Randomized and non-randomized designs for causal inference with longitudinal data in rare disorders

In the United States, approximately 7000 rare diseases affect 30 million patients, and only 10% of these diseases have existing therapies. Sound study design and causal inference methods are essential to demonstrate the therapeutic efficacy, safety, and effectiveness of new therapies. In the rare diseases setting, several factors challenge the use of typical parallel control designs: the small patient population size, genotypic and phenotypic diversity, and the complexity and incomplete understanding of the disorder’s progression. Repeated measures, when spaced appropriately relative to disease progression and exploited in design and analysis, can increase study power and reduce variability in treatment effect estimation. This paper reviews these longitudinal designs and draws the parallel between some new and existing randomized studies in rare diseases and their less well-known controlled observational study designs. We show that self-controlled randomized crossover and N-of-1 designs have similar considerations as the observational case series and case-crossover designs. Also, randomized sequential designs have similar considerations to longitudinal cohort studies using sequential matching or weighting to control confounding. We discuss design and analysis considerations for valid causal inference and illustrate them with examples of analyses in multiple rare disorders, including urea cycle disorder and cystic fibrosis.

OTHR-08. Efficacy of anti-epileptic drug prophylaxis on seizure prevention in patients with brain metastases: A systematic review and meta-analysis

Introduction Seizures can occur in patients with brain metastasis and are often debilitating, leading to morbidity, mortality, and economic burden. Implementation of anti-epileptic drugs (AEDs) prophylaxis remains controversial, and provider dependent as current Level III guidelines recommend against their use. This systematic review gathers the current evidence on the effectiveness of AED prophylaxis on preventing new-onset seizures in patients with BM. Associated adverse effects of AED usage in this population are also reported. Methods Using PRISMA guidelines, a pertinent search was conducted on Embase, PubMed, and Web of Science to identify journal articles that reported AED prophylaxis as a variable to modify seizure frequency in adult patients with BM. Data of interest included AED agent, new-onset seizure frequency, and safety profile. A meta-analysis was performed to calculate odds ratio using Der-Simonian and Laird methods to compare AED group with control for new seizures. Heterogeneity was determined by Cochran Q test and I2. Results Our search returned 175 publications of which 5 retrospective cohort studies met inclusion criteria. A total of 1,292 patients (283 receiving AED prophylaxis, and 1,009 in control group) were included across the studies. AEDs used were phenobarbital, levetiracetam, phenytoin, and valproate. Meta-analysis showed no difference in seizure frequency between the AED and the control group (OR = 0.98; 95%-CI: 0.56–1.72). Heterogeneity: I2 = 7%. Adverse events were not reported in the publications. Conclusion Our meta-analysis suggests that there is no improvement in frequency of new seizures with AED prophylaxis in BM patients, supporting current guidelines. However, the evidence is based on a small patient population and retrospective studies. Additional studies are needed to determine efficacy of prophylaxis with newer AEDs and establish guidelines to target therapies for improving morbidity, mortality, and quality of life in patients with BM.

Gamma Knife Radiosurgery for Cavernous Malformations of Basal Ganglia and Thalamus: A Retrospective Study of 53 Patients

<b><i>Introduction:</i></b> Gamma Knife radiosurgery (GKRS) has been used to treat cavernous malformations (CMs) located in basal ganglia and thalamus. However, previous reports are limited by small patient population. <b><i>Methods:</i></b> We retrospectively reviewed the clinical and radiological data of 53 patients with CMs of basal ganglia and thalamus who underwent GKRS at West China Hospital between May 2009 and July 2018. All patients suffered at least once bleeding before GKRS. The mean volume of these lesions was 1.77 cm³, and the mean marginal dose was 13.2 Gy. After treatment, patients were followed to determine the change in symptom and hemorrhage event. <b><i>Results:</i></b> The mean follow-up period was 52.1 months (6.2–104.3 months). The calculated annual hemorrhage rate (AHR) was 48.5% prior to GKRS and 3.0% after treatment (<i>p</i> &#x3c; 0.001). The Kaplan-Meier analysis revealed that 2-, 3-, and 5-year hemorrhage-free survival were 88, 80.9, and 80.9%, respectively. Preexisting symptoms were resolved in 11 patients, improved in 14, and stable in 5. Only 2 patients (3.8%) developed new neurological deficit. <b><i>Conclusion:</i></b> Our study suggests that AHR after GKRS was comparable to the recorded AHR of natural history (3.1–4.1%) in previous studies. GKRS is a safe and effective treatment modality for CMs of basal ganglia and thalamus. Considering the relative insufficient understanding of natural history of CMs, future study warrants longer follow-up.

