Efficacy and Safety of Fibrinogen Concentrate for On-demand Treatment of Acute Bleeding and for Surgical Prophylaxis in Subjects with Congenital Fibrinogen Deficiency - A Phase 3 Study

2019 ◽  
Author(s):  
F. Peyvandi ◽  
B. Schwartz ◽  
C. Solomon ◽  
S. Knaub
Keyword(s):  
Efficacy And Safety ◽  
Fibrinogen Concentrate ◽  
Surgical Prophylaxis ◽  
Phase 3 ◽  
Acute Bleeding ◽  
On Demand

scholarly journals Efficacy and Safety of Fibrinogen Concentrate for on-Demand Treatment of Acute Bleeding and for Surgical Prophylaxis in Subjects with Congenital Fibrinogen Deficiency — a Phase 3 Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2502-2502
Author(s):  
Flora Peyvandi ◽  
Bruce A. Schwartz ◽  
Sigurd Knaub
Keyword(s):  
Advisory Board ◽  
Fibrinogen Concentration ◽  
Fibrinogen Concentrate ◽  
Surgical Prophylaxis ◽  
Phase 3 ◽  
Acute Bleeding ◽  
On Demand ◽  
Congenital Afibrinogenemia ◽  
Hemostatic Efficacy ◽  
Good For

Abstract Introduction: Congenital afibrinogenemia is a rare inherited disorder characterized by an absence of plasma fibrinogen. Affected individuals have a highly variable bleeding tendency, which can be severe and include life-threatening bleeding and spontaneous/trauma-related bleeds. Therapeutic substitution with human fibrinogen concentrate (HFC) can correct the hemostatic defect and arrest bleeding. The FORMA-02 study investigated the hemostatic efficacy of a new plasma-derived, double virus-inactivated HFC (Fibryga, Octapharma) for on-demand treatment of bleeding episodes (BEs) and for surgical prophylaxis in patients with afibrinogenemia. Methods: FORMA-02 was a prospective, open-label, uncontrolled, multicenter Phase 3 study. A total of 25 patients with congenital afibrinogenemia (≥12 years) received the new HFC for treatment of a BE and/or for surgical prophylaxis. HFC was individually dosed to achieve a recommended target fibrinogen plasma level dependent on the bleeding type or surgery type (minor or major). The primary endpoint was the efficacy of the new HFC for on-demand treatment of the first BE after signed consent was obtained. Secondary endpoints included hemostatic efficacy of the HFC for the treatment of all BEs during the study period and its efficacy in preventing bleeding during and after surgery. Hemostatic efficacy was assessed by investigators and an Independent Data Monitoring and Endpoint Adjudication Committee (IDMEAC) using objective four-point scales, with treatment success defined as a rating of excellent or good. Thromboelastometry maximum clot firmness (MCF) was also investigated as a surrogate marker of efficacy. Results: A total of 25 patients received the new HFC for treatment of a BE (N=24) and/or surgical prophylaxis (N=9). The mean±SD dose of HFC was 65.51±26.47 mg/kg per BE (89 events) and 40.45±30.78 mg/kg per surgery for surgical prophylaxis (12 events). Hemostatic efficacy for treatment of the first BE (primary endpoint) was rated as excellent or good for all patients by both the investigator and the IDMEAC (Success: 100%; 90% CI 0.89-1.00). When all BEs were evaluated (N=89 BEs in 24 patients), hemostatic efficacy was rated as excellent or good for 96.6% of events by the investigator and 98.9% by the IDMEAC. The first HFC infusion for treatment of the first BE for each patient led to a mean increase in blood fibrinogen concentration of 114.74±25.28 mg/dL 1 hour after administration, while the MCF increased by a mean of 6.48±3.07 mm. Intraoperative hemostatic efficacy for surgical prophylaxis was rated by the surgeon and the IDMEAC as excellent or good for 100% of the 12 surgeries that were performed (success: 100%; 90%CI 0.82-1.00). Postoperative efficacy was also rated as excellent or good in all cases. The first HFC infusion for each surgery led to a mean increase in blood fibrinogen concentration of 104.55±43.64 mg/dL at 1 hour after administration. A total of 15 serious adverse events (SAEs) occurred in 5 patients; only one was deemed to be related to the HFC by the investigator. This was a digital ischemia that resolved without sequelae. No inhibitory anti-fibrinogen antibodies were detected and there were no severe allergic or hypersensitivity reactions related to the HFC. Conclusions: These data indicate that the new HFC was efficacious for on-demand treatment of acute bleeding and for surgical prophylaxis in patients with congenital afibrinogenemia, with hemostatic efficacy rated as 100% in both settings. The HFC showed an acceptable safety profile in this study population. Disclosures Peyvandi: Grifols: Speakers Bureau; Octapharma US: Honoraria; Roche: Speakers Bureau; Shire: Speakers Bureau; Octapharma US: Honoraria; Roche: Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Shire: Speakers Bureau; Novo Nordisk: Speakers Bureau; Sobi: Speakers Bureau; Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Shire: Speakers Bureau; Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria; Novo Nordisk: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Kedrion: Consultancy; Kedrion: Consultancy; Kedrion: Consultancy; Kedrion: Consultancy; Kedrion: Consultancy; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Novo Nordisk: Speakers Bureau; Grifols: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Sobi: Speakers Bureau; Sobi: Speakers Bureau; Sobi: Speakers Bureau. Schwartz:Octapharma US: Employment. Knaub:Octapharma AG: Employment.

