Evidence of uncontrolled hypertension (defined as systolic blood pressure 160 mmhg and/or diastolic blood pressure 100 mmhg); uncontrolled

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1 Supplemental Table 1. Exclusion criteria Patients were excluded from the study if they met the following criteria Were perimenopausal or had reached menopause (defined as FSH concentration >10 IU/L) Menstruation in the 30 days before the baseline visit Presence of a clinically relevant disease or abnormalities (particularly abnormal vaginal bleeding) that prevented the patient from participating in the study, put them at risk, or would interfere with the study results A significant illness in the 2 weeks preceding the study Evidence of uncontrolled hypertension (defined as systolic blood pressure 160 mmhg and/or diastolic blood pressure 100 mmhg); uncontrolled diabetes; or significant pulmonary, renal, hepatic, endocrine, or other systemic disease A hysterectomy or bilateral oophorectomy or both History of Gilbert's syndrome, infectious hepatitis, or other significant hepatic disease History of gastric or small intestinal surgery or current disease that causes malabsorption History of or current hyperthyroidism Abnormal ECG, marked prolongation of QT/QTc interval, additional risk factors for Torsades de Pointes, or the use of concomitant medications that prolong the QT/QTc interval Positive human immunodeficiency virus (HIV), hepatitis B, or hepatitis C serology at screening History of hypersensitivity to >2 chemical classes of drugs 1

2 Alcohol or substance abuse or consumed 3 alcoholic drinks per day Blood loss of >200 ml in the 30 days from baseline, >500 ml in the 56 days from baseline, >1350 ml in 1 year from baseline, or donation of blood products in the 14 days before baseline Neoplastic disease in the past 5 years (except adequately treated basal cell, squamous cell skin cancer, or in situ cervical cancer) Abnormal or unexplained laboratory test results (aspartate aminotransferase >1.5 times ULN; alanine aminotransferase >1.5 times ULN; total bilirubin >1.5 times ULN; serum creatinine >2.0 times ULN; hematocrit less than LLN; prolactin >2.0 times ULN) Withdrawal from oral contraceptives and LH concentrations <3 IU/L in the 7 days before the start of the study Use of potent or moderate CYP3A4 or CYP2C9 inhibitors, potent or moderate CYP3A4 or CYP2C9 inducers, hormonal contraceptives, antiandrogenic drugs, or other medications within specified time periods Pregnancy or not using an adequate form of birth control Involvement in the planning and/or conduct of the study (applied to any Quintiles or AstraZeneca employee and their close relatives and/or staff at the study site, regardless of their role in accordance with their internal procedures) Previous randomization to treatment in the present study Inability to understand or cooperate with the requirements of the study Was legally or mentally incapacitated Reporting suicidal ideation of Type 4 or 5 in the past 2 months or suicidal behaviour in the past 6 months as measured by the C-SSRS at baseline ECG, electrocardiogram; FSH, follicle-stimulating hormone; LH, luteinizing hormone; LLN, lower limit of normal; ULN, upper limit of normal. 2

3 Supplemental Table 2. Baseline-adjusted changes in LH AUC, total testosterone C avg,, free testosterone C avg, LH AUC:FSH AUC ratio, and LH pulsatility parameters relative to placebo Parameter Day AZD mg/day AZD mg/day AZD mg/day Luteinizing hormone AUC n n n All analyzed patients ( to 29.47) ( to 16.16) ( to 29.64) ( to 5.94) ( to 47.64) ( to 13.58) ( to 40.01) ( to 18.64) ( to 24.90) Non-ovulating patients a ( to 26.79) ( to 41.36) ( to 6.62) Total testosterone C avg All analyzed patients ( to 11.51) ( to 11.93) ( to 13.89) ( to 20.77) ( to 17.01) ( to 0.63) ( to 14.16) ( to 16.12) ( to 13.26) Non-ovulating patients a ( to 19.90) ( to 14.64) ( to 5.32) 1

4 Free testosterone C avg All analyzed patients ( to 20.13) ( to 25.84) ( to 0.14) ( to 31.68) ( to 38.21) ( to 3.68) ( to 18.75) ( to 17.58) ( to 6.80) Non-ovulating patients a ( 8.46 to 36.10) ( to 27.03) ( to 7.32) LH number of pulses/8 hours a All analyzed patients ( 2.89 to 0.23) ( 2.83 to 0.46) ( 5.10 to 2.00) ( 2.08 to 1.24) ( 2.62 to 0.81) ( 2.85 to 0.46) ( 3.13 to 0.03) ( 2.97 to 0.18) ( 5.38 to 2.42) Non-ovulating patients a ( 1.80 to 1.51) ( 2.81 to 0.45) ( 3.48 to 0.30) LH basal secretion All analyzed patients ( to 77.22) ( to 53.26) ( to 53.61) ( to ) ( to ) ( to 45.44) ( to 58.31) ( to 72.06) ( to 59.57) Non-ovulating patients a ( to ) ( to 86.80) ( to 14.97) LH mass-per-pulse All analyzed patients ( 5.88 to ) ( 17.05to ) ( to 92.37) ( to 76.50) ( to 97.78) ( to 66.26) 2

