IV (total score and subscores I-IV).
6. Levodopa-equivalent dosage.
7. Safety outcome measures: ● Safety laboratory tests (hematology, chemistry and coagulation) from baseline over time. ● Incidence of treatment‐emergent abnormal laboratory values and abnormal laboratory values reported as AEs. ● Incidence and severity of AEs. ● Incidence of ADAs. ● ECG assessments from baseline over time; incidence of abnormal ECG assessments.
8. Safety outcome measures: Blood pressure (BP [systolic and diastolic], heart rate, and orthostatic measurement from baseline over time, incidence of abnormal blood pressure [systolic and diastolic], heart rate, and orthostatic changes). ● Incidence of exacerbation of motor and psychiatric side‐effects (including C‐SSRS).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Tuebingen AöR

Sponsor organisation

Universitaetsklinikum Tuebingen AöR

Address

Geissweg 3, Innenstadt Innenstadt

City

Tuebingen

Postcode

72076

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Tuebingen AöR

Contact name

Kathrin Brockmann

Public contact point

Organisation

Universitaetsklinikum Tuebingen AöR

Contact name

Kathrin Brockmann

Third parties 10

Locations

6 EU/EEA countries · 10 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 44 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications