NCT07055087尚未招募2 期
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
适应症
干预措施
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 120
- 试验地点
- 8
- 主要终点
- Parkinson's Disease Cognitive Composite Score (PDCCS)
研究概览
简要总结
This is a proof-of-concept trial to investigate the efficacy of prasinezumab to slow or prevent cognitive decline in people with Parkinson's disease carrying a severe mutation in the GBA (glucocerebrosidase) gene. The duration of the intervention per patient will be 104 weeks with monthly infusions. The investigators plan to enroll 120 participants (60 participants per treatment arm). This study will be conducted across Europe in the following countries: France, Germany, Italy, Luxembourg, Spain, Sweden, UK.
详细描述
This is a proof-of-concept (POC) prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial to investigate the efficacy of the intravenously (IV) applied monoclonal anti-α-synuclein antibody prasinezumab to slow or prevent cognitive decline in people with Parkinson's disease (PD) carrying a severe mutation in the GBA (glucocerebrosidase) gene (PDGBA_severe). The duration of the intervention per patient will be 104 weeks with monthly infusions. The investigators plan to enroll 120 participants (60 participants per treatment arm).
This study will be conducted across Europe in the following countries: France, Germany, Italy, Luxembourg, Spain, Sweden, UK.
Randomization will be 1:1 prasinezumab (1500mg) versus placebo (saline infusion). Randomization will be stratified by sex, age group (< 55 years vs ≥ 55 years), and baseline Montreal Cognitive Assessment (MoCA) (≤ 25) to ensure balance of these factors between the prasinezumab and placebo group.
Participants, aged 35 to 80 years, diagnosed with PD and carrying a known severe mutation in the GBA gene according to the definition for PD (see Supplemental Table 1 for a list of applicable mutations). MoCA at Screening must be ≥ 21.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 35 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of PD according to MDS-Criteria.
- •Known heterozygous severe GBA mutation (based on PD-related pathogenicity).
- •-> In case of slow recruitment after 6 months, inclusion of the GBA risk variant E326K as back-up strategy is possible (based on PD-related pathogenicity). This will be communicated by the sponsor beforehand.
- •HY in dopaminergic ON ≤
- •35 to 80 years of age at the time of signing the Informed Consent.
- •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.
排除标准
- •Current or Past Medical History:
- •Known pathogenic mutation carriers of the following familial PD genes: PRKN, PINK1, DJ1, LRRK
- •Medical history indicating a Parkinsonian syndrome other than sporadic PD (progressive supranuclear palsy, multiple system atrophy, drug-induced parkinsonism, essential tremor, primary dystonia).
- •A diagnosis of a significant CNS disease other than PD.
- •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.
- •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.
- •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:
- •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).
- •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.
- •Any active infectious disease at Screening.
- •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]).
- •Any febrile illness within one week prior to first dose administration.
- •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.
- •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)
- •The following cardiovascular conditions:
- •Myocardial infarction in the last 12 months prior to baseline.
- •Known history or documentation of uncontrolled bradycardia on more than one occasion within three months prior to baseline.
- •Resting pulse rate (PR) greater than
- •Known history or documentation of uncontrolled hypertension on more than one occasion within three months prior to baseline.
- •Clinically significant cardiovascular disease including any of the following: unstable angina, decompensated congestive heart failure, clinically significant arrhythmias.
- •Clinically significant abnormalities in laboratory test results at the Screening visit, including hepatic and renal panels, complete blood count, and urinalysis, including:
- •Total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 times the upper limit of normal (ULN).
- •Serum creatinine > 1.5 times the ULN.
- •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
- •A clinically significant abnormal thyroid-stimulating hormone (TSH) test.
- •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.
- •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
- •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.
- •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 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).
- •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.
- •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.
- •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.
- •Medications and treatments:
- •If on treatment with symptomatic therapy: no stable dosage for at least 90 days before Baseline of following drugs/drug classes:
- •dopamine agonists,
- •MAO-B inhibitors,
- •COMT inhibitors,
- •amantadine, and/or
- •levodopa. Note: pumps for continuous levodopa treatment are acceptable if on stable dosage for at least 90 days before Baseline
- •Manifest Gaucher's Disease and treatment for Gaucher's Disease:
- •enzyme replacement therapy (ERT),
- •substrate reduction therapy (SRT). Note: A second PD-associated risk variant in the GBA gene, namely E326K and T396M is allowed
- •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.
- •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.
- •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.
- •Prior and concomitant participation in a putative disease-modifying investigational trial with surgical, or stem cell intervention in PD.
- •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.
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研究组 & 干预措施
Prasinezumab
Experimental
prasinezumab 1500 mg monthly infusion
干预措施: Prasinezumab (Drug)
Sodium chloride 0,9% infusion
Placebo Comparator
saline infusion (0,9 % sodium chloride) monthly infusion
干预措施: Sodium Chloride (Drug)
结局指标
主要结局
Parkinson's Disease Cognitive Composite Score (PDCCS)
时间窗: week 104
To assess the efficacy of prasinezumab compared with placebo on cognitive function at week 104 measured by the Parkinson's Disease Cognitive Composite Score (PDCCS). Composite score that includes the following cognitive tests: * LNS (Attention) * Derived-Sem. Fluency-Animal T-Score (Executive function) * Derived-Delayed Recall T-Score (Memory) * MoCA (Global cognition) Per single Test: Group Mean and Standard Deviation (SD) at Baseline = reference ZBaseline = (xBaseline - Group MeanBaseline) / SDBaseline ZFollow-up = (xFollow-up - Group MeanBaseline) / SDBaseline Mean of Z-Scores of relevant Tests per Patient per Visit Min-Max: n.a. (higher values mean a better outcome)
次要结局
- Cognitive function (MoCA_z)(week 104)
- PD-MCI(week 104)
- PDD(week 104)
- MDS-UPDRS I-IV(week 104)
- Levodopa-equivalent dosage(week 104)
- Cognitive function per cognitive domain: Attention and working Memory (1/2)(week 104)
- Cognitive function per cognitive domain: Attention and working Memory (2/2)(week 104)
- Cognitive function per cognitive domain: executive (1/3)(week 104)
- Cognitive function per cognitive domain: executive (2/3)(week 104)
- Cognitive function per cognitive domain: executive (3/3)(week 104)
- Cognitive function per cognitive domain: memory (1/2)(week 104)
- Cognitive function per cognitive domain: memory (2/2)(week 104)
- Cognitive function per cognitive domain: visuospatial (1/2)(week 104)
- Cognitive function per cognitive domain: visuospatial (2/2)(week 104)
- Cognitive function per cognitive domain: language (2/2)(week 104)
- Cognitive function per cognitive domain: language (1/2)(week 104)
研究者
研究点 (8)
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