Pku PhenylketonuriaPhase 4NCT04227080
BH4 Responsiveness in PAH Deficiency PKU Patients
A Phase 4 study testing BH4 in people with Pku Phenylketonuria and PAH Deficiency, run by Taipei Veterans General Hospital, Taiwan.
Trial summary
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). Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Pku Phenylketonuria, PAH Deficiency
- What is being tested?
- BH4
- Type of treatment
- Pill or oral medicine
- How many people
- 40 participants
- Where
- No sites listed yet
- Study dates
- Jun 2020to Jun 2022
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Subjects have a confirmed diagnosis of PAH deficiency PKU, defined as baseline blood Phe levels of >360 umol/L
- Subject and/or parent or guardian must be capable of understanding and providing written informed consent
- For PAH deficiency PKU newborns, they should be identified as non-BH4 responders by 24-hour BH4 loading test after birth
- For PAH deficiency PKU older pediatric and adult patients, they should be identified as non-BH4 responders by 24-hour BH4 loading test and currently use Phe-restricted diet control alone
Who cannot join
- Perceived to be unreliable or unavailable for study participation or, if under the age of 18, had parents or legal guardians who the investigator perceived to be unreliable or unavailable
- Used any investigational agent other than Kuvan within 30 days of screening, or required any investigational agent or investigational vaccine prior to completion of all scheduled study assessments
- Pregnant or breastfeeding, or considering pregnancy
- Concurrent disease or condition that would interfere with study participation or safety (eg, seizure disorder, asthma or other condition requiring oral or parenteral corticosteroid administration, insulin-dependent diabetes, or organ transplantation recipient)
- Serious neuropsychiatric illness (eg, major depression) not currently under medical management
- Required concomitant treatment with any drug known to inhibit folate synthesis (eg, methotrexate)
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- Clinical diagnosis of primary BH4 deficiency
- Patients him/herself or his/her caregivers are unable or unwilling to sign informed consent or to comply with the requirements of the study
- Patient attend other clinical trials should not be included
About this study
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.
Read the detailed description
Objectives
- Changes of blood Phe level from baseline at the 7th, 14th, and 28th day
- Percentage of the study patients whose blood Phe level decreases for >= 30%
- Percentage of the study patients whose Phe tolerance increase from baseline for >=50%
- 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.
- Conditions
- Pku Phenylketonuria, PAH Deficiency
- Being tested
- BH4
- Keywords
- Phenylketonuria, PAH Deficiency, Kuvan
- Medical subject headings
- Phenylketonurias
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BH4Drug
oral administration of 20 mg/kg KUVAN (BH4)
What is being measured
The primary outcome is the main question the study is designed to answer.
Changes of blood Phe level from baseline
Changes of blood Phe level from baseline at the 7th, 14th, and 28th day
Measured: 7th, 14th, and 28th day
Secondary outcomes (3)
Phe level decreases for >= 30%
Percentage of the study patients whose blood Phe level decreases for >= 30%
Measured: 7th, 14th, and 28th day
Phe tolerance increase from baseline for >=50%
Percentage of the study patients whose Phe tolerance increase from baseline for >=50%
Measured: 7th, 14th, and 28th day
PAH gene mutation and Phe level
Correlation between PAH gene mutation and blood Phe level reduction
Measured: 7th, 14th, and 28th day
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Jan 2020
- Study startJun 2020 (estimated)
- Primary completionDec 2021 (estimated)
- Study completionJun 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Pku PhenylketonuriaStudies of the same condition, open and under way.
- More trials run by Taipei Veterans General Hospital, TaiwanThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 40 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Taipei Veterans General Hospital, Taiwan
- Sponsor type
- Other government
- Collaborators
- BioMarin Pharmaceutical
- Responsible party
- Principal investigator, vghtpe user, Taipei Veterans General Hospital, Taiwan
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04227080
- Sponsor's protocol ID
- Version 1.0, 2018/03/21
- Status last verified
- Jan 2020
- First submitted
- 10 Jan 2020
- Last updated
- 13 Jan 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 13 Jan 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04227080
- Acronym / sponsor ID
- Version 1.0, 2018/03/21
- Conditions
- Pku Phenylketonuria, PAH Deficiency
- Keywords
- Phenylketonuria, PAH Deficiency, Kuvan
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 40 participants (estimated)
- Lead sponsor
- Taipei Veterans General Hospital, TaiwanOther government
- Collaborators
- BioMarin Pharmaceutical
- Study start
- Jun 2020 (estimated)
- Primary completion
- Dec 2021 (estimated)
- Study completion
- Jun 2022 (estimated)
- First posted
- 13 Jan 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Objectives
- Changes of blood Phe level from baseline at the 7th, 14th, and 28th day
- Percentage of the study patients whose blood Phe level decreases for >= 30%
- Percentage of the study patients whose Phe tolerance increase from baseline for >=50%
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (4 listed)
- Subjects have a confirmed diagnosis of PAH deficiency PKU, defined as baseline blood Phe levels of >360 umol/L
- Subject and/or parent or guardian must be capable of understanding and providing written informed consent
- For PAH deficiency PKU newborns, they should be identified as non-BH4 responders by 24-hour BH4 loading test after birth
- For PAH deficiency PKU older pediatric and adult patients, they should be identified as non-BH4 responders by 24-hour BH4 loading test and currently use Phe-restricted diet control alone
Key exclusion criteria (9 listed)
- Perceived to be unreliable or unavailable for study participation or, if under the age of 18, had parents or legal guardians who the investigator perceived to be unreliable or unavailable
- Used any investigational agent other than Kuvan within 30 days of screening, or required any investigational agent or investigational vaccine prior to completion of all scheduled study assessments
- Pregnant or breastfeeding, or considering pregnancy
- Concurrent disease or condition that would interfere with study participation or safety (eg, seizure disorder, asthma or other condition requiring oral or parenteral corticosteroid administration, insulin-dependent diabetes, or organ transplantation recipient)
- Serious neuropsychiatric illness (eg, major depression) not currently under medical management
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BH4oral administration of 20 mg/kg KUVAN (BH4) | Drug | – |
Primary outcome
Changes of blood Phe level from baseline
Time frame: 7th, 14th, and 28th day
Changes of blood Phe level from baseline at the 7th, 14th, and 28th day
3 secondary outcomes
Phe level decreases for >= 30%
Time frame: 7th, 14th, and 28th day
Phe tolerance increase from baseline for >=50%
Time frame: 7th, 14th, and 28th day
PAH gene mutation and Phe level
Time frame: 7th, 14th, and 28th day
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Jan 2020.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing BH4 in people with Pku Phenylketonuria and PAH Deficiency, run by Taipei Veterans General Hospital, Taiwan.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 13 Jan 2020. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Changes of blood Phe level from baseline (time frame: 7th, 14th, and 28th day). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Jan 2020.