Substantial challenges in study design and methodology exist during clinical trial development to examine treatment response in patients with a rare disease, especially those with predominant central nervous system involvement and heterogeneity in clinical manifestations and natural history. Here we discuss crucial decisions which may significantly impact success of the study, including patient selection and recruitment, identification and selection of endpoints, determination of the study duration, consideration of control groups including natural history controls, and selection of appropriate statistical analyses. We review strategies for the successful development of a clinical trial to evaluate treatment of a rare disease with a focus on inborn errors of metabolism (IEMs) that present with movement disorders. The strategies presented using pantothenate kinase-associated neurodegeneration (PKAN) as the rare disease example can be applied to other rare diseases, particularly IEMs with movement disorders (e.g., other neurodegeneration with brain iron accumulation disorders, lysosomal storage disorders). The significant challenges associated with designing a clinical trial in rare disease can sometimes be successfully met through strategic engagement with experts in the rare disease, seeking regulatory and biostatistical guidance, and early involvement of patients and families. In addition to these strategies, we discuss the urgent need for a paradigm shift within the regulatory processes to help accelerate medical product development and bring new innovations and advances to patients with rare neurodegenerative diseases who need them earlier in disease progression and prior to clinical manifestations.

Thrombosis is the most common and a life-threatening complication in patients with Paroxysmal Nocturnal Hemoglobinuria. One-third of patients with PNH experience at least one thromboembolic event during the course of the disease, with thrombosis being the most common cause of death in these patients. The mechanism of thrombosis in PNH is complex and continues to be of great research interest. Since the introduction of C5 complement inhibitors in the treatment of PNH, the incidence of thromboembolic events has decreased substantially. We retrospectively analyzed data concerning the thrombotic episodes of 41 patients with PNH from 14 different national hematology centers in Greece. Sixteen patients (39%) experienced at least one episode of thrombosis, including, seven (43.8%) at diagnosis, seven (43.8%) during the course of the disease and two (12.5%) patients prior to PNH diagnosis. Nearly half of these individuals (n=7, 43.8%) had multiple episodes of thrombosis during the course of their disease. The most common sites of thrombosis were intra-abdominal veins. Three out of 26 patients developed thrombosis while on eculizumab. In none of the 16 patients, the thrombotic event was fatal. Our findings, despite the small number of patients, confirmed that thrombosis continues to be a significant complication of PNH affecting more than one third of the patients.

Background and Objectives: Rare diseases (RDs) are life-threatening or chronically impairing conditions that affect about 6% of the world\'s population. RDs are often called \'orphan\' diseases, since people suffering from them attract little support from national health systems. Aim: The aim of this study is to describe the clinical characteristics of, and the available laboratory examinations for, patients who were hospitalized in a tertiary referral center and finally received a diagnosis associated with a Rare Neurological Disease (RND). Materials and Methods: Patients that were hospitalized in our clinic from 1 January 2014 to 31 March 2022 and were finally diagnosed with an RND were consecutively included. The RND classification was performed according to the ORPHAcode system. Results: A total of 342 out of 11.850 (2.9%) adult patients admitted to our department during this period received a diagnosis associated with an RND. The most common diagnosis (N = 80, 23%) involved an RND presenting with dementia, followed by a motor neuron disease spectrum disorder (N = 64, 18.7%). Family history indicative of an RND was present in only 21 patients (6.1%). Fifty-five (16%) people had previously been misdiagnosed with another neurological condition. The mean time delay between disease onset and diagnosis was 4.24 ± 0.41 years. Conclusions: Our data indicate that a broad spectrum of RNDs may reach a tertiary Neurological Center after a significant delay. Moreover, our data underline the need for a network of reference centers, both at a national and international level, expected to support research on the diagnosis and treatment of RND.

