EPID Multiple Sclerosis Pregnancy Study

Study Overview
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Brief Summary
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Multiple Sclerosis (MS) is the most common chronic neurologic disability in young adult females in their childbearing ages. Little evidence is available regarding the association between exposure to IFN-beta (β) products and adverse pregnancy outcomes. Therefore the four marketing holders of IFN-β are conducting a European-wide IFN-β pregnancy registry. Additionally, the Committee for Medicinal Products for Human Use (CHMP) has requested a study to enable identification of pregnancy outcomes in the MS population unexposed to IFN-β products for comparison with the ongoing European IFN-β Pregnancy Registry.

Detailed Description
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Information will be obtained from the Drugs and Pregnancy Project database (DPP - FIN) and the Medical Birth Register (MBR - SWE, NOR). The Finnish DPP and Norwegian MBR include information on all stillbirths of foetuses with a birth weight of at least 500 g or with a gestational age of at least 22+0 Gestational Week (GW). The Swedish MBR includes data on stillbirths after 28 GW The estimated number of pregnancies in MS patients needed is 1671, encompassing data from: i) FIN: 1 January 1996 - 31 December 2014; ii) SWE: 1 July 2005 - 31 December 2014; iii) NOR: 1 January 2004 - 31 December 2014.

Official Title
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Pregnancy Outcomes in Multiple Sclerosis Populations Exposed and Unexposed to Interferon β - a Register-based Study in the Nordic Countries

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Betaseron (Interferon beta-1b, BAY86-5046), Bayer HealthCare AG
* Drug: Extavia (interferon beta-1b), Novartis Pharma AG
* Drug: Rebif (interferon beta-1a), Merck Serono Europe Ltd
* Drug: Plegridy (peginterferon beta-1a), Biogen Idec Ltd
* Drug: Avonex (interferon beta-1a), Biogen Idec Ltd
* Drug: MSDMDs other than Betaseron (Interferon beta-1b, BAY86-5046)
* Other: No MSDMDs therapy (control)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women who have had a pregnancy with a recorded outcome consisting of an induced abortion, spontaneous abortion, ectopic pregnancy, or birth during the study period in FIN, SWE or NOR with the event being documented in the relevant databases.
Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| IFN-β / Cohort 1<br>Exposure to IFN-β only | Drug: Betaseron (Interferon beta-1b, BAY86-5046), Bayer HealthCare AG<br>* Information will be obtained from the databses DPP (FIN) and MBR (SWE, NOR)<br>Drug: Extavia (interferon beta-1b), Novartis Pharma AG<br>* Information will be obtained from the databses DPP (FIN) and MBR (SWE, NOR)<br>Drug: Rebif (interferon beta-1a), Merck Serono Europe Ltd<br>* Information will be obtained from the databses DPP (FIN) and MBR (SWE, NOR)<br>Drug: Plegridy (peginterferon beta-1a), Biogen Idec Ltd<br>* Information will be obtained from the databses DPP (FIN) and MBR (SWE, NOR)<br>Drug: Avonex (interferon beta-1a), Biogen Idec Ltd<br>* Information will be obtained from the databses DPP (FIN) and MBR (SWE, NOR)<br>|
| IFN-β + other MSDMDs / Cohort 2<br>Women with MS exposed to IFN-β regardless of exposure to other MSDMDs | Drug: Betaseron (Interferon beta-1b, BAY86-5046), Bayer HealthCare AG<br>* Information will be obtained from the databses DPP (FIN) and MBR (SWE, NOR)<br>Drug: Extavia (interferon beta-1b), Novartis Pharma AG<br>* Information will be obtained from the databses DPP (FIN) and MBR (SWE, NOR)<br>Drug: Rebif (interferon beta-1a), Merck Serono Europe Ltd<br>* Information will be obtained from the databses DPP (FIN) and MBR (SWE, NOR)<br>Drug: Avonex (interferon beta-1a), Biogen Idec Ltd<br>* Information will be obtained from the databses DPP (FIN) and MBR (SWE, NOR)<br>Drug: MSDMDs other than Betaseron (Interferon beta-1b, BAY86-5046)<br>* Information will be obtained from the databses DPP (FIN) and MBR (SWE, NOR)<br>|
| No MSDMDs / Cohort 3<br>Women with MS exposed with no exposure to any MSDMDs | Other: No MSDMDs therapy (control)<br>* Information will be obtained from the databses DPP (FIN) and MBR (SWE, NOR)<br>|
