A Placebo-Controlled Effectiveness in INPH Shunting (PENS) Trial: Proof of Concept
Phase: NA
Conditions: Idiopathic Normal Pressure Hydrocephalus (INPH)
Sponsor: Johns Hopkins University

A Placebo-Controlled Eﬀectiveness in INPH
Shunting (PENS) Trial: Proof of Concept
Adult Hydrocephalus Clinical Research Network
(AHCRN) Protocol Number 002
Protocol Version 4.0
Version Date: May 8, 2020

Copyright c⃝2016 - 2018. University of Utah School of Medicine on behalf of the
Principal Investigator, Mark Luciano, M.D. and the Adult Hydrocephalus Clinical
Research Network. All rights reserved.
This protocol is AHCRN Protocol Number 002, and has been approved by Mark
Luciano, M.D., Johns Hopkins University, for implementation with PENS investigators.
This study is supported by the Hydrocephalus Association as part of its mission to
promote a cure for hydrocephalus and improve the lives of those aﬀected by the
condition.
This document was prepared by the AHCRN Data Coordinating Center located
at the University of Utah School of Medicine, Salt Lake City, Utah. The document
was written and typeset using LATEX2ε.

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PROTOCOL TITLE:
A Placebo-Controlled Eﬀectiveness in INPH Shunting (PENS) Trial: Proof of
Concept
Short Title: PENS Protocol
Lead Investigator:
Mark Luciano, MD
Johns Hopkins University
Protocol Version: 4.0
Version Date: May 8, 2020
I conﬁrm that I have read this protocol, I understand it, and I will conduct the study
according to the protocol. I will also work consistently with the ethical principles that
have their origin in the Declaration of Helsinki and will adhere to the Ethical and
Regulatory Considerations as stated. I conﬁrm that if I or any of my staﬀare members
of the Institutional Review Board, we will abstain from voting on this protocol, its
future renewals, and its future amendments.
Principal Investigator Name:
Principal Investigator Signature:
Date:
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Contents
Contents
5
List of Tables
7
List of Figures
7
1
Study Summary
8
1.1
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
1.2
Primary Hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
1.3
Study Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
1.3.1
Primary Objective
. . . . . . . . . . . . . . . . . . . . . . . .
8
1.3.2
Secondary Objectives . . . . . . . . . . . . . . . . . . . . . . .
8
1.4
Participant Eligibility . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
1.4.1
Inclusion Criteria: . . . . . . . . . . . . . . . . . . . . . . . . .
9
1.4.2
Exclusion Criteria: . . . . . . . . . . . . . . . . . . . . . . . .
10
2
Rationale and Background
11
2.1
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
2.2
Rationale for Current Study . . . . . . . . . . . . . . . . . . . . . . .
12
3
Study Design and Data Collection
13
3.1
Study Design
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
3.1.1
Overview of Interventions
. . . . . . . . . . . . . . . . . . . .
15
3.1.2
Functional Measures . . . . . . . . . . . . . . . . . . . . . . .
17
3.2
Study Data Collection
. . . . . . . . . . . . . . . . . . . . . . . . . .
19
4
Detailed Study Interventions
21
4.1
Shunt Implantation . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
4.2
Blinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
4.3
Unblinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
4.4
One-Month Post-Surgery Remote Visit . . . . . . . . . . . . . . . . .
22
4.5
Two-Month Post-Surgery Remote Visit . . . . . . . . . . . . . . . . .
22
4.6
Four-Month Post-Surgery Visit: Primary Objective Measurements and
Shunt Setting Change
. . . . . . . . . . . . . . . . . . . . . . . . . .
23
4.7
Post-Surgery Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
4.8
Five-Month Post-Surgery Remote Visit . . . . . . . . . . . . . . . . .
23
4.9
Eight-Month Post-Surgery Visit . . . . . . . . . . . . . . . . . . . . .
23
4.10 Twelve-Month Post-Surgery Visit . . . . . . . . . . . . . . . . . . . .
23
4.11 Other Therapy Guidelines . . . . . . . . . . . . . . . . . . . . . . . .
24
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5
Data Analysis
24
5.1
General Analytic Issues . . . . . . . . . . . . . . . . . . . . . . . . . .
24
5.2
Primary Analysis: Is Shunting Eﬀective? . . . . . . . . . . . . . . . .
25
5.3
Secondary Analyses of Gait Velocity Change . . . . . . . . . . . . . .
25
5.4
Secondary Analysis and Secondary Endpoint Analysis . . . . . . . . .
25
5.5
Secondary Analysis: Safety . . . . . . . . . . . . . . . . . . . . . . . .
26
5.6
Power Analysis for Primary Outcome . . . . . . . . . . . . . . . . . .
26
6
Study Organization
27
6.1
Participating Institutions . . . . . . . . . . . . . . . . . . . . . . . . .
27
7
Data Management
28
7.1
Clinical Site Data Management
. . . . . . . . . . . . . . . . . . . . .
28
7.2
Electronic Data Capture System: OpenClinica . . . . . . . . . . . . .
28
7.3
Study Monitoring
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
28
7.3.1
Site Monitoring Plan . . . . . . . . . . . . . . . . . . . . . . .
29
7.3.2
Clinical Site Monitoring
. . . . . . . . . . . . . . . . . . . . .
29
7.3.3
Remote Monitoring . . . . . . . . . . . . . . . . . . . . . . . .
29
7.4
Data Coordinating Center (DCC) . . . . . . . . . . . . . . . . . . . .
30
7.4.1
Data Center Description . . . . . . . . . . . . . . . . . . . . .
30
7.4.2
Security and Conﬁdentiality . . . . . . . . . . . . . . . . . . .
31
7.5
Record Access . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
32
8
Devices
32
9
Protection of Human Subjects
33
9.1
Central Institutional Review Board (CIRB)/ Research Ethics Board
(REB) Approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
9.2
Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
9.3
Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
9.4
Beneﬁts
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
35
10 Data and Safety Monitoring Plan
35
10.1 Data Safety Monitoring Board (DSMB) . . . . . . . . . . . . . . . . .
35
10.2 Adverse Events Reporting . . . . . . . . . . . . . . . . . . . . . . . .
36
10.2.1 Deﬁnitions, Relatedness, Seriousness and Expectedness . . . .
36
10.2.2 Time Period for Adverse Events . . . . . . . . . . . . . . . . .
39
10.2.3 Data Collection Procedures for Adverse Events
. . . . . . . .
39
10.2.4 Unanticipated Problems (UP) . . . . . . . . . . . . . . . . . .
40
10.2.5 Monitoring Serious Adverse Events . . . . . . . . . . . . . . .
40
10.2.6 Follow-up of Serious, Unexpected and Related Adverse Events
41
11 Study Training
41
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12 Regulatory Issues
41
12.1 Health Insurance Portability and Accountability Act (HIPAA) . . . .
41
12.2 Inclusion of Women and Minorities . . . . . . . . . . . . . . . . . . .
42
12.3 ClinicalTrials.gov Requirements . . . . . . . . . . . . . . . . . . . . .
42
12.4 Retention of Records . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
12.5 Public Use Data Set
. . . . . . . . . . . . . . . . . . . . . . . . . . .
42
13 Monitoring and Quality Assurance
43
13.1 Tracking Participant Enrollment . . . . . . . . . . . . . . . . . . . . .
43
13.2 Monitoring and Screening Compliance
. . . . . . . . . . . . . . . . .
43
13.3 DSMB Evaluation of Screening and Registry Data . . . . . . . . . . .
43
14 Bibliography
44
List of Tables
1
Schedule of Assessments . . . . . . . . . . . . . . . . . . . . . . . . .
16
2
Power Analysis for Primary Outcome . . . . . . . . . . . . . . . . . .
27
List of Figures
1
Workﬂow
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
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1
Study Summary
1.1
Abstract
Although idiopathic normal pressure hydrocephalus (INPH) has been recognized for
ﬁve decades, barriers still exist in recognition, referral and accurate diagnosis. Hes-
itance in referring elderly patients for surgical treatment of INPH results from an
incomplete understanding of its pathophysiology, controversy over the appropriate
diagnostic work up, and a signiﬁcant concern about the eﬀectiveness and complications
of surgical treatment. The approach to screening, diagnosis and treatment of INPH
varies throughout the world, though success rates in experienced centers are similar in
uncontrolled studies.
The lack of consensus regarding tests predicting outcome of surgery in INPH,
and the skepticism of INPH in the neurology and neurosurgery communities reﬂect
the limitations of INPH clinical research to support current INPH practices. INPH
clinical research paradigms have not changed for over 20 years. A survey described the
uncertainty surrounding the treatment of INPH and the need for a placebo-controlled
study. Convincing proof of shunting eﬀectiveness is likely to increase the number of
INPH patients getting adequate treatment.1
The Placebo-Controlled Eﬀectiveness in INPH Shunting (PENS) trial is a multi-
center blinded, randomized, placebo-controlled design investigation of cerebrospinal
ﬂuid (CSF) shunt surgery.
1.2
Primary Hypothesis
The primary hypothesis of the PENS trial is that treatment of idiopathic normal
pressure hydrocephalus (INPH) with an open shunt results in improved gait velocity.
1.3
Study Objectives
1.3.1
Primary Objective
The primary study objective is the evaluation of CSF shunting in INPH participants
through a group comparison of improvement from baseline at four months between
active and placebo-controlled groups, using the primary endpoint of gait velocity, to
test the primary hypothesis as above.
1.3.2
Secondary Objectives
1. Evaluate the clinical improvement of all study participants at eight months of
active shunting, using the primary outcome of gait velocity.
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2. Evaluate the eﬀect of shunting between active and placebo-controlled groups at
four months using secondary clinical outcome measures as listed below.
3. Evaluate the clinical improvement of all study participants at eight months of
active shunting using secondary clinical outcome measures.
4. Identify novel CSF biomarkers that diﬀerentiate participants with INPH from
Alzheimer’s disease (AD) participants and other dementias, adjusting the typical
cut-oﬀs of traditional AD related biomarkers for altered volume of distribution
when CSF is available from clinical testing.
5. Identify speciﬁc biomarkers associated with improved medium term (eight month
outcomes) response to active shunting, enabling improved selection of participants
in future trials.
6. Compare adverse events (AEs) in the active versus placebo-controlled group at
four months and at eight months of active shunting.
The secondary clinical outcome measures are improvement in measures of cognition
and mood, function, bladder control and frequency of adverse eﬀects:
• Cognition and Mood:
– Montreal Cognitive Assessment Test (MoCA)
– Symbol Digit Modalities Test (SDMT)
– Beck Depression Inventory, 2nd edition (BDI-II)
– Lawton Activities of Daily Living/Independence in Activities of Daily
Living (ADL/IADL)
• Function: Modiﬁed Rankin Scale (MRS)
• Bladder Control: Overactive Bladder Questionnaire, short form (OAB-q sf.)
• Adverse Events: Frequency of falls, surgical and non-surgical complications,
related and unrelated
1.4
Participant Eligibility
1.4.1
Inclusion Criteria:
Participants will be eligible for enrollment if they meet all of the following inclusion
criteria:
1. Age ≥60 years; and
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2. Diagnosis of INPH based on the Investigator’s clinical judgement based on
criteria and testing as described in the INPH Guidelines2; and
3. Evans Ratio ≥0.30; and
4. One positive supplementary test to include large volume Lumbar Puncture or
extended CSF drainage per institutional standards3; and
5. History or evidence of gait impairment (such as decreased step height or length,
decreased speed, retropulsion as described in the INPH Guidelines2) 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, after being properly informed
of the nature and risks of the study and prior to engaging in any study-related
procedures.
1.4.2
Exclusion Criteria:
Participants will be ineligible for enrollment if any of the following exclusion criteria
are met:
1. Unable to walk 10 meters with or without an assistive device; or
2. Baseline fastest gait velocity >1 m/sec 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 pro-
gramming; or
4. Participant is not medically cleared for shunt surgery per local standards; or
5. Secondary NPH. (Prior encephalitis, meningitis, subarachnoid hemorrhage, trau-
matic brain injury (including concussion) within two years or with brain injury or
skull fracture on baseline imaging, brain abscess, brain tumor, obstructive hydro-
cephalus (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. Current treatment with anticoagulation medications or expected to be on anti-
coagulation medications in future based on clinician evaluation; or
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9. Symptomatic cerebral or cerebellar infarction within 6 months from screening
(asymptomatic lacunar infarctions are permitted); or
10. Diagnosis of Parkinsonian syndrome that, in the investigator’s judgment, will
complicate the outcome evaluation; or
11. 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
12. Diagnosis of dementia disorder where the investigator considers cognition deﬁcit
limits participation in the study; or
13. 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.
2
Rationale and Background
2.1
Background
INPH is underdiagnosed because of widespread skepticism regarding diagnostic tests
and treatment outcomes. Although thousands of shunts are implanted for INPH
each year, a signiﬁcant proportion of neurologists and neurosurgeons do not believe
that INPH can be diagnosed accurately. Further, many physicians believe that shunt
surgery does not improve patient outcome, or that the risk of complications is far
greater than the odds of beneﬁt.
Demonstration of the clinical eﬀectiveness of shunt surgery on INPH in a placebo-
controlled trial may change physicians’ practice regarding the need to evaluate and
treat properly selected patients for INPH. As a result, the number of appropriately
treated patients should increase signiﬁcantly. Appropriate treatment will result in a
reduction of unnecessary impairment and disability, a diminished need for health care
services (including nursing home) among the elderly INPH population, with associated
reduction in long-term health care expenditures,4 and a signiﬁcant economic and
psychosocial impact on patients and families. Additional advances in treatment will
be facilitated by quantitation of true physiological eﬀects, allowing comparison in
subsequent studies. Attention may then focus on the identiﬁcation of subpopula-
tion that can beneﬁt and demonstrate improvement in shunting materials and methods.
INPH clinical research paradigms have not changed for over 20 years. The lack of
consensus regarding INPH diagnostic tests among INPH experts, and the skepticism
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of INPH in the neurology and neurosurgery communities reﬂect the limitations of
INPH clinical research to support current INPH practices. While studies showing
eﬃcacy have been performed by Dutch, European, and Japanese centers,5–7 these
studies were not placebo controlled and were discrepant in diagnostic method and
outcome measures that left questions about true eﬀectiveness and patient selection.
2.2
Rationale for Current Study
Subjective factors in evaluation of INPH treatment response, along with the strong
potential of surgery and an implanted shunt to elicit a placebo response, have made
a scientiﬁcally convincing demonstration of the true physiological treatment eﬀect
of shunting in INPH diﬃcult. Few studies have attempted to evaluate the extent
of physiological versus placebo-induced shunt improvement in INPH. These studies
have been small and have often used invasive procedures such as ligature around the
distal shunt catheter to produce the placebo condition. This has made true blinding
diﬃcult and required a minor surgical procedure to remove the ligature and reverse
the placebo condition.
Our study would be the ﬁrst to take advantage of the virtual oﬀsetting of a
programmable valve system to result in a blinded non-invasive placebo-controlled
study, as we ﬁrst proposed in 2012.8
There is a strong scientiﬁc and public health imperative to do such an evaluation.
A placebo-controlled study is necessary to determine the clinical response to shunt
surgery for INPH. Either result of this study will have an important impact on care
of the elderly: If shunting is proven eﬀective, it may be oﬀered to a proportion of
the much larger group of INPH candidates that have been estimated.9, 10 Further,
a placebo-controlled study allows the evaluation of the placebo vs. physiological
eﬀect that will identify objective thresholds that distinguish shunt responders from
non-responders. Alternately, if no diﬀerence in clinical or physiological response exists
between the shunt and placebo groups, then the existence of shunt-responsive INPH
may be questioned and would signiﬁcantly reduce the number of elderly patients
undergoing unnecessary diagnostic procedures and surgery.
The most common reason for failure to improve on the diagnostic tests as well
as shunt surgery is the prevalence of AD in the aging population. AD is known to
cause ventriculomegaly; and gait abnormalities have been described even in prodromal
AD, making the distinction from INPH a clinical challenge. Therefore, CSF will be
collected to potentially identify biomarkers that improve the clinician’s ability to
diﬀerentiate between these two conditions.
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Diﬃculty in distinguishing INPH from other common age related neurodegenerative
disorders that present with similar symptoms like Lewy body dementia and vascular
dementia is considered one of the reasons for poor long term shunt responsiveness and
is purely based on radiologic assessment and INPH speciﬁc diagnostic tests. Moreover,
with increasing age, it is not surprising that INPH can coexist with other age related
neurodegenerative disorders which over time would be expected to reduce the beneﬁt
from shunt surgery even though the shunt optimally treats INPH. The Inﬁnium Neuro
Consortium ArrayR is a new neurogenomic tool with expertly-selected content for the
interrogation of genomic variants associated with common neurodegenerative diseases.
The array includes 180,000 markers focused on characterization of neurodegenerative
diseases. The consortium gathered previously identiﬁed markers found in known
neurodegenerative disease genes including Alzheimers Disease, Parkinsons Disease,
Progressive Supranuclear Palsy (PSP)/Corticobasal Degeneration (CBD), Multiple
System Atrophy (MSA), Frontotemporal Dementia (FTD), Dementia with Lewy
Bodies (DLB), all disorders that are in the diﬀerential diagnosis with INPH. Saliva
genotyping will be analyzed using saliva samples collected after enrollment to ascertain
the prevalence of common neurodegenerative disorders in those selected for the
PENS trial to discover if the lack of responsiveness in those who have received shunt
treatment for 12 months could be explained by the prevalence of any single nucleotide
polymorphisms (SNPs) related to the above neurodegenerative disorders.
3
Study Design and Data Collection
3.1
Study Design
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 study participants in
the closed Shunt group will be adjusted to setting 4. To maintain blinding, all study
participants will be adjusted/ mock adjusted to the active setting in a similar fashion.
Participants 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 participants in each group will have shunt adjustments
according to clinical standards at each center.
