PRL2019 in the Treatment of Juvenile Fibromyalgia

Reduction in musculoskeletal pain intensity, measured by the 21-numbered circle Visual Analogue Scale (VAS)14, where 0 corresponds to "no pain" and 10 to "worst imaginable pain". Baseline is defined as the mean VAS scores recorded over the 7 days preceding the start of each treatment period (i.e. before Period 1 start and before crossover to Period 2). The treatment effect is calculated as the change from baseline to the mean VAS score recorded over the last 7 days of the treatment period. A patient will be defined as a responder if achieving a 3 2 points reduction in the weekly average VAS score from baseline.

The VAS will be self-reported by all enrolled patients.

Abdominal pain intensity will be assessed using the 21-numbered circle Visual Analogue Scale (VAS) (0-10, with half-point scores permitted), where higher scores indicate greater symptom severity.

To asses change in fatigue intensity from baseline following treatment with Gabapral. Fatigue intensity will be assessed using the 21-numbered circle Visual Analogue Scale (VAS) (0-10, with half-point scores permitted), where higher scores indicate greater symptom severity.

These Functional outcomes include functional disability assessed using the Functional Disability Inventory (FDI). The FDI comprises 15 items, each rated on a 5-point Likert scale (0 = no trouble, 4 = impossible), yielding a total score ranging from 0 to 60, with higher scores indicating greater functional disability

Change in headache intensity from baseline following treatment with Gabapral. Headache intensity will be assessed using the 21-numbered circle Visual Analogue Scale (VAS) (0-10, with half-point scores permitted), where higher scores indicate greater symptom severity.

Change in global assessment of disease severity from baseline following treatment with Gabapral. Global disease severity will be assessed using the 21-numbered circle Visual Analogue Scale (VAS) (0-10, with half-point scores permitted), where higher scores indicate greater symptom severity.

Change in widespread pain from baseline following treatment with Gabapral. Widespread pain will be assessed using the Widespread Pain Index (WPI) (0-19), where higher scores indicate greater widespread pain.

Change in symptom severity from baseline following treatment with Gabapral. Symptom severity will be assessed using the Symptom Severity Score (SSS) (0-12), where higher scores indicate greater symptom severity.

Change in depressive symptoms from baseline following treatment with Gabapral. Depressive symptoms will be assessed using validated instruments, including the Children's Depression Inventory - Second Edition (CDI-2) (0-56) or the Beck Depression Inventory - Second Edition (BDI-II) (0-63). Higher scores indicate greater depressive symptom severity. Scoring will follow the standardized procedures defined in the respective manuals.

Change in anxiety symptoms from baseline following treatment with Gabapral. Anxiety symptoms will be assessed using validated instruments, including the Multidimensional Anxiety Scale for Children - Second Edition (MASC-2) (0-150) or the State-Trait Anxiety Inventory for Youth (STAI-Y) (20-80 for each subscale). Higher scores indicate greater anxiety symptom severity. Scoring will follow the standardized procedures defined in the respective manuals.

Gut microbiota composition will be characterised from fecal samples collected before and after each treatment period using shotgun metagenomic sequencing. Results will be reported as the relative abundance of bacterial taxa at the phylum, genus, and species levels together with alpha- and beta-diversity metrics, summarized descriptively at each study time point.

Changes from baseline in gut microbiota taxonomic composition and diversity, determined by shotgun metagenomic sequencing of fecal samples, and in fecal and plasma metabolomic profiles, determined by untargeted metabolomic analysis, will be evaluated after each treatment period. Metabolomic results will be summarised as differential metabolite abundances (up- and down-regulated metabolites) together with pathway enrichment analyses to identify biological pathways associated with treatment response.