Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Kulkarni AV, Schiff SJ, Mbabazi-Kabachelor E, et al. Endoscopic treatment versus shunting for infant hydrocephalus in Uganda. N Engl J Med 2017;377: DOI: /NEJMoa

2 This supplement contains the following items: 1. Original protocol, final protocol, summary of changes. 2. Original statistical analysis plan, final statistical analysis plan, summary of changes.

3 CHeRP Protocol Outline: All protocols must include the following sections. If a section is not applicable for the current protocol please indicate why this is the case. TITLE: Neurocognitive Outcomes and Changes in Brain and Cerebral Spinal Fluid (CSF) Volume after Treatment of Post Infectious Hydrocephalus (PIH) in Ugandan Infants by Shunting versus Endoscopic Third Ventriculostomy/Choroid Plexus Cauterization (ETV/CPC) A. Specific Aims/Objectives The specific aims of this R21 application are to develop our partnering Ugandan site as a more effective and independent collaborator for future investigations, and to provide key preliminary data to prepare for future collaborative R01 level research and clinical trials. 1) Develop CCHU as an independent site for hydrocephalus research and clinical trials CCHU is a high volume center for the treatment of infant hydrocephalus in sub Saharan Africa, and provides the great majority of treatment for this condition in Uganda and surrounding regions. CCHU has been the site of previously published clinical investigations by the PI s collaborating on this R21 application, and holds great potential for developing into an independently functioning partner in future investigations. This aim will be accomplished by the following: a) Provide a social worker for patient outreach to maximize patient follow up data acquisition b) Provide computer, software, and training for on site determination of brain/csf volumes c) Provide the Bayley Scales of Infant Development assessment tools and training for a dedicated staff member to competently perform the assessments and collect the data. d) Fund a Ugandan medical officer to be the on site project coordinator e) Train Ugandan staff to perform on site statistical analysis and clinical trial design 2) Correlate brain/csf volume metrics with neurocognitive development during PIH treatment We have developed a method for determining brain and CSF volumes from CT images. In contrast to prior standard measures (head circumference and frontal occipital horn ratio, FOHR), we have now developed a way to relate the neurocognitive outcomes in childhood hydrocephalus with meaningful metrics that can be used to compare treatment modalities. Using these metrics, we are in a position to propose this prospective comparison of VPS vs. ETV/CPC for PIH in rural Uganda, correlating treatment modality, neurodevelopmental outcome, and volumetric changes. This aim will be accomplished by correlating neurodevelopmental outcomes as determined by the Bayley Scales of Infant Development with brain/csf volumetrics. Version 1.1 Activated January 24 th 2013 Page 1 of 8

4 3) Test the hypothesis that treatment of PIH by ETV/CPC is as good as or better than shunt placement in regard to neurocognitive development by a randomized controlled trial We do not know the best treatment for PIH in regard to maximizing brain development. Although successful treatment by ETV/CPC avoids shunt dependence and the long term risk of shunt failure, we demonstrated no significant difference in 5 year survival between the two modalities among Ugandan myelomeningocele infants or infants with PIH. 12, 14 We also demonstrated no significant difference in early neurocognitive development between the two modalities in a retrospective cohort study of myelomeningocele infants. 6 We will carry out a randomized controlled trial of shunt placement vs. ETV/CPC for PIH in Ugandan infants to test the hypothesis that ETV/CPC is as good as or better than shunt placement in regard to neurodevelopmental outcome (using the Bayley Scales of Infant Development) and in normalizing brain/csf volumetrics. 4) Determine the feasibility of employing preoperative brain/csf volume parameters to guide therapy Ideally, the normal brain and CSF growth curve provides the optimal treatment target for children with hydrocephalus. It is possible that a patient s preoperative starting point in relation to the curve may influence both the ultimate post treatment outcome and the optimal treatment choice. This study will examine the neurocognitive outcomes for patients with different preoperative brain/csf volume metrics in an attempt to determine whether differences exist among groups as to best initial management as determined by follow up treatment images and cognitive assessment. As well, these results may ultimately provide a pre treatment prediction tool for prospectively choosing the optimal therapy for such children. B. Background and Significance In sub Saharan Africa post infectious hydrocephalus (PIH) is a common, treatable cause of childhood brain injury that should be preventable. The magnitude of this problem has previously been unrecognized. We estimate that 100, ,000 infants develop hydrocephalus in sub Saharan Africa each year 1. In contrast to the industrialized countries, our work suggests that most of the cases of hydrocephalus (60%) in Uganda are PIH 2 and that Gram negative coliform bacteria are potentially important pathogens in PIH with seasonal variance. 10, 15 In the developing world, the majority of these children have no opportunity for treatment because pediatric neurosurgical specialty care has not previously been available 1,2,3. These children often suffer brain injury from the infection (which can lead to cerebral palsy, epilepsy, visual impairment, and death), as well as the secondary hydrocephalus 1 5. Therefore, the prevention and improved treatment of PIH provides an important opportunity to save and improve the lives of many thousands of children worldwide; but to do this, we need to better understand the causes and optimal treatment of PIH. We do not yet know the optimal treatment of PIH in Africa. Shunt placement is the traditional treatment for PIH in the industrialized countries. Even though we established the efficacy of an inexpensive shunt system in this setting 3, shunt dependence remains an exceptionally dangerous post treatment condition in rural sub Saharan Africa 1 9. We have pioneered a novel treatment (combined endoscopic third ventriculostomy and endoscopic choroid plexus cauterization, ETV/CPC) that avoids shunt dependence in the majority of patients and has a lower risk of failure than shunting after six months 4, 5, 9, 11. In the case of myelomeningocele infants with hydrocephalus, we recently showed that ETV/CPC was at least as good as shunting in regard to early neurocognitive development 6. We have trained neurosurgeons and equipped centers for the ETV/CPC procedure in 20 developing countries (initially through our long standing partnership with the International Federation for Spina Bifida and Hydrocephalus (IF) which helped support our International Program to Advance the Treatment of Hydrocephalus (ipath) [ and currently through our nonprofit organization CURE Hydrocephalus [ We have developed a clinical scoring instrument to predict the outcome for ETV/CPC 7,8. However, the comparative effectiveness in promoting brain development for ETV or ETV/CPC versus shunting has not been established. Thus far, no prospective study has ever established the relative efficacy of these treatment modalities in this regard for any Version 1.1 Activated January 24 th 2013 Page 2 of 8

5 etiology of hydrocephalus. The absence of a safety net for maintenance of shunt function in rural Africa provides a compelling argument for ETV/CPC. However, five year survival among infants treated for PIH in Uganda was not affected by the method of hydrocephalus treatment due to a high mortality from unrelated conditions 14 In going forward with medical efforts to expand access to treatment for infants with PIH, we wish to establish the optimum treatment protocol in regard to early childhood brain development by a randomized controlled trial of ETV/CPC vs. shunt placement. The proposed study will develop the research site and provide preliminary data for future collaborative R01 level research and clinical trials. C. Preliminary Studies We traditionally measure and treat the accumulation of CSF in hydrocephalus, yet we seek neurocognitive outcomes that depend upon normal brain growth and volume. Since brain geometry is distorted remarkably in hydrocephalus, and especially in PIH secondary to the sequelae of the initial ventriculitis, the determination of brain volume is difficult to ascertain visually. Without normative brain volume growth curves, we have had no way to define the optimal treatment targets for hydrocephalus normal brain growth without damaging fluid accumulation. We tested the feasibility of creating normative and hydrocephalic brain growth curves in a murine model of hydrocephalus. We found that normative brain growth curves permitted us to distinguish between different patterns of hydrocephalus to which standard measures, head circumference and frontal occipital horn ratio (FOHR) were insensitive. 16 Translating such findings to clinical use required that we develop a reliable and automated method of segmenting brain and CSF from clinical images, both MRI and CT, and developing normative growth curves for children. Following the results of Withey et al 2009, we developed an accurate particle filter that permits automated edge tracing for both MRI and CT in the settings of substantial image noise (9%) and inhomogeneity (40%). This methodology consists of three steps: a likelihood map based upon global intensity thresholds, detection of edge boundaries using a radon transform (Drew et al 2010), and a robust particle tracker. We then, under IRB oversight, used this automated routine to analyze 42 images from 34 normal children archived at the NIH Pediatric MRI Data Repository at the Montreal Neurological Institute. We focused on equal numbers of males and females, at ages two weeks, six months, 1, 2, 3, 6, and 18 years. Males have a larger average brain size which is well known to correlate with body mass. The coefficients of determination for a simple power law fit to the male and female curves are very high (R2 = 0.86 and 0.90 respectively). Note that normal CSF accumulation is relatively stable after two to three years of age. Also note that the head circumference curve increases at a rate incommensurate with brain growth from ages five to 18 years, reflective of skull and scalp thickening that adds about 5 cm to adult head circumference. Intriguingly, brain growth did not correlate well with FOHR (R2 = 0.11), but correlated very well with CSF volumes (R2 = 0.81). In Warf et al , we studied the neurocognitive outcomes of 93 Ugandan spina bifida children, with and without hydrocephalus. Their hydrocephalus was treated with a mixture of ventriculoperitoneal shunts (VPS) and ETV/CPC. The FOHR metric did not correlate with cognitive performance as measured on six scales of the Bayley Scales of Infant Development (BSID). We reanalyzed the data from 33 patients from Warf et al 2009, 16 Males and 17 Females, whose FOHR measurements were from CT scans at ages one to 49 months. There were nine VPS, 17 ETV/CPC, and seven without hydrocephalus. We adapted our particle filter to segment brain and CSF volumes from CT scans. We found that both brain volume, and to a lesser but important degree, CSF volume, were significant multivariate Version 1.1 Activated January 24 th 2013 Page 3 of 8

6 discriminators of neurocognitive outcome. Summing the BSID scores that most contributed to discrimination in this context (cognitive, fine motor, expressive language), so that the normal scaled scores (normalized for age) equaled 30, we find highly significant two way and three way linear discrimination of children doing well (larger brains and smaller CSF volumes), versus those doing poorly (smaller brains and more CSF). These combined volumetric findings, the development of the method, and the neurocognitive correlations, are being prepared for submission to the Journal of Neurosurgery at this time. These findings show that, in contrast to prior standard measures (head circumference and FOHR), we have now developed a way to relate the neurocognitive outcomes in childhood hydrocephalus with meaningful metrics of comparative treatment modalities. Using these metrics, we are in a position to propose this prospective comparison of VPS vs ETV/CPC for PIH in rural Uganda, correlating treatment modality, neurodevelopmental outcome, and volumetric changes. D. Design and Methods (1) Study Design We will a) develop CCHU as an independent site for hydrocephalus research and clinical trials; b) correlate brain/csf volume metrics with neurocognitive development during PIH treatment; c) test the hypothesis that treatment of PIH by ETV/CPC is as good as or better than shunt placement in regard to neurocognitive development by a randomized controlled trial; and d) determine the feasibility of employing preoperative brain/csf volume parameters to guide therapy This is a randomized controlled trial of ETV/CPC vs. ventriculo peritoneal shunt placement for the treatment of PIH in Ugandan infants. The affiliate centers are: CURE Children s Hospital of Uganda Mbale, Uganda (where the study will be carried out) Boston Children's Hospital Boston, MA, USA (where the PI is located) Penn State University University Park, PA University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada Subjects will be infants six months of age or younger presenting to CURE Children s Hospital of Uganda (CCHU) for treatment of PIH. These infants would be undergoing surgical treatment for the condition regardless of entry into the study and would also be receiving the same preoperative and postoperative imaging studies. Both shunt placement and ETV/CPC are standard treatments for PIH both currently performed at CCHU. We have demonstrated the safety and efficacy of both procedures in treating the condition in this context, and have demonstrated, in non randomized studies, no difference in early cognitive development or five year survival between the two treatment modalities in a population of Ugandan infants with myelomeningocele requiring treatment for hydrocephalus. It is not known which treatment for PIH is better in regard to brain development. (2) Patient Selection and Inclusion/Exclusion Criteria Infants who present at less than 180 days (six months) old with symptomatic hydrocephalus meeting our previously established definition of PIH based on clinical and CT parameters 2. Patients Version 1.1 Activated January 24 th 2013 Page 4 of 8

7 from the following districts will be eligible for inclusion: Bugiri, Busia, Iganga, Jinja, Kampala, Kamuli, Kapchorwa, Katakwi, Kumi, Mayuge, Mbale, Mukono, Pallisa, Sironko, Soroti, and Tororo. (3) Description of Study Treatments or Exposures/Predictors After informed parental consent is obtained, patients will be randomized to undergo ETV/CPC or shunting. We will use a block randomization scheme and treatment will be allocated based on sealed, opaque, ordered envelopes. At recruitment, baseline data will be collected including: age, weight, head circumference, other clinical parameters, neurodevelopmental status (using the Bayley Scales of Infant Development), and brain/csf volume. The ETV/CPC arm will comprise a standard frontal approach with flexible endoscopy as previously described 4. If the ETV is not technically feasible, then shunting will be performed. These crossovers will still be analyzed as ETV/CPC in the primary intention to treat analysis. The shunting arm will comprise a standard frontal approach ventriculoperitoneal shunt using a silastic Chhabra system, as previously described 3. (4) Definition of Primary and Secondary Outcomes/Endpoints Primary outcome: Neurocognition as measured by the BSID III Cognitive Scale at 12 months. Secondary outcomes: The following will be measured as secondary outcomes: BSID III Language and Motor Scales, mortality, treatment failure requiring repeat surgery, infection, number of surgeries, days spent in hospital, and brain/csf volumes using linear discrimination analysis (5) Data Collection Methods, Assessments, Interventions and Schedule (what assessments performed, how often) Patients will be monitored in hospital for a minimum of three days. Major peri operative complications will be recorded before discharge. They will then be seen at routine out patient visits at two weeks and at one, three, six, and 12 months post surgery. At each visit they will undergo physical exam, including head circumference measurement, and receive cranial ultrasonography. A head CT will be performed at the six and 12 month visit. A home visit every two to four weeks by the social worker will augment the outpatient clinic appointments, and a home visit will be prompted if a scheduled clinic appointment is missed. Any acute clinical deterioration will mandate an urgent unscheduled visit for assessment. The Bayley Scales of Infant Development (BSID III) will be administered by a trained researcher, blinded to treatment allocation, at six and 12 months. We have previously used a culturally modified version of the BSID successfully in Ugandan infants 6 similar to that reported by Drotar and colleagues 13. Success of either treatment will be defined as: shift in head circumference growth to a normal or less than normal rate as plotted on a standard growth chart, decompression of the anterior fontanel, relief from symptoms of elevated intracranial pressure (such as irritability and vomiting), resolution of eye findings (for example, sunsetting or sixth cranial nerve palsy), and a decrease or arrest in ventriculomegaly as determined on ultrasonography or CT scanning by using the frontaloccipital horn ratio 2 9, 11,12. If the child does not meet these criteria, this will be considered a failure Version 1.1 Activated January 24 th 2013 Page 5 of 8

8 of treatment and ETV/CPC patients will undergo shunting and shunted patients will undergo shunt revision. (6) Study Timeline (as applicable) Patients will be accrued over one year and followed as a part of this study for 12 months postsurgery. E. Adverse Event Criteria and Reporting Procedures Dr. Benjamin Warf and Dr. Steven Schiff will alternate in conducting site visits to ensure that they are in compliance with safety standards. Outcome monitoring and adverse event will all be reported through appropriate channels of the Human Studies Committee. A Data Safety Monitoring Committee has been formed, and is composed of disinterested parties that include two American academic pediatric neurosurgeons, one African pediatric neurosurgeon (Professor and Chairman of Neurosurgery at University of Cape Town), the Head of Pediatrics at Mbarara University of Science and Technology, MUST, (in Uganda), and an American trained Ugandan biostatistician at MUST. F. Data Management Methods All data will be de identified and stored for later off line analysis. The investigator in charge of the study at CCHU will perform safety monitoring throughout the study. G. Quality Control Method Data will be collected on patients presenting with PIH. Subject information obtained for research purposes will be placed in the infant patient s medical record. The results of the research will be kept in a separate research file maintained by the principal investigator and the site clinical coordinator. In this manner it will be unlikely that others within the hospitals, an insurance company or employer would ever have access to this information. We will respect the confidentiality of the patients and when collecting information that reveals the subjects identity, we will routinely use a coding system to identify the patients. All the data will be accessible only by a password protected server using subject identification numbers as identifiers. No patient identifiers will appear in any presentations or publications related to this research. H. Data Analysis Plan Baseline status between the treatment groups, including age at surgery, brain/csf volumes, and developmental status, will be assessed for comparability. The primary analysis will compare 12 month BSID III Cognitive Scale between ETV/CPC and shunting (intention to treat) using t test. Several secondary analyses will be carried out, including: comparison of BSID III Motor and Language Scales, comparison of mortality, comparison of brain/csf volumes, and survival analysis for time to treatment failure. Because we expect that there will be a number of cross overs from ETV/CPC to shunting, we will also perform astreated analyses. Version 1.1 Activated January 24 th 2013 Page 6 of 8

9 CURE Children s Hospital of Uganda is located in Mbale, Uganda and will serve as the single site for subject recruitment and enrollment under the direction of the site PI Dr. John Mugamba, M.D. This nongovernment, not for profit pediatric neurosurgery specialty hospital will generate the human subject data. It is fully equipped for all aspects of the project, has a memorandum of understanding with the Ugandan Ministry of Health, and provides the vast majority of care for infants with hydrocephalus in Uganda, treating around 500 new infant cases each year. The North American Centers include Children's Hospital Boston, Penn State University (PSU) located in University Park, PA and University of Toronto and Hospital for Sick Children located in Toronto, Ontario, Canada. Boston Children s will be the coordinating center for this study and Dr. Warf will serve as the overall study PI which include the management of logistical infrastructure, capacity building, and data analysis. Steven Schiff, MD, PhD, site PI at PSU, will be responsible for brain/csf volume analysis, technology development, study design, onsite technical training, and long distance technical support. Toronto site PI, Abhaya Kulkarni, MD, PhD will be responsible for experimental and clinical trial design, epidemiology, neurocognitive assessment, and statistical analysis. Dr. Warf will report to the Data Safety Monitoring Committee. I. Statistical Power and Sample Considerations Our best available data suggest that the BSID III Cognitive Scale for this population will be approximately six with a standard deviation of four (normal population mean is ten). The minimal clinically meaningful difference in score would be an improvement of three, to bring the mean to nine. Based on these values, with alpha=0.05 and 90% power, and accounting for 20% mortality and 5% follow up loss, we estimate recruiting 50 infants per arm (100 patients total). Based on the current treatment volumes at CCHU, this number of patients will be easily recruited in less than one year. J. Study Organization This is a randomized controlled trial of ETV/CPC vs. ventriculo peritoneal shunt placement for the treatment of PIH in Ugandan infants. The affiliate centers are: CURE International Children s Hospital Mbale, Uganda (where the study will be carried out) Boston Children's Hospital Boston, MA, USA (where the PI is located) Penn State University University Park, PA University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada K. References 1. Warf BC, Alkire BC, Bhai S, Hughes C, Schiff S, Vincent J, Meara J Costs and benefits of neurosurgical intervention for infant hydrocephalus in sub Saharan Africa. J Neurosurg Pediatrics 8: , 2011 Clinical article 2. Warf BC. Hydrocephalus in Uganda: predominance of infectious origin and primary management with endoscopic third ventriculostomy. J Neurosurg (Pediatrics 1), 102:1 15, Warf BC. Comparison of One Year Outcomes for the ChaabraTM and Codman Hakim Micro PrecisionTM shunt systems in Uganda: A Prospective Study in 195 Children. J Neurosurg (Pediatrics 4), 102: , Warf BC. Comparison of endoscopic third ventriculostomy alone and combined with choroid plexus cauterization in infants younger than 1 year of age: a prospective study in 550 African children. J Neurosurg (6 Suppl Pediatrics), 103: , Version 1.1 Activated January 24 th 2013 Page 7 of 8

10 5. Warf BC, Campbell JW. Combined endoscopic third ventriculostomy and choroid plexus cauterization (ETV/CPC) as primary treatment of hydrocephalus for infants with myelomeningocele: Long term results of a prospective intention to treat study in 115 African infants. J Neurosurg Pediatrics, 2: , Warf BC, Ondoma S, Kulkarni A, Donnelly R, Ampeire M, Akona J, Kabachelor C, Mulondo R, Nsubuga B. Neurocognitive outcome and ventricular volume in myelomeningocele children treated for hydrocephalus in Uganda. J Neurosurg Pediatrics 4: , Warf BC, Mugamba J, Kulkarni A. Endoscopic third ventriculostomy in the treatment of childhood hydrocephalus in Uganda: report of a scoring system that predicts success. J Neurosurg Pediatrics 5: , Warf BC, Kulkarni A. Intraoperative assessment of cerebral aqueduct patency and cisternal scarring: impact on success of endoscopic third ventriculostomy in 403 African children. J Neurosurg Pediatrics 5: , Kulkarni A, Warf BC, Drake J, Mallucci C, Sgouros S, Constantini S. Surgery for hydrocephalus in sub Saharan Africa versus developed nations: a risk adjusted comparison of outcome. Child s Nervous System (published online DOI /s x June 16, 2010) 10. Li L, Padhi A, Ranjeva SL, Donaldson SC, Warf B, Mugamba J, Johnson J, Opio Z, Jayarao B, Kapur V, Poss M, Schiff S. Association of Bacteria with Hydrocephalus in Ugandan Infants. J Neurosurg Pediatrics 7:73 87, Warf BC, Stagno V, Mugamba J. Encephalocele in Uganda: Ethnic variation in lesion location, endoscopic management of hydrocephalus, and survival in 110 consecutive children. J Neurosurg Pediatrics 7:88 93, Warf BC, Wright EJ, Kulkarni AV. Factors affecting survival of infants with myelomeningocele in southeastern Uganda. J Neurosurg Pediatrics 7: , Drotar D, Olness K, Wiznitzer M, Guay L, et al. Neurodevelopmental outcomes in Ugandan infants with human immunodeficiency virus type 1 infection. Pediatrics 100:5 11, Warf BC, Dagi AR, Nsbuga B, Schiff SJ. Five year survival and outcome of treatment for post infectious hydrocephalus in Ugandan infants. J Neurosurg Pediatrics 8: , Schiff SJ, Ranjeva S, Sauer T, Warf BC. Rainfall drives hydrocephalus in East Africa. J Neurosurg Pediatrics 10: , J Neurosurg Pediatr Jul;6(1):1 10. The dynamics of brain and cerebrospinal fluid growth in normal versus hydrocephalic mice. Mandell JG, Neuberger T, Drapaca CS, Webb AG, Schiff SJ. Version 1.1 Activated January 24 th 2013 Page 8 of 8

11 Consent Form (English version) Why is this research study being conducted? What is its purpose? Your child is being asked to participate in this study because he or she has been diagnosed with hydrocephalus and requires treatment of their condition with one of the two procedures described below. Hydrocephalus is a condition of the brain that happens when too much of the normal water in the brain, called cerebrospinal fluid (CSF), builds up in the normal spaces of the brain and causes them to swell. This causes the babies head to grow too large and also causes pressure inside the brain. This can make the baby sick and also interferes with the growth and development of the brain. If hydrocephalus is not treated, it causes permanent damage to the brain and can even cause the baby to die. World over, infants with hydrocephalus are mainly treated using a shunt, which is a device made of soft plastic tubing that moves extra fluid from the brain to the abdomen. Surgery is required to insert a shunt into the brain and the abdomen. In recent years, we have developed another treatment called Endoscopic Third Ventriculostomy (ETV) with Choroid Plexus Cauterization (ETV/CPC). Endoscopic means looking inside the body using an endoscope, which is a tool used for viewing small spaces or cavities. Third Ventriculostomy refers to the part of the brain, a ventricle or cavity that the surgeon will view using the endoscope and then will create a hole in the bottom of the ventricle so that the extra fluid can move freely. Choroid plexus is a structure inside the ventricles that is separate from the brain and makes some of the fluid (CSF). Cauterization means to burn and the surgeon will use a tiny wire with a weak electric current to burn away some of choroid plexus in order to reduce the production of fluid. The main advantage of ETV/CPC is that, when it is successful, it tends to continue to be successful for the rest of the child s life; whereas, a shunt may stop working and require an operation to fix it at any point in the future. There is also a higher risk of infection (around ten infections in every 100 shunts placed) compared to ETV/CPC (less than 1 infection in every 100 ETV/CPC operations performed.) However, ETV/CPC when it can be performed is only successful in about two out of three infants. When ETV/CPC is not successful, the patient will require another operation to place a shunt. We have studied patients who have had ETV/CPC and have learned that, over five years, the likelihood of surviving is the same for either treatment. What we do not know is whether one treatment may be better for helping the brain to grow and develop in the early months of life, since a shunt tends to reduce the fluid in the brain more quickly and make the ventricles smaller than ETV/CPC. So, it is not certain which is the better overall treatment for your child, and this is what we need to find out. Dr. Mugamba, the neurosurgeon conducting this study at CCHU, will determine in a random manner (like flipping a coin ) which surgical procedure your child will undergo. A list of equal numbers of A s and B s will be generated in random order and matched to patient 1, patient 2, and so on for a total of 100 patients. The order in which your child is entered into the study will be matched with the A or B on the list, which will determine which of the two treatments will be performed. Consent form Page 1 of 6

12 We are doing this research in order to measure the results of these procedures in children less than six months of age who have hydrocephalus as the result of a brain infection. We call this post infectious hydrocephalus, or PIH, and it is the most common cause of hydrocephalus in Ugandan babies. The original brain infection that causes PIH may have already caused damage to the brain that will affect your child s development in the future; but if the hydrocephalus is not treated it will continue to cause even more damage or may result in death. Both the shunt and the ETV/CPC will treat the hydrocephalus; but research that has already been done has not studied if one of these procedures is better than the other for helping the baby s brain to develop. This study gives us the opportunity to evaluate our patients in more detail than we otherwise do in order to measure their brain growth and development. Children in the study will have special testing to measure their developmental progress as well as special imaging to evaluate the progress of their brain growth. We will also be able to follow your child s progress more closely than we usually do. We hope this will help us learn how to improve our treatment of such children in the future. Who is conducting this research study, and where is it being conducted? At CURE Children s Hospital Uganda (CCHU), Dr. John Mugamba is the site Principal Investigator (PI) and he is responsible for this research study at this site. This is a multi site research study that is being conducted at four different locations. The main location is Boston Children s Hospital (BCH) located in Boston, Massachusetts, USA. Dr. Benjamin Warf is the site PI and he is also the overall Principal Investigator for the entire study. Dr. Warf was the Medical Director of CURE Children s Hospital of Uganda (CCHU) from 2000 through 2006, and is still our Director of Research even though he now lives in the U.S. Dr. Steven Schiff is a site PI at Penn State University (PSU) in Pennsylvania, USA and Dr. Abhaya Kulkarni is a site PI for Toronto Hospital for Sick Kids in Toronto, Canada. Patients are being enrolled only at CCHU. Data that is collected from patients will be sent to BCH, PSU, and Toronto Hospital for Sick Kids in order to be studied. Funds to conduct this study are provided by the Fogarty International Center (FIC), which is part of the National Institutes of Health (NIH). These institutions are United States federal organizations. Because Dr. Warf is the overall PI for this research study, his employer Boston Children s Hospital received the funds that were awarded to conduct this study according to federal regulations. How are individuals selected for this research study? How many will participate? Patients are invited to participate in this study if they have PIH and are less than six months old. We will enroll up to 100 patients. To ensure that we are able to safely and properly conduct follow up care and take care of your child if the treatment fails or if there are any complications, we are only enrolling patients from the following districts, which are fairly close to the hospital: Bugiri, Busia, Iganga, Jinja, Kampala, Kamuli, Kapchorwa, Katakwi, Kumi, Mayuge, Mbale, Mukono, Pallisa, Sironko, Soroti, Tororo. We have previously shown that for patients living in these districts there was no increased risk of dying within five years whether they had a shunt or had been successfully treated by ETV/CPC. Consent form Page 2 of 6

13 What do I have to do if I am in this research study? We will first discuss the details of the study with you and answer any questions that you may have about the study. Then we will request that you sign this informed consent if you are still interested in participating in the study. You and your child will be asked to return to CCHU for follow up visits two weeks, one month, three months, six months (with CT scan), and 12 months (with CT scan) after surgery. These are usual visits any child would receive at CCHU, but there will be extra testing of your child s development at six months and 12 months that is being done only for this study. A member of our staff may also visit you at home between clinic appointments to see how things are going, or come to see you if you are unable to come to your clinic appointment. The Informed Consent document will be translated to the local vernacular/dialect understood by you. For parents who are unable to read, an interpreter will be used to explain the study verbally. We will use the signature or a thumbprint on the CONSENT FORM and it will be considered a mark of acceptance to join the research. Benefits to subject and to others? There are no benefits either financially or clinically to you or your child for participating in this study. The information gained in this study will be used to determine the most appropriate initial treatment method for infants who develop PIH in the future. However, involvement in the study will allow us to more closely monitor your child s developmental progress than we are otherwise able to do, and our research staff will be available to come visit you at home if needed, which is something we do not typically have the resources to do. Risks or discomforts to the subject? The risks or discomforts are actually treatment related and not because of the research. The general anesthesia and surgery risks and discomforts would be the same while treating your child with or without this research study. Both treatments carry the same low risk of anesthesia complications, bleeding, and death. The infection risk for shunt placement at CCHU is 9.5% within three months of surgery, whereas the infection risk of ETV/CPC is lower (less than 1%). The risk of treatment failure that requires another operation within the first six months is higher for ETV/CPC (40%) compared to shunt placement (25%); but, by one year from surgery 60% of those who had an ETV/CPC have remained successful, compared to 54% of those who had a shunt placed, which is quite similar. If the ETV/CPC fails, a shunt is usually placed at that point, although sometimes the ETV opening may have closed and it may be appropriate to suggest reopening it instead of placing a shunt. There is a continued possibility for the shunt to malfunction over the years, and it is average for a child to have two or three shunt operations for this problem over their lifetime. Late failure of the ETV/CPC does occur, but this is unusual. For children with post infectious hydrocephalus (PIH), we have shown no significant difference Consent form Page 3 of 6

14 in five year survival between those treated with a shunt and those treated by ETV/CPC. For infants with PIH, we do not know which treatment is better for brain growth and development. Are there costs associated with this research study? Will I receive any payments? There are no extra costs as a result of participation in this study. You and your family will not receive any payments as a result of participating in this study. Confidentiality? While we use every method available to us to protect you and your child s confidentiality, there is a slight chance of loss of confidentiality. The patient information will only be accessible to the parties involved in the research. You/your child may have the right to get some of the information that was shared with others for research, treatment or payment but only after analysis is done. If I do not want to take part in this research study, what are the other choices? Your and your child s participation in this research is voluntary. Your child will receive either a VP shunt or ETV/CPC whether you enroll for the study or not. If you decide not to join the study, this will not affect the treatment your child is going to receive, now or in the future. If you decide not to join the study then either an ETV/CPC or a shunt placement will be recommended, depending upon the results of your child s CT scan or findings at the time of surgery. Our current practice is usually to perform ETV/CPC as the first procedure if it looks possible and safe. However, only children in the study will have the additional testing and enhanced follow up described above. You can ask to stop your and your child s participation in the study at any time of your choosing and this will not affect the subsequent care your child receives What are my rights as a research participant? Participation in this study is voluntary, and refusal to participate or withdrawal from the study will in no way affect the medical care your child will receive at CCHU. Any significant finding will be communicated to the parents/guardians Who may see, use or share your health information? You/your child s health information is protected by a law called the Health Information Portability and Accountability Act (HIPAA). In general, anyone who is involved in this research including those funding and regulating the study may see the data, including information about your child. For example, the following people might see information about you: Research staff at Boston Children s Hospital involved in this study Consent form Page 4 of 6

15 Medical staff at Boston Children s Hospital directly involved in your care that is related to the research or arises from it. Other researchers and centers that are a part of this study, including people who oversee research at that hospital. People at Boston Children s Hospital who oversee, advise, and evaluate research and care. This includes the ethics board and quality improvement program People from agencies and organizations that provide accreditation and oversight of research. People that oversee the study information such as data safety monitoring boards, clinical research organizations, data coordinating centers, and others. Sponsors or others who fund the research, including the United States government or private sponsors. Companies that manufacture drugs or devices used in this research. In the United States, federal and state agencies that oversee or review research information, such as the Food and Drug Administration, the Department of Health and Human Services, the National Institutes of Health, and public health and safety authorities People or groups that are hired to provide services related to this research or research at Boston Children s Hospital, including services providers, such as laboratories, and others If some law or court requires us to share the information, we would have to follow that law or final ruling. Some people or groups who get your health information might not have to follow the same privacy rules. Once your information is shared outside of Boston Children s Hospital, we cannot promise that it will remain private. If you/your child decide to share private information with anyone not involved in the study, the United States federal law designed to protect privacy may no longer apply to this information. Other laws may or may not protect sharing of private health information. If you have a question about this you may contact the Boston Children s Hospital Privacy Office at , which is set up to help you understand privacy and confidentiality. Because research is ongoing we cannot give you an exact time when we will destroy this information. Researchers continue to use data for many years so it is not possible to know when they will be done. We will also create a code for the research information we collect about your child so identifying information will not remain with the data and will be kept separately. The results of this research may be published in a medical book or journal or be used for teaching purposes. However your name or identifying information will not be used without your specific permission. Your privacy rights Consent form Page 5 of 6

16 If you do not want your child to participate in this study, you do not have to. If you do want to participate, however, you must sign this form. If you do not sign this form, it will not affect your care or your child s care at CURE Children s Hospital Uganda now or in the future and there will be no penalty or loss of benefits. You can withdraw your child from the study and end your permission for CCHU and Boston Children s Hospital to use or share the protected information that was collected as part of the research; however you cannot get back information that was already shared with others. Once you remove your permission, no more private health information will be collected. If you wish to withdraw your health information you will need to do so in writing. You/your child may have the right to get some of the information that was shared with others for research or treatment. This information is available after the study analysis is done and will be stored at CCHU and Boston Children s Hospital. To request the information, please contact the Hospital Administrator at CCHU or Boston Children s Hospital s Privacy Officer at PARENT CONSENT I. Parent of.. do understand that my decision to have my child participate in this study is voluntary. I further understand the purpose of the study / research, the risks and discomforts to my child, the benefits to him/her and to others. All these have been explained to me in the language I understand. I do realize that in the use of information generated from this study, the identity of my child will remain anonymous except to the investigators involved in the study. I have been assured that refusal to participate involves no penalty or loss of benefits in terms of treating my child and that I can choose to withdraw my child from the study at any time. I am also made to understand that in case of any questions, Dr. J. Mugamba of CURE Children's Hospital of Uganda, P.O Box 903, Mbale; Telephone: / will be available to answer questions and will report any significant new findings to me. I acknowledge my consent to participate by signing below or using my thumb print as a mark of acceptance. Parent signature/thumb print: Date (MM/DD/YEAR): Witness signature: Date (MM/DD/YEAR): Consent form Page 6 of 6

