Study code: RGD-77425 Gedeon Richter Plc. PASS final report PASS information Title Butoconazole use in pregnancy: population-based case- control studies on adverse pregnancy outcomes in Hungary (study protocol RGD-77425). Version identifier of the final Version 1.0 study report Date of last version of the final 21th November 2016 study report EU PAS register number ENCEPP/SDPP/4282; web link to study record: http://www.encepp.eu/encepp/viewResource.htm?id=12924 Active substance butoconazole (test drug); clotrimazole, miconazole, nystatin, metronidazole (therapeutic controls); celecoxib, diclofenac, ibuprofen, indomethacin, naproxen, rofecoxib; carbamazepine, isotretinoin, lithium, valproic acid (active controls and confounding factors). Medicinal product all approved products in Hungary containing the above active substances Product reference the relevant gynecology products are not centrally authorized. Procedure number not applicable (MAH initiated study) Marketing authorisation Gedeon Richter Plc. holder(s) Joint PASS No Research question and The primary objective is to evaluate butoconazole treatment objectives as a potential risk factor for teratogenicity and/or spontaneous abortion in a population-based retrospective study in Hungary, based on National Health Insurance Fund Administration Database (OEP database) records. Secondary objectives: to evaluate therapeutic controls as risk factors in the same analyses, for comparative purposes. To collect epidemiologic data on all outcomes of butoconazole exposed pregnancies. To evaluate the effect of butoconazole and clotrimazole on birthweight. Country(-ies) of study Hungary Author János G. Pitter MD, PhD Syreon Research Institute Kft. 119 Thököly street, Budapest 1146, Hungary Marketing authorisation holder(s): Marketing authorisation Gedeon Richter Plc. holder(s) 19-21 Gyömrői út, Budapest 1103, Hungary phone: +36 1 432 7433 email: [email protected] MAH contact person Beáta Horváth MD, PhD Report version: Final CONFIDENTIAL Page 1 / 271 Date: 21th November 2016 Study code: RGD-77425 Gedeon Richter Plc. PASS final report Table of Contents SIGNATURE PAGE .................................................................................................................... 11 1. Abstract ................................................................................................................................. 12 2. List of abbreviations ............................................................................................................. 13 3. Investigators .......................................................................................................................... 14 4. Other responsible parties ...................................................................................................... 14 5. Milestones ............................................................................................................................. 17 6. Rationale and background ................................................................................................... 18 6.1. Non-clinical reproductive toxicity data on butoconazole ......................................... 18 6.2. Clinical data on butoconazole in pregnancy .............................................................. 19 6.3. Recommendations on butoconazole use in pregnancy ............................................. 20 6.4. Expected contribution of the current study to the filling of the gaps in current knowledge ................................................................................................................................ 20 7. Research question and objectives ........................................................................................ 22 8. Amendments and updates .................................................................................................... 24 9. Research methods ................................................................................................................. 37 9.1. Study design .................................................................................................................. 37 9.1.1. Design of the spontaneous abortion case-control study ................................................................... 38 9.1.2. Design of the congenital anomaly case-control study ..................................................................... 46 9.1.3. Design of Amendment 2 low birthweight analyses ......................................................................... 53 9.2. Setting ............................................................................................................................ 57 9.2.1. Persons and place ............................................................................................................................. 57 9.2.2. Time period: .................................................................................................................................... 57 9.3. Subjects ......................................................................................................................... 57 9.4. Variables ....................................................................................................................... 57 9.4.1. Pregnancy outcomes ........................................................................................................................ 57 9.4.2. Time periods of the pregnancy ........................................................................................................ 58 9.4.3. Investigated drugs ............................................................................................................................ 58 9.4.4. Investigated confounding factors ..................................................................................................... 59 9.4.5. Drug exposure.................................................................................................................................. 59 9.5. Data sources and measurements ................................................................................. 59 9.6. Bias ................................................................................................................................ 60 9.7. Study size ...................................................................................................................... 60 9.8. Data transformation .................................................................................................... 61 9.8.1. Estimation of maternal socioeconomic status .................................................................................. 61 9.8.2. Determination of gestational age in the OEP database .................................................................... 62 9.8.3. Cure numbers as exposition units for gynecology anti-infective drugs ........................................... 66 9.9. Statistical methods ....................................................................................................... 67 9.9.1. Main summary measures ................................................................................................................. 67 9.9.2. Main statistical methods .................................................................................................................. 67 9.9.3. Missing values ................................................................................................................................. 67 9.9.4. Sensitivity analyses .......................................................................................................................... 67 9.9.5. Amendments to the statistical plan .................................................................................................. 67 Report version: Final CONFIDENTIAL Page 2 / 271 Date: 21th November 2016 Study code: RGD-77425 Gedeon Richter Plc. PASS final report 9.10. Quality control .......................................................................................................... 68 10. Results ................................................................................................................................... 69 10.1. Participants ............................................................................................................... 69 10.2. Descriptive data ........................................................................................................ 70 10.2.1. Study population characteristics ...................................................................................................... 70 10.2.2. Geographic pattern of congenital anomaly diagnoses ..................................................................... 72 10.2.3. Time profile of first congenital anomaly diagnoses ......................................................................... 73 10.2.4. Time thresholds for redundant reporting of pregnancy outcomes ................................................... 80 10.2.5. Descriptive analysis of birth weight data (Amendment 1)............................................................... 84 10.2.6. Descriptive comparison of butoconazole and clotrimazole exposed pregnancies in Amendment 2 regression models on low birthweight............................................................................................................... 87 10.3. Outcome data ............................................................................................................ 91 10.3.1. Summary