Trial Outcomes & Findings for Fluorodeoxyglucose Positron Emission Tomography (FDG PET) Findings in Patients With Phenylketonuria Before and After KUVAN Therapy (NCT NCT00986973)

NCT ID: NCT00986973

Last Updated: 2015-06-08

Results Overview

Plasma phenylalanine level (mg/dl) served as the primary means of evaluating brain glucose metabolism before and after sapropterin (KUVAN) therapy. Blood tests for phenylalanine levels (Phe) were collected before and 4 months after sapropterin (KUVAN) therapy. All subjects received KUVAN at a dose of 20/mg/kg/day for four months. The goal was to estimate the change in blood glucose metabolism after treatment with Sapropterin (if any), with the hypothesis that treatment would decrease plasma Phe levels.

• Recruitment status: COMPLETED
• Study phase: NA
• Target enrollment: 6 participants
• Primary outcome timeframe: Measurements were obtained at the beginning and conclusion of each study period (baseline and 4 months)
• Results posted on: 2015-06-08

Participant Flow

Patients with Classical PKU who were being followed at Children's Hospital of Philadelphia were recruited between 2010 and 2011. Study participation was presented during routine clinic visits and interested subjects were screened for eligibility. A flier was posted on PKU support group websites help recruit additional subjects.

Six adults (4 male and 2 females) were interested in participating in the study, each signed informed consent forms and were screened for eligibility. All six were enrolled.

Participant milestones

Measure	Sapropterin (KUVAN) All subjects received 20 mg/kg/day Sapropterin (KUVAN) for four months. Subjects were examined with fluorodeoxyglucose positron emission tomography (FDG-PET) brain imaging, physical and neurological exam, blood tests for phenylalanine (Phe) and tyrosine levels, and neuropsychological testing before and 4 months after KUVAN therapy. Subjects' Phe and tyrosine levels were monitored weekly during the study and subjects kept 3-day diet records to allow for calculation of Phe intake.
Overall Study STARTED	6
Overall Study COMPLETED	5
Overall Study NOT COMPLETED	1

Reasons for withdrawal

Measure

Sapropterin (KUVAN) All subjects received 20 mg/kg/day Sapropterin (KUVAN) for four months. Subjects were examined with fluorodeoxyglucose positron emission tomography (FDG-PET) brain imaging, physical and neurological exam, blood tests for phenylalanine (Phe) and tyrosine levels, and neuropsychological testing before and 4 months after KUVAN therapy. Subjects' Phe and tyrosine levels were monitored weekly during the study and subjects kept 3-day diet records to allow for calculation of Phe intake.

Overall Study Withdrawn by study team

1

Baseline Characteristics

Fluorodeoxyglucose Positron Emission Tomography (FDG PET) Findings in Patients With Phenylketonuria Before and After KUVAN Therapy

Baseline characteristics by cohort

Measure	Sapropterin (KUVAN) n=6 Participants All subjects received 20 mg/kg/day KUVAN for four months.
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	6 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants
Age, Continuous	31 years STANDARD_DEVIATION 11.8 • n=5 Participants
Sex: Female, Male Female	2 Participants n=5 Participants
Sex: Female, Male Male	4 Participants n=5 Participants
Region of Enrollment United States	6 participants n=5 Participants

PRIMARY outcome

Timeframe: Measurements were obtained at the beginning and conclusion of each study period (baseline and 4 months)

Population: 1 subject was withdrawn from the study due to poor compliance with KUVAN therapy.

Plasma phenylalanine level (mg/dl) served as the primary means of evaluating brain glucose metabolism before and after sapropterin (KUVAN) therapy. Blood tests for phenylalanine levels (Phe) were collected before and 4 months after sapropterin (KUVAN) therapy. All subjects received KUVAN at a dose of 20/mg/kg/day for four months. The goal was to estimate the change in blood glucose metabolism after treatment with Sapropterin (if any), with the hypothesis that treatment would decrease plasma Phe levels.

Outcome measures

Measure	Sapropterin (KUVAN) Therapy n=5 Participants All subjects received KUVAN at a dose of 20/mg/kg/day for four months. Blood Phe levels were measured drawn before therapy and 4 months after starting therapy.
Plasma Phenylalanine Level (mg/dl) Phe Level Before KUVAN Therapy (mg/dl)	18.0 mg/dl Standard Deviation 18.95
Plasma Phenylalanine Level (mg/dl) Phe Level 4 Months After KUVAN Therapy (mg/dl)	17.2 mg/dl Standard Deviation 16.35

SECONDARY outcome

Timeframe: Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)

Population: 1 Subject was withdrawn from the study due to poor compliance with KUVAN therapy and did not complete all HVLT assessments.

The Hopkins Verbal Learning Test-Revised (HVLT) is a neuropsychological test designed to assess verbal memory. The test consists of 12 nouns (targets) with four words drawn from each of three semantic categories. Raw scores are derived for Total Recall (across three learning trials), Delayed Recall (after 20-25 minute delay), Retention (% retained), and a Recognition Discrimination Index (true positives minus false positives). The maximum total for each recall trial (Learning Trials 1 to 3, Delayed Recall Trial 4) is 12. Raw scores are converted to "T-scores" by means of age-based tables provided in test manual (T-scores can go from 0 - 100, with higher scores correlating with higher verbal memory function). Median HVLT Total Recall and HVLT Delayed Recall T-scores at baseline and 4 months after Sapropterin therapy were compared.

Outcome measures

Measure	Sapropterin (KUVAN) Therapy n=5 Participants All subjects received KUVAN at a dose of 20/mg/kg/day for four months. Blood Phe levels were measured drawn before therapy and 4 months after starting therapy.
Hopkins Verbal Learning Test (HVLT) Total Recall HVLT Total Recall T-Score at Baseline	51 units on a scale Interval 27.5 to 57.0
Hopkins Verbal Learning Test (HVLT) Total Recall HVLT Total Recall T-Score Post-Sapropterin	53 units on a scale Interval 29.0 to 54.0

SECONDARY outcome

Timeframe: Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)

Population: 1 Subject was withdrawn from the study due to poor compliance with KUVAN therapy and did not complete all HVLT assessments.

The Hopkins Verbal Learning Test-Revised (HVLT) is a neuropsychological test designed to assess verbal memory. The test consists of 12 nouns (targets) with four words drawn from each of three semantic categories. Raw scores are derived for Total Recall (across three learning trials), Delayed Recall (after 20-25 minute delay), Retention (% retained), and a Recognition Discrimination Index (true positives minus false positives). The maximum total for each recall trial (Learning Trials 1 to 3, Delayed Recall Trial 4) is 12. Raw scores are converted to "T-scores" by means of age-based tables provided in test manual (T-scores can go from 0 - 100, with higher scores correlating with higher verbal memory function). Median HVLT Total Recall and HVLT Delayed Recall T-scores at baseline and 4 months after Sapropterin therapy were compared.

Outcome measures

Measure	Sapropterin (KUVAN) Therapy n=5 Participants All subjects received KUVAN at a dose of 20/mg/kg/day for four months. Blood Phe levels were measured drawn before therapy and 4 months after starting therapy.
Hopkins Verbal Learning Test (HVLT) Delayed Recall HVLT Delayed Recall T-Score at Baseline	47 units on a scale Interval 25.0 to 75.0
Hopkins Verbal Learning Test (HVLT) Delayed Recall HVLT Delayed Recall T-Score Post-Sapropterin	49 units on a scale Interval 33.5 to 56.5

SECONDARY outcome

Timeframe: Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)

Population: 1 Subject was withdrawn from the study due to poor compliance with KUVAN therapy and did not complete all PASATassessments.

The Adapted Paced Auditory Serial Addition Task (PASAT) is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability. For Rates #1 and #2, single digits are presented every 3 seconds and the patient must add each new digit to the one immediately prior to it. The score for PASAT is the total number of correct answers (out of 60, for a total possible score ranging from 0-60 with higher score preferred as it indicates higher auditory processing speed) for each trial. All scores are expressed as "z-scores" which are generated based on norms for 101 healthy adults, with separate norms for <12 years of education versus >12years of education. Using a reference population as a basis of comparison, the "z-score" is the number of standard deviations the score is above (positive) or below (negative) the mean of the reference population (zero). Possible z-scores lie on a continuous scale.

Outcome measures

Measure	Sapropterin (KUVAN) Therapy n=5 Participants All subjects received KUVAN at a dose of 20/mg/kg/day for four months. Blood Phe levels were measured drawn before therapy and 4 months after starting therapy.
Paced Auditory Serial Addition Task (PASAT) PASAT Z-score at Baseline	0.4700 units on a scale Interval -0.6375 to 0.745
Paced Auditory Serial Addition Task (PASAT) PASAT Rate #1 Z-score Post-Sapropterin	0.94 units on a scale Interval 0.8075 to 1.1775

SECONDARY outcome

Timeframe: Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)

Population: 1 Subject was withdrawn from the study due to poor compliance with KUVAN therapy and did not complete all SMTD assessments.

The symbol-digit modalities test (SDMT) was developed to identify individuals with neurological impairment. The SDMT requires individuals to identify nine different symbols corresponding to the numbers 1 through 9, and to practice writing the correct number under the corresponding symbol. Then they manually fill the blank space under each symbol with the corresponding number. A second oral administration is then completed. The participant is given a blank copy of the test and asked to state the correct number for each corresponding symbol. The participant is given 90 s to complete each of these administrations. A written and oral score is calculated by totaling the number of correct answers for each section. The score is the number of correctly coded items from 0-110 in 90 seconds, with a higher score representing less neurological impairment with respect to attention, scanning abilities and motor skills. The total raw score was used for purposes of this study.

Outcome measures

Measure	Sapropterin (KUVAN) Therapy n=5 Participants All subjects received KUVAN at a dose of 20/mg/kg/day for four months. Blood Phe levels were measured drawn before therapy and 4 months after starting therapy.
Symbol-Digit Modalities Test (SMTD) SDMT Raw Score at Baseline	63 units on a scale Interval 38.0 to 75.5
Symbol-Digit Modalities Test (SMTD) SDMT Raw Score Post-Sapropterin	79 units on a scale Interval 41.5 to 80.5

SECONDARY outcome

Timeframe: Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)

Population: 1 Subject was withdrawn from the study due to poor compliance with KUVAN therapy and did not complete all WAIS-IV assessments.

The Wechsler Adult Intelligence Scale (WAIS) is a test designed to measure intelligence in adults and older adolescents. It is composed of 10 core subtests and five supplemental subtests, with the 10 core subtests comprising the Full Scale intelligence quotient (IQ). Contained within the WAIS is an assessment of digit-coding which consists of nine digit-symbol pairs followed by a list of digits. Under each digit the subject should write down the corresponding symbol as fast as possible. The number of correct symbols within the allowed time (e.g. 90 or 120 sec) is measured, with a higher score representative of a higher performance component of IQ/intelligence.

Outcome measures

Measure	Sapropterin (KUVAN) Therapy n=5 Participants All subjects received KUVAN at a dose of 20/mg/kg/day for four months. Blood Phe levels were measured drawn before therapy and 4 months after starting therapy.
Wechsler Adult Intelligence Scale (WAIS-IV)-Digit Span WAIS-IV Digit Span Raw Score at Baseline	33 Number of correct symbols Interval 19.5 to 35.5
Wechsler Adult Intelligence Scale (WAIS-IV)-Digit Span WAIS-IV Digit Span Raw Score after Sapropterin	37 Number of correct symbols Interval 19.5 to 38.0

SECONDARY outcome

Timeframe: Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months)

Population: 1 Subject was withdrawn from the study due to poor compliance with KUVAN therapy and did not complete all assessments.

The Delis-Kaplan Executive Function System (D-KEFS) is a neuropsychological test is used to measure a variety of verbal and nonverbal executive functions for both children and adults. Among the 9 subtests is the Verbal Fluency Test which measures letter fluency, category fluency, and category switching. Verbal Fluency Test. This subtest requires an individual to randomly generate words based upon given parameters (ex., as words beginning with the letter F) and the believed areas of executive function assessed are cognitive flexibility, response inhibition, and verbal fluency. Raw scores are calculated based on the number of correct answers, which are then converted to scaled scores with a mean of 10 and standard deviation of 3. Higher scaled score represents a higher level of executive verbal and nonverbal function.

Outcome measures

Measure	Sapropterin (KUVAN) Therapy n=5 Participants All subjects received KUVAN at a dose of 20/mg/kg/day for four months. Blood Phe levels were measured drawn before therapy and 4 months after starting therapy.
Delis-Kaplan Executive Function System Verbal Fluency Subtest (D-KEFS) Scaled D-KEFS Fluency Score at baseline	10 units on a scale Interval 5.0 to 10.0
Delis-Kaplan Executive Function System Verbal Fluency Subtest (D-KEFS) Scaled D-KEFS Fluency Score after Sapropterin	11 units on a scale Interval 5.0 to 12.5

Adverse Events

Sapropterin (KUVAN) Therapy

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

Dr. Can Ficicioglu

The Children's Hospital of Philadelphia

Phone: 2155905876

Email: ficicioglu@email.chop.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place