Clinical trial NCT03862274: Examining Developmental Outcomes of Children Diagnosed With CLN2 Disease
Official title: Examining Developmental Outcomes of Children Diagnosed With CLN2 Disease
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Batten Disease
CLN2
Neuronal Ceroid-Lipofuscinoses
Lead sponsor: Nationwide Children's Hospital
Sponsor class: OTHER
Collaborators: name: BioMarin Pharmaceutical
First posted: 2019-03-05
Enrollment: 30
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: OTHER
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients that have a TPP1 enzyme deficiency and/or confirmed molecular diagnosis of pathogenic variants in the TPP1 gene are eligible to participate if they are untreated or are receiving cerliponase alfa.

Brief summary: The investigators propose a study to assess cognitive and developmental outcomes of patients with CLN2 that are untreated and receiving cerliponase alfa. This study aims to validate standardized assessment measures to establish a standard of care. The secondary aim is to compare cognitive and developmental outcomes of patients with CLN2 that are receiving celiponase alfa to a natural history cohort. To accomplish specific aims of the study, the investigators will use a multi-method approach to collect retrospective data collected as standard of care and prospective developmental data in children with CLN2 disease. The investigators will use a combination of standardized measures that include direct assessment and parent report of child development. The investigators focus will also include multiple measures of development including language, motor, social-emotional, and adaptive functioning.

Detailed description: CLN2 disease is a predominantly late infantile form of neuronal ceroid lipofuscinosis and one of the many genetic isoforms of Batten disease. Mutations in the CLN2 gene are characterized by deficient lysosomal serine protease TPP1, an enzyme that metabolizes intracellular lysosomal storage materials. Accumulations of intracellular deposits occur over time and in many organs of individuals with CLN2 disease and lead to neurodegeneration and, eventually, death. CLN2 disease is an extremely rare genetic disease affecting around 1 per 200,000 live births. Symptoms emerge early in life typically between the ages of 2 and 4 years of age and include seizures, as well as loss of motor, language, and vision functioning. Development further declines in early childhood and by age 6 years, children with CLN2 are often unable to walk or sit unsupported and become blind. The progression of the disease is rapid with death typically occurring in mid-childhood between the ages of 10 and 15 years of age.

Recently, enzyme replacement therapy (ERT), cerliponase alfa, which is a recombinant form of human TPPI, was the first FDA-approved treatment to slow the progression of motor decline in children with CLN2. Cerliponase alfa is expected to restore TPP1 enzyme activity in the brain and alter neurodegeneration and disease progression. Animal models suggest promising treatment outcomes as cerliponase alfa significantly delayed the onset of clinical signs, preserved motor and cognitive function, and prolonged life. Initial results from a clinical trial further demonstrated that patients receiving cerliponase alfa had less motor declines, as measured by the CLN2 Clinical Rating Scale, compared to a natural history cohort. Despite these promising results, little is known about the trajectory of other developmental domains, including language, social-emotional, and adaptive functioning of children receiving cerliponase alfa. Likewise, the developmental trajectory of untreated patients with CLN2 is not well understood. Therefore, it is important to understand developmental outcomes and the progression of CLN2 in a natural history cohort in order to compare the effectiveness of treatment outcomes.

Eligibility criteria: Inclusion Criteria:

* Patients that have a TPP1 enzyme deficiency
* Patients have confirmed molecular diagnosis of pathogenic variants in the TPP1 gene
* Patients that are enrolled in post-marketing studies will be allowed to enroll into the current study

Exclusion Criteria:

* Patients without a diagnosis of CLN2 and deficiency of TPP1
* Patients that are currently enrolled as part of a larger multi-center clinical trial

Primary outcomes:
measure: Changes in Visual Reception Skills on the Mullen Scales of Early Learning
timeFrame: up to 4 years
measure: Changes in Fine Motor Skills on the Mullen Scales of Early Learning
timeFrame: up to 4 years
measure: Changes in Receptive Language Skills on the Mullen Scales of Early Learning
timeFrame: up to 4 years
measure: Changes in Expressive Language Skills on the Mullen Scales of Early Learning
timeFrame: up to 4 years
measure: Motor and Language Changes on the CLN2 disease rating scale
timeFrame: up to 4 years
Secondary outcomes:
measure: Changes in Receptive Language Skills on the Preschool Language Scales
timeFrame: up to 4 years
measure: Changes in Expressive Language Skills on the Preschool Language Scales
timeFrame: up to 4 years
Other outcomes:
Locations:
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
Study officials:
affiliation: Nationwide Children's Hospital
name: Jessica Scherr, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Nationwide Children's Hospital
name: Emily de los Reyes, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Schulz A, Kohlschutter A, Mink J, Simonati A, Williams R. NCL diseases - clinical perspectives. Biochim Biophys Acta. 2013 Nov;1832(11):1801-6. doi: 10.1016/j.bbadis.2013.04.008. Epub 2013 Apr 17.
citation: Schulz A, Ajayi T, Specchio N, de Los Reyes E, Gissen P, Ballon D, Dyke JP, Cahan H, Slasor P, Jacoby D, Kohlschutter A; CLN2 Study Group. Study of Intraventricular Cerliponase Alfa for CLN2 Disease. N Engl J Med. 2018 May 17;378(20):1898-1907. doi: 10.1056/NEJMoa1712649. Epub 2018 Apr 24.
citation: Wisniewski KE, Zhong N, Philippart M. Pheno/genotypic correlations of neuronal ceroid lipofuscinoses. Neurology. 2001 Aug 28;57(4):576-81. doi: 10.1212/wnl.57.4.576.
citation: Worgall S, Kekatpure MV, Heier L, Ballon D, Dyke JP, Shungu D, Mao X, Kosofsky B, Kaplitt MG, Souweidane MM, Sondhi D, Hackett NR, Hollmann C, Crystal RG. Neurological deterioration in late infantile neuronal ceroid lipofuscinosis. Neurology. 2007 Aug 7;69(6):521-35. doi: 10.1212/01.wnl.0000267885.47092.40.
citation: Williams RE, Aberg L, Autti T, Goebel HH, Kohlschutter A, Lonnqvist T. Diagnosis of the neuronal ceroid lipofuscinoses: an update. Biochim Biophys Acta. 2006 Oct;1762(10):865-72. doi: 10.1016/j.bbadis.2006.07.001. Epub 2006 Jul 12.