To date, there is no approved local therapeutic agent for the treatment of epistaxis due to hereditary hemorrhagic telangiectasia (HHT). Several case reports suggest the topical use of timolol. This monocentric, prospective, randomized, placebo-controlled, double-blinded, cross-over study investigated whether the effectiveness of the standard treatment with a pulsed diode laser can be increased by also using timolol nasal spray. The primary outcome was severity of epistaxis after three months, while the main secondary outcome was severity of epistaxis and subjective satisfaction after one month. Twenty patients were allocated and treated, of which 18 patients completed both 3-month treatment sequences. Timolol was well tolerated by all patients. Epistaxis Severity Score after three months, the primary outcome measure, showed a beneficial, but statistically nonsignificant (p = 0.084), effect of additional timolol application. Epistaxis Severity Score (p = 0.010) and patients\' satisfaction with their nosebleeds after one month (p = 0.050) showed statistically significant benefits. This placebo-controlled, randomized trial provides some evidence that timolol nasal spray positively impacts epistaxis severity and subjective satisfaction in HHT patients when additively applied to standard laser therapy after one month. However, the effect of timolol was observed to diminish over time. Trials with larger sample sizes are warranted to confirm these findings.

BACKGROUND: Data on institutional structures of sarcoma care in Germany are scarce. The utilization of an interdisciplinary tumor board (IDTB) is an essential part of modern cancer care. We investigated to which extent and when IDTB are used in sarcoma care. We hypothesized that IDTB before treatment initiation were used more often at certified cancer centers and at high-volume centers and that IDTB utilization increased over time.
METHODS: From 2017 to 2020 we conducted a prospective cohort study, undertaking major efforts to include the whole spectrum of sarcoma treatment facilities. To analyze potential predictors of IDTB utilization, we calculated multivariable logistic regressions.
RESULTS: Patients and survivors (n = 1,309) from 39 study centers (22 tertiary referral hospitals, 9 other hospitals, and 8 office-based practices) participated; 88.3% of the patients were discussed at some stage of their disease in an IDTB (56.1% before treatment, 78% after therapy, and 85.9% in metastatic disease). Hypotheses were confirmed regarding the utilization of IDTB in certified cancer centers (vs. all others: OR = 5.39; 95% CI 3.28-8.85) and the time of diagnosis (2018/2019 vs. until 2013: OR = 4.95; 95% CI 2.67-9.21).
CONCLUSIONS: Our study adds to the evidence regarding the institutional structures of sarcoma care in Germany. Utilization of a tumor board before therapy seems to be in an implementation process that is making progress but is far from complete. Certification is a possible tool to accelerate this development.

Geographically dispersed patients, inconsistent treatment tracking, and limited infrastructure slow research for many orphan diseases. We assess the feasibility of a patient-powered study design to overcome these challenges for Castleman disease, a rare hematologic disorder. Here, we report initial results from the ACCELERATE natural history registry. ACCELERATE includes a traditional physician-reported arm and a patient-powered arm, which enables patients to directly contribute medical data and biospecimens. This study design enables successful enrollment, with the 5-year minimum enrollment goal being met in 2 years. A median of 683 clinical, laboratory, and imaging data elements are captured per patient in the patient-powered arm compared with 37 in the physician-reported arm. These data reveal subgrouping characteristics, identify off-label treatments, support treatment guidelines, and are used in 17 clinical and translational studies. This feasibility study demonstrates that the direct-to-patient design is effective for collecting natural history data and biospecimens, tracking therapies, and providing critical research infrastructure.

Wolfram syndrome (WS) is a rare, progressive disorder characterized by childhood-onset diabetes mellitus, optic nerve atrophy, hearing loss, diabetes insipidus, and neurodegeneration. Currently, there is no effective treatment for WS, and patients typically die between 30 and 40 years of age. WS is primarily caused by autosomal recessive mutations in the Wolfram syndrome 1 (WFS1) gene (OMIM 222300), which encodes for wolframin (WFS1). This disorder is therefore a valuable monogenic model for prevalent diseases, particularly diabetes mellitus and neurodegeneration. Whereas reduced survival and secretion are known cellular impairments causing WS, the underlying molecular pathways and the physiological function of WFS1 remain incompletely described. Here, we characterize WFS1 as a regulator of intracellular calcium homeostasis, review our current understanding of the disease mechanism of WS, and discuss candidate treatment approaches. These insights will facilitate identification of new therapeutic strategies not only for WS but also for diabetes mellitus and neurodegeneration.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder which primarily affects the gastrointestinal and nervous systems. This disease is caused by mutations in the nuclear TYMP gene, which encodes for thymidine phosphorylase, an enzyme required for the normal metabolism of deoxynucleosides, thymidine, and deoxyuridine. The subsequent elevated systemic concentrations of deoxynucleosides lead to increased intracellular concentrations of their corresponding triphosphates, and ultimately mitochondrial failure due to progressive accumulation of mitochondrial DNA (mtDNA) defects and mtDNA depletion. Currently, there are no treatments for MNGIE where effectiveness has been evidenced in clinical trials. This Phase 2, multi-centre, multiple dose, open label trial without a control will investigate the application of erythrocyte-encapsulated thymidine phosphorylase (EE-TP) as an enzyme replacement therapy for MNGIE. Three EE-TP dose levels are planned with patients receiving the dose level that achieves metabolic correction. The study duration is 31 months, comprising 28 days of screening, 90 days of run-in, 24 months of treatment and 90 days of post-dose follow-up. The primary objectives are to determine the safety, tolerability, pharmacodynamics, and efficacy of multiple doses of EE-TP. The secondary objectives are to assess EE-TP immunogenicity after multiple dose administrations and changes in clinical assessments, and the pharmacodynamics effect of EE-TP on clinical assessments.

