Primary efficacy endpoint
Speech Disturbance, ataxia
ADVERSE EVENTS, EVENTS, DISEASE
The original SARA scale is an eight-item clinical rating scale (range 0–40, where 0 is the best neurological status and 40 is the worst). It is a reliable and valid clinical scale with a high internal consistency that measures the severity of symptoms and ataxia and increases with disease stage [The original unmodified SARA was selected as the primary endpoint based on advice from EU National Regulatory Authorities (including Germany, Portugal, Spain, and the Netherlands) and the UK Medicines and Healthcare product Regulatory Authority. In the USA, the primary endpoint is the modified SARA (mSARA). This modification was based on the explicit advice of the US Food and Drug Administration, which requested the instrument be modified to:Include the domains that are the most clinically meaningful towards understanding the functional aspects of ataxia/symptoms in NPC patientsRemove domains where there is no/little movement and which may impact the interpretation and power of the tool (i.e., improve the reliability and sensitivity of the instrument)Accordingly, the mSARA was developed as a six-item clinical rating scale consisting of the original Gait, Speech Disturbance, Finger Chase, Nose-Finger test, Fast Alternating Hand Movement, and Heel-shin slide domains. It ranges from a score of 0 to 30, where 0 is the best neurological status and 30 is the worst.The SARA scale will be the basis for the primary efficacy estimand. The mSARA scale will be considered as a supplementary estimand. Withdrawal from study medication due to adverse events and the taking of prohibited medication will be considered as intercurrent events (ICEs) and a treatment policy strategy will be considered for these ICEs. Withdrawal or early termination from the study for unspecified reasons and lost to follow-up will not be considered as ICEs, and the subsequent data will be considered as “missing.” Should these events occur, a last observation carried forward approach will be adopted based on observations at visits 2, 3 for period 1 and visits 4, 5 for period 2.The model for analysis will be an analysis of covariance model with the difference in the SARA scores at the end of periods I and II as the dependent variable and SARA at baseline (visit 2) as the independent variable together with an indicator variable for sequence [