Idiopathic Normal Pressure Hydrocephalus (INPH)
Conditions
Brief summary
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
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.
Interventions
Brain shunt surgery using a programmable CSF shunt valve
Sponsors
University of Utah
Integra LifeSciences Corporation
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
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 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.
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Gait Velocity | Baseline and 4 months | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cognition as Assessed by the Montreal Cognitive Assessment (MoCA) Score | Baseline and 4 Months | 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. |
| Change in Bladder Control as Assessed by the Overactive Bladder Questionnaire, Short Form | Baseline and 4 months | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Gait Velocity From Shunt Activation to 8 Months After Active Shunting | Up 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). |
| Change in Cognition Using MoCA From Baseline to 8 Months After Active Shunting | Baseline and 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. |
| Change in Bladder Control From Baseline to 8 Months After Active Shunting | Baseline and 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. |
| Change in Function Using ADL/IADL From Baseline to 8 Months After Active Shunting | Baseline and 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. |
| Change in Function as Assessed by the Lawton Activities of Daily Living/Independence in Activities of Daily Living (ADL/IADL) Test Score | Baseline and 4 months | 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. |
| Change in Cognition Using SDMT From Baseline to 8 Months After Active Shunting | Baseline and 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. |
| Number of Patients With Falls | 4 months | Evaluate the effect of shunting between active and placebo-controlled groups at four months by assessing the number of patients with falls. |
| Frequency of Adverse Effects | 8 months | 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. |
| Adverse Events | 4 and 8 months of active shunting | Compare adverse events (AEs) in the active versus placebo-controlled group at four months and at eight months of active shunting. |
| Change in Function Using MRS From Baseline to 8 Months After Active Shunting | Baseline and 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. |
| Change in Function as Assessed by the Modified Rankin Scale (MRS) | Baseline and 4 months | 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. |
| Change in Cognition as Assessed by the Symbol Digit Modalities Test (SDMT) | Baseline and 4 months | 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. |
Countries
Canada, Sweden, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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
programmable CSF shunt valve: Brain shunt surgery using a programmable CSF shunt valve | 9 |
| 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.
programmable CSF shunt valve: Brain shunt surgery using a programmable CSF shunt valve | 9 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 1 |
Baseline characteristics
| Characteristic | Closed Shunt Group | Total | Open Shunt Group |
|---|---|---|---|
| Age, Continuous | 74.5 years | 74.2 years | 74.0 years |
| Evans' Ratio | 0.37 no unit | 0.37 no unit | 0.36 no unit |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 18 Participants | 9 Participants |
| Region of Enrollment Canada | 3 Participants | 6 Participants | 3 Participants |
| Region of Enrollment Sweden | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment United States | 5 Participants | 10 Participants | 5 Participants |
| Sex: Female, Male Female | 4 Participants | 8 Participants | 4 Participants |
| Sex: Female, Male Male | 5 Participants | 10 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 9 | 1 / 9 |
| other Total, other adverse events | 6 / 9 | 4 / 9 |
| serious Total, serious adverse events | 3 / 9 | 1 / 9 |
Outcome results
Primary
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).
Time frame: Baseline and 4 months
Population: Randomized patients alive at Month 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Shunt Group | Change in Gait Velocity | 0.28 meters per second | Standard Deviation 0.284 |
| Closed Shunt Group | Change in Gait Velocity | 0.04 meters per second | Standard Deviation 0.167 |
p-value: 0.07195% CI: [-0.02, 0.46]ANCOVA
Secondary
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.
Time frame: Baseline and 4 months
Population: Randomized patients alive at Month 4 with Outcome Data at Baseline and Month 4.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Shunt Group | Change in Bladder Control as Assessed by the Overactive Bladder Questionnaire, Short Form | -23.3 score on a scale | Standard Deviation 19.89 |
| Closed Shunt Group | Change in Bladder Control as Assessed by the Overactive Bladder Questionnaire, Short Form | 2.1 score on a scale | Standard Deviation 17.81 |
p-value: 0.007ANCOVA
Secondary
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.
Time frame: Baseline and 4 Months
Population: Randomized patients alive at Month 4
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Shunt Group | Change in Cognition as Assessed by the Montreal Cognitive Assessment (MoCA) Score | -0.13 score on a scale | Standard Deviation 3.643 |
| Closed Shunt Group | Change in Cognition as Assessed by the Montreal Cognitive Assessment (MoCA) Score | 1.63 score on a scale | Standard Deviation 1.598 |
p-value: 0.337ANCOVA
Other Pre-specified
Adverse Events
Compare adverse events (AEs) in the active versus placebo-controlled group at four months and at eight months of active shunting.
