Trial Outcomes & Findings for Phenylketonuria, Oxidative Stress, and BH4 (NCT NCT01395394)

Last Updated: 2014-08-28

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

12 participants

Primary outcome timeframe

Lipid peroxidation will be measured every other hour for six hours at baseline (study visit 1) for all study groups

Results posted on

2014-08-28

Participant Flow

Participant milestones

Participant milestones
Measure	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	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	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
Baseline Study Visit STARTED	4	3	5
Baseline Study Visit COMPLETED	3	3	5
Baseline Study Visit NOT COMPLETED	1	0	0
Study Visit 2 (Non-responders Only) STARTED	3	0	0
Study Visit 2 (Non-responders Only) COMPLETED	3	0	0
Study Visit 2 (Non-responders Only) NOT COMPLETED	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	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	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	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
Baseline Study Visit Protocol Violation	1	0	0

Baseline Characteristics

Phenylketonuria, Oxidative Stress, and BH4

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	BH4 Non-Responders n=4 Participants 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	Healthy Controls n=3 Participants 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	BH4 Responders n=5 Participants 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	Total n=12 Participants Total of all reporting groups
Age, Continuous	33.9 years STANDARD_DEVIATION 13.4 • n=93 Participants	33.5 years STANDARD_DEVIATION 15.7 • n=4 Participants	18.5 years STANDARD_DEVIATION 3.8 • n=27 Participants	27.4 years STANDARD_DEVIATION 12.6 • n=483 Participants
Age, Categorical <=18 years	1 Participants n=93 Participants	1 Participants n=4 Participants	2 Participants n=27 Participants	4 Participants n=483 Participants
Age, Categorical Between 18 and 65 years	3 Participants n=93 Participants	2 Participants n=4 Participants	3 Participants n=27 Participants	8 Participants n=483 Participants
Age, Categorical >=65 years	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Sex: Female, Male Female	1 Participants n=93 Participants	1 Participants n=4 Participants	0 Participants n=27 Participants	2 Participants n=483 Participants
Sex: Female, Male Male	3 Participants n=93 Participants	2 Participants n=4 Participants	5 Participants n=27 Participants	10 Participants n=483 Participants
Region of Enrollment United States	4 participants n=93 Participants	3 participants n=4 Participants	5 participants n=27 Participants	12 participants n=483 Participants
high-sensitivity CRP	1.3 mg/L STANDARD_DEVIATION 1.2 • n=93 Participants	0.61 mg/L STANDARD_DEVIATION 0.14 • n=4 Participants	1.04 mg/L STANDARD_DEVIATION 1.48 • n=27 Participants	1.06 mg/L STANDARD_DEVIATION 1.19 • n=483 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	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	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	BH4 Responders n=3 Participants 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
Lipid Peroxidation Baseline (prior to meal challenge)	—	—	0.57 umole/L Standard Deviation 0.33
Lipid Peroxidation 2-hours post meal	—	—	0.62 umole/L Standard Deviation 0.53
Lipid Peroxidation 4-hours post meal	—	—	0.73 umole/L Standard Deviation 0.39
Lipid Peroxidation 6-hours post meal	—	—	0.78 umole/L Standard Deviation 0.47

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	BH4 Non-Responders n=3 Participants 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	Healthy Controls n=2 Participants 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	BH4 Responders n=5 Participants 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
C-Reactive Protein (CRP) Baseline, prior to meal challenge (n=3, 2, 5)	1.46 mg/dl Standard Deviation 1.47	0.61 mg/dl Standard Deviation 0.14	1.04 mg/dl Standard Deviation 1.48
C-Reactive Protein (CRP) 2-hours post meal (n=3, 2, 5)	1.50 mg/dl Standard Deviation 1.49	0.58 mg/dl Standard Deviation 0.12	0.99 mg/dl Standard Deviation 1.40
C-Reactive Protein (CRP) 4-hours post meal (n=3, 2, 5)	1.55 mg/dl Standard Deviation 1.50	0.55 mg/dl Standard Deviation 0.18	0.96 mg/dl Standard Deviation 1.33
C-Reactive Protein (CRP) 6-hours post meal (n=3, 2, 5)	1.59 mg/dl Standard Deviation 1.60	0.55 mg/dl Standard Deviation 0.11	0.90 mg/dl Standard Deviation 1.24
C-Reactive Protein (CRP) Baseline V2, prior to meal challenge (n=3, 0, 0)	1.51 mg/dl Standard Deviation 1.56	NA mg/dl Standard Deviation NA Controls did not complete Study Visit 2	NA mg/dl Standard Deviation NA BH4 Responders did not complete Study Visit 2
C-Reactive Protein (CRP) 2-hours post meal (V2; n=3, 0, 0)	1.55 mg/dl Standard Deviation 1.67	NA mg/dl Standard Deviation NA Controls did not complete Study Visit 2	NA mg/dl Standard Deviation NA BH4 Responders did not complete Study Visit 2
C-Reactive Protein (CRP) 4-hours post meal (V2; n=3, 0, 0)	1.79 mg/dl Standard Deviation 2.11	NA mg/dl Standard Deviation NA Controls did not complete Study Visit 2	NA mg/dl Standard Deviation NA BH4 Responders did not complete Study Visit 2
C-Reactive Protein (CRP) 6-hours post meal (V2; n=3, 0, 0)	1.58 mg/dl Standard Deviation 1.69	NA mg/dl Standard Deviation NA Controls did not complete Study Visit 2	NA mg/dl Standard Deviation NA BH4 Responders did not complete Study Visit 2

Adverse Events

BH4 Non-Responders

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Healthy Controls

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

BH4 Responders

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Kathryn Coakley

Emory University

Phone: 404-778-1286

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place