Phenylketonuria
Conditions
Keywords
Phenylketonuria, PKU, tetrahydrobiopterin, sapropterin dihydrochloride, BH4, Kuvan, Oxidative stress
Brief summary
The purpose of this study is to see how tetrahydrobiopterin therapy (BH4; also known as sapropterin dihydrochloride or Kuvan) affects measures of oxidative stress and endothelial function in patients with Phenylketonuria (PKU).
Detailed description
Oxidative stress will be induced by having participants eat a meal in polyunsaturated fats. The investigators will see how participants respond to the meal challenge over the course of 6 hours. * PKU participants who are currently on BH4 therapy will be evaluated while taking BH4 with the meal at a single study visit. * PKU participants who did not responded to BH4 therapy will be evaluated twice. At the first study visit the investigators will see how you react to the meal challenge when you are not given BH4. You will be given BH4 for two weeks, then return for a second meal challenge study visit while taking BH4. * Healthy controls will be evaluated after consuming the meal only (no BH4) at a single study visit.
Interventions
DRUGKuvan
Participants in the BH4 Non-Responder group will be given a 20 mg/kg body weight/day dose of Kuvan to take on a daily basis for two weeks. The last dose will be administered at the participant's study visit 2.
OTHERMeal Challenge
At each study visit, patients will receive a meal high in polyunsaturated fats that will promote a transitory increase in oxidative stress measures and endothelial dysfunction
Sponsors
Emory University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
10 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Have read, understood, and signed this consent form (and assent form, if \<18 years old) * Are between the ages of 10-45 years * Weigh at least 75 pounds (34 kg) * Meet group-specific criteria
Exclusion criteria
* Smoke * Have any history of cardiovascular disease * Have hepatic impairment, or demonstrate abnormal baseline liver function lab test results * Have donated blood within 3 months prior to the study or are anemic as shown by the baseline lab results * Are unwilling to discontinue dietary supplements (excluding medical food) two weeks prior to their first study visit * Are currently take medications that will interfere with the interpretation of selected endpoints (such as lipid-lowering medication) * Are currently pregnant or breastfeeding * Excluding PKU, have a chronic illness, disorder, or condition (including but not limited to diabetes, hypertension, cancer) * Have taken any investigational drug (including Kuvan for Kuvan-unresponsive participants & controls) within 3 months prior to the study * In the opinion of the Investigator, should not be included in the study for any reason, including inability to follow study procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Lipid Peroxidation | Lipid peroxidation will be measured every other hour for six hours at baseline (study visit 1) for all study groups | Markers will be assessed every other hour for each 6-hour study visit. Kuvan responders and healthy controls will only be assessed at one 6-hour study visit. Kuvan non-responders will be assessed at two study visits (a baseline visit, and a visit after two weeks of Kuvan therapy). Values will be assessed groupwise and also assessed for intrapersonal change in the Kuvan non-responsive group. Time frame of participation is estimated at one month. |
| C-Reactive Protein (CRP) | CRP will be measured every other hour for six hours at baseline (study visit 1) for all study groups and again during a second visit 2 weeks after baseline in BH4 Non-Responders only (study visit 2) | Markers will be assessed every other hour for each 6-hour study visit. Kuvan responders and healthy controls will only be assessed at one 6-hour study visit. Kuvan non-responders will be assessed at two study visits (a baseline visit, and a visit after two weeks of Kuvan therapy). Values will be assessed groupwise and also assessed for intrapersonal change in the Kuvan non-responsive group. Time frame of participation is estimated at one month. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BH4 Non-Responders Participants in this group have PKU and were deemed unresponsive to the drug. They will attend their first study visit, and proceed through the meal challenge without BH4. They will then take BH4 for 2 weeks. The second meal challenge will be performed with the participant's final dose of BH4.
Kuvan: Participants in the BH4 Non-Responder group will be given a 20 mg/kg body weight/day dose of Kuvan to take on a daily basis for two weeks. The last dose will be administered at the participant's study visit 2.
