Predictors of Progression Independent of Relapse Activity in Relapsing Remitting Multiple Sclerosis (RRMS)

August 7, 2026 updated by: Omnia Abd El Nasser Badry, Assiut University

Predictors of Progression Independent of Relapse Activity in Relapsing Remitting Multiple Sclerosis: Multimodal Prospective Cohort Study at Assiut University Hospital

The goal of this prospective observational cohort study is to determine the frequency of progression independent of relapse activity (PIRA) and identify its clinical, radiological, neuroaxonal, and functional predictors in patients with early relapsing-remitting multiple sclerosis (RRMS). The study aims to facilitate early identification of patients at increased risk of disability progression independent of relapses and to support individualized therapeutic decision-making.

The main questions it aims to answer are:

What is the frequency of PIRA in patients with early RRMS? Which demographic and clinical characteristics are associated with the development of PIRA? Which MRI biomarkers, including lesion burden, brain atrophy, spinal cord involvement, and paramagnetic rim lesions (where available), are associated with PIRA? Can optical coherence tomography (OCT) measurements, including peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell-inner plexiform layer (mGCIPL) thickness, predict PIRA? Are serum biomarkers, including neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), associated with an increased risk of PIRA? Which baseline factors independently predict disability progression?

Participants will undergo comprehensive baseline and follow-up assessments, including collection of demographic and clinical data, neurological examination with Expanded Disability Status Scale (EDSS) scoring, brain and spinal cord MRI, OCT assessment, laboratory evaluation of serum biomarkers (where available), and validated functional and patient-reported outcome measures. Participants will be followed longitudinally to identify confirmed disability accumulation (CDA) and classify disability progression as PIRA or relapse-associated worsening (RAW).

The primary outcome is the occurrence of PIRA, defined as confirmed disability accumulation independent of clinical relapses during follow-up. Secondary outcomes include identification of independent clinical, imaging, OCT, and laboratory predictors of PIRA and evaluation of their association with long-term disability progression. The findings may improve early risk stratification and support timely initiation of high-efficacy disease-modifying therapies in patients with early RRMS.

Study Overview

Status

Not yet recruiting

Conditions

Detailed Description

The goal of this prospective observational cohort study is to determine the frequency of progression independent of relapse activity (PIRA) and identify its clinical, radiological, neuroaxonal, and functional predictors in patients with early relapsing-remitting multiple sclerosis (RRMS) attending the Multiple Sclerosis Unit at Assiut University Hospital. Although relapses have traditionally been considered the primary driver of disability accumulation in RRMS, growing evidence indicates that disability may also progress independently of clinical relapses. This phenomenon, known as PIRA, has emerged as a major contributor to long-term disability and an early manifestation of the progressive disease process. Early identification of patients at risk for PIRA may facilitate timely initiation of high-efficacy disease-modifying therapies (DMTs), improve individualized treatment strategies, and reduce long-term neurological disability.

PIRA is defined as confirmed disability accumulation (CDA) occurring during a relapse-free period and is increasingly recognized as a reflection of chronic neurodegenerative processes and compartmentalized inflammation within the central nervous system. Recent studies suggest that PIRA may occur even during the earliest stages of RRMS and is associated with accelerated brain atrophy, greater gray matter loss, increased risk of conversion to secondary progressive multiple sclerosis (SPMS), and poorer long-term functional outcomes. Despite its clinical importance, reliable predictors of PIRA remain insufficiently established, particularly in patients with early RRMS. This study seeks to address this knowledge gap by integrating clinical assessments with advanced imaging, laboratory biomarkers, optical coherence tomography (OCT), and validated functional outcome measures.

The main questions this study aims to answer are:

What is the frequency of PIRA among patients with early RRMS during the study follow-up period? Which demographic and clinical characteristics are associated with the development of PIRA? Which MRI characteristics, including lesion burden, lesion location, spinal cord involvement, brain atrophy, and chronic inflammatory imaging biomarkers, are associated with subsequent PIRA? Can retinal neuroaxonal measurements obtained by OCT, including peripapillary retinal nerve fiber layer (pRNFL) thickness and macular ganglion cell-inner plexiform layer (mGCIPL) thickness, predict future disability progression independent of relapses? Are circulating biomarkers of neuroaxonal injury and astroglial activation, including serum neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), associated with the occurrence of PIRA? Which baseline variables independently predict disability progression after adjustment for potential confounding factors? Does combining clinical, radiological, OCT, and laboratory biomarkers improve prediction of PIRA compared with individual markers alone?

Participants diagnosed with early RRMS according to the 2024 McDonald diagnostic criteria and meeting the study eligibility criteria will be prospectively enrolled and followed according to the study protocol.

Each participant will undergo standardized baseline and follow-up evaluations including:

Collection of demographic data, disease duration, clinical presentation, relapse history, disease-modifying therapy exposure, vascular risk factors, and other relevant medical history.

Comprehensive neurological examination with disability assessment using the Expanded Disability Status Scale (EDSS) to determine baseline disability and detect confirmed disability accumulation during follow-up.

Brain and spinal cord magnetic resonance imaging (MRI) using standardized imaging protocols to evaluate T2 lesion burden, gadolinium-enhancing lesions (when clinically indicated), lesion distribution, brain atrophy measures, spinal cord lesions, and, where available, advanced imaging biomarkers such as chronic active lesions or paramagnetic rim lesions.

Optical coherence tomography (OCT) assessment of retinal neuroaxonal integrity through measurement of pRNFL and mGCIPL thickness.

Laboratory assessment of serum biomarkers including neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), where available, to evaluate neuroaxonal injury and chronic astroglial activation.