Procedures and data collection in the trial are displayed in Table 1. Initial baseline
assessments should be done by an AHCRN trained assessor prior to or at least two
weeks post lumbar puncture (LP) or external lumbar drainage (ELD). Please note
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STUDY ENDS
CLOSED SHUNT
SETTING 8
ACTIVE SHUNT 
SETTING 4
ACTIVE SHUNT 
SETTING 4
MOCK SETTING CHANGE 
BASELINE / SCREENING
(STANDARD NPH TESTING)
REPEAT BASELINE 
(IF APPLICABLE*)
INFORMED 
CONSENT
EXCLUSION
6 WEEKS
0 WEEKS
SHUNT SURGERY
RANDOMIZATION
1 & 2 MONTH SAFETY
FOLLOW UP
1 & 2 MONTH SAFETY
FOLLOW UP
4 MONTH FOLLOW UP
(4 MONTHS OFF)
4 MONTH FOLLOW UP
(4 MONTHS ACTIVE)
PRIMARY ANALYSIS
STANDARD CLINICAL EVALUATION
4 + MONTHS
5 MONTH SAFETY
FOLLOW UP
8 MONTH FOLLOW UP
(4 MONTHS ACTIVE)
8 MONTH FOLLOW UP
(8 MONTHS OFF)
5 MONTH SAFETY
FOLLOW UP
12 MONTH FOLLOW UP
(8 MONTHS ACTIVE)
12 MONTH FOLLOW UP
(12 MONTHS OFF)
8 + MONTHS
12 + MONTHS
SECONDARY ANALYSIS
STANDARD CLINICAL EVALUATION
SECONDARY ANALYSIS
STANDARD CLINICAL EVALUATION
Study Valve
Adjustment
Study Valve
Adjustment
Figure 1: Workﬂow
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that if initial baseline assessments for eligibility are completed by non-AHCRN trained
personnel, the gait velocity, MoCA, and SDMT, assessments should be repeated by an
AHCRN trained assessor on the day of or after the participant consents and within
6 weeks of the scheduled surgery. If initial baseline assessments are all completed
by an AHCRN trained assessor and the surgery is delayed, only the gait assessment
should be repeated by the same AHCRN assessor within 6 weeks of the scheduled
surgery. Follow-up items listed will have an acceptable window of -14 days to +30
days. Acceptable time between the standard clinical baseline evaluation and surgery
is up to six weeks.
Clinical investigators at each site will be neurosurgeons or neurologists. Site staﬀ
will screen each clinic patient for potential eligibility. A screening log will be completed
for all patients meeting study inclusion criteria, whether eligible or not eligible. After
a potential study candidate has been identiﬁed at the site, site staﬀwill ask the patient
if they would like to hear about the research study. Those who indicate that they
are not interested will receive standard treatment. Patients who express interest in
participating will be provided with a copy of the informed consent document to review.
The site staﬀwill answer any questions or concerns relating to the study. The patient
will be informed about the objectives of the study and the potential risks. Patients
who choose to participate must sign an informed consent document prior to shunt
insertion procedure. Patients who consent to the study will be scheduled for the shunt
procedure. Prior to the procedure, site staﬀwill review baseline assessments to make
sure they are all completed.
Randomization to open shunt or closed shunt settings will occur at the time
of the surgery. Neurosurgeon will perform randomization using an Internet-based
randomization system; a block randomization design will be used, with the treatment
assignment stratiﬁed by site so as to keep participants within a center approximately
balanced between groups as the study progresses.
3.1.1
Overview of Interventions
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
participants. Randomization will be to active or placebo (closed) shunt settings. At
the time of the standard four-month evaluation, all study participants will be similarly
non-invasively adjusted to bring all participants in both groups to the active setting
while maintaining blinding of the participants. All settings will be veriﬁed by the
adjusting neurosurgeon.
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Item
Screening/
Consenting/
Enrollment
Surgery
One-
Month
Safety
Follow-up
Two-
Month
Safety
Follow-up
Four-
Month
Follow-up
Five-
Month
Safety
Follow-up
Eight-
Month
Follow-up
Twelve-
Month
Follow-up
Screening
X
CSF Sample (optional)
X
Consenting
X
Randomization
X
Saliva Sample***
(optional)
X
Surgery
X
Shunt Programming
X
X
Pre-OP Imaging
X
Post-OP CT Scan
X
X
Gait Velocity Testing
X*/**
X
X
X
MoCA
X**
X
X
X
SDMT
X**
X
X
X
BDI-II
X
X
X
X
Lawton ADL/IADL
X
X
X
X
MRS
X
X
X
X
OAB-q Short Form Symp-
tom Severity Subscale
X
X
X
X
History
X
Physical Exam
X
Concomitant Medications
X
X
X
X
X
X
AEs****
X
X
SAEs*****/Neurological/
Urological AEs*
X
X
X
X
X
X
X
* If surgery is delayed, assessment should be repeated by same AHCRN trained assessor that performed initial assessment for eligibility. See section 3.2
** Assessment should be repeated by an AHCRN trained assessor if initial assessment was performed by non-AHCRN trained personnel (i.e. Physical
Therapy). See section 3.2
*** Saliva samples will not be collected for participants who have provided blood samples for other hydrocephalus research
**** Adverse events can be reported at the discretion of the clinician
***** Serious adverse events
Table 1: Schedule of Assessments
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3.1.2
Functional Measures
In-clinic standardized assessment of functional measures is strongly preferred in this
trial. However, if patients are unable to return for testing due to risks associated with
the COVID-19 pandemic, related hospital closures, or unexpected situations limiting
access to the clinic or inability to access the blinded assessor, functional measures may
be done remotely if it can be arranged with participant and possible family members,
suitable app, or video evaluation.
Gait Velocity:
Gait velocity will be assessed at baseline (prior to randomization)
by an AHCRN trained blinded assessor and post-operatively at four, eight and twelve
months by the same blinded assessor. While velocity measurement is a standard
clinical measurement, we request the following method for uniformity and quality.
Study participants will be assessed by an AHCRN trained assessor who is blinded to
randomization (for assessments that take place after surgery) under conditions that
are standardized and similar at each measurement, e.g., similar footwear to what is
usually worn.
Every eﬀort should be made to ensure that each participant is assessed by the same
blinded assessor at every follow up clinic visit. Study participants are encouraged
to walk in the same manner relative to their status at inclusion and relative to their
assistive device, i.e., if a walker or a cane was used in the baseline gait velocity assess-
ment, then the same assistive device (if needed) should be used in the post-operative
gait assessment. The test surface should be consistent, i.e., always a hard surface, or
always a carpeted surface. Hard surfaces are recommended. The 10-meter distance
should be measured and marked on the ﬂoor so that the examiner can time prop-
erly. The participant is instructed to start walking at the start line and continue to
walk as quickly as they feel comfortable, yet safely until they are beyond the ﬁnish line.
The examiner starts the clock when the participants leading foot takes its ﬁrst
step and stops the clock when the participants leading foot crosses over the ﬁnish
line. The time in minutes and seconds (to 1/10th second) are recorded. Three gait
velocity tests are performed and recorded. The best (fastest) of all three gait velocity
tests will be used to determine eligibility, including percentage of improvement if over
1m/sec, and used for the primary analysis, although the mean will also be evaluated
and auxiliary analyses will evaluate these endpoints. Training for uniform assessment
of this primary outcome measure will be performed at each center.
Montreal Cognitive Assessment (MoCA:)
MoCA will be administered at base-
line (prior to randomization) by an AHCRN trained blinded assessor and post-
operatively by the same blinded assessor at four, eight and twelve months. The
MoCA was designed as a rapid screening instrument for mild cognitive dysfunction. It
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assesses diﬀerent cognitive domains: attention and concentration, executive functions,
memory, language, visuo-constructional skills, conceptual thinking, calculations, and
orientation. Time to administer the MoCA is approximately 10 minutes. The total
possible score is 30 points; a score of 26 or above is considered normal. Only MoCA
version 1 should be used in this trial.
Symbol Digit Modalities Test (SDMT):
The SDMT provides a measure of
sustained attention and processing speed and requires approximately ﬁve minutes
to perform. SDMT will be administered in a standardized fashion at baseline (prior
to randomization) by an AHCRN trained blinded assessor and post-operatively by
the same blinded assessor at four, eight and twelve months. Only the standard form
should be used in this study.
Beck Depression Inventory- Second Edition (BDI-II):
The Beck Depression
Inventory is a 21-item self-report questionnaire that measures cognitive, aﬀective,
somatic, and performance-related symptoms of depression requiring ﬁve to ten minutes
to perform. Study participants will be asked to complete the inventory at baseline
(prior to randomization) and post-operatively at four, eight and twelve months. The
test is scored according to the scoring instructions.
Lawton ADL/IADL Scale:
The Lawton Scale is a 16-item questionnaire used
to assess independent living skills requiring ﬁve to ten minutes to complete. The
ADL/IADL Questionnaire11 was modiﬁed for the Older Americans Resources and Ser-
vices (OARS) Program developed at the Duke University Center for the Study of Aging
and Human Development (2010), and has been published by Psychological Assessment
Resources as part of the Calibrated Neuropsychological Normative System.12 Both
self- and informant- ratings are available. For each form, the respondent is asked to
rate the examinee’s level of everyday functional independence for six physical activities
of daily living (ADLs) and nine instrumental activities of daily living (IADLs). The
respondent also rates examinee for incontinence. The test is scored according to the
scoring instructions. Study participants will be asked to complete the assessment
at baseline (prior to randomization) and post-operatively at four, eight and twelve
months.
Modiﬁed Rankin Scale (MRS):
The MRS is a six point disability scale with
possible scores ranging from zero to ﬁve. The examiner completes the scale based on
the history and examination of the participant. The test is scored according to the
scoring instructions. The scale will be completed at baseline (prior to randomization)
by an AHCRN trained blinded assessor and post-operatively by the same blinded
assessor at four, eight and twelve months.
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Overactive Bladder-q Short Form (OAB-q) Symptom Severity Subscale:
The OAB-q SF is a brief, self-administered, participant-reported outcomes tool with
two scales assessing symptom bother and health-related quality of life (HR-QOL) in
participants with OAB.
This questionnaire asks how much the participant has been bothered by selected
bladder symptoms during the past four weeks. The participant is instructed to indicate
which answer best describes the extent to which the participant was bothered by each
symptom during the past four weeks. The test is scored according to the scoring
instructions. Study participants will be asked to complete the form at baseline (prior
to randomization) and post-operatively at four, eight and twelve months.