5 ( 2.06 to ) ( 0.08 to ) ( 3.99 to ) Non-ovulating patients a ( to 70.68) ( to ) ( to 53.96) LH AUC:FSH AUC ratio All analyzed patients ( 0.50 to 0.49) ( 0.78 to 0.15) ( 1.17 to 0.23) ( 0.96 to 0.07) ( 0.98 to 0.04) ( 1.21 to 0.23) ( 0.59 to 0.44) ( 0.77 to 0.20) ( 1.16 to 0.17) Non-ovulating patients a ( 0.86 to 0.26) ( 0.98 to 0.09) ( 1.39 to 0.35) Data are baseline-adjusted percentage changes in geometric means relative to placebo (95% confidence interval) unless otherwise stated. Values in bold correspond to nominal P <.05. a Patients with no biochemical evidence of ovulation (serum progesterone <6 ng/dl [19.1 nmol/l] at all study visits). b Baseline-adjusted differences in arithmetic means relative to placebo (95% confidence interval). AUC, area under the concentration time curve (0 8 hours post-dose); C avg, average concentration over 8 hours post-dose; FSH, follicle-stimulating hormone; LH, luteinizing hormone. 3

6 Supplemental Table 3. Pharmacokinetic parameters for AZD4901 and its metabolite AZ Parameter AZD mg/day AZD mg/day AZD mg/day Day 7 Day 28 Day 7 Day 28 Day 7 Day 28 AZD4901 AUC (h ng/ml) 1590 (585) 1690 (517) 2440 (802) 2500 (741) 4400 (1400) 3800 (794) C max (ng/ml) 335 (128) 342 (104) 497 (148) 471 (110) 835 (213) 732 (155) T max (h) 2.11 (0.85) 1.82 (0.72) 1.54 (0.57) 1.81 (0.63) 1.68 (0.37) 1.90 (1.09) AZ AUC (h ng/ml) 607 (275) 605 (191) 1150 (485) 1090 (445) 2120 (709) 1880 (446) C max (ng/ml) 88.4 (35.2) 87.4 (25.0) 166 (66.4) 157 (58.9) 315 (130) 276 (76.5) T max (h) 5.57 (1.74) 5.86 (1.99) 2.18 (2.02) 3.65 (2.35) 2.77 (2.09) 2.43 (2.08) AZ :AZD4901 ratio AUC 0.38 (0.098) 0.37 (0.078) 0.46 (0.134) 0.44 (0.136) 0.48 (0.118) 0.50 (0.111) C max 0.27 (0.068) 0.26 (0.051) 0.33 (0.092) 0.33 (0.082) 0.37 (0.089) 0.38 (0.073) Data are arithmetic mean (standard deviation).auc, area under the concentration time curve (0 8 hours post-dose); C max, maximum concentration; T max, time to maximum concentration. 1

7 Supplemental Table 4. Summary of biochemical measurements at baseline and on days 7 and 28 AZD mg/day AZD mg/day AZD mg/day Placebo Follicle stimulating hormone C avg (IU/L) Baseline 6.15 ± 2.06 (13) 4.57 ± 1.67 (15) 4.52 ± 1.49 (14) 4.68± 1.35 (13) Day ± 1.98 (13) 4.73 ± 1.07 (15) 3.79 ± 1.45 (14) 5.12 ± 1.35 (16) Day ± 1.53 (13) 5.28 ± 1.21 (12) 5.25 ± 1.44 (13) 4.53 ± 1.49 (15) Luteinizing hormone AUC (hour IU/L) Baseline 78.3 ± 28.0 (13) 73.0 ± 36.7 (15) 73.7 ± 30.1 (15) 72.7 ± 40.6 (13) Day ± 79.8 (14) 66.2 ± 30.4 (15) 47.9 ± 36.9 (15) 78.8 ± 40.0 (16) Day ± 63.7 (13) 74.1 ± 31.9 (13) 55.4 ± 29.2 (14) 73.2 ± 40.3 (14) Luteinizing hormone mass per pulse (IU/L) Baseline 9.19 ± 3.98 (13) 10.0 ± 6.58 (14) 9.93 ± 5.46 (14) 7.86 ± 5.57 (13) Day ± 11.3 (14) 10.4 ± 5.37 (13) 12.0 ± 8.53 (15) 8.85 ± 6.45 (16) Day ± 9.61 (13) 11.1 ± 6.97 (13) 10.2 ± 6.16 (13) 9.18 ± 5.41 (14) 1

