<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03788343</url>
  </required_header>
  <id_info>
    <org_study_id>2018-01609</org_study_id>
    <secondary_id>3837</secondary_id>
    <nct_id>NCT03788343</nct_id>
  </id_info>
  <brief_title>Phenylalanine and Its Impact on Cognition</brief_title>
  <acronym>PICO</acronym>
  <official_title>PICO: Phenylalanine and Its Impact on Cognition - Impact of Phenylalanine on Cognitive, Cerebral and Neurometabolic Parameters in Adult Patients With Phenylketonuria</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Insel Gruppe AG, University Hospital Bern</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Zurich</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Insel Gruppe AG, University Hospital Bern</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The PICO-Study is a randomized, placebo-controlled, crossover, non-inferiority trial&#xD;
      conducted to add evidence to the current European treatment guidelines for adult patients&#xD;
      with phenylketonuria.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Phenylketonuria (PKU) is a rare autosomal recessive disorder caused by deficiency of the&#xD;
      phenylalanine hydroxylase enzyme leading to an impaired conversion of the amino acid&#xD;
      phenylalanine (Phe) to tyrosine. Increased Phe concentrations in blood and brain during&#xD;
      childhood can lead to severe intellectual disability, epilepsy and behavioral problems.&#xD;
      However, since the introduction of newborn screening and early treatment with a dietary&#xD;
      restriction of Phe (low protein diet) and Phe-free protein substitutes (amino acid mixtures)&#xD;
      initiated soon after birth, patient with PKU no longer develop profound and irreversible&#xD;
      intellectual disability. While there is a wide agreement on the treatment strategy and target&#xD;
      Phe concentrations in childhood, no consensus on the safe Phe concentrations in adulthood has&#xD;
      been reached so far. Traditionally, the low protein diet had been enforced only during&#xD;
      childhood and adolescence, leaving adult patients with PKU &quot;off-diet&quot;. Over the last decade,&#xD;
      observational and cross-sectional studies associated high Phe in early-treated adult patients&#xD;
      with cognitive problems, psychiatric symptoms and behavioral abnormalities. These association&#xD;
      studies and one small interventional study led to substantially differing recommendations of&#xD;
      national and international guidelines with regard to Phe target levels in adult patients with&#xD;
      PKU. One of these guidelines is the highly controversial grade D recommendation of the most&#xD;
      recent European guidelines to keep Phe concentrations below 600 μmol/L throughout adulthood.&#xD;
      Consequently, the recommendations are not only unequally accepted by the treating metabolic&#xD;
      specialists, more than 50 % of adults with PKU exhibit substantial difficulty in maintaining&#xD;
      the compliance necessary to reach the recommended target Phe concentrations. Therefore,&#xD;
      prospective intervention studies in adult patients with PKU are strongly needed to evaluate&#xD;
      the effects of dietary restrictions on cognition, cerebral markers and quality of life. The&#xD;
      PICO-Study aims at adding evidence to current guidelines and improving treatment&#xD;
      recommendations. To this end, adult patients with PKU will participate in a randomized,&#xD;
      placebo-controlled, double-blind, crossover, non-inferiority trial. With the intervention,&#xD;
      the project evaluates the impact of temporarily elevated blood Phe levels on cognition and&#xD;
      functional properties of the brain of adult patients. Results of the PICO-Study will help to&#xD;
      increase knowledge about impaired cognitive functioning and neural abnormalities in adult&#xD;
      patients with PKU and will improve guidelines on dietary treatment in these patients. Such&#xD;
      guidelines can greatly influence clinical routine as well as patients' adherence to their&#xD;
      diet and ultimately their quality of life.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 19, 2019</start_date>
  <completion_date type="Actual">June 17, 2022</completion_date>
  <primary_completion_date type="Actual">June 17, 2022</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Working memory (accuracy)</measure>
    <time_frame>After intervention phase 1 (after 4 weeks from baseline)</time_frame>
    <description>Influence of 4 weeks of oral Phe administration vs. Placebo on working memory performance, assessed using accuracy in the n-back task of the Test of Attentional Performance (TAP) in adult patients with phenylketonuria (PKU).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Working memory (accuracy)</measure>
    <time_frame>After intervention phase 2 (after 12 weeks from baseline)</time_frame>
