Nanofiltered C1 esterase inhibitor for treatment of laryngeal attacks in patients with hereditary angioedema Marc A. Riedl, M.D., M.S.,1 William R. Lumry, M.D.,2 H. Henry Li, M.D., Ph.D.,3 Timothy J. Craig, D.O.,4 David Fitts, M.P.H., Ph.D.,5 Ira Kalfus, M.D.,6 and Marc E. Uknis, M.D.7
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ABSTRACT
Background: Laryngeal edema is a life-threatening manifestation of hereditary angioedema (HAE), an autosomal-dominant disorder caused by quantitative or functional C1 esterase inhibitor (C1 INH) deficiency. The preparation of nanofiltered C1 INH (C1 INH-nf) used in this study is indicated for routine prophylaxis against angioedema attacks in the United States and for treatment, preprocedure prevention, and routine prevention of HAE in Europe. The objective of this analysis was to evaluate the effectiveness and tolerability of C1 INH-nf when used for the treatment of laryngeal attacks. Methods: A post hoc analysis of an open-label treatment study evaluated the effectiveness of C1 INH-nf in the treatment of laryngeal attacks in patients with HAE. Outcomes included unequivocal or clinical relief rates and time from treatment to onset of relief. Data were compiled from this and three other studies for post hoc dosing and tolerability analyses. In all studies, C1 INH-nf at 1000 U was administered i.v., with a second 1000-U dose given after 60 minutes if indicated. Results: In the open-label treatment study, 60 (50/84) and 77% (65/84) of attacks achieved unequivocal relief within 1 and 4 hours, respectively, after treatment. Time to unequivocal relief was shorter with prompt treatment. When C1 INH-nf was administered within 4 hours of symptom onset, clinical relief was achieved in 94% (45/48) of attacks within 4 hours after treatment. Of 265 attacks from the four studies, 62% received two 1000-U doses of C1 INH-nf. No serious adverse events occurring within 7 days after treatment were attributed to study drug, and only one patient required intubation after receiving C1 INH-nf (14.5 hours after symptom onset). Conclusion: This analysis supports that C1 INH-nf is an effective and well-tolerated therapy for laryngeal angioedema attacks. (Am J Rhinol Allergy 27, 517–521, 2013; doi: 10.2500/ajra.2013.27.3973)
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ereditary angioedema (HAE; types I and II) is a serious, debilitating disease caused by a functional or quantitative C1 esterase inhibitor (C1 INH) deficiency due to an autosomal-dominant mutation in the C1INH gene.1 Angioedema attacks are characterized by intermittent episodes of localized edema at various body sites, including the face, extremities, and abdomen. Angioedema of the upper airways (referred to as laryngeal edema or laryngeal attacks in the remainder of this article) is a potentially fatal manifestation of HAE.2 Although laryngeal attacks are uncommon, comprising 0.9% of
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From the 1Department of Clinical Immunology and Allergy, University of California– Los Angeles, David Geffen School of Medicine, Los Angeles, California, 2Allergy and Asthma Research Association Research Center, Dallas, Texas, 3Department of Immunology, Institute for Asthma and Allergy, Chevy Chase, Maryland, 4Department of Medicine and Department of Pediatrics, Penn State University College of Medicine, Hershey, Pennsylvania, 5ViroPharma, Inc., Exton, Pennsylvania, 6M2G Consulting, New York, New York, and 7ViroPharma, Inc., Exton, Pennsylvania Funded by ViroPharma, Inc. (Exton, PA) Current address for MA Riedl is University of California–San Diego, California MA Riedl was a consultant and/or speaker for ViroPharma Incorporated, CSL Behring, Dyax, Shire, Isis, and BioCryst; his institution received research funding from ViroPharma Incorporated for this study and has received research funding from Pharming, CSL Behring, Dyax, and Shire. WR Lumry was as a consultant and speaker for CSL Behring, Dyax, Shire, and ViroPharma Incorporated and has received research funding from CSL Behring, Dyax, Pharming, Shire, and ViroPharma Incorporated. HH Li received travel funding from ViroPharma Incorporated for this study and has served as a consultant and speaker for ViroPharma Incorporated, CSL Behring, Shire, and Dyax; his institution received research funding for this study. TJ Craig was a consultant for CSL Behring and a speaker for ViroPharma Incorporated, CSL Behring, Shire, and Dyax; his institution received an educational grant from Dyax and ViroPharma Incorporated and has received research funding from CSL Behring, ViroPharma Incorporated, Shire, Dyax, and Pharming. I Kalfus is the former Vice President of Medical Affairs for Lev Pharmaceuticals (original sponsor of nanofiltered study drug acquired by ViroPharma Incorporated) and was a consultant for ViroPharma Incorporated. D Fitts and ME Uknis are full-time employees of ViroPharma Incorporated; employee compensation includes stock options awards. Address correspondence to Marc A. Riedl, M.D., M.S., 9500 Gilman Drive, Mail Code 0732, Stein Clinical Research Building, Room 205, La Jolla, CA 92093-0732 E-mail address: [email protected] Copyright © 2013, OceanSide Publications, Inc., U.S.A.
