Non-Phenylketonuric HyperphenylalaninemiaNCT04896281
Phenylalanine-free Diet for Patients With Secondary Hyperphenylalaninemia in ICU
A study testing Phenylalanine-free milk in people with Non-Phenylketonuric Hyperphenylalaninemia, run by Chang Gung Memorial Hospital at 1 site in Taiwan.
Trial summary
Hyperphenylalaninemia is not only present in patients with congenital phenylketonuria. In adults with critical illness, hyperphenylalaninemia is noted in some patients and is associated with high mortality rate. Hyperphenylalaninemia can cause metabolic acidosis, brain dysfunction, and metabolic disturbance. Read more about this study
- Who is it for?
- Ages 20 years and older
- Conditions the study is for
- Non-Phenylketonuric Hyperphenylalaninemia
- What is being tested?
- Phenylalanine-free milk
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 100 participants
- Where
- 1 siteTaiwan
- Study dates
- 30 Jul 2021to 31 Dec 2026
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
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 20 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- had Acute Physiology And Chronic Health Evaluation (APACHE II) scores of ≥15;
- were expected to stay in the ICU >48 hours;
- patients with baseline PHE levels of ≥95 uM;
- were over 20 years old.
Who cannot join
- patients with comorbid disorders other than the main cause for admission that might compromise their survival within three months, such as terminal stage cancer;
- patients with expected survival <3 days.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Taiwan1 site, 1 recruiting
- Recruiting
Chang Gung Memorial Hospital
Keelung, 402
CHAO-HUNG WANG, MD, +886-2-24313131 ext. 2923, bearty54@gmail.com
CHAO-HUNG WANG, MD
About this study
Official title: Phenylalanine-free Diet Lowers the Blood Phenylalanine Levels in Patients With High Phenylalanine Level in the Intensive Care Unit
Hyperphenylalaninemia is not only present in patients with congenital phenylketonuria. In adults with critical illness, hyperphenylalaninemia is noted in some patients and is associated with high mortality rate. Hyperphenylalaninemia can cause metabolic acidosis, brain dysfunction, and metabolic disturbance. The investigators would like to see whether the phenylalanine-free milk for congenital phenylketonuria is also effective in lowering the blood phenylalanine concentrations in patients with critical illness in intensive care unit and hyperphenylalaninemia.
Read the detailed description
Background:
Patients in the intensive care unit often suffer from problems such as high metabolic rate and high tissue breakdown rate under the severe stress of critical diseases. Phenylalanine is an amino acid in the human body and is rich in muscle tissue. However, current studies have found that if the concentration of phenylalanine in the blood is abnormally increased, it may indicate that the tissue is decomposing in large quantities. This phenomenon may be related to disease severity. Our recent observational study of patients in the intensive care unit (ICU) found that patients with elevated blood phenylalanine had a four-fold increase in mortality within one year.
The most common cause of phenylalanine concentration elevation in the blood is a rare disease that occurs in infants with congenital metabolic abnormalities, called congenital phenylketonuria (PKU). The abnormally elevated phenylalanine concentration can lead to toxicity and cause brain hypoplasia, mental retardation, consciousness disturbance, and even seizure. These PKU patients must be treated with milk diet that contains low amount of phenylalanine in order to lower the phenylalanine concentrations. At present, in medicine, although there have been clear medical care strategy for infants with congenital PKU, there is still no clear medical care strategy for adult patients.
Research purpose: To investigate whether patients with high blood phenylalanine concentration in the intensive care unit can reduce the blood phenylalanine concentration by a diet without phenylalanine, so as to develop personalized high-quality and specific treatments.
Methods:
The investigators aim to have complete study in 70 patients (based on our previous study, to recruit 70 patients with high phenylalanine, the investigators need 300 ICU patients for screening).
Intervention protocol:
Once a plasma phenylalanine level of ≥ 95 μM is noted, phenylalanine-free diet (Phenex-2®, Abbott Nutrition, Ohio, USA; or Phenyl-Free 2®, Mead Johnson Nutrition, Minnesota, USA) is started as the only nutrition source for enteral feeding, as per the recommendation of dieticians, in the following 4 days. The phenylalanine-free diet is free of phenylalanine but is enriched with protein, potassium, tyrosine, and antioxidant micronutrients. After the completion of the study, diet will be back to normal diet for all patients.
Study end points: the 5-day study period completed.
Blood sampling and examination for Phenylalanine measurement (dry blood spot) Fasting phenylalanine level will be measured by LC/MS-MS using the dry blood spot method (blood sample is collected by finger sting) in all included patients in the next morning after informed consent signed. Blood applied on filter cards is dried for at least 3 h at room temperature. Dry blood spot cards are stored at room temperature for 0-6 days prior to analyses. Phenylalanine concentrations in dry blood spot are measured with LC-MS/MS, using a calibration curve in 0.1 N HCl. The report will be received one day after dry blood spot collected. Once the result of measurement shows the concentration of phenylalanine ≥95 μM, this patient is enrolled for formal study. All enrolled patients will take the measurement of phenylalanine levels by dry blood spot every 12 hours for the following 4 days until study protocol finished.
