A Study to Evaluate the Performance of a Diagnostic Test in ALS

April 29, 2016 updated by: Andreas Jeromin, Iron Horse Diagnostics, Inc.

A Study to Evaluate the Sensitivity, Specificity, and Overall Accuracy of an Amyotrophic Lateral Sclerosis Diagnostic Test Developed by Iron Horse Diagnostics

Prospective multicenter study of subjects who were recently diagnosed with amyotrophic lateral sclerosis (ALS) or another neurodegenerative disease (including spinal cord diseases, muscle diseases and neurological diseases such as multiple sclerosis, multifocal motor neuropathy, myasthenia gravis and spinal muscular atrophy) or who are currently undergoing diagnostic procedures for the aforementioned diseases.

Approximately 300 subjects will be enrolled. Subjects will undergo a lumbar puncture (LP) for cerebro-spinal fluid (CSF) collection; blood collection for serum, plasma, RNA, and DNA (optional); urine collection (optional); and skin biopsy (optional) in a single visit. No study treatment will be administered.

Subjects will be managed and treated by their respective physicians; choice of therapy or laboratory tests will not be impacted by the study. Clinical diagnosis may be confirmed by the subject's physician and communicated to the study's Principal Investigator (PI) by scheduled telephone calls.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Unknown

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

ALS, also known as Lou Gehrig's disease, is a rapidly progressive, degenerative disease of motor neurons in the brain and spinal cord that leads to muscle atrophy and spasticity in limb and bulbar muscles. Clinical presentations of this fatal disease include weakness, loss of ambulation, oropharyngeal dysfunction, weight loss, and ultimately respiratory failure. Average survival is approximately 3 years after symptom onset. The initial symptoms are similar to other neuropathies (e.g., motor neuropathy, progressive muscle atrophy, etc.) and include limb weakness leading to partial or total paralysis, and increasing difficulties in speech and breathing. ALS clinical diagnosis typically takes 12 months from symptom onset and relies on exclusion of other potential causes of the clinical symptoms. To date there are no FDA-approved diagnostic tests for ALS. Diagnostic tools for accurate and early diagnosis are under investigation. These tools would not only permit early intervention, but also would improve clinical trial design for new drug therapies.

Axonal degeneration and inflammation are among proposed pathogenic mechanisms for ALS; therefore, proteins that function within these pathways are being evaluated as potential biomarkers. Iron Horse Diagnostics, Inc. (Iron Horse) has focused its ALS diagnostic efforts on studying the levels of cytoskeletal and inflammatory proteins in the cerebrospinal fluid (CSF) of ALS patients.

Cytoskeletal proteins, including neurofilament proteins and tau, have been shown to be elevated in the CSF of patients with various neurodegenerative diseases. Interestingly, levels of phosphorylated neurofilament heavy subunit (pNfH) have been found to be significantly increased in the CSF of ALS patients as compared with healthy subjects, Alzheimer's disease patients or disease mimics Numerous inflammatory proteins, including cytokines and complement proteins, have been shown to be altered in ALS; complement proteins, including complement c3 (C3), have been found to be increased in the CSF of ALS patients.

Iron Horse has evaluated CSF samples from 106 subjects (45 ALS patients, 25 disease controls with a range of neurodegenerative conditions, and 36 healthy controls.CSF levels of pNfH, tau, C3, and C reactive protein (CRP) were measured. pNfH was significantly elevated in CSF from ALS subjects as compared with healthy and disease controls; there were no significant differences for CRP or tau. To further distinguish between ALS subjects and disease controls, data from cytoskeletal and inflammatory pathways were combined. A ratio of CSF levels of pNfH and C3 showed significant differences between ALS and both the disease and healthy control groups. Results were verified on a separate test set of CSF samples. Overall, the predictive pNfH/C3 ratio identified ALS with 87.3 % sensitivity and 94.6% specificity in a total of 71 ALS subjects, 52 disease control subjects, and 40 healthy subjects.

In the same study, it was observed that plasma levels of pNfH were significantly elevated in ALS subjects as compared with healthy controls; however there was no significant difference between ALS and disease controls. Comparison of pNfH levels between the CSF and plasma for each study subject revealed a weak correlation between plasma and CSF pNfH levels.

The accuracy of pNfH and pNfH/C3 ratio as ALS predictors has also been tested by Iron Horse in a recent prospective, blinded study in collaboration with the Northeast ALS Consortium (NEALS) [unpublished data]. CSF (n=126) and plasma (n=220) samples were collected from subjects from 30 medical centers across the United States (US) who were undergoing diagnostic assessment for neurodegenerative conditions or who were recently diagnosed with ALS. Accuracy for predicting ALS diagnosis was 93% for CSF pNfH/C3 ratio and 82% for pNfH plasma levels.

