Pregnancy Outcomes During the Clinical Development Program of Cladribine in Multiple Sclerosis: An Integrated Analysis of Safety

Gavin Giovannoni, Andrew Galazka, Regina Schick, Thomas Leist, Giancarlo Comi, Xavier Montalban, Doris Damian, Fernando Dangond, Stuart Cook, Gavin Giovannoni, Andrew Galazka, Regina Schick, Thomas Leist, Giancarlo Comi, Xavier Montalban, Doris Damian, Fernando Dangond, Stuart Cook

Abstract

Introduction: Although use of contraception was pre-specified during cladribine clinical trials for multiple sclerosis, some pregnancies did occur.

Objective: This analysis reports on pregnancy outcomes in the cladribine clinical development program.

Methods: Pregnancy outcomes in female patients (direct pregnancies) and those arising from partner pregnancies (i.e., female partners of male study participants with multiple sclerosis) were evaluated from an integrated safety analysis of ten studies of cladribine in multiple sclerosis (nine clinical trials and a long-term safety registry), with patients treated with cladribine tablets, parenteral cladribine, or placebo (all-exposed cohort; 1976 patients received cladribine and 802 received placebo). Pregnancies that occurred during the 'at-risk' period for cladribine (during treatment or within 6 months thereafter) are reported as a separate group.

Results: In the all-exposed cohort, 70 direct pregnancies occurred among 62 female patients (cladribine, n = 49; placebo, n = 21). Pregnancy outcomes were: live births (cladribine, n = 19 [38.8%]; placebo, n = 9 [42.9%]), elective terminations (cladribine, n = 14 [28.6%]; placebo, n = 4 [19.0%]), spontaneous abortions (cladribine, n = 11 [22.4%]; placebo, n = 5 [23.8%]), and therapeutic terminations (cladribine, n = 5 [10.2%]; placebo, n = 2 [9.5%]); in the remaining placebo recipient, the pregnancy outcome was unknown. There were two reports of congenital malformations (cladribine, n = 1; placebo, n = 1), both of which occurred with pregnancies arising > 2 years after exposure to the last dose of study medication. Sixteen direct pregnancies occurred during the 'at-risk' period for cladribine; outcomes for these were: live births, n = 3 (18.8%); elective terminations, n = 10 (62.5%); spontaneous abortions, n = 2 (12.5%); and therapeutic terminations, n = 1 (6.2%). Corresponding findings for direct pregnancies among placebo recipients were (n = 11): live births, n = 5 (45.5%); elective terminations, n = 2 (18.2%); spontaneous abortions, n = 3 (27.3%); and unknown, n = 1 (9.1%). No cases of congenital malformation were reported for pregnancies during the 'at-risk' period. There were an additional nine partner pregnancies in female partners of cladribine-treated male patients, all of which resulted in live births; of these, two pregnancies occurred within the 'at-risk' period for cladribine.

Conclusions: While limited by the small number of pregnancies and related data from the cladribine clinical development program, highlighting the need for further study, the observations made in the present analysis were generally consistent with epidemiological data on pregnancy outcomes for the general population or women with multiple sclerosis. There were no congenital malformations in pregnancies that occurred during cladribine treatment or within 6 months after the last dose. As the data available for cladribine-exposed pregnancies in patients with multiple sclerosis are limited, a non-interventional post-authorization safety study has been initiated to obtain more information on this subject.

Clinical trial registration: CLARITY: NCT00213135; CLARITY Extension: NCT00641537; ORACLE MS: NCT00725985; ONWARD: NCT00436826; PREMIERE: NCT01013350.

Conflict of interest statement

Gavin Giovannoni has received speaker honoraria and consulting fees from AbbVie, Actelion, Atara Bio, Almirall, Bayer Schering Pharma, Biogen Idec, FivePrime, GlaxoSmithKline, GW Pharma, Ironwood, Merck & Co., Merck KGaA, Novartis, Pfizer Inc., Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd, Sanofi-Genzyme, UCB, and Vertex Pharmaceuticals; and has received research support unrelated to this study from Biogen Idec, Ironwood, Merck & Co., and Novartis. Andrew Galazka is an employee of Merck, Aubonne, Switzerland, a division of Merck KGaA, Darmstadt, Germany. Regina Schick is an employee of Merck KGaA, Darmstadt, Germany. Thomas Leist has received consultancy fees or clinical research grants from Acorda, Bayer, Biogen, Daiichi, EMD Serono, Novartis, ONO, Pfizer, and Teva Neuroscience. Giancarlo Comi has received consulting fees from Bayer Schering, Biogen Idec, Genentech-Roche, Merck, Novartis, Receptos, Sanofi-Aventis, and Teva Pharmaceutical Industries Ltd; lecture fees from Bayer Schering, Biogen Dompè, Merck, Novartis, Sanofi-Aventis, Serono Symposia International Foundation, and Teva Pharmaceutical Industries Ltd; and trial grant support from Bayer Schering, Biogen Dompè, Biogen Idec, Genentech-Roche, Merck, Novartis, Receptos, Sanofi-Aventis, and Teva Pharmaceutical Industries Ltd. Xavier Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Actelion, Bayer, Biogen, Celgene, Excemed, Genzyme, Merck, MSIF, NMSS, Novartis, Roche, Sanofi-Genzyme, and Teva Pharmaceuticals. Doris Damian and Fernando Dangond are employees of EMD Serono Research & Development Institute, Inc., a business of Merck KGaA, Darmstadt, Germany. Stuart Cook has received honoraria for lectures/consultations from Actinobac Biomed, Inc., Bayer HealthCare, Biogen Idec, Merck KGaA, Neurology Reviews, Sanofi-Aventis, and Teva Pharmaceuticals; has served on advisory boards for Actinobac Biomed, Inc., Bayer HealthCare, Biogen Idec, Merck KGaA, and Teva Pharmaceuticals; and received grant support from Bayer HealthCare.

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