    <description>Influence of 4 weeks of oral Phe administration vs. Placebo on working memory performance, assessed using accuracy in the n-back task of the Test of Attentional Performance (TAP) in adult patients with PKU.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Working memory (reaction time)</measure>
    <time_frame>4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)</time_frame>
    <description>Influence of 4 weeks of oral Phe administration vs. Placebo on working memory performance, assessed using reaction time in the n-back task of the Test of Attentional Performance (TAP) in adult patients with PKU.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Inhibition</measure>
    <time_frame>4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)</time_frame>
    <description>Influence of 4 weeks of oral Phe administration vs. Placebo on inhibition assessed using the third condition of the color-word interference test of the Delis-Kaplan Executive Function System (D-KEFS) in adult patients with PKU.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cognitive flexibility</measure>
    <time_frame>4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)</time_frame>
    <description>Influence of 4 weeks of oral Phe administration vs. Placebo on cognitive flexibility assessed using the fourth condition of the color-word interference test of the D-KEFS in adult patients with PKU.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional Magnetic Resonance Imaging (fMRI) (working memory)</measure>
    <time_frame>4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)</time_frame>
    <description>Influence of 4 weeks of oral Phe administration vs. Placebo on intensity of cerebral activation during a working memory task assessed using an n-back task in the MR scanner in adult patients with PKU.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Resting-state fMRI</measure>
    <time_frame>4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)</time_frame>
    <description>Influence of 4 weeks of oral Phe administration vs. Placebo on strength of functional connectivity in brain regions related to working memory as assessed by resting-state fMRI in adult patients with PKU.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Magnetic Resonance Spectroscopy (MRS)</measure>
    <time_frame>4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)</time_frame>
    <description>Influence of 4 weeks of oral Phe administration vs. Placebo on brain Phe concentrations as measured by MRS in adult patients with PKU.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Diffusion Tensor Imaging (DTI)</measure>
    <time_frame>4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)</time_frame>
    <description>Influence of 4 weeks of oral Phe administration vs. Placebo on white matter integrity assessed using DTI in adult patients with PKU.</description>
  </other_outcome>
  <other_outcome>
    <measure>Arterial Spin Labeling (ASL)</measure>
    <time_frame>4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)</time_frame>
    <description>Influence of 4 weeks of oral Phe administration vs. Placebo on cerebral blood flow assessed using ASL in adult patients with PKU.</description>
  </other_outcome>
  <other_outcome>
    <measure>Structural MRI (cortical thickness) &amp; working memory</measure>
    <time_frame>Baseline</time_frame>
    <description>Relationship between cortical thickness and working memory (n-back task of the Test of Attentional Performance (TAP)) in adult patients with PKU.</description>
  </other_outcome>
  <other_outcome>
    <measure>Structural MRI (cortical surface area) &amp; working memory</measure>
    <time_frame>Baseline</time_frame>
    <description>Relationship between cortical surface area and working memory (n-back task of the Test of Attentional Performance (TAP)) in adult patients with PKU.</description>
  </other_outcome>
  <other_outcome>
    <measure>Structural MRI (cortical volume) &amp; working memory</measure>
    <time_frame>Baseline</time_frame>
    <description>Relationship between cortical volume and working memory (n-back task of the Test of Attentional Performance (TAP)) in adult patients with PKU.</description>
  </other_outcome>
  <other_outcome>
    <measure>Structural MRI (cortical curvature) &amp; working memory</measure>
    <time_frame>Baseline</time_frame>
    <description>Relationship between cortical curvature and working memory (n-back task of the Test of Attentional Performance (TAP)) in adult patients with PKU.</description>
  </other_outcome>
  <other_outcome>
    <measure>MRS &amp; working memory</measure>
    <time_frame>Baseline</time_frame>
    <description>Relationship between brain concentrations of Phe (MRS) and working memory (n-back task of the Test of Attentional Performance (TAP)) in adult patients with PKU.</description>
  </other_outcome>
  <other_outcome>
    <measure>Blood concentration of Phe &amp; working memory</measure>
    <time_frame>Baseline</time_frame>
