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Estriol-RRMS

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

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Year of Publication: 2016

Authors: Rhonda R Voskuhl, HeJing Wang, T C Jackson Wu, ..., Robert Elashoff

Journal: The Lancet Neurology

Citation: Lancet Neurol 2016; 15: 35–46

Link: http://dx.doi.org/10.1016/S1474-4422(15)00322-1

Clinical Question

Does oral estriol treatment, added to glatiramer acetate, reduce relapse rates in women with relapsing-remitting multiple sclerosis?

Bottom Line

Estriol 8 mg daily plus glatiramer acetate reduced the annualized confirmed relapse rate by 37% compared to placebo plus glatiramer acetate (rate ratio 0.63, p=0.077), meeting the pre-specified phase 2 significance threshold of p<0.10. Treatment was well tolerated over 24 months with no increase in serious adverse events, supporting further investigation in a phase 3 trial.

Major Points

  • Relapses decrease >70% during the third trimester of pregnancy when estriol is highest; this trial tested whether exogenous estriol could replicate this protective effect
  • Estriol 8 mg daily achieved serum concentrations equivalent to early second trimester of pregnancy
  • Primary endpoint met at pre-specified phase 2 threshold (p<0.10): 37% relative reduction in confirmed relapse rate
  • At 12 months (before glatiramer acetate reached full potency), estriol showed 51% relapse reduction (p=0.016)
  • Post-hoc MRI analyses showed less cortical grey matter atrophy at 12 months in estriol group (p=0.056)
  • Cognitive improvement (PASAT) correlated with higher estriol concentrations and cortical grey matter preservation
  • Estriol concentrations declined by 24 months due to reduced compliance, potentially attenuating late treatment effects
  • Irregular menses more common with estriol (23% vs 4%), but vaginal infections less common (1% vs 11%)
  • No concerning signals for breast or uterine pathology over 24 months

Design

Study Type: Randomized, double-blind, placebo-controlled, parallel group, phase 2 trial

Randomization: 1

Blinding: Patients, treating physicians, and all investigators assessing outcomes were masked. Study statisticians and pharmacy staff were unmasked but had no patient interaction. Placebo matched estriol by appearance and taste.

Enrollment Period: June 28, 2007 to Jan 9, 2014

Follow-up Duration: 24 months

Centers: 16

Countries: USA

Sample Size: 158

Analysis: Intention-to-treat. Negative binomial regression for relapse rates adjusted for age, baseline EDSS (<2 vs β‰₯2), relapses in prior 12 months (≀1 vs >1), time since diagnosis (<1 vs β‰₯1 year), previous glatiramer acetate treatment, and previous interferon beta treatment. Kaplan-Meier and Cox proportional hazards for time-to-event. Linear mixed effects models for repeated measures. Pre-specified significance level Ξ±=0.10 for phase 2 trial.

Inclusion Criteria

  • Women aged 18–50 years
  • Diagnosis of relapsing-remitting multiple sclerosis according to McDonald criteria
  • Baseline EDSS score of 0–4.5
  • Relapsing disease activity in the previous 24 months

Exclusion Criteria

  • Progressive multiple sclerosis
  • Taking glatiramer acetate for more than 2 months before randomisation
  • Currently smoking
  • Other concurrent disease-modifying treatments
  • Concurrent hormonal treatments

Arms

FieldControlEstriol + Glatiramer Acetate
InterventionOral placebo (matched by appearance and taste) daily plus glatiramer acetate 20 mg/day subcutaneous injection plus second placebo matched to progestin for 2 weeks every 3 months starting at 6 monthsOral estriol 8 mg daily plus glatiramer acetate 20 mg/day subcutaneous injection plus norethindrone 0.7 mg daily for 2 weeks every 3 months starting at 6 months (for uterine protection)
Duration24 months with 4-week taper24 months with 4-week taper