Phenylalanine measurement by UPLC:
In the meanwhile, fasting blood will be collected by venipuncture in EDTA-containing tubes on the morning of screening, 2 and 4 days after diet intervention. The collected blood will be used to measure phenylalanine level by UPLC (ultra-performance liquid chromatography). Plasma samples (100μL) are precipitated with 10% sulfosalicylic acid. After protein precipitation and centrifugation, derivatization is initiated by AQC in acetonitrile. Amino acids are then analyzed using the ACQUITY UPLC System, consisting of a Binary Solvent Manager, a Sample Manager, and a Tunable UV detector. The investigators use EmpowerTM 2 Software to control the system and collect data. Separations are performed on a 2.1×100mm ACQUITY BEH C18 column at a flow rate of 0.70mL/min. The average intra-assay coefficient of variation is 2.6% for phenylalanine. The total coefficient of variation is 2.7% for phenylalanine. The detection limit is 3.3μM for phenylalanine. The linear range is 25-500 μM.
APACHE II scores Disease severity is evaluated by calculating APACHE II score on the first day of ICU admission.
- Being tested
- Phenylalanine-free milk
- Keywords
- phenylalanine, intensive care unit, nutritional intervention
- Medical subject headings
- Phenylketonurias
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Phenylalanine-free milkDietary supplement
Once a plasma PHE level of ≥ 95 μM is noted, phenylalanine-free diet (Phenex-2®, Abbott Nutrition, Ohio, USA; or Phenyl-Free 2®, Mead Johnson Nutrition, Minnesota, USA) is started as the only nutrition source for enteral feeding, as per the recommendation of dieticians, in the following 4 days. The phenylalanine-free diet is free of PHE but is enriched with protein, potassium, tyrosine, and antioxidant micronutrients. After the completion of the study, diet will be back to normal diet for all patients.
| Study group | Role | What they receive |
|---|---|---|
| phenylalanine-free diet | Experimental | phenylalanine-free diet for patients with hyperphenylalaninemia Receives: Dietary Supplement: Phenylalanine-free milk |
What is being measured
The primary outcome is the main question the study is designed to answer.
fasting plasma phenylalanine concentration
fasting plasma phenylalanine concentration at baseline and at the end of intervention
Measured: Baseline to day 5
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 May 2021
- Study start30 Jul 2021
- Primary completion31 Dec 2026 (estimated)
- Study completion31 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Non-Phenylketonuric HyperphenylalaninemiaStudies of the same condition, open and under way.
- More trials run by Chang Gung Memorial HospitalThe 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 N/A
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 100 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Chang Gung Memorial Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- CHAO-HUNG WANG, MD, PhD, Principal investigator, Chang Gung Memorial Hospital, Keelung
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04896281
- Sponsor's protocol ID
- 202100028A3
- Status last verified
- Mar 2026
- First submitted
- 26 Apr 2021
- Last updated
- 20 Mar 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: undecided
Study at a glance
From the registry record, last updated by the sponsor on 20 Mar 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phenylalanine-free Diet Lowers the Blood Phenylalanine Levels in Patients With High Phenylalanine Level in the Intensive Care Unit
- ClinicalTrials.gov ID
- NCT04896281
- Acronym / sponsor ID
- 202100028A3
- Keywords
- phenylalanine, intensive care unit, nutritional intervention
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 100 participants (estimated)
- Lead sponsor
- Chang Gung Memorial HospitalUniversity, hospital or other
- Study start
- 30 Jul 2021 (actual)
- Primary completion
- 31 Dec 2026 (estimated)
- Study completion
- 31 Dec 2026 (estimated)
- First posted
- 21 May 2021 (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.
Hyperphenylalaninemia is not only present in patients with congenital phenylketonuria. In adults with critical illness, hyperphenylalaninemia is noted in some patients and is associated with high mortality rate. Hyperphenylalaninemia can cause metabolic acidosis, brain dysfunction, and metabolic disturbance. The investigators would like to see whether the phenylalanine-free milk for congenital phenylketonuria is also effective in lowering the blood phenylalanine concentrations in patients with critical illness in intensive care unit and hyperphenylalaninemia.
Detailed description
Background:
Patients in the intensive care unit often suffer from problems such as high metabolic rate and high tissue breakdown rate under the severe stress of critical diseases. Phenylalanine is an amino acid in the human body and is rich in muscle tissue. However, current studies have found that if the concentration of phenylalanine in the blood is abnormally increased, it may indicate that the tissue is decomposing in large quantities. This phenomenon may be related to disease severity. Our recent observational study of patients in the intensive care unit (ICU) found that patients with elevated blood phenylalanine had a four-fold increase in mortality within one year.
The most common cause of phenylalanine concentration elevation in the blood is a rare disease that occurs in infants with congenital metabolic abnormalities, called congenital phenylketonuria (PKU). The abnormally elevated phenylalanine concentration can lead to toxicity and cause brain hypoplasia, mental retardation, consciousness disturbance, and even seizure. These PKU patients must be treated with milk diet that contains low amount of phenylalanine in order to lower the phenylalanine concentrations. At present, in medicine, although there have been clear medical care strategy for infants with congenital PKU, there is still no clear medical care strategy for adult patients.
