Study No.: Title: Rationale: Phase Study Period: Study Design: Centres: Indication: Treatment: Objectives: Primary Outcome/Efficacy Variable:

Transcription

1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: LAM30007 Title: Open-Label, Multicenter, Randomized Trial to Evaluate the Development of Components of Polycystic Ovary Syndrome (PCOS) in Female Subjects Initiating Lamotrigine or Valproate Either as Monotherapy for Newly Diagnosed Epilepsy or as Adjunctive Therapy for Inadequately Controlled Epilepsy Rationale: Women with epilepsy are more likely to experience polycystic ovary syndrome (PCOS) than are women in the general population. PCOS is a reproductive endocrine disorder characterized by signs and symptoms of androgen excess and associated with metabolic and cardiovascular abnormalities. However, there is little prospective data regarding PCOS in women taking antiepileptic drugs (AEDs). This study was designed to address the paucity of prospective data about the prevalence and development of components of PCOS in women with epilepsy starting treatment with lamotrigine () or valproate (). Phase: IV Study Period: 09Nov Feb2004 Study Design: Open-label, randomized, multicenter study following changes in menstrual, endocrine, and metabolic function in women who initiated either or either as monotherapy for newly diagnosed/untreated epilepsy or as adjunctive therapy for inadequately controlled epilepsy. Centres: 76 centers in 16 countries Indication: Epilepsy Treatment: at mg/day depending on initial or adjunctive therapy and background AED; at 1000 mg/day not to exceed 60 mg/kg/day Objectives: To determine the development of symptoms of polycystic ovary syndrome (PCOS) in women with epilepsy who were randomized 1:1 to receive or as monotherapy or adjunctive therapy for 1 year. Primary Outcome/Efficacy Variable: The proportion of subjects in each treatment group who developed PCOS symptoms at any time during the study. PCOS symptoms were defined as: Ovulatory dysfunction - the presence of >2 anovulatory cycles as measured by urinary pregnanediol glucuronide assays during two 3-month periods during the study. Hyperandrogenism - defined as total or free serum testosterone, or dehydroepiandrosterone sulfate (DHEA-S) concentration exceeding the 95 th percentile of regularly ovulating women in the early follicular phase (days 1 to 6) of the menstrual cycle. Secondary Outcome/Efficacy Variable(s): The proportion of subjects with polycystic ovaries (PCO), defined as sonographic evidence of 10 peripherally oriented 2- to 8-mm cysts surrounding an increased stroma in at least 1 ovary as determined by a central sonographer The proportion of subjects with PCOS defined by the presence of both ovulatory dysfunction and hyperandrogenism The proportion of subjects with anovulatory menstrual cycles Development of menstrual irregularities Changes from the Screening Visit to the End-of-Study Visit in concentrations of serum androgens (i.e., total and free testosterone, androstenedione, and DHEA-S) and sex-hormone binding globulin (SHBG) Changes from the Screening Visit to the End-of-Study Visit in concentrations of serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and in the LH/FSH ratio Changes from the Screening Visit to the End-of-Study Visit in concentrations of serum lipids (i.e., total cholesterol, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, and triglycerides) The proportion of subjects with hyperinsulinemia, defined as a fasting measurement above the upper limit of the normal range Changes from the Screening Visit to the End-of-Study Visit in concentrations of serum insulin (under both fasting conditions and during the 2-hour glucose-loading test) Changes from the Screening Visit to the End-of-Study Visit in weight Changes from the Screening Visit to the End-of-Study Visit in body mass index (BMI) Changes from the Screening Visit to the End-of-Study Visit in seizure frequency Changes from the Screening Visit to the End-of-Study Visit in health-related quality of life as measured by the SEALS (Side Effect and Life Satisfaction Scale) and stress questionnaires Among women who had PCO and/or hyperandrogenism at the Screening Visit, the proportion of subjects with development or aggravation of additional components of PCOS Statistical Methods: The Intent-to-Treat (ITT) efficacy population was defined as all randomized subjects who 1

2 received at least one dose of study drug who were found to not have components of PCOS at screen (i.e. hyperandrogenism). The Screen PCOS population was defined as all randomized subjects who received at least one dose of study drug who had components of PCOS at screen (i.e. hyperandrogenism).the safety population was defined as all randomized subjects who received at least one dose of study drug. The primary efficacy endpoint, the proportion of subjects who developed PCOS symptoms, was compared between treatment groups using the Mantel-Haenszel Chi-Square test, adjusted for grouped center and epilepsy at enrollment (i.e., newly diagnosed/untreated or inadequately controlled). Ovulatory dysfunction, PCOS (both hyperandrogenism and ovulatory dysfunction), and PCO via sonography were analyzed in the same manner as the primary endpoint. Estimates of treatment effect were provided using odds ratios and 95% confidence intervals (CIs). Changes from screening were analyzed using analysis of covariance (ANCOVA), where screening values served as a covariate. 95% confidence intervals around treatment group differences were constructed. If underlying assumptions did not hold, then the appropriate non-parametric analogs (i.e. non-parametric ANCOVA) were used The Mantel-Haenszel chi-square test was used to analyze hyperinsulinemia, seizure freedom and the stress questionnaire with 95% confidence intervals around the odds ratios. Menstrual cycle frequency was analyzed using loglinear poisson regression to construct a 95% confidence interval around the treatment difference. The log exposure time (in number of cycles) was used as the offset function. Study Population: Females, 13 to 40 years of age who: had a confident diagnosis of epilepsy and were: newly diagnosed with less than 2 weeks of treatment for seizures or had inadequately controlled epilepsy while receiving a single chronic AED had regular menstrual cycles were not using hormonal medication were not pregnant, less than 6 months post-partum, or breast-feeding had BMI equal or less than 35 kg/m 2 had never received or Number of Subjects: Planned, N Randomised, N Completed, n (%) 170 (77) 170 (76) Total Number Subjects Withdrawn, n (%) 52 (23) 55 (24) Withdrawn due to Adverse Events n (%) 9 (4) 9 (4) Withdrawn due to Lack of Efficacy n (%) 2 (<1) 1 (<1) Withdrawn for other reasons n (%) 41 (18) 45 (20) Demographics N (ITT Population) Females (%) Mean Age, years (SD) 21.9 (6.4) 22.8 (7.2) White, n (%) 106 (53) 105 (50) Primary Efficacy Results (ITT Population): Proportion exhibiting symptoms of PCOS (ovulatory dysfunction or hyperandrogenism) p-value PCOS Symptoms (38) (54) Secondary Outcome Variables: All using ITT Population, with the exception of the aggravation of PCOS Symptoms endpoint, which uses the Screen PCOS Population 95% CI Subjects with treatment-emergent PCO (40) (40) (0.358,1.590) Subjects with PCOS, n (%) (2) (9) (0.050, 0.698) Subjects with anovulatory menstrual cycles (20) (31) (0.310, 0.933) 2

3 Menstrual irregularities (frequency, length, regularity) Frequency, % Mean (SD) (15.94) Length, days Mean (SD) (10.34) Regularity, days Mean (SD) (18.84) 95% n Value n Value CI (16.22) (4.55) (15.76) (0.944, 1.063) - (95% CI) 0.1 (-1.2, 1.4) -0.2 (-3.6, 3.2) Serum Androgens and SHBG n Value n Value - (95% CI) Total Testosterone, ng/dl Mean (SD) change (14.8) (-10.1,-3.6) (17.0) Free Testosterone, ng/dl Mean (SD) change (0.012) (0.012) ( , ) Androstenedione, ng/dl Mean (SD) change (1.8) (2.3) DHEA-S, ug/dl Mean (SD) change (57.6) (54.2) SHBG, nmol/l Mean (SD) change (32.3) LH, IU/L Mean (SD) change (6.62) FSH, IU/L Mean (SD) change (7.25) LH:FSH, IU/L Mean (SD) change (1.23) Serum Lipids (41.7) (5.04) (2.64) (0.70) (-0.478, 0.390) 28.0 (15.4, 40.6) (-23.8, -8.4) (-1.33, 0.61) 0.55 (-0.62, 1.72) (-0.22, 0.18) Difference Between n Value n Value - (95% CI) Total Cholesterol, mg/dl Mean (SD) change (29.9) (27.7) 2.2 (-3.2, 7.6) HDL Cholesterol, mg dl Mean (SD) change (10.0) (9.1) 3.4 (1.5, 5.3) LDL Cholesterol, mg/dl Mean (SD) change (22.6) (21.8) 0.7 (-3.4, 4.9) 3

4 Triglycerides, mg/dl Mean (SD) change (36.0) (37.1) -9.2 (-16.5, -2.0) Insulin Difference Between n Value n Value - (95% CI) Fasting Insulin, µiu/ml Mean (SD) change (8.62) hours post-dose Insulin, µiu/ml Mean (SD) change (18.68) (62.90) (59.36) (-4.52, 0.57) (-13.27, 11.86) Odds Ratio (95% CI) Subjects with Hyperinsulinemia (6) (40) (0.255,1.49) Weight and BMI n Value n Value - (95% CI) Weight, kg Mean (SD) change (3.6) (4.2) (-3.45, -1.86) BMI, kg/m 2 Mean (SD) change (1.5) (1.7) (-1.35, -0.71) Seizure Freedom, n (%) Odds Ratio (95% CI) All Subjects 75 (37) 98 (46) (0.469, 1.059) Newly Diagnosed Subjects 60 (38) 87 (48) Subjects with Inadequately Controlled Seizures 15 (37) 11 (35) Quality of Life Measures n Value n Value - (95% CI) SEALS Total Score Mean (SD) change (17.46) (16.70) (-18.46, 17.89) Odds Ratio (95% CI) Stress Questionnaire Mean (SD) change (23) (16) (-1.35, -0.71) Aggravation of Symptoms of PCOS Serum Androgens and SHBG N=18 N=11 n Value n Value - (95% CI) Total Testosterone, ng/dl Mean (SD) change (15.6) (22.5) -6.9 (-20.2, 6.5) Free Testosterone, ng/dl Mean (SD) change (0.024) (0.018) ( , ) 4