An Alternative Pipeline for Glioblastoma Therapeutics: A Systematic Review of Drug Repurposing in Glioblastoma

The treatment of glioblastoma (GBM) remains a significant challenge, with outcome for most pa-tients remaining poor. Although novel therapies have been developed, several obstacles restrict the incentive of drug developers to continue these efforts including the exorbitant cost, high failure rate and relatively small patient population. Repositioning drugs that have well-characterized mechanistic and safety profiles is an attractive alternative for drug development in GBM. In ad-dition, the relative ease with which repurposed agents can be transitioned to the clinic further supports their potential for examination in patients. Here, a systematic analysis of the literature and clinical trials provides a comprehensive review of primary articles and unpublished trials that use repurposed drugs for the treatment of GBM. The findings demonstrate that numerous drug classes that have a range of initial indications have efficacy against preclinical GBM models and that certain agents have shown significant potential for clinical benefit. With examination in randomized, placebo-controlled trials and the targeting of particular GBM subgroups, it is pos-sible that repurposing can be a cost-effective approach to identify agents for use in multimodal anti-GBM strategies.

Epidemiology of Tumor-Induced Osteomalacia in Denmark

Tumor-induced osteomalacia (TIO) is a rare, acquired condition of phosphate wasting due to phosphaturic mesenchymal tumors. Because the incidence and prevalence of TIO is unknown, we conducted an observational cohort study using national Danish health registers for the period 2008 to 2018 to obtain such information. The study also aimed to describe the demographics of the TIO population and the prognosis. The operational definition was based on hypophosphatemia or adult osteomalacia diagnoses, combined with prescriptions used in the initial management and procedures consistent with advanced imaging used for locating tumors. The incidence of TIO in Denmark was found to be below 0.13 per 100,000 person years for the total population of the country and 0.10 per 100,000 in adult-onset disease. The prevalence of TIO was estimated to be no more than 0.70 per 100,000 persons for the total population and 0.43 per 100,000 in adults. In 2018, there were a maximum of nine new cases of TIO in Danish adults. Mortality was low but few patients fulfilled the protocol cure criterion during the observation period. TIO has no ICD-10 code and limitations to the study include lack of information on serum biochemistry and on the use of phosphate supplements. Strengths include the use of long-term longitudinal, national hospital and prescription data from a country with universal healthcare. Given the very small patient population with TIO and the known delay to diagnosis and cure, management of patients with suspected TIO should be centralized.

Understanding Home Hemodialysis Patient Attrition: A Cohort Study

Background: Home hemodialysis (HHD) offers a flexible, patient-centered modality for patients with kidney failure. Growth in HHD is achieved by increasing the number of patients starting HHD and reducing attrition with strategies to prevent the modifiable reasons for loss. Objective: Our primary objective was to describe a Canadian HHD population in terms of technique failure and time to exit from HHD in order to understand reasons for exit. Our secondary objectives include the following: (1) determining reasons for training failure, (2) reasons for early exit from HHD, and (3) timing of program exit. Design: A retrospective cohort study of incident adult HHD patients between January 1, 2013—June 30, 2020. Setting: Alberta Kidney Care South, AKC-S HHD program. Participants: Patients who started training for HHD in AKC-S. Methods: A retrospective, cohort study of incident adult HHD patients with primary outcome time on home hemodialysis, secondary outcomes include reason for train failure, time to and reasons for technique failure. Cox-proportional hazard model to determine associations between patient characteristics and technique failure. The cumulative probability of technique failure over time was reported using a competing risks model. Results: A total of 167 patients entered HHD. Training failure occurred in 20 (12%), at 3.1 [2.0, 5.5] weeks; these patients were older ( P < .001) and had 2 or more comorbidities ( P < .001). Reasons for HHD exit after training included transplant (35; 21%), death (8; 4.8%), and technique failure (24; 14.4%). Overall, the median time to HHD exit, was 23 months [11, 41] and the median time of technique failure was 17 months [8.9, 36]. Reasons for technique failure included: psychosocial reasons (37%) at a median time 8.9 months [7.7, 13], safety (12.5%) at 19 months [19, 36], and medical (37.5%) at 26 months [11, 50]. Limitations: Small patient population with quality of data limited by the electronic-based medical record and non-standardized definitions of reasons for exit. Conclusions: Training failure is a particularly important source of patient loss. Reasons for exit differ according to duration on HHD. Early interventions aimed at reducing train failure and increasing psychosocial supports may help program growth.

Initial investigation of free-breathing 3D whole-heart stress myocardial perfusion MRI

Objective: Myocardial first-pass perfusion imaging with MRI is well-established clinically. However, it is potentially weakened by limited myocardial coverage compared to nuclear medicine. Clinical evaluations of whole-heart MRI perfusion by 3D methods, while promising, have to date had the limit of breathhold requirements at stress. This work aims to develop a new free-breathing 3D myocardial perfusion method, and to test its performance in a small patient population. Methods: This work required tolerance to respiratory motion for stress investigations, and therefore employed a “stack-of-stars” hybrid Cartesian-radial MRI acquisition method. The MRI sequence was highly optimised for rapid acquisition and combined with a compressed sensing reconstruction. Stress and rest datasets were acquired in four healthy volunteers, and in six patients with coronary artery disease (CAD), which were compared against clinical reference information.Results: This free-breathing method produced datasets that appeared consistent with clinical reference data in detecting moderate-to-strong induced perfusion abnormalities. However, the majority of the mild defects identified clinically were not detected by the method, potentially due to the presence of transient myocardial artefacts present in the images. Discussion: The feasibility of detecting CAD using this 3D first-pass perfusion sequence during free-breathing is demonstrated. Good agreement on typical moderate-to-strong CAD cases is promising, however, questions still remain on the sensitivity of the technique to milder cases.