Meal Challenge: At each study visit, patients will receive a meal high in polyunsaturated fats that will promote a transitory increase in oxidative stress measures and endothelial dysfunction | 4 |
| Healthy Controls Participants in this group match an enrolled PKU participant in terms of age, gender, and body mass index class. They will participate in a single study visit and will not be given BH4.
Meal Challenge: At each study visit, patients will receive a meal high in polyunsaturated fats that will promote a transitory increase in oxidative stress measures and endothelial dysfunction | 3 |
| BH4 Responders Participants in this group will use their already prescribed BH4 with the meal challenge and be assessed at a single study visit. They will take their prescribed BH4 with the meal.
Meal Challenge: At each study visit, patients will receive a meal high in polyunsaturated fats that will promote a transitory increase in oxidative stress measures and endothelial dysfunction | 5 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Baseline Study Visit | Protocol Violation | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | BH4 Non-Responders | Healthy Controls | BH4 Responders |
|---|---|---|---|---|
| Age, Categorical <=18 years | 4 Participants | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 3 Participants | 2 Participants | 3 Participants |
| Age, Continuous | 27.4 years STANDARD_DEVIATION 12.6 | 33.9 years STANDARD_DEVIATION 13.4 | 33.5 years STANDARD_DEVIATION 15.7 | 18.5 years STANDARD_DEVIATION 3.8 |
| high-sensitivity CRP | 1.06 mg/L STANDARD_DEVIATION 1.19 | 1.3 mg/L STANDARD_DEVIATION 1.2 | 0.61 mg/L STANDARD_DEVIATION 0.14 | 1.04 mg/L STANDARD_DEVIATION 1.48 |
| Region of Enrollment United States | 12 participants | 4 participants | 3 participants | 5 participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Male | 10 Participants | 3 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 4 | 0 / 3 | 0 / 5 |
| serious Total, serious adverse events | 0 / 4 | 0 / 3 | 0 / 5 |
Outcome results
Primary
C-Reactive Protein (CRP)
Markers will be assessed every other hour for each 6-hour study visit. Kuvan responders and healthy controls will only be assessed at one 6-hour study visit. Kuvan non-responders will be assessed at two study visits (a baseline visit, and a visit after two weeks of Kuvan therapy). Values will be assessed groupwise and also assessed for intrapersonal change in the Kuvan non-responsive group. Time frame of participation is estimated at one month.
Time frame: CRP will be measured every other hour for six hours at baseline (study visit 1) for all study groups and again during a second visit 2 weeks after baseline in BH4 Non-Responders only (study visit 2)
Population: Study was terminated due to difficulty recruiting patients, thus analysis was limited to preliminary data on 11 patients only. CRP was measured in 10 subjects - data were unavailable for 1 control participant due to inadequate sample volume.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BH4 Non-Responders | C-Reactive Protein (CRP) | Baseline, prior to meal challenge (n=3, 2, 5) | 1.46 mg/dl | Standard Deviation 1.47 |
| BH4 Non-Responders | C-Reactive Protein (CRP) | 2-hours post meal (n=3, 2, 5) | 1.50 mg/dl | Standard Deviation 1.49 |
| BH4 Non-Responders | C-Reactive Protein (CRP) | 4-hours post meal (n=3, 2, 5) | 1.55 mg/dl | Standard Deviation 1.5 |
| BH4 Non-Responders | C-Reactive Protein (CRP) | 6-hours post meal (n=3, 2, 5) | 1.59 mg/dl | Standard Deviation 1.6 |
| BH4 Non-Responders | C-Reactive Protein (CRP) | Baseline V2, prior to meal challenge (n=3, 0, 0) | 1.51 mg/dl | Standard Deviation 1.56 |