    <description>Relationship between blood concentrations of Phe and working memory (n-back task of the Test of Attentional Performance (TAP)) in adult patients with PKU.</description>
  </other_outcome>
  <other_outcome>
    <measure>Working memory (accuracy): Patients vs. Controls</measure>
    <time_frame>Baseline</time_frame>
    <description>Differences in working memory performance, assessed using accuracy in the n-back task of the Test of Attentional Performance (TAP) between adult patients with PKU and healthy controls.</description>
  </other_outcome>
  <other_outcome>
    <measure>Working memory (reaction time): Patients vs. Controls</measure>
    <time_frame>Baseline</time_frame>
    <description>Differences in working memory performance, assessed using reaction time in the n-back task of the Test of Attentional Performance (TAP) between adult patients with PKU and healthy controls.</description>
  </other_outcome>
  <other_outcome>
    <measure>Inhibition: Patients vs. Controls</measure>
    <time_frame>Baseline</time_frame>
    <description>Differences in inhibition assessed using the third condition of the color-word interference test of the Delis-Kaplan Executive Function System (D-KEFS) between adult patients with PKU and healthy controls.</description>
  </other_outcome>
  <other_outcome>
    <measure>Cognitive flexibility: Patients vs. Controls</measure>
    <time_frame>Baseline</time_frame>
    <description>Differences in cognitive flexibility assessed using the fourth condition of the color-word interference test of the D-KEFS between adult patients with PKU and healthy controls.</description>
  </other_outcome>
  <other_outcome>
    <measure>DTI: Patients vs. Controls</measure>
    <time_frame>Baseline</time_frame>
    <description>Differences in white matter integrity (DTI) between adult patients with PKU and healthy controls.</description>
  </other_outcome>
  <other_outcome>
    <measure>fMRI of working memory: Patients vs. Controls</measure>
    <time_frame>Baseline</time_frame>
    <description>Differences in intensity of cerebral activation during a working memory task assessed using an n-back task in the MR scanner between adult patients with PKU and healthy controls.</description>
  </other_outcome>
  <other_outcome>
    <measure>ASL: Patients vs. Controls</measure>
    <time_frame>Baseline</time_frame>
    <description>Differences in cerebral blood flow assessed using ASL between adult patients with PKU and healthy controls.</description>
  </other_outcome>
  <other_outcome>
    <measure>Resting-state fMRI: Patients vs. Controls</measure>
    <time_frame>Baseline</time_frame>
    <description>Differences in strength of functional connectivity in brain regions related to working memory as assessed by resting-state fMRI between adult patients with PKU and healthy controls.</description>
  </other_outcome>
  <other_outcome>
    <measure>Structural MRI (cortical thickness): Patients vs. Controls</measure>
    <time_frame>Baseline</time_frame>
    <description>Differences in cortical thickness between adult patients with PKU and healthy controls.</description>
  </other_outcome>
  <other_outcome>
    <measure>Structural MRI (cortical surface area): Patients vs. Controls</measure>
    <time_frame>Baseline</time_frame>
    <description>Differences in cortical surface area between adult patients with PKU and healthy controls.</description>
  </other_outcome>
  <other_outcome>
    <measure>Structural MRI (cortical volume): Patients vs. Controls</measure>
    <time_frame>Baseline</time_frame>
    <description>Differences in cortical volume between adult patients with PKU and healthy controls.</description>
  </other_outcome>
  <other_outcome>
    <measure>Structural MRI (cortical curvature): Patients vs. Controls</measure>
    <time_frame>Baseline</time_frame>
    <description>Differences in cortical curvature between adult patients with PKU and healthy controls.</description>
  </other_outcome>
  <other_outcome>
    <measure>Mood (POMS)</measure>
    <time_frame>4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)</time_frame>
    <description>Influence of 4 weeks of oral Phe administration vs. Placebo on mood assessed using the short form of the Profile of Mood States (POMS) in adult patients with PKU.</description>
  </other_outcome>
  <other_outcome>
    <measure>Mood (BDI-II)</measure>
    <time_frame>4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)</time_frame>
    <description>Influence of 4 weeks of oral Phe administration vs. Placebo on mood assessed using Beck's Depression Inventory (BDI-II) in adult patients with PKU. The total score indicates severity, ranging from 0 (no depression) to 63 (severe depression).</description>
  </other_outcome>
  <other_outcome>
    <measure>PKU Quality of Life</measure>
    <time_frame>4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)</time_frame>
    <description>Influence of 4 weeks of oral Phe administration vs. Placebo on the total score in the questionnaire PKU quality of life (PKUQOL) in adult patients with PKU.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">90</enrollment>
