Clinical trial NCT05081128: Efficacy in iNPH Shunting (PENS) Trial
Official title: A Placebo-Controlled Efficacy in iNPH Shunting (PENS) Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Idiopathic Normal Pressure Hydrocephalus (INPH)
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2021-10-18
Enrollment: 100
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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 three-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.
Primary purpose: TREATMENT

Brief summary: The Placebo-Controlled Efficacy 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 efficacy in iNPH patients.

Detailed description: 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 three months, the closed shunt group will have zero months of active treatment, and the open shunt group will have three months of active treatment. At three 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 three months of active treatment, unless judged medically necessary by the treating team. Following the three month visit, all subjects in each group will have shunt adjustments according to clinical standards at each center.

Eligibility criteria: Inclusion Criteria:

1. Age ≥ 60 years; and
2. Diagnosis of iNPH and recommendation for shunt surgery based on the Investigator's clinical judgement based on criteria and testing as described in the iNPH Guidelines;
3. Evans Ratio ≥ 0.30; and
4. One positive supplementary test to include either large volume Lumbar Puncture or extended CSF drainage per institutional standards; and
5. 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
6. Participant has the sensory motor skills, communication skills and understanding to comply with the testing and reporting required in the PENS trial; and
7. Participant is able to give written informed consent.

Exclusion Criteria:

1. Unable to walk 10 meters with or without an assistive device; or
2. Baseline fastest gait velocity (out of three gait trials) \>1 m/sec prior to drainage trial and fastest gait velocity improvement is \< 30% with or without an assistive device; or
3. Unable to return to the study center for follow up evaluation and shunt programming; or
4. Participant is not medically cleared for shunt surgery per local standards; or
5. 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
6. Prior or existing shunts, endoscopic third ventriculostomy, or any previous surgical intervention for hydrocephalus; or
7. Previous intracranial neurosurgical procedure; or
8. Symptomatic cerebral or cerebellar infarction occurring within 6 months from screening (asymptomatic lacunar infarctions are permitted); or
9. Diagnosis of Parkinsonian syndrome that, in the investigator's judgment, will complicate the outcome evaluation; or
10. 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
11. Diagnosis of dementia disorder where the investigator considers cognition deficit limits participation in the study; or
12. Conditions impairing gait that are considered to be unrelated to hydrocephalus, such as hemiparesis, spasticity, cerebellar ataxia or musculoskeletal and joint disease, which will interfere with gait assessment or the potential for gait improvement.
13. Individuals with contraindication to MRI (e.g., implanted electric and electronic devices, aneurysm clip(s), any metallic fragment or foreign body, coronary and peripheral artery stents, cardiac pacemaker, known claustrophobia, or known/possible pregnancy or breast-feeding) will be excluded according to institutional guidelines.

Primary outcomes:
measure: Change in Gait velocity
timeFrame: Baseline and 3 months
Secondary outcomes:
measure: Cognition as assessed by the Montreal Cognitive Assessment (MoCA)
timeFrame: Baseline and 3 months
measure: Bladder Control as assessed by the Overactive Bladder Questionnaire, short form
timeFrame: Baseline and 3 months
measure: Balance and Gait as assessed by the Tinetti Score
timeFrame: Baseline and 3 months
Other outcomes:
measure: Bladder Control as assessed by the Overactive Bladder Questionnaire, short form
timeFrame: Baseline and 12 months of active shunting
measure: Change in Gait velocity
timeFrame: Baseline and 12 months of active shunting
measure: Cognition as assessed by the Montreal Cognitive Assessment (MoCA)
timeFrame: Baseline and 12 months of active shunting
Locations:
city: Davis
country: United States
facility: University of California, Davis
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Santa Monica
country: United States
facility: Pacific Neuroscience Institute
state: California
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: New York University Langone Health
state: New York
city: New York
country: United States
facility: Mount Sinai Health System
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Medical Center
state: North Carolina
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center
state: Texas
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Vancouver
country: Canada
facility: University of British Columbia
city: Umeå
country: Sweden
facility: Umeå University
Study officials:
affiliation: Johns Hopkins University
name: Mark Luciano, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Utah
name: Richard Holubkov, PhD
role: STUDY_DIRECTOR
References: