The Current State of Clinical Trials Studying Hydrocephalus: An Analysis of ClinicalTrials.gov

Introduction Hydrocephalus is a significant public health concern estimated to affect 380,000 new individuals annually. In addition, it exhibits an increasingly high financial burden for the healthcare industry. Clinical trials are the gold standard for evaluating preventative and therapeutic strategies to bring potential treatments to the forefront of clinical practice. Methods A study of the ClinicalTrials.gov was conducted in April 2019 to examine all current and previously reported clinical trials studying hydrocephalus. Studies were reviewed to extrapolate information to characterize the current state of research being conducted for hydrocephalus. Results In total, 80 clinical trials met inclusion criteria and were analyzed: 48.8% were observation and 51.2% were interventional. Of those, 55% have been completed while 30.0% are still recruiting, and 15.0% are not yet recruiting. The United States has the most clinical trials (42.0%) and a plurality of trials has a sample size of 0-50 participants. The majority of studies included only adults (53.8%). Of those studies, 54.0% were cohort and the majority were prospective (74.0%). Of the different types of hydrocephalus, normal pressure hydrocephalus and pediatric hydrocephalus have generated the most interest for research comprising a majority of the clinical trial registry. While 44 of the trials are complete, only 20 have published results in peer-reviewed literature highlighting the need for improvement in publishing study results even if the results of the trials are null. Conclusion Most clinical trials to date have pertained to the treatment of normal pressure hydrocephalus and pediatric hydrocephalus. While great advancements have been made for the treatment of hydrocephalus, there remains much room for improvements in therapeutic interventional modalities as well as ensuring the reporting of all undertaken clinical trials.


Introduction
Hydrocephalus is a significant public health concern estimated to affect 380,000 new individuals annually. In addition, it exhibits an increasingly high financial burden for the healthcare industry. Clinical trials are the gold standard for evaluating preventative and therapeutic strategies to bring potential treatments to the forefront of clinical practice.

Methods
A study of the ClinicalTrials.gov was conducted in April 2019 to examine all current and previously reported clinical trials studying hydrocephalus. Studies were reviewed to extrapolate information to characterize the current state of research being conducted for hydrocephalus.

Results
In total, 80 clinical trials met inclusion criteria and were analyzed: 48.8% were observation and 51.2% were interventional. Of those, 55% have been completed while 30.0% are still recruiting, and 15.0% are not yet recruiting. The United States has the most clinical trials (42.0%) and a plurality of trials has a sample size of 0-50 participants. The majority of studies included only adults (53.8%). Of those studies, 54.0% were cohort and the majority were prospective (74.0%). Of the different types of hydrocephalus, normal pressure hydrocephalus and pediatric hydrocephalus have generated the most interest for research comprising a majority of the clinical trial registry. While 44 of the trials are complete, only 20 have published results in peerreviewed literature highlighting the need for improvement in publishing study results even if the results of the trials are null.

Conclusion
Most clinical trials to date have pertained to the treatment of normal pressure hydrocephalus and pediatric hydrocephalus. While great advancements have been made for the treatment of hydrocephalus, there remains much room for improvements in therapeutic interventional modalities as well as ensuring the reporting of all undertaken clinical trials.

Introduction
Hydrocephalus, first described by Hippocrates as early as the fifth century BCE, is an abnormal accumulation of cerebrospinal fluid (CSF) within the ventricles of the brain either due to insufficient CSF reabsorption or CSF overproduction [1]. It is a significant public health concern estimated to affect 380,000 new individuals annually [2]. As a result, CSF diversion procedures such as ventriculoperitoneal shunting (VPS) and endoscopic third ventriculostomy (ETV) accrue a total cost of $2 billion nationwide [3]. One study suggests that treating hydrocephalus in the elderly, has the potential to lower five-year Medicare expenditures by approximately $184.3 million in the United States [4].
Hydrocephalus can develop for a variety of reasons. Obstructive, or noncommunicating, hydrocephalus occurs when CSF does not flow properly between ventricles or out of the ventricles due to an obstruction. This obstruction can be the result of congenital malformations or ventricular narrowing due to other pathologies such as cancer or trauma [5]. Nonobstructive, or communicating, hydrocephalus occurs when CSF flows out of the ventricles and into the spinal canal, but the tissue surrounding the brain and spinal cord is unable to reabsorb it adequately enough to prevent excess accumulation of the fluid [6]. Major types of hydrocephalus include congenital hydrocephalus, acquired hydrocephalus, and normal pressure hydrocephalus (NPH) [7].
In 2012, researchers from across the globe convened at the symposium, "Opportunities in Hydrocephalus Research: Pathways to Better Outcomes," ultimately recommending four areas of hydrocephalus research to most efficiently improve patient care [8]. These include: discovering genetic and pathophysiologic causes of the diagnosis, developing improved biomarkers for diagnosis, discovering new bioengineering and surgical advances for treatment, and also enhancing neuropsychological and quality of life initiatives. These comprehensive recommendations accentuate most of the ongoing research of hydrocephalus and have the potential to refine diagnoses, improve clinical outcomes, and reduce healthcare expenditure [9,10].
Clinical trials remain the gold standard for evaluating novel diagnostic, preventative, and therapeutic strategies before it reaches the forefront of clinical practice [11]. Therefore, the present study examined a major worldwide registry, ClinicalTrials.gov, for all trials involving hydrocephalus. This analysis identified and characterized the current state of clinical trials focused on hydrocephalus. This analysis attempts to understand what steps have already been taken, and what areas of research remain to be explored in order to continue improving the management of hydrocephalus.

