Effect of Lanadelumab Compared with Placebo on Prevention of Hereditary Angioedema Attacks : a Randomized Clinical Trial

Importance: Current treatments for long-term prophylaxis in hereditary angioedema have limitations. Objective: To assess the efficacy of lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, in preventing hereditary angioedema attacks. Design, Setting, and Participants: Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 41 sites in Canada, Europe, Jordan, and the United States. Patients were randomized between March 3, 2016, and September 9, 2016; last day of follow-up was April 13, 2017. Randomization was 2:1 lanadelumab to placebo; patients assigned to lanadelumab were further randomized 1:1:1 to 1 of the 3 dose regimens. Patients 12 years or older with hereditary angioedema type I or II underwent a 4-week run-in period and those with 1 or more hereditary angioedema attacks during run-in were randomized. Interventions: Twenty-six-week treatment with subcutaneous lanadelumab 150 mg every 4 weeks (n = 28), 300 mg every 4 weeks (n = 29), 300 mg every 2 weeks (n = 27), or placebo (n = 41). All patients received injections every 2 weeks, with those in the every-4-week group receiving placebo in between active treatments. Main Outcome and Measures: Primary efficacy end point was the number of investigator-confirmed attacks of hereditary angioedema over the treatment period. Results: Among 125 patients randomized (mean age, 40.7 years [SD, 14.7 years]; 88 females [70.4%]; 113 white [90.4%]), 113 (90.4%) completed the study. During the run-in period, the mean number of hereditary angioedema attacks per month in the placebo group was 4.0; for the lanadelumab groups, 3.2 for the every-4-week 150-mg group; 3.7 for the every-4-week 300-mg group; and 3.5 for the every-2-week 300-mg group. During the treatment period, the mean number of attacks per month for the placebo group was 1.97; for the lanadelumab groups, 0.48 for the every-4-week 150-mg group; 0.53 for the every-4-week 300-mg group; and 0.26 for the every-2-week 300-mg group. Compared with placebo, the mean differences in the attack rate per month were -1.49 (95% CI, -1.90 to -1.08; P <.001); -1.44 (95% CI, -1.84 to -1.04; P <.001); and -1.71 (95% CI, -2.09 to -1.33; P <.001). The most commonly occurring adverse events with greater frequency in the lanadelumab treatment groups were injection site reactions (34.1% placebo, 52.4% lanadelumab) and dizziness (0% placebo, 6.0% lanadelumab). Conclusions and Relevance: Among patients with hereditary angioedema type I or II, treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo. These findings support the use of lanadelumab as a prophylactic therapy for hereditary angioedema. Further research is needed to determine long-term safety and efficacy. Trial Registration: EudraCT Identifier: 2015-003943-20; ClinicalTrials.gov Identifier: NCT02586805

Search For Poliovirus Carriers Among People With Primary Immune Deficiency Diseases In The United States, Mexico, Brazil, And The United Kingdom

