Dentatorubral-pallidoluysian Atrophy Natural History and Biomarkers Study (DRPLA NHBS)

DRPLA Natural History and Biomarkers Study (DRPLA NHBS) is a prospective observational study that will lay the foundation for clinical trials in DRPLA. The aims of this project are:

• To characterize the natural history of DRPLA in both juvenile- and adult-onset patients and study different modalities of biomarkers in this condition.
• To identify genetic factors and biomarkers that could predict disease progression.
• To provide a platform to support the design and conduct of clinical trials.

This study has three arms:

1. Adult Participants: this arm of the study will require participants to be 16 years old or over to participate.
2. Pediatric Participants: this arm of the study will require participants to be under 16 years old to participate.
3. Remote Participants: patients that cannot or do not wish to travel to one of the study sites can participate in this arm of the study, irrespective of their age.

Participants will have an annual visit for three years (baseline visit and two follow-up visits, three visits in total). Subjects who complete the whole protocol will be assessed on two consecutive days to reduce patient burden.

This project will allow for a better understanding of DRPLA and its course, and therefore allow for future clinical trials on this condition to be more precisely and effectively conducted.

Study Overview

• Status: Recruiting
• Conditions: Dentatorubral-Pallidoluysian Atrophy
• Intervention / Treatment: Other: Positive genetic test for pathological expansion in ATN1

• Study Type: Observational
• Enrollment (Estimated): 225

Contacts and Locations

• Study Contact: Name: Paola Giunti; Phone Number: +44 7899974923; Email: p.giunti@ucl.ac.uk
• Study Contact Backup: Name: Hector Garcia-Moreno; Email: h.garcia-moreno@ucl.ac.uk

Study Locations

• United Kingdom
  • London, United Kingdom, WC1N 3BG
    • Recruiting
    • University College London
    • Contact: Paola Giunti; Phone Number: +44 7899974923; Email: p.giunti@ucl.ac.uk
• United States
  • New York
    • New York, New York, United States, 10017
      • Recruiting
      • NYU Grossman School of Medicine
      • Contact: Claire Miller; Phone Number: 212-263-4838; Email: Claire.Miller@nyulangone.org
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7025
      • Recruiting
      • University of North Carolina at Chapel Hill
      • Contact: Yael Shiloh-Malawsky; Phone Number: 919-966-2528; Email: yaelm@neurology.unc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Community and/or clinical sample

Description

Inclusion criteria for the Adult Protocol:

1. DRPLA adult participants must be 16 years old or over at the time of enrollment, to participate.
2. DRPLA adult participants must have a genetic diagnosis of DRPLA and CAG repeat expansion >35.
3. Patient is able to read, understand, and provide written informed consent (signed and dated). If the patient is under the age of 18 or is unable to provide consent, the patient must have a parent or caregiver capable of providing informed consent (signed and dated) and able to attend all scheduled study visits, and provide feedback regarding the participant's symptoms and performance as described in the protocol.
4. Adult pre-symptomatic subjects must have a positive genetic test for the DRPLA expansion without symptoms compatible with the disease, and be 16 years old or over at the time of enrollment.
5. Adult Family/Community control participants must be 16 years old or over at the time of enrollment to participate. Blood-relatives must not have a genetic diagnosis of DRPLA or their genetic status is unknown.

Exclusion criteria for the Adult Protocol:

1. Individuals with an ataxia condition other than DRPLA.
2. Failure to sign the consent form will result in study exclusion.
3. Has any condition or circumstance that, in the opinion of the Investigator, makes the participant unsuitable for enrolment. These may include medical conditions which might affect the measurement of biomarkers.
4. Participants will be excluded from the lumbar puncture, and skin biopsy procedures if they have a history of severe allergic or anaphylactic reactions or other adverse reactions to local anesthetics used in the study.
5. For family/community controls: those individuals with neurological conditions (other than primary headache disorders) will be excluded.

