Idiopathic Normal Pressure Hydrocephalus (INPH)
Conditions
Keywords
normal pressure hydrocephalus, iNPH, Acetazolamide, Diamox, RCT
Brief summary
A pharmacological treatment to patients with normal pressure hydrocephalus (NPH) is missing. The aim is to investigate if acetazolamide given to patients with NPH improves gait function and study the pathophysiological mechanisms leading to reduced symptoms. Patients will be randomized to acetazolamide or placebo and duration of treatment will be from diagnosis to the day of shunt surgery. Target dose is 500 mg/day. Study design is a double-blind randomized controlled trial and the plan is to include 42-50 patients. The study is investigator-initiated without financial sponsorship from the industry.
Detailed description
Background: The only available treatment for normal pressure hydrocephalus (NPH) is implantation of a neurosurgical shunt system that reduces symptoms in two out of three cases. Postoperative complications are common, causing reoperations in 20-30% within the first years after surgery. A pharmacological treatment is missing. In three previous studies, acetazolamide, a reversible inhibitor of the carbonic anhydrase enzyme, was used as treatment off-label. In the first of these studies, 15 patients with NPH were treated with doses 250-500 mg/day and 10 patients improved (Aimard G et. al.). The second study was a case report of one patient with NPH who improved after receiving the dose 500 mg/day (Garcia-Gasco P et. al.). The most recent study used doses of 125-375 mg/day and included 8 patients of whom 5 improved. Furthermore, the last study reported a reduction of the periventricular edema that is often present in the white matter close to the lateral ventricles in patients with NPH (Alperin N et. al.). These three studies were open label with no blinding or control group. Study design: Study design is a double-blind randomized placebo-controlled trial. The study is investigator-initiated without financial sponsorship from the industry. The plan is to consecutively include 42-50 patients with NPH. Patients will be randomized to acetazolamide or placebo and take the study drug from diagnosis (baseline) to admission for shunt surgery. Waiting time for shunt surgery at the center of the study is approximately 4-8 months at the moment. The dose will be titrated to 250 mg x 2 during 4-6 weeks. Two phone visits with a study nurse and routine blood samples are controlled during the titration phase to rule out side effects. Evaluations of clinical symptoms and blood samples for blood biomarkers are collected at baseline, after 3 months and when the study drug is stopped. Lumbar cerebrospinal fluid (CSF) is collected at baseline and intraventricular CSF is collected during shunt surgery. All patients are investigated after shunt surgery, 3 months postoperatively with evaluation of symptoms and blood samples. Blood- and CSF samples are stored in a biobank. In a subgroup of 24-26 patients, an MRI of the brain is performed before the start of study drug and after 3 months. In this subgroup also assessments of symptoms and blood samples for analysis of plasma biomarkers will be collected in connection with the MRI scans.
Interventions
DRUGAcetazolamide
Target dose: 500 mg / day
DRUGPlacebo
Placebo
Sponsors
Uppsala University Hospital
Uppsala University
Swedish Society for Medical Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Double-blind randomized trial.
Eligibility
Sex/Gender
ALL
Age
50 Years to 82 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of idiopathic normal pressure hydrocephalus according to international guidelines 2. Age ≥ 50 years and ≤ 82 years 3. Cognitive function with Mini-Mental State Examination \> 20 points or cognitive domain of iNPH scale ≥ 30 points. 4. MRI image characteristic of normal pressure hydrocephalus, defined as callosal angle \< 90 degrees and dilated lateral ventricles or pattern of disproportionately enlarged subarachnoid space hydrocephalus (DESH). 5. Signed informed consent form
Exclusion criteria
1.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportional change in gait function | Change from baseline gait function immediately after intervention (at time of shunt surgery) | Gait function is determined by one variable that is calculated as the mean time and number of steps of three different gait tests: 10 meter walking in self chosen speed, timed up and go test (TUG) and 3 m walking backwards. The two fastest attempts of three attempts for each test are documented. The mean time and number of steps of the two fastest attempts for the three tests are calculated to a single variable and the proportional difference between study visits is used as the primary outcome variable. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in idiopathic normal pressure hydrocephalus (iNPH) scale | Change from baseline iNPH-scale score immediately after intervention (at time of shunt surgery) | Swedish idiopathic normal pressure hydrocephalus (iNPH) scale that is a combination of subscales for gait, balance, cognition and continence. Minimum value is 0 and maximum value is 100. High values indicate better function. |
| Change in volume of periventricular hyperintensities | Change from baseline at 3 months | Measured using volumetric MRI |
| Change in cerebral blood perfusion | Change from baseline at 3 months | Measured using pseudo continuous arterial spin labeling (MRI perfusion) |
| Change in quantified CSF flow in cerebral aqueduct | Change from baseline at 3 months | Measured using phase contrast MRI |
| Change in parenchymal water content | Change from baseline at 3 months | Measured using Synthetic MRI |
| Change in cerebral myelin volume | Change from baseline at 3 months | Measured using Synthetic MRI |
| Changes in plasma biomarkers | Change from baseline immediately after intervention (at time of shunt surgery) | Change in plasma levels of neurofilament light chain protein, Total-tau, amyloid beta-42, glial fibrillary acidic protein will be measured using Quanterix (SIMOA). |
| Change in CSF biomarkers | Change from baseline immediately after intervention (at time of shunt surgery) | CSF levels of neurofilament light chain protein, Total-tau, amyloid beta-42, glial fibrillary acidic protein will be measured using Quanterix (SIMOA). |
| Changes in plasma and CSF proteins | Change from baseline immediately after intervention (at time of shunt surgery) | Semi-quantified levels of approximately 200 proteins are measured with proximity extension assay (Neurology panel and Neuro exploratory panel, Olink.com). |
| Patients self reported assessment of symptoms | Change from baseline immediately after intervention (at time of shunt surgery) | Gait, cognition, continence, balance, activities of daily life and quality of life is rated by patients on a questionnaire using 4-level scales. |
| Change in Euro-Quality of Life-5 dimension-5L (EQ-5D-5L) descriptive system | Change from baseline EQ-5D-5L score immediately after intervention (at time of shunt surgery) | Measured using EQ-5D-5L using the descriptive system. |
| Change in Euro-Quality of Life-5 dimension-5L (EQ-5D-5L) VAS | Change from baseline EQ-5D-5L score immediately after intervention (at time of shunt surgery) | Measured using the visual analogue scale (VAS) in EQ-5D-5L. |
Countries
Sweden
Contacts
PRINCIPAL_INVESTIGATORJohan Virhammar, MD, PhD
Department of Neuroscience, Uppsala University
Outcome results
None listed