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all attacks, approximately one-half of all HAE patients experience laryngeal edema during their lifetime.3 Historical data suggest that before the availability of treatment and prevention options, mortality from asphyxiation was as high as 30% in patients with HAE.4,5 A recent retrospective study reflects a similarly high mortality rate in HAE patients, especially in those who are undiagnosed.6 Of the patients who died from asphyxiation during a laryngeal attack, 90% were previously undiagnosed. Nevertheless, 10% of patients who died from laryngeal attacks had an established diagnosis of HAE. In an era during which effective therapies exist, there is an ongoing need to educate health care providers about HAE and the treatment of laryngeal or airway involvement. Evidence-based recommendations for the treatment of angioedema attacks include administration of C1 INH concentrate, ecallantide, a kallikrein inhibitor, and icatibant, a bradykinin B2-receptor antagonist.7,8 Currently, there are limited data on treatment options and outcomes for laryngeal angioedema attacks. The preparation of nanofiltered C1 INH (C1 INH-nf; human; Cinryze; ViroPharma, Inc., Exton, PA) used in this study is currently approved in the United States and Canada for routine prophylaxis against angioedema attacks9 and approved in Europe for treatment, preprocedure prevention, and routine prevention of angioedema attacks.10 In the phase 3 development studies for Cinryze, subjects who presented with laryngeal attacks were treated with open-label C1 INH-nf. The objective of this analysis was to evaluate the effectiveness and tolerability of C1 INH-nf when it was used specifically for the treatment of laryngeal attacks.
METHODS Clinical Effectiveness The clinical protocol, protocol amendments, and informed consent forms were reviewed and approved by an Independent Ethics Committee/Institutional Review Board for each investigative site. A post hoc analysis of an open-label treatment study (LEVP 2006-1; clinicaltrials.gov identifier: NCT00438815)11 was conducted to evaluate the effectiveness of C1 INH-nf specifically for the treatment of laryngeal attacks. In this open-label treatment study, subjects could receive
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517
Minutes to Unequivocal Relief
240
180
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120
60
0 ≤2 Hours
>2, ≤3 Hours
>3, ≤4 Hours
Time From HAE Laryngeal Attack Onset to First Infusion 1 Infusion
≥2 Infusions
Median Time to Beginning of Relief (minutes)
treatment for multiple attacks; qualifying attacks included all laryngeal attacks and moderate or severe gastrointestinal, facial, genitourinary, or extremity attacks. Per protocol, subjects were to report to the study center for treatment within 4 hours from onset of an attack, although this was not always possible. Subjects received a 1000-U i.v. injection of C1 INH-nf, which could have been repeated 60 minutes later if there was no substantial relief. After receiving C1 INH-nf, subjects rated their symptom relief every 15 minutes postinfusion (up to 4 hours) or until substantial relief of symptoms was achieved. Subjects were monitored during this time, and additional supportive treatment (e.g., intubation) was provided if needed. After collection of a 60-minute postinfusion blood sample, subjects could have been discharged home by the investigator if deemed clinically appropriate. If subjects received a second dose, discharge was allowed 30 minutes after the second infusion, after measurement of vital signs and investigator approval. For the purpose of this analysis, clinical effectiveness was measured by the percentage of subjects who achieved “unequivocal relief” or “clinical relief,” as well as the time to onset of relief. Unequivocal relief of the laryngeal attack was defined as at least three consecutive reports that symptoms were “present, symptoms better,” “absent but present before,” or “absent now and before.” Clinical relief was defined as one or more assessment of improvement followed by cessation of symptom assessment due to patient discharge by the investigator. The first assessment of improvement represented beginning of relief.
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>4 Hours
Figure 1. Minutes to beginning of unequivocal relief by time from attack onset to initial treatment (open-label treatment study [LEVP 2006-1]).
Data were collected in all studies about the number of infusions needed to treat each laryngeal attack and the time from attack onset to initiation of treatment. Determination of clinical effectiveness was confined to the openlabel treatment study (LEVP 2006-1) subjects in whom symptom relief was recorded per protocol. Because laryngeal attacks were excluded from randomization in the placebo-controlled treatment study (LEVP 2005-1/A) and were not the subject of end point analyses in the prevention studies (LEVP 2005-1/B, LEVP 2006-4), data on time to attack resolution were not systematically collected. Therefore, in this analysis, laryngeal attacks treated with C1 INH-nf in these three studies were evaluated for dosing and tolerability only. Notably, in all four studies, treatment failures for laryngeal attacks would have been reported as serious adverse events (SAEs; e.g., intubation and/or hospitalization for observation) per standards of Good Clinical Practice; hence, analysis of safety data also provides valuable information on the overall effectiveness of therapy. Tolerability was further evaluated based on the number and type of SAEs that occurred within 7 days after treatment of the laryngeal attack. Formal statistical analyses were not performed on these subgroup data, and all data summaries are descriptive.
RESULTS A total of 85 unique subjects experienced 267 laryngeal attacks and received C1 INH-nf across the four studies; the number of subjects was adjusted for overlapping patient participation across studies.
Dosing and Tolerability
Clinical Effectiveness
Dosing and tolerability data were evaluated for HAE subjects treated for laryngeal attacks from four different studies: a placebocontrolled treatment study (LEVP 2005-1/A; clinicaltrials.gov identifier: NCT00289211), a placebo-controlled prevention study (LEVP 2005-1/B; clinicaltrials.gov identifier: NCT01005888), the open-label treatment study described previously, and an open-label prevention study (LEVP 2006-4; clinicaltrials.gov identifier: NCT00462709).11–13 In all four studies, subjects were to report to the study center within 4 hours from onset of any attack. Laryngeal attacks were treated with open-label C1 INH-nf with the same dosing as described previously.
