REtinal Markers In Neuroinflammatory Diseases ("REMIND")

Multiple Sclerosis Clinical Trial

Official title:

Retinal Markers in Neuroinflammatory Diseases: a Prospective Observational Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06369766
• Other study ID #: 2023-02144; ko23Papadopoulou4
• Status: Recruiting
• Start date: January 31, 2024
• Est. completion date: February 2029

Study information

• Verified date: April 2024
• Source: University Hospital, Basel, Switzerland
• Contact: Athina Papadopoulou, PD Dr. med.
• Phone: +41 61 32 85704
• Email: Athina.Papadopoulou[@]usb.ch
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The goal of this observational study, including patients with Multiple Sclerosis, patients with other neuroinflammatory diseases and healthy controls, is to determine the predictive value of retinal markers in predicting disease progression. Participants complete a questionnaire and undergo various non-invasive retinal routine clinical examinations.

Description:

Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) and represents one of the most common neurological disorders affecting young adults worldwide and often leads to significant disability over time. While MS typically presents with recurrent neurological symptoms known as relapses, most patients also experience progressive neurological deterioration independent of relapses, referred to as progression independent of relapse activity (PIRA). PIRA is a major contributor to long-term disability and represents a significant challenge in the management of MS. Early identification of patients at high risk to develop PIRA is crucial for therapeutic decisions and testing treatment efficacy, highlighting the urgent need for accurate predictive markers of progression in MS.

The primary objective of this longitudinal, observational, prospective, single center study is to investigate the predictive value of various retinal markers in predicting PIRA in MS patients.

The study assesses several easily obtained, non-invasive retinal measures:

• Neuroaxonal loss in the retina: This serves as a marker of neurodegeneration in the CNS. It will be assessed by measuring the volume of the ganglion cell-inner plexiform layer and the thickness of the peripapillary retinal nerve fiber layer using optical coherence tomography (OCT).

• Neuroinflammation in the retina: This will be assessed by evaluating thickening of other retinal layers in OCT, particularly the inner nuclear layer.

• Fixation instability of the patients: This serves as a marker of global neuronal dysfunction in the CNS. It will be measured using Scanner Laser Ophthalmoscopy-OCT.

• Structural changes of the retinal vessels: Particularly, the arteriolar and venular diameters will be assessed. This serves as a marker of systemic microvascular health and will be measured using static retinal vessel analysis.

• Functional/perfusional changes of the retinal vessels: For a subgroup of patients, this will be evaluated using OCT-angiography, and/or dynamic retinal vessel analysis, and/or laser speckle flowgraphy. These measures provide insights into the functional and perfusional changes of the retinal vessels.

As secondary objectives, this study comprises:

• Comparison with other biomarkers of neuroaxonal damage to determine whether the retinal markers are independent and/or stronger predictors of PIRA.

• Comparison with the retinal markers of Healthy Controls and patients with other neuroinflammatory diseases of the CNS to understand the differences in mechanisms of damage.

• Investigating the associations among the various retinal measures to understand the relationship between neuroaxonal loss, functional deficits and vascular changes in MS.

Data will be collected at baseline and annually over up to 5 years, or for some MS patients, up to 10 years, to evaluate changes in retinal markers and their correlation with disease progression. This comprehensive assessment will provide valuable insights into the utility of retinal markers in predicting PIRA and their relationship with disease severity and progression in MS.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 500
• Est. completion date: February 2029
• Est. primary completion date: December 2028
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. All groups:

• Age >18 years old

2. Patients with Multiple Sclerosis:

• Diagnosis of Multiple Sclerosis, according to the last revisions of the McDonald Criteria (2017)

3. Patients with other neuroinflammatory diseases:

• Diagnosis of Neuromyelitis optica spectrum disorder or Myelin oligodendrocyte glycoprotein antibody disease or other neuroinflammatory disorders other than Multiple Sclerosis

Exclusion Criteria:

1. All groups:

• Inability to undergo Optical Coherence Tomography (OCT) and/or retinal vessel imaging (e.g. severe nystagmus that prevents eye fixation on both eyes)

• Presence of any ocular pathology that may interfere with the validity of the OCT/retinal vessel analysis (cataracts, glaucoma, history of refractive defects >6 D etc.).

• Pregnancy and Lactation

2. Healthy Controls

• History of other neurological conditions: participants with a history of other significant neurological conditions that might interfere with the assessment or interpretation of the signs and symptoms will be excluded (e.g. confirmed Stroke, Acute disseminated encephalomyelitis, Chronic inflammatory Demyelinating Disease, Polyneuropathy, etc.)

