Evaluation of Acetazolamide Sodium on Gait in Patients with Normal Pressure Hydrocephalus: A Double-Blind, Randomized, Placebo-Controlled Trial

The primary objective of this study is to examine the effect of **acetazolamide** on gait in patients with normal pressure hydrocephalus. This is clinically relevant as gait disturbances are a significant symptom of normal pressure hydrocephalus, impacting patient mobility and quality of life. Understanding the impact of acetazolamide on gait can inform treatment strategies and improve patient outcomes.

Secondary objectives include evaluating changes in subjective symptoms and quality of life over time, assessing changes in MRI parameters such as periventricular white matter hyperintensities, cerebral blood flow, and brain morphology, and determining the safety profile and side effects of acetazolamide. Additionally, the study aims to measure changes in the concentration of biomarkers in both blood and cerebrospinal fluid following treatment. These secondary objectives provide a comprehensive understanding of the treatment's impact on various clinical and biological parameters, contributing to a holistic assessment of acetazolamide's therapeutic potential in normal pressure hydrocephalus.

The clinical trial focuses on evaluating the effect of acetazolamide on gait in patients diagnosed with **normal pressure hydrocephalus**. The study population includes both male and female participants, aged between 50 and 82 years, who have been diagnosed with idiopathic normal pressure hydrocephalus according to international guidelines. Participants are required to have a cognitive function with a Mini-Mental State Examination score greater than 20 points or a cognitive domain score of the iNPH scale of 30 points or more. Additionally, an MRI image indicative of iNPH, such as a callosal angle less than 95 degrees and dilated lateral ventricles, or an image consistent with disproportionately enlarged subarachnoid space hydrocephalus (DESH), is necessary. The trial includes a vulnerable population, and all participants must provide a signed informed consent form. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the effect of **acetazolamide** on gait in patients diagnosed with normal pressure hydrocephalus. This study is a **randomized**, **double-blind**, and **controlled** trial, conducted in Phase 4, with an estimated completion date of July 15, 2025. The trial involves the administration of acetazolamide, a carbonic anhydrase inhibitor, in a capsulated form, with a maximum daily dose of 500 mg, over a treatment period of up to 9 months. Participants will be randomly assigned to receive either the active drug or a placebo, which is a size 00el capsule shell filled with microcrystalline cellulose.

The trial will commence with a screening visit to confirm eligibility based on specific inclusion criteria, such as a diagnosis of idiopathic normal pressure hydrocephalus, age between 50 and 82 years, and cognitive function assessed by the Mini-Mental State Examination. Following successful screening, participants will be enrolled and undergo baseline assessments. The primary endpoint is the relative change in gait, measured by the time and steps required to walk a distance of 10 meters, timed up-and-go (TUG), and walking backwards for 3 meters. Secondary endpoints include quality of life assessments, volumetric analysis of brain MRI, symptomatic changes in motor skills, cognition, and continence, and analysis of blood and cerebrospinal fluid biomarkers.

Participants will attend regular follow-up visits throughout the trial to monitor safety, efficacy, and adherence to the study protocol. These visits will include clinical evaluations, laboratory tests, and completion of questionnaires. The end-of-study visit will involve final assessments to evaluate the overall impact of the treatment. The expected length of participant involvement is approximately 9 months, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial aims to provide valuable insights into the therapeutic potential of acetazolamide for improving gait in patients with normal pressure hydrocephalus.

The clinical trial involves the administration of **ACETAZOLAMIDE SODIUM**, a chemical compound classified as a carbonic anhydrase inhibitor. The pharmaceutical form of this medication is identified as PHF00231MIG, and it is administered orally. The maximum daily dose is 500 mg, with a total treatment period not exceeding 9 days. The medication is encapsulated for oral use, ensuring ease of administration and compliance. The active substance, acetazolamide sodium, is chemically derived and is intended to evaluate its effect on gait in patients diagnosed with normal pressure hydrocephalus.

The study also includes a **placebo** control, which is a Size 00el capsule shell filled with microcrystalline cellulose. This placebo is designed to match the experimental medication in appearance and administration route, ensuring the double-blind nature of the trial. The placebo is administered orally, following the same dosing schedule as the active treatment, to maintain consistency across the study groups. Compliance with the dosing regimen is monitored throughout the trial to ensure the integrity of the study results.

Efficacy in the clinical trial titled "Double-blind randomized acetazolamide trial in normal pressure hydrocephalus (DRAIN)" will be assessed using both primary and secondary endpoints. The primary endpoint focuses on the relative change in gait between walking trials. This is measured by evaluating the sum of time and steps required to walk a distance of 10 meters, perform a timed up-and-go (TUG) test, and walk backwards for 3 meters. These assessments will provide a comprehensive evaluation of gait improvement in patients with normal pressure hydrocephalus.

Secondary endpoints include a variety of measures to assess broader impacts of the treatment. Quality of life will be evaluated using the EQ-5D-5L self-completion questionnaire, along with additional questionnaires that estimate the patient's experience of symptoms and side effects. The volume of periventricular white matter will be calculated through volumetric analysis of brain MRI, providing insight into structural changes. The total symptomatic change in motor skills, cognition, and continence will be assessed using the Swedish iNPH scale. Additionally, blood and cerebrospinal fluid biomarkers, including **neurofilament light chain protein (NFL)**, amyloid-beta-42, Tau, and glial fibrillary acidic protein (GFAp), will be measured to evaluate biochemical changes associated with the treatment.