Study to Explore the Effect of Mefloquine in Participants With Progressive Multifocal Leukoencephalopathy (PML)

Study Overview
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Brief Summary
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The primary objective of the study was to explore whether mefloquine can delay or stop progression of progressive multifocal leukoencephalopathy (PML) as measured by JC virus (human polyomavirus or JCV) deoxyribonucleic acid (DNA) levels in cerebrospinal fluid (CSF). The secondary objective of the study was to explore whether mefloquine can delay or stop progression of PML based on neurological deterioration, magnetic resonance imaging (MRI) measures of brain lesion evolution or the formation of new lesions, and mortality.

Official Title
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A Randomized, Rater-Blinded Study to Explore the Effect of Mefloquine in Subjects With Progressive Multifocal Leukoencephalopathy (PML)

Conditions
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Progressive Multifocal Leukoencephalopathy

Intervention / Treatment
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* Drug: mefloquine


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of PML confirmed by detection of JCV DNA in CSF. Onset of PML symptoms within 6 months prior to study. Key Exclusion Criteria: Other opportunistic infection of the central nervous system. Current severe illness or any other conditions that, in the opinion of the Investigator, would make the subject unsuitable for enrollment. Active severe mental illness (e.g., depression, anxiety, psychosis, and schizophrenia). Hypersensitivity to mefloquine, quinine, or quinidine, or to any component of these drugs. Current treatment with quinine, quinidine, chloroquine, or halofantrine. Note: Other protocol-defined criteria may also apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Local standard of care<br>All participants received local standard of care, which may have included any treatment or procedure that the Investigator would normally use in the treatment of a PML patient at their study site or hospital. Participants in this treatment arm had the option of adding 250 mg mefloquine by mouth at Week 4 (Day 28) or Week 8 (Day 56) daily for 3 days, and then weekly through Week 24. | |
| Experimental: Local standard of care plus mefloquine 250 mg<br>All participants received local standard of care, which may have included any treatment or procedure that the Investigator would normally use in the treatment of a PML patient at their study site or hospital. Participants received 250 mg mefloquine by mouth on Days 0, 1, and 2 and then weekly through Week 24. | Drug: mefloquine<br>* 250 mg orally each day for 3 days and then weekly up to 6 months.<br>* Other names: Mefliam®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 4 in JC Virus (JCV) Load in Cerebrospinal Fluid (CSF) | Change from baseline to Week 4 in JC viral load in CSF is expressed as log10 copies/mL. Negative values indicate a reduction in viral load. Only participants with measurable baseline values are included. Post-baseline values of 'Below the Limit of Quantification' or 'Below Limit of Detection' or 'Negative' were set to 50. Log10 (50) = 1.699 | Day 0 (baseline), Week 4 | 
| Change From Baseline to Week 8 in JC Virus (JCV) Load in Cerebrospinal Fluid (CSF) | Change from baseline to Week 8 in JC viral load in CSF is expressed as log10 copies/mL. Negative values indicate a reduction in viral load. Only participants with measurable baseline values are included. Post-baseline values of 'Below the Limit of Quantification' or 'Below Limit of Detection' or 'Negative' were set to 50. Log10 (50) = 1.699 | Day 0 (baseline), Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 4 and Week 8 in the Expanded Disability Status Scale (EDSS) Score | EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death) was calculated. Negative change scores indicate improvement. | Day 0 (baseline), Week 4 and 8 | 
| Change From Baseline to Week 4 and Week 8 in Karnofsky Performance Status (KPS) Index Score | The KPS Index classifies participants' functional impairment. KPS can be used to compare effectiveness of different therapies and to assess the prognosis in individual participants. KPS was recorded on an 11-point scale (0, 10, 20, 30, 40, 50, 60, 70, 80, 90, and 100.) where '0=Dead' and '100=Normal, no complaints, no evidence of disease'. The lower the KPS score, the worse the survival for most serious illnesses. The KPS index is subdivided into 3 categories: incapacitated (0 to 40), self-care (50 to 70), and normal activity (80 to 100). Negative change from baseline scores indicate improved prognosis. | Day 0 (baseline), Week 4, Week 8 | 
| Change From Baseline to Week 4 and Week 8 in Symbol Digit Modalities Test (SDMT) | The SDMT is a simple substitution task. The test gives participants 90 seconds to pair specific numbers with given geometric figures as a measure for screening cognitive impairment. The total score is the total number of correctly completed boxes in the time allowed. The test score range is from 0 (worst outcome) to 110 (best outcome). Negative change from baseline scores indicates a worsening outcome. | Day 0 (baseline), Week 4, Week 8 | 
| Change From Baseline to Week 4 and Week 8 in Participants' Neurological Function Using a Visual Analog Scale (VAS) | Participants rate their neurological function on a scale of 100 mm line, where the 0 end of the scale indicates poor neurological function and 100 indicates excellent neurological function. VAS was not required for participants who had physical or cognitive impairments that limited their ability to perform the assessment. Negative change from baseline scores indicates a worsening outcome. | Day 0 (baseline), Week 4, Week 8 | 
| Participants With Gadolinium (Gd)-Enhanced Lesions at Baseline, Week 4 and Week 8 as Seen on Magnetic Resonance Imaging (MRI) Scans of Participants' Brains |  | Day 0 (baseline), Week 4, Week 8 | 
| Change From Baseline to Week 4 and Week 8 in T1 Lesion Volume as Seen on Magnetic Resonance Imaging (MRI) Scans of Participants' Brains |  | Day 0 (baseline), Week 4, Week 8 | 
| Change From Baseline to Week 4 and Week 8 in T2 Lesion Volume as Seen on Magnetic Resonance Imaging (MRI) Scans of Participants' Brains |  | Day 0 (baseline), Week 4, Week 8 | 
| Participants Who Died Within 6 Months | The death event is counted under the treatment arm relative to adding mefloquine to the treatment regimen. | Day 1 up to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PML, Human Polyomavirus JC, HIV, Central Nervous System Disease, Mefloquine, JC Virus