In the open-label treatment study (LEVP 2006-1), 37 subjects experienced 84 separate laryngeal attacks. Of the laryngeal attacks treated with C1 INH-nf, 60% (50/84) achieved unequivocal relief within 1 hour of the initial dose and 77% (65/84) achieved unequivocal relief within 4 hours of the initial dose. Of these 84 attacks, 37 received a second dose. Time to unequivocal relief was shorter when treatment was given promptly. When C1 INH-nf was administered ⬎4 hours after symptom onset (n ⫽ 32), the majority of patients required two or more infusions (n ⫽ 20) and the median time to beginning of unequivocal relief for these patients was 180 minutes (Fig. 1).
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Figure 2. Response rate within 4 hours after start of the first dose of nanofiltered C1 esterase inhibitor (C1 INH-nf) and time to beginning of unequivocal relief by attack number (open-label treatment study [LEVP 2006-1]). aResponse rate—number of subjects with unequivocal relief within 4 hr/number of subjects with attacks ⫻100. b Represents the number of subjects with the corresponding number of laryngeal hereditary angioedema (HAE) attacks. cTime from initial infusion to the first of at least three consecutive reports of symptom relief.
Response Rate Within 4 Hours (%)a
100 90
84
80
80
75
75 67
70 60
3
4
10
6
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38
75
23
50 40 30 20 10
0 Laryngeal Attack Number Number of Subjectsb Median Time to Beginning of Relief (min)c
1
2
37
16
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30
100
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80 70
Proportion (%)
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75
57
54
47
50
4
≥2 Infusionsa
1 Infusion
90
60
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5
46
43
40
25
30 20 10
Figure 3. Proportion of laryngeal hereditary angioedema (HAE) attacks treated with one or two or more infusions, by time from onset of attack to initial treatment (all studies; n ⫽ 262 laryngeal attacks). aSix attacks were treated with more than two infusions. bPrecise time of onset of the attack was not available for five laryngeal attacks.
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N=34 N=30
N=15 N=13
N=20 N=26
N=31 N=93
≤2 Hours
>2, ≤3 Hours
>3, ≤4 Hours
>4 Hours
0
Time From HAE Laryngeal Attack Onset to First Infusion Number (%) of Laryngeal Attacks Treated Within Each Timeframe (n=262)b
64 (24)
Response rates and times to unequivocal relief were similar with increasing numbers of attacks; C1 INH-nf remained an effective treatment despite repeated use for laryngeal attacks. After their first laryngeal attack, 31 of 37 subjects (84%) achieved unequivocal relief within 4 hours after the start of the first dose of C1 INH-nf, and the median time to beginning of unequivocal relief was 60 minutes. For subjects with multiple separate laryngeal attacks (n ⫽ 16), the response rate for the second attack was 75%, and the median time to beginning of unequivocal relief was 30 minutes (Fig. 2). Data for clinical relief were obtained for 78 of the 84 laryngeal attacks in the open-label treatment study, and clinical relief was achieved in 65% (51/78) of attacks within 1 hour of the initial dose and 90% (70/78) of attacks within 4 hours of the initial dose. Of these 78 attacks, 33 received a second dose. Prompt C1 INH-nf administra-
28 (11)
46 (18)
124 (47)
tion increased clinical relief rates. Of the 49 attacks treated within 4 hours of symptom onset, 48 had outcomes reported. The rates of clinical relief achieved within 1 and 4 hours after treatment were 71 (34/48) and 94% (45/48), respectively.
Dosing Dosing data were available for 265/267 laryngeal attacks in 85 unique subjects across the four studies. Of these, 38% (101/265) were treated with one dose (1000 U) of C1 INH-nf. The majority (62% [164/265]) of laryngeal attacks were treated with two or more doses of C1 INH-nf. Analyses for time to initiation of treatment across all four studies were conducted on 262/267 laryngeal attacks; the precise times of onset of attack were not available for five laryngeal attacks.
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A delay in treatment after attack onset was associated with the need for multiple doses of C1 INH-nf for symptom relief. Of the 262 laryngeal attacks, 47% (124/262) were treated ⬎4 hours after attack onset, and 75% (93/124) of these attacks required two or more infusions to respond to treatment (Fig. 3). When subjects were treated within 4 hours of symptom onset, the proportions of subjects receiving one or two or more infusions of C1 INH-nf were similar (Fig. 3).
Tolerability
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Across the four studies, a total of 14 subjects experienced SAEs within 7 days after treatment of the laryngeal attack. None of the SAEs were reported to be related to study drug, and no subjects discontinued study treatment as a result of an SAE. Only one subject required intubation after being treated with C1 INH-nf. This subject received two doses of C1 INH-nf for treatment of a laryngeal attack. The first infusion was administered 14.5 hours after attack onset, and the second dose was administered 1 hour after the first dose. All attacks in this study were graded by the investigator as mild, moderate, or severe, and this particular attack was graded as “severe” on presentation. On the day after treatment, the subject had decompensation of his airway and was intubated. The subject was extubated 2 days later. No subjects required surgical intervention, such as cricothyrotomy or tracheotomy.