17 CHeRP Protocol Outline: All protocols must include the following sections. If a section is not applicable for the current protocol please indicate why this is the case. TITLE: Neurocognitive Outcomes and Changes in Brain and Cerebral Spinal Fluid (CSF) Volume after Treatment of Post-Infectious Hydrocephalus (PIH) in Ugandan Infants by Shunting versus Endoscopic Third Ventriculostomy/Choroid Plexus Cauterization (ETV/CPC) A. Specific Aims/Objectives The specific aims of this R21 application are to develop our partnering Ugandan site as a more effective and independent collaborator for future investigations, and to provide key preliminary data to prepare for future collaborative R01 level research and clinical trials. 1) Develop CCHU as an independent site for hydrocephalus research and clinical trials CCHU is a high volume center for the treatment of infant hydrocephalus in sub-saharan Africa, and provides the great majority of treatment for this condition in Uganda and surrounding regions. CCHU has been the site of previously published clinical investigations by the PI s collaborating on this R21 application, and holds great potential for developing into an independently functioning partner in future investigations. This aim will be accomplished by the following: a) Provide a social worker for patient outreach to maximize patient follow-up data acquisition b) Provide computer, software, and training for on-site determination of brain/csf volumes c) Provide the Bayley Scales of Infant Development assessment tools and training for a dedicated staff member to competently perform the assessments and collect the data. d) Fund a Ugandan medical officer to be the on-site project coordinator e) Train Ugandan staff to perform on-site statistical analysis and clinical trial design 2) Correlate brain/csf volume metrics with neurocognitive development during PIH treatment We have developed a method for determining brain and CSF volumes from CT images. In contrast to prior standard measures (head circumference and frontal-occipital horn ratio, FOHR), we have now developed a way to relate the neurocognitive outcomes in childhood hydrocephalus with meaningful metrics that can be used to compare treatment modalities. Using these metrics, we are in a position to propose this prospective comparison of VPS vs. ETV/CPC for PIH in rural Uganda, correlating treatment modality, neurodevelopmental outcome, and volumetric changes. This aim will be accomplished by correlating neurodevelopmental outcomes as determined by the Bayley Scales of Infant Development with brain/csf volumetrics. Version 1.10 Activated November 01 st 2016 Page 1 of 9

18 3) Test the hypothesis that treatment of PIH by ETV/CPC is as good as or better than shunt placement in regard to neurocognitive development by a randomized controlled trial We do not know the best treatment for PIH in regard to maximizing brain development. Although successful treatment by ETV/CPC avoids shunt dependence and the long-term risk of shunt failure, we demonstrated no significant difference in 5-year survival between the two modalities among Ugandan myelomeningocele infants or infants with PIH. 12, 14 We also demonstrated no significant difference in early neurocognitive development between the two modalities in a retrospective cohort study of myelomeningocele infants. 6 We will carry out a randomized controlled trial of shunt placement vs. ETV/CPC for PIH in Ugandan infants to test the hypothesis that ETV/CPC is as good as or better than shunt placement in regard to neurodevelopmental outcome (using the Bayley Scales of Infant Development) and in normalizing brain/csf volumetrics. 4) Determine the feasibility of employing preoperative brain/csf volume parameters to guide therapy Ideally, the normal brain and CSF growth curve provides the optimal treatment target for children with hydrocephalus. It is possible that a patient s preoperative starting point in relation to the curve may influence both the ultimate post-treatment outcome and the optimal treatment choice. This study will examine the neurocognitive outcomes for patients with different preoperative brain/csf volume metrics in an attempt to determine whether differences exist among groups as to best initial management as determined by follow-up treatment images and cognitive assessment. As well, these results may ultimately provide a pre-treatment prediction tool for prospectively choosing the optimal therapy for such children. 5) Perform cost analysis for the two surgical procedures (ETV/CPC versus VP shunting) As of October 2016, we aim to determine the cost of performing a VP shunt and the cost of performing an ETV/CPC at the CURE hospital. The study will involve using existing data from within the database, average their care to obtain specific expenditures of both procedures. As such, a retrospective cost analysis of the intended intervention (ETV/CPC v. VP Shunt) between the existing post-infectious hydrocephalus cohort will be performed. B. Background and Significance In sub-saharan Africa post-infectious hydrocephalus (PIH) is a common, treatable cause of childhood brain injury that should be preventable. The magnitude of this problem has previously been unrecognized. We estimate that 100, ,000 infants develop hydrocephalus in sub-saharan Africa each year 1. In contrast to the industrialized countries, our work suggests that most of the cases of hydrocephalus (60%) in Uganda are PIH 2 and that Gram negative coliform bacteria are potentially important pathogens in PIH with seasonal variance. 10, 15 In the developing world, the majority of these children have no opportunity for treatment because pediatric neurosurgical specialty care has not previously been available 1,2,3. These children often suffer brain injury from the infection (which can lead to cerebral palsy, epilepsy, visual impairment, and death), as well as the secondary hydrocephalus 1-5. Therefore, the prevention and improved treatment of PIH provides an important opportunity to save and improve the lives of many thousands of children worldwide; but to do this, we need to better understand the causes and optimal treatment of PIH. We do not yet know the optimal treatment of PIH in Africa. Shunt placement is the traditional treatment for PIH in the industrialized countries. Even though we established the efficacy of an inexpensive shunt system in this setting 3, shunt dependence remains an exceptionally dangerous post-treatment condition in rural sub- Saharan Africa 1-9. We have pioneered a novel treatment (combined endoscopic third ventriculostomy and endoscopic choroid plexus cauterization, ETV/CPC) that avoids shunt-dependence in the majority of patients and has a lower risk of failure than shunting after six months 4, 5, 9, 11. In the case of myelomeningocele infants with hydrocephalus, we recently showed that ETV/CPC was at least as good as shunting in regard to early neurocognitive development 6. We have trained neurosurgeons and equipped centers for the ETV/CPC Version 1.10 Activated November 01 st 2016 Page 2 of 9