Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial

Voskuhl, Rhonda R.; Wang, He Jing; Wu, Tao; Sicotte, Nancy L.; Nakamura, Kunio; Kurth, Florian; Itoh, Noriko; Bardens, Jenny; Bernard, Jacqueline; Corboy, John R.; Cross, Anne H.; Dhib‐Jalbut, Suhayl; Ford, Corey C.; Frohman, Elliot M.; Giesser, Barbara; Jacobs, Dina; Kasper, Lloyd H.; Lynch, Sharon G.; Parry, Gareth; Racke, Michael K.; Reder, Anthony T.; Rose, John; Wingerchuk, Dean M.; MacKenzie-Graham, Allan; Arnold, Douglas L.; Tseng, Chi Hong; Elashoff, Robert M.

doi:10.1016/s1474-4422(15)00322-1

Cited by 160 publications

(148 citation statements)

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“…In the published phase 2 trial, estriol + GA as compared to placebo + GA treatment improved cognitive performance in analyses including all time points ( p = 0.038, between groups) (Voskuhl et al., 2016). As the placebo + GA group took the PASAT at the same time points as the estriol + GA group, this between‐group difference was not due to a practice effect.…”

Section: Resultsmentioning

confidence: 99%

“…To estimate the difference in PASAT score change between the two study groups over all time points, baseline PASAT scores were used as an interaction term with treatment and month in the model. All patients’ follow‐up data over all 24 months were included (Voskuhl et al., 2016). …”

Section: Methodsmentioning

confidence: 99%

“…Cortical GM volumes were determined using pairwise Jacobian integration (PJI) as described (Voskuhl et al., 2016). …”

Section: Methodsmentioning

confidence: 99%

“…The region of treatment‐induced sparing (TIS) was defined as the collection of clusters of GM that were significantly preserved in estriol + GA‐treated, but not in placebo + GA‐treated, subjects after 12 months of treatment (Figure 2) (Table 2) (Voskuhl et al., 2016). We observed clusters of preserved GM in the estriol + GA‐treated subjects, but none in the placebo +GA‐treated subjects.…”

Section: Methodsmentioning

confidence: 99%

“…We hypothesize that determining the effects of treatment on localized GM atrophy using this unbiased, biology‐driven, VBM approach may lead to neuroprotective treatments optimized for specific brain regions and specific clinical disabilities. To this end, in a recently completed phase 2 clinical trial, we demonstrated that estriol treatment led to the preservation of localized GM compared to placebo in patients with MS and that higher levels of estriol in the blood were correlated with better performance on the PASAT (Voskuhl et al., 2016). Here, we investigate relationships between estriol treatment‐induced localized GM preservation and traditional MRI and clinical disability measures.…”

Section: Introductionmentioning

confidence: 99%

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Estriol‐mediated neuroprotection in multiple sclerosis localized by voxel‐based morphometry

et al. 2018

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IntroductionProgressive gray matter (GM) atrophy is a hallmark of multiple sclerosis (MS). Cognitive impairment has been observed in 40%–70% of MS patients and has been linked to GM atrophy. In a phase 2 trial of estriol treatment in women with relapsing–remitting MS (RRMS), higher estriol levels correlated with greater improvement on the paced auditory serial addition test (PASAT) and imaging revealed sparing of localized GM in estriol‐treated compared to placebo‐treated patients. To better understand the significance of this GM sparing, the current study explored the relationships between the GM sparing and traditional MRI measures and clinical outcomes.MethodsSixty‐two estriol‐ and forty‐nine placebo‐treated RRMS patients underwent clinical evaluations and brain MRI. Voxel‐based morphometry (VBM) was used to evaluate voxelwise GM sparing from high‐resolution T1‐weighted scans.ResultsA region of treatment‐induced sparing (TIS) was defined as the areas where GM was spared in estriol‐ as compared to placebo‐treated groups, localized primarily within the frontal and parietal cortices. We observed that TIS volume was directly correlated with improvement on the PASAT. Next, a longitudinal cognitive disability‐specific atlas (DSA) was defined by correlating voxelwise GM volumes with PASAT scores, that is, areas where less GM correlated with less improvement in PASAT scores. Finally, overlap between the TIS and the longitudinal cognitive DSA revealed a specific region of cortical GM that was preserved in estriol‐treated subjects that was associated with better performance on the PASAT.ConclusionsDiscovery of this region of overlap was biology driven, not based on an a priori structure of interest. It included the medial frontal cortex, an area previously implicated in problem solving and attention. These findings indicate that localized GM sparing during estriol treatment was associated with improvement in cognitive testing, suggesting a clinically relevant, disability‐specific biomarker for clinical trials of candidate neuroprotective treatments in MS.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Cortical GM volumes were determined using pairwise Jacobian integration (PJI) as described (Voskuhl et al., 2016). …”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Estriol‐mediated neuroprotection in multiple sclerosis localized by voxel‐based morphometry

et al. 2018

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Rebound Relapses After Ceasing Another Disease-Modifying Treatment in Patients With Multiple Sclerosis

Voskuhl

2016

JAMA Neurol

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Disability-Specific Atlases of Gray Matter Loss in Relapsing-Remitting Multiple Sclerosis

et al. 2016

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IMPORTANCE Multiple sclerosis (MS) is characterized by progressive gray matter atrophy that strongly correlates with clinical disability, however it is not known if localized gray matter atrophy correlates with specific disabilities in MS patients. OBJECTIVE Our objective in this study was to understand the relationship between localized gray matter atrophy and clinical disability in a biology-driven, as opposed to a hypothesis-driven, manner. DESIGN, SETTING, AND PARTICIPANTS Magnetic resonance images were acquired from 133 female subjects with relapsing-remitting MS and analyzed using voxel-based morphometry (VBM) as well as volumetry. A regression analysis was then used to determine if voxelwise gray matter atrophy was associated with specific clinical deficits. MAIN OUTCOME AND MEASURES Voxelwise correlation of gray matter change with clinical outcome measures. RESULTS Worse performance on the multiple sclerosis functional composite correlated with voxelwise gray matter volume loss in the middle cingulate cortex and a cluster in the precentral gyrus bilaterally. In addition, worse performance on the Paced Auditory Serial Addition Test correlated with volume loss in the auditory and premotor cortex, while worse performance on the 9-hole peg test correlated with gray matter volume loss in Brodmann area 44 (Broca’s area). Finally, voxelwise gray matter loss in the right paracentral lobulus correlated with bowel and bladder disability. Thus, deficits in specific clinical tests were directly related to localized gray matter loss in clinically eloquent locations. CONCLUSIONS AND RELEVANCE These biology-driven data indicate that specific disabilities in MS are associated with voxelwise gray matter loss in distinct locations. This approach may be used to develop disability-specific biomarkers for use in future clinical trials of neuroprotective treatments in MS.

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Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial

Cited by 160 publications

References 47 publications

Estriol‐mediated neuroprotection in multiple sclerosis localized by voxel‐based morphometry

Estriol‐mediated neuroprotection in multiple sclerosis localized by voxel‐based morphometry

Rebound Relapses After Ceasing Another Disease-Modifying Treatment in Patients With Multiple Sclerosis

Disability-Specific Atlases of Gray Matter Loss in Relapsing-Remitting Multiple Sclerosis

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