| Study characteristics |
| Methods |
Study design: 1‐arm, cross‐over randomised controlled trial, assessor and participant blinded
Number randomised: 18 (9 active VP shunt, 9 initially inactive VP shunt)
Exclusions: all participants received intended immediate intervention. 2 participants became medically unwell during study (1 gallbladder necrosis, 1 contralateral stroke).
Length of follow‐up: 12 months
How data were handled: intention‐to‐treat |
| Participants |
Country: United States, Canada, Sweden
Setting: multicentre
Baseline characteristics:
Immediate‐shunt group
Mean age in years: 74 Female: 44%
Delayed‐shunt group
Mean age in years: 74.5 Female: 44%
Number of Hakim symptoms: gait + 1 other
Inclusion criteria:
Diagnosis of iNPH based on the investigator's clinical judgement based on criteria and testing as described in the INPH Guidelines Evans ratio ≥ 0.30 1 positive supplementary test to include large‐volume lumbar puncture or extended CSF drainage per institutional standards History or evidence of gait impairment ≥ 6 months Patient has the sensory motor skills, communication skills, and understanding to comply with the testing and reporting required in the PENS trial Patient 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:
Inability to walk 10 metres with or without an assistive device or baseline fastest gait velocity > 1 m/s and fastest gait velocity improvement is ≤ 30% with or without an assistive device Inability to return to the study centre for follow‐up Not medically cleared for shunt surgery per local standards Secondary NPH (prior encephalitis, meningitis, subarachnoid haemorrhage, traumatic brain injury (including concussion) within 2 years or with brain injury or skull fracture on baseline imaging) Brain abscess, brain tumour, obstructive hydrocephalus (including acquired aqueductal stenosis and carcinomatous meningitis) Prior or existing shunts, endoscopic third ventriculostomy, or any previous surgical intervention for hydrocephalus Previous intracranial neurosurgical procedure Treatment with anticoagulation Symptomatic cerebral infarction within 6 months from screening Diagnosis of Parkinsonian syndrome that, in the investigator’s judgement, would complicate the outcome evaluation Conditions impairing gait that are considered to be unrelated to hydrocephalus, such as hemiparesis, spasticity, cerebellar ataxia or musculoskeletal and joint disease, which would interfere with gait assessment or the potential for gait improvement
Entry modification:
Some entry criteria were modified based on the initial experience of the trial. Initially, a MoCA score of > 18 was required, but this was eliminated. Similarly, patients with a diagnosis of a movement or psychiatric disorder were initially excluded, but patients with these comorbidities were subsequently eligible for the study if the site principal investigator judged that the disorder did not interfere with the patient’s ability to respond to CSF drainage or shunt surgery.
|
| Interventions |
Intervention 1: active VP shunt
Intervention 2: initially inactive VP shunt changed to active at 4 months |
| Outcomes |
Primary outcome:
Improvement in gait velocity measured by 10 MWT
Secondary outcomes:
MoCA; Symbol Digit Modalities Test; Overactive Bladder Questionnaire, short form; Beck Depression Inventory, Second Edition; Lawton Activities of Daily Living/Independent Activities of Daily Living Questionnaire; and mRS scores |
| Notes |
Sources of support: this study was supported by Integra LifeSciences, without control of study design, data collection, analysis, or publication. Other support and consultation were provided by the Hydrocephalus Association through the Adult Hydrocephalus Clinical Research Network, the National Center for Advancing Translational Sciences (Grant U24TR001609 in support of the Johns Hopkins‐Tufts Trial Innovation Center) for consultation on recruitment, and the National Institute on Aging (U19‐AG033655) for initial protocol review. Neurosurgery administrative support was also provided to the Johns Hopkins Neurosurgery CSF Disorders Center through George Berry and William Lickle.
Possible conflicts of interest: Dr Holubkov is on the Data Safety Monitoring Board Service for Pfizer Inc. Dr Moghekar is a non‐paid member of the Medical Advisory Board at the nonprofit Hydrocephalus Association. Dr Hamilton has been paid by Integra Canada and Integra International for general educational lectures at professional meetings not related to the contents of this paper, and received a one‐time consultant fee under USD 2000 from CereVasc Inc, for whom he is a current member of the Data Safety Monitoring Board. |
