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

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

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.

Study Overview

• Status: Completed
• Conditions: Idiopathic Normal Pressure Hydrocephalus (INPH)
• Intervention / Treatment: Device: programmable CSF shunt valve

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 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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • University of Calgary
  • British Colombia
    • Vancouver, British Colombia, Canada, V5Z 1M9
      • Vancouver General Hospital/University of British Colombia
• Sweden
  • Umeå, Sweden
    • Umea University
• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Medicine
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Washington
    • Seattle, Washington, United States, 98196
      • University of Washington Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Open Shunt Group; 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; Brain shunt surgery using a programmable CSF shunt valve; Other Names: FDA-approved Certas Plus with Siphonguard
Sham Comparator: Closed Shunt Group; 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; Brain shunt surgery using a programmable CSF shunt valve; Other Names: FDA-approved Certas Plus with Siphonguard

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Function as Assessed by the Lawton Activities of Daily Living/Independence in Activities of Daily Living (ADL/IADL) Test Score	Evaluate the effect of shunting between active and placebo-controlled groups on change from baseline to four months using ADL/IADL test to assess function. Scores on the Lawton ADL/IADL scale range from 0 to 32 where a lower score indicates less independence in physical and instrumental daily living skills.	Baseline and 4 months
Change in Function as Assessed by the Modified Rankin Scale (MRS)	Evaluate the effect of shunting between active and placebo-controlled groups at four months using MRS to assess function. Scores on the MRS range from 0 to 6 where higher scores signify increased disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability.	Baseline and 4 months
Change in Cognition as Assessed by the Symbol Digit Modalities Test (SDMT)	Evaluate the effect of shunting between active and placebo-controlled groups at four months using SDMT to assess cognition. Scores on the SDMT range from 0 to 110 where lower scores are associated with reduced psychomotor speed.	Baseline and 4 months
Change in Gait Velocity From Shunt Activation to 8 Months After Active Shunting	Evaluate the clinical improvement of all study participants at eight months of active shunting, using the primary outcome of gait velocity. For patients assigned to Open shunt, active shunting is from Baseline to Month 8 of the study. For patients assigned to Closed Shunt, active shunting is from Month 4 of the study (immediately prior to opening of initially Closed shunt) to Month 12 (i.e., after 8 months of the patient having an open shunt).	Up to 8 months after active shunting
Change in Cognition Using MoCA From Baseline to 8 Months After Active Shunting	Evaluate the clinical improvement of all study participants at eight months of active shunting using MoCA to assess cognition. Scores on the MoCA range from 0 to 30 where lower scores signify greater cognitive impairment.	Baseline and 8 months after active shunting
Change in Bladder Control From Baseline to 8 Months After Active Shunting	Evaluate the clinical improvement of all study participants at eight months of active shunting using OAB-q test 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 8 months after active shunting
Change in Function Using ADL/IADL From Baseline to 8 Months After Active Shunting	Evaluate the effect of shunting between active and placebo-controlled groups on change from baseline to four months using ADL/IADL test to assess function. Scores on the Lawton ADL/IADL scale range from 0 to 32 where a lower score indicates less independence in physical and instrumental daily living skills.	Baseline and 8 months after active shunting
Change in Function Using MRS From Baseline to 8 Months After Active Shunting	Evaluate the effect of shunting between active and placebo-controlled groups at four months using MRS to assess function. Scores on the MRS range from 0 to 6 where higher scores signify increased disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability.	Baseline and 8 months after active shunting
Change in Cognition Using SDMT From Baseline to 8 Months After Active Shunting	Evaluate the clinical improvement of all study participants at eight months of active shunting using SDMT to assess cognition. Scores on the SDMT range from 0 to 110 where lower scores are associated with reduced psychomotor speed.	Baseline and 8 months after active shunting
Number of Patients With Falls	Evaluate the effect of shunting between active and placebo-controlled groups at four months by assessing the number of patients with falls.	4 months
Frequency of Adverse Effects	Evaluate the clinical improvement of all study participants at eight months of active shunting by assessing the frequency of falls, surgical and non-surgical complications, related and unrelated.	8 months
Adverse Events	Compare adverse events (AEs) in the active versus placebo-controlled group at four months and at eight months of active shunting.	4 and 8 months of active shunting

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: University of Utah; Integra LifeSciences Corporation
• Investigators: Principal Investigator: Mark Luciano, MD, Johns Hopkins University

Study record dates

Study Major Dates

• Study Start (Actual): May 21, 2018
• Primary Completion (Actual): March 19, 2021
• Study Completion (Actual): May 18, 2021

Study Registration Dates

• First Submitted: November 14, 2017
• First Submitted That Met QC Criteria: November 17, 2017
• First Posted (Actual): November 22, 2017

Study Record Updates

• Last Update Posted (Actual): August 2, 2022
• Last Update Submitted That Met QC Criteria: July 29, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hydrocephalus; Hydrocephalus, Normal Pressure
• Other Study ID Numbers: IRB00083576

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

After subject enrollment and follow up have been completed, the Data Coordinating Center (DCC) of the study will prepare a final study database for analysis. A releasable database will be produced and completely de-identified in accordance with the definitions provided in the Health insurance Portability and Accountability Act (HIPAA). Namely, all identifiers specified in HIPAA will be re-coded in a manner that will make it impossible to deduce or impute the specific identity of any patient. The database will not contain any institutional identifiers.

The DCC will also prepare a data dictionary that provides a concise definition of every data element included in the database. If specific data elements have idiosyncrasies that might affect interpretation or analysis, this will be discussed in the dictionary document.

In accordance with policies determined by the investigators and funding sponsors, the releasable database will be provided to users in electronic form.

• IPD Sharing Time Frame: One year after publication of the results of the primary analysis.
• IPD Sharing Access Criteria: individual participant data (IPD) will be made available to researchers submitting a request for data that includes an analytic plan approved by the Institutional Review Board (IRB) at their institution
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No