  <condition>Phenylketonuria</condition>
  <arm_group>
    <arm_group_label>Phenylalanine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Capsules containing 250 mg Phenylalanine (Phe). The daily dose will be chosen according to gender and weight at the time of T1 and will be divided in 3 separate doses. The assigned dose of the IMP will be kept throughout the whole study and weight fluctuations will not be considered.&#xD;
Female&#xD;
&lt;60 kg: 1500 mg per day (divided in 3 doses): 250 mg 2-2-2-0&#xD;
≥60 kg: 2000 mg per day (divided in 3 doses): 250 mg 2-2-4-0&#xD;
Male&#xD;
&lt;60 kg: 2500 mg per day (divided in 3 doses): 250 mg 4-2-4-0&#xD;
≥60 kg: 3000 mg per day (divided in 3 doses): 250 mg 4-4-4-0&#xD;
Phe capsules can be ingested before, during or after a meal or together with other amino acid supplements. The last capsule of the given intervention period will be timed to be ingested with the last meal before the study visit.&#xD;
Patients will take Phe for 4 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Capsules containing 250mg Placebo. Placebo capsules will be administered in identical manner to Phe capsules.&#xD;
Patients will take the Placebo for 4 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Phenylalanine</intervention_name>
    <description>The study product Phenylalanine, a dietary supplement, is authorized in Switzerland, but not designated for this patient group.</description>
    <arm_group_label>Phenylalanine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo capsules are indistinguishable in their appearance from Phe capsules</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        PATIENTS&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  PKU diagnosed after a positive newborn screening&#xD;
&#xD;
          -  Treatment with Phe-restricted diet starting within the first 30 days of life&#xD;
&#xD;
          -  Age ≥18 years&#xD;
&#xD;
          -  Capable of following the study design&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with PKU not following a Phe-restricted diet within 6 months before the study&#xD;
&#xD;
          -  Phe concentration above 1600 µmol/L within 6 months before the study&#xD;
&#xD;
          -  Concomitant disease states suspected to significantly affect primary or secondary&#xD;
             outcomes, e. g. untreated vitamin B12 deficiency&#xD;
&#xD;
          -  Known or suspected non-compliance, drug or alcohol abuse&#xD;
&#xD;
          -  Change in medications likely to significantly interfere with cognitive function&#xD;
             testing&#xD;
&#xD;
          -  Known or suspected hypersensitivity or allergy to one of the ingredients of the&#xD;
             placebo&#xD;
&#xD;
          -  Women who are pregnant or intent to get pregnant during the course of the study or who&#xD;
             are breast feeding&#xD;
&#xD;
          -  Female participants of childbearing potential, not using and not willing to continue&#xD;
             using one (or more) highly efficient (Pearl index less than 1) method of contraception&#xD;
             for the entire study duration.&#xD;
&#xD;
          -  Inability to follow the procedures of the study, e. g. due to language problems (lack&#xD;
             of fluency in German or French), psychological disorders, dementia, etc. of the&#xD;
             participant.&#xD;
&#xD;
          -  Participation in another interventional study within the 30 days preceding and during&#xD;
             the present study.&#xD;
&#xD;
          -  Previous enrolment into the current study&#xD;
&#xD;
          -  Conditions interfering with MRI such as magnetic (metallic) particles in the skull or&#xD;
             brain, cardiac pacemaker, deep brain stimulators, cochlear implant, braces or&#xD;
             permanent retainers&#xD;
&#xD;
        HEALTHY CONTROLS&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥18 years&#xD;
&#xD;
          -  Comparable to patients with regard to age, gender and educational level&#xD;
&#xD;
          -  Capable of following the study design&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known or suspected drug or alcohol abuse&#xD;
&#xD;
          -  Change in medications likely to significantly interfere with cognitive function&#xD;
             testing&#xD;
&#xD;
          -  Women who are pregnant or intent to get pregnant during the course of the study or who&#xD;
             are breast feeding&#xD;
&#xD;
          -  Inability to follow the procedures of the study, e. g. due to language problems (lack&#xD;
             of fluency in German or French), psychological disorders, dementia, etc. of the&#xD;
             participant.&#xD;
&#xD;
          -  Participation in another interventional study within the 30 days preceding and during&#xD;
             the present study.&#xD;
&#xD;
          -  Previous enrolment into the current study&#xD;
&#xD;
          -  Conditions interfering with MRI such as magnetic (metallic) particles in the skull or&#xD;