| BH4 Non-Responders | C-Reactive Protein (CRP) | 2-hours post meal (V2; n=3, 0, 0) | 1.55 mg/dl | Standard Deviation 1.67 |
| BH4 Non-Responders | C-Reactive Protein (CRP) | 4-hours post meal (V2; n=3, 0, 0) | 1.79 mg/dl | Standard Deviation 2.11 |
| BH4 Non-Responders | C-Reactive Protein (CRP) | 6-hours post meal (V2; n=3, 0, 0) | 1.58 mg/dl | Standard Deviation 1.69 |
| Healthy Controls | C-Reactive Protein (CRP) | 4-hours post meal (n=3, 2, 5) | 0.55 mg/dl | Standard Deviation 0.18 |
| Healthy Controls | C-Reactive Protein (CRP) | 4-hours post meal (V2; n=3, 0, 0) | NA mg/dl | — |
| Healthy Controls | C-Reactive Protein (CRP) | 6-hours post meal (n=3, 2, 5) | 0.55 mg/dl | Standard Deviation 0.11 |
| Healthy Controls | C-Reactive Protein (CRP) | Baseline V2, prior to meal challenge (n=3, 0, 0) | NA mg/dl | — |
| Healthy Controls | C-Reactive Protein (CRP) | 2-hours post meal (V2; n=3, 0, 0) | NA mg/dl | — |
| Healthy Controls | C-Reactive Protein (CRP) | Baseline, prior to meal challenge (n=3, 2, 5) | 0.61 mg/dl | Standard Deviation 0.14 |
| Healthy Controls | C-Reactive Protein (CRP) | 2-hours post meal (n=3, 2, 5) | 0.58 mg/dl | Standard Deviation 0.12 |
| Healthy Controls | C-Reactive Protein (CRP) | 6-hours post meal (V2; n=3, 0, 0) | NA mg/dl | — |
| BH4 Responders | C-Reactive Protein (CRP) | 4-hours post meal (n=3, 2, 5) | 0.96 mg/dl | Standard Deviation 1.33 |
| BH4 Responders | C-Reactive Protein (CRP) | 2-hours post meal (n=3, 2, 5) | 0.99 mg/dl | Standard Deviation 1.4 |
| BH4 Responders | C-Reactive Protein (CRP) | Baseline, prior to meal challenge (n=3, 2, 5) | 1.04 mg/dl | Standard Deviation 1.48 |
| BH4 Responders | C-Reactive Protein (CRP) | 6-hours post meal (n=3, 2, 5) | 0.90 mg/dl | Standard Deviation 1.24 |
| BH4 Responders | C-Reactive Protein (CRP) | 4-hours post meal (V2; n=3, 0, 0) | NA mg/dl | — |
| BH4 Responders | C-Reactive Protein (CRP) | 2-hours post meal (V2; n=3, 0, 0) | NA mg/dl | — |
| BH4 Responders | C-Reactive Protein (CRP) | Baseline V2, prior to meal challenge (n=3, 0, 0) | NA mg/dl | — |
| BH4 Responders | C-Reactive Protein (CRP) | 6-hours post meal (V2; n=3, 0, 0) | NA mg/dl | — |
Primary
Lipid Peroxidation
Markers will be assessed every other hour for each 6-hour study visit. Kuvan responders and healthy controls will only be assessed at one 6-hour study visit. Kuvan non-responders will be assessed at two study visits (a baseline visit, and a visit after two weeks of Kuvan therapy). Values will be assessed groupwise and also assessed for intrapersonal change in the Kuvan non-responsive group. Time frame of participation is estimated at one month.
Time frame: Lipid peroxidation will be measured every other hour for six hours at baseline (study visit 1) for all study groups
Population: Study was terminated due to difficulty recruiting patients, thus analysis was limited to preliminary data on 11 patients only. TBARS was measured in 3 BH4 responders only - data were unavailable for 8 other participants (2 responders, 3 non-responders, and 3 controls) due to inadequate sample volume.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BH4 Responders | Lipid Peroxidation | Baseline (prior to meal challenge) | 0.57 umole/L | Standard Deviation 0.33 |
| BH4 Responders | Lipid Peroxidation | 2-hours post meal | 0.62 umole/L | Standard Deviation 0.53 |
| BH4 Responders | Lipid Peroxidation | 4-hours post meal | 0.73 umole/L | Standard Deviation 0.39 |
| BH4 Responders | Lipid Peroxidation | 6-hours post meal | 0.78 umole/L | Standard Deviation 0.47 |