5 DHEA-S, ug/dl Mean (SD) change (58.8) (85.3) 51.2 (-5.9, 108.3) Safety Results (Safety Population): AEs and SAEs were collected from start of therapy through 3 weeks post discontinuation of study medication. (N=219) (N=222) Most Frequent Adverse Events On-Therapy n (%) n (%) Subjects with any AE(s), n(%) 123 (56) 122 (55) Headache 29 (13) 39 (18) Pyrexia 15 (7) 13 (6) Nasopharyngitis 12 (5) 11 (5) Dizziness 11 (5) 10 (5) All Rash 1 10 (5) 9 (4) Abdominal Pain 6 (3) 3 (1) Vomiting 6 (3) 16 (7) Asthenia 5 (2) 0 Influenza 5 (2) 2 (<1) Pharyngitis 5 (2) 3 (1) Dysmennorhea 5 (2) 1 (<1) Alopecia 3 (1) 25 (11) Tremor 2 (<1) 18 (8) Nausea 3 (1) 16 (7) Weight Increase 0 11 (5) 1 All Rash consists of Angioneurotic Edema, Erythema Multiforme, Rash, Rash Macular, Rash Morbilliform, Rash Papular and Urticaria Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] Non-fatal SAEs Any Subject 5 (2) [1] 8 (4) [1] Convulsion 1 (<1) [0] 0 Dizziness 1 (<1) [0] 0 Encephalopathy 1 (<1) [1] 1 (<1) [1] Myoclonic epilepsy 1 (<1) [0] 0 Asthenia 1 (<1) [0] 0 Tuberculosis 1 (<1) [0] 0 Joint Injury 1 (<1) [0] Dyskinesia 0 1 (<1) [1] Grand Mal convulsion 0 2 (<1) [0] Sensory disturbance 0 1 (<1) [0] Somnolence 0 1 (<1) [0] Hepatitis A 0 1 (<1) [0] Hyperammonaemia 0 1 (<1) [1] Abortion, spontaneous 0 1 (<1) [0] Suicide attempt 0 1 (<1) [0] Calculus ureteric 0 1 (<1) [0] Cervical dysplasia 0 1 (<1) [0] Metrorrhagia 0 1 (<1) [0] Fatal SAEs, n (%) Any Subject 0 0 5

6 Conclusion: In this open label study, significantly fewer women with epilepsy developed PCOS symptoms while receiving therapy with compared to those receiving therapy with for up to 1 year. Publications: Abstract: Higher incidence of components of polycystic ovary syndrome in young women with epilepsy treated with valproate versus lamotrigine. Morrell, Martha J MD, Hayes, Frances S MD, Sluss, Patrick M PhD, Warnock, Clay R, Conklin, Heather S, and Isojarvi, Jouko I. MD PhD 3 59th Annual Meeting of the American Epilepsy Society held jointly with the American Clinical Neurophysiology Society 12/2/2005 Washington, DC; USA Abstract: Higher incidence of components of polycystic ovary syndrome in young women with epilepsy treated with valproate versus lamotrigine. Morrell, M. J., Hayes, F. J., Sluss, P., Warnock, C. R., and Isojarvi, J. I. T. 26th International Epilepsy Congress 8/28/2005 Paris; France Abstract: Higher incidence of symptoms of polycystic ovary syndrome in women with epilepsy treated with valproate versus lamotrigine. Morrell, Martha, Bhatt, Mohitt, Ozkara, Cigdem, Hayes, Frances, Sluss, Patrick, Adams, Judith, Warnock, Clay R., and Isojarvi, Jouko 57th Annual Meeting of the American Academy of Neurology 4/9/2005 Miami Beach, FL; USA Abstract: Reproductive endocrine characteristics of women with newly diagnosed or inadequately controlled epilepsy: a preliminary analysis. M Bar, R Borgohain F Hayes C. R Warnock H Co 6th European Congress on Epileptology 5/30/2004 Vienna; Austria Abstract: Reproductive endocrine characteristics of women with newly diagnosed or inadequately controlled epilepsya preliminary analysis. Rupam Borgohain MBBS, DM Michal Bar MD Frances Hayes MD Clay R. Warnock Heather Conklin Sarah Jarman and Martha Morrell MD. 1 57th Annual Meeting of the American Epilepsy Society 12/5/2003 Boston, MA; USA Date Updated: 30-Oct