D-SPARK: A Clinical Trial of D-Serine for Modifying Parkinson's Disease Progression

Официальное название

D-SPARK: A Randomized Double Blind Clinical Trial of D-Serine for Modifying Parkinson's Disease Progression

Обзор

This clinical study, designed as a randomized, double-blind, placebo-controlled trial, aims to investigate if modulation of the N-methyl-D-aspartate receptor (NMDAR) via its co-agonist D-serine has therapeutic benefits in Parkinson's disease (PD). All patients will receive both placebo and D-serine over different time periods during the study. Preclinical studies have shown that blocking glycine transporters, which elevates endogenous glycine levels, can restore NMDAR function and improve motor deficits in PD models. A clinical trial demonstrated that oral D-serine (30 mg/kg/day for 6 weeks) significantly reduced extrapyramidal and abnormal involuntary movements in PD patients compared to placebo, with improvements observed in both motor and non-motor symptoms. D-serine supplementation has shown an acceptable safety profile with doses up to 120 mg/kg showing no significant adverse effects in clinical studies. The D-SPARK trial primarily aims to determine the efficacy of D-serine supplementation on clinical severity of PD as measured by the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Secondary aims are to determine the efficacy of D-serine supplementation on improving dopaminergic nigrostriatal innervation as measured by single-photon emission tomography (SPECT) based imaging of the dopamine transporter (DaT-scan) and cognition as measured by the California Verbal Learning Test version 2 (CLVT-II). The study will include 100 persons with Parkinson's disease (PwPD) diagnosed no longer than 5 years before baseline. Participants will be randomly assigned to receive D-Serine 4000 mg daily or placebo for defined periods of time during a 58 week treatment period, followed by a 12 week washout period. Participants will undergo: * Clinical evaluations, including clinical rating scales and questionnaires. * Cognitive assessments. * Bio sampling of whole blood and blood plasma. * Single-photon emission tomography (SPECT) imaging of dopamine transporter levels (DaT-scan) The outcomes of this study could potentially demonstrate that D-serine reduces symptom severity in Parkinson's disease and/or has an impact on the clinical trajectory of Parkinson's disease, benefiting persons living with Parkinson's disease, their families and society as a whole.

Подробное описание

The study design is a randomized, double-blind, placebo-controlled trial.

The trial consists of 3 stages followed by a washout period.

* Screening and antiparkinsonian treatment optimization:

\--- Potential participants will be screened for eligibility and consented for participation. Treatment of Parkinson's disease with dopaminergic drugs will be initiated/adjusted until an optimal, stable effect of treatment is established. This treatment regimen will be maintained throughout the first 32 weeks of the intervention stage, after which changes will be allowed. If an optimal, stable dose is not achieved during screening, these participants will not proceed further and will not be included in the study. * Intervention stage:

\--- Participants will undergo randomization and will be assigned to receive either placebo or D-serine during different portions of the intervention phase. Participants will receive study drug (placebo or D-serine) for a total of 58 weeks. Thirty-two weeks after starting study drug, participants may have their dopaminergic drugs adjusted, if necessary. * Washout stage:

* Upon completion of the intervention period, participants will discontinue study drug and will be followed for an additional 12 weeks. A final study visit will occur 12 weeks after discontinuation of study drug.

Вмешательства

• Пищевая добавка D-serine
  D-serine 2 x 500 mg and 2 x Placebo oral capsules administered twice daily the first week of intervention, then uptitrated to D-serine 4 x 500 mg twice daily for the remainder of the intervention.
• Пищевая добавка Placebo
  Placebo 2 x oral capsules administered twice daily.

Первичные конечные точки

• Change in MDS-UPDRS Total Score (sum of Parts I-III). [Срок оценки: 26 weeks.]

Вторичные конечные точки (4)

• Change in mean striatal binding ratio (SBR) of the putamen bilaterally, measured by [¹²³I] FP-CIT Single-Photon Emission Computed Tomography (SPECT) Imaging of the Dopamine Transporter (DaT-scan). [Срок оценки: 26 Weeks.]
• Change in MDS-UPDRS part III score. [Срок оценки: 26 Weeks.]
• Change in EQ-5D-5L index value. [Срок оценки: 26 Weeks.]
• Change in CVLT-II total Score and sub-scores. [Срок оценки: 26 Weeks.]

Критерии участия

Критерии включения

• A clinical diagnosis of PD\* according to the clinically established MDS clinical diagnostic criteria for Parkinson's disease within 5 years.
• \[¹²³I\]FP-CIT single photon emission CT (DaTscan) confirming dopaminergic nigrostriatal denervation.
• Hoehn and Yahr score < 3 at enrollment.
• Optimal symptomatic PD treatment, not requiring adjustments, for at least 2 weeks.
• Age ≥40 and ≤ 80 years at time of enrollment.

Критерии исключения

• Dementia or neurodegenerative disorder other than PD at baseline visit.
• Atypical parkinsonism (PSP, MSA, CBD vascular parkinsonism, or drug induced parkinsonism).
• Any known monogenic cause of PD (GBA1 variation is accepted).
• Any psychiatric disorder that would interfere with compliance in the study.
• Any severe somatic illness that would make the individual unable to comply and participate in the study.
• Use of D-serine supplementation within 90 days of enrolment.
• Metabolic, neoplastic, or other physically or mentally debilitating disorder at baseline visit.
• Active of planned pregnancy during trial period.
• Cognitive impairment as measured by the Mini Mental Status Exam MMSE) < 20.
• Weight < 45 kg.
• Urinary albumin/creatinine ratio ≥ 20 mg/mmol at time of enrollment.
• Participants will be excluded if they have CKD stage 3 or higher, defined as:

• Estimated golumerular filtration rate (eGFR) < 60 mL/min/1.73min\^2 at screening, calculated using the CKD-EPI 2021 creatinine equation.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Перекрёстный дизайн

Маскирование

Тройное слепое

Основная цель

Лечение

Центры проведения

Норвегия · 11 центров

• Nevro Arendal Soerlandsklinikken — Arendal
• Akershus University Hospital — Lørenskog
• Vestre Viken Hospital — Drammen
• Molde Hospital — Molde
• Bodø Hospital (Nordland Hospital) — Bodø
• Oslo University Hospital — Oslo
• Haugesund Hospital — Haugesund
• University Hospital of North Norway — Tromsø
• … и ещё 3 центра

Идентификаторы

NCT: NCT07312110 · REK: 929216

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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