Cerebrospinal Fluid (CSF) Collection:
If CSF is available or becomes available
from clinical testing, the study participant will be asked to give a permission to use
the CSF for PENS trial.
Saliva Collection:
Saliva will be collected after obtaining participant’s consent to
the study. Results from genotyping will not be reported to the study participants as
the testing will not be carried out in a clinical laboratory improvement amendments
(CLIA) certiﬁed lab. Saliva samples will not be collected for participants who have
provided research blood samples for other Hydrocephalus research in the AHCRN
network.
3.2
Study Data Collection
Clinical data will be collected at the time of enrollment and throughout the intervention
period. Follow-up information will be collected at four, eight and twelve months for
both groups. This section provides a summary of the data that will be collected.
Screening, Enrollment and Randomization Period:
Participants will be screened
and evaluated for inclusion and exclusion criteria by the clinical investigator with
assistance from research coordinator or co-investigator. The clinical investigator must
sign oﬀon participant eligibility before participant is randomized. Participants will be
asked for permission to enter the trial, and a participant will be enrolled if he or she
meets all eligibility criteria and consent is obtained. Demographic information will
only be collected from consented participants. Demographic information will include:
date of birth, gender, race, and ethnicity. Enrolled participants will then be scheduled
for their surgery date where they will be randomized, and receive either an open or
closed shunt as previously deﬁned.
Baseline Period:
Baseline data elements will be collected on all participants who
have been enrolled into the study. Information to be collected during this period
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include medical and surgical history, physical examination, MRI or CT scan (within
six months), gait testing, MoCA, SDMT, BDI-II, ADL/IADL, MRS, and OAB-q sf.
Note: If initial screening gait velocity, MoCA, and SDMT assessments are per-
formed by non-AHCRN trained personnel (e.g. Physical Therapy), these assessments
should be repeated by an AHCRN trained assessor within the 6 week window of
surgery date. The BDI, ADL/IADL, MRS and OAB-q will not need to be repeated
as long as they are completed within the 6 week window of surgery date.
If surgery is delayed and all initial screening assessments were performed by an
AHCRN trained assessor, then only the gait velocity test needs to be repeated by the
same AHCRN trained assessor that did the initial screening assessments within the
six weeks period of the new surgery date.
Primary Endpoint (Four Months After Shunt Surgery):
Data elements will
be collected on all participants who have been enrolled and randomized into the study
and return for evaluation. The primary endpoint of gait velocity will be collected at
baseline and at four months post surgery to derive velocity change for the primary
objective. Velocity will be measured at subsequent follow-up visits for analysis of
secondary objectives.
Secondary Endpoints (Four, Eight and Twelve Months After Shunt Surgery):
Data elements will be collected on all participants who have been enrolled and ran-
domized into the study and return for evaluation. Information to be collected include
adverse events, concomitant medications, falls, gait testing, MoCA, SDMT, BDI-II,
ADL/IADL, MRS, and OAB-q sf.
Secondary Safety Endpoints (One, Two, Four, Five, Eight and Twelve
Months After Shunt Surgery):
1. Delayed treatment: increased frequency of falls. Since imbalance is an important
clinical risk in INPH, the occurrence of falls will be noted at each follow up visit
along with any associated injury or required medical treatment.
2. Programming errors:
• Lower than intended- risk of overdrainage: headache or subdural hematoma.
• Higher than intended- risk of decreased shunt eﬀectiveness and delayed
improvement.
3. Expected surgical complications: these are the expected adverse events listed in
section 10.2.1.
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Participant Withdrawal:
All participants withdrawn early from the study must
have a reason for withdrawal recorded on the appropriate data collection form, and
the circumstances leading to withdrawal must be described.
• If the study intervention is discontinued by the clinical care team because of
adverse events, this does not constitute participant withdrawal from the study.
All participants randomized in this study will be analyzed as per the intention-
to-treat principle.
• If the participant is determined ineligible after consent but before randomization,
the participant will be withdrawn from the study and their medical record will
no longer be reviewed for neurological, urological or serious adverse events.
A participant may choose to withdraw from the study at any time and the clinician
will determine the most appropriate treatment for the participant. Since participants
in the closed group undergo treatment delay, this delay may be terminated by shunt
programming to an open state as long as this change is considered medically necessary.
The medical course of the participant will continue to be reviewed for neurological,
urological or serious adverse events until 12-month post-surgery clinic visit. If the
participant experienced such adverse event from the time of surgery to twelve months
post operatively, the adverse event will be followed until resolution or 12-month study
visit, whichever is earlier.
4
Detailed Study Interventions
4.1
Shunt Implantation
Surgical shunt implantation is the major procedure taking place in the study. However,
since participant selection for surgery and the method of surgery are all part of
the surgeon’s standard care, it is not considered an intervention of the study. The
implanted shunt will be an FDA-approved programmable CSF shunt (Certas Plus
with SiphonguardTM, Codman, Johnson and Johnson, Raynham, MA USA). The
implantation will follow the standard practice and preference of the neurosurgeon.
4.2
Blinding
The neurosurgeon performing the implantation surgery will be aware of the assigned
setting. A blinded AHCRN trained assessor will perform the gait and cognitive
tests during the follow-up visits and will remain blinded to the treatment assignment
throughout the course of the study. Other support staﬀwill enter data for the trial.
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The neurosurgeon performing the surgery will pre-set the adjustable valves to one
of the two designated settings, while the shunt is in the sterile packaging, outside of the
operating room, just before the operative case. The setting 4 or 8 will be determined
by the randomization that the neurosurgeon will access directly. The setting will be
performed and veriﬁed by the neurosurgeon alone, without assistance.
The setting will be recorded as “PENS study assigned setting” in the medical
record. This variation from standard practice is necessary to preserve blinding of
participants and other investigators. If it is necessary for clinical reasons outside the
research protocol (and at any institution) to determine the shunt setting, the standard
shunt indicator tool can be used to assess the valve setting at any time. Follow up per
protocol schedule will continue for those participants whose shunt setting is modiﬁed.
4.3
Unblinding
As noted in Section 4, the neurosurgeon performing the surgery will be unblinded to
the study participant treatment group and will not play a role in administering the
study outcome assessments. The neurosurgeon or other medical personnel will assess
the assigned/current valve setting using an indicator tool if this is deemed medically
necessary to allow potential valve adjustment. Medical necessity is deﬁned as clinician
concern for participant risk for injury due to over- (subdural hematoma development)
or under- (acute progressive hydrocephalus) drainage. The study participant will
continue to receive standard appropriate medical treatment and remain in the study
for data collection.
4.4
One-Month Post-Surgery Remote Visit
At one month post-surgery (−14/+30 days), participants will be contacted by phone
or seen in the clinic and asked about any adverse events that participants have
experienced since surgery and their current list of concomitant medications.
4.5
Two-Month Post-Surgery Remote Visit
At two months post-surgery (−14/+30 days), participants will be contacted by phone
or seen in the clinic and asked about any neurological, urological or serious adverse
events that participants have experienced since their one-month follow up phone call
and their current list of concomitant medications.
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4.6
Four-Month Post-Surgery Visit: Primary Objective Mea-
surements and Shunt Setting Change
At the four-month time point (−14/+30 days), the following will be performed: gait
velocity, MoCA, SDMT, BDI-II, Lawton ADL/IADL Scale, MRS, OAB-q, assessment
of adverse events, veriﬁcation of concomitant medications and shunt programming
using the Certas Plus Indicator Tool in both groups.
For study participants assigned to the closed shunt group (setting 8), the shunt
will be set to setting 4 and left at that setting for four months. For participants
assigned to the open shunt group (setting 4), the shunt will be set at the discretion of
the treating physician according to each center’s standards. In this way both groups
will receive four months of drainage at the same setting (setting 4) and thereafter be
allowed to have adjustments for further optimization.
4.7
Post-Surgery Imaging
As part of the standard of care, a CT scan will be done at approximately one month
after shunt implantation. A second CT scan will be done at approximately one month
after shunt programming (ﬁve months post-surgery).
4.8
Five-Month Post-Surgery Remote Visit
At ﬁve months post-surgery (−14/+30 days), participants will be contacted by phone
or seen in the clinic and asked about any neurological, urological or serious adverse
events that participants have experienced since their four-month follow up phone call
and their current list of concomitant medications.
4.9
Eight-Month Post-Surgery Visit
At the eight-month time point (−14/+30 days), the open group will have experienced
eight months of active shunting with the ﬁrst four months restricted to setting 4 and
the subsequent four months allowing for the possibility of adjustment as clinically
indicated by the neurosurgeon. The closed group will have experienced only four
months of active shunting at setting 4. After this time the closed group will be followed
for an additional four months of active shunting allowing for discretionary changes by
the neurosurgeon before ﬁnal assessment. The setting of all shunts will be reconﬁrmed
at the eight month post-op visit.
4.10
Twelve-Month Post-Surgery Visit
Following completion of all study evaluations for the secondary endpoint analysis
at eight months of active shunting for the closed shunt group, the unblinded neuro-
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surgeon will conﬁrm the shunt setting with the Certas Indicator Tool. Participant’s
participation in the study will be complete at this time. The cohort assignment will
be revealed to the participant at this 12-month visit (−14/+30 days).
