Lynne Smith

Multicentre, randomized, open-label study of on-demand treatment with two prophylaxis regimens of recombinant coagulation factor IX in haemophilia B subjects

Few randomized studies have reported on the use of factor IX (FIX) for secondary prophylaxis in haemophilia B patients. This study aimed to evaluate the efficacy and safety of two secondary prophylaxis regimens of recombinant coagulation FIX, nonacog alfa, compared with on‐demand therapy. Male subjects aged 6–65 years with severe or moderately severe haemophilia B (FIX:C ≤ 2, n = 50) and ≥12 bleeding episodes (including ≥6 haemarthroses episodes) within 12 months of study participation were enrolled in this multicentre, randomized, open‐label, four‐period crossover trial. The primary measure was the annualized bleeding rate (ABR) of two prophylactic regimens vs. on‐demand therapy. In the intent‐to‐treat group, mean ABR values were 35.1, 2.6 and 4.6 for the first on‐demand period, the 50 IU kg−1 twice‐weekly period, and the 100 IU kg−1 once‐weekly period respectively. Differences in ABR between the first on‐demand period and both prophylaxis regimens were significant (P < 0.0001); no significant differences were observed between prophylaxis regimens (P = 0.22). Seven serious adverse events occurred in five subjects, none related to study drug. Results demonstrated that secondary prophylaxis therapy with nonacog alfa 50 IU kg−1 twice weekly or 100 IU kg−1 once weekly reduced ABR by 89.4% relative to on‐demand treatment. Both prophylaxis regimens demonstrated favourable safety profiles in subjects with haemophilia B.

An overview of four studies of a continuous oral contraceptive (levonorgestrel 90 mcg/ethinyl estradiol 20 mcg) on premenstrual dysphoric disorder and premenstrual syndrome.

BACKGROUND This article presents an overview of four studies that evaluated a continuous oral contraceptive (OC) containing levonorgestrel (90 mcg) and ethinyl estradiol (20 mcg; LNG/EE) for managing premenstrual dysphoric disorder (PMDD) and premenstrual syndrome (PMS). STUDY DESIGN Three randomized, double-blind, placebo-controlled trials and one open-label, single-treatment substudy examined mean changes from baseline in the Daily Record of Severity of Problems (DRSP) or Penn Daily Symptom Rating (DSR). RESULTS Improvements from baseline in mean DRSP and DSR scores were observed, but results were not consistent among the studies. Mean percent improvement of premenstrual symptoms ranged from 30% to 59% in controlled trials and 56% to 81% in an open-label substudy. A large placebo effect was also observed in the placebo-controlled studies. Continuous LNG/EE yielded a favorable safety profile. CONCLUSIONS These data, although not consistent, indicate that continuous LNG/EE may reduce the symptoms of PMDD and PMS, providing an option for women who are appropriate candidates for a continuous OC as a contraceptive, the approved indication for this medication.

Continuous oral levonorgestrel/ethinyl estradiol for treating premenstrual dysphoric disorder

BACKGROUND The study was conducted to investigate continuous daily levonorgestrel 90 mcg/ethinyl estradiol 20 mcg (LNG/EE) on premenstrual dysphoric disorder (PMDD). STUDY DESIGN In this multicenter, randomized, double-blind, placebo-controlled study, women with PMDD received LNG/EE (n=186) or placebo (n=181) daily for 112 days and completed the Daily Record of Severity of Problems (DRSP). RESULTS Mean DRSP change from baseline to late luteal phase was significantly greater with LNG/EE than placebo at the late luteal phase of the first estimated cycle (-30.52±1.73 [SE] vs. -22.47±1.77; p<.001) and the worst 5 days during the last on-therapy estimated cycle (-26.77±1.83 vs. -20.89±1.82; p=.016). Other primary end points were not statistically significant. Significantly more subject taking LNG/EE (52%) than placebo (40%) responded (≥50% improvement in the DRSP 7-day late luteal phase score and Clinical Global Impression of Severity score of ≥1 improvement) at last on-therapy cycle (p=.025). CONCLUSIONS Continuous daily LNG 90 mcg/EE 20 mcg was well tolerated and may be useful for managing the physical, psychological and behavioral symptoms and loss of work productivity related to PMDD.

