Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial.

BACKGROUND: Inhibition of proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) resulted in large reductions of low-density lipoprotein cholesterol (LDL-C) in phase 1 trials. We assessed the efficacy and safety of various doses and dosing intervals of REGN727, a monoclonal antibody to PCSK9, added to statins, to further lower LDL-C in patients with heterozygous familial hypercholesterolaemia. METHODS: This multicentre, randomised, placebo-controlled phase 2 trial was done at 16 lipid clinics in the USA and Canada. Between Jan 18, 2011, and Nov 7, 2011, we enrolled adults with heterozygous familial hypercholesterolaemia and LDL-C concentrations of 2·6 mmol/L or higher on stable diet and statin dose, with or without ezetimibe. Patients were randomly assigned to receive REGN727 150 mg, 200 mg, or 300 mg every 4 weeks, or 150 mg every 2 weeks, or placebo every 2 weeks (ratio 1:1:1:1:1). Randomisation was stratified by concomitant use of ezetimibe at baseline. Investigators, study staff, and patients were masked to treatment group. Blinding was maintained by administration of placebo alternating with REGN727 for the groups of 4 week dosing. The primary endpoint was mean percent reduction in LDL-C from baseline at week 12 and was analysed in the modified intention-to-treat population with an analysis of covariance (ANCOVA) model with treatment group. This trial is registered in ClinicalTrials.gov, number NCT 01266876. FINDINGS: 77 patients were randomly assigned to study groups (15-16 patients per group) and all were analysed. Least-squares (LS) mean LDL-C reduction from baseline to week 12 was 28·9% (SE 5·08) for 150 mg every 4 weeks (p=0·0113), 31·54% (4·91) for 200 mg every 4 weeks (p=0·0035), 42·53% (5·09) for 300 mg every 4 weeks (p<0·0001), and 67·90% (4·85) for 150 mg every 2 weeks (p<0·0001), compared with 10·65% (5·04) with placebo. One serious adverse event was reported with placebo and none with REGN727. No increases of more than three times the upper limit of normal were reported for hepatic transaminases or creatinine kinase. The most common adverse event was injection-site reaction with one patient in the group of 300 mg REGN727 terminating treatment. INTERPRETATION: REGN727 was well tolerated and achieved substantial further LDL-C reduction in patients with heterozygous familial hypercholesterolaemia and elevated LDL-C treated with high-dose statins, with or without ezetimibe. REGN727 has the potential to provide optimum control of LDL-C in patients with this disorder. FUNDING: Sanofi US and Regeneron Pharmaceuticals Incorporated.

Conception rates in clomiphene citrate cycles with and without hormone supplementation: a pilot study.

OBJECTIVE: A trial was conducted to examine the effects of a timed sequence of hormone supplementation (HS) with oral estradiol (E(2)) and vaginal progesterone (P) following clomiphene citrate (CC) therapy to determine if this regimen can increase pregnancy rates in CC cycles. METHODS: This study was a randomized, open-label study. Seventy-one oligo-ovulatory women were randomized into one of two groups; those who received CC plus HS (n = 34) and those who received no HS (n = 37). All subjects received 100 mg CC orally from cycle days 3 to 7. Subjects randomized to HS started oral E(2) at a dose of 1.5 mg BID on cycle day 8. All subjects monitored urine luteinizing hormone (LH) levels starting on cycle day 10; additionally, intercourse was encouraged starting on cycle day 10. Subjects receiving HS discontinued E(2) with LH surge and started using vaginal progesterone gel (Prochieve 8%) daily for 2 weeks starting 3 days after LH surge. All subjects had a pregnancy test (Assure) 2 weeks after LH surge. If pregnancy occurred, the subject continued using vaginal progesterone gel daily for an additional 10 weeks. RESULTS: Sixty-five (65) subjects (31 CC plus HS and 34 no HS) completed the study. Fifty of the 65 subjects (77%) (23 [74%] CC plus HS, 27 [79%] no HS) who completed the study ovulated. The mean (range) progesterone (P) concentration for these 50 subjects was 1662.6 (340 to 5690) ng/dL, and mean and median P levels were slightly higher, but not statistically significant, in the HS group compared with the no HS group. Pregnancy rates were clinically, but not statistically, different between the treatment groups. Of the 50 responders, 12% became pregnant (17% CC plus HS, 7% no HS). CONCLUSION: These findings show a potential supportive effect on pregnancy rates in the CC plus oral estradiol and vaginal progesterone gel group compared to CC alone that needs to be confirmed in a larger study.