8 Luteinizing hormone pulse frequency (number of pulses/8 hours) Baseline 6.38 ± 2.14 (13) 5.50 ± 2.35 (14) 5.79 ± 2.08 (14) 7.15 ± 2.27 (13) Day ± 1.99 (14) 5.85 ± 1.68 (13) 3.73 ± 2.09 (15) 6.75 ± 2.57 (16) Day ± 2.42 (13) 5.38 ± 1.33 (13) 5.15 ± 1.63 (13) 6.21 ± 2.39 (14) Luteinizing hormone basal secretion (IU/L) Baseline 147 ± 57.0 (13) 146 ± 107 (14) 123 ± 84.0 (14) 155 ± 94.6 (13) Day ± 151 (14) 105 ± 74.4 (13) 63.4 ± 96.8 (15) 153 ± 85.9 (16) Day ± 134 (13) 125 ± 85.3 (13) 64.8 ± 52.1 (13) 123 ± 102 (14) Total testosterone C avg (nmol/l) Baseline 1.96 ± (14) 2.07 ± (16) 2.25 ± (15) 1.68 ± (16) Day ± (14) 2.03 ± (16) 1.65 ± (15) 1.77 ± (16) Day ± (14) 2.02 ± (13) 1.81 ± (14) 1.72 ± (15) 2

9 Free testosterone C avg (pmol/l) Baseline 66.3 ± 37.8 (14) 72.3 ± 32.7 (15) 91.9 ± 30.1 (14) 84.5 ± 57.4 (16) Day ± 33.2 (13) 70.2 ± 32.5 (16) 70.2 ± 32.2 (14) 82.5 ± 64.5 (16) Day ± 40.4 (14) 76.0 ± 30.2 (13) 74.9 ± 32.5 (14) 83.7 ± 61.8 (15) Estradiol concentration (pmol/l) Baseline 240 ± 135 (15) 300 ± 158 (17) 322 ± 242 (17) 254 ± 169 (16) Day ± 154 (15) 226 ± 180 (17) 252 ± 199 (17) 190 ± 55.5 (16) Day ± 137 (15) 202 ± 188 (14) 248 ± 266 (16) 220 ± 100 (16) Progesterone concentration (nmol/l) Baseline 2.75 ± 2.63 (14) 4.23 ± 5.89 (17) 9.74 ± 14.7 (16) 3.16 ± 5.33 (16) Day ± 7.69 (15) 3.42 ± 5.36 (16) 4.77 ± 6.85 (17) 1.47 ± (16) Day ± 8.05 (15) 1.66 ± 0.97 (13) 1.48 ± 1.59 (15) 6.90 ± 12.3 (16) 3

10 Thyroid stimulating hormone concentration (mu/l) Baseline 2.62 ± 1.03 (15) 2.73 ± 1.91 (17) 2.24 ± (15) 2.06 ± (16) Day ± (15) 2.56 ± 1.30 (16) 2.49 ± 1.05 (17) 1.58 ± (16) Day ± (15) 2.47 ± 1.24 (12) ± 1.57 (15) 1.65 ± (16) Prolactin concentration (miu/l) Baseline 239 ± 75.9 (14) 291 ± 169 (17) 192 ± 70.9 (17) 221 ± 100 (16) Day ± 110 (15) 240 ± 142 (16) 213 ± 98.1 (17) 179 ± 60.0 (16) Day ± 61.2 (15) 232 ± 84.0 (14) 200 ± 61.6 (15) 197 ± 79.6 (16) Glycated hemoglobin (%) Baseline 4.93 ± (15) 5.25 ± (17) 5.24 ± (17) 5.14 ± (16) Day ± 0.32 (14) 5.27 ± (16) 5.19 ± (16) 5.10 ± (14) Day ± (14) 5.26 ± (14) 5.04 ± (16) 4.95 ± (15) 4

11 Glycated hemoglobin (mmol/mol) a Baseline 30 ± 3.6 (15) 34 ± 4.6 (17) 33 ± 2.8 (17) 32 ± 3.9 (16) Day 7 29 ± 2.2 (14) 34 ± 4.9 (16) 33 ± 2.5 (16) 32 ± 4.5 (14) Day ± 3.5 (14) 34 ± 5.5 (14) 31 ± 2.7 (16) 31 ± 4.0 (15) Data are arithmetic mean±standard deviation (number of patients for whom data were available). a Values calculated from arithmetic means and standard deviations of glycated hemoglobin (%) in Supplemental Table 4 using the formula HbA 1c (mmol/mol) = HbA 1c (%) 23.5 (Hoelzel W, Weykamp C, Jeppsson JO, Miedema K, Barr JR, Goodall I, Hoshino T, John WG, Kobold U, Little R, Mosca A, Mauri P, Paroni R, Susanto F, Takei I, Thienpont L, Umemoto M, Wiedmeyer HM. IFCC reference system for measurement of hemoglobin A1c in human blood and the national standardization schemes in the United States, Japan, and Sweden: a method-comparison study. Clin Chem. 2004; 50: ). AUC, area under the concentration time curve (0 8 hours post-dose); C avg, average concentration (0 8 hours post-dose). 5