Once‐weekly prophylactic treatment vs. on‐demand treatment with nonacog alfa in patients with moderately severe to severe haemophilia B

Limited data are available on optimal prophylaxis regimens of factor IX (FIX) replacements for patients with haemophilia B.

Safety and bleeding profile of continuous levonorgestrel 90 mcg/ethinyl estradiol 20 mcg based on 2 years of clinical trial data in Canada

BACKGROUND The study was conducted to evaluate bleeding profile and safety of continuous oral contraceptive (OC) containing levonorgestrel (LNG) 90 mcg/ethinyl estradiol (EE) 20 mcg. STUDY DESIGN Healthy women who participated at seven Canadian sites in 1-year open-label study of LNG 90 mcg/EE 20 mcg daily were eligible for this second-year extension study. Primary end points included bleeding profile and adverse events. RESULTS Seventy-nine women enrolled without interrupting pill taking; 62 (78.5%) completed. Adverse events were comparable to cyclic OC regimens, except unscheduled vaginal bleeding. Amenorrhea and absence of bleeding increased to about 80% and 90%, respectively, by Pill Pack 18. Mean (median) number of bleeding days for the last two 90-day intervals was 1.1 (0) and 0.7 (0) days, respectively. CONCLUSIONS Continuous LNG 90 mcg/EE 20 mcg had a safety profile similar to low-dose cyclic OCs. Short-term safety profile remained excellent, with increasing rates of amenorrhea and decreasing incidence of unscheduled bleeding and/or spotting.

Pharmacokinetics, Efficacy, and Safety of Nonacog Alfa in Previously Treated Patients with Moderately Severe to Severe Hemophilia B.

PURPOSE Nonacog alfa, a recombinant factor IX (FIX) product, is used for FIX replacement in the treatment and prevention of bleeding events in patients with hemophilia B. This study aimed to provide supplemental pharmacokinetic (PK), efficacy, and safety data for nonacog alfa when administered as part of usual hemophilia care, including on-demand treatment, routine prophylaxis, and surgical prophylaxis. METHODS Men with previously treated severe or moderately severe hemophilia B (FIX activity ≤2%) were enrolled in this prospective, open-label, nonrandomized, multicenter study. An initial 72-hour PK assessment was performed wherein patients received a single dose of nonacog alfa (75 IU/kg) as an infusion over 10 minutes. A final 72-hour PK assessment was performed at the patients last visit, after a minimum washout period of 4 days. Correlations between Cmax after the first dose and body weight and body mass index (BMI) were assessed post hoc using Spearman test after evaluating normality. FINDINGS In total, 23 patients (age, 12-59 years; weight, 44-173 kg; and BMI, 16.3-45.1) with previous exposure to FIX products (median, 460 days; range, 150-2400 days) were enrolled; 21 were evaluable for efficacy. The median number of exposure days per efficacy-evaluable patient in this study was 48 (range, 31-103). The FIX activity profiles showed multiphasic disposition characteristics, with initial mean (SD) PK profiles as follows: Cmax, 61.4 (12.5) IU/dL; AUC∞, 1055 (227) IU·h/dL; t½, 23.7 (5.6) hours; and recovery, 0.818 (0.167) IU/dL. Mean plasma FIX activity versus time profiles were essentially identical upon initial exposure and after repeated use (n = 17), and bioequivalence was confirmed. No apparent relationship was observed between Cmax and either body weight (P > 0.1732) or BMI (P > 0.1235). IMPLICATIONS The FIX activity profile after administration of nonacog alfa is predictable and is not altered after repeated exposure during usual hemophilia care. PK parameters are consistent with nonacog alfa use for FIX replacement in on-demand treatment, routine prophylaxis, and surgical prophylaxis in patients with hemophilia B.

