Clinical trial NCT06412653: Prospective Pilot Trial to Address Feasibility and Safety of Oral Zinc in GNAO1 Associated Disorders
Official title: Prospective Pilot Trial to Address the Feasibility and Safety of Treatment With Oral Zinc in GNAO1 Associated Disorders
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: GNAO1
Dystonia
Epilepsy
Development Delay
Developmental and Epileptic Encephalopathy 17
Neurodevelopmental Disorder With Involuntary Movements
Choreoathetosis
Keywords: GNAO1
Lead sponsor: Children's University Hospital Cologne, Germany
Sponsor class: OTHER
Collaborators: name: The Clinical Trials Centre Cologne
name: University of Cologne
name: University of Geneva, Switzerland
First posted: 2024-05-14
Enrollment: 12
Sex: ALL
Minimum age (years): 6
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Prospective single arm, open-label pilot trial
Primary purpose: TREATMENT

Brief summary: The goal of this clinical trial is to investigate feasibility and safety of an oral therapy with zinc in patients affected by Guanine nucleotide-binding protein G(o) subunit alpha (GNAO1) associated disorders.

The main questions it aims to answer are:

* Is a daily oral therapy with zinc in GNAO1 associated disorders a safe and feasible therapy?
* Are there potential changes in general motor skills, general behaviour and well being, day/night rhythm, level of dyskinesia and dystonia, frequency of seizures, quality of life and changes in the microbiome of the patients.

Participants with GNAO1 associated disorders will be given an oral zinc therapy for 6 month and will be assessed in 3 visits and 2 phone calls within this trial.


Eligibility criteria: Inclusion Criteria:

* GNAO1 associated neurological disorder, documented by either

  * Proven pathogenic or likely pathogenic mutation in GNAO1 or
  * a variant of unknown significance in GNAO1 and clinical symptoms likely to be consistent with GNAO1 as determined by the investigators and
  * at least one of the common symptoms of GNAO1: Movement disorder (Dystonia, Chorea, Ataxia, clonic), central muscular hypotonia, epilepsy, global developmental delay
* Age: 6 month - 30 years
* GMFM ≤ 75
* written informed consent prior to any trial-related procedure (according to age and status of psycho-intellectual development)

  * of parents or legal guardian
  * of parents or legal guardian and patient
  * of the patient
* stable on following concomitant treatments for at least 3 months prior to trial inclusion: anti-seizure drugs (ASD); baclofen, Deep brain stimulation settings

Exclusion Criteria:

* Treatment of Zinc in the last 4 months before inclusion
* known other genetic variants that are known to cause symptoms like observed in GNAO1-related disorders, additional to the proven GNAO1 mutation
* implantation of Deep brain stimulation planned during the duration of the trial, i.e. in the six months after inclusion
* start of intrathecal baclofen therapy planned during the duration of the trial, i.e. in the six months after inclusion
* Known allergy/hypersensitivity to the scheduled trial drug
* Concomitant participation in other clinical drugs with investigational drugs or with competing interventions
* sexually active patients who are not willing to use/ not using a highly effective contraception method with a pearl-index \< 1. Sexually active patients, unless surgically sterile, must be using a highly effective contraception method (including oral, transdermal, injectable or implanted contraceptives, intrauterine device (IUD), using a condom of the sexual partner or sterile sexual partner) and must agree to continue using such precautions during the whole study period.
* Pregnant women and nursing mothers

Primary outcomes:
measure: Feasibility of daily treatment with oral zinc in GNAO1 as assessed by diary.
timeFrame: From first visit at Inclusion to visit after 6 month
measure: Safety of daily administered zinc in GNAO1 as assessed by regular evaluation of the side effects
timeFrame: From first visit at inclusion until last phone call after 7 month
measure: Safety of daily administered zinc in GNAO1 as assessed by regular blood tests
timeFrame: Blood analysis at baseline, after 3 and 6 month
Secondary outcomes:
measure: Level of motor-skills assessed by Gross-motor function measure
timeFrame: Compare measure at baseline to visit after 3 and 6 month
measure: Change in quality of life score assessed by Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) questionnaire for caregivers
timeFrame: Compare measure at baseline to visit after 3 and 6 month
measure: Level of Dystonia assessed by the Burke-Fahn-Marsden Dystonia Rating scale
timeFrame: Compare measure at baseline to visit after 3 and 6 month
measure: Level of dyskinesia assessed by the Abnormal involuntary movement scale (AIMS)
timeFrame: Compare measure at baseline to visit after 3 and 6 month
measure: Level of dyskinesia assessed by a movement log for parents/caregivers
timeFrame: Compare first two weeks of treatment to two weeks before the end of the trial
measure: Changes in sleep assessed by diary for parents/caregivers
timeFrame: Compare first two weeks of treatment to two weeks before the end of the trial
measure: Changes in general behaviour assessed by diary.
timeFrame: Compare answers of diary of first two weeks of treatment to two weeks before the end of the trial
measure: Changes in seizure frequency assessed by seizure log.
timeFrame: Compare first two weeks of treatment to two weeks before the end of the trial
measure: Changes in seizure duration assessed by seizure log.
timeFrame: Compare first two weeks of treatment to two weeks before the end of the trial
measure: Changes in serum level of zinc assessed by regular blood analysis
timeFrame: Serum controls at baseline, after 3 and 6 month
measure: Microbiome of stool assessed by regular analysis
timeFrame: Samples compared from baseline to samples collected after 3 and 6 month
Other outcomes:
Locations:
city: Cologne
country: Germany
facility: Children's Hospital, University Hospital Cologne, University of Cologne
Study officials:
affiliation: Children's Hospital, University Hospital Cologne, University of Cologne
name: Moritz Thiel, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Larasati YA, Savitsky M, Koval A, Solis GP, Valnohova J, Katanaev VL. Restoration of the GTPase activity and cellular interactions of Galphao mutants by Zn2+ in GNAO1 encephalopathy models. Sci Adv. 2022 Oct 7;8(40):eabn9350. doi: 10.1126/sciadv.abn9350. Epub 2022 Oct 7.
citation: Thiel M, Bamborschke D, Janzarik WG, Assmann B, Zittel S, Patzer S, Auhuber A, Opp J, Matzker E, Bevot A, Seeger J, van Baalen A, Stuve B, Brockmann K, Cirak S, Koy A. Genotype-phenotype correlation and treatment effects in young patients with GNAO1-associated disorders. J Neurol Neurosurg Psychiatry. 2023 Oct;94(10):806-815. doi: 10.1136/jnnp-2022-330261. Epub 2023 May 24.
citation: Briere L, Thiel M, Sweetser DA, Koy A, Axeen E. GNAO1-Related Disorder. 2023 Nov 9. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from http://www.ncbi.nlm.nih.gov/books/NBK597155/
citation: Savitsky M, Solis GP, Kryuchkov M, Katanaev VL. Humanization of Drosophila Galphao to Model GNAO1 Paediatric Encephalopathies. Biomedicines. 2020 Oct 6;8(10):395. doi: 10.3390/biomedicines8100395.