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Background: Progressive supranuclear palsy (PSP) is a rare and fatal neurodegenerative disorder for which there are currently no disease-modifying treatments. Recent trials of potential therapies had durations of 12 months, which may be insufficient because of nonrandom missingness due to death. Longer durations, incorporating PSP Rating Scale and survival, can reduce the potential for type II error. Selecting efficacy measures more sensitive to disease modification may facilitate identification of treatment effect., Objective: The objective of this study was to evaluate the simulated phase 3 PSP trial assessing the effect of disease-modifying intervention on a novel combined primary endpoint comprising function (PSP Rating Scale) and survival, the Combined Assessment of Function and Survival (CAFS), and to determine operating characteristics of the CAFS., Methods: To simulate PSP progression in the trial population, we developed models of PSP Rating Scale and survival using data from published clinical studies. These models were used to define operating characteristics of the CAFS for use in a phase 3 trial., Results: The sample size determined (N = 384; 1:1 randomization) would provide >80% power to detect significant treatment effects on the CAFS compared with placebo. The CAFS provides good operating characteristics and increased power to detect moderate treatment effects on the PSP Rating Scale. We propose a trial design allowing potential detection of treatment effects at a preplanned interim analysis after participants complete 12 months of treatment, with assessment of effects of treatment (≤24 months) on survival., Conclusions: Use of the CAFS could provide a comprehensive and robust estimate of the clinical benefit of future therapies. © 2024 UCB. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 UCB. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: This review highlights the recent scientific advances that have enabled rational design of novel clinical trials for pantothenate kinase-associated neurodegeneration (PKAN), a rare autosomal recessive neurogenetic disorder associated with progressive neurodegenerative changes and functional impairment. PKAN is caused by genetic variants in the PANK2 gene that result in dysfunction in pantothenate kinase 2 (PANK2) enzyme activity, with consequent disruption of coenzyme A (CoA) synthesis, and subsequent accumulation of brain iron. The clinical phenotype is varied and may include dystonia, rigidity, bradykinesia, postural instability, spasticity, loss of ambulation and ability to communicate, feeding difficulties, psychiatric issues, and cognitive and visual impairment. There are several symptom-targeted treatments, but these do not provide sustained benefit as the disorder progresses., Objectives: A detailed understanding of the molecular and biochemical pathogenesis of PKAN has opened the door for the design of novel rationally designed therapeutics that target the underlying mechanisms., Methods: Two large double-blind phase 3 clinical trials have been completed for deferiprone (an iron chelation treatment) and fosmetpantotenate (precursor replacement therapy). A pilot open-label trial of pantethine as a potential precursor replacement strategy has also been completed, and a trial of 4-phosphopantetheine has begun enrollment. Several other compounds have been evaluated in pre-clinical studies, and additional clinical trials may be anticipated., Conclusions: Experience with these trials has encouraged a critical evaluation of optimal trial designs, as well as the development of PKAN-specific measures to monitor outcomes. PKAN provides a valuable example for understanding targeted drug development and clinical trial design for rare disorders. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Background: Pantothenate kinase-associated neurodegeneration is a progressive neurological disorder occurring in both childhood and adulthood. The objective of this study was to design and pilot-test a disease-specific clinical rating scale for the assessment of patients with pantothenate kinase-associated neurodegeneration., Methods: In this international cross-sectional study, patients were examined at the referral centers following a standardized protocol. The motor examination was filmed, allowing 3 independent specialists in movement disorders to analyze 28 patients for interrater reliability assessment. The scale included 34 items (maximal score, 135) encompassing 6 subscales for cognition, behavior, disability, parkinsonism, dystonia, and other neurological signs., Results: Forty-seven genetically confirmed patients (30 ± 17 years; range, 6-77 years) were examined with the scale (mean score, 62 ± 21; range, 20-106). Dystonia with prominent cranial involvement and atypical parkinsonian features were present in all patients. Other common signs were cognitive impairment, psychiatric features, and slow and hypometric saccades. Dystonia, parkinsonism, and other neurological features had a moderate to strong correlation with disability. The scale showed good internal consistency for the total scale (Cronbach's α = 0.87). On interrater analysis, weighted kappa values (0.30-0.93) showed substantial or excellent agreement in 85% of the items. The scale also discriminated a subgroup of homozygous c.1583C>T patients with lower scores, supporting construct validity for the scale., Conclusions: The proposed scale seems to be a reliable and valid instrument for the assessment of pediatric and adult patients with pantothenate kinase-associated neurodegeneration. Additional validation studies with a larger sample size will be required to confirm the present results and to complete the scale validation testing. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)