4.11
Other Therapy Guidelines
Standard therapies and medications should be administered according to standard
post-operative care at the local site. This includes use of psychoactive medications,
occupational and physical therapy, etc. If a study participant must be treated with oral
or intravenous anti-coagulation medications, the clinician will use clinical judgement
about shunt adjustment following local SOC.
5
Data Analysis
5.1
General Analytic Issues
All analyses will be undertaken by the intention-to-treat (ITT) principle, wherein all
participants randomly assigned to a treatment arm will be counted in that arm regard-
less of adherence to protocol or possible crossover to the other treatment arm except
for adverse events, which will use the as-treated principle (compare the participants
based on the treatment regimen that they received).
Therefore, this clinical trial will assess whether open (early treatment) group versus
closed (delayed treatment) group leads to an increase in gait velocity from baseline in
the open group, and a signiﬁcantly higher increase in gait velocity than the closed
group at four months after shunt surgery. The alpha level for the trial is 0.05. All
tests of signiﬁcance comparing treatment arms will be two-sided.
Secondary analyses of eﬃcacy (which will be clearly noted as non-primary in all
publications), as well as safety analyses presented to the Data Safety Monitoring
Board (DSMB), will compare study participants according to the treatment actually
received. Adherence to the assigned treatment is expected to be high, in the range of
85-90%, based on experience in previous interventional studies.
Participants who drop out or inadvertently crossover will be followed and included
in the ITT analysis. Baseline characteristics will be analyzed to determine if there is
a need to adjust for diﬀerences between groups in exploratory analyses. Sensitivity
analyses will be performed to assess the possibility and consequences of non-random
loss to follow-up. The proportions of participants experiencing an unscheduled health
care visit or any potential adverse eﬀect, as reported by the caregivers, will be compared
between groups using the Mantel-Haenszel test, stratiﬁed by site.
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5.2
Primary Analysis: Is Shunting Eﬀective?
Group comparison of closed shunt versus open shunt groups at four months. The
primary analysis will compare change in gait velocity from baseline to four months after
surgery between the closed and opened groups. An analysis of covariance approach will
be used to maximize statistical power. Speciﬁcally, a linear regression model will be ﬁt
with four-month gait velocity as the outcome, and assigned treatment arm as a binary
predictor along with continuous baseline gait velocity. Signiﬁcance and magnitude
of treatment eﬀect will be assessed via the estimated coeﬃcient of treatment in the
model and its standard error. For purposes of assessing a signiﬁcant treatment eﬀect,
the primary outcome of gait velocity will be compared between the assigned treatment
arm using a two-sided test with a Type I error of 0.05.
5.3
Secondary Analyses of Gait Velocity Change
1. Delay eﬀect: group comparison of change after four and eight months of active
shunting. A secondary analysis will compare the change in gait velocity after
four and eight months of active shunting in the open group versus active shunting
in the closed group, to assess whether the delay in opening the shunt may have
an eﬀect on improvement in gait velocity.
2. Overall shunting eﬀect: combined-group active shunting eﬀect: gait velocity
change will also be assessed in all participants after four and eight months of
active shunting; treatment arms may be combined in this latter analysis if there
is no evidence of a diﬀerence in eﬀects (see above).
These secondary gait velocity analyses, which will be performed using intention-
to-treat as well as treatment received, will implement a linear mixed model using all
available data from participants in the trial, and a time-varying indicator of treatment
(open or closed) as a predictor along with study time point. Appropriate coeﬃcient
estimates and standard errors from this model will be used to quantify and compare
treatment eﬀects of interest.
5.4
Secondary Analysis and Secondary Endpoint Analysis
The secondary eﬃcacy outcomes of the trial will parallel the three analyses described
for the primary endpoint of gait velocity change but will involve the secondary end-
points.
These will include the cognitive endpoint of change in MoCA from baseline to
four months, and the neuropsychological endpoints of SDMT, BDI-II and ADL/IADL
from baseline to four months in a group comparison. Each of these three endpoints
will be analyzed using a Type I error of 0.05/3 to determine formal signiﬁcance, using
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analysis of covariance as for the primary outcome analysis. In addition to the formal
primary and secondary outcomes analyses, other instruments collected in this trial
(MRS, and OAB-q sf) will be analyzed as exploratory outcomes, and all non-primary
outcomes will be examined for evidence of eﬀects at four months and eight months
after shunting, using approaches analogous to those described above. While formal
correction for multiple comparisons will not be performed, publications will clearly
identify these analyses as exploratory.
5.5
Secondary Analysis: Safety
Safety outcomes of this study will include rates of speciﬁc adverse events listed in Safety
endpoints. Safety data will be reported to the DSMB by treatment each participant re-
ceived, with chi-squared tests (exact with mid-p-value, due to small sample sizes) used
to compare rates of outcomes between independent study groups. In any safety report-
ing settings where the same study participant is in both the open and closed groups,
this will be noted in the reports and appropriate statistical approaches such as strat-
iﬁcation or conditioning will be used to adjust comparisons as appropriate and feasible.
Overall rates of AEs and SAEs will also be reported by treatment received. In addi-
tion to the customary presentation of AEs as serious/not serious and related/unrelated,
AEs will also be reported according to surgical/nonsurgical.
5.6
Power Analysis for Primary Outcome
Pilot data on change in gait velocity, from 96 participants in a multisite NPH database
(NPH centers at Cleveland Clinic, Sinai Hospital and Umea University) with baseline
gait velocities of 1.0 m/s or less, had a standard deviation of 0.31 m/s for the post-
treatment gait velocity, with a Pearson correlation of 0.44 between baseline and
follow-up gait velocity. Using these estimates in appropriate, conservative sample size
calculations,13 the proposed analysis of covariance approach for the primary analysis
requires the following number of participants completing the study for adequate power,
using a two-sided testing approach with 0.05 Type I error:
Therefore, a target sample size of 34 participants, 17 per study arm, will yield
80% power to detect a signiﬁcant treatment eﬀect if the true beneﬁt of early start
versus delayed start on gait velocity at four months is at least 0.275 m/s, and over
85% power if the true beneﬁt is at least 0.3 m/s. The study will plan on enrolling 40
participants to account for possible attrition to no less than 34.
Interim Analyses and Stopping Rules
This small clinical trial will have limited
power to detect a treatment eﬀect if its true magnitude is less than the assumptions
of the above Section; in the absence of statistical signiﬁcance, estimates of eﬀect for
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Assumed
Four-
Month
Mean
Velocity
Change:
Closed
Arm
Assumed
Four-
Month
Mean
Velocity
Change:
Open
Arm
Total
Number
Required
for
80%
Power
Total
Number
Required
for 85%
Total
Number
Required
for
90%
Power
0.05
0.3
40
46
54
0.05
0.325
34
38
46
0.05
0.35
30
32
38
0.05
0.375
26
28
32
Table 2: Power Analysis for Primary Outcome
primary as well as secondary outcomes will be used to design subsequent trials. As
the largest possible sample size is optimal for this setting, the DSMB will be asked to
evaluate interim safety outcomes only for the determination of whether the study is
to continue. Interim review of eﬃcacy data will not be performed.
6
Study Organization
6.1
Participating Institutions
This study will be conducted at approximately six sites in the United States, Canada
and Europe. Several sites are participating in the Adult Hydrocephalus Research
Network (AHCRN) and have already contributed data to the AHCRN Registry. Other
institutions may be added as needed to achieve target enrollment, in the case of
center attrition or low accrual rate. The University of Utah will serve as the Data
Coordinating Center (DCC) which will provide support for protocol adherence, EDC
data management, and for-cause monitoring. The Johns Hopkins University Brain
Injury Outcomes Coordinating Center will be acting as the Clinical Coordinating
Center (CCC) which will provide support for study start-up, contracts, training, and
regulatory documentation, and eBinder management. The total duration of the study
is three years and nine months: three months for start-up, two years for participant
recruitment, one year for follow up completion, and six months for data analysis and
submission of manuscript for publication. Target recruitment is 40 participants to
allow for attrition to 34 completed participants in one year, or approximately six to
nine participants per participating site. It is anticipated that participating sites will
each recruit between ﬁve and nine participants over one year. Each Center evaluates
between 50 and 100 participants annually for INPH and performs shunt surgery in
approximately 50% of participants evaluated. Thus, with ﬁve centers in the study,
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approximately 250 participants per year receive shunt surgery and will be potentially
eligible for the study. Accrual of the target sample size of 40 participants would
require just over 15% of all eligible participants to agree to study participation and
an attrition rate of 15%.
The proposed study is a multi-center blinded, randomized, placebo-controlled
investigation of CSF shunt surgery for participants who are considered candidates for
CSF shunting for INPH based on the 2005 NPH guidelines.3
7
Data Management
7.1
Clinical Site Data Management
Study data may be recorded on paper forms, or directly entered into the electronic
data capture (EDC) system. Paper forms will be retained at the clinical center and
data will be entered by clinical site staﬀinto the EDC system provided by the DCC at
the University of Utah School of Medicine. The investigator at each participating site
is responsible for all aspects of study implementation, including participants follow-up,
collection of accurate study data, and correct entry of the data into the data collection
system. These tasks may be speciﬁcally delegated to other individuals at the site,
but the site investigator is responsible to supervise all aspects of the study, and is
responsible to assure that all staﬀinvolved in this study are adequately trained to
perform the delegated tasks.
7.2
Electronic Data Capture System: OpenClinica
The DCC uses an open source clinical trial data management system called OpenClinica.
