Clinical trial NCT05356377: Preliminary Study of Brain Effects of Palynziq-Related Changes in Phenylalanine in Individuals With PKU
Official title: A Preliminary Study of the Neurological and Neuropsychological Effects of Palynziq-Related Changes in Phenylalanine in Individuals With Phenylketonuria (PKU)
Study type: OBSERVATIONAL
Overall status: ENROLLING_BY_INVITATION
Conditions: Phenylketonurias
Lead sponsor: University of Missouri-Columbia
Sponsor class: OTHER
Collaborators: name: BioMarin Pharmaceutical
First posted: 2022-05-02
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Participants who meet 3 primary criteria: (1) have previously completed baseline (pre-Palynziq) neurocognitive \& neuroimaging evaluations as part of other studies at University of Missouri of Boston Children's Hospital, (2) have since been prescribed Palnyziq by their primary metabolic care providers, and (3) have demonstrated a prolonged blood phe response to Palynziq as reflected by 3+ months of phe levels below 360 umol/L.

Brief summary: The goal of the proposed study is to elucidate neurologic and neuropsychological improvements associated with Palynziq-related reduction in plasma Phe levels in individuals with PKU. To this end, investigators will utilize state-of-the-art neuropsychological and multi-modal neuroimaging methods to examine the effects of large Phe level reduction (levels \<360 μmol/L for at least 3 consecutive months) on GM and WM brain structures, brain concentrations of Phe, functionality of brain networks, and associated cognitive functioning in a sample of individuals with PKU who are being treated with Palyzniq.

Detailed description: Past studies have documented PKU-related disruptions in brain phenylalanine (Phe) levels, white matter (WM) and gray matter (GM) brain structures, functional connectivity, and neurocognitive functioning. Additional research suggests that the disruptive effects of excessive blood Phe levels likely contribute to these abnormalities, and treatment aimed at lower Phe levels may lead to significant improvements.

Within this context, the primary aim is to test the hypotheses that Palynziq-related reductions in blood Phe levels will be associated with:

1. A decrease in brain Phe levels as measured by magnetic resonance spectroscopy (MRS).
2. A decrease in the extent and severity of WM abnormalities as evidenced by increased mean diffusivity values - a measure of microstructural WM integrity that is derived via diffusion-weighted magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI).
3. Closer-to-normal volumetric measurements for GM structures. Nature of this effect will be dependent on structure. For example, PKU is associated with increased volume in basal ganglia but decreased volume in posterior cortex and cerebellum (Aldridge et al., 2020; Bodner et al., 2012; Christ et al., 2016).
4. An increase in functional connectivity within the brain's functional networks as measured by resting state functional MRI (fMRI).
5. Improved performance on neurocognitive tests of executive function, attention, processing speed, and motor control.

To accomplish this aim, a total sample of up to 13 adults with PKU who have previously completed baseline (pre-Palnyziq) neurocognitive and neuroimaging evaluations will be recruited from the two sites (University of Missouri, Boston Children's Hospital). Participants will be reassessed following a significant and prolonged Phe response to Palynziq (as reflected by at least 3 consecutive months of Phe levels below 360 μmol/L).

Eligibility criteria: Inclusion Criteria:

* Age 18-55 years
* Participants identified by newborn screening with PKU as evidenced by a blood Phe level ≥ 360μmol/L; received treatment within the first 30 days of life
* Previously received a neuropsychological and neuroimaging evaluation (as part of previously described MU or BCH studies) prior to enrollment in the present study (while Palynziq-naïve).
* Capable of providing informed consent
* Presently being treated with Palynziq and has demonstrated a prolonged Phe response to Palynziq (as reflected by at least 3 consecutive months of Phe levels below 360 μmol/L)

Exclusion Criteria:

* History of major neurologic disorder unrelated to PKU
* Contraindications for safe MRI participation such as (a) pregnancy or plans to become pregnant during period of study enrollment; or (b) metallic objects inside the body (e.g., surgical staples left in the body following surgery, middle ear prosthesis, metal foreign objects lodged inside the eye, heart pacemakers).
* Current participation in an interventional clinical trial (not Palynziq-related).

Primary outcomes:
measure: Neurologic Integrity
timeFrame: Single timepoint for 1 hour
measure: Neuropsychological Functioning
timeFrame: Single timepoint for 2 hours
Secondary outcomes:
measure: Cookie Theft Picture Test
timeFrame: Single timepoint for 10 minutes
measure: In-the-moment Psychoemotional Symptomatology
timeFrame: 30 minutes total per day for 7 consecutive days
Other outcomes:
Locations:
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Columbia
country: United States
facility: University of Missouri
state: Missouri
Study officials:
affiliation: University of Missouri-Columbia
name: Shawn Christ, PhD
role: PRINCIPAL_INVESTIGATOR
References: