Idiopathic Normal Pressure Hydrocephalus (INPH)
Conditions
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.
Interventions
Brain shunt surgery using a programmable CSF shunt valve
Sponsors
Johns Hopkins University
National Institute of Neurological Disorders and Stroke (NINDS)
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 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.
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Gait Velocity | Baseline and 3 months | Evaluation of CSF shunting in iNPH patients through a group comparison of change from baseline at three months between active and placebo-controlled groups, using the primary endpoint of gait velocity (in meters per second). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cognition as Assessed by the Montreal Cognitive Assessment (MoCA) | Baseline and 3 months | Evaluate the effect of shunting between active and placebo-controlled groups at three months using MoCA test to assess cognition. Scores on the MoCA range from 0 to 30, with a score of 26 and higher generally considered normal. |
| Change in Bladder Control as Assessed by the Overactive Bladder Questionnaire, Short Form | Baseline and 3 months | Evaluate the effect of shunting between active and placebo-controlled groups at three months using Overactive Bladder Questionnaire, short form (OAB-q sf.) to assess bladder control. Total score range 0- to 100, with lower score indicating greater effect, i.e., worse QOL. |
| Change in Balance and Gait as Assessed by the Tinetti Score | Baseline and 3 months | Evaluate the effect of shunting between active and placebo-controlled groups at three months using Tinetti Score to assess balance and gait. Scores on the Tinetti range from 0 to 28. The higher the score the better the gait and balance performance. |
Countries
Canada, Sweden, United States
Contacts
PRINCIPAL_INVESTIGATORMark Luciano, MD, PhD
Johns Hopkins University
STUDY_DIRECTORRichard Holubkov, PhD
University of Utah
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 75.1 Years STANDARD_DEVIATION 5.7 |
| Baseline Gait Velocity (m/s) | 0.87 m/s STANDARD_DEVIATION 0.25 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 45 Participants |
| Sex: Female, Male Female | 25 Participants |
| Sex: Female, Male Male | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 49 | 3 / 50 |
| other Total, other adverse events | 39 / 49 | 40 / 50 |
| serious Total, serious adverse events | 18 / 49 | 16 / 50 |
Outcome results
None listed