OpenClinica is an open source electronic data capture (EDC) system developed by
OpenClinica, LLC. OpenClinica is backed by an open source community comprising
over 18,000 registered individuals from hundreds of leading industry, academic, and
government research institutions in over 100 countries around the world. The DCC at
the University of Utah is using this application to support clinical research studies that
are conducted within the Adult Hydrocephalus Clinical Research Network (AHCRN).
7.3
Study Monitoring
The investigators recognize the importance of ensuring data of excellent quality. Site
monitoring is critical to this process. Site monitoring has been a very eﬀective tool
for maintaining data quality in previous studies, and we will utilize this process to
ensure excellent quality data in the proposed study. Our site monitoring plan is
designed to identify problems with sites and methods for handling problems that arise.
Site monitors must be provided with full access to study materials and the medical
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records for study participants. If the medical records are in electronic form, the clinical
investigator or an authorized individual must provide any assistance necessary to
facilitate the site monitor’s review of data in the electronic medical record.
7.3.1
Site Monitoring Plan
A supplemental study-speciﬁc monitoring plan, separate from the protocol will be
completed which outlines speciﬁc criteria for monitoring. This plan will include the
number of planned site visits, criteria for focused visits, or additional visits, a plan
for chart review and a follow up plan for non-compliant sites. The monitoring plan
also describes the type of monitoring that will take place (e.g. sample of all study
participants within a site; key data or all data), the schedule of visits, how they
are reported and a time frame to resolve any issues found. Remote site monitoring
schedules will be determined by the CCC or DCC in coordination with the study
principal investigator.
7.3.2
Clinical Site Monitoring
Site monitoring visits, when necessary, will be performed by a trained site monitor
during the study period to ensure regulatory compliance, participant safety, and to
monitor the quality of data collected. Source documents, regulatory documents and
data collection forms may be reviewed. Interim visits will take place depending on
grant budget, site enrollment, and compliance issues identiﬁed. The site monitor will
provide each site with a written report, and sites will be required to follow up on any
deﬁciencies. The site initiation may take place in person or remotely as group training
made up of site investigators and research coordinators.
7.3.3
Remote Monitoring
Remote monitoring is essential for this study. Remote monitoring involves detailed
review of the data entered by the site and consultations with the site investigator
and/or research coordinator to review safety and data quality. This may require
uploading de-identiﬁed copies of speciﬁc parts of the medical record, regulatory
documentation, or other source documents. Those materials will be compared against
the data recorded in the electronic data capture system. This helps assure protocol
compliance and accurate data collection. More remote monitoring activities may be
conducted early in the trial to assure protocol compliance and identify any training
issues that may exist. Documentation will be retained in accordance with Federal
requirements. Safety of participants will be monitored and ensured in accordance with
the DSMB plan.
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7.4
Data Coordinating Center (DCC)
The DCC is located in Salt Lake City, Utah, and is based at the University of
Utah School of Medicine. The DCC personnel include data analysts, programmers,
biostatisticians, project managers and other staﬀthat assist in the overall planning,
design, and implementation of the study projects. Services provided include data
management, data storage, quality assurance, and monitoring.
7.4.1
Data Center Description
The Data Coordinating Center (DCC) in the Department of Pediatrics at the Univer-
sity of Utah School of Medicine provides data coordination and management services
for a variety of national research networks. Anchoring these services is a new state-
of-the-art, energy eﬃcient data center completed in 2013. The data center facility
supports more than 1200 users around the world and provides a secure, reliable,
enterprise-wide infrastructure for delivering critical DCC systems and services. The
new data center was built using high industry standards and energy eﬃcient cooling
solutions. The data center is cooled by Rittal’s LCP inline cooling technology, pro-
viding eﬃciency, redundancy and modularity. Cooling is based upon a hot/cold aisle
design that allows for even air distribution with minimal hot spots. The data center
electrical power system contains a redundant Mitsubishi uninterruptible power system
(UPS) with a diesel backup generator. The data center is protected with a FM200
ﬁre suppression system, early warning smoke detectors and a heat detection warning
system to act as a secondary system to the smoke detectors. Security guards are
on-site conducting access control and rounds 24/7/365. Entry into the data center is
restricted by card access and layered security measures and controls. The data center
and external building access points are monitored with video surveillance.
In 2011 the data center began a large scale VMware server virtualization deploy-
ment. Currently, the data center has virtualized about 95% of its environment. The
virtual environment consists of more than 160 virtual servers and nearly 20 physical
servers. The data center’s virtualization solution provides key advantages:
• high availability – in the event of hardware failure, virtual servers automatically
go back online in a seamless process.
• ﬂexible infrastructure – disk storage, memory and processor capacity can be
increased or reallocated at any time.
• rapid deployment – servers can be provisioned on-demand with minimal waiting
on hardware of software.
The data center also enhanced its storage resources by implementing a networked
storage system to support its virtualized environment. The data center currently
manages over 50 terabytes of data. The storage solution consists of Dell’s EqualLogic
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PS Series Storage system for providing a virtualized storage area network (SAN).
Some of the beneﬁts that are realized through this technology are:
• storage architecture is no longer a bottleneck for IT services;
• performance is better than with the previous architecture;
• tiered storage is now possible;
• provisioning and reclamation of SAN disk will be much easier; and most impor-
tant,
• the new architecture includes a redesign of the SAN fabric to include complete
redundancy.
Production servers running critical applications are clustered and conﬁgured for
failover events. Servers are backed up with encryption through a dedicated backup
server that connects across an internal 10 gigabit network to a tape drive. DCC
storage area networking (SAN) applications, clusters, and switch-to-switch links are
also on a 10 gigabit network. Incremental backups occur hourly Monday through
Friday from 6 am to 6 pm. Incremental backups also are performed each night with
full system backups occurring every Friday. Tapes are stored in a ﬁreproof safe inside
the data center facility, and full backups are taken oﬀsite on a weekly basis to an
oﬀ-site commercial storage facility.
In the event of catastrophic failure, such as a ﬁre in the server facility, daily
backups would probably survive because of the ﬁre suppression system and ﬁreproof
safe, but there would be obvious delay in re-establishing data center function because
the servers will not survive such a disaster. Total destruction of the data center facility
could cause the loss of up to one week’s data. In future investments, the data center
is making co-location, disaster recovery and business continuity solutions a top priority.
DCC information systems are available 24 hours a day, 7 days a week to all users
unless a scheduled maintenance interruption is required. If this occurs, we notify all
users of the relevant systems, and data entry can be deferred until after the interruption
is over. Critical systems availability has exceeded 99.9% for the past two years, and
there has been no unscheduled downtime in over ﬁve years.
7.4.2
Security and Conﬁdentiality
The data center coordinates the network infrastructure and security with the Health
Sciences Campus (HSC) information systems at the University of Utah. This provides
us with eﬀective ﬁrewall hardware, automatic network intrusion detection, and the
expertise of dedicated security experts working at the University. Network equipment
includes four high-speed switches. User authentication is centralized with two Windows
2008 domain servers. Communication over public networks is encrypted with virtual
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point-to-point sessions using transport security layer (TLS) or virtual private network
(VPN) technologies, both of which provide at least 128 bit encryption. All of our
Web-based systems use the TLS protocol to transmit data securely over the Internet.
Direct access to data center machines is only available while physically located inside
our oﬃces, or via a VPN client.
All network traﬃc is monitored for intrusion attempts, security scans are regularly
run against our servers, and our IT staﬀis notiﬁed of intrusion alerts. Security is
maintained with Windows 2008 user/group domain-level security. Users are required
to change their passwords every 90 days, and workstations time out after 5 minutes
of inactivity. All ﬁles are protected at group and user levels; database security is
handled in a similar manner with group-level access to databases, tables, and views
in Microsoft SQL Server. Finally, all laptop computers in use in the DCC or in the
Department of Pediatrics are whole-disk encrypted.
The data center uses control center tools to continuously monitor systems and
failure alerts. Environmental and network systems are also monitored to ensure up
time. Highly trained system administrators on staﬀare available to respond in high
risk emergency events.
All personnel involved with the DCC have signed conﬁdentiality agreements
concerning data encountered in the course of their daily work. All personnel (including
administrative staﬀ) have received Human Subjects Protection and Health Information
Portability and Accountability Act (HIPAA) education. We require all users to sign
speciﬁc agreements concerning security, conﬁdentiality, and use of our information
systems, before access is provided.
7.5
Record Access
The medical record and study ﬁles (including informed consent) must be made available
to authorized representatives of the CCC and DCC, upon request, for source veriﬁcation
of study documentation. In addition, medical information and data generated by
this study must be available for inspection upon request by representatives (when
applicable) of the Food and Drug Administration (FDA), National Institute of Health
(NIH), other Federal funders, and the IRB for each study site.
8
Devices
There are 5 major manufacturers of shunts. Until now the valves were either diﬀerential
pressure valves or ﬂow-regulated valves and none of them had the ability to be turned
oﬀeven if clinically indicated. Thus doing a placebo study of shunts often involved
tying a ligature in the shunt catheter with variable results and adding complexity and
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additional intervention to untie the ligature. With the release of the new Codman
Certas Plus 2.0, a “virtual oﬀ” setting is now available to stop ﬂow of CSF through
the shunt system unless intracranial pressures exceed 400 mm which has not been
documented in participants with INPH. This shunt would also rapidly enable lowering
settings if indicated in the judgement of the treating physician in the placebo arm
without necessitating invasive intervention. No other commercially available shunt
appropriate for treating NPH oﬀers these features.