| No IFN-β + other MSDMDs / Cohort 4<br>Women with MS exposed to IFN-β exposure regardless of exposure to other MSDMDs | Drug: MSDMDs other than Betaseron (Interferon beta-1b, BAY86-5046)<br>* Information will be obtained from the databses DPP (FIN) and MBR (SWE, NOR)<br>|
| Other MSDMDs / Cohort 5<br>Women with MS exposed to other MSDMD only excluding IFN-β or glatiramer acetate (Copaxone) or dimethyl fumarate (Tecfidera) | Drug: MSDMDs other than Betaseron (Interferon beta-1b, BAY86-5046)<br>* Information will be obtained from the databses DPP (FIN) and MBR (SWE, NOR)<br>|
| Control / Cohort 6<br>Women from the general population without MS | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serious adverse pregnancy outcome due to different regimes of IFN-β exposure defined as a composite endpoint including presence of elective Termination of Pregnancy due to Foetal Anomaly (TOPFA), Major Congenital Anomaly (MCA) or stillbirth | Cohort 1: Exposure to IFN-β only Cohort 2: All patients with IFN-β exposure regardless of exposure to other MS Disease Modifying Drug (MSDMDs) Cohort 3: No exposure to any MSDMDs Cohort 4: All patients with no IFN-β exposure regardless of exposure to other MSDMDs | Retrospective Data analysis: MS patients data encompassing approximately 19 years | 
| Elective TOPFA for other reasons than IFN-β exposure | Cohort 1: Exposure to IFN-β only Cohort 2: All patients with IFN-β exposure regardless of exposure to other MS Disease Modifying Drug (MSDMDs) Cohort 3: No exposure to any MSDMDs Cohort 4: All patients with no IFN-β exposure regardless of exposure to other MSDMDs | Retrospective Data analysis: MS patients data encompassing approximately 19 years | 
| Elective termination for other reasonsthan IFN-β exposure | Cohort 1: Exposure to IFN-β only Cohort 2: All patients with IFN-β exposure regardless of exposure to other MS Disease Modifying Drug (MSDMDs) Cohort 3: No exposure to any MSDMDs Cohort 4: All patients with no IFN-β exposure regardless of exposure to other MSDMDs | Retrospective Data analysis: MS patients data encompassing approximately 19 years | 
| Stillbirth due to different regimes of IFN-β exposure | Cohort 1: Exposure to IFN-β only Cohort 2: All patients with IFN-β exposure regardless of exposure to other MS Disease Modifying Drug (MSDMDs) Cohort 3: No exposure to any MSDMDs Cohort 4: All patients with no IFN-β exposure regardless of exposure to other MSDMDs | Retrospective Data analysis: MS patients data encompassing approximately 19 years | 
| Live birth while different regimes of IFN-β exposure | Cohort 1: Exposure to IFN-β only Cohort 2: All patients with IFN-β exposure regardless of exposure to other MS Disease Modifying Drug (MSDMDs) Cohort 3: No exposure to any MSDMDs Cohort 4: All patients with no IFN-β exposure regardless of exposure to other MSDMDs | Retrospective Data analysis: MS patients data encompassing approximately 19 years | 
| MCA due to different regimes of IFN-β exposure | Cohort 1: Exposure to IFN-β only Cohort 2: All patients with IFN-β exposure regardless of exposure to other MS Disease Modifying Drug (MSDMDs) Cohort 3: No exposure to any MSDMDs Cohort 4: All patients with no IFN-β exposure regardless of exposure to other MSDMDs | Retrospective Data analysis: MS patients data encompassing approximately 19 years | 
| Comparison of the prevalence of serious adverse pregnancy outcome due to different regimes of IFN-β exposure defined as a composite endpoint including elective TOPFA, MCA or stillbirth | Women with MS exposed to IFN-β only (cohort 1) vs. unexposed to any MSDMDs (cohort 3) and Women with MS exposed to IFN-β only (cohort 1) vs. unexposed to IFN-β regardless of exposure to other MSDMDs (cohort 4) | Retrospective Data analysis: MS patients data encompassing approximately 19 years | 
| Comparison of the prevalence of elective termination for other reasons than due to different regimes of IFN-β exposure | Women with MS exposed to IFN-β only (cohort 1) vs. unexposed to any MSDMDs (cohort 3) and Women with MS exposed to IFN-β only (cohort 1) vs. unexposed to IFN-β regardless of exposure to other MSDMDs (cohort 4) | Retrospective Data analysis: MS patients data encompassing approximately 19 years | 
| Comparison of the prevalence of stillbirth due to different regimes of IFN-β exposure | Women with MS exposed to IFN-β only (cohort 1) vs. unexposed to any MSDMDs (cohort 3) and Women with MS exposed to IFN-β only (cohort 1) vs. unexposed to IFN-β regardless of exposure to other MSDMDs (cohort 4) | Retrospective Data analysis: MS patients data encompassing approximately 19 years | 
