IIHS

Description of the Study

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A Multi-Center, Prospective, Randomized Study

Under the Aegis of:

The International Federation for Neuroendoscopy (IFNE)

The International Society for Pediatric Neurosurgery (ISPN)

 

Steering Committee

Shlomi Constantini (Tel Aviv, Israel, P.I.)

Spyros Sgouros (Athens, Greece)

Abhaya Kulkarni (Toronto, Canada)

 

Monitoring Committee

Maurice Choux (Marseille, France)

Flemming Gjerris (Copenhagen, Denmark)

John Kestle (Salt Lake City, USA)

 

International Advisory Board

Rick Abbot (New York, USA)

Bernhard Bauer (Hanover, Germany)

Giuseppe Cinalli (Naples, Italy)

Concezio DiRocco (Rome, Italy)

Andre Grotenhuis (Nijmegen, Netherlands)

Dieter Hellwig (Marburg, Germany)

Conor Mallucci (Liverpool, England)

Shizuo Oi (Tokyo, Japan)

Yael Leitner-pediatric neurologist (Tel Aviv, Israel)

Rina Eshel-pediatric neuropsychologist (Tel Aviv, Israel)

 

Trial Information

(You can obtain full information on the trial by contacting Dr S. Constantini)

Acronyms and Abbreviations

The following table lists the acronyms and abbreviations used in this document.
CSF:Cerebral Spinal Fluid
ETV:Endoscopic Third Ventriculostomy
HCP:Hydrocephalus
HOQ:Hydrocephalus Outcome Questionnaire
HUI:Health Utilities Index
IIHS:International Infant Hydrocephalus Study
INEBS:International NeuroEndoscopy Biopsy Study
ISGNE:International Study Group for NeuroEndoscopy
ISPN:International Society for Pediatric Neurosurgery
NPH:Normal Pressure Hydrocephalus
TVH:Triventricular Hydrocephalus
VSR:Ventricular Size Ratio

 

1. Specific Aims

To provide a structured, comprehensive, statistically meaningful comparison of the long term benefits and costs of endoscopic third ventriculostomy (ETV) versus CSF shunting as a treatment for infants under 24 months of age with triventricular hydrocephalus (TVH).

Long term outcome analysis will include not only the single facet of shunt dependence, but a more comprehensive analysis of treatment effect and patient outcome that includes various aspects of quality of life, such as hospitalization or other sickness time and neurodevelopmental evaluations over the course of 5-7 years.

 

2. Background and Rationale

Two treatment options

Intra-ventricular obstructive hydrocephalus (HCP) is currently treated through one of the following two approaches:

a. Extra-cranial CSF diversion through ventricular shunts. Extra-cranial shunting has been the standard approach over the past few decades, since functional shunts were first developed and inserted successfully.

b. Intra-cranial internal CSF diversion using endoscopic techniques.

The principles of internal diversion were clear from the time neurosurgeons first understood the nature of HCP. However, internal diversion was never really practical or successful on a large scale until the more recent development of neuroendoscopy. There is currently a revived interest in diversionary HCP treatment through neuroendoscopic surgical techniques, with the primary focus on endoscopic third ventriculostomy (ETV). During two recent meetings of the International Study Group for Neuroendoscopy (ISGNE), (Japan, 2002 and Naples, 2003), a consensus was reached on the need to promote research and prospective studies investigating the value of neuroendoscopy in the treatment of various forms of hydrocephalus.

 

ETV vs. CSF Shunting: an ongoing controversy

While the benefits of neuroendoscopy to resolve intra-ventricular obstruction in many HCP patients seem clear to some neurosurgeons, there is still a great deal of uncertainty among many others.

Many obstructive HCP patients worldwide are shunted due to an ongoing skeptical attitude towards endoscopic third ventriculostomy (ETV), its complications, and long-term efficacy.

There have been, to date, no definitive studies comparing the two approaches of ETV vs. CSF shunting in an attempt to clarify the situation and determine the optimal treatment for obstructive HCP in the general population.

Nevertheless, despite some skepticism and controversy over the benefits of ETV for obstructive HCP in general, most pediatric neurosurgeons believe that obstructive HCP patients, if more than 2 years old, should be offered an ETV, feeling that performing a shunt is almost unethical. At the very least, patients and families should be offered a choice of ETV or shunting, when applicable.

As controversial as the issue of ETV vs. shunting has been, the benefits of ETV are even less clearly defined for specific subsets of HCP patients, such as infants with obstructive HCP presenting in the first 2 years of life. This lack of clarity is not helped by the total lack of standardized studies analyzing the alternatives in infants.

 

Shunt freedom

The only criterion for success used in most studies has been some variation on the single point of freedom from shunt dependency.

However, this standard for success has not been consistently defined or applied. Some studies insist on total shunt freedom after a single ETV attempt, while other studies include as success shunt freedom after a repeat ETV as well.

Inconsistent short-term follow-up times often do not define or address the risks of delayed failure. Given the wide range of definitions for success and failure, it is not surprising that an incredibly wide range of success rates has been reported.

For example, while some groups have reported a success rate (shunt free, long-term, symptomatic relief) of up to 70-80% 10, others have achieved only a 30% shunt-free survival rate.

 

Neurodevelopment

Relying on a single criterion of shunt freedom completely ignores other related, and equally significant, aspects of patient success and failure, such as neurodevelopmental progress.

The long-term neurodevelopmental effects of shunting versus ETV are a major concern, especially for the group of infants under 2 years of age. Success for these children cannot be defined exclusively in terms of shunt-freedom. Some neurosurgeons argue that ETV may in some children lead to an arrested form of HCP that compromises the developing brain. Other neurosurgeons are more concerned with the long-term complications of shunting and claim that ETV is a more "physiological" solution and therefore better for the infant's brain. Careful evaluation of neurodevelopment must be an essential element of any study focusing on hydrocephalus treatment in infants.

 

Morbidity and mortality

Most published studies also ignore the issue of long-term morbidity and mortality. With regard to the risk of immediate peri-operative complications, shunt insertion appears to entail a smaller potential for life-threatening sequelae.

However, shunts do entail a significant risk of infection, which may have a detrimental effect on a child's development. Shunts also seem to suffer a significantly higher lifetime rate of revisions. These shunt revisions would also entail their own associated risks and complications.

Cost comparison, both human and financial, including hospitalization time, number of surgeries, need for repeated scans, and number of sick days, are also important issues that have not been explored.

 

Addressing the uncertainties

Due to the lack of clear superiority for either surgical technique, we feel that randomization in this clearly defined subgroup of infants under 2 years of age, with obstructive HCP, is not only ethical but also a duty for all of us as an international group.

We therefore propose a prospective, randomized study of CSF shunting vs. ETV for patients diagnosed in the first 2 years of life with tri-ventricular HCP. Families who are presented with both options in a non-biased way and elect to choose one may also be included in the study. The study incorporates standard surgical techniques that have been employed for years, and does not mandate any additional procedures for the children and their families.

The proposed International Infant Hydrocephalus Study (IIHS) is designed to provide a comprehensive assessment of the relative benefits and risks of shunting vs. ETV in infantile obstructive hydrocephalus. IIHS is the first international collaborative study on the long-term survival of patients with infantile hydrocephalus.

 

International collaboration

Our international group has already conducted a number of collaborative studies, through which a network of collaborating clinicians has been established.

The first study (20 patients / 4 centers) on the merits of repeat-ETV was published in Child's Nervous System in 2001. 49

The second study (101 patients / 7 centers) on the merits of ETV following infection and/or hemorrhage was published in the Journal of Neurosurgery in 2002. 48

A third international retrospective study on the safety and validity of endoscopic biopsies (INEBS) is currently under way. Data will be collected from more than 15 centers worldwide during 2004.

A fourth international study on the endoscopic treatment of pineal tumors will be distributed soon. (Professor Shizuo Oi)

The International Infant Hydrocephalus Study is a significantly more ambitious undertaking than any previous study in the field of infant hydrocephalus and endoscopy. IIHS is also important to all of us on more than one level: On a fundamental level, through this large-scale, randomized, prospective study, we hope to achieve statistically meaningful results for issues that to date have had no objective basis for resolution. The IIHS is the only study to date that focuses on long-term developmental outcomes for hydrocephalic infants. As such, the IIHS will serve as an essential tool, providing the means for better prenatal counseling when obstructive hydrocephalus is diagnosed in-utero. On a more important level, through this study we hope to strengthen international collaboration in this field and demonstrate that our group can assure cooperation and settle important debates in a scientific manner. The international framework that we construct with IIHS will serve as a foundation and platform for future international prospective studies.

As such, we deeply appreciate your willingness to consider joining us in this endeavor.

 

3. Participation

Medical Center Eligibility

Strong neuro-endoscopic orientation.

More than 10 neuroendoscopic procedures per year per surgeon.

At least 5 ETV operations in infants per surgeon in total.

Strong commitment to study design, informed consent, and smooth data supply.

Ability to follow at least 5 years.

Ethical Committee Approval secured as per local institutional rules.

Strong commitment to terms of randomization policy: Clear understanding that eligible patients will preferably go to a randomized arm, unless family specifies non-randomization. With non-randomized patients, parental preference may prevail as long as the surgeon presents the family with the current data and shows no personal bias! Eligible patients who were not randomized due to surgeon's decision should still be enrolled as per study protocol. Randomization status of each patient must be noted in patient data forms.

Patient recruitment will begin in 2004 and last for 2-4 years. Follow-up data must be collected for up to five years from end of recruitment. Participation in this study entails a long, ongoing commitment for all of us. Every single participant must be responsible for recruiting all appropriate patients at their centers, and maintaining an ongoing, accurate flow of data for every single patient included in the study.

 

Patient Eligibility-Inclusion & Exclusion Criteria

The subjects of this study are infants under 24 months of age at time of operation, presenting to neurosurgical institutions worldwide with symptomatic triventricular hydrocephalus (TVH).

 

Patient Inclusion

No previous treatment for HCP

Under 2 year of age at time of surgery

Full-term pregnancy (>36 weeks)

Mandatory pre-operative imaging

A pre-operative MRI that includes mid-sagittal T1 & T2 scans is mandatory. The following must be clearly visible on the scans: a. tri-ventricular HCP b. proof on mid-sagittal T2 MR or CINE of no flow through aqueduct

Presence of CSF collection over the convexity and/or inter-hemispheric fissure is acceptable

Configuration of third ventricle floor could vary

Deformed tectal plate is acceptable

Posterior fossa fluid collections may be included as long as:

-Aqueduct is closed

-Vermis preserved (complete Dandy Walker Syndrome excluded)

-Questionable flow in AQ acceptable as long as TVH exists

History or suggestion of intra-ventricular bleed (intra-uterine or post-natal) and infection qualifies. (excluding Neonatal IVH)

Ability to follow at least 5 years

 

Patient Exclusion

Open Spina Bifida

Complete Dandy Walker syndrome (Vermian agenesis / dysgenesis)

Prematurity

Neonatal IVH

Perinatal asphyxia

Severe dysmorphic anatomical features (e.g. Agenesis of Corpus Callosum, Heterotopias, large cysts)

CNS tumor

 

Eligible Non-enrolled Patients

It is expected that all eligible patients will be identified and considered for entry into the trial. To ensure this, all neurosurgeons and neuroradiologists at participating medical centers should be made aware of the study and encouraged to identify eligible patients.

Despite these attempts, it is anticipated that some eligible patients will not be enrolled, either due to physician preference, patient preference, logistic restraints, or initial oversight. These patients will be identified by regular review of the operative lists looking for infants under 24 months old who had either an ETV or CSF shunting performed. In these cases, baseline criteria will be recorded retrospectively, allowing us to assess for systematic differences between enrolled and non-enrolled patients.

 

4. Study Design-Treatment Allocation

The International Infant Hydrocephalus Study (IIHS) is an international multi-center, prospective, controlled, randomized study of the treatment of newly diagnosed obstructive hydrocephalus in infants below 2 years of age. Data will be centrally collected prospectively and contemporaneously over the course of at least 5 years of follow-up.

Because there might be some reluctance on the part of families to submit to randomization, the study design incorporates both a randomized and non-randomized arm. This design is termed a "comprehensive cohort design".

With this comprehensive cohort design, the following information is given to the families of all eligible patients. Families are offered:

A comprehensive, unbiased, balanced explanation of all treatment options available at the time of initial assessment.

A simple, clear description of the IIHS study, accompanied by printed documentation.

The opportunity to participate in the IIHS study, including randomization, treatment, and long-term follow-up.

If both surgeon and family agree, the patient is randomized to either the ETV or shunting arms. Each participating center is given a simple, but effective, randomization allocation scheme.

If the family expresses a strong preference for a given treatment option, then that treatment option will be selected. The basis for inclusion in a specific treatment arm (randomization or parental preference) must be specified in the patient data form.

Participating centers are strongly encouraged to provide data for all patients who fit the inclusion criteria, whether or not they were included in the study for any reason. The exact reasons for non-inclusion must be specified in the patient data form. Participating centers must do their best to minimize the incidence of "idiopathic" or "institutional" non-inclusion! Over an extended period of time, given a combination of unbiased parental preference, medical circumstances, and general randomization, the patient population of both treatment arms (ETV and shunt) is expected to be more or less equivalent. This equivalence between the two study arms is essential for the study to have maximum statistical significance. For the non-randomized subset, the importance of a complete absence of any bias introduced by the treating surgeon cannot be overstressed! Inadequately sorted patients due to any sort of "selection bias" can throw the validity of all study results into question. In either case, the child will be tracked over the next 5-7 years with the same IIHS follow-up protocol. Patients will always have the option to not join the study, or to drop out of the study at any stage. Participation or withdrawal from the study will not alter their post-operative treatment in any way.

 

5. Failure and Cross-Over Patients

Following the initial surgery (ETV or shunt), patients are treated as per departmental and surgeon's routine. Adverse events are specified in the appropriate study forms. Standards for declaring the original treatment a failure must be defined as homogenously as possible.

For failing patients, the treating surgeon decides whether to repeat the original treatment (i.e., a repeat ETV for a patient in the ETV group or a shunt revision for a patient in the shunt group), or whether to "cross over" (i.e., attempt an ETV for shunted patients or insert a shunt into an ETV patient). The treatment decision, together with a clear explanation of the treatment rationale, must be specified in the appropriate study form. If a "failure" has occurred and a second surgical treatment has taken place (either shunt or ETV), the patient data and treatment plan are analyzed and patient status within IIHS is updated appropriately.

 

6. Imaging Requirements

A pre-operative MR is a prerequisite for entering the patient into the study.

Once the patient has been enrolled, post-operative imaging (MR for post-ETV and CT for post shunting patients) is required within 12 months of the initial surgery. At 3 years, imaging is again required (MR for post-ETV and CT or MR for post shunting patients).

We plan to collect the original imaging data from all participating centers. Individual arrangements will be explored with each site.

 

7. Information Flow and Follow-Up

Email and website entries are the preferred mode of communication. The steering committee will employ coordinators to facilitate smooth data collection and coordination.

Patient information will be collected both on paper and online, through a password-protected link on this site, which will also be available via a link from the ISPN web site. Online technical support will be provided to ensure a smooth flow of information. Electronic data will be stored and backed up in Birmingham, UK. Paper backups will be stored at each center.

Once a neurosurgeon decides to join IIHS, the study coordinators will provide the participating neurosurgeon with a complete information package, including all necessary documentation for Ethical Committee Approval Application, Patient Information, and Trial Protocols. A preliminary list of IIHS forms is included at the end of this proposal document.

 

8. Evaluating Study Outcome

Outcome measurement

Success and failure for each IIHS participant are not defined by a single black&white data point. Rather, this study uses a more sophisticated standard, combining a primary factor with a weighted set of secondary factors to reach a more meaningful measure of patient status and condition.

Primary

The primary evaluation standard for each study participant is based on the neuro-behavioral outcome when the patient reaches 5 years of age.

Secondary

The secondary evaluation standard for each study participant is based on a combination of the following factors:

Number of operations

Surgical morbidity

Need for second surgery at follow-up

Hospitalization time overall during the first 5 years

Need for repeat radiological scans

Death rate

Complications

-CNS Infection

-Focal neurological deficit

-Significant bleeds

-Seizures requiring medications

Radiological evaluation at 3 years of age

-Ventricular size

-The existence of flow void (ETV group)

 

Neurodevelopmental Assessment

Critical Element of Study Outcome Analysis

The long-term neurodevelopmental effects of shunting versus ETV are a major concern for the group of infants under 2 years of age.

Careful, comprehensive, objective, standardized evaluation of the participants' development and abilities over the long term, over the course of the critical infant and preschool developmental period, is an essential element this study, since the primary criteria for success or failure for each study participant is based on the neuro-behavioral outcome when the patient reaches 5 to 7 years of age. For this reason, a schedule of careful assessments of each child's development is included in the IIHS design. We have chosen a set of comprehensive, objective evaluation tests that are standardized, with consistent, numeric scoring scales, to enable objective, statistically meaningful comparisons and analyses of the results, for a large patient body that is drawn from a broad range of place over an extended period of time.

Evaluation Test Schedule

A detailed list of scheduled tests and evaluations will be provided. This schedule includes detailed clinical questionnaires, a series of radiological scans, and a set of neurodevelopmental tests, completed at set points in time over the course of each patient's follow-up. The neurodevelopmental test series includes the following benchmark tests:

Pre-operative Neurodevelopmental Assessment, based on the Denver Developmental Screening Test
Pre-operative, baseline evaluation. A complete set of neurodevelopmental evaluation tests, designed for ages 1 month-24 months, will be provided. These tests are designed to be thorough while at the same time clear, fast, and simple to administer during the short time period before the initial surgery. The initial pre-operative evaluation is completed using the test form that most closely matches the infant's current age.
Post-operative Assessments
Post-operative, ongoing evaluations to track the patient's development and progress over time on a regular basis. Testing is scheduled at regular intervals for the ages of 12 months, 24 months, 3 years, 5 years, and (optionally) 7 years. Developmental assessments are based on the following:

At the ages of 12, 24, and 36 months, a continuation of the Denver Developmental Screening Test used as a pre-operative baseline.

At the ages of 5 and 7 years, a combination of:

-A functional testing chart based on The Health Utilities Index (HUI(r)).

-A functional testing chart based on The Hydrocephalus Outcome Questionnaire (HOQ).

-An optional evaluation using the standard Wechsler testing system, for a more in-depth evaluation of neurodevelopment, functioning, and intelligence.

 

Statistical Analysis

Power analysis
Attaining statistically significant results is a crucial element of IIHS. Realistically, this requires the active participation of multiple medical centers, where patient recruitment will continue for 2-4 years, until the goal of recruiting a minimum of 80-100 patients is achieved. We hope to ultimately succeed in recruiting approximately 200 patients, for more meaningful long-term analysis and results. The basis for this sample size estimate is explained here. See Appendix F for a more detailed analysis of the statistical aspects of the IIHS.
Sample size
The sample size estimate is based on the ability to detect a statistically significant difference between the treatment groups for the primary outcome: the Health Utilities Index score at 5 years of age. The following estimations and assumptions have been made:

-The mean HUI score for the control (CSF shunt) group will be approximately 0.77. This is based on previous work in which the HUI was administered to a large group of children with shunted hydrocephalus and the mean utility score was found to be 0.77. 22 30 Data from this same sample also demonstrated that the standard deviation of the HUI scores in this population was approximately 0.20.

-The magnitude of the clinically meaningful difference in the primary outcome is judged to be an approximately 0.10 increase in the HUI score in the ETV cohort (i.e., a mean utility score of 0.87). This is also based on earlier work which suggested that values around 0.10 corresponded to meaningful differences in health status within this population. 22 30

-An alpha value of 0.05 has been chosen.

-A beta error of 0.2, for a power of 80%, has been chosen.

Based on the preceding set of baseline assumptions, and using the independent-samples t-test, it is estimated that at least 64 patients per group are required to reach statistical significance. However, this is only a preliminary, minimal figure. The actual recruitment minimum must be greater, as we must realistically anticipate that some patients may be lost to follow-up and not reach the final 5 year end-point. If we conservatively allow for an approximately 30% loss to follow-up, the sample size estimate can be adjusted to 91 patients per group. (And of course, the more patients recruited, the more meaningful the results of the final analysis.)

 

Data Analysis

Data analysis will consist of baseline evaluations, a primary analysis, and several secondary analyses. The baseline evaluation will compare the characteristics of the ETV and CSF shunt groups, both within the randomized cohort and between the randomized and nonrandomized cohort.

The primary analysis will consist of a comparison of the mean HUI utility score at 5 years of age between the ETV-randomized patients and CSF shunt-randomized patients. This will be performed with both a simple independent-samples t-test and with a multivariable analysis of covariance, adjusting for several baseline variables.

 

9. Ethical Considerations

Potential Harm and Mechanisms to Minimize Harm

Patients in the IIHS are symptomatic from TVH and require some form of surgical intervention. In this study they will undergo either an ETV or CSF shunt procedure. These patients would require a surgical procedure whether or not they were enrolled in the study. The risks of these procedures are well documented. Briefly, they include brain hemorrhages, increased neurological deficit (transient or permanent), infection, endocrinological deficit, and procedure failure. To minimize the level of risk for both groups, only centers with significant experience in performing these procedures will be allowed to participate in this study. Enrollment in the study will involve additional follow-up visits at 12, 18, and 24 months and at 3, 5, and 7 years. This would be very similar to the follow-up patients would routinely require outside the study, and is expected to cause only minimal inconvenience. Study participants will also be required to undergo 2 sets of follow-up imaging (early post-operative, and at 3 years). Although there may be some radiation exposure with these, this is, again, similar to the elements of routine follow-up that they would receive outside the study. Whenever deemed appropriate by the attending surgeon, a follow-up MRI will be requested instead of CT, in order to minimize radiation exposure. Follow-up MRI is mandatory for the ETV group in order to assess flow through the ETV site.

 

Potential Benefits

There may be no direct benefit to patients participating in the study. However, if one arm proves more efficacious, the patients enrolled in that arm will have benefited. In addition, regularly scheduled developmental evaluations mean that any developmental problems are caught as early as possible, enabling early intervention where relevant, with all the attendant benefits. It is widely acknowledged that patients recruited in clinical trials benefit greatly from the systematic follow-up that is required by the trial.

 

Alternatives

If parents prefer not to enroll their child in the study, the choice of therapy will be decided by them in conjunction with their doctors. Actively choosing the preferred means of treatment does not actually preclude the patient's enrollment in the study, since such patients can still be included in the non-randomized arm. However, the family will still be given the option of not enrolling in the study at all. It must be stressed to the family that the quality of care received by their child will in no way depend on their enrolment in the study. The family must also be told that even if they agree to enroll in the study, they can withdraw at any time without at all affecting the quality of care they receive.

 

Consent

Parents will initially be approached by a participating staff member about enrolling their child in the study. A full discussion of the potential harm, potential benefit, and alternatives will be undertaken by the attending physician. It must be stressed that participation is entirely voluntary and that they can withdraw from the study at any time.

 

Confidentiality

Complete patient confidentiality is assured because IIHS will only collect and store anonymous patient data. The following personal data will be collected for each patient:

* Local hospital registration number

* Patient initials

* Date of birth

Data will not be analyzed by center or surgeon.

 

10. Credits & Data

At this point we have received expressions of interest or tentative commitments from medical centers. We are planning to produce one article for publication after the 1-year follow-up data is collected and analyzed, and a second article for publication after the 5-year follow-up data is collected and analyzed. The main publication of study results will credit by name the supporting organizations (ISGNE and ISPN) and the steering committee members, and will acknowledge by name in a separate table the individual contributing surgeons. Other future spin off publications based on the data collected are expected, such as long-term issues, complications, etc. At that time, (i.e., after the first main publication), suggestions for additional data stratification and publications will be explored. Contributing surgeons will be acknowledged by name in an appendix to every public presentation or publication. Because of the small numbers expected from each center, no data analysis will be performed for individual centers. However, if individual surgeons request information on their individual complication rate, for example for education purposes, this will be provided. Individual centers will be allowed to utilize their own patients' data for individual publication only after the first 1-year post-operative analysis has been completed.

 

11. Financial Remuneration

If the funding process is successful, a small honorarium will be supplied. Details will be provided later.

 

12. Conclusion

All approved participants will be provided with more detailed documentation, which can be used for local Ethics Committee Approval. If you agree with the rationale and design of the IIHS, we ask you to contact Dr Constantini, to obtain full documentation, which will ensure your place in the study.

We would like to thank you in advance for your collaboration.

 

Shlomi Constantini (PI) (Tel Aviv) Spyros Sgouros (Athens) Abhaya Kulkarni (Toronto)
sconsts@netvision.net.il sgouros@med.uoa.gr abhaya.kulkarni@sickkids.ca