DISCUSSION Data are limited regarding the therapeutic options for laryngeal attacks, a life-threatening manifestation of HAE that occurs at least once in about one-half of HAE patients during their lifetime.3 This analysis of patients treated with C1 INH-nf for laryngeal attacks provides insight on the tolerability and clinical effectiveness of C1 INH-nf for this potentially life-threatening type of attack. Previous reports have shown C1 INH to maintain effectiveness in the treatment of angioedema attacks despite repeated administration.11,14 Similar to its effectiveness in angioedema attacks at other anatomic sites in the open-label treatment study,11 C1 INH-nf was shown to be effective in treating laryngeal angioedema attacks and remained effective even after repeated use to treat subsequent attacks. Compared with the proportion of all attacks treated with C1 INH-nf that achieved unequivocal relief within 1 and 4 hours after initiation of treatment (68 [412/609] and 87% [529/609], respectively),11 a smaller proportion of laryngeal attacks achieved unequivocal relief within 1 and 4 hours after the first treatment dose (60 and 77%, respectively). It may be that laryngeal edema is a more severe form of angioedema attack, evokes more concern on the part of the treating physician and/or patient, or, more likely, a combination. In the aforementioned open-label treatment study, laryngeal and facial attacks had lower response rates (77 and 75%, respectively) within 4 hours compared with response rates for gastrointestinal (90%), genitourinary (100%), or extremity attacks (92%).11 The responsiveness of a patient to C1 INH-nf treatment may be correlated with the timeliness of drug administration after onset of a laryngeal attack. When treatment was initiated ⬎4 hours after attack onset, the majority of attacks (75%) required a second 1000-U dose of C1 INH-nf. It is possible that higher doses of C1 INH may be necessary to treat some patients, particularly those with delayed presentation for treatment. In a placebo-controlled study, 20 U/kg of another C1 INH concentrate showed more rapid onset of relief compared with 10-U/kg dosing in the treatment of facial and abdominal angioedema attacks.15 An open-label extension study confirmed the efficacy of 20-U/kg dosing of C1 INH.16 Although 1000 U of C1 INH-nf has been used effectively in clinical trials in the treatment of angioedema attacks,11–13 62% of laryngeal attacks in the four studies required more than one 1000-U dose of C1 INH-nf. Therefore, the authors believe it is reasonable to consider earlier administration of a second dose or starting with a higher dose, especially if administration is delayed beyond 4 hours.
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Consensus statements from the Hereditary Angioedema International Working Group and the World Allergy Organization confirm that patients should be taught how to self-administer C1 INH for prompt treatment of attacks.7,8 The World Allergy Organization strongly recommends that patients with HAE prepare an action plan and carry on-demand medication to treat an angioedema attack because all attacks should be treated as early as possible. In particular, treatment of attacks involving the upper airways is essential.8 Clinical experience has shown that the progression of laryngeal edema is unpredictable, and patients may benefit from being prepared for emergency situations.17 Guidelines recommend that patients report immediately to the hospital if laryngeal symptoms persist after initial treatment.7 Because of the potential lethal nature of laryngeal attacks, the authors recommend that all HAE patients who experience laryngeal or facial edema be evaluated promptly by a medical professional, even if C1 INH or any other treatment is self-administered. None of the SAEs occurring within 7 days after treatment of a laryngeal attack were considered related to the study drug. Of the 267 laryngeal attacks documented in the four studies, in only one attack did the subject require intubation after being treated. Notably, this attack was not treated with C1 INH-nf until 14.5 hours after the onset of symptoms. Throughout this subject’s participation in the study, he was treated for a total of six laryngeal angioedema attacks outside the protocol-defined window of 4 hours from onset of symptoms. For all attacks in the open-label treatment study,11 none of the treatmentemergent SAEs were attributed to the study drug. Of the nonserious adverse events, two events (injection site pain and rash) were possibly related to the study drug, but were of mild or moderate intensity. The subjects in this study tolerated C1 INH-nf infusions well. A limitation of this post hoc analysis is that the development program was not specifically designed to evaluate laryngeal angioedema attacks. In fact, subjects presenting with laryngeal attacks were not eligible to be randomized in the pivotal treatment study. In a lifethreatening indication such as laryngeal edema, it would have been unethical to perform a placebo-controlled trial. Although patients enrolled in this development program received open-label C1 INH-nf for laryngeal edema, data compiled from these studies provide valuable information on the effectiveness of C1 INH-nf for treating laryngeal attacks of HAE.
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CONCLUSIONS Results from this subset analysis of HAE patients with laryngeal edema treated in a clinical trial setting indicate that C1 INH-nf is generally well tolerated and is a clinically effective therapy for laryngeal angioedema attacks.
ACKNOWLEDGMENTS Grace H. Lee, Pharm.D., of Scientific Therapeutics Information, Inc. (Madison, NJ) provided writing and editorial assistance in the preparation of the article but did not meet the criteria for authorship.
REFERENCES 1. 2. 3.
