A Placebo-Controlled Effectiveness in INPH Shunting (PENS) Trial

Study Overview
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Brief Summary
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The Placebo-Controlled Effectiveness in Idiopathic Normal Pressure Hydrocephalus (iNPH) Shunting (PENS) trial is a multi-center blinded, randomized, placebo-controlled design investigation of cerebrospinal fluid (CSF) shunt surgery to study the shunt effectiveness in iNPH patients.

Detailed Description
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The primary intervention will be setting the FDA-approved Certas Plus with Siphonguard, programmable CSF shunt valve to active (open shunt group)(setting 4)(110 mm H2O) or placebo (closed shunt group)(setting 8)(>400 mm H2O)in a 1:1 ratio. By the time of the primary objective evaluation at four months, the closed shunt group will have zero months of active treatment, and the open shunt group will have four months of active treatment. At four months, shunts for subjects in the closed shunt group will be adjusted to setting 4. To maintain blinding, all patients will be adjusted/ mock adjusted to the active setting in a similar fashion. Patients from both groups will not be adjusted before four months of active treatment, unless judged medically necessary by the treating team. Following four months of active treatment, all subjects in each group will have shunt adjustments according to clinical standards at each center.

Official Title
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A Placebo-Controlled Effectiveness in INPH Shunting (PENS) Trial: Proof of Concept

Conditions
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Idiopathic Normal Pressure Hydrocephalus (INPH)

Intervention / Treatment
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* Device: programmable CSF shunt valve


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 60 years; and Diagnosis of INPH based on the Investigator's clinical judgement based on criteria and testing as described in the INPH Guidelines; and Evans Ratio ≥ 0.30; and One positive supplementary test to include large volume Lumbar Puncture or extended CSF drainage per institutional standards; and History or evidence of gait impairment (such as decreased step height or length,decreased speed, retropulsion as described in the INPH Guidelines) duration ≥ 6 months; and Participant has the sensory motor skills, communication skills and understanding to comply with the testing and reporting required in the PENS trial; and Participant is able to give written informed consent, after being properly informed of the nature and risks of the study and prior to engaging in any study-related procedures. Exclusion Criteria: Unable to walk 10 meters with or without an assistive device; or Baseline fastest gait velocity>1 m/sec and fastest gait velocity improvement is ≤ 30% with or without an assistive device; or Unable to return to the study center for follow up evaluation and shunt programming; or Participant is not medically cleared for shunt surgery per local standards; or Secondary NPH. (Prior encephalitis, meningitis, subarachnoid hemorrhage, traumatic brain injury (including concussion) within two years or with brain injury or skull fracture on baseline imaging, brain abscess, brain tumor, obstructive hydrocephalus (including acquired aqueductal stenosis and carcinomatous meningitis)); or Prior or existing shunts, endoscopic third ventriculostomy, or any previous surgical intervention for hydrocephalus; or Previous intracranial neurosurgical procedure; or Current treatment with anticoagulation medications or expected to be on anticoagulation medications in future based on clinician evaluation; or Symptomatic cerebral or cerebellar infarction within 6 months from screening(asymptomatic lacunar infarctions are permitted); or Diagnosis of Parkinsonian syndrome that, in the investigator's judgment, will complicate the outcome evaluation; or Diagnosis of schizophrenia or any psychiatric diagnosis (including depression) that in the investigator's judgment will complicate the outcome evaluation (such as neuroleptic treatment for schizophrenia); or Diagnosis of dementia disorder where the investigator considers cognition deficit limits participation in the study; or Conditions impairing gait that are considered to be unrelated to hydrocephalus, such as hemiparesis, spasticity, cerebellar ataxia or musculoskeletal and joint disease.

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The primary intervention will be the initiation of the randomized initial shunt valve opening pressure setting to create a delayed treatment group in half of the study patients. Randomization will be to active or placebo (closed) shunt settings. At the time of the standard four-month evaluation, all subjects will be similarly non-invasively adjusted to bring all subjects in both groups to the active setting while maintaining blinding of the subjects. All settings will be verified by the adjusting neurosurgeon.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Open Shunt Group<br>FDA-approved Certas Plus with Siphonguard, programmable CSF shunt valve setting to active (open shunt group)(setting 4)(110 mm H2O) at time of shunt implantation | Device: programmable CSF shunt valve<br>* Brain shunt surgery using a programmable CSF shunt valve<br>* Other names: FDA-approved Certas Plus with Siphonguard;|
| Sham Comparator: Closed Shunt Group<br>FDA-approved Certas Plus with Siphonguard, programmable CSF shunt valve setting to placebo (closed shunt group)(setting 8)(>400 mm H2O) at time of shunt implantation followed by setting to active (setting 4) (110 mm H2O) four months after the procedure. | Device: programmable CSF shunt valve<br>* Brain shunt surgery using a programmable CSF shunt valve<br>* Other names: FDA-approved Certas Plus with Siphonguard;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Gait Velocity | Evaluation of CSF shunting in Idiopathic Normal Pressure Hydrocephalus (INPH) patients through a group comparison of improvement from baseline at four months between active and placebo-controlled groups, using the primary endpoint of gait velocity in meters per second (m/s). | Baseline and 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Cognition as Assessed by the Montreal Cognitive Assessment (MoCA) Score | Evaluate the effect of shunting between active and placebo-controlled groups at four months using MoCA test to assess cognition. Scores on the MoCA range from 0 to 30 where lower scores signify greater cognitive impairment. | Baseline and 4 Months | 
| Change in Bladder Control as Assessed by the Overactive Bladder Questionnaire, Short Form | Evaluate the effect of shunting between active and placebo-controlled groups at four months using Overactive Bladder Questionnaire, short form (OAB-q sf.) to assess bladder control. The OAB-q SF is scored from 0 to 100 with lower scores indicating worse QOL due to bladder control. | Baseline and 4 months |