9
Protection of Human Subjects
9.1
Central Institutional Review Board (CIRB)/ Research
Ethics Board (REB) Approval
For this trial, A central IRB model will be adopted. Johns Hopkins IRB will serve as
the central IRB for the national participating sites. In addition to the CIRB approval,
each clinical center must inform their local IRB to fulﬁll any additional local regulatory
requirements. International sites, however, must obtain approval from their respective
IRB/REB prior to participating in the study. The designated regulatory staﬀat
Johns Hopkins will track IRB/REB approval status at the international participating
centers and will not permit participant enrollment without documentation of initial
IRB/REB approval and maintenance of that approval throughout subsequent years of
the project.
9.2
Informed Consent
This protocol requires that participants sign a consent form. The participant will be
informed about the objectives of the study and the potential risks. Participants with
INPH will be approached to provide permission to participation in the study. Informed
consent will be obtained prior to initiation of study activities. Documentation of
informed consent will be maintained at the study site.
9.3
Risks
Medical risks:
Participants are selected for shunt surgery because the clinical as-
sessment of risks and beneﬁts has been found to be favorable. Therefore, participation
in the trial is expected to carry the same risk/beneﬁt proﬁle as shunt surgery.
Complications of shunting in this study are expected to be similar to shunt surgery in
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standard surgical practice. Based on the European Multicenter Study,6 the expected
complications and rates are:
1. Cerebral hemorrhage at the time of surgery <1%.
2. Shunt or wound infection <2%.
3. Wound dehiscence <1%.
4. Subdural hygroma 10%.
5. Subdural hematoma 6%.
6. Hematoma or hygroma requiring evacuation 1%.
7. Distal catheter failure 4%.
8. Proximal catheter failure 4%.
9. Valve failure 4%.
Risk of Delayed Start:
A recent study of the natural history of INPH in which
shunt surgery was inadvertently delayed for at least six months for 33 participants
in Gothenberg, Sweden, found that without treatment, some participants improved
while others worsened before surgery.14 There is a potential risk of worsening gait
and a tendency of falling among participants over the course of the ﬁrst four months
in the placebo group. If a fall is clinically signiﬁcant, it may result in medical or
surgical complications. However, in a recently published open-label randomization
study that randomized 93 participants with idiopathic normal pressure hydrocephalus
to an immediate vs. postponed treatment group over a similar time period (one year),
the proportion of participants with serious adverse events did not diﬀer signiﬁcantly
between the groups.7
Additionally, no published experience and little anecdotal experience exist with
shunt function following four months in the virtual oﬀsetting of >400 mm H2O that
will be used in the closed shunt group. The potential for increased shunt occlusion
after four months of no ﬂow is possible, though less likely with CSF. The risk of
CSF leak due to shunt closure is minimal especially in these participants with normal
pressure. Other than identifying improvement in outcome measures at four months of
active shunting, or identifying signiﬁcant reduction in ventricular size or other imaging
markers consistent with a functioning shunt at four months of active shunting, the
only methods to conﬁrm shunt function are radionuclide shunt patency study or, in
Europe, CSF infusion testing. These will be performed only as clinically indicated
after participants have experienced four months of active shunting.
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Steps Taken to Minimize the Risks:
To minimize overall risks from delay, the
accepted time between initial observation and surgical treatment will be limited to six
weeks. In addition, this study will collect data on fall frequency, injury and treatment.
This data will be reviewed by the clinician and DSMB. Rigorous surgical technique
and antisepsis are standard clinical care in shunt implantation. Clinical monitoring
for expected complications such as infection are performed so that early intervention
may occur. Study participants will be contacted at one and two months post-surgery
to ensure their safety. Standard practice recommends the removal of a shunt when
determined to be infected.
Legal Risks:
Every eﬀort will be made to keep the information in the study
conﬁdential:
1. Study participants will be assigned a code number and the code number only
will be used to identify the clinical/cognitive/biomarker/scanning data;
2. The computers on which the data will be stored are password protected;
3. Written documents concerning the study will be kept in locked areas at the sites.
9.4
Beneﬁts
Direct Beneﬁts:
By taking part of this trial, participants will receive a shunt
treatment that might improve their condition and help prevent further deterioration
of their health.
Indirect Beneﬁts:
By being part of the ﬁrst truly randomized study of shunt
surgery in INPH, the participants will help physicians understand the role of surgery
in treatment. The ﬁndings from this trial would also help in the design of future
studies that could determine the degree of improvement in various domains to help
prognosticate accurately and the subpopulation that would derive the maximum
beneﬁt from shunt surgery.
10
Data and Safety Monitoring Plan
10.1
Data Safety Monitoring Board (DSMB)
The study will have a DSMB. The DSMB will have a charter, may approve the
protocol prior to implementation, and will review interim analyses as applicable.
The purpose of the DSMB is to advise the Principal Investigator(s) regarding the
continuing safety of study participants and the continuing validity and scientiﬁc
merit of the study. The DSMB is responsible for monitoring accrual of study par-
ticipants, adherence to the study protocol, assessments of data quality, performance
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of individual clinical center and review of serious adverse events and other safety issues.
The DCC will send reports relating to these topics to DSMB members prior to
each DSMB meeting. Interim analyses are anticipated after 10 participants, and
then again after approximately two thirds of the target sample size of 40, have been
randomized, treated, and have 4-month evaluations available. The DCC will staﬀthe
DSMB meetings and produce minutes of open sessions. Minutes of closed or executive
sessions of the DSMB will be produced and retained by the DSMB Chairperson.
These closed minutes will not be available outside the DSMB prior to the end of the
study. The DSMB Chairperson will prepare a summary of each DSMB meeting that
conveys the public conclusions of the DSMB, with respect to protocol alterations and
recommendations concerning continuation of the study. When the summary is provided
to the DCC, the DCC will send the summary to all clinical center investigators for
submission to their respective Institutional Review Boards/Research Ethics Board(s).
10.2
Adverse Events Reporting
Assuring participant safety is an essential component of this protocol. Each partic-
ipating clinical center investigator has primary responsibility for the safety of the
individual participants under his or her care. Clinical visits will occur at months 4, 8
and 12 months. Site staﬀwill also call study participants or see them in the clinic
at one and two months. Clinical investigators may schedule additional clinic visits
according to their standard of care or as needed for clinical reasons. The clinical
sites will record all new or worsening symptoms or events as reported by the study
participant or documented in the medical records for 30 days after shunt insertion
and shunt adjustment. Participating sites will report all neurological, urological and
serious adverse events throughout the course of the trial. Other pertinent adverse
events can be reported at the discretion of the clinician. All adverse events meeting
these deﬁnitions occurring after study randomization through ﬁnal follow up visit will
be entered into the electronic data entry system provided by the DCC. In accordance
with designated IRB/REB requirements, investigators may be required to report such
events to the IRB/REB in addition to notifying the DCC.
10.2.1
Deﬁnitions, Relatedness, Seriousness and Expectedness
Deﬁnition:
An adverse event (AE) is any untoward medical occurrence experienced
by a subject. An event constitutes a disease, a set of related signs or symptoms,
or a single sign or symptom. For purposes of this trial, adverse events that occur
from the time of randomization until 12- month follow up visit will be recorded as
described above. The principal investigator (PI) at each clinical site will evaluate
all adverse events. Adverse events not previously documented in the study will be
recorded on the Adverse Event Record Log. The nature of each experience, date and
time (where appropriate) of onset, outcome, course, and relationship to treatment
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should be established.
Falls, however, will be recorded on separate case report forms for the duration of
the study and will not be collected on the AE record forms. On the other hand, serious
adverse events resulting from falls will be reported as described below in Section
10.2.5.
Relatedness:
The suspected relationship between study interventions and any
adverse event will be determined by the site investigator using the following criteria.
Relatedness may not be assessed by a research coordinator, and must be assessed by
an investigator.
Not Related: The event is clearly related to other factors, such as the subject’s
clinical state, therapeutic interventions, and concomitant drugs or procedures
administered to the subject.
Possibly Related: The event follows compatible temporal sequence from the time
of beginning the assigned study intervention, but could have been produced by
other factors such as the study subject’s clinical state, therapeutic interventions
or concomitant drugs administered to the subject.
Probably Related: The event follows a reasonable temporal sequence from the time of
beginning the assigned study intervention, and cannot reasonably be explained by
other factors such as the study subject’s clinical state, therapeutic interventions
or concomitant drugs administered to the subject.
Seriousness:
The seriousness of clinical adverse events will be recorded by the site
investigator and categorized. A serious adverse event (SAE) is an adverse event that:
• results in death; or
• is life-threatening (the participant was, in the view of the clinical site investigator,
in immediate danger of death from the event as it occurred); or
• requires inparticipant hospitalization or prolongs an existing hospitalization; or
• results in persistent or signiﬁcant disability or incapacity; or
• results in congenital anomaly/birth defect); or
• any other event that, based upon appropriate medical judgment, may jeopardize
the subjects health and may require medical or surgical intervention to prevent
one of the other outcomes listed in this deﬁnition.
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Expectedness of the Event:
All adverse events reportable per protocol, including
serious adverse events, will be evaluated as to whether their occurrence was expected
(as described in the protocol or consent forms) or unexpected.