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Zuraw BL. Clinical practice: Hereditary angioedema. N Engl J Med 359:1027–1036, 2008. Lumry WR. Hereditary angioedema: A case of near fatal laryngeal swelling in a 41-year-old woman. Allergy Asthma Proc 32(suppl 1):S13–-S15, 2011. Bork K, Meng G, Staubach P, et al. Hereditary angioedema: New findings concerning symptoms, affected organs, and course. Am J Med 119:267–274, 2006. Frank MM, Gelfand JA, and Atkinson JP. Hereditary angioedema: The clinical syndrome and its management. Ann Intern Med 84:580– 593, 1976. Zilberberg MD, Nathanson BH, Jacobsen T, et al. Descriptive epidemiology of hereditary angioedema hospitalizations in the United States, 2004–2007. Allergy Asthma Proc 32:248–254, 2011.
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8. 9. 10. 11.
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Bork K, Hardt J, and Witzke G. Fatal laryngeal attacks and mortality in hereditary angioedema due to C1-INH deficiency. J Allergy Clin Immunol 130:692–697, 2012. Cicardi M, Bork K, Caballero T, et al, on behalf of HAWK (Hereditary Angioedema International Working Group). Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: Consensus report of an International Working Group. Allergy 67:147–157, 2012. Craig T, Aygo¨ren Pu¨rsu¨n E, Bork K, et al. WAO guideline for the management of hereditary angioedema. WAO J 5:182–199, 2012. ViroPharma Biologics, Inc. Cinryze package insert. Exton, PA; 2012. ViroPharma SPRL. Cinryze summary of product characteristics. Brussels, Belgium; 2011. Riedl MA, Hurewitz DS, Levy R, et al. Nanofiltered C1 esterase inhibitor (human) for the treatment of acute attacks of hereditary angioedema: An open-label trial. Ann Allergy Asthma Immunol 108:49–53, 2012. Zuraw BL, and Kalfus I. Safety and efficacy of prophylactic nanofiltered C1-inhibitor in hereditary angioedema. Am J Med 125:938.e1–938.e7, 2012.
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Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med 363:513–522, 2010. Craig TJ, Bewtra AK, Hurewitz D, et al. Treatment response after repeated administration of C1 esterase inhibitor for successive acute hereditary angioedema attacks. Allergy Asthma Proc 33:354–361, 2012. Craig TJ, Levy RJ, Wasserman RL, et al. Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol 124:801– 808, 2009. Craig TJ, Bewtra AK, Bahna SL, et al. C1 esterase inhibitor concentrate in 1085 hereditary angioedema attacks: Final results of the I.M.P.A.C.T. 2 study. Allergy 66:1604–1611, 2011. Bewtra AK, Levy RJ, Jacobson KW, et al. C1-inhibitor therapy for hereditary angioedema attacks: Prospective patient assessments of health-related quality of life. Allergy Asthma Proc 33:427–431, 2012. e
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ABSTRACT
Background: Laryngeal edema is a life-threatening manifestation of hereditary angioedema (HAE), an autosomal-dominant disorder caused by quantitative or functional C1 esterase inhibitor (C1 INH) deficiency. The preparation of nanofiltered C1 INH (C1 INH-nf) used in this study is indicated for routine prophylaxis against angioedema attacks in the United States and for treatment, preprocedure prevention, and routine prevention of HAE in Europe. The objective of this analysis was to evaluate the effectiveness and tolerability of C1 INH-nf when used for the treatment of laryngeal attacks. Methods: A post hoc analysis of an open-label treatment study evaluated the effectiveness of C1 INH-nf in the treatment of laryngeal attacks in patients with HAE. Outcomes included unequivocal or clinical relief rates and time from treatment to onset of relief. Data were compiled from this and three other studies for post hoc dosing and tolerability analyses. In all studies, C1 INH-nf at 1000 U was administered i.v., with a second 1000-U dose given after 60 minutes if indicated. Results: In the open-label treatment study, 60 (50/84) and 77% (65/84) of attacks achieved unequivocal relief within 1 and 4 hours, respectively, after treatment. Time to unequivocal relief was shorter with prompt treatment. When C1 INH-nf was administered within 4 hours of symptom onset, clinical relief was achieved in 94% (45/48) of attacks within 4 hours after treatment. Of 265 attacks from the four studies, 62% received two 1000-U doses of C1 INH-nf. No serious adverse events occurring within 7 days after treatment were attributed to study drug, and only one patient required intubation after receiving C1 INH-nf (14.5 hours after symptom onset). Conclusion: This analysis supports that C1 INH-nf is an effective and well-tolerated therapy for laryngeal angioedema attacks. (Am J Rhinol Allergy 27, 517–521, 2013; doi: 10.2500/ajra.2013.27.3973)
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ereditary angioedema (HAE; types I and II) is a serious, debilitating disease caused by a functional or quantitative C1 esterase inhibitor (C1 INH) deficiency due to an autosomal-dominant mutation in the C1INH gene.1 Angioedema attacks are characterized by intermittent episodes of localized edema at various body sites, including the face, extremities, and abdomen. Angioedema of the upper airways (referred to as laryngeal edema or laryngeal attacks in the remainder of this article) is a potentially fatal manifestation of HAE.2 Although laryngeal attacks are uncommon, comprising 0.9% of
