PAH Deficiency Clinical Trial
Official title:
To Evaluate BH4 Responsiveness in PAH Deficiency PKU Patients Who Failed to Achieve 30% Blood Phe Reduction Within 24-hour BH4 Loading Test by Extending the Period of BH4 Response Test: A Pilot Study in Taiwan
Most forms of Phenylketonuria and hyperphenylalanemia are caused by mutations in the PAH gene
(phenylalanine hydroxylase) which is responsible for the conversion of Phe into tyrosine, in
the presence of the molecular oxygen and cofactor tetrahydrobiopterin (BH4). To prevent
mental retardation due to the buildup of neurotoxic metabolites of Phe, patients with severe
PKU must be treated with a low-Phe diet starting early in their life [1]. Although
Phe-restricted diet control is essential for avoiding neurological impairment, the life-long
compliance with this dietary control is not optimally maintained, particularly in adulthood
and adolescence [2]. Non-adherence to dietary control after successful treatment in early
childhood may contribute to lower intelligence quotient (IQ), emotional and behavioral
disorders, including attention deficit disorders, depression, anxiety, and agoraphobia.
In recent years, another therapeutic approach for managing PKU is to supplement a synthetic
form of BH4 along with diet control. Kure et al. and several other research teams had
indicated that treatment with BH4 might lower down the Phe level in a subset of PKU patients
[3-7]. BH4 acts as a pharmacological chaperone to stabilize mutant enzymes with disrupted
tetramer assembly and increased sensitivity to proteolytic cleavage and aggregation. The
BH4-supplementation therapy (Kuvan) can be used to loosen or even replace burdensome dietary
treatment of PKU patients. Correct and efficient identification of BH4-responsive patients is
important, both to improve the fast assessment, as well as to avoid false expectations and
unnecessary costs. Unfortunately, there is still no golden standard on how to assess BH4
responsiveness most efficiently.
In Taiwan, high-dose BH4 [20mg/kg] loading is the standard test to identify patients who are
responsible to BH4 treatment, for PAH deficiency PKU patients with more than 30% decrease in
Phe level within 24 hours after BH4 challenge were BH4-responsive patients and eligible for
national health insurance coverage of continuous BH4 treatment. In clinical studies, blood
Phe levels in patients who are BH4-responsive typically decrease within 24 hours after a
single administration of Kuvan, although the maximal effect on blood Phe levels may take up
to a month. A Phase IV open-label trial showed that of 64% of patients responded to Kuvan
within 7 days whereas 10% responded between 8-28 days. To the best of our knowledge, there's
no previous study which evaluated longer than 7 days BH4 response test in Asian countries,
and for the purpose to help PAH deficiency PKU patients achieve optimal Phe control and
neurocognitive outcomes, it's definitely worthy to extend the period of BH4 response test to
identity more patients who can benefit from Kuvan treatment.
Objectives
1. Changes of blood Phe level from baseline at the 7th, 14th, and 28th day
2. Percentage of the study patients whose blood Phe level decreases for >= 30%
3. Percentage of the study patients whose Phe tolerance increase from baseline for >=50%
4. Correlation between PAH gene mutation and blood Phe level reduction
Study Design and Methodology The PAH deficiency PKU patients who failed to achieve 30% blood
Phe reduction within 24-hour BH4 loading test will be enrolled to this study. Baseline
protein intake will be calculated and baseline blood phenylalanine levels will be established
prior to starting the trial. During the entire testing period, patients will have no dietary
restrictions. Blood Phe will be measured on day 1, 7, 14 and 28 days after oral
administration of 20 mg/kg KUVAN in 40 patients whose initial plasma Phe results were ≥360
umol/L. In this study, the efficacy of BH4 will be evaluated on 7, 14 and 28 days to
determine whether a patient is BH4-responsive. The total duration of patient participation in
the study will be up to 3 months (1 month of BH4 efficacy evaluation and up to 8 weeks of
screening).
- Health status assessments：A complete physical examination will be performed at all study
visits. The physical examination will include appearance, eyes, ears, nose, head,
throat, neck, chest, lungs, heart, abdomen, extremities, skin and musculoskeletal
system. Weight will be measured at first visit, without shoes and having removed all
outwear such as jackets, sweaters or sweatshirts and heavy pocket items. Clinically
significant findings at screening will be reported as medical history and as adverse
event after the screening visit.
- Vital sign：Vital signs measurement will be recorded at all study visits and will include
body temperature, respiration, blood pressure and heart rate after the patients has sat
quietly for at least 5 minutes.
- Nutrition assessment：Baseline protein intake will be calculated from 3-day photographic
food records, and baseline blood Phe level will be established after a 3-5 hour fasting
prior to starting BH4 loading. During the entire testing period, patients will have no
dietary restrictions, but will be asked to keep a stable diet throughout the study.
Patients will be required to keep a diary and photographic food records for three days
of each week containing a record of all foods and beverages ingested including synthetic
and low protein containing foods. Dietary records will be reviewed by a single qualified
metabolic dietician and monitored for calorie intake, natural protein intake, synthetic
protein intake, and total Phe intake.
- Laboratory assessments：All routine clinical laboratory assessments will be performed by
central laboratory. The laboratory evaluations will include :
- Serum nutritional biomarkers : total protein, albumin, total cholesterol, total
triglyceride, LDL (low-density lipoprotein cholesterol), HDL (high-density
lipoprotein cholesterol), Iron, Ferritin
- Blood phenylalanine and tyrosine : Blood phenylalanine and tyrosine levels will be
measured prior to BH4 loading test, and on day 1, 7, 14 and 28 days following kuvan
20 mg/kg/day.
- PAH gene evaluation in all patients
- Urine pTerin and DHPR enzyme activity analysis - Patients with defect in the
synthesis and recycling of BH4 will be excluded by analysis of urinary pterins and
dihydropteridine reductase activity in erythrocytes. pTerins (neopterin and
biopterin) metabolism will be analyzed in each visit.
- Dispense study drug - Subjects will receive 20 mg/kg Kuvan administered orally once
daily for 28 days.
;
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