Expected:
An event is considered expected if it is known to be associated with
the underlying condition (i.e. hydrocephalus) or is related to the study intervention
(i.e. shunt placement); and is mentioned in the protocol, informed consent or other
study documents. An event may be expected despite the study participant’s clinical
state immediately prior to the event. For this protocol, expected adverse events
include:6
1. Subdural hygroma.
2. Subdural hematoma.
3. Hematoma or hygroma requiring evacuation.
4. Epidural hemorrhage.
5. Subarachnoid hemorrhage.
6. Intraventricular hemorrhage.
7. Intraparenchymal hemorrhage.
8. Seizure, acute or chronic.
9. Vascular injury, pseudoaneurysm, dural sinus injury.
10. CSF leak.
11. Bacterial meningitis.
12. Shunt or wound infection.
13. Wound dehiscence.
14. New or increased neurologic deﬁcit.
15. Proximal or distal shunt mis- or displacement.
16. Distal or distal catheter failure.
17. Valve failure.
18. Iatrogenic injury due to shunt passer.
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Unexpected:
An event is considered unexpected if there are no prior data
linking this event with either the condition or intervention under study or an event
that occurred unexpectedly in the course of surgical treatment.
Treatment or Action Taken:
For each adverse event, the clinical site will record
whether an intervention was required:
• Intervention: Surgery or interventional procedure
• Other Treatment: e.g. medications, therapy, etc.
• Change in shunt setting
• None: No action taken
Outcome of Event:
Finally, the clinical site will record the clinical outcome of
each adverse event as follows:
• Death
• Recovered and the participant returned to baseline status
• Recovered with permanent sequelae
• Symptoms continue
10.2.2
Time Period for Adverse Events
For purposes of this trial, adverse events will be recorded for 30 days after shunt
insertion and shunt adjustment while serious, neurological and urological adverse
events will be collected throughout the trial from time of randomization to 12-months
follow-up. However, events that occur following participant consent to participate in
the trial, but prior to randomization, will not be reported as adverse events. These
should be recorded as baseline conditions.
If the event has not resolved by the
12-month study visit, the status of the event at this time point should be reported.
10.2.3
Data Collection Procedures for Adverse Events
After randomization, adverse events, whether expected or unexpected, will be recorded
according to the date of ﬁrst occurrence, severity, and their duration, as well as any
treatment prescribed. Any medical condition that presents prior to randomization will
be recorded in the participant’s baseline history at study entry but will not be recorded
as an adverse event at subsequent evaluations if it remains unchanged. However,
worsening of a medical condition that was present at the time prior to randomization
will be considered a new adverse event and will be recorded.
Falls will be recorded on a separate case report forms (CRFs). Therefore, they
will not be recorded as adverse events.
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Abnormal laboratory values that are clinically signiﬁcant will be recorded as ad-
verse events and the clinical site investigator will assess the severity and relationship
to the study. Laboratory values that are abnormal prior to randomization and that
do not worsen will not be recorded as adverse events.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) coding vocabulary. Coding will be done centrally at the DCC because this
requires speciﬁc training.
10.2.4
Unanticipated Problems (UP)
Unanticipated problems (UP) are deﬁned as incidents, experiences, or outcomes that
are unexpected, related to participation in the study, and suggest that the research
places subjects at a greater risk of harm than was previously known or recognized.
The site investigator will report unanticipated problems to the DCC within 24
hours. A detailed completed report will be required to be sent to the DCC within
3 working days of the event. After receipt of the complete report, the DCC will
report these unanticipated problems to the DSMB in an expedited manner (within 24
hours). In accordance with designated IRB/REB requirements, the site investigator
may be required to report such unanticipated problems to the IRB/REB in addition
to notifying the DCC. In the event that the medical monitor believes that such an
event warrants emergent suspension of enrollment in the trial, and the DSMB cannot
be reached expeditiously, the DCC will notify all site investigators to cease enrollment
in the trial. Resumption of enrollment will not occur without consent of the DSMB.
10.2.5
Monitoring Serious Adverse Events
A physician from the DCC will act as the medical monitor for this study. If the medical
monitor is unavailable, a qualiﬁed physician will be designated to fulﬁll this function.
Site investigators and/or research coordinators will report all serious adverse events to
the DCC within 24 hours of the event or from the time the investigator became aware
of the event. A detailed completed report will be required to be sent to the DCC
within 3 working days of the event. After receipt of the complete report, the DCC
will report any serious, unexpected, and study-related adverse events to the DSMB in
an expedited manner (within 24 hours). In accordance with designated IRB/REB
requirements, the clinical site investigator may be required to report such events to
the IRB/REB in addition to notifying the DCC. The medical monitor will assess these
serious adverse events reported from clinical sites in the trial. For each of these serious
adverse events, the site investigator will provide suﬃcient medical history and clinical
details for a safety assessment to be made. All SAE reports will be retained at the DCC.
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In the unlikely event that the medical monitor believes an unexpected and study-
related SAE warrants emergent cessation of enrollment in the trial, the DSMB will
be immediately consulted. If the DSMB concurs with the judgment of the medical
monitor, or if the DSMB cannot be reached expeditiously, the DCC will notify all site
investigators to cease enrollment in the trial and will instruct them to report this to
their designated IRB/REB. Resumption of enrollment will not occur without approval
of the DSMB. Sites are expected to report serious, unexpected, and study-related
SAEs per their designated IRB/REB’s expedited reporting requirements. The DSMB
will review all adverse events during scheduled DSMB meetings.
10.2.6
Follow-up of Serious, Unexpected and Related Adverse Events
All serious, unexpected and related adverse events, that are unresolved at the time of
the participant’s termination from the study or discharge from the hospital, will be
followed by the site investigators until the events are resolved, participant is lost to
follow-up, the adverse event is otherwise explained or has stabilized, or 12 months
have passed from the time of randomization. Adverse experiences that begin after
termination from the study will not be recorded as study adverse events.
11
Study Training
A formal training program for investigators and research staﬀwill be held prior to
the start of enrollment. The training program will cover regulatory topics and good
clinical practice. The training will also provide in depth explanations regarding study
procedures, clinical care, adverse event reporting, data entry procedures, quality
assurance, site monitoring, and the informed consent process. A manual of operations
will be provided to each clinical center investigator prior to the start of enrollment.
The manual will detail speciﬁc information about the study procedures, regulatory
information, safety reporting, and other necessary information. Updates and revisions
to the manual will be made available electronically.
12
Regulatory Issues
12.1
Health Insurance Portability and Accountability Act
(HIPAA)
Data elements collected include the date of birth and date of admission. Prior to
statistical analyses, dates will be used to calculate participant age at the time of the
study events. The ﬁnal data sets (used for study analyses and archived at the end of
the study) will be de–identiﬁed, and will exclude these speciﬁc dates.
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Data elements for race, ethnicity, and gender are also being collected. These
demographic data are required for Federal reporting purposes to delineate participant
accrual by race, ethnicity, and gender.
For purposes of the DCC handling potential protected health information (PHI)
and producing the de–identiﬁed research data sets that will be used for analyses, all
study sites have been oﬀered a Business Associate Agreement with the University of
Utah. Copies of executed Business Associate Agreements are maintained at the DCC.
12.2
Inclusion of Women and Minorities
There will be no exclusion of participants based on gender, race, or ethnicity.
12.3
ClinicalTrials.gov Requirements
This trial will be registered at ClinicalTrials.gov in accordance with Federal regulations.
12.4
Retention of Records
For federally funded studies subject to the Common Rule, records relating to the
research conducted shall be retained for at least three years after completion of the
research. These guidelines will be followed for this trial. Completion of the research
for this protocol should be anticipated to include planned primary and secondary
analyses, as well as subsequent derivative analyses. Completion of the research also
entails completion of all publications relating to the research. All records shall be
accessible for inspection and copying by authorized representatives of the regulatory
authorities at reasonable times and in a reasonable manner [45 CFR x46.115(b)].
12.5
Public Use Data Set
After subject enrollment and follow up have been completed, the DCC 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 recoded in a manner that will make it impossible to deduce or
impute the speciﬁc identity of any participant. 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.
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13
Monitoring and Quality Assurance
13.1
Tracking Participant Enrollment
Patients that meet all inclusion criteria will be entered into the OpenClinica database.
This data, together with the randomization log and the utilization of ICD10 and CPT
codes, will allow assessment of numbers of eligible patients, percentage of eligible
patients who are approached for consent, and the proportions of eligible/consented
participants who are successfully randomized. These results will be regularly reviewed
by the DCC or CCC and by the DSMB during scheduled meetings (as described
below).
13.2
Monitoring and Screening Compliance
As described above, a screening log will be completed for all participants who met the
study clinical criteria and were sent for further evaluation, showing ﬁnal eligibility and
ultimate disposition of eligible participants. In addition, it is expected that several
of the centers participating in PENS will also participate in the AHCRN Registry,
which has been established to track the evaluation of participants seen for adult
hydrocephalus. Its goal is to establish a general database of adult hydrocephalus
participants to facilitate research in INPH. This Registry has been approved under a
separate IRB and is separate from the PENS study.
Assessment of the screening and randomization logs will facilitate assessment of site
performance in approaching and assessing participants. At centers participating in the
AHCRN Registry, comparison of key characteristics between PENS trial participants
and INPH participants enrolled in the registry will further allow an informal assess-
ment of representativeness of PENS trial participants, with respect to key baseline
clinical characteristics. While imprecise, such a comparison could detect instances of
substantial bias in characteristics of INPH participants recruited into PENS versus
others not approached or enrolled.
Protocol compliance will be independently monitored to review the screening data
and participant characteristics as described above.
13.3
DSMB Evaluation of Screening and Registry Data
An independent DSMB for the PENS trial will evaluate components of the trial, in-
cluding the screening and participant characteristic data. Study data will be presented
to the DSMB on a regular basis, in groupings of certain number of randomizations
determined by the enrollment rate, throughout the trial.
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14
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