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From the 1Department of Clinical Immunology and Allergy, University of California– Los Angeles, David Geffen School of Medicine, Los Angeles, California, 2Allergy and Asthma Research Association Research Center, Dallas, Texas, 3Department of Immunology, Institute for Asthma and Allergy, Chevy Chase, Maryland, 4Department of Medicine and Department of Pediatrics, Penn State University College of Medicine, Hershey, Pennsylvania, 5ViroPharma, Inc., Exton, Pennsylvania, 6M2G Consulting, New York, New York, and 7ViroPharma, Inc., Exton, Pennsylvania Funded by ViroPharma, Inc. (Exton, PA) Current address for MA Riedl is University of California–San Diego, California MA Riedl was a consultant and/or speaker for ViroPharma Incorporated, CSL Behring, Dyax, Shire, Isis, and BioCryst; his institution received research funding from ViroPharma Incorporated for this study and has received research funding from Pharming, CSL Behring, Dyax, and Shire. WR Lumry was as a consultant and speaker for CSL Behring, Dyax, Shire, and ViroPharma Incorporated and has received research funding from CSL Behring, Dyax, Pharming, Shire, and ViroPharma Incorporated. HH Li received travel funding from ViroPharma Incorporated for this study and has served as a consultant and speaker for ViroPharma Incorporated, CSL Behring, Shire, and Dyax; his institution received research funding for this study. TJ Craig was a consultant for CSL Behring and a speaker for ViroPharma Incorporated, CSL Behring, Shire, and Dyax; his institution received an educational grant from Dyax and ViroPharma Incorporated and has received research funding from CSL Behring, ViroPharma Incorporated, Shire, Dyax, and Pharming. I Kalfus is the former Vice President of Medical Affairs for Lev Pharmaceuticals (original sponsor of nanofiltered study drug acquired by ViroPharma Incorporated) and was a consultant for ViroPharma Incorporated. D Fitts and ME Uknis are full-time employees of ViroPharma Incorporated; employee compensation includes stock options awards. Address correspondence to Marc A. Riedl, M.D., M.S., 9500 Gilman Drive, Mail Code 0732, Stein Clinical Research Building, Room 205, La Jolla, CA 92093-0732 E-mail address: [email protected] Copyright © 2013, OceanSide Publications, Inc., U.S.A.
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all attacks, approximately one-half of all HAE patients experience laryngeal edema during their lifetime.3 Historical data suggest that before the availability of treatment and prevention options, mortality from asphyxiation was as high as 30% in patients with HAE.4,5 A recent retrospective study reflects a similarly high mortality rate in HAE patients, especially in those who are undiagnosed.6 Of the patients who died from asphyxiation during a laryngeal attack, 90% were previously undiagnosed. Nevertheless, 10% of patients who died from laryngeal attacks had an established diagnosis of HAE. In an era during which effective therapies exist, there is an ongoing need to educate health care providers about HAE and the treatment of laryngeal or airway involvement. Evidence-based recommendations for the treatment of angioedema attacks include administration of C1 INH concentrate, ecallantide, a kallikrein inhibitor, and icatibant, a bradykinin B2-receptor antagonist.7,8 Currently, there are limited data on treatment options and outcomes for laryngeal angioedema attacks. The preparation of nanofiltered C1 INH (C1 INH-nf; human; Cinryze; ViroPharma, Inc., Exton, PA) used in this study is currently approved in the United States and Canada for routine prophylaxis against angioedema attacks9 and approved in Europe for treatment, preprocedure prevention, and routine prevention of angioedema attacks.10 In the phase 3 development studies for Cinryze, subjects who presented with laryngeal attacks were treated with open-label C1 INH-nf. The objective of this analysis was to evaluate the effectiveness and tolerability of C1 INH-nf when it was used specifically for the treatment of laryngeal attacks.
METHODS Clinical Effectiveness The clinical protocol, protocol amendments, and informed consent forms were reviewed and approved by an Independent Ethics Committee/Institutional Review Board for each investigative site. A post hoc analysis of an open-label treatment study (LEVP 2006-1; clinicaltrials.gov identifier: NCT00438815)11 was conducted to evaluate the effectiveness of C1 INH-nf specifically for the treatment of laryngeal attacks. In this open-label treatment study, subjects could receive
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517
Minutes to Unequivocal Relief
240
180
Y P
120
60
0 ≤2 Hours
>2, ≤3 Hours
>3, ≤4 Hours
Time From HAE Laryngeal Attack Onset to First Infusion 1 Infusion
≥2 Infusions
Median Time to Beginning of Relief (minutes)
treatment for multiple attacks; qualifying attacks included all laryngeal attacks and moderate or severe gastrointestinal, facial, genitourinary, or extremity attacks. Per protocol, subjects were to report to the study center for treatment within 4 hours from onset of an attack, although this was not always possible. Subjects received a 1000-U i.v. injection of C1 INH-nf, which could have been repeated 60 minutes later if there was no substantial relief. After receiving C1 INH-nf, subjects rated their symptom relief every 15 minutes postinfusion (up to 4 hours) or until substantial relief of symptoms was achieved. Subjects were monitored during this time, and additional supportive treatment (e.g., intubation) was provided if needed. After collection of a 60-minute postinfusion blood sample, subjects could have been discharged home by the investigator if deemed clinically appropriate. If subjects received a second dose, discharge was allowed 30 minutes after the second infusion, after measurement of vital signs and investigator approval. For the purpose of this analysis, clinical effectiveness was measured by the percentage of subjects who achieved “unequivocal relief” or “clinical relief,” as well as the time to onset of relief. Unequivocal relief of the laryngeal attack was defined as at least three consecutive reports that symptoms were “present, symptoms better,” “absent but present before,” or “absent now and before.” Clinical relief was defined as one or more assessment of improvement followed by cessation of symptom assessment due to patient discharge by the investigator. The first assessment of improvement represented beginning of relief.
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>4 Hours
Figure 1. Minutes to beginning of unequivocal relief by time from attack onset to initial treatment (open-label treatment study [LEVP 2006-1]).
Data were collected in all studies about the number of infusions needed to treat each laryngeal attack and the time from attack onset to initiation of treatment. Determination of clinical effectiveness was confined to the openlabel treatment study (LEVP 2006-1) subjects in whom symptom relief was recorded per protocol. Because laryngeal attacks were excluded from randomization in the placebo-controlled treatment study (LEVP 2005-1/A) and were not the subject of end point analyses in the prevention studies (LEVP 2005-1/B, LEVP 2006-4), data on time to attack resolution were not systematically collected. Therefore, in this analysis, laryngeal attacks treated with C1 INH-nf in these three studies were evaluated for dosing and tolerability only. Notably, in all four studies, treatment failures for laryngeal attacks would have been reported as serious adverse events (SAEs; e.g., intubation and/or hospitalization for observation) per standards of Good Clinical Practice; hence, analysis of safety data also provides valuable information on the overall effectiveness of therapy. Tolerability was further evaluated based on the number and type of SAEs that occurred within 7 days after treatment of the laryngeal attack. Formal statistical analyses were not performed on these subgroup data, and all data summaries are descriptive.
RESULTS A total of 85 unique subjects experienced 267 laryngeal attacks and received C1 INH-nf across the four studies; the number of subjects was adjusted for overlapping patient participation across studies.
Dosing and Tolerability
Clinical Effectiveness
Dosing and tolerability data were evaluated for HAE subjects treated for laryngeal attacks from four different studies: a placebocontrolled treatment study (LEVP 2005-1/A; clinicaltrials.gov identifier: NCT00289211), a placebo-controlled prevention study (LEVP 2005-1/B; clinicaltrials.gov identifier: NCT01005888), the open-label treatment study described previously, and an open-label prevention study (LEVP 2006-4; clinicaltrials.gov identifier: NCT00462709).11–13 In all four studies, subjects were to report to the study center within 4 hours from onset of any attack. Laryngeal attacks were treated with open-label C1 INH-nf with the same dosing as described previously.
In the open-label treatment study (LEVP 2006-1), 37 subjects experienced 84 separate laryngeal attacks. Of the laryngeal attacks treated with C1 INH-nf, 60% (50/84) achieved unequivocal relief within 1 hour of the initial dose and 77% (65/84) achieved unequivocal relief within 4 hours of the initial dose. Of these 84 attacks, 37 received a second dose. Time to unequivocal relief was shorter when treatment was given promptly. When C1 INH-nf was administered ⬎4 hours after symptom onset (n ⫽ 32), the majority of patients required two or more infusions (n ⫽ 20) and the median time to beginning of unequivocal relief for these patients was 180 minutes (Fig. 1).
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Figure 2. Response rate within 4 hours after start of the first dose of nanofiltered C1 esterase inhibitor (C1 INH-nf) and time to beginning of unequivocal relief by attack number (open-label treatment study [LEVP 2006-1]). aResponse rate—number of subjects with unequivocal relief within 4 hr/number of subjects with attacks ⫻100. b Represents the number of subjects with the corresponding number of laryngeal hereditary angioedema (HAE) attacks. cTime from initial infusion to the first of at least three consecutive reports of symptom relief.
Response Rate Within 4 Hours (%)a
100 90
84
80
80
75
75 67
70 60
3
4
10
6
Y P
38
75
23
50 40 30 20 10
0 Laryngeal Attack Number Number of Subjectsb Median Time to Beginning of Relief (min)c
1
2
37
16
60
30
100
T
80 70
Proportion (%)
O N 53
75
57
54
47
50
4
≥2 Infusionsa
1 Infusion
90
60
O C
5
46
43
40
25
30 20 10
Figure 3. Proportion of laryngeal hereditary angioedema (HAE) attacks treated with one or two or more infusions, by time from onset of attack to initial treatment (all studies; n ⫽ 262 laryngeal attacks). aSix attacks were treated with more than two infusions. bPrecise time of onset of the attack was not available for five laryngeal attacks.
O D
N=34 N=30
N=15 N=13
N=20 N=26
N=31 N=93
≤2 Hours
>2, ≤3 Hours
>3, ≤4 Hours
>4 Hours
0
Time From HAE Laryngeal Attack Onset to First Infusion Number (%) of Laryngeal Attacks Treated Within Each Timeframe (n=262)b
64 (24)
Response rates and times to unequivocal relief were similar with increasing numbers of attacks; C1 INH-nf remained an effective treatment despite repeated use for laryngeal attacks. After their first laryngeal attack, 31 of 37 subjects (84%) achieved unequivocal relief within 4 hours after the start of the first dose of C1 INH-nf, and the median time to beginning of unequivocal relief was 60 minutes. For subjects with multiple separate laryngeal attacks (n ⫽ 16), the response rate for the second attack was 75%, and the median time to beginning of unequivocal relief was 30 minutes (Fig. 2). Data for clinical relief were obtained for 78 of the 84 laryngeal attacks in the open-label treatment study, and clinical relief was achieved in 65% (51/78) of attacks within 1 hour of the initial dose and 90% (70/78) of attacks within 4 hours of the initial dose. Of these 78 attacks, 33 received a second dose. Prompt C1 INH-nf administra-
28 (11)
46 (18)
124 (47)
tion increased clinical relief rates. Of the 49 attacks treated within 4 hours of symptom onset, 48 had outcomes reported. The rates of clinical relief achieved within 1 and 4 hours after treatment were 71 (34/48) and 94% (45/48), respectively.
