European Study of Prodromal iNPH

Обзор

To investigate if progression from prodromal into symptomatic NPH can be predicted from advanced neuroimaging, biomarkers in cerebrospinal fluid (CSF) and plasma and investigate the unknown mechanisms causing deterioration by investigating longitudinal changes in the above-mentioned variables. Three different cohorts with both asymptomatic and symptomatic patients as well as healthy controls will be investigated over time, both without intervention and before and after shunt surgery.

Подробное описание

Three prospective cohorts will be included during five years from seven European centers.

Group 1 - Prodromal NPH. Patients with imaging features associated with iNPH and no symptoms, or to little symptoms to motivate shunt surgery, will be included prospectively. At baseline, an MRI of the brain will be performed and a lumbar puncture to collect CSF as well as blood samples. The patients will be followed with a standardized scheme that will go on for as long as the patient chose to remain in the study or until the patient develops symptoms and are referred for shunt surgery. The study scheme includes repeated assessments of symptoms, MRI of the brain, CSF samples and blood samples. The following study visits are planned before surgery: baseline, 6 months, 1st year, 2nd year, 4th year, 6th year. After shunt surgery, clinical evaluations and blood samples will be collected at four assessments during five years post-operative.

Group 2 - Healthy controls - For every patient in Group 1, one patient can be included in Group 2. They will be investigated with the same protocol as Group 1 but only follow the protocol for one cycle (Baseline to year 4).

Group 3 - Symptomatic NPH - For each included individual in Group 1 (prodromal NPH), two patients are included in Group 3 (symptomatic NPH). These patients are consecutively included at each centre from routine patients that are planned for shunt surgery. They should be age matched with the individual in Group 1 (+/- 3 years). Their investigations will be identical with the post-operative routine for five years as Group 1.

Вмешательства

• Процедура Shunt surgery
  Shunt surgery according to each local centers routine

Первичные конечные точки

• Frequency of patients with prodromal iNPH that requires shunt surgery within 6 years from inclusion. [Срок оценки: From date of inclusion until decision of shunt surgery, assessed up to 72 months]
• Frequency of patients with prodromal iNPH that progress to symptomatic iNPH [Срок оценки: From date of inclusion until 20 points reduction in total iNPH-scale score or 20% reduction in gait speed, assessed up to 72 months]
• Post operative improvement in iNPH-scale score in patients with mild, moderate and severe preoperative symptoms [Срок оценки: Change from preoperative (last visit before surgery) iNPH scale at 3 months, 12 months, 36 months and 60 months follow-up.]

Вторичные конечные точки (9)

• Change in white matter hyperintensities (WMH) [Срок оценки: Change from baseline at 24 months, at 48 months and at time of decision of shunt surgery, assessed up to 72 months]
• Change in brain morphology [Срок оценки: Change from baseline at 24 months, at 48 months and at time of decision of shunt surgery, assessed up to 72 months]
• Change in ventricular volume [Срок оценки: Change from baseline at 24 months, at 48 months and at time of decision of shunt surgery, assessed up to 72 months]
• Change in parenchymal water content [Срок оценки: Change from baseline at 24 months, at 48 months and at time of decision of shunt surgery, assessed up to 72 months]
• Change in cerebral myelin volume [Срок оценки: Change from baseline at 24 months, at 48 months and at time of decision of shunt surgery, assessed up to 72 months]
• Changes in plasma biomarkers [Срок оценки: Change from baseline at 6 months, 12 months, 24 months, 48 months and at time of decision of shunt surgery, assessed up to 72 months]
• Changes in cerebrospinal fluid (CSF) biomarkers [Срок оценки: Change from baseline at 6 months, 12 months, 24 months, 48 months and at time of decision of shunt surgery, assessed up to 72 months]
• Changes in plasma and cerebrospinal fluid (CSF) proteins [Срок оценки: Change from baseline at 6 months, 12 months, 24 months, 48 months and at time of decision of shunt surgery, assessed up to 72 months]
• Change in quality of life [Срок оценки: Change from baseline at 6 months, 12 months, 24 months, 48 months and at time of decision of shunt surgery, assessed up to 72 months]

Критерии участия

Inclusion criteria - Group 1 - prodromal iNPH

• Brain imaging with both:

• Evans index > 0.3
• Callosal angle ≤ 90 º or:
• Disproportionately enlarged subarachnoid space hydrocephalus (DESH) - defined as: enlarged ventricles, dilated sylvian fissures and tight sulci at the high convexity.
• Absence of symptoms or too mild symptoms to motivate shunt surgery according to local routine, and all of the following:

• Normal gait pattern, or slight disturbance of the gait pattern that is not considered to be caused by a disease in the central nervous system (CNS).
• Gait velocity (maximum gait speed), men ≥ 1.4 m/s; women ≥ 1.25 m/s.
• Rombergs test with eyes open > 60 seconds
• Mini Mental State Examination (MMSE) ≥ 27 or Montreal Cognitive Assessment (MoCA) ≥ 23
• Informed consent

Exclusion criteria - Group 1 - prodromal iNPH

• Contraindication for MRI
• Other serious disease with expected survival less than three years
• Other type of hydrocephalus:

• non-communicating hydrocephalus
• secondary communicating hydrocephalus
• suspected congenital hydrocephalus (severely enlarged ventricles, narrow sylvian fissures and normal non-compressed sulci at the high convexity or morphological findings consistent with PaVM18)
• Anticoagulants in a dose that hinders lumbar puncture

Inclusion criteria - Group 2 - healthy controls

• Age > 65 years

Exclusion criteria - Group 2 - healthy controls:

• Imaging findings meet inclusion criteria of Group 1
• Previously known relevant neurological disease
• Pathological gait pattern with unknown reason.
• MMSE < 27 or MoCA < 26.
• Anticoagulants in a dose that hinders lumbar puncture

Inclusion criteria Group 3 symptomatic iNPH

• iNPH diagnosis according to international guidelines.19
• Age matched with the individual in Group 1 (+/- 3 years)

Exclusion criteria Group 3 symptomatic iNPH

• Previous stroke (clinical stroke, not only radiologically verified)
• Other serious disease with expected survival less than three years

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

Здоровые добровольцы: Да

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Швеция · 5 центров

• Sahlgrenska University Hospital — Gothenburg
• Linköping University Hospital — Linköping
• Karolinska University Hospital — Stockholm
• Umeå University Hospital — Umeå
• Uppsala University Hospital — Uppsala

Финляндия · 1 центр

• Kuopio University Hospital — Kuopio

Италия · 1 центр

• Bellaria Hospital — Bologna

Идентификаторы

NCT: NCT05910944 · STOP iNPH

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