scholarly journals Efficacy and Safety of Human Fibrinogen Concentrate for the Treatment of Patients with Congenital Fibrinogen Deficiency: Combined Results of the FORMA-02 and FORMA-04 Clinical Trials

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-12
Author(s):  
Claudia Djambas Khayat ◽  
Irina Kruzhkova ◽  
Cristina Solomon ◽  
Bruce A. Schwartz ◽  
Flora Peyvandi
Keyword(s):  
Pediatric Patients ◽  
Efficacy And Safety ◽  
Fibrinogen Concentrate ◽  
Surgical Prophylaxis ◽  
Bleeding Events ◽  
Phase 3 ◽  
Human Fibrinogen ◽  
Patients Âgés ◽  
Bleeding Episodes ◽  
Hemostatic Efficacy

Introduction: Congenital fibrinogen deficiency (CFD) is a rare disorder which results from a complete lack (afibrinogenemia) or low levels (hypofibrinogenemia) of functional fibrinogen. Treatment with human fibrinogen concentrate (HFC) can treat bleeding episodes and prevent blood loss in surgical treatment in patients with CFD. Herein we report combined data from two clinical studies on the efficacy and safety of HFC for the treatment of bleeding episodes (BEs) and surgical prophylaxis in adult, adolescent and pediatric patients. Methods: Both FORMA-02 and FORMA-04 were multinational, multicenter, prospective, open-label, uncontrolled Phase 3 studies for the use of HFC in adult and pediatric patients with CFD. They reported the hemostatic efficacy and safety of human fibrinogen concentrate (HFC: Fibryga® Octapharma) for on-demand treatment of BEs and surgical prophylaxis using objective criteria. Efficacy was assessed by the trial investigators and adjudicated by an independent data monitoring and end-point adjudication committee (IDMEAC). All adverse events (AEs) and serious AEs were recorded. Results: The two studies included a total of 39 patients who received HFC. The median (range) age across both studies was 17 (1-54) years, with 14 pediatric (aged 0-11), 6 adolescent (aged 12-18) and 19 adult patients (aged >18). Treatment of Bleeding Events 32 patients received HFC for the treatment of 99 bleeding events (BEs), 97 minor and 4 major. Of these, 72 were spontaneous, and 27 were due to trauma. 10 BEs occurred in pediatric patients (8 minor, 2 major), and 89 in adult/adolescents (87 minor, 2 major). The mean (±SD) total dose per BE was 65.51 mg/kg (±26.47) for adult/adolescent patients (ages 12-54) and 93.78 (±64.60) for pediatric patients (ages 0-11). Investigator-assessed and IDMEAC rated hemostatic efficacy are shown in Table 1. Overall hemostatic efficacy was rated as success (rating of excellent or good) for 99.0% of BEs by the IDMEAC. Treatment efficacy results were comparable when analyzed by age subgroup of adult (≥18 years), adolescent (>12-<18 years) and in two groups of pediatric patients (<6 years and 6-12 years). Surgical prophylaxis A total of 12 patients received HFC across 15 surgeries (13 minor and 2 major), 3 in pediatric patients (major: splenectomy; minor: circumcision and pulpectomy), and 12 in adults/adolescents (major: eye enucleation with socket reconstruction; minor: knee radioisotope synovectomy [n=2], dental extraction [n=3], circumcision [n=2], excision of circumcision scar bud, root canal operation, skin biopsy, and debridement of superficial necrosis). Mean (±SD) loading dose administered prior to surgery was 77.39 (±20.22) in adult/adolescent patients and 78.50 mg/kg (±27.96) for pediatric patients. Seven surgeries required multiple infusions, with the two major surgeries requiring 5 and 7 maintenance infusions, and the five minor surgeries requiring median (range) 3 (1-4) maintenance infusions. Intra- and post-operative hemostatic efficacy for all surgeries is shown in Table 1. Overall hemostatic efficacy of all the procedures was rated 100% successful by both the investigator and IDMEAC assessment. Safety A total of 101 AEs occurred in 23 patients (59.0%), including 16 serious AEs in 6 patients. Of these, 5 AEs in 4 patients were considered to be possibly related to treatment. These included a mild skin reaction (itchiness and redness), ischemia due to digital microthrombi, peripheral phlebitis of the upper limbs, and a portal vein thrombosis following splenectomy. No allergic/hypersensitivity reactions or deaths were observed during either of the studies. Conclusions: HFC treatment was shown to be efficacious for on-demand treatment of BEs and perioperative prophylaxis in this rare CFD population, across two Phase 3 clinical trials. Efficacy was comparable for adult, adolescent and pediatric patients. A favorable safety profile was seen for the treatment of patients with congenital afibrinogenemia with HFC. Disclosures Djambas Khayat: Octapharma: Research Funding. Kruzhkova:Octapharma: Current Employment. Solomon:Octapharma: Current Employment. Schwartz:Octapharma: Current Employment. Peyvandi:Octapharma: Research Funding. OffLabel Disclosure: On label use: Fibryga for treatment of bleeding episodes Off label use: Use of Fibryga as surgical prophylaxis in the US

