A Phase 3 Substudy to Evaluate Executive Function in Adults With PKU Who Are Participating in the Phase 3 Study, 165-302

Study Overview
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Brief Summary
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A Phase 3 substudy to evaluate executive function in adults with phenylketonuria who are participating in the phase 3 Study, 165-302. Approximately 100 subjects, aged ≥ 18 to ≤ 70 years old, with PKU will be enrolled.

Detailed Description
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Study 165-303, is a Phase 3 substudy enrolling approximately 100 subjects, aged ≥ 18 to ≤ 70 years old, with PKU who are participating in the Phase 3 study, 165-302. Per the 165-303 protocol, the investigator does not assign a specific intervention to the study participants. In accordance with the protocol for Study 165-303, subjects were asked to perform selected set of three tasks from the CANTAB tool (Rapid Visual Processing [RVP], Spatial Working Memory [SWM], and Stop Signal Task [SST]) to assess executive function and each subject's self perception of their current state was measured using a subject global assessment questionnaire that contains seven questions about current state perception of attention, energy level, tiredness, confusion, sadness, anger and tension. The time points for administering the above tools are as follows, which coincide with time points in part 2 and part 4 of Study 165-302: screening (entry into Part 2 165-302 Day 1 of Week 1), baseline visit (Part 2 Week 8), and 3 additional study visits at different time points in the Part 4 of 165-302 study.

Official Title
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A Phase 3 Substudy to Evaluate Executive Function in Adults With Phenylketonuria Who Are Participating in the Phase 3 Study, 165-302

Conditions
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Phenylketonuria

Intervention / Treatment
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* Other: Administration of CANTAB and Subject Global Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are currently participating in Part 1 of Study 165-302 and meet the criteria for participation in Part 2 of 165-302 Are willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to any research-related procedures. Have the ability to complete the CANTAB and subject global assessment. Are willing and able to comply with all study procedures. Exclusion Criteria: Any condition that, in the view of the investigator, places the subject at high risk of poor compliance or terminating early from the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Other: Administration of CANTAB and Subject Global Assessment|At designated visits, subject will perform the CANTAB tasks and complete the Subject Global Assessment Questionnaire|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Rapid Visual Processing (RVP) Mean Response Latency (CANTAB Task) | The RVP task measures sustained attention. In this task, a series of random digits continuously appears in the middle of the screen. Subjects are asked to recognize a specific sequence of digits and are asked to press a button on the screen whenever this specific sequence of digits appears within this series of continuous digits. RVP mean latency is the mean response latency during assessment sequence blocks where the subject responded correctly (Latency units are milliseconds). Lower scores represent better performance. Observed range for Pooled Active: -103.1 to 65.5 (change from baseline) Observed range for Pooled Placebo: -10.4 to 39.0 (change from baseline) | Baseline to Part 2 Week 8 | 
| Change From Baseline in Spatial Working Memory (SWM) Between Errors 4-8 Boxes (CANTAB Task) | The SWM task measures visuospatial working memory. During this task, a number of boxes appears on a screen. The objective of the task is to find a token under a box and to place this token in a designated area. There is only one token under one box during each round and the location of the token rotates in each round to a different box, other than a box within which the token was found in previous rounds. The subject is therefore asked to remember which boxes previously contained tokens so as to better the chances and speed of finding tokens under boxes which did not previously contain tokens. SWM between errors measures the total number of times the subject revisits a box in which a token has previously been found in the same problem (calculated for assessed problems only). Observed range for Pooled Active: -8 to 1 (change from baseline) Observed range for Pooled Placebo: -5 to 12 (change from baseline) Lower scores represent better performance. | Baseline to Part 2 Week 8 | 
| Change From Baseline in Stop Signal Task (SST) Stop Signal Reaction T (CANTAB Task) | The SST task measures inhibitory control and cognitive flexibility. The SST is a 2-part task. During part 1, an arrow appears on the screen and subjects are asked to press an arrow button on the screen corresponding with the direction of the arrow displayed. During part 2 of the task, subjects follow the same instructions as in part 1; however, they are asked to withhold their response (do not press an arrow button) if they hear an auditory signal (beep) when the arrow is displayed. SST stop signal delay is the length of time between the go stimulus and the stop stimulus at which the subject is able to successfully inhibit their response on 50% of trials. Lower time represents better performance. Observed range for Pooled Active: -31.6 to 48.7 (change from baseline) Observed range for Pooled Placebo: 47.8 to 72.5 (change from baseline) | Baseline to Part 2 Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in RVP A Prime - Signal Detection Measure of Sensitivity to the Target (CANTAB Task) | The RVP task measures sustained attention. In this task, a series of random digits continuously appears in the middle of the screen. Subjects are asked to recognize a specific sequence of digits and are asked to press a button on the screen whenever this specific sequence of digits appears within this series of continuous digits. RVP A prime represents the signal detection measure of sensitivity to the target, regardless of response tendency. In essence, measure of how good the subject is at detecting target sequences. Observed range for Pooled Active: -0.004 to 0.030 (change from baseline) Observed range for Pooled Placebo: -0.057 to -0.001 (change from baseline) A higher score on the test represents a better performance. | Baseline to Part 2 Week 8 | 
| Change From the Baseline in SWM Strategy 6-8 Boxes - Number of Distinct Boxes Used by the Subject to Begin a New Search for a Token(CANTAB Task) | The SWM task measures visuospatial working memory. During this task, a number of boxes appears on a screen. The objective of the task is to find a token under a box and to place this token in a designated area. There is only one token under one box during each round and the location of the token rotates in each round to a different box, other than a box within which the token was found in previous rounds. The subject is therefore asked to remember which boxes previously contained tokens so as to better the chances and speed of finding tokens under boxes which did not previously contain tokens. For assessed problems with six boxes or more, SWM strategy is the number of distinct boxes used by the subject to begin a new search for a token (within the same problem). A high score represents poor use of this strategy and a low score equates to effective use. Observed range for Pooled Active: -3 to 3 (change from baseline) Observed range for Pooled Placebo: -3 to 1(change from baseline) | Baseline to Part 2 Week 8 | 
| Change From Baseline in SST Proportion of Successful Stops - Measures the Proportion of Completed Stop Trials That Were Successful Stops (CANTAB Task) | The SST task measures inhibitory control and cognitive flexibility. The SST is a 2-part task. During part 1, an arrow appears on the screen and subjects are asked to press an arrow button on the screen corresponding with the direction of the arrow displayed. During part 2 of the task, subjects follow the same instructions as in part 1; however, they are asked to withhold their response (do not press an arrow button) if they hear an auditory signal (beep) when the arrow is displayed. SST stop signal delay is the length of time between the go stimulus and the stop stimulus at which the subject is able to successfully inhibit their response on 50% of trials. SST proportion of successful stops measures the proportion of completed stop trials that were successful stops. A higher score on the test represents a better performance. Observed range for Pooled Active: -0.1 to 0.05 (change from baseline) Observed range for Pooled Placebo: 0.0 to 0.0 (change from baseline) | Baseline to Part 2 Week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PEG-PAL, PKU, Pegvaliase, BMN 165, rAv-PAL PEG, PRISM 302, PRISM 303, BioMarin, 165-302