| Comparison of the prevalence of live birth due to different regimes of IFN-β exposure | Women with MS exposed to IFN-β only (cohort 1) vs. unexposed to any MSDMDs (cohort 3) and Women with MS exposed to IFN-β only (cohort 1) vs. unexposed to IFN-β regardless of exposure to other MSDMDs (cohort 4) | Retrospective Data analysis: MS patients data encompassing approximately 19 years | 
| Comparison of the prevalence of MCA due to different regimes of IFN-β exposure | Women with MS exposed to IFN-β only (cohort 1) vs. unexposed to any MSDMDs (cohort 3) and Women with MS exposed to IFN-β only (cohort 1) vs. unexposed to IFN-β regardless of exposure to other MSDMDs (cohort 4) | Retrospective Data analysis: MS patients data encompassing approximately 19 years | 
| Comparison of the prevalence of Elective TOPFA due to different regimes of IFN-β exposure | Women with MS exposed to IFN-β only (cohort 1) vs. unexposed to any MSDMDs (cohort 3) and Women with MS exposed to IFN-β only (cohort 1) vs. unexposed to IFN-β regardless of exposure to other MSDMDs (cohort 4) | Retrospective Data analysis: MS patients data encompassing approximately 19 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of the prevalence of ectopic pregnancies due to different regimes of IFN-β exposure | Women with MS exposed to IFN-β only (cohort 1) vs. unexposed to any MSDMDs (cohort 3), Women with MS exposed to IFN-β only (cohort 1) vs. unexposed to IFN-β regardless of exposure to other MSDMDs (cohort 4) Women with MS exposed to IFN-β regardless of exposure to other MSDMDs (cohort 2) vs. unexposed to any MSDMDs (cohort 3) | Retrospective Data analysis: MS patients data encompassing approximately 19 years | 
| Comparison of the prevalence of spontaneous abortions due to different regimes of IFN-β exposure | Women with MS exposed to IFN-β only (cohort 1) vs. unexposed to any MSDMDs (cohort 3), Women with MS exposed to IFN-β only (cohort 1) vs. unexposed to IFN-β regardless of exposure to other MSDMDs (cohort 4) Women with MS exposed to IFN-β regardless of exposure to other MSDMDs (cohort 2) vs. unexposed to any MSDMDs (cohort 3) | Retrospective Data analysis: MS patients data encompassing approximately 19 years | 
| Prevalence of elective TOPFA stratified by specific patient characteristics | Patient characteristics: country, year of pregnancy outcome, chronic diseases, exposure to any teratogenic medications, time since MS diagnosis, duration of MS treatment, maternal age, gestational age, weight of the newborn | Retrospective Data analysis: MS patients data encompassing approximately 19 years | 
| Prevalence of stillbirth stratified by specific patient characteristics | Patient characteristics: country, year of pregnancy outcome, chronic diseases, exposure to any teratogenic medications, time since MS diagnosis, duration of MS treatment, maternal age, gestational age, weight of the newborn | Retrospective Data analysis: MS patients data encompassing approximately 19 years | 
| Prevalence of live birth stratified by specific patient characteristics | Patient characteristics: country, year of pregnancy outcome, chronic diseases, exposure to any teratogenic medications, time since MS diagnosis, duration of MS treatment, maternal age, gestational age, weight of the newborn | Retrospective Data analysis: MS patients data encompassing approximately 19 years | 
| Prevalence of MCA stratified by specific patient characteristics | Patient characteristics: country, year of pregnancy outcome, chronic diseases, exposure to any teratogenic medications, time since MS diagnosis, duration of MS treatment, maternal age, gestational age, weight of the newborn | Retrospective Data analysis: MS patients data encompassing approximately 19 years | 
| Comparison of the prevalence of ectopic pregnancies due to different regimes of IFN-β exposure | Patient characteristics: country, year of pregnancy outcome, chronic diseases, exposure to any teratogenic medications, time since MS diagnosis, duration of MS treatment, maternal age, gestational age, weight of the newborn | Retrospective Data analysis: MS patients data encompassing approximately 19 years |