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Table 14Comparative studies of LNAAs for the treatment of PKU

Author, Year, Formulation/Dosage
Total N
Age, Mean Years ± SDKey Points
Crossover Trials
Schindeler 2007124

Phase 1: Phe-free medical food, Phe-restricted diet, LNAAs
Phase 2: Phe-free medical food, Phe-restricted diet, placebo
Phase 3: No Phe-free medical food, Phe-restricted diet, LNAAs
Phase 4: No Phe-free medical food, Phe-restricted diet, placebo

250 mg/kg/day in 3 equal daily doses, each phase for 14 days with a 4 week washout period in between phases

N = 16

Quality: Fair
24 years 9 months (median)

11 – 45 (range)
  • All participants had early treated, classic PKU; none had excellent dietary control prior to treatment
  • Brain Phe levels did not differ by phase
  • Median plasma Phe levels increased from phase 1 (639 μmol/L, range 149-1044) to phase 4 (1180 μmol/L, range 641-1744),
  • Plasma Phe was reduced in most subjects (9/16) by an average of 25% during phase 1 during which they took LNAAs and Phe-free medical food.
  • No difference in plasma Phe reduction was observed with LNAAs plus formula or without LNAAs plus formula. In the absence of Phe-free medical food, LNAAs was associated with greater reductions in Phe than placebo. However, plasma Phe levels remained high for all participants, including those taking the LNAAs formulation (958 μmol for those not on Phe-free medical food).
Matalon 2007125

G1: LNAA/Placebo
G2: Placebo/LNAAs

0.5 g/kg/day in 3 doses taken with meals, for 1 week


Quality: Poor
11 - 32
  • Study was conducted in 6 centers in the U.S., Italy, Denmark,Russia and Brazil
  • Participants were instructed to continue diet while in the trial
  • Blood Phe levels were significantly reduced on LNAAs from a mean blood Phe of 932.9 μmol /L at baseline to 568.4 μmol/L at one week (39% decline)
  • Seven participants were adherent to Phe formula and had a decline from a baseline mean of 531.6 μmol /L to 281.5 μmol/L at one week, an average decline of 250.1 [plus, equals] 173.7 (47% decline)
  • In comparison, blood Phe was not reduced on placebo
Matalon 200616

G1: 0.5 g/kg/day NeoPhe
G2: 1.0 g/kg/day NeoPhe 0.5 g/kg/day or 1.0 g/kg/day of NeoPhe in 3 doses taken before meals, for 1 week


Quality: Poor
G1: 20.5
G2: 16.5
  • Participants were enrolled at 3 centers in Ukraine, Russia and the U.S.
  • Participants were not on a restricted diet; Phe intake was more than 500 mg/day
  • Of 11 participants enrolled in the trial, 8 received 0.5 mg/kg/day of LNAAs and 3 received 1.0 g/kg/day
  • In the 8 participants taking 0.5 g/kg/day, blood Phe levels decreased significantly from the baseline mean of 957.4 μmol/L to 458.4 μmol/L after one week on LNAAs, a decline of 52%.
  • Among the 3 participants who took 1 g/kg/day of LNAAs, the mean blood Phe level decreased from the baseline level of 1230 μmol/L to 549.0 μmol L, a decline of 55%.

LNAAs = large neutral amino acids; N = number; Phe = phenylalanine

From: Results

Cover of Adjuvant Treatment for Phenylketonuria (PKU)
Adjuvant Treatment for Phenylketonuria (PKU) [Internet].
Comparative Effectiveness Reviews, No. 56.
Lindegren ML, Krishnaswami S, Fonnesbeck C, et al.

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