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Annualized confirmed relapse rate at 24 months. Confirmed relapse defined as new or worsening neurological symptoms lasting β‰₯48 hours in a patient stable or improving for β‰₯30 days, accompanied by objective change (worsening by β‰₯0.5 points on EDSS or β‰₯1.0 points on pyramidal, cerebellar, brainstem, or visual functional system scores), not due to fatigue alone, and not associated with fever or infection.Primary0.37 relapses/year (95% CI 0.25–0.53)0.25 relapses/year (95% CI 0.17–0.37)0.077
Time to first confirmed relapse at 24 monthsSecondary42.9% (95% CI 32.1–55.5)33.3% (95% CI 23.8–45.4)0.63 (HR)0.096
Annualized relapse event rate at 24 monthsSecondary0.46 relapses/year (95% CI 0.32–0.65)0.32 relapses/year (95% CI 0.22–0.46)0.65 (RR)0.098
Time to first relapse event at 24 monthsSecondary46.9% (95% CI 35.9–59.3)40.5% (95% CI 30.0–53.0)0.70 (HR)0.179
Annualized confirmed relapse rate at 12 months (exploratory)Secondary0.48 relapses/year (95% CI 0.33–0.69)0.25 relapses/year (95% CI 0.16–0.40)0.49 (RR)0.016
Fatigue (MFIS) change from baseline at 24 monthsSecondary0.5 (SD 12.8)-5.0 (SD 14.0)0.009
PASAT change from baseline at 12 months (all patients)Secondary0.13 (SD 4.46)1.93 (SD 5.59)0.054
PASAT change at 12 months (baseline score <55, post-hoc)Secondary1.60 (SD 5.99)4.70 (SD 6.56)0.011
Cortical grey matter % change at 12 months (post-hoc)Secondary-0.72% (SD 0.80)-0.44% (SD 0.92)0.056
Disability progression over 24 monthsSecondary15.8% (95% CI 8.8–27.6)11.4% (95% CI 5.9–21.7)0.81 (HR)0.664
Any adverse eventAdverse67 (88%)76 (93%)0.21
Serious adverse eventsAdverse10 (13%)8 (10%)0.54
Irregular menses or spottingAdverse3 (4%)19 (23%)0.0005
Vaginal infectionAdverse8 (11%)1 (1%)0.012
Upper respiratory tract infectionAdverse26 (34%)22 (27%)0.31
Urinary tract infectionAdverse10 (13%)15 (18%)0.34
Glatiramer acetate injection area abnormalitiesAdverse12 (16%)21 (26%)0.13
FatigueAdverse8 (11%)13 (16%)0.30
Depression or anxietyAdverse9 (12%)12 (15%)0.56
Endometrium thickness >8 mmAdverse27 (36%)24 (29%)0.46
Uterine fibroidsAdverse8 (11%)8 (10%)0.91
B-cell lymphomaAdverse1 (1%)0 (0%)0.49

Subgroup Analysis

Post-hoc analysis showed that in patients with baseline PASAT score <55 (lower cognitive function), estriol treatment resulted in significantly greater PASAT improvement at 12 months (4.70 vs 1.60 points, p=0.011), whereas no significant effect was seen in patients with baseline PASAT β‰₯55 (p=0.694). In patients without enhancing lesions at baseline, those in the estriol group had significantly less cortical grey matter atrophy at 12 months (p=0.043), suggesting neuroprotective effects independent of anti-inflammatory effects. In patients with enhancing lesions at baseline, the estriol group had more white matter atrophy (p=0.012), consistent with pseudoatrophy from resolving inflammation.

Criticisms

  • Small sample size (n=158) limited statistical power; actual relapse rates were lower than anticipated, reducing power from 80% to 74%
  • Both arms received glatiramer acetate, making it difficult to isolate the independent effect of estriol
  • Estriol serum concentrations declined significantly by 24 months due to compliance issues, potentially attenuating late treatment effects
  • Menstrual irregularities in the estriol group (23% vs 4%) may have partially unmasked treatment allocation
  • Phase 2 significance threshold of p<0.10 is less stringent than conventional p<0.05
  • Long-term safety of estriol beyond 24 months remains unknown
  • Results applicable only to women of reproductive age; cannot be extrapolated to men or postmenopausal women
  • MRI volumetric outcomes showing grey matter preservation were post-hoc analyses
  • Single-country (USA) study limits generalizability

Funding

National Institutes of Health, National Multiple Sclerosis Society, Conrad N Hilton Foundation, Jack H Skirball Foundation, Sherak Family Foundation, and the California Community Foundation. Synthetic Biologics provided estriol and placebo free of charge.

Based on: Estriol-RRMS (The Lancet Neurology, 2016)

Authors: Rhonda R Voskuhl, HeJing Wang, T C Jackson Wu, ..., Robert Elashoff

Citation: Lancet Neurol 2016; 15: 35–46

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