scholarly journals Efficacy and safety of fibrinogen concentrate for on‐demand treatment of bleeding and surgical prophylaxis in paediatric patients with congenital fibrinogen deficiency

Haemophilia ◽  
2020 ◽  
Author(s):  
Claudia Djambas Khayat ◽  
Sunil Lohade ◽  
Fulton D’Souza ◽  
Latha Gowda Shamanur ◽  
Omid Reza Zekavat ◽  
...  
Keyword(s):  
Efficacy And Safety ◽  
Fibrinogen Concentrate ◽  
Surgical Prophylaxis ◽  
On Demand ◽  
Paediatric Patients

scholarly journals Efficacy of Human Fibrinogen Concentrate for on-Demand Treatment of Acute Bleeding and to Prevent Bleeding during and after Surgery in Subjects with Congenital Fibrinogen Deficiency

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1404-1404
Author(s):  
Bruce A. Schwartz ◽  
Cecil Ross ◽  
Bella Madan ◽  
Toshko Jelev Lissitchkov ◽  
Mehran Karimi ◽  
...  
Keyword(s):  
Adverse Events ◽  
Success Rate ◽  
Research Funding ◽  
Fibrinogen Concentrate ◽  
Surgical Prophylaxis ◽  
Serious Adverse Events ◽  
Human Fibrinogen ◽  
On Demand ◽  
Hemostatic Efficacy ◽  
Maximum Clot Firmness