Administration of validated functional and patient-reported outcome measures evaluating cognition, fatigue, depression, quality of life, and physical function, according to the study protocol.

Prospective follow-up to identify confirmed disability accumulation, classify disability progression as PIRA or relapse-associated worsening (RAW), and evaluate disability persistence throughout the observation period.

The primary outcome is the frequency of PIRA, defined as confirmed disability accumulation occurring independently of clinical relapses according to established international criteria.

Secondary outcomes include identification of independent clinical, MRI, OCT, laboratory, and functional predictors of PIRA; determination of factors associated with persistent disability progression; evaluation of the relationship between imaging biomarkers and disability accumulation; and development of a predictive model for early identification of patients at increased risk of PIRA.

The findings of this study are expected to improve understanding of the mechanisms underlying disability progression in early RRMS and provide evidence for integrating multimodal biomarkers into routine clinical practice. Early identification of patients at increased risk of PIRA may facilitate individualized treatment decisions, support earlier use of high-efficacy disease-modifying therapies, and ultimately improve long-term neurological outcomes.

Study Type

Observational

Enrollment (Estimated)

180

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 Backup

Study Locations

  • Egypt
    • Asyut Governorate
      • Asyut, Asyut Governorate, Egypt, 71515

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

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

Yes

Sampling Method

Probability Sample

Study Population

Patients with early relapsing-remitting multiple sclerosis (RRMS) will be recruited consecutively from the Neurology Department, Assiut University Hospital, and followed prospectively for 24 months.

Description

Inclusion Criteria:

  • RRMS diagnosis per 2024 McDonald Criteria Disease duration ≤ 5 years from disease onset At least 1 year on disease-modifying therapy (DMT) Age 18-55 years (both sexes) Written informed consent obtained

Exclusion Criteria:

  • • Alternative diagnosis confirmed (e.g., NMOSD, vasculitis)

    • Confirmed RAW
    • SPMS or progressive onset at baseline
    • Any systemic or neurological disorders affecting either mobility or cognition
    • Psychoactive drug use
    • Recent optic neuritis within the previous six months.
    • Any ophthalmological condition known to affect retinal nerve fiber layer (RNFL) or ganglion cell-inner plexiform layer (GCIPL) thickness.

Glaucoma. Diabetic retinopathy. Retinal vascular disease. High myopia (>6 diopters). Previous ocular trauma or intraocular surgery (except uncomplicated cataract surgery >6 months).

Media opacity preventing reliable OCT acquisition.

• Incomplete follow up or poor compliance

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

Cohorts and Interventions

Group / Cohort
relapsing remitting multiple sclerosis
Patients with early relapsing-remitting multiple sclerosis enrolled in the study and followed prospectively to determine the occurrence of progression independent of relapse activity (PIRA). Participants will subsequently be classified into PIRA and non-PIRA groups according to the study outcome.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of participants who develop progression independent of relapse activity (PIRA) during the 2-year follow-up
Time Frame: Baseline assessment with follow-up evaluations every 6 months for 24 months
Percentage of participants who meet the predefined study criteria for confirmed progression independent of relapse activity (PIRA), based on Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) criteria in the absence of clinical relapse.
Baseline assessment with follow-up evaluations every 6 months for 24 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Adjusted odds ratio for development of PIRA according to baseline MRI biomarkers
Time Frame: Baseline assessment with follow-up evaluations every 12 months for 24 months
Baseline & follow up after 1 year MRI biomarkers, including T2 lesion number, gadolinium-enhancing lesions, whole-brain volume (cm³), cortical volume (cm³), thalamic volume (cm³), black holes, paramagnetic rim lesions (PRLs), and slowly expanding lesions (SELs), will be evaluated as predictors of development of PIRA using multivariable logistic regression. Results will be reported as adjusted odds ratios with 95% confidence intervals
Baseline assessment with follow-up evaluations every 12 months for 24 months
Adjusted odds ratio for development of PIRA according to baseline optical coherence tomography (OCT) biomarkers
Time Frame: Baseline assessment with follow-up evaluations every 12 months for 24 months
Baseline spectral-domain OCT measurements & follow up after 1 year , including peripapillary retinal nerve fiber layer (pRNFL) thickness (µm) and macular ganglion cell-inner plexiform layer (GCIPL) thickness (µm), will be evaluated as predictors of development of PIRA using multivariable logistic regression. Results will be reported as adjusted odds ratios with 95% confidence intervals
Baseline assessment with follow-up evaluations every 12 months for 24 months
Adjusted odds ratio for development of PIRA according to baseline visual evoked potential (VEP) P100 latency.
Time Frame: Baseline assessment with follow-up evaluations every 6 months for 24 months
Baseline visual evoked potential P100 latency (milliseconds) will be evaluated as a predictor of development of PIRA using multivariable logistic regression. Results will be reported as adjusted odds ratios with 95% confidence intervals.
Baseline assessment with follow-up evaluations every 6 months for 24 months

Collaborators and Investigators

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

Sponsor

Assiut University

Investigators

  • Principal Investigator: omnia A badry, assistant, Assiut university neurology hospital

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 (Estimated)

September 1, 2026

Primary Completion (Estimated)

September 1, 2028

Study Completion (Estimated)

December 1, 2028

Study Registration Dates

First Submitted

July 29, 2026

First Submitted That Met QC Criteria

August 7, 2026

First Posted (Actual)

August 13, 2026

Study Record Updates

Last Update Posted (Actual)

August 13, 2026

Last Update Submitted That Met QC Criteria

August 7, 2026

Last Verified

July 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 04-2026-100514

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

data is available with the corresponding author on reasonable request

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

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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