2025-523570-17-00招募中2 期
A randomized, Phase 2a, double-blinded, biomarker-driven, placebo-controlled study to assess safety, CNS penetration, and target engagement of Mirivadelgat in Parkinson’s disease – SLEIPNIR-2, a sub-protocol in the SLEIPNIR platform trial
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 45
- 试验地点
- 1
- 主要终点
- Incidence and severity of adverse events (AEs) and serious adverse events (SAEs); treatment adherence based on dosing compliance and study drug discontinuation rate.
研究概览
简要总结
To assess the safety and tolerability of a Mirivadelgat in participants with PD. To evaluate the central nervous system (CNS) exposure of the active Mirivadelgat metabolite AD-835 in participants with PD at steady state, following 12 weeks of treatment with Mirivadelgat (300 mg per day). To assess the effect of Mirivadelgat (300 mg/day) compared with placebo on CSF levels of 4-hydroxy-2-nonenal (4-HNE) protein adducts.
入排标准
- 年龄范围
- 18 years 至 65+ years（18-64 Years, 65+ Years）
- 接受健康志愿者
- 否
入选标准
- •Participants must be 40 to 85 years of age inclusive, at the time of signing the informed consent.
- •Participants who are diagnosed with clinically established PD as defined by the MDS Clinical Diagnostic Criteria13, meeting all of the following: a. Diagnosis of PD within 10 years of enrollment b. Hoehn and Yahr score of ≤3 in the ON dopaminergic state at enrolment c. On stable anti-parkinsonian treatment (no commencement of new anti-parkinsonian medications, or changes in doses of current anti-parkinsonian medications for a period of at least 2 weeks) prior to baseline
- •Body weight within 45-120 kg (inclusive)
- •Male or female assigned at birth, inclusive of all gender identities. Contraceptive requirements apply during the entire treatment period, and following a washout period of 8 weeks after last intake of the last study intervention, or within 5 half-lives of the experimental treatment, whichever is longer. For additional details see protocol section 7.1
- •Signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
- •Presence of dopaminergic nigrostriatal denervation documented by dopamine transporter (DAT) single photon emission tomography (SPECT) or positron emission tomography (PET), or [18F]DOPA-PET
- •Lack of evidence of other neurodegenerative disorders or any severe somatic or mental illness that may interfere with the study
- •Are able to undergo MRI, blood sampling, and lumbar puncture (LP).
排除标准
- •Known or suspected cause of parkinsonism other than neurodegenerative idiopathic PD, including but not limited to atypical parkinsonian syndromes (e.g., progressive supranuclear palsy (PSP), or multiple system atrophy (MSA), corticobasal syndrome (CBS), dementia with Lewy bodies (DLB)), drug-induced parkinsonism (e.g., neuroleptics, metoclopramide, etc.), encephalitis, known monogenic disorders, etc.
- •History of active malignancy. At Investigator’s discretion, participants with a history of malignancy that is considered cured can participate.
- •History of solid organ transplantation.
- •History of alcohol/substance abuse within 1 year from baseline.
- •History of any psychiatric disorder that would interfere with the participant's ability to comply with the study, as determined by the Investigator.
- •History of any somatic illness that would interfere with the participant's ability to comply with the study, as determined by the Investigator.
- •Participant is enrolled in a current clinical trial, or has been enrolled in a clinical trial of an experimental therapy within 12 weeks prior to baseline (first dose) or within 5 half-lives of the IMP (whichever is longer), or has been enrolled in a SLEIPNIR cohort within 26 weeks prior to baseline (first dose) or within 5 half-lives of the previous IMP (whichever is longer), or has participated in two SLEIPNIR cohorts already.
- •Prolonged QT-interval with QTcF > 480 ms at screening or baseline (the mean of the triplicate QTcF values will be used). QT intervals will be corrected for heart rate using Fridericia’s formula (QTcF = QT / RR^(1/3)), in accordance with ICH E14 recommendations.
- •Any ECG abnormality or rhythm disturbance that, in the opinion of the investigator, poses a significant risk of ventricular arrhythmia.
- •History or positive test result at Screening for human immunodeficiency virus (HIV).
- •History or positive test result at Screening for hepatitis C virus antibody.
- •Known or suspected neurodegenerative disorders other than neurodegenerative idiopathic PD.
- •Current hepatitis B virus (HBV) infection (defined as positive for hepatitis B surface antigen [HbsAg]). Participants with immunity to hepatitis B from previous natural infection (defined as negative HbsAg, positive anti-HBc, and positive hepatitis B surface antibody [anti-HBs]) or vaccination (defined as negative HbsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate in the study.
- •Currently active infection or serious infection (e.g., pneumonia, septicemia) within 8 weeks before Day 1, as determined by the Investigator.
- •Liver function test results (ALAT, ASAT, bilirubin) ≥ 1.5 times the upper limit of normal at the Screening Visit. a. Participants with previously diagnosed Gilbert’s syndrome and elevated levels of bilirubin consistent with such diagnosis may be allowed in the study.
- •Urinary albumin/creatinine ratio (ACR) ≥ 20 mg/mmol at time of enrollment.