DIPG-25. KETOGENIC DIET IN DIFFUSE INTRINSIC PONTINE GLIOMA IN CHILDREN: A RETROSPECTIVE STUDY INVESTIGATING THE FEASIBILITY

PURPOSE Diffuse Intrinsic Pontine Glioma (DIPG) is one of the most devastating diseases amongst children with cancer, thus novel strategies are urgently needed. We aimed to retrospectively evaluate the feasibility of the carbohydrate restricted ketogenic diet (KD) in DIPG patients. METHODS Searches of MEDLINE and Embase identified four publications meeting the inclusion criteria (diagnosis of DIPG and exposition to a KD ≥ 3 months). One additional case was identified by contact with experts. The minimal feasibility criteria were defined as the ability to use the KD for ≥ 3 months. Individual patient data were extracted from the publications or obtained from investigators. RESULTS Five patients (males, n=3; median age 4.4 years; range, 2.5–17 years) met the inclusion criteria (one patient – identified and not included - was on KD &lt; 3 months due to disease progression). Further feasibility analyses showed a duration of the KD of ≥ 3 months and less than 7 months (n=2), &gt; 7 months and less than 1 year (n= 2), and two years (n=1), respectively. CONCLUSION These results – based on a small patient population – suggest that the KD appears to be a feasible treatment option for children with DIPG. The potential duration of the KD is limited by the aggressive clinical behavior of DIPG. The safety analysis is currently being retrospectively assessed. These data should encourage further studies on a larger scale; ideally assessing the impact of the KD in DIPG patients in a randomized controlled trial.

MODL-13. GENETICALLY ENGINEERED PIG MODEL OF RHABDOID TUMOR PREDISPOSITION SYNDROME-1

Atypical teratoid/rhabdoid tumor (AT/RT) is the most common malignant CNS tumor of children below 6 months of age. The majority of AT/RT demonstrate genomic alterations in the SMARCB1 gene. There are two major hurdles in the development of safe and effective treatments for AT/RT: first, the mouse models do not fully recapitulate the disease seen in patients and their predictivity of clinical efficacy is still unproven. Second, due to a small patient population, the ability to recruit enough patients for clinical trials is challenging. Genetic studies have demonstrated that germline deletion of SMARCB1 exons 4 and 5 predisposes to AT/RT at an early age. Comparison of human, swine, and mouse SMARCB1 genes show similarities in gene and protein structure, with 100% amino acid identity between swine and human SMARCB1 isoforms. Thus, we hypothesized that germline deletion of exons 4 and 5 will predispose heterozygote swine to AT/RT development. SMARCB1+/- founder pigs are obtained using a CRISPR/Cas9 mediated gene-editing of conventional crossbred swine embryos, followed by embryo transfer into female swine surrogates. They are evaluated for clinical criteria used to diagnose AT/RT and by MRI at 6, 12, and 24 months of age, followed by histopathology and molecular analysis of the tumors as they are detected. Generating a large animal model of AT/RT would represent a breakthrough in the field from a genomic, pathophysiologic, pre-clinical and therapeutic perspective.

Personalized Treatment Response Assessment for Rare Childhood Tumors Using Microcalorimetry–Exemplified by Use of Carbonic Anhydrase IX and Aquaporin 1 Inhibitors

We present a novel approach to a personalized therapeutic concept for solid tumors. We illustrate this on a rare childhood tumor for which only a generalized treatment concept exists using carbonic anhydrase IX and aquaporin 1 inhibitors. The use of microcalorimetry as a refined in vitro method for evaluation of drug susceptibility in organotypic slice culture has not previously been established. Rapid microcalorimetric drug response assessment can refine a general treatment concept when it is applied in cases in which tumors do not respond to conventional chemo-radiation treatment. For solid tumors, which do not respond to classical treatment, and especially for rare tumors without an established protocol rapid microcalorimetric drug response testing presents an elegant novel approach to test alternative therapeutic approaches. While improved treatment concepts have led to improved outcome over the past decades, the prognosis of high risk disease is still poor and rethinking of clinical trial design is necessary. A small patient population combined with the necessity to assess experimental therapies for rare solid tumors rather at the time of diagnosis than in relapsed or refractory patients provides great challenges. The possibility to rapidly compare established protocols with innovative therapeutics presents an elegant novel approach to refine and personalize treatment.