Inclusion Criteria for the Pediatric Protocol:

a. DRPLA pediatric participants must be under 16 years old at the time of enrollment, to participate.

f. DRPLA pediatric participants must have a genetic diagnosis of DRPLA and CAG repeat expansion >35.

g. If the patient is under the age of 18 or is unable to provide consent, the patient must have a parent or caregiver capable of providing informed consent (signed and dated) and able to attend all scheduled study visits, and provide feedback regarding the participant's symptoms and performance as described in the protocol.

h. Pediatric Family/Community control participants must be under 16 years old at the time of enrollment to participate. Blood-relatives must not have a genetic diagnosis of DRPLA or their genetic status is unknown.

Exclusion Criteria for the Pediatric Protocol:

f. Individuals with an ataxia condition other than DRPLA. g. Failure to sign the consent form will result in study exclusion. h. Has any condition or circumstance that, in the opinion of the Investigator, makes the participant unsuitable for enrolment. These may include medical conditions which might affect the measurement of biomarkers.

i. Participants will be excluded from the lumbar puncture, and skin biopsy procedures if they have a history of severe allergic or anaphylactic reactions or other adverse reactions to local anesthetics used in the study.

j. For family/community controls: those individuals with neurological conditions (other than primary headache disorders) will be excluded.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
DRPLA-mutation carrier; Subjects with a positive genetic test for a pathological expansion in the ATN1 gene.	Other: Positive genetic test for pathological expansion in ATN1; Positive genetic test for pathological expansion in ATN1
Volunteer control; Subjects without neurological conditions (other than primary headache disorders), without a family history of DRPLA or a previous negative genetic test for pathological expansions in the ATN1 gene.	Other: Positive genetic test for pathological expansion in ATN1; Positive genetic test for pathological expansion in ATN1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain atrophy	Brain MRI is used to measure atrophy. Atrophy is expected to be observed in DRPLA patients, and in particular in the brainstem, superior cerebellar peduncle, cerebellum and thalamus.	3 years
Neurofilament plasma concentration (NfL)	Blood and CSF samples will be measured for NfL, a brain-derived protein.	3 years
Scale for the assessment and rating of ataxia (SARA)	Progression of ataxia is measured using a validated ataxia scale, SARA. Scores range from 0 (no ataxia) to 40 (most severe ataxia).	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inventory of non-ataxia signs (INAS)	The occurrence of accompanying non-ataxia symptoms is assessed using INAS.	3 years
Upper limb function test AIM-S	Hand dexterity and upper limb function is assessed using the AIM-S spoon test.	3 years
Redenlab DRPLA specific speech battery	Speech is assessed using the Redenlab software speech battery.	3 years
Clinical Assessment of Dysphagia in Neurodegeneration (CADN)	Dysphagia is assessed using the CADN, an assessment of swallowing in neurodegenerative disease.	3 years
Tau plasma concentration	Blood and CSF samples will be measured for Tau, a brain-derived protein.	3 years
Glial fibrillary acidic protein (GFAP) concentration	Blood and CSF samples will be measured for GFAP, a brain-derived protein.	3 years
Ubiquitin carboxyterminal hydrolase L1 (UCH-L1) concentration	Blood and CSF samples will be measured for UCH-L1, a brain-derived protein.	3 years

Collaborators and Investigators

• Sponsor: University College, London
• Collaborators: University of North Carolina, Chapel Hill; NYU Grossman School of Medicine
• Investigators: Principal Investigator: Paola Giunti, University College, London

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2022
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): April 1, 2026

Study Registration Dates

• First Submitted: February 15, 2024
• First Submitted That Met QC Criteria: February 15, 2024
• First Posted (Actual): February 22, 2024

Study Record Updates

• Last Update Posted (Actual): May 10, 2024
• Last Update Submitted That Met QC Criteria: May 8, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Epilepsy; Ataxia; Chorea; Dentatorubral-Pallidoluysian Atrophy
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy, Generalized; Epileptic Syndromes; Pathological Conditions, Anatomical; Epilepsy; Epilepsies, Myoclonic; Atrophy; Myoclonic Epilepsies, Progressive
• Other Study ID Numbers: 142048

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Data sharing will be decided upon publication of study results and agreements with other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No