Lack of seasonal variation in bleeding and patient-assessed pain patterns in patients with haemophilia B receiving on-demand therapy.

Spontaneous haemorrhage in patients with haemophilia is generally considered to occur randomly and without a predictable temporal or seasonal pattern; however, there is a lack of evidence in the literature on the effects of weather, temperature and atmosphere on bleeding episodes. This post hoc analysis of a multicentre, open‐label crossover study examined the influence of seasonality on bleeding frequency and patient‐assessed pain in patients with moderately severe and severe (FIX C ≤ 2%) haemophilia B. Fifty patients were enrolled and treated on‐demand for 16 weeks; 47 were subsequently randomized to one of two prophylactic regimens (nonacog alfa 100 IU kg−1 once weekly or 50 IU kg−1 twice weekly) for 16 weeks. Patients then underwent an 8‐week washout period of on‐demand therapy before being crossed over to the other prophylactic regimen for 16 weeks. Bleeding episodes during the on‐demand treatment periods were analysed. To assess for temporal trends, data were graphed as scatter plots. The primary end point was the annualized bleeding rate (ABR). Additional measures included raw and median pain scores during every joint bleeding event (spontaneous or traumatic), with pain scored using the Brief Pain Inventory (0 = ‘no pain’ to 10 = ‘pain as bad as you can imagine’). The observed ABRs during the on‐demand periods showed no distinguishable trend over time. Analysis of pain associated with joint bleeding episodes also did not demonstrate any discernible temporal trend. No apparent seasonal variation in bleeding pattern or patient‐reported pain was observed in this analysis of patients with haemophilia B.

Nonacog alfa: an analysis of safety data from six prospective clinical studies in different patient populations with haemophilia B treated with different therapeutic modalities.

Nonacog alfa is a recombinant factor IX (FIX) product indicated for treatment and prevention of bleeding episodes in patients with haemophilia B. This posthoc analysis evaluated the safety of nonacog alfa in key clinical studies across 15 years. Data were pooled from six prospective studies that utilized on-demand, prophylactic and preventive nonacog alfa regimens: three open-label, nonrandomized studies that assessed efficacy and safety; a bioequivalence study of original and reformulated nonacog alfa; an open-label, randomized study that compared on-demand and prophylactic treatment; and a noninterventional observational registry study that evaluated safety. Safety assessments included adverse events, serious adverse events (SAEs) and events of special interest. In total, 412 patients received nonacog alfa treatment. Adverse events occurred in 220 patients (53.4%), the most common being pyrexia (n = 63), nasopharyngitis (n = 53) and cough (n = 52). Forty-eight patients (11.7%) experienced treatment-related adverse events; the most common were hypersensitivity (n = 6), urticaria (n = 6), FIX inhibition (n = 5) and pyrexia (n = 4). Seventy-four patients (18.0%) developed SAEs. Thirty-seven events of special interest occurred in 31 (7.5%) patients. Events of special interest included allergic-type manifestations (n = 15), inhibitor development (n = 5), lack of effect (n = 8), red blood cell agglutination in tubing or syringe (n = 7), and thrombogenicity (n = 2). Six patients (1.5%) withdrew due to seven adverse events: hypersensitivity (n = 3), drug eruption, pruritic rash, urticaria and decreased therapeutic response (n = 1 each). Four patients died during the study; no deaths were related to study medication. This pooled safety analysis in haemophilia B patients confirmed the safety of nonacog alfa across various patient populations.

Clinical experience with moroctocog alfa (AF-CC) in younger paediatric patients with severe haemophilia A: Two open-label studies

The pharmacokinetics (PK), efficacy and safety of moroctocog alfa (AF‐CC) have been demonstrated in haemophilia A patients aged ≥6 years.