- •Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 at screening, calculated using the CKD-EPI 2021 creatinine equation14: eGFR = 142 × min(Scr/K, 1)α × max(Scr/K, 1)-1.200 × 0.9938Age × (1.012 - if female) Where: - Scr is serum creatinine, - K is 0.7 for females and 0.9 for males, - α is -0.241 for females and -0.302 for males, - min indicates the minimum of Scr/K or 1, - max indicates the maximum of Scr/K or
- •Screening value for hemoglobin < 12 g/dL for men or < 11 g/dL for women.
- •Platelet count < 145 x 109/L for men or < 165 x 109/L for women
- •Use of Mucuna pruriens within 90 days before baseline and for the duration of the study.
- •Use of any recreational drugs within 7 days before baseline and for the duration of the study.
- •Use of strong CYP3A inhibitors within 14 days or five half-lives (whichever is longer) prior to randomization. In addition, the use of strong CYP3A inhibitors is prohibited during the treatment period. Strong CYP3A inhibitors will be defined according to current FDA and ICH M12–aligned drug–drug interaction classifications and confirmed by medical/pharmacy review and relevant SmPC/product information. Examples include, but are not limited to: clarithromycin, itraconazole, ketoconazole, posaconazole, voriconazole, ritonavir- or cobicistat-containing regimens, indinavir, and telaprevir.
- •MoCA score < 23, dementia, or other significant cognitive impairment that, in the opinion of the Investigator, would interfere with study evaluation.
- •Any contraindications to having a brain MRI (e.g., pacemaker; MRI-incompatible implants; claustrophobia that cannot be managed without general anesthesia, etc.).
- •Any contraindications to having a lumbar puncture. Contraindications as defined by institutional guidelines: a. Increased intracranial pressure and/or space-occupying lesion b. Spinal epidural abscess c. Infection in or near the puncture site d. Known spinal stenosis with myelopathy or spinal cord compression above level of puncture e. Known spinal or cranial developmental abnormalities that pose a significant risk or interfere with the procedure f. Increased risk of bleeding: • Platelet count < 40 x 109/L • INR 1.4 • Use of anticoagulants other than acetylsalicylic acid (ASA 75 mg once daily) • Use of NSAIDs that cannot be discontinued within the recommended timeframe according to institutional guidelines for each specific drug • Known increased bleeding risk from other causes, deemed clinically significant by the investigator
- •Known hypersensitivity and/or allergies to active Mirivadelgat, the placebo, or their excipients
- •Participant is currently prescribed a drug/nutraceutical known to interact with Mirivadelgat.
- •Previous participation in the SLEIPNIR 2 study arm covered by this sub-protocol.
- •Unable to attend the clinic visits in the practically defined OFF medication state.
- •Use of dopaminergic therapy pumps of any kind (levodopa, apomorphine, etc.).
- •History of any brain surgery for PD (e.g., pallidotomy, deep brain stimulation, or fetal tissue transplant) or history of focused ultrasound treatment at any time; or history of neuromodulation procedures, including, but not limited to, transcranial magnetic stimulation (TMS), transcranial direct or alternating current stimulation (tDCS/tACS) that have been performed within 90 days of screening.
- •A moderate or high suicide risk on the Columbia Suicide Severity Rating Scale (C-SSRS) at screening.
- •History of unstable angina, myocardial infarction, chronic heart failure (New York Heart Association Class 3 or 4), or clinically significant conduction abnormalities (e.g., unstable atrial fibrillation) within 1 year before Screening.
- •Poorly controlled diabetes mellitus, as defined by having dosage adjustment of diabetic medication within 3 months before dosing (Day 1) or glycosylated hemoglobin ≥ 8% at Screening.
研究组 & 干预措施
Mirivadelgat
Test
干预措施: Mirivadelgat (Drug)
结局指标
主要结局
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs); treatment adherence based on dosing compliance and study drug discontinuation rate.
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs); treatment adherence based on dosing compliance and study drug discontinuation rate.
CSF-to-plasma concentration ratio of the Mirivadelgat metabolite AD-835 at Week 12, measured by LC-MS.
CSF-to-plasma concentration ratio of the Mirivadelgat metabolite AD-835 at Week 12, measured by LC-MS.
Change from baseline to Week 12 in CSF total 4-HNE protein adduct levels, measured by validated ELISA assay.
Change from baseline to Week 12 in CSF total 4-HNE protein adduct levels, measured by validated ELISA assay.
次要结局
- Change from baseline to Week 12 in CSF levels of 4-HNE, measured by ELISA, or other relevant method.
- Change from baseline to Week 12 in CSF levels of TBARS (nmol malondialdehyde [MDA] equivalents per mL), measured using a validated thiobarbituric acid reactive substances (TBARS) spectrophotometric assay.
- Change from baseline to Week 12 in CSF levels of 4-HNE-α-synuclein using a custom sandwich ELISA assay.
- Change from baseline to Week 12 in the following brain bioenergetic indices: • Inorganic phosphate to ATP ratio (Pi/ATP), reflecting ATP turnover and energy consumption. • Phosphocreatine to inorganic phosphate (PCr/Pi) ratio, reflecting cellular energetic state and phosphorylation potential. • Phosphocreatine to ATP ratio (PCr/ATP), reflecting ATP resynthesis reserve and energetic state. measured by phosphorus magnetic resonance spectroscopy (31P-MRS) in the posterior brain.
研究者
Charalampos Tzoulis
Scientific
Helse Bergen HF
研究点 (1)
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