             brain, cardiac pacemaker, deep brain stimulators, cochlear implant, braces or&#xD;
             permanent retainers&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Regula Everts, Prof. Dr. phil.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism (UDEM), Inselspital, Bern University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism (UDEM), Inselspital, Bern University Hospital</name>
      <address>
        <city>Bern</city>
        <zip>3010</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Switzerland</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>December 17, 2018</study_first_submitted>
  <study_first_submitted_qc>December 21, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 27, 2018</study_first_posted>
  <last_update_submitted>March 6, 2023</last_update_submitted>
  <last_update_submitted_qc>March 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 7, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Phenylketonuria</keyword>
  <keyword>PKU</keyword>
  <keyword>Phenylalanine</keyword>
  <keyword>Diet</keyword>
  <keyword>Neuropsychology</keyword>
  <keyword>Working Memory</keyword>
  <keyword>Neuroimaging</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Phenylketonurias</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03788343
org study id: 2018-01609
secondary id: 3837
nct id: NCT03788343
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The PICO-Study is a randomized, placebo-controlled, crossover, non-inferiority trial
      conducted to add evidence to the current European treatment guidelines for adult patients
      with phenylketonuria.
Phenylketonuria (PKU) is a rare autosomal recessive disorder caused by deficiency of the
      phenylalanine hydroxylase enzyme leading to an impaired conversion of the amino acid
      phenylalanine (Phe) to tyrosine. Increased Phe concentrations in blood and brain during
      childhood can lead to severe intellectual disability, epilepsy and behavioral problems.
      However, since the introduction of newborn screening and early treatment with a dietary
      restriction of Phe (low protein diet) and Phe-free protein substitutes (amino acid mixtures)
      initiated soon after birth, patient with PKU no longer develop profound and irreversible
      intellectual disability. While there is a wide agreement on the treatment strategy and target
      Phe concentrations in childhood, no consensus on the safe Phe concentrations in adulthood has
      been reached so far. Traditionally, the low protein diet had been enforced only during
      childhood and adolescence, leaving adult patients with PKU "off-diet". Over the last decade,
      observational and cross-sectional studies associated high Phe in early-treated adult patients
      with cognitive problems, psychiatric symptoms and behavioral abnormalities. These association
      studies and one small interventional study led to substantially differing recommendations of
      national and international guidelines with regard to Phe target levels in adult patients with
      PKU. One of these guidelines is the highly controversial grade D recommendation of the most
      recent European guidelines to keep Phe concentrations below 600 μmol/L throughout adulthood.
      Consequently, the recommendations are not only unequally accepted by the treating metabolic
      specialists, more than 50 % of adults with PKU exhibit substantial difficulty in maintaining
      the compliance necessary to reach the recommended target Phe concentrations. Therefore,
      prospective intervention studies in adult patients with PKU are strongly needed to evaluate
      the effects of dietary restrictions on cognition, cerebral markers and quality of life. The
      PICO-Study aims at adding evidence to current guidelines and improving treatment
      recommendations. To this end, adult patients with PKU will participate in a randomized,
      placebo-controlled, double-blind, crossover, non-inferiority trial. With the intervention,
      the project evaluates the impact of temporarily elevated blood Phe levels on cognition and
      functional properties of the brain of adult patients. Results of the PICO-Study will help to
      increase knowledge about impaired cognitive functioning and neural abnormalities in adult
      patients with PKU and will improve guidelines on dietary treatment in these patients. Such
      guidelines can greatly influence clinical routine as well as patients' adherence to their
      diet and ultimately their quality of life.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Supportive Care
masking: Double (Participant, Investigator)
measure: Working memory (accuracy)
time frame: After intervention phase 1 (after 4 weeks from baseline)
description: Influence of 4 weeks of oral Phe administration vs. Placebo on working memory performance, assessed using accuracy in the n-back task of the Test of Attentional Performance (TAP) in adult patients with phenylketonuria (PKU).
