Trial reportNutrients2026
Effects of a Prolonged-Release Protein Substitute on 24-h Phenylalanine and Tyrosine Profiles in Phenylketonuria: A Randomized Crossover Study.
Trial report in Nutrients, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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7 authors.
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Abstract
BACKGROUND/
objectivesAchieving optimal metabolic control in phenylketonuria (PKU) remains challenging, particularly in adolescents and adults. Conventional free amino acid-based protein substitutes are absorbed rapidly, whereas prolonged-release formulations are designed to provide a more gradual amino acid release profile. Whether this translates into more favorable 24 h Phe and Tyr profiles and improved short-term biochemical parameters of metabolic control remains uncertain. This study evaluated whether a prolonged-release amino acid-based protein substitute (PR-AA) could improve 24 h metabolic control compared with standard protein substitutes.
methodsThis randomized, controlled, open-label crossover study included adolescents and adults with PKU aged ≥16 years. Participants received either conventional protein substitutes (standard of care; SC) or PR-AA three times daily for two consecutive days, followed by crossover to the alternate treatment. Blood spot samples were collected at five time points over 24 h on the second day of each treatment period. The primary outcome was the 24 h blood Phe profile. Secondary outcomes included blood Tyr, Phe/Tyr ratio, and exploratory assessment of branched-chain amino acids (BCAAs).
resultsTwenty-one patients were enrolled, of whom 16 were included in the intention-to-treat analysis and 12 in the per-protocol analysis. PR-AA treatment resulted in significantly lower mean blood Phe levels over 24 h compared with SC (522 ± 194 vs. 561 ± 165 µmol/L; p = 0.0009), corresponding to a reduction of approximately 6-7%. The effect was consistently observed throughout the 24-h assessment period, particularly during the early morning, and became detectable after only two days of treatment. PR-AA was also associated with significantly higher blood Tyr levels (approximately +18-20%; p < 0.05) and a lower Phe/Tyr ratio (approximately -20%; p < 0.001) compared with SC. Exploratory analyses demonstrated modestly lower and more stable BCAA profiles with PR-AA. No significant carryover effects or treatment-related safety concerns were observed.
conclusionsShort-term treatment with a prolonged-release protein substitute was associated with modest but consistent improvements in short-term biochemical parameters of metabolic control in adolescents and adults with PKU, including lower blood Phe and higher Tyr levels, resulting in a reduced Phe/Tyr ratio. These findings suggest that optimizing amino acid delivery kinetics may represent a promising strategy to improve short-term metabolic control in PKU. Given the preliminary nature of these findings and the limited number of participants who completed the study protocol, larger studies with longer follow-up, including direct clinical and neurocognitive outcomes and formal variability metrics, are needed to determine the clinical relevance of these biochemical effects.
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