Galactosialidosis (GS; OMIM #256540) is a rare multisystemic inborn glycoprotein storage disease caused by biallelic mutations in the cathepsin A gene resulting in combined deficiency of the lysosomal enzymes β-galactosidase and α-neuraminidase. The precise understanding of the natural course of the disease is limited. Development of enzyme replacement therapy is at the preclinical stage. The purpose of this research project was to quantitatively characterize the natural history of the condition. Quantitative analysis of all published cases in the literature with sufficient data (N = 142 patients) was carried out. Main outcome variables were survival, diagnostic delay, description of symptoms, biomarker-phenotype associations, and radiological findings. STROBE criteria were respected. Median survival age of the cohort was 48 years. Median age of onset was 4.25 years with interquartile range (IQR) 1 to 16 years. Median age at diagnosis was 19 (IQR: 8.92-29) years, with median diagnostic delay of 8 (IQR: 4-12) years. Patients with residual β-galactosidase activity of more than 8.6% (leukocytes) survived significantly longer than patients with lower enzyme activities.

Studies of interventions to prevent the many neurological complications of sickle cell disease must take into account multiple outcomes of variable severity, with limited sample size. The goals of the studies presented were to use investigator preferences across outcomes to determine an attitude-based weighting of relevant clinical outcomes and to establish a valid composite outcome for a clinical trial.
In Study 1, investigators were surveyed about their practice regarding hydroxyurea therapy and opinions about outcomes for the \"Hydroxyurea to Prevent the Central Nervous System Complications of Sickle Cell Disease Trial\" (HU Prevent), and their minimally acceptable relative risk reduction for the two outcome components, motor and neurocognitive deficits. In Study 2, HU Prevent investigators provided overall weights for these two components. In Study 3, they provided more granular rankings, ratings, and maximum number acceptable to harm. A weighted composite outcome, the Stroke Consequences Risk Score, was constructed that incorporates the major neurologic complications of sickle cell disease. The Stroke Consequences Risk Score represents the 3-year risk of suffering the adverse consequences of stroke. In Study 4, the results of the Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP2) and Silent Infarct Transfusion Trials were reanalyzed in light of the composite outcome.
In total, 22 to 27 investigators participated per study. In Study 1, across three samplings between 2009 and 2015, the average minimally acceptable relative risk reduction ranged from 0.36 to 0.50, at or below the target effect size of 0.50. In 2015, 21 (91%) reported that a placebo-controlled trial is reasonable; 23 (100%), that it is ethical; and 22 (96%), that they would change their practice, if the results of the trial were positive. In Studies 2 and 3, the weight elicited for a cognitive decline (of 10 IQ points) from the overall assessment was 0.67 (and for motor deficit, the complementary 0.33); from ranking, 0.6; from rating, 0.58; and from maximal number acceptable to harm, 0.5. Using data from two major clinical trials, Study 4 demonstrated the same conclusions as the original trials using the Stroke Consequences Risk Score, with smaller p-values for both reanalyses. An assessment of acceptability was performed as well.
This set of studies provides the rationale, justification, and validation for the use of a weighted composite outcome and confirms the need for the phase III HU Prevent study. Surveys of investigators in multi-center studies can provide the basis of clinically meaningful outcomes that foster the translation of study results into practice while increasing the efficiency of a study.