Objective: To estimate the rate of long-term poliovirus excretors in people known to have B-cell immune deficiency disorders. Methods: An active search for chronic excretors was conducted among 306 persons known to have immunoglobulin G (IgG) deficiency in the United States, Mexico, Brazil, and the United Kingdom, and 40 people with IgA deficiency in the United States. Written informed consent or assent was obtained from the participants or their legal guardians, and the studies were formally approved. Stool samples were collected from participants and cultured for polioviruses. Calculation of the confidence interval for the proportion of participants with persistent poliovirus excretion was based on the binomial distribution. Findings: No individuals with long-term excretion of polioviruses were identified. Most participants had received oral poliovirus vaccine (OPV) and almost all had been exposed to household contacts who had received OPV. Polioviruses of recent vaccine origin were transiently found in four individuals in Mexico and Brazil, where OPV is recommended for all children. Conclusion: Although chronic poliovirus excretion can occur in immunodeficient persons, it appears to be rare.82138Benyesh-Melnick, M., Melnick, J.L., Rawls, W.E., Wimberly, I., Oro, J.B., Ben-Porath, E., Studies of the immunogenicity, communicability and genetic stability of oral poliovaccine administered during the winter (1967) American Journal of Epidemiology, 86, pp. 112-136Melnick, J.L., Benyesh-Melnick, M., Brennan, J.C., Studies on live poliovirus vaccines. Its neurotropic activity in monkeys and its increased neurovirulence after multiplication in vaccinated children (1959) JAMA, 171, pp. 1165-1172Gelfand, H.M., Potash, L., LeBlanc, D.R., Fox, J.P., Revised preliminary report on the Louisiana observations of the natural spread within families of living vaccine strains of poliovirus (1959) Live Poliovirus Vaccines: Papers Presented and Discussions Held at the First International Conference on Live Poliovirus Vaccines, , Special Publication No. 44. Washington (DC): Pan American Sanitary BureauFox, J.P., Gelfand, H.M., LeBlanc, D.R., Potash, L., Clemmer, D.I., LaPenta, D., The spread of vaccine strains of poliovirus in the household and in the community in southern Louisiana (1961) International Poliomyelitis Congress, Ed. Poliomyelitis: Papers and Discussions Presented at the Fifth International Poliomyelitis Conference, pp. 368-383. , Philadelphia: LippincottSutter, R.W., Cochi, S.L., Melnick, J.L., Live attenuated poliovirus vaccines (1999) Vaccines, 3rd Ed., pp. 364-408. , Plotkin SA, Orenstein WA, editors. Philadelphia: WB SaundersModlin, J.F., Coxsackieviruses, echoviruses, and newer enteroviruses (2000) Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 5th Ed., pp. 1904-1919. , Mandell GL, Bennett JE, Dolin R, editors. Philadelphia (PA): Churchill-LivingstoneWood, D.J., Sutter, R.W., Dowdle, W.R., Stopping poliovirus vaccination after eradication: Issues and challenges (2000) Bulletin of the World Health Organization, 78, pp. 347-357Kew, O.M., Sutter, R.W., Nottay, B.K., McDonough, M.J., Prevots, D.R., Quick, L., Prolonged replication of a type 1 vaccine-derived poliovirus in an immunodeficient patient (1998) Journal of Clinical Microbiology, 36, pp. 2893-2899Buttinelli, G., Donati, V., Fiore, S., Marturano, J., Plebani, A., Balestri, P., Nucleotide variation in Sabin type 2 poliovirus from an immunodeficient patient with poliomyelitis (2003) Journal of General Virology, 84, pp. 1215-1221John, T.J., Walker, D.H., Enterovirus infections, including poliomyelitis (1999) Tropical Infectious Diseases, Principles, Pathogens, and Practice, pp. 1123-1132. , Guerrant RL, Walker DH, Weller PF, editors. Philadelphia: Churchill LivingstoneMinor, P., Characteristics of poliovirus strains from long-term excretors with primary immunodeficiencies (2001) Developmental Biology, 105, pp. 75-80Minor, P.D., Ferguson, J.A., Icenogle, J.P., Antigenic and molecular evolution of the vaccine strain of type 3 poliovirus during the period of excretion by a primary vaccinee (1986) Journal of General Virology, 67, pp. 693-706Dunn, G., Begg, N.T., Cammack, N., Minor, P.D., Virus excretion and mutation by infants following primary vaccination with live oral poliovaccine from two sources (1990) Journal of Medical Virology, 32, pp. 92-95Sutter, R.W., Tangermann, R.H., Aylward, R.B., Cochi, S.L., Poliomyelitis eradication: Progress, challenges for the end game, and preparation for the post-eradication era (2001) Infectious Disease Clinics of North America, 15, pp. 41-64Conley, M.E., Notarangelo, L.D., Etzioni, A., Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and eSID (European Society for Immunodeficiencies) (1999) Clinical Immunology, 93, pp. 190-197(1997) Manual of the Virological Investigation of Poliomyelitis, , Geneva: World Health Organization. WHO document WHO/EPI/GEN/9701Liu, H.M., Zheng, D.P., Zhang, L.B., Oberste, M.S., Pallansch, M.A., Kew, O.M., Molecular evolution of a type 1 wild-vaccine poliovirus recombinant during widespread circulation in China (2000) Journal of Virology, 74, pp. 11153-11161Savilahti, E., Klemola, T., Carlsson, B., Mellander, L., Stenvik, M., Hovi, T., Inadequacy of mucosal IgM antibodies in selective IgA deficiency excretion of attenuated polio viruses is prolonged (1988) Journal of Clinical Immunology, 8, pp. 89-94Triki, H., Barbouche, M.R., Bahri, O., Bejaoui, M., Dellagi, K., Community-acquired poliovirus infection in children with primary immunodeficiency in Tunisia (2003) Journal of Clinical Microbiology, 41, pp. 1203-1211Hammon, W.D., Coriell, L.L., Wehrle, P.F., Stokes, J., Evaluation of Red Cross gammaglobulin as a prophylactic agent for poliomyelitis. 4. Final report of results based on clinical diagnosis (1953) JAMA, 151, pp. 1272-1285Halliday, E., Winkelstein, J., Webster, A.D., Enteroviral infections in primary immunodeficiency (PID): A survey of morbidity and mortality (2003) The Journal of Infection, 46, pp. 1-8Buttinelli, G., Donati, V., Fiore, S., Marturano, J., Plebani, A., Balestri, P., Nucleotide variation in Sabin type 2 poliovirus from an immunodeficient patient with poliomyelitis (2003) Journal of General Virology, 84, pp. 1215-1221Cunningham-Rundles, C., Bodian, C., Common variable immunodeficiency: Clinical and immunological features of 248 patients (1999) Clinical Immunology, 92, pp. 34-48Kew, O., Morris-Glasgow, V., Landaverde, M., Burns, C., Shaw, J., Garib, Z., Outbreak of poliomyelitis in Hispaniola associated with circulating type 1 vaccine-derived poliovirus (2002) Science, 296, pp. 356-359Halsey, N.A., Commentary: Poliomyelitis and unnecessary injections (2003) International Journal of Epidemiology, 32, pp. 278-279Halsey, N.A., Combination vaccines: Defining and addressing current safety concerns (2001) Clinical Infectious Diseases, 33 (SUPPL. 4), pp. S312-S31

Prevention of hereditary angioedema attacks with a subcutaneous C1 inhibitor

BACKGROUND: Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS: We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (\ue2\u89\ua550% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS: Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. CONCLUSIONS: In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks