These 527 AEs occurred in 15 subjects. Table 4 Attributes of the β-cyano-L-Alanine 47 serious adverse events (SAEs) and 527 non-SAE adverse events* occurring during the RICH study, among the 16 subjects who received at least one dose of rituximab
Bleeding Events??????31 (66)??????9 (56)??????428 (81)??????15 (94)??????459 (80)??????15 (94)???????? Joint Bleeding21 (45)6 (38)293 (56)15 (94)314 (55)15 (94)?? Hematomas7 (15)5 (31)105 (20)14 (88)112 (20)14 (88)?? Subdural hematoma2 (4)1 (6)0 (0)0 (0)2 (<1)1 (6)?? Mallory Weiss tear1 (2)1 (6)0 (0)0 (0)1 (<1)1 (6)?? Haematuria0 (0)0 (0)1 (<1)1 (6)1 (<1)1 (6)?? Bleeding, Other0 (0)0 (0)29 (6)6 (38)29 (5)6 (38)Non-Bleeding Events??????16 (34)??????10 (63)??????99 (19)??????11 (69)??????115 (20)??????13 (81)??????Infection??????5 (11)??????4 (25)??????5 (1)??????3 (11)??????10 (2)??????5 (31)???????? Central line infection1 (2)1 (6)0 (0)0 (0)1 (<1)1 (6)?? Conjunctivitis0 (0)0 (0)1 (<1)1 (6)1 (<1)1 (6)?? Herpes Zoster1 (2)1 (6)0 (0)0 (0)1 (<1)1 (6)?? Pulmonary infection1 (2)1 (6)0 (0)0 (0)1 (<1)1 (6)?? Sepsis, Septic Arthritis1 (2)1 (6)1 (<1)1 (6)2 (<1)1 (6)?? Sinusitis0 (0)0 (0)1 (<1)1 (6)1 (<1)1 (6)?? Streptococcus0 (0)0 (0)2 (<1)1 (6)2 (<1)1 (6)?? Viral meningitis1 (2)1 (6)0 (0)0 (0)1 (<1)1 (6)Laboratory Abnormality??????0 (0)??????0 (0)??????21 (4)??????2 (13)??????21 (4)??????2 (13)???????? Anaemia0 (0)0 (0)3 (1)1 (6)3 (1)1 (6)?? ALT abnormality0 (0)0 (0)10 (2)1 (6)10 (2)1 (6)?? WBC abnormality0 (0)0 (0)7 (1)2 (13)7 (1)2 (13)?? Other0 (0)0 (0)1 (<1)1 (6)1 (<1)1 (6)Orthopaedic Events??????0 (0)??????0 (0)??????6 (1)??????3 (11)??????6 (1)??????3 (19)???????? Joint pain0 (0)0 (0)4 (1)2 (13)4 (1)2 (13)?? Joint loss of motion0 (0)0 (0)2 (<1)2 (13)2 (<1)2 (13)Surgery??????4 (9)??????4 (25)??????0 (0)??????0 (0)??????4 (1)??????4 (25)???????? Port Placement2 (4)2 (13)0 (0)0 (0)2 (<1)2 (13)?? Synovectomy2 (4)2 (13)0 (0)0 (0)2 (<1)2 (13)Other??????7 (15)??????5 (31)??????67 (13)??????10 (63)??????74 (13)??????11 (69)???????? Abdominal Pain0 (0)0 (0)3 (1)2 (13)3 (1)2 (13)?? Allergic reaction1 (2)1 (6)1 (<1)1 (6)2 (<1)2 (13)?? Anorexia, nausea, vomit0 (0)0 (0)8 (2)1 (6)8 (1)1 (6)?? Asthma0 (0)0 (0)3 (1)1 (6)3 (1)1 (6)?? Bells Palsy0 (0)0 (0)1 (<1)1 (6)1 (<1)1 (6)?? Cold, Chills, Cough0 (0)0 (0)15 (3)6 (38)15 (3)6 (38)?? β-cyano-L-Alanine Cold Sore0 (0)0 (0)1 (<1)1 (6)1 (<1)1 (6)?? Diarrhoea1 (2)1 (6)1 (<1)1 (6)2 (<1)2 (13)?? Dyspepsia0 (0)0 (0)1 (<1)1 (6)1 (<1)1 (6)?? Dyspnoea1 (2)1 (6)0 (0)0 (0)1 (<1)1 (6)?? Fatigue, Lethargy0 (0)0 (0)3 (1)2 (13)3 (1)2 (13)?? Fever1 (2)1 (6)4 (1)2 (13)5 (1)2 (13)?? Fracture1 (2)1 (6)0 (0)0 (0)1 (<1)1 (6)?? Headache1 (2)1 (6)2 (<1)2 (13)3 (1)3 (19)?? Head Injury0 (0)0 (0)2 (<1)2 (13)2 (<1)2 (13)?? Hypertension0 (0)0 (0)1 (<1)1 (6)1 (<1)1 (6)?? Hypotension1 (2)1 (6)4 (1)1 (6)5 (1)2 (13)?? Lymphadenopathy0 (0)0 (0)1 (<1)1 (6)1 (<1)1 (6)?? Myalgia0 (0)0 (0)2 (<1)1 (6)2 (<1)1 (6)?? Pain0 (0)0 (0)3 (1)2 (13)3 (1)2 (13)?? Photophobia0 (0)0 (0)1 (<1)1 (6)1 (<1)1 (6)?? Pulmonary Hypertension0 (0)0 (0)1 (<1)1 (6)1 (<1)1 (6)?? Rash0 (0)0 (0)3 (1)2 (13)3 (1)2 (13)?? Sunburn0 (0)0 (0)1 β-cyano-L-Alanine (<1)1 (6)1 (<1)1 (6)?? Sweating0 (0)0 (0)1 (<1)1 (6)1 (<1)1 (6)?? Toothache0 (0)0 (0)1 (<1)1 (6)1 (<1)1 (6)?? Vaccination Site Reaction0 (0)0 (0)1 (<1)1 (6)1 (<1)1 (6)?? Wheezing0 (0)0 (0)2 (<1)1 (6)2 (<1)1 (6) Open in a separate window *Includes 3 bleeding events with onset before date of consent but ongoing at baseline Of all adverse events, 459 (80%) events occurring among 15 subjects were classified as bleeding events. Of sixteen subjects who received at least one dose of rituximab, three (18.8%) met the criteria for a major response, defined as a fall in inhibitor titre to <5 BU, persisting after FVIII re-challenge. One subject had a minor response, defined as a fall in inhibitor titre to <5 BU, increasing to 5C10 BU after FVIII re-challenge, but <50% of the original peak inhibitor titre. Rituximab is useful in lowering inhibitor levels in patients, but its effect as a solo treatment strategy is modest. Future studies are indicated to determine the role of rituximab as an adjunctive therapy in immune tolerisation strategies. Keywords: Anti-CD20, Antibodies, Monoclonal, Murine-Derived, Blood Coagulation Inhibitor, CD20 Antibody, Haemophilia A INTRODUCTION For many patients with congenital haemophilia A, the genetic absence or dysfunction of the Factor VIII (FVIII) protein causes an immune response to infused Ifng FVIII replacement therapy. High titre alloreactive FVIII antibodies, or inhibitors, that neutralize the function of infused FVIII develop in as many as 30C40% of patients with severe haemophilia A,[1C2] and up to 13% of those with mild or moderate haemophilia A.[3] Treatment of bleeding in patients with high titre inhibitors is difficult. The major therapeutic modalities consist of agents that bypass the need for Factor VIII, such as prothrombin complex or recombinant Factor VIIa concentrates. However, neither of these therapies leads to the predictable and effective hemostasis provided by Factor VIII replacement therapy. Patients with persistent inhibitors thus suffer consequences of serious, poorly controlled bleeding, which often leads to restrictive joint disease, prolonged hospitalizations, and in some cases, early death.[4C7] The only approach that has been shown to eradicate inhibitors in patients with congenital haemophilia is immune tolerance induction (ITI) therapy which involves regular (usually daily) exposure to FVIII concentrates to promote immunologic acceptance of the FVIII protein.[8] ITI is almost always indicated as first line treatment in patients who have had an inhibitor for less than a year. However, a significant portion (up to 50%) of patients will fail ITI, resulting in the presence of permanent inhibitors.[9C12] In addition, patients with long standing inhibitors are not usually considered candidates for ITI because inhibitors present for longer than a year are typically refractory to ITI, and because older age at ITI initiation reduces ITI success.[10] Ultimately, as many as 15C20% of these patients have permanent life-long inhibitors. Rituximab (Rituxan?) is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen. At a dose of 375mg/m2 weekly 4 weeks, circulating B cells are depleted within the first one to three doses with sustained depletion for up to 6C9 months. B-cell recovery begins at approximately 6 months following completion of treatment. Median B-cell levels return to normal by 12 months following completion of treatment.[13] Due to its profound effect on circulating B lymphocytes, rituximab has been used to successfully treat a variety of autoimmune disorders,[14C18] including acquired haemophilia due to autoantibodies directed against FVIII.[19C22] Anecdotal reports have suggested that rituximab may also have benefit in the management of FVIII alloantibodies (inhibitors) in patients with congenital haemophilia A.[23C25] The purpose of the RICH study was to determine if rituximab given in 4 weekly doses could reduce the titre and anamnestic response of FVIII inhibitors following exposure to infused FVIII in patients with severe congenital haemophilia A who have high-responding inhibitors. MATERIALS AND METHODS Study Development and Oversight The Rituximab for the Treatment of Inhibitors in Congenital Hemophilia A (RICH) Study was designed by members of the Haemophilia Subcommittee of the Transfusion Medicine/Hemostasis (TMH) Clinical Trials Network as a proof-of-concept trial to determine whether four weeks of rituximab treatment could significantly reduce or eliminate high titre inhibitors in patients with severe haemophilia A. The protocol, which was registered at ClinicalTrials.gov as NCT00331006 and under IND BB-12417 for off-label study of rituximab, was opened at 13 sites in the United States, each of which obtained approval from an Institutional Review Board. All adults enrolled provided written informed consent; consent for children was obtained from a parent or legal guardian. Assent was provided by children where required by local policy. Central laboratory testing for inhibitor titres was performed at Orthopaedic Hospital Special Coagulation Laboratory (Los Angeles, CA). Central data coordination was performed by the.