measure: Working memory (accuracy)
time frame: After intervention phase 2 (after 12 weeks from baseline)
description: Influence of 4 weeks of oral Phe administration vs. Placebo on working memory performance, assessed using accuracy in the n-back task of the Test of Attentional Performance (TAP) in adult patients with PKU.
measure: Working memory (reaction time)
time frame: 4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)
description: Influence of 4 weeks of oral Phe administration vs. Placebo on working memory performance, assessed using reaction time in the n-back task of the Test of Attentional Performance (TAP) in adult patients with PKU.
measure: Inhibition
time frame: 4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)
description: Influence of 4 weeks of oral Phe administration vs. Placebo on inhibition assessed using the third condition of the color-word interference test of the Delis-Kaplan Executive Function System (D-KEFS) in adult patients with PKU.
measure: Cognitive flexibility
time frame: 4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)
description: Influence of 4 weeks of oral Phe administration vs. Placebo on cognitive flexibility assessed using the fourth condition of the color-word interference test of the D-KEFS in adult patients with PKU.
measure: Functional Magnetic Resonance Imaging (fMRI) (working memory)
time frame: 4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)
description: Influence of 4 weeks of oral Phe administration vs. Placebo on intensity of cerebral activation during a working memory task assessed using an n-back task in the MR scanner in adult patients with PKU.
measure: Resting-state fMRI
time frame: 4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)
description: Influence of 4 weeks of oral Phe administration vs. Placebo on strength of functional connectivity in brain regions related to working memory as assessed by resting-state fMRI in adult patients with PKU.
measure: Magnetic Resonance Spectroscopy (MRS)
time frame: 4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)
description: Influence of 4 weeks of oral Phe administration vs. Placebo on brain Phe concentrations as measured by MRS in adult patients with PKU.
measure: Diffusion Tensor Imaging (DTI)
time frame: 4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)
description: Influence of 4 weeks of oral Phe administration vs. Placebo on white matter integrity assessed using DTI in adult patients with PKU.
measure: Arterial Spin Labeling (ASL)
time frame: 4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)
description: Influence of 4 weeks of oral Phe administration vs. Placebo on cerebral blood flow assessed using ASL in adult patients with PKU.
measure: Structural MRI (cortical thickness) & working memory
time frame: Baseline
description: Relationship between cortical thickness and working memory (n-back task of the Test of Attentional Performance (TAP)) in adult patients with PKU.
measure: Structural MRI (cortical surface area) & working memory
time frame: Baseline
description: Relationship between cortical surface area and working memory (n-back task of the Test of Attentional Performance (TAP)) in adult patients with PKU.
measure: Structural MRI (cortical volume) & working memory
time frame: Baseline
description: Relationship between cortical volume and working memory (n-back task of the Test of Attentional Performance (TAP)) in adult patients with PKU.
measure: Structural MRI (cortical curvature) & working memory
time frame: Baseline
description: Relationship between cortical curvature and working memory (n-back task of the Test of Attentional Performance (TAP)) in adult patients with PKU.
measure: MRS & working memory
time frame: Baseline
description: Relationship between brain concentrations of Phe (MRS) and working memory (n-back task of the Test of Attentional Performance (TAP)) in adult patients with PKU.
measure: Blood concentration of Phe & working memory
time frame: Baseline
description: Relationship between blood concentrations of Phe and working memory (n-back task of the Test of Attentional Performance (TAP)) in adult patients with PKU.
measure: Working memory (accuracy): Patients vs. Controls
time frame: Baseline
description: Differences in working memory performance, assessed using accuracy in the n-back task of the Test of Attentional Performance (TAP) between adult patients with PKU and healthy controls.
measure: Working memory (reaction time): Patients vs. Controls
time frame: Baseline
description: Differences in working memory performance, assessed using reaction time in the n-back task of the Test of Attentional Performance (TAP) between adult patients with PKU and healthy controls.
measure: Inhibition: Patients vs. Controls
time frame: Baseline
description: Differences in inhibition assessed using the third condition of the color-word interference test of the Delis-Kaplan Executive Function System (D-KEFS) between adult patients with PKU and healthy controls.