Time frame: 4 and 8 months of active shunting
Other Pre-specified
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.
Time frame: Baseline and 8 months after active shunting
Population: Patients with outcome data available at baseline and at 8 months after active shunting
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Shunt Group | Change in Bladder Control From Baseline to 8 Months After Active Shunting | -25.0 score on a scale | Standard Deviation 29.42 |
p-value: 0.013t-test, 2 sided
Other Pre-specified
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.
Time frame: Baseline and 4 months
Population: Randomized Patients Alive at Month 4.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Shunt Group | Change in Cognition as Assessed by the Symbol Digit Modalities Test (SDMT) | -0.3 score on a scale | Standard Deviation 6.61 |
| Closed Shunt Group | Change in Cognition as Assessed by the Symbol Digit Modalities Test (SDMT) | -0.1 score on a scale | Standard Deviation 4.02 |
p-value: 0.78ANCOVA
Other Pre-specified
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.
Time frame: Baseline and 8 months after active shunting
Population: all patients with MoCA available at baseline and after 8 months of active shunting
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Shunt Group | Change in Cognition Using MoCA From Baseline to 8 Months After Active Shunting | 1.0 score on a scale | Standard Deviation 2.92 |
p-value: 0.24t-test, 2 sided
Other Pre-specified
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.
Time frame: Baseline and 8 months after active shunting
Population: All patients with SDMT data available at baseline and 8 months after active shunting
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Shunt Group | Change in Cognition Using SDMT From Baseline to 8 Months After Active Shunting | 5.8 score on a scale | Standard Deviation 7.21 |
p-value: 0.013t-test, 2 sided
Other Pre-specified
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.
Time frame: Baseline and 4 months
Population: Randomized Patients alive at Month 4 with Outcome Data for both Baseline and Month 4.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Shunt Group | Change in Function as Assessed by the Lawton Activities of Daily Living/Independence in Activities of Daily Living (ADL/IADL) Test Score | -5.7 score on a scale | Standard Deviation 6.73 |
| Closed Shunt Group | Change in Function as Assessed by the Lawton Activities of Daily Living/Independence in Activities of Daily Living (ADL/IADL) Test Score | 1.4 score on a scale | Standard Deviation 3.89 |
p-value: 0.201ANCOVA
Other Pre-specified
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.
Time frame: Baseline and 4 months
Population: Randomized Patients Alive at Month 4.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Shunt Group | Change in Function as Assessed by the Modified Rankin Scale (MRS) | -0.88 score on a scale | Standard Deviation 1.126 |
| Closed Shunt Group | Change in Function as Assessed by the Modified Rankin Scale (MRS) | -0.13 score on a scale | Standard Deviation 0.641 |
p-value: 0.172ANCOVA
Other Pre-specified
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.
Time frame: Baseline and 8 months after active shunting
Population: All participants with outcome data available at baseline and after 8 months of active shunting
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Shunt Group | Change in Function Using ADL/IADL From Baseline to 8 Months After Active Shunting | -4.7 score on a scale | Standard Deviation 5.88 |
p-value: 0.019t-test, 2 sided
Other Pre-specified
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.
Time frame: Baseline and 8 months after active shunting
Population: All randomizred patients with MRS data at baseline and at 8 months of active shunting.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Shunt Group | Change in Function Using MRS From Baseline to 8 Months After Active Shunting | -0.6 score on a scale | Standard Deviation 0.96 |
p-value: 0.04t-test, 2 sided
Other Pre-specified
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).
Time frame: Up to 8 months after active shunting
Population: All randomized patients alive with gait velocity evaluated 8 months after active shunting.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Shunt Group | Change in Gait Velocity From Shunt Activation to 8 Months After Active Shunting | 0.38 meters per second | Standard Deviation 0.229 |
p-value: <0.001t-test, 2 sided
Other Pre-specified
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.
Time frame: 8 months
Other Pre-specified
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.
Time frame: 4 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Open Shunt Group | Number of Patients With Falls | 0 Participants |
| Closed Shunt Group | Number of Patients With Falls | 2 Participants |
p-value: 0.235Fisher Exact