The prospective study proposed in this concept will test the sensitivity, specificity, and overall accuracy of pNfH and pNfH/C3 ratio as ALS predictors on a separate sample set. CSF and matching plasma samples will be collected at up to 6 neurodegenerative clinics from up to 300 subjects who were recently diagnosed with ALS or another similar neurologic disease or who are currently undergoing diagnostic procedures.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
300

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • United States
    • Ohio
      • Cleveland, Ohio, United States, 44195
        • Recruiting
        • Cleveland Clinic
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

17 years to 76 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

ALS and other motoneuron diseases (ALS mimics)

Description

Inclusion Criteria:

  • To be eligible to participate in this study, candidates must meet the following eligibility criteria at the Screening Visit:

    1. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local subject privacy regulations.
    2. Aged 21 to 80 years old, inclusive.

    3. Must meet one of the following:

      • Recent diagnosis of sporadic or familial ALS (within 18 months of first visit for ALS symptoms) according to the World Federation of Neurology El Escorial criteria (revised according to the Airlie House Conference 1998 [Brooks 1999] ).
      • Recent diagnosis of neuromuscular disease other than ALS (within 12 months of first visit for neurologic symptoms).
      • Undergoing diagnostic procedures for neuromuscular disease.
    4. Willingness and medical ability to comply with scheduled visits, LP for CSF collection, laboratory tests, and other study procedures.

Exclusion Criteria:

  • Candidates will be excluded from study entry if any of the following exclusion criteria exist at the Screening Visit:

    1. Any contraindications to having an LP, including but not limited to:

      • Platelet count <100,000/µL.
      • History of bleeding disorder.
      • Use of platelet antiaggregant or anticoagulant drugs, including but not limited to clopidogrel, dipyridamole, ticlopidine , and warfarin. Use of aspirin at a prophylactic dose of 75-325 mg r less is acceptable.
      • History of intolerance to the LP procedure.
      • Evidence of topical or other skin infection at the LP site.
      • Prior spinal fusion surgery or other spinal surgery at the LP site.
    2. If undergoing skin biopsy, evidence of topical or other skin infection at the biopsy site.
    3. History of allergy or other adverse reaction to local anesthetics used in the study.
    4. History of traumatic central nervous system injury or stroke.
    5. History of chronic liver or renal failure.
    6. Requirement for artificial respiration, including tracheostomy and any use of bilevel positive airway pressure (BiPAP) therapy.
    7. Female subjects who are pregnant or currently breastfeeding.
    8. Current enrollment in any other investigational drug, medical devices, or disease study.
    9. Other unspecified reasons that, in the opinion of the Investigator or Iron Horse, make the subject unsuitable for enrollment.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Amyotrophic lateral sclerosis
Participants recently diagnosed with ALS in a neuromuscular clinic, using the ALS functional rating scale (ALSFRS-R). Lumbar puncture (LP) for cerebro-spinal fluid (CSF) collection The ALSFRS-R is a quickly administered (5 min) ordinal rating scale used to determine a subject's assessment of their capability and independence in 12 functional activities. There are 12 questions, graded by the subject 0-4 (4 is normal). Score of 0 (worst) to 48 (best). Reflects speech and swallowing, fine motor skills, large motor skills, and breathing.
Procedure: Lumbar puncture
Collection of biofluids to determine the accuracy, sensitivity and specificity of a diagnostic test developed by Iron Horse Diagnostics
ALS mimics
Other motorneuron disorders, isolated upper and lower motoneuron disorders Lumbar puncture (LP) for cerebro-spinal fluid (CSF) collection
Procedure: Lumbar puncture
Collection of biofluids to determine the accuracy, sensitivity and specificity of a diagnostic test developed by Iron Horse Diagnostics

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Biomarker Measurement of phosphorylated neurofilament heavy chain (pNfH) and complement C3 in CSF
Time Frame: Baseline
Sensitivity, specificity, and overall accuracy of cerebro-spinal fluid (CSF) phosphorylated neurofilament (pNfH) pNfH/C3 ratio to identify ALS in a cohort of subjects who were recently diagnosed with ALS or another neurodegenerative disease or who are currently undergoing diagnostic procedures in the US. These are quantitative measurements of 2 proteins (pNfH) and C3 in cerebrospinal fluid (CSF), pNfH and C3 measurements will be reported in ng/ml and a single quantitative protein measurement of pNfH in ng/ml in plasma. In CS. The ratio of pNfH to C3 will be determined, both measurements for pNfH and C3 in CSF were made in ng/ml. In addition, the single biomarker measurements of pNfH and C3 in ng/ml will be presented. These biomarkers will be measured post-hoc and not for diagnostic decisions.
Baseline

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
ALS Functional Rating Scale (ALSFRS-R)
Time Frame: At baseline
ALSFRS-R is a quickly administered (5 min) ordinal rating scale used to determine a subject's assessment of their capability and independence in 12 functional activities. There are 12 questions, graded by the subject 0-4 (4 is normal). Score of 0 (worst) to 48 (best). Reflects speech and swallowing, fine motor skills, large motor skills, and breathing.
At baseline

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Iron Horse Diagnostics, Inc.

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Andreas Jeromin, PhD, Iron Horse Diagnostics

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 1, 2015

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
August 1, 2016

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 1, 2016

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
April 4, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 29, 2016

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
May 3, 2016

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 3, 2016

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 29, 2016

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • IronHorseDx001

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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