Materials And Methods
ClinicalTrials.gov is a public trial registry provided by the United States National Library of Medicine and the United States Food and Drug Administration that contains over 301,795 research studies conducted in 208 countries and all 50 states. The authors conducted a search on April 8, 2019 to examine all current clinical trials studying hydrocephalus.
The trials were obtained from the ClinicalTrials.gov website using the advanced search function for the search term "hydrocephalus" under "condition." Of those identified by this search criteria, clinical trials were excluded from the analysis if they were suspended, terminated, withdrawn, or had unknown status. For the trials that met inclusion criteria, the following information was used in the final analysis: registered identifier number, official title, recruitment status, study type, primary purpose, year of initiation, intervention, country, study type, sample size, year of initiation, year of completion, time perspective, primary purpose, intervention, participant age, country of origin, and primary outcome. In addition, an effort was made to retrieve the results of completed trials for further analysis. For all completed trials, an online Medline database search for published results was conducted on May 2, 2019, using each clinical trial's registered identifier number. Descriptive statistics were used to analyze the variables.

Results
In total, 123 trials were identified. Of these identified, 43 trials were excluded from the analysis due to suspended, terminated, withdrawn, or unknown status. The remaining 80 studies were included in this study. A complete list of included studies can be found in Appendix 1.
Among the 80 eligible trials, 39 (48.8%) were observational and 41 were interventional (51.2%). The trials took place from 1992 to 2019, with 43 (53.8%) studies beginning after 2013. Therefore, there appears to be an increasing trend of clinical trials since 1992 ( Figure 1). The majority of trials, 44 (55.0%), have been completed, 24 (30.0%) are still recruiting, and the remaining 12 (15.0%) are not yet recruiting. Of the 44 completed trials, the average time to completion was 50 months.

FIGURE 1: Number of Clinical Trials Beginning Stratified by Year
The United States of America has the most clinical trials, 45 (42.0%), with the rest originating in predominantly westernized or European countries ( Table 1). Enrollment in these trials included a wide range: 30 (37.5%) trials had a sample size of 0-50, 21    Of all clinical trials, 25 (31.3%) are studying pediatric hydrocephalus. Of these studies, six are studying improving shunt function, six focus on improving current imaging modalities and advancing novel imaging techniques for diagnosis, five compare the effects of ETV to VPS for treatment, two provide data for registries to support hypothesis generation and study design development for clinical trials, two are studying cognitive and development outcomes, two are testing potential alternative anesthetics for obtaining MRI in this challenging population, one is studying CSF biomarkers to assess the severity of disease and response to treatment, and one is studying head circumference of hydrocephalic Ehlers-Danlos patients who develop dysautonomia later in life.
Of all clinical trials, four (5.0%) are studying post-hemorrhagic hydrocephalus. These trials are examining whether early use of lumbar puncture leads to less shunt surgery, assessing the optimal conditions for EVD cessation, determining the role of proteomics in cerebral vasospasm following SAH, and evaluating hydrocephalus as a predictor of functional disability and quality of life.
The remaining 23 (28.8%) trials study all forms of hydrocephalus. Ten trials are examining the effectiveness of VPS and improving current techniques for treatment, five are focused on improving current imaging techniques for diagnosis, two are studying alternative methods to measure intracranial pressure, two are investigating CSF flow dynamics, and one study each is focused on patient education, prevention, and improving cognitive function.
To date, only four of the 44 completed trials have posted a statistical analysis on ClincalTrials.gov. Efforts were made to obtain the results of the other 40 trials and a search of the Medline database demonstrated that 20 of the studies had published results in peerreviewed literature.