12 Supplemental Table 5. Number of patients dosed with AZD4901 who reported adverse events, by preferred term Adverse event AZD4901 AZD4901 AZD4901 Placebo Total 20 mg/day 40 mg/day 80 mg/day (n = 15) (n = 17) (n = 17) (n = 16) (n = 65) Headache Nasopharyngitis Dizziness Nausea Vaginal hemorrhage Muscle spasms Increased hepatic enzyme 2 2 Rash 2 2 Acne Influenza-like illness Upper respiratory tract infection Abdominal pain

13 Upper abdominal pain Constipation 1 1 Vulvovaginal mycotic infection 1 1 Pelvic pain 1 1 Muscle strain 1 1 Conjunctivitis 1 1 Lower abdominal pain 1 1 Sleep apnea syndrome 1 1 Procedural dizziness 1 1 Tooth fracture 1 1 Allergic rhinitis 1 1 Ear pain 1 1 Appendicitis 1 1 Nodule 1 1 Migraine 1 1 2

14 Presyncope 1 1 Syncope 1 1 Abdominal distension 1 1 Diarrhea 1 1 Increased alanine aminotransferase level 1 1 Increased aspartate aminotransferase level 1 1 Nephrolithiasis 1 1 Pyrexia 1 1 Hot flush 1 1 Vaginal discharge 1 1 Gastrointestinal infection 1 1 A patient may have reported the same adverse event several times. 3

15 Supplemental Table 6. Health-related quality of life assessed using the 36-item Short-Form Health Survey Domain AZD mg/day AZD mg/day AZD mg/day Placebo Baseline Day 28 Baseline Day 28 Baseline Day 28 Baseline Day 28 Physical Functioning 51.3 (9.7) 54.3 (4.0) 47.8 (11.3) 51.2 (10.7) 55.7 (3.4) 55.6 (3.8) 54.5 (3.5) 55.6 (2.3) Role Physical 52.8 (7.1) 54.4 (4.1) 54.8 (4.2) 53.6 (5.1) 54.1 (6.6) 55.5 (4.4) 53.6 (9.7) 55.3 (2.5) Bodily Pain 54.4 (10.7) 56.5 (7.5) 55.5 (8.1) 53.9 (8.1) 58.3 (6.2) 57.3 (5.6) 58.1 (6.4) 57.0 (4.5) General Health 50.4 (11.3) 51.4 (10.5) 50.2 (8.0) 51.0 (6.9) 53.3 (8.0) 55.5 (8.5) 53.6 (6.1) 52.4 (4.6) Vitality 53.1 (10.9) 51.9 (10.4) 53.5 (8.4) 53.3 (9.1) 53.4 (8.1) 56.3 (6.9) 52.1 (8.7) 53.7 (7.3) Social Functioning 53.6 (7.4) 55.3 (4.5) 53.5 (5.2) 53.5 (7.9) 54.1 (6.3) 54.3 (6.1) 51.4 (10.0) 53.8 (6.3) Role Emotional 53.8 (6.0) 55.3 (2.2) 53.2 (4.3) 53.2 (7.5) 55.0 (1.7) 55.9 (0.0) 47.9 (14.6) 53.9 (4.3) Mental Health 54.1 (6.5) 53.8 (6.8) 56.1 (3.0) 54.8 (9.9) 55.4 (6.7) 55.6 (5.1) 54.2 (8.4) 53.4 (6.8) Data are arithmetic mean (standard deviation). Each score is calculated on a scale of 0 to 100, with lower scores indicating poorer quality of life. Improvement in HRQoL is reflected in an increase in score from baseline. HRQoL, health-related quality of life. 1

16 Appendix 1. List of participating sites 1. Miami Research Associates, Miami, FL, USA 2. Bio-Kinetic Clinical Applications, Inc., Springfield, MO, USA 3. Washington University School of Medicine, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, St Louis, MO, USA 4. Charité Research Organisation GmbH, Berlin, Germany 5. BioKinetic Europe, Belfast, Northern Ireland 6. Edinburgh Fertility and Reproductive Endocrine Centre, Royal Infirmary of Edinburgh, Edinburgh, UK 7. Quintiles Drug Research Unit at Guy s Hospital, London UK 8. Compass Research Phase 1, Orlando, FL, USA 9. The University of Chicago, Department of Medicine, Section of Endocrinology, Chicago, IL, USA 1