This randomized, placebo-controlled, double-blind, multicenter clinical trial will assess the efficacy of adjunctive cyclic progesterone therapy in lessening the frequency of intractable seizures in women with localization-related epilepsy. There is considerable scientific evidence to suggest that estrogen generally increases while progesterone decreases neuronal excitability and seizures. Preliminary open trials suggest that the cyclic administration of adjunctive natural progesterone supplement may lessen seizure frequency by over 50% in the majority of women with catamenially exacerbated intractable seizures. Oral synthetic progestins, in contrast, have not shown significant efficacy. Progesterone is not widely prescribed because its benefits have yet to be conclusively demonstrated. We have shown the feasibility and safety of a progesterone trial, using 150 subjects in the initial phase of this investigation. We now propose proceeding with the completion of this definitive investigation of 640 subjects. During the baseline phase, seizure and menstrual charts document baseline seizure frequency and determine if seizure occurrence shows a catamenial pattern of exacerbation. The subjects are then divided into catamenial and non-catamenial strata. Each stratum is randomized in a 2:1 ratio into progesterone and placebo treatment groups. Seizure frequency during 3 months of treatment is compared to baseline, while monitoring antiepileptic drug and hormone levels. This clinical trial has considerable potential significance for women with epilepsy. Approximately 30% have persistent seizures despite antiepileptic drug use. It is estimated that 35% of these women have catamenial seizure exacerbation. If this group responds favorably to hormonal therapy, 1 would expect that progesterone may benefit approximately (1,000,000 x .30 x .35) 100,000 women with catamenial epilepsy and perhaps many more women with no a priori demonstrated hormonal sensitivity to seizure occurrence.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS039466-04A1
Application #
6979877
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Jacobs, Margaret
Project Start
1999-12-01
Project End
2008-05-31
Budget Start
2005-09-20
Budget End
2006-05-31
Support Year
4
Fiscal Year
2005
Total Cost
$3,304,242
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Herzog, Andrew G (2015) Catamenial epilepsy: Update on prevalence, pathophysiology and treatment from the findings of the NIH Progesterone Treatment Trial. Seizure 28:18-25
Herzog, Andrew G; Fowler, Kristen M; Sperling, Michael R et al. (2015) Distribution of seizures across the menstrual cycle in women with epilepsy. Epilepsia 56:e58-62
Herzog, Andrew G; Frye, Cheryl A; Progesterone Trial Study Group (2014) Allopregnanolone levels and seizure frequency in progesterone-treated women with epilepsy. Neurology 83:345-8
Herzog, A G; Fowler, K M; Smithson, S D et al. (2012) Progesterone vs placebo therapy for women with epilepsy: A randomized clinical trial. Neurology 78:1959-66
Herzog, Andrew G; Fowler, Kristen M; Sperling, Michael R et al. (2011) Variation of seizure frequency with ovulatory status of menstrual cycles. Epilepsia 52:1843-8
Quigg, M; Smithson, S D; Fowler, K M et al. (2009) Laterality and location influence catamenial seizure expression in women with partial epilepsy. Neurology 73:223-7
Meador, Kimford J (2009) The essential neurologic examination: what should medical students be taught? Neurology 73:2133-4; author reply 2134
Quigg, Mark; Fowler, Kristen M; Herzog, Andrew G et al. (2008) Circalunar and ultralunar periodicities in women with partial seizures. Epilepsia 49:1081-5
Herzog, Andrew G; Fowler, Kristen M; NIH Progesterone Trial Study Group (2008) Sensitivity and specificity of the association between catamenial seizure patterns and ovulation. Neurology 70:486-7
Harden, Cynthia L; Maroof, David Aaron; Nikolov, Blagovest et al. (2007) The effect of seizure severity on quality of life in epilepsy. Epilepsy Behav 11:208-11

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