Atorvastatin-associated muscle symptoms in adults with familial hypercholesterolaemia: a randomized double-blind n-of-1 crossover trial

The primary objective is to determine the proportion of adults with familial hypercholesterolaemia and self-perceived statin-associated muscle symptoms who have true statin-dependent muscle symptoms versus nocebo or misattributed muscle symptoms. This is clinically relevant for distinguishing causally related adverse effects from symptoms not attributable to statin exposure. The secondary objective is to describe the diagnostic performance of a candidate biomarker, defined by the pattern of atorvastatin metabolites in blood, for differentiating participants classified with statin-dependent muscle symptoms from those with nocebo or misattributed symptoms.

The sponsor did not provide the total number of participants or a detailed description of the study population. The trial population consisted of adult familial hypercholesterolaemia patients, including both women and men. Participants were selected on the basis of a genetically verified diagnosis of heterozygous familial hypercholesterolaemia or a clinical diagnosis with a Dutch Lipid Clinic Network Score of at least 9, together with a history of self-perceived statin-associated muscle symptoms on at least two different statins and prior statin discontinuation because of these symptoms. Additional requirements included age of at least 18 years, ability to provide informed consent, expected compliance with study requirements, and access to a smartphone, tablet, or personal computer. For women of childbearing potential, a negative pregnancy test and willingness to use highly effective contraception or sexual abstinence during the intervention were required. No lifestyle information such as diet, physical activity, or habits was provided.

This is a randomized, double-blind, controlled phase IV n-of-1 crossover trial in adults with familial hypercholesterolaemia and self-perceived statin-associated muscle symptoms. The study compares treatment periods with atorvastatin, placebo, and no study treatment. The overall trial duration is planned from August 2026 to December 2028. Participation is expected to last for the full individual study period defined in the protocol. A screening visit is used to verify eligibility, including age, diagnosis, prior statin-associated muscle symptoms, prior statin discontinuation, and other protocol requirements. Eligible participants then undergo the randomized crossover treatment periods and any scheduled follow-up assessments to evaluate muscle symptom intensity and related outcomes. An end-of-study visit is performed after completion of the assigned periods to finalize assessments. Early termination may occur if informed consent is withdrawn, if protocol requirements are no longer met, if compliance is inadequate, or if other conditions arise that prevent continuation according to the protocol.

The investigational treatment was atorvastatin, administered as film-coated tablets containing 80 mg by oral route. The study used a randomized, double-blinded n-of-1 crossover design with treatment periods including atorvastatin, placebo, and no study treatment. Dosing was given according to the study schedule, and treatment adherence was monitored during the trial.

The non-experimental treatment was placebo, provided as encapsulated placebo tablets for oral administration. The placebo was used in blinded treatment periods and followed the same study schedule as the active treatment. Compliance monitoring was applied during placebo administration in the same manner as for the investigational medication.

Efficacy will be assessed by comparing the individual mean difference in muscular symptom intensity over the last two weeks of each treatment period, specifically week 5 to week 6, between atorvastatin and placebo. The primary efficacy endpoint is defined on a 0 to 100 units rating scale, with a clinically relevant difference of at least 10 units and a 25% difference. Secondary efficacy assessments include the area under the Receiver Operating Characteristic curve, as well as diagnostic sensitivity and specificity.