Understanding Clinical Phenotype and Collecting Biomarker Samples in C9ORF72 ALS

This research study is being performed to better understand a specific form of Amyotrophic Lateral Sclerosis (ALS) caused by a mutation (or abnormality) of the C9ORF72 gene. This mutation is the most common genetic cause of ALS, and is present in 40% of ALS patients with a family history of ALS and 5-10% of ALS patients without a family history of ALS.

Study Overview

• Status: Completed
• Conditions: C9ORF72 Amyotrophic Lateral Sclerosis (ALS)

Detailed Description

Individuals diagnosed with ALS, who are confirmed to carry the Chromosome 9 Open Reading Frame 72 (C9ORF72) gene mutation by CLIA-certified lab results, are eligible for enrollment. Researchers want to understand the natural history of C9ORF72 related ALS in terms of measures of rate of progression as well as understanding how the size of the hexanucleotide repeat expansion influences disease parameters. The investigators hope that the intense study of patients with the C9ORF72 mutation will ultimately help us develop treatments for this common form of ALS.

Objectives:

• Enroll a total of 120 C9ORF72 ALS participants with known mutation at the time of enrollment.
• Determine the C9ORF72 hexanucleotide repeat expansion size in all subjects
• Define ALS disease course
• Determine to what degree the disease course correlates with expansion size
• Collect biomarker samples (blood, DNA and CSF)

Eligibility:

- Adults over age 18 with known C9ORF72 ALS status

Design:

Participants will have up to 9 in-person visits (this includes two Optional visits for lumbar puncture procedures) and 5 telephone interviews over 3 years. Each in-person visit may be tied to a regular clinic visit if subject is local (except for the optional lumbar puncture visits) or if the subject is from out of town one initial visit can be set up with all other visits performed via a telephone call and medical records review.

At each in town visit, subjects will undergo a blood draw (optional lumbar puncture) and two questionnaires (ALS Functional Rating Scale - revised ALSFRS-R) which measures motor function and the ALS-Cognitive Behavioral Screen (ALS-CBS) which will detect signs of Frontal Temporal Dementia and a breathing test to determine Slow Vital Capacity (SVC) measurements.

For out of town subjects - blood draws can be scheduled locally and sent to the study site for analysis. The ALSFRS-R can be performed over the phone along with other study related questions.

The C9ORF72 mutation is called a "dominant" mutation, which means that their children have a 50% chance of inheriting the gene. Most people who inherit the C9ORF72 mutation will develop either ALS or the related disease called fronto-temporal dementia. However, it may be possible for someone to test positive for the C9ORF72 gene mutation and never develop symptoms. Furthermore, in addition to C9ORF72, there are many other gene mutations that can cause ALS. This study will not test these other genes, and therefore a negative test result for the C9ORF72 mutation will not exclude the possibility that you have a heritable form of ALS.

In order to understand the natural history of C9ORF72 related ALS in terms of measures of rate of progression, the investigators need to understand how the size of the hexanucleotide repeat expansion influences disease parameters. A C9ORF72-focused clinical trial defining an accurate historical control population, will be critical since there may not be enough subjects for a placebo controlled trial. To be ready for upcoming therapeutic trials, the investigators need to start the detailed characterization of the C9ORF72 patients immediately.

• Study Type: Observational
• Enrollment (Actual): 128

Contacts and Locations

Study Locations

• Netherlands
  • Utrecht, Netherlands
    • UMC Utrecht
• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins
  • Massachusetts
    • Amherst, Massachusetts, United States, 01003
      • University of Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University in St. Louis
  • New York
    • New York, New York, United States, 10027
      • Columbia University Medical Center
  • Virginia
    • Virginia Beach, Virginia, United States, 23454
      • Sentara Health Care / Sentara Neurology Specialists

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Known positive C9ORF72 ALS status upon enrollment

Description

Inclusion:

1. Males or females of any race aged 18 or older
2. Known positive C9ORF72 ALS status via CLIA-certified lab results.
3. Capable of providing informed consent and following study procedures. In the event that an individual lacks the ability to provide informed consent, informed consent may be sought from the individual's legal, surrogate representative.
4. Geographically accessible to the site.

Exclusion:

1. Geographically inaccessible to the site
2. C9ORF72 ALS negative via CLIA-certified lab results

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Individuals diagnosed with known positive C9ORF72 ALS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Collection of clinical data and biomarker samples	The primary outcome measures will be the collection of clinical data (ALSFRS, ALS-CBS and SVC) to determine rates of disease progression and collection of biomarkers samples (blood, CSF) to be correlated with the clinical measures.	December 2017

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation of repeat expansion size with clinical outcome measures and determination of C9ORF72 patients eligibility for clinical trials	The secondary outcome measures include determination of the C9ORF72 hexanucleotide repeat expansion size and correlating this with the outcome measures of disease progression collected (ALSFRS-R/month, decrease in SVC/month and ALS Cognitive Screen) and determination of C9ORF72 ALS patients that may be available for a clinical trial.	December 2017

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: Johns Hopkins University; Massachusetts General Hospital; Columbia University; UMC Utrecht; Biogen; Cedars-Sinai Medical Center; ALS Association; University of Massachusetts, Amherst
• Investigators: Principal Investigator: Timothy M Miller, MD, PhD, Washington University School of Medicine

Publications and helpful links

General Publications

• Cammack AJ, Atassi N, Hyman T, van den Berg LH, Harms M, Baloh RH, Brown RH, van Es MA, Veldink JH, de Vries BS, Rothstein JD, Drain C, Jockel-Balsarotti J, Malcolm A, Boodram S, Salter A, Wightman N, Yu H, Sherman AV, Esparza TJ, McKenna-Yasek D, Owegi MA, Douthwright C; Alzheimer's Disease Neuroimaging Initiative, McCampbell A, Ferguson T, Cruchaga C, Cudkowicz M, Miller TM. Prospective natural history study of C9orf72 ALS clinical characteristics and biomarkers. Neurology. 2019 Oct 22;93(17):e1605-e1617. doi: 10.1212/WNL.0000000000008359. Epub 2019 Oct 2.

Study record dates

Study Major Dates

• Study Start: February 1, 2015
• Primary Completion (Actual): December 31, 2017
• Study Completion (Actual): October 2, 2018

Study Registration Dates

• First Submitted: February 11, 2016
• First Submitted That Met QC Criteria: February 18, 2016
• First Posted (Estimate): February 19, 2016

Study Record Updates

• Last Update Posted (Actual): July 8, 2021
• Last Update Submitted That Met QC Criteria: July 2, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Amyotrophic Lateral Sclerosis; ALS; Biomarkers; Natural history; C9ORF72 gene mutation; Chromosome 9 open reading frame 72 protein; Amyotrophic Lateral Sclerosis, Familial; Amyotrophic Lateral Sclerosis, Sporadic; Frontotemporal Dementia-Amyotrophic Lateral Sclerosis
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: 14LGCA123

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

IPD Plan Description

The study design has a robust plan to share de-identified data (but personally identifiable data will not be shared). When study information is shared, it will be "de-identified", meaning that the study will remove all personal identifiers so that all collected data and samples are stored under a unique subject ID study code ("coded"). In other words, the study has been designed to keep personal details separate from all samples and study information.

The results of this trial will be published in peer-reviewed journals. No personal identifiers will be included.