Dosing Dosing data were available for 265/267 laryngeal attacks in 85 unique subjects across the four studies. Of these, 38% (101/265) were treated with one dose (1000 U) of C1 INH-nf. The majority (62% [164/265]) of laryngeal attacks were treated with two or more doses of C1 INH-nf. Analyses for time to initiation of treatment across all four studies were conducted on 262/267 laryngeal attacks; the precise times of onset of attack were not available for five laryngeal attacks.
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A delay in treatment after attack onset was associated with the need for multiple doses of C1 INH-nf for symptom relief. Of the 262 laryngeal attacks, 47% (124/262) were treated ⬎4 hours after attack onset, and 75% (93/124) of these attacks required two or more infusions to respond to treatment (Fig. 3). When subjects were treated within 4 hours of symptom onset, the proportions of subjects receiving one or two or more infusions of C1 INH-nf were similar (Fig. 3).
Tolerability
Y P
Across the four studies, a total of 14 subjects experienced SAEs within 7 days after treatment of the laryngeal attack. None of the SAEs were reported to be related to study drug, and no subjects discontinued study treatment as a result of an SAE. Only one subject required intubation after being treated with C1 INH-nf. This subject received two doses of C1 INH-nf for treatment of a laryngeal attack. The first infusion was administered 14.5 hours after attack onset, and the second dose was administered 1 hour after the first dose. All attacks in this study were graded by the investigator as mild, moderate, or severe, and this particular attack was graded as “severe” on presentation. On the day after treatment, the subject had decompensation of his airway and was intubated. The subject was extubated 2 days later. No subjects required surgical intervention, such as cricothyrotomy or tracheotomy.
DISCUSSION Data are limited regarding the therapeutic options for laryngeal attacks, a life-threatening manifestation of HAE that occurs at least once in about one-half of HAE patients during their lifetime.3 This analysis of patients treated with C1 INH-nf for laryngeal attacks provides insight on the tolerability and clinical effectiveness of C1 INH-nf for this potentially life-threatening type of attack. Previous reports have shown C1 INH to maintain effectiveness in the treatment of angioedema attacks despite repeated administration.11,14 Similar to its effectiveness in angioedema attacks at other anatomic sites in the open-label treatment study,11 C1 INH-nf was shown to be effective in treating laryngeal angioedema attacks and remained effective even after repeated use to treat subsequent attacks. Compared with the proportion of all attacks treated with C1 INH-nf that achieved unequivocal relief within 1 and 4 hours after initiation of treatment (68 [412/609] and 87% [529/609], respectively),11 a smaller proportion of laryngeal attacks achieved unequivocal relief within 1 and 4 hours after the first treatment dose (60 and 77%, respectively). It may be that laryngeal edema is a more severe form of angioedema attack, evokes more concern on the part of the treating physician and/or patient, or, more likely, a combination. In the aforementioned open-label treatment study, laryngeal and facial attacks had lower response rates (77 and 75%, respectively) within 4 hours compared with response rates for gastrointestinal (90%), genitourinary (100%), or extremity attacks (92%).11 The responsiveness of a patient to C1 INH-nf treatment may be correlated with the timeliness of drug administration after onset of a laryngeal attack. When treatment was initiated ⬎4 hours after attack onset, the majority of attacks (75%) required a second 1000-U dose of C1 INH-nf. It is possible that higher doses of C1 INH may be necessary to treat some patients, particularly those with delayed presentation for treatment. In a placebo-controlled study, 20 U/kg of another C1 INH concentrate showed more rapid onset of relief compared with 10-U/kg dosing in the treatment of facial and abdominal angioedema attacks.15 An open-label extension study confirmed the efficacy of 20-U/kg dosing of C1 INH.16 Although 1000 U of C1 INH-nf has been used effectively in clinical trials in the treatment of angioedema attacks,11–13 62% of laryngeal attacks in the four studies required more than one 1000-U dose of C1 INH-nf. Therefore, the authors believe it is reasonable to consider earlier administration of a second dose or starting with a higher dose, especially if administration is delayed beyond 4 hours.
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520
Consensus statements from the Hereditary Angioedema International Working Group and the World Allergy Organization confirm that patients should be taught how to self-administer C1 INH for prompt treatment of attacks.7,8 The World Allergy Organization strongly recommends that patients with HAE prepare an action plan and carry on-demand medication to treat an angioedema attack because all attacks should be treated as early as possible. In particular, treatment of attacks involving the upper airways is essential.8 Clinical experience has shown that the progression of laryngeal edema is unpredictable, and patients may benefit from being prepared for emergency situations.17 Guidelines recommend that patients report immediately to the hospital if laryngeal symptoms persist after initial treatment.7 Because of the potential lethal nature of laryngeal attacks, the authors recommend that all HAE patients who experience laryngeal or facial edema be evaluated promptly by a medical professional, even if C1 INH or any other treatment is self-administered. None of the SAEs occurring within