Abstract Patients with congenital afibrinogenaemia and hypofibrinogenaemia, frequently experience severe bleeding episodes starting already at birth or during early childhood. Bleeding may occur after a minor trauma or a surgical intervention into the skin, mucosa, muscles, gastrointestinal tract, or the brain. Therapeutic substitution with human fibrinogen concentrate (HFC) corrects the haemostatic defect and arrests bleeding in these patients. Octafibrin (Octapharma OPG, Vienna, Austria) is a plasma-derived, highly purified, lyophilized fibrinogen concentrate with two dedicated virus inactivation/removal steps was used in this study. This study was prospective, open-label and multinational, in adult and adolescent a- or hypofibrinogenemic patients, to investigate the safety and efficacy of Octafibrin a new HFC in the treatment of on-demand bleeding (BE) and surgical prophylaxis. A planned interim analysis comprises data of 11 adult and 2 adolescent patients. Efficacy was assessed using a 4 point objective scale completed by the investigator and adjudicated by an independent data monitoring and endpoint adjudication committee (IDMEAC) for each bleeding or surgical episode. Eleven of the 13 patients experienced a total of 23 minor BEs. Sixteen BEs (69.6%) were spontaneous and 7 (30.4%) were traumatic. A majority of BEs (21/23) required one HFC infusion (91.3%) and 2 (8.7%) BEs required two infusions. The median (range) dose of HFCadministered for the treatment of all BEs was 57.5 mg/kg (33.9-71.4 mg/kg) per infusion and 58.8 mg/kg (33.9-101.7 mg/kg) per BE. The success rate (efficacy rating of excellent or good) for all BEs was 100% (90% CI: 0.88, 1.00) as adjudicated by the IDMEAC (all excellent). Maximum clot firmness (MCF) using thromboelastometry (ROTEM®) performed in plasma was also determined for the first infusions administered for the treatment of all 23 BEs in the 11 BE patients. The mean (±SD) change in MCF from baseline (MCF 0) to 1 hour after the first infusion of HFCwas 6.5 mm (±2.0) (95% CI: 5.65, 7.40; p<0.0001). This significant overall increase in MCF from baseline coincided with the 100% haemostatic efficacy for all BEs. Four patients underwent 4 surgeries (3 major 1 minor, two of these patients were treated for both BE and surgery). The post-operative success rate (haemostatic efficacy excellent or good) was 100% (90% CI 0.5, 1.0), as assessed by the investigator and the IDMEAC. There have been no reports of serious adverse events related to the infusion of the HFC. In conclusion this study showed 100% hemostatic efficacy in on-demand treatment with HFC in bleeding patients with congenital fibrinogen deficiency. Also hemostatic efficacy in surgical prophylaxis in 4 patients was rated excellent/good. Maximum clot firmness values showed a statistically significant increase from baseline to 1 hour post-infusion in all patients after HFCadministrations reflecting the successful treatment of bleeding events. There were no related serious adverse events, no thromboembolic events, no allergic or severe hypersensitivity reactions, and no anti-fibrinogen antibodies that developed during the study. Disclosures Schwartz: Octapharma: Employment. Knaub:Octapharma: Employment. Peyvandi:Bayer: Speakers Bureau; Biotest: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; Ablynx: Membership on an entity's Board of Directors or advisory committees, Other: research funding paid to Luigi Villa Foundation, Research Funding; CSL Behring: Speakers Bureau; Grifols: Speakers Bureau; Alexion: Other: research funding paid to Luigi Villa Foundation, Research Funding; Octapharma: Consultancy; Kedrion Biopharma: Consultancy, Other: research funding paid to Luigi Villa Foundation, Research Funding; LFB: Consultancy; Novo Nordisk: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; SOBI: Speakers Bureau.

The Crimson 1 Study: A Phase 3 Study to Evaluate the Efficacy and Safety of Subcutaneous Marzeptocog Alfa (activated) for on-Demand Treatment and Control of Bleeding Episodes in Subjects with Hemophilia A or Hemophilia B, with Inhibitors

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Linda Neuman ◽  
Shraddha Desai ◽  
Tom Knudsen ◽  
Frank Del Greco ◽  
Howard Levy
Keyword(s):  
Initial Dose ◽  
Hemophilia A ◽  
Factor Vii ◽  
Coagulation Disorder ◽  
Efficacy And Safety ◽  
Publicly Traded ◽  
Phase 3 ◽  
On Demand ◽  
History Of ◽  
Bleeding Episodes

