1.
Efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors (ATLAS-INH): a multicentre, open-label, randomised phase 3 trial
Young G, Srivastava A, Kavakli K, Ross C, Sathar J, You CW, Tran H, Sun J, Wu R, Poloskey S, et al
Lancet (London, England). 2023
Abstract
BACKGROUND Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance haemostasis in people with haemophilia A or haemophilia B, irrespective of inhibitor status. We evaluated the efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors. METHODS This multicentre, randomised, open-label phase 3 study was done at 26 sites (primarily secondary or tertiary centres) in 12 countries. Men, boys, and young adults aged 12 years or older with severe haemophilia A or haemophilia B with inhibitors previously treated with on-demand bypassing agents were randomly assigned (2:1) to receive once-a-month 80 mg subcutaneous fitusiran prophylaxis (fitusiran prophylaxis group) or to continue with bypassing agents on-demand (bypassing agents on-demand group) for 9 months. The primary endpoint was mean annualised bleeding rate during the efficacy period in the intention-to-treat population estimated by negative binomial model. Safety was assessed as a secondary endpoint in the safety population. This trial is complete and is registered with ClinicalTrials.gov, NCT03417102. FINDINGS Between Feb 14, 2018, and June 23, 2021, 85 participants were screened for inclusion, of whom 57 (67%; 57 [100%] men; median age 27·0 years [IQR 19·5-33·5]) were randomly assigned: 19 (33%) participants to the bypassing agent on-demand group and 38 (67%) participants to the fitusiran prophylaxis. Negative binomial model-based mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (1·7 [95% CI 1·0-2·7]) than in the bypassing agents on-demand group (18·1 [10·6-30·8]), corresponding to a 90·8% (95% CI 80·8-95·6) reduction in annualised bleeding rate in favour of fitusiran prophylaxis (p<0·0001). 25 (66%) participants had zero treated bleeds in the fitusiran prophylaxis group versus one (5%) in the bypassing agents on-demand group. The most frequent treatment-emergent adverse event in the fitusiran prophylaxis group was increased alanine aminotransferase in 13 (32%) of 41 participants in the safety population; there were no increased alanine aminotransferase treatment-emergent adverse events in the bypassing agents on-demand group. Suspected or confirmed thromboembolic events were reported in two (5%) participants in the fitusiran prophylaxis group. No deaths were reported. INTERPRETATION Subcutaneous fitusiran prophylaxis resulted in statistically significant reductions in annualised bleeding rate in participants with haemophilia A or haemophilia B with inhibitors, with two-thirds of participants having zero bleeds. Fitusiran prophylaxis might show haemostatic efficacy in participants with haemophilia A or haemophilia B with inhibitors; therefore, the therapeutic might have the potential to improve the management of people with haemophilia. FUNDING Sanofi.
2.
Efficacy of ormeloxifene versus oral contraceptive in the management of abnormal uterine bleeding due to uterine leiomyoma
Kriplani A, Srivastava A, Kulshrestha V, Kachhawa G, Agarwal N, Bhatla N, Hari S
The Journal of Obstetrics and Gynaecology Research. 2016;42((12):):1744-1752
Abstract
AIM: To compare ormeloxifene with combined oral contraceptive (COC) in abnormal uterine bleeding (AUB) due to leiomyoma (AUB-L). METHODS Fifty women with AUB-L were randomized after informed consent and institute ethics clearance. Group I (n = 25) was given ormeloxifene (a SERM i.e. selective estrogen receptor modulator) 60 mg twice per week and group II (n = 25) was given COC (ethinyl estradiol 30 mug with desogestrel 150 mug) on days 1-21 for 6 months. Menstrual blood loss was assessed on pictorial blood loss assessment chart (PBAC) score and leiomyoma volume was assessed on ultrasound. Fibroids were classified according to FIGO-PALM-COEIN classification for AUB where leiomyomas were further sub-classified as types 0 to 8 according to their location. Follow up was done at 1, 3, 6 and 9 months. RESULTS Mean PBAC score reduced by 81% with ormeloxifene (group I) compared with 43.8% for COC (group II). After 6 months, 18 patients (72%) in group I had PBAC score in the non-menorrhagic range (<100) compared with only two (8%) in group II. In group I, PBAC score in FIGO-PALM-COEIN leiomyoma types 2, 3, 4, 5, 6 reduced by 90.2%, 82.5%, 93.3%, 56.4% and 100%, respectively and 14 (56%) developed amenorrhea; compared with reduction of 64%, 27.5%, 25.9% in types 4, 5 and 6, respectively in group II. Dysmenorrhea visual analog scale score decreased in both groups. Mean leiomyoma volume increased in both groups: by 25.7% with ormeloxifene versus 16.9% with COC; only grade 2 leiomyoma in group I reduced by 44%. One patient in group II with grade 2 leiomyoma discontinued treatment at 3 months. Seven patients (28%) developed ovarian cyst in group I with no other major adverse effect in either group. CONCLUSION Ormeloxifene with its convenient twice-weekly dosage schedule was effective in treating AUB-L, with 72% of patients responding to 6-month treatment compared with 8% with COC, even though leiomyoma volume increased insignificantly with both ormeloxifene and COCs.