Related Conditions & MeSH terms

• Multiple Sclerosis

Intervention

Diagnostic Test:
• Optical coherence tomography (OCT)
OCT is used to measure: peripapillary retinal nerve fiber layer (mean thickness in µm) ganglion cell-inner plexiform layer (volume in mm^3 and mean thickness in µm) other retinal layers (inner nuclear layer, outer plexiform layer, outer nerve layer; volumes in mm^3 and mean thickness in µm). The "scanner laser ophthalmoscopy"-function of the OCT device is used to continuously record the exact location of each participant's fixation point in relation to their fovea and thereby allows the assessment of the fixation instability. In a subgroup of participants, the "angiography"-module of the OCT device is used to image the retinal blood flow and thereby allows to measure the vascular area density of the superficial retinal capillary plexus and deep retinal capillary plexus.
• Static retinal vessel analyzer
Static retinal vessel analyzer is used to determine: central retinal arteriolar diameter equivalents (in µm) central retinal venular diameter equivalents (in µm) arteriolar-to-venular diameter ratio
• Dynamic retinal vessel analyzer
In a subgroup of participants, the dynamic retinal vessel analyzer is used to determine the arteriolar ficker light-induced dilatation, venular ficker light-induced dilatation, and Arteriolar constriction, measured in % dilatation in comparison to baseline.
• Laser speckle flowgraphy system
In a subgroup of participants, the laser speckle flowgraphy system is used to measure the relative ocular blood flow as expressed in arbitary units of Mean Blur Rate.

Other:
• Questionnaire
All study participants will be asked to fill in a questionnaire with various questions regarding existing eye diseases, other diseases (including vascular diseases/risk factors), and daily physical activity that could influence the results of the retinal examinations. Physical activity will be assessed using an adapted form of the standardized Global Physical Activity Questionnaire.

Locations

Country	Name	City	State
Switzerland	University Hospital Basel, Department of Neurology	Basel

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Basel, Switzerland	University of Basel

Country where clinical trial is conducted

Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Occurence of Progression Independent of Relapse Activity (PIRA)	The group of "Multiple Sclerosis patients" undergo a detailed neurological interview and examination for the calculation of the Expanded Disability Status Scale (EDSS) at each clinical visit every 6 or 12 months. The EDSS worsening is used to define PIRA retrospectively (increase of =1.5 points if baseline EDSS was 0 points, increase of =1.0 points if baseline EDSS was 1-5.5 points or increase of =0.5 point if baseline EDSS was >5.5 points), with no relapse between the reference- event- and confirmation score visits. Relapse is defined as objectively observed signs typical of an acute CNS inflammatory demyelinating event, with duration of at least 24hours in the absence of fever or infection, separated from the last relapse by =30 days. The occurence of PIRA (yes/no) is assessed at the end of the follow-up period of the different retinal markers (5 years or for a subgroup up to 10 years after baseline).	5 Years (or for a subgroup up to 10 years) after baseline
Primary	Neuroaxonal loss in the retina (as marker of neurodegeneration in the CNS)	To determine the neuroaxonal loss in the retina, the thickness of the peripapillary retinal nerve fiber layer and the volume of the ganglion cell-inner plexiform layer are assessed by optical coherence tomography (OCT).	Baseline and once every year over up to 5 years
Primary	Neuroinflammation in the retina	To determine the neuroinflammation in the retina, the thickening of the outer plexiform layer, outer nerve layer and ,in particular, of the inner nuclear layer are assessed by OCT.	Baseline and once every year over up to 5 years
Primary	Fixation instability (as marker of global neuronal dysfunction in the CNS)	To determine the fixation instability, visual fixation measurements are recorded via the "Scanner Laser Ophthalmoscopy"-function of the OCT device (as described by Mallery et al., 2018; PMID: 29340646).	Baseline and once every year over up to 5 years
Primary	Structural changes of the retinal vessels (as marker of systemic microvascular health)	To determine structural changes of the retinal vessels, the retinal arterior and venular diameters are measured by static retinal vessel analysis.	Baseline and once every year over up to 5 years
Primary	(For a subgroup of participants) Functional/perfusional changes of the retinal vessels	To determine the functional/perfusional changes of the retinal vessels, a subgroup of participants (patients= 100, Healthy Controls= 50) undergoes additional examinations: OCT-Angiography: measurement of retinal perfusion; Dynamic Retinal vessel analysis: measurement examining the motility and function of the retinal vessels; Laser Speckle Flowgraphy: measurement of ocular perfusion	Baseline and once every year over up to 5 years
Secondary	Relative value of retinal markers for the prediction of PIRA compared to or combined with other biomarkers of neuroaxonal damage	Data regarding other biomarkers (serum neurofilament light chain and brain volume on magnet resonance imaging) that are already available within the clinical routine and/or the SMSC study are used to assess the relative value of the retinal markers described above under primary outcome measures 2-6 in predicting PIRA, both independently or in combination with these other biomarkers.	Baseline and once every year over up to 5 years
Secondary	Comparison of the examined retinal markers of Multiple Sclerosis patients with Healthy Controls and with patients with other neuroinflammatory diseases of the CNS	Examined retinal markers are compared between the different groups to understand the relationship among the different measures independently of disease.	Baseline and once every year over up to 5 years
Secondary	The relationship between neuroaxonal loss, functional deficits and vascular changes in Multiple Sclerosis	Investigation of the associations among the examined retinal measures to understand the relationship between neuroaxonal loss, functional deficits and vascular changes in Multiple Sclerosis.	Baseline and once every year over up to 5 years