measure: Cognitive flexibility: Patients vs. Controls
time frame: Baseline
description: Differences in cognitive flexibility assessed using the fourth condition of the color-word interference test of the D-KEFS between adult patients with PKU and healthy controls.
measure: DTI: Patients vs. Controls
time frame: Baseline
description: Differences in white matter integrity (DTI) between adult patients with PKU and healthy controls.
measure: fMRI of working memory: Patients vs. Controls
time frame: Baseline
description: Differences in intensity of cerebral activation during a working memory task assessed using an n-back task in the MR scanner between adult patients with PKU and healthy controls.
measure: ASL: Patients vs. Controls
time frame: Baseline
description: Differences in cerebral blood flow assessed using ASL between adult patients with PKU and healthy controls.
measure: Resting-state fMRI: Patients vs. Controls
time frame: Baseline
description: Differences in strength of functional connectivity in brain regions related to working memory as assessed by resting-state fMRI between adult patients with PKU and healthy controls.
measure: Structural MRI (cortical thickness): Patients vs. Controls
time frame: Baseline
description: Differences in cortical thickness between adult patients with PKU and healthy controls.
measure: Structural MRI (cortical surface area): Patients vs. Controls
time frame: Baseline
description: Differences in cortical surface area between adult patients with PKU and healthy controls.
measure: Structural MRI (cortical volume): Patients vs. Controls
time frame: Baseline
description: Differences in cortical volume between adult patients with PKU and healthy controls.
measure: Structural MRI (cortical curvature): Patients vs. Controls
time frame: Baseline
description: Differences in cortical curvature between adult patients with PKU and healthy controls.
measure: Mood (POMS)
time frame: 4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)
description: Influence of 4 weeks of oral Phe administration vs. Placebo on mood assessed using the short form of the Profile of Mood States (POMS) in adult patients with PKU.
measure: Mood (BDI-II)
time frame: 4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)
description: Influence of 4 weeks of oral Phe administration vs. Placebo on mood assessed using Beck's Depression Inventory (BDI-II) in adult patients with PKU. The total score indicates severity, ranging from 0 (no depression) to 63 (severe depression).
measure: PKU Quality of Life
time frame: 4 times: baseline, after intervention phase 1 (4 weeks from baseline), after washout (8 weeks from baseline), after intervention phase 2 (12 weeks from baseline)
description: Influence of 4 weeks of oral Phe administration vs. Placebo on the total score in the questionnaire PKU quality of life (PKUQOL) in adult patients with PKU.
arm group label: Phenylalanine
arm group type: Experimental
description: Capsules containing 250 mg Phenylalanine (Phe). The daily dose will be chosen according to gender and weight at the time of T1 and will be divided in 3 separate doses. The assigned dose of the IMP will be kept throughout the whole study and weight fluctuations will not be considered.
Female
<60 kg: 1500 mg per day (divided in 3 doses): 250 mg 2-2-2-0
≥60 kg: 2000 mg per day (divided in 3 doses): 250 mg 2-2-4-0
Male
<60 kg: 2500 mg per day (divided in 3 doses): 250 mg 4-2-4-0
≥60 kg: 3000 mg per day (divided in 3 doses): 250 mg 4-4-4-0
Phe capsules can be ingested before, during or after a meal or together with other amino acid supplements. The last capsule of the given intervention period will be timed to be ingested with the last meal before the study visit.
Patients will take Phe for 4 weeks.
arm group label: Placebo
arm group type: Placebo Comparator
description: Capsules containing 250mg Placebo. Placebo capsules will be administered in identical manner to Phe capsules.
Patients will take the Placebo for 4 weeks.
intervention type: Dietary Supplement
intervention name: Phenylalanine
description: The study product Phenylalanine, a dietary supplement, is authorized in Switzerland, but not designated for this patient group.
arm group label: Phenylalanine
intervention type: Drug
intervention name: Placebo
description: Placebo capsules are indistinguishable in their appearance from Phe capsules
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Regula Everts, Prof. Dr. phil.
role: Principal Investigator
affiliation: Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism (UDEM), Inselspital, Bern University Hospital
facility: 
country: Switzerland
responsible party type: Sponsor
mesh term: Phenylketonurias
sharing ipd: No