Discussion
Advancements in the diagnosis and treatment of hydrocephalus have rapidly improved over the last century [12]. From the first attempt to create a permanent ventriculo-subarachnoidsubgaleal CSF diversion by Mikulicz in 1893, to the first functional valve implantation devised by Nulsen and Spitz in 1949, the basis of treatment for hydrocephalus has largely remained the same [13,14]. In spite of several innovations and technical modifications, shunts, which have evolved and matured to become the standard of care for all types of hydrocephalus, are not without complications [15]. Further, since shunts remain a source of lifetime concern for the patient, parents, and family, the desire for shunt freedom has led to a resurgence of ETV techniques and other endeavors that aim to change the current standard [16]. Of the different types of hydrocephalus, NPH and pediatric hydrocephalus have generated the most research interest and comprise a majority of the current clinical trial registry.
There has been a sharp increase in the number of trials being conducted since 2013, which holds promise for future trends in hydrocephalus research and clinical management. This study found that the clinical trials were almost evenly split into interventional and observational studies. This demonstrates that while great advancements have been made for the treatment of hydrocephalus, there remains much room for improvements in current interventions due to the low number of interventional clinical trials. While more than half of the trials are reported as complete, only four have results available on ClinicalTrials.gov and only 20 of these have published their results in peer-reviewed literature. Therefore, there should be an encouragement for the neurosurgical community to publish results of all clinical trials, even if the findings are null or negative.
NPH is the most common form of hydrocephalus in adults, and it is estimated that over 700,000 people in the United States have NPH. It is characterized by dilated cerebral ventricles and it presents with a clinical trial involving impaired gait, cognition, and urinary control [17]. It is estimated that over 700,000 people in the United States have NPH [18]. Pediatric hydrocephalus has a prevalence of approximately 6 in 10,000 live births, with a neonatal mortality rate of 13% before hospital discharge [19]. According to nationally representative data from 2008, pediatric hydrocephalus accounts for 38,200 to 39,900 hospital admissions, 391,000 to 433,000 hospital days, and $1.4 to $2.0 billion in total hospital charges annually in the United States [20]. Because NPH and pediatric hydrocephalus are both prevalent diseases with a high cost of care, the completion and publication of the ongoing research will help clarify causes, hasten diagnosis, improve treatment, and increase the quality of life.
NPH is difficult to diagnose because of its insidious onset and nonspecific symptomatology. However, it is one of only a few reversible causes of dementia, making early diagnosis critical. The published results of clinical trials studying NPH demonstrate that much remains to be learned from this complex pathology and that NPH is a multi-etiological clinical entity, possibly overlapping pathophysiologically with cerebrovascular disease and Alzheimer's disease [21]. A high level of clinical suspicion is necessary to piece together the clinical picture and ultimately make the diagnosis. MRI is a useful modality because it allows for MR phase imaging of CSF flow which provides pathophysiological information of potential clinical importance [22]. Additionally, new neuropsychological tests have been developed to assess cognitive impairment, which can assist in early diagnosis and improve outcomes [23].
Current evidence-based guidelines and best practices for hydrocephalus treatment suggest that shunts are superior to ETV in infants [24]. Regarding imaging, the degree of fetal ventriculomegaly based on the ultrasound and MRI measurements had a predictive value for successful live birth while ultrasound-guided shunt insertion was unable to consistently place catheters into the frontal horn of the ventricles. However, laparoscopically guided distal VPS placement provides definite patient benefit by allowing shunt placement under direct vision, all while allowing for reduced trauma to the abdominal wall and avoiding intra-abdominal adhesions [25][26][27].
A majority of the clinical trials of hydrocephalus included in the database have begun over the last five years. Since the average time to completion of the completed trials was 50 months, we can expect a host of new results to become available over the next few years. Practitioners should anticipate the publication of these results and look for practice-changing recommendations.

Limitations
First, while ClinicalTrials.gov accounts for more than 80% of all studies in the World Health Organization's International Clinical Trials Registry platform, it does not include all clinical trials [28]. Second, this study only analyzes the characteristics of the registered trials but does not assess the quality of the research being conducted. As more data become available, the quality of the research will have to be further scrutinized.

Conclusions
The current study provides an overview of registered trials on ClinicalTrials.

Disclosures
Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.