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1. In this randomized controlled trial, N-acetyl-L-leucine (NALL) improved neurologic status in Niemann-Pick Disease type C more effectively than a placebo.

2. Patients showed a significant reduction in neurological symptoms after taking NALL.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Niemann-Pick Disease Type C is an inherited lysosomal storage disorder following the autosomal recessive pattern leading to premature death. The current treatment method relies on miglustat, a drug used in lysosomal storage disorders, to delay the progression of neurological symptoms typically produced by this disease. One proposed treatment method is NALL, the L-enantiomer of N-acetyl-DL-leucine. This agent can correct metabolic dysfunction, improve adenosine triphosphate (ATP) production, and cross the blood-brain barrier by uptake through monocarboxylate transporters. After the six-week trial, a multinational phase assessor-blinded 2b clinical trial of children and adults with Niemann-Pick disease showed reduced symptoms with increased quality of life. The patients received either NALL or the placebo two to three times daily, with doses differing depending on age and weight. When patients were receiving the NALL treatment, they had a significant reduction in neurologic signs, and many deteriorated when switched to the placebo. Overall, patients who received NALL had better neurological outcomes than patients receiving the placebo. However, the findings from this trial are limited by the length of follow-up time.

Click here to read this study in the NEJM

In-Depth [randomized controlled trial]: This randomized control trial included 60 participants aged five to 67 years, with half assigned to start with NALL then switch to the placebo (sequence 1), and the other half assigned to start with placebo and move to NALL (sequence 2). To be eligible for the study, participants had to be over the age of 4 and have a Niemann-Pick disease type C diagnosis. They must also have presented with signs and symptoms and cleared any prohibited medications from their system. The mean Scale for the Assessment and Rating of Ataxia (SARA) scores at baseline were 15.88±7.50 for the NALL group and 15.68±7.39 for the placebo group. In the first period, the mean baseline SARA scores were determined to be 14.90±7.49 and 16.87±7.51 for the NALL and placebo groups. After 12 weeks of receiving NALL treatment, the mean change from baseline was -1.97±2.43 points, whereas the mean change for the placebo group was -0.60±2.39 points (least-squares mean difference, -1.28 points; 95% Confidence Interval [CI], -1.91 to -0.65; p<0.001). When individuals switched from taking NALL to the placebo, their neurological symptoms worsened. Regarding adverse events, 79 occurred in the 36 participants receiving NALL, while 75 occurred in the participants in the placebo group. However, all participants continued in the trial despite adverse events. There is no validated biomarker associated with the disease. Thus, no clear endpoint defines clinical improvement, limiting the results. In summary, NALL treatment effectively reduced neurological signs compared to the placebo.

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