European Study of Prodromal iNPH (STOP iNPH)

November 27, 2023 updated by: Johan Virhammar
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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Observational

Enrollment (Estimated)

140

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Sampling Method

Non-Probability Sample

Study Population

Patients in Group 1 can be included from patients referred to a tertiary hydrocephalus center after investigations/work-up have shown too mild symptoms to motivate shunt surgery.

Healthy age-matched controls (Group 2) can be included by advertising and by asking relatives to patients in Group 1 and Group 3.

For each included individual in Group 1 (prodromal iNPH), two patients are included in Group 3 (symptomatic iNPH). These patients are consecutively included at each center from routine patients that are planned for shunt surgery. They should be age matched with the individual in Group 1 (+/- 3 years).

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Group 1 - prodromal iNPH
Individuals with typical imaging findings consistent with iNPH but none or too mild symptoms to motivate shunt surgery.
Procedure: Shunt surgery
Shunt surgery according to each local centers routine
Group 2 - Healthy controls
Age matched healthy controls
Group 3 - symptomatic iNPH
Patients with symptomatic iNPH
Procedure: Shunt surgery
Shunt surgery according to each local centers routine

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Frequency of patients with prodromal iNPH that requires shunt surgery within 6 years from inclusion.
Time Frame: From date of inclusion until decision of shunt surgery, assessed up to 72 months
Symptoms are assessed with the idiopathic Normal Pressure Hydrocephalus scale (iNPH-scale) with addition of the gait tests: 10 meter walking in maximum speed, timed up and go test (TUG) and 3 m walking backwards. Each center decides when symptoms have progressed enough to motivate shunt surgery according to local traditions and routine. Low values in time and steps of the gait tests indicate good performance and high values of the iNPH-scale (range: 0-100) indicates good performance.
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
Time Frame: From date of inclusion until 20 points reduction in total iNPH-scale score or 20% reduction in gait speed, assessed up to 72 months
Symptoms are assessed with the iNPH-scale with addition of the gait tests: 10 meter walking in maximum speed, timed up and go test (TUG) and 3 m walking backwards. A patient is considered symptomatic when total iNPH-scale is reduced by at least 20 points or the mean speed of the gait tests are reduced by 20%. Low values in time and steps of the gait tests indicate good performance and high values of the iNPH-scale (range: 0-100) indicates good performance.
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
Time Frame: Change from preoperative (last visit before surgery) iNPH scale at 3 months, 12 months, 36 months and 60 months follow-up.
Differences in short (3 and 12 months) and long-term outcome (36 and 60 months) measured as change between preoperative and postoperative iNPH-scale score will be compared between patients with mild, moderate and severe preoperative symptoms. High values of the iNPH-scale (range: 0-100) indicates good performance.
Change from preoperative (last visit before surgery) iNPH scale at 3 months, 12 months, 36 months and 60 months follow-up.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in white matter hyperintensities (WMH)
Time Frame: Change from baseline at 24 months, at 48 months and at time of decision of shunt surgery, assessed up to 72 months
Assess change in volume (mL) of white matter hyperintensities (WMH) measured with volumetric magnetic resonance imaging (MRI) and calculate associations between change in WMH and change in symptoms.
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
Time Frame: Change from baseline at 24 months, at 48 months and at time of decision of shunt surgery, assessed up to 72 months
Assess change in brain morphology assessed with the idiopathic Normal Pressure Hydrocephalus (iNPH) Radscale and calculate associations between change in iNPH Radscale and change in symptoms.
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
Time Frame: Change from baseline at 24 months, at 48 months and at time of decision of shunt surgery, assessed up to 72 months
Assess change in ventricular volume (mL) measured with volumetric magnetic resonance imaging (MRI) and calculate associations between change in ventricular volume and change in symptoms.
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
Time Frame: Change from baseline at 24 months, at 48 months and at time of decision of shunt surgery, assessed up to 72 months
Assess change in parenchymal water content (mL) measured with Synthetic MR and calculate associations between change in parenchymal water and change in symptoms.
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
Time Frame: Change from baseline at 24 months, at 48 months and at time of decision of shunt surgery, assessed up to 72 months
Assess change in cerebral myelin volume (mL) measured with Synthetic MR and calculate associations between change in cerebral myelin volume and change in symptoms.
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
Time Frame: 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 plasma levels of neurofilament light chain protein (ng/L), Total-tau (ng/L), amyloid beta-42 (ng/L), glial fibrillary acidic protein (ng/L) will be measured using Quanterix (SIMOA).
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
Time Frame: 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 CSF levels of neurofilament light chain protein (ng/L), Total-tau (ng/L), amyloid beta-42 (ng/L), glial fibrillary acidic protein (ng/L) will be measured using Quanterix (SIMOA).
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
Time Frame: 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
Semi-quantified levels of approximately 200 proteins are measured with proximity extension assay (Neurology panel and Neuro exploratory panel, Olink.com). Measured semi-quantitative in the unit NPX.
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
Time Frame: 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
Quality of life assessed by EQ-5D-5L (EuroQoL 5 Dimensions 5 Levels). A self-assessment questionnaire with five different aspects of quality of life scored on five-level scales.
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Johan Virhammar

Collaborators

Swedish Society for Medical Research

Investigators

  • Principal Investigator: Johan Virhammar, MD, PhD, Uppsala University Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 1, 2023

Primary Completion (Estimated)

December 31, 2035

Study Completion (Estimated)

December 31, 2035

Study Registration Dates

First Submitted

May 10, 2023

First Submitted That Met QC Criteria

June 17, 2023

First Posted (Actual)

June 20, 2023

Study Record Updates

Last Update Posted (Actual)

November 30, 2023

Last Update Submitted That Met QC Criteria

November 27, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STOP iNPH

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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