Acetazolamide Trial in Normal Pressure Hydrocephalus (DRAIN)

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.

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.

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.

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 plasma levels of neurofilament light chain protein, Total-tau, amyloid beta-42, glial fibrillary acidic protein will be measured using Quanterix (SIMOA).

CSF levels of neurofilament light chain protein, Total-tau, amyloid beta-42, glial fibrillary acidic protein will be measured using Quanterix (SIMOA).

Semi-quantified levels of approximately 200 proteins are measured with proximity extension assay (Neurology panel and Neuro exploratory panel, Olink.com).

Gait, cognition, continence, balance, activities of daily life and quality of life is rated by patients on a questionnaire using 4-level scales.

Inclusion Criteria: Diagnosis of idiopathic normal pressure hydrocephalus according to international guidelines Age ≥ 50 years and ≤ 82 years Cognitive function with Mini-Mental State Examination > 20 points MRI image characteristic of normal pressure hydrocephalus, defined as callosal angle < 90 degrees, tight high convexity, dilated Sylvian fissures, and presence of periventricular white matter hyperintensities Signed informed consent form Exclusion Criteria: Exclusion criteria for MRI examination Participation in another medical trial Other disease likely to impact the symptoms of the patient Wheelchair user or unable to walk without support Reduced kidney function with GFR < 50 Reduced liver function (increased INR or alanine transaminase concentrations in plasma) Known heart failure Low concentrations of electrolytes in blood plasma that, according to the investigator, prevents participation in the study Angle-closure glaucoma Allergy to acetazolamide, sulfonamides, or sulfonamide derivatives Treatment with phenytoin, valproate, carbamazepine, lithium, oral anticoagulants, thiazide-diuretics, or acetylsalicylic acid > 100 mg/day Inability to swallow capsules of the same size as the investigational medicinal products (will be tested using empty capsules when the patient is asked to participate in the study) Average walking time for the three walking tests < 11 seconds Average walking time for the three walking tests > 50 seconds Inability to comply with the study treatment independently, and a concurrent lack of individuals to help the patient comply with the treatment during the study period Fertile woman without highly effective contraception. A Fertile woman will be tested with pregnancy test before inclusion is possible.

Individual participant data that underlie the results reported in any publications from this study, can be shared after deidentification.

From publication of the first article from this study, ending 10 years following the last published article from this study.

Researchers who provide a methodologically sound proposal can contact the principal investigator of the study.

Aimard G, Vighetto A, Gabet JY, Bret P, Henry E. [Acetazolamide: an alternative to shunting in normal pressure hydrocephalus? Preliminary results]. Rev Neurol (Paris). 1990;146(6-7):437-9. French.

Adams RD, Fisher CM, Hakim S, Ojemann RG, Sweet WH. SYMPTOMATIC OCCULT HYDROCEPHALUS WITH "NORMAL" CEREBROSPINAL-FLUID PRESSURE. A TREATABLE SYNDROME. N Engl J Med. 1965 Jul 15;273:117-26. doi: 10.1056/NEJM196507152730301. No abstract available.

Garcia-Gasco P, Salame Gamarra F, Tenllado Doblas P, Chazarra Talens C. [Complete resolution of chronic hydrocephalus of adult with acetazolamide]. Med Clin (Barc). 2005 Apr 9;124(13):516-7. doi: 10.1157/13073568. No abstract available. Spanish.

Alperin N, Oliu CJ, Bagci AM, Lee SH, Kovanlikaya I, Adams D, Katzen H, Ivkovic M, Heier L, Relkin N. Low-dose acetazolamide reverses periventricular white matter hyperintensities in iNPH. Neurology. 2014 Apr 15;82(15):1347-51. doi: 10.1212/WNL.0000000000000313. Epub 2014 Mar 14.

Relkin N, Marmarou A, Klinge P, Bergsneider M, Black PM. Diagnosing idiopathic normal-pressure hydrocephalus. Neurosurgery. 2005 Sep;57(3 Suppl):S4-16; discussion ii-v. doi: 10.1227/01.neu.0000168185.29659.c5.

Hellstrom P, Klinge P, Tans J, Wikkelso C. A new scale for assessment of severity and outcome in iNPH. Acta Neurol Scand. 2012 Oct;126(4):229-37. doi: 10.1111/j.1600-0404.2012.01677.x. Epub 2012 May 16.