Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK.
Merck, Aubonne, Switzerland, a division of Merck KGaA, Darmstadt, Germany.
Drug Saf. 2020 Jul;43(7):635-643. doi: 10.1007/s40264-020-00948-x.
Although use of contraception was pre-specified during cladribine clinical trials for multiple sclerosis, some pregnancies did occur.
This analysis reports on pregnancy outcomes in the cladribine clinical development program.
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.
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.
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.
CLARITY: NCT00213135; CLARITY Extension: NCT00641537; ORACLE MS: NCT00725985; ONWARD: NCT00436826; PREMIERE: NCT01013350.
虽然在 cladribine 多发性硬化症临床试验中预先规定了避孕措施，但仍有一些妊娠发生。
本分析报告 cladribine 临床开发项目中的妊娠结局。
从 10 项 cladribine 多发性硬化症研究的综合安全性分析中评估女性患者（直接妊娠）和其伴侣妊娠（即多发性硬化症男性研究参与者的女性伴侣）的妊娠结局，患者接受 cladribine 片剂、 cladribine 注射液或安慰剂治疗（所有暴露队列；1976 名患者接受 cladribine 治疗，802 名患者接受安慰剂治疗）。在 cladribine （治疗期间或之后 6 个月内）“风险期”发生的妊娠作为一个单独的组报告。
在所有暴露队列中，62 名女性患者中有 70 例直接妊娠（ cladribine，n=49；安慰剂，n=21）。妊娠结局为：活产（ cladribine，n=19 [38.8%]；安慰剂，n=9 [42.9%]）、选择性终止妊娠（ cladribine，n=14 [28.6%]；安慰剂，n=4 [19.0%]）、自然流产（ cladribine，n=11 [22.4%]；安慰剂，n=5 [23.8%]）和治疗性终止妊娠（ cladribine，n=5 [10.2%]；安慰剂，n=2 [9.5%]）；在其余安慰剂接受者中，妊娠结局未知。有两例先天性畸形报告（ cladribine，n=1；安慰剂，n=1），均发生在暴露于研究药物最后一剂后 2 年以上的妊娠中。16 例直接妊娠发生在 cladribine 的“风险期”；这些妊娠的结局为：活产，n=3（18.8%）；选择性终止妊娠，n=10（62.5%）；自然流产，n=2（12.5%）；治疗性终止妊娠，n=1（6.2%）。安慰剂接受者中直接妊娠的相应发现为（n=11）：活产，n=5（45.5%）；选择性终止妊娠，n=2（18.2%）；自然流产，n=3（27.3%）；未知，n=1（9.1%）。在“风险期”内妊娠无先天性畸形报告。 cladribine 治疗的男性患者的女性伴侣中又有 9 例妊娠，均为活产；其中 2 例妊娠发生在 cladribine 的“风险期”内。
虽然受 cladribine 临床开发项目中妊娠数量和相关数据有限的限制，需要进一步研究，但本分析中的观察结果通常与一般人群或多发性硬化症女性的妊娠结局的流行病学数据一致。在 cladribine 治疗期间或最后一剂后 6 个月内发生的妊娠无先天性畸形。由于多发性硬化症患者 cladribine 暴露妊娠的数据有限，已启动一项非干预性上市后安全性研究，以获取更多关于这一主题的信息。
CLARITY：NCT00213135；CLARITY 扩展：NCT00641537；ORACLE MS：NCT00725985；ONWARD：NCT00436826；PREMIERE：NCT01013350。