Background Hemophilia A (HA) and HB are X-linked bleeding disorders caused by a deficiency of Factor VIII (HA) or Factor IX (HB). A significant number of individuals with HA and HB develop inhibitors against the wild-type FVIII or FIX, respectively, and thereby become refractory to factor replacement treatment. Treatment of episodic bleeding in these individuals requires technical expertise to gain the requisite intravenous (IV) access and is often associated with pain. This causes delays in administration, which results in prolonged bleeding and accumulation of blood in the joint or other bleeding site. Currently approved FVIIa containing products take 6-24 hours to achieve hemostasis and maintain efficacy. Marzeptacog alfa (activated) (MarzAA), a novel variant activated recombinant Factor VII (rFVIIa), is being developed for subcutaneous (SQ) administration to address this important unmet need. Data from the Phase 1 study, MAA-102, demonstrated that SQ MarzAA is quickly absorbed and has the potential to achieve and maintain plasma levels in the desired range with an acceptable safety profile. This open-label, global, multi-center, randomized, cross-over Phase 3 study will evaluate the efficacy and safety of MarzAA for on demand treatment of spontaneous or traumatic bleeding episodes in adolescents and adults with congenital HA or HB with inhibitors. MarzAA will be compared to the Standard of Care (SOC). Approximately 60 subjects will be enrolled at 54 sites in 19 countries. Study Design and Methods Key inclusion criteria: Eligible male or female subjects ≥ 12 years of age must have: confirmed diagnosis of HA or HB unresponsive to or intolerant of standard replacement therapy; history of bleeding with annualized bleeding rate of ≥ 8; investigator-confirmed subject's ability to identify bleeding episodes and administer MarzAA SQ and infuse SOC IV at home. Key exclusion criteria: Subjects should not have had previous exposure to SQ administration of rFVIIa or exposure to any other variant rFVIIa; known positive antibody or hypersensitivity to MarzAA, FVIIa, or variants thereof; history of other coagulation disorder(s); platelet count &lt;50,000/µL; CD4 T cell count &lt;200 cells/mm3. Treatment: Subjects &gt;17 years of age will be randomized in blocks to target treatment of approximately 5 bleeds with MarzAA and an additional 5 bleeds with SOC in either order, Sequence A or Sequence B, with a washout period to assess anti-drug antibodies (ADA) status between treatments. A total of 488 eligible bleeds will be treated, ~244 bleeds with each treatment, until ≥80% of patients have ≥3 bleeds treated with MarzAA and SOC. Pharmacokinetic samples will be collected during the MarzAA treatment period. Subjects 12-17 years of age will be enrolled after a positive DSMB assessment of 30 eligible bleeds treated with MarzAA. Subjects will administer 60 µg/kg SQ dose of MarzAA, at 3-hour intervals, for up to 3 doses as required to achieve hemostasis. Endpoints: Primary endpoint includes percentage of treated bleeds resulting in effective hemostasis (excellent or good) at 24 hours after the initial dose. Key secondary endpoints include time to cessation of bleeding after the initial dose; percentage of treated bleeds resulting in effective hemostasis at fixed timepoints; percentage of those that maintain hemostasis at 48 hours after the initial dose; use and amount of rescue therapy. Key safety endpoints include the incidence of adverse events; occurrence of thrombotic events and binding and/or neutralizing anti-drug antibodies. Key exploratory endpoints include assess patient satisfaction with the Treatment Satisfaction Questionnaire for Medicine- 9; assessment of pain using the Visual Analogue Scale; time required to administer treatment. Statistics: The goal is to demonstrate the true proportion of bleeds effectively treated with MarzAA is not inferior to SOC. Using a baseline efficacy of 85% for SOC, with a -12% margin of non-inferiority, treatment of 244 bleeds in each group provides 90% power with a one-sided 2.5% significance level to substantiate this result. Figure Disclosures Neuman: Catalyst Biosciences: Current Employment, Current equity holder in publicly-traded company. Desai:Catalyst Biosciences: Current Employment, Current equity holder in publicly-traded company. Knudsen:Catalyst Biosciences: Current Employment, Current equity holder in publicly-traded company. Del Greco:Catalyst Biosciences: Current Employment, Current equity holder in publicly-traded company. Levy:Catalyst Biosciences: Current Employment, Current equity holder in publicly-traded company.

Long-term Efficacy and Safety of Brodalumab in Patients With Psoriasis Disease Duration <10 and ≥10 Years: Analysis of Two Phase 3 Studies

2019 ◽  
Vol 3 ◽  
pp. S25
Author(s):  
Benjamin Ehst ◽  
George Han ◽  
Scott Guenthner ◽  
Kimberly Eads ◽  
Abby Jacobson
Keyword(s):  
Disease Duration ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Two Phase ◽  
Term Efficacy

Abstract not available.

The Efficacy and Safety of FMX101, Minocycline Foam 4%, for the Treatment of Acne Vulgaris: A Pooled Analysis of Phase 2 and Phase 3 Studies

2017 ◽  
Vol 1 ◽  
pp. s49
Author(s):  
Linda Stein Gold ◽  
Sunil Dhawan ◽  
Jonathan Weiss ◽  
Zoe D Draelos ◽  
Herman Ellman
Keyword(s):  
Acne Vulgaris ◽  
Pooled Analysis ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Phase 3

Abstract Not Available

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