Research purpose: To investigate whether patients with high blood phenylalanine concentration in the intensive care unit can reduce the blood phenylalanine concentration by a diet without phenylalanine, so as to develop personalized high-quality and specific treatments.
Methods:
The investigators aim to have complete study in 70 patients (based on our previous study, to recruit 70 patients with high phenylalanine, the investigators need 300 ICU patients for screening).
Intervention protocol:
Once a plasma phenylalanine level of ≥ 95 μM is noted, phenylalanine-free diet (Phenex-2®, Abbott Nutrition, Ohio, USA; or Phenyl-Free 2®, Mead Johnson Nutrition, Minnesota, USA) is started as the only nutrition source for enteral feeding, as per the recommendation of dieticians, in the following 4 days. The phenylalanine-free diet is free of phenylalanine but is enriched with protein, potassium, tyrosine, and antioxidant micronutrients. After the completion of the study, diet will be back to normal diet for all patients.
Study end points: the 5-day study period completed.
Blood sampling and examination for Phenylalanine measurement (dry blood spot) Fasting phenylalanine level will be measured by LC/MS-MS using the dry blood spot method (blood sample is collected by finger sting) in all included patients in the next morning after informed consent signed. Blood applied on filter cards is dried for at least 3 h at room temperature. Dry blood spot cards are stored at room temperature for 0-6 days prior to analyses. Phenylalanine concentrations in dry blood spot are measured with LC-MS/MS, using a calibration curve in 0.1 N HCl. The report will be received one day after dry blood spot collected. Once the result of measurement shows the concentration of phenylalanine ≥95 μM, this patient is enrolled for formal study. All enrolled patients will take the measurement of phenylalanine levels by dry blood spot every 12 hours for the following 4 days until study protocol finished.
Phenylalanine measurement by UPLC:
In the meanwhile, fasting blood will be collected by venipuncture in EDTA-containing tubes on the morning of screening, 2 and 4 days after diet intervention. The collected blood will be used to measure phenylalanine level by UPLC (ultra-performance liquid chromatography). Plasma samples (100μL) are precipitated with 10% sulfosalicylic acid. After protein precipitation and centrifugation, derivatization is initiated by AQC in acetonitrile. Amino acids are then analyzed using the ACQUITY UPLC System, consisting of a Binary Solvent Manager, a Sample Manager, and a Tunable UV detector. The investigators use EmpowerTM 2 Software to control the system and collect data. Separations are performed on a 2.1×100mm ACQUITY BEH C18 column at a flow rate of 0.70mL/min. The average intra-assay coefficient of variation is 2.6% for phenylalanine. The total coefficient of variation is 2.7% for phenylalanine. The detection limit is 3.3μM for phenylalanine. The linear range is 25-500 μM.
APACHE II scores Disease severity is evaluated by calculating APACHE II score on the first day of ICU admission.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| phenylalanine-free diet | Experimental | Dietary Supplement: Phenylalanine-free milkphenylalanine-free diet for patients with hyperphenylalaninemia |
Who may qualify
- Ages
- 20 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- had Acute Physiology And Chronic Health Evaluation (APACHE II) scores of ≥15;
- were expected to stay in the ICU >48 hours;
- patients with baseline PHE levels of ≥95 uM;
- were over 20 years old.
Key exclusion criteria (2 listed)
- patients with comorbid disorders other than the main cause for admission that might compromise their survival within three months, such as terminal stage cancer;
- patients with expected survival <3 days.
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 |
|---|---|---|
| Phenylalanine-free milkOnce a plasma PHE level of ≥ 95 μM is noted, phenylalanine-free diet (Phenex-2®, Abbott Nutrition, Ohio, USA; or Phenyl-Free 2®, Mead Johnson Nutrition, Minnesota, USA) is started as the only nutrition source for enteral feeding, as per the recommendation of dieticians, in the following 4 days. The phenylalanine-free diet is free of PHE but is enriched with protein, potassium, tyrosine, and antioxidant micronutrients. After the completion of the study, diet will be back to normal diet for all patients. | Dietary supplement | phenylalanine-free diet |
Primary outcome
fasting plasma phenylalanine concentration
Time frame: Baseline to day 5
fasting plasma phenylalanine concentration at baseline and at the end of intervention
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Mar 2026.
- Individual participant dataSharing planned: No. undecided
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.
CHAO-HUNG WANG, MD, PhD principal investigator
Chang Gung Memorial Hospital, Keelung
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Phenylalanine-free milk in people with Non-Phenylketonuric Hyperphenylalaninemia, run by Chang Gung Memorial Hospital at 1 site in 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 2 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: looking for participants now, as of the sponsor's last update on 20 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Taiwan. Whether a site is taking part right now should be confirmed with that site. See every site.
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.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact CHAO-HUNG WANG, MD, PhD (0224313131 ext. 2923, bearty@cgmh.org.tw), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
fasting plasma phenylalanine concentration (time frame: Baseline to day 5). 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 20 Mar 2026.