Normal Pressure HydrocephalusSTOP iNPHNCT05910944
European Study of Prodromal iNPH
An observational study of Normal Pressure Hydrocephalus and Hydrocephalus, run by Johan Virhammar at 7 sites in 3 countries.
Trial summary
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. Read more about this study
- Who is it for?
- Any ageHealthy volunteers can take part
- Conditions the study is for
- Normal Pressure Hydrocephalus, Hydrocephalus
- What is being tested?
- Shunt surgery
- Type of treatment
- Surgery or procedure
- How many people
- 140 participants
- Where
- 7 sitesin 3 countries
- Study dates
- 1 Nov 2023to 31 Dec 2035
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
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).
Who may be able to join
- 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).
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- 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
- Age > 65 years
- iNPH diagnosis according to international guidelines.19
- Age matched with the individual in Group 1 (+/- 3 years)
Who cannot join
- 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)
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- Anticoagulants in a dose that hinders lumbar puncture
- 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
- Previous stroke (clinical stroke, not only radiologically verified)
- Other serious disease with expected survival less than three years
Trial locations and contacts
7 sites in 3 countries. Contact the study team or a site near you to ask about taking part.
7 sites in 3 countries
Sweden5 sites, 5 recruiting
- Not yet recruiting
Sahlgrenska University Hospital
Gothenburg
Mats Tullberg, MD, PhD, mats.tullberg@neuro.gu.se
- Not yet recruiting
Linköping University Hospital
Linköping
Fredrik Lundin, MD, PhD, Fredrik.Lundin@regionostergotland.se
Katarina Laurell, MD, PhD, katarina.laurell@neuro.uu.se
- Not yet recruiting
Karolinska University Hospital
Stockholm
Lisa Arvidsson, MD, PhD, lisa.arvidsson@regionstockholm.se
Jens Tomner, MD, jens.tomner@regionstockholm.se
- Not yet recruiting
Umeå University Hospital
Umeå
William Hansson, MD, william.hansson@umu.se
Jan Malm, MD, PhD, jan.malm@umu.se
- Recruiting
Uppsala University Hospital
Uppsala
Johan Virhammar, MD, PhD, johan.virhammar@neuro.uu.se
Finland1 site, 1 recruiting
- Not yet recruiting
Kuopio University Hospital
Kuopio
Ville Leinonen, MD, PhD, Ville.Leinonen@kuh.fi
Italy1 site, 1 recruiting
- Recruiting
Bellaria Hospital
Bologna
Giorgio Palandri, MD, PhD, giopalandri@gmail.com
About this study
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.
Read the 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.
- Conditions
- Normal Pressure Hydrocephalus, Hydrocephalus
- Being tested
- Shunt surgery
- Keywords
- natural history, cerebrospinal fluid, biomarkers, long term follow-up
- Medical subject headings
- Hydrocephalus, Normal Pressure, Hydrocephalus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Shunt surgeryProcedure or surgery
Shunt surgery according to each local centers routine
| Study group | Role | What they receive |
|---|---|---|
| Group 1 - prodromal iNPH | Individuals with typical imaging findings consistent with iNPH but none or too mild symptoms to motivate shunt surgery. Receives: Procedure: Shunt surgery | |
| Group 2 - Healthy controls | Age matched healthy controls | |
| Group 3 - symptomatic iNPH | Patients with symptomatic iNPH Receives: Procedure: Shunt surgery |
What is being measured
The primary outcome is the main question the study is designed to answer.
Frequency of patients with prodromal iNPH that requires shunt surgery within 6 years from inclusion.
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.
Measured: 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
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.
Measured: 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
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.
Measured: Change from preoperative (last visit before surgery) iNPH scale at 3 months, 12 months, 36 months and 60 months follow-up.
Secondary outcomes (9)
Change in white matter hyperintensities (WMH)
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.
Measured: 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
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.
Measured: 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
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.
Measured: 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
Assess change in parenchymal water content (mL) measured with Synthetic MR and calculate associations between change in parenchymal water and change in symptoms.
Measured: 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
Assess change in cerebral myelin volume (mL) measured with Synthetic MR and calculate associations between change in cerebral myelin volume and change in symptoms.
Measured: 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
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).
Measured: 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
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).
Measured: 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
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.
Measured: 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
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.
Measured: 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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Jun 2023
- Study start1 Nov 2023
- Primary completion31 Dec 2035 (estimated)
- Study completion31 Dec 2035 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Normal Pressure HydrocephalusStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 140 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Johan Virhammar
- Sponsor type
- University, hospital or other
- Collaborators
- Swedish Society for Medical Research
- Responsible party
- Sponsor-investigator, Johan Virhammar, Uppsala University Hospital
- Investigators
- Johan Virhammar, MD, PhD, Principal investigator, Uppsala University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05910944
- Sponsor's protocol ID
- STOP iNPH
- Acronym
- STOP iNPH
- Status last verified
- Apr 2026
- First submitted
- 10 May 2023
- Last updated
- 30 Apr 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 30 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- European Study of Prodromal iNPH
- ClinicalTrials.gov ID
- NCT05910944
- Acronym / sponsor ID
- STOP iNPH / STOP iNPH
- Conditions
- Normal Pressure Hydrocephalus, Hydrocephalus
- Keywords
- natural history, cerebrospinal fluid, biomarkers, long term follow-up
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 140 participants (estimated)
- Lead sponsor
- Johan VirhammarUniversity, hospital or other
- Collaborators
- Swedish Society for Medical Research
- Study start
- 1 Nov 2023 (actual)
- Primary completion
- 31 Dec 2035 (estimated)
- Study completion
- 31 Dec 2035 (estimated)
- First posted
- 20 Jun 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Group 1 - prodromal iNPH | – | Procedure: Shunt surgeryIndividuals with typical imaging findings consistent with iNPH but none or too mild symptoms to motivate shunt surgery. |
| Group 2 - Healthy controls | – | –Age matched healthy controls |
| Group 3 - symptomatic iNPH | – | Procedure: Shunt surgeryPatients with symptomatic iNPH |
Who may qualify
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
- 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).
Key inclusion criteria (13 listed)
- Brain imaging with both:
- Absence of symptoms or too mild symptoms to motivate shunt surgery according to local routine, and all of the following:
- Informed consent
- Age > 65 years
- iNPH diagnosis according to international guidelines.19
Key exclusion criteria (14 listed)
- Contraindication for MRI
- Other serious disease with expected survival less than three years
- Other type of hydrocephalus:
- Anticoagulants in a dose that hinders lumbar puncture
- Imaging findings meet inclusion criteria of Group 1
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Shunt surgeryShunt surgery according to each local centers routine | Procedure or surgery | Group 1 - prodromal iNPH, Group 3 - symptomatic iNPH |
Primary outcome
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.
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.
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.
9 secondary outcomes
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
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
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
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
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
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
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
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
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
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Apr 2026.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Johan Virhammar, MD, PhD principal investigator
Uppsala University Hospital
7 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Normal Pressure Hydrocephalus and Hydrocephalus, run by Johan Virhammar at 7 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 30 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in Sweden, Finland, Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Johan Virhammar, MD, PhD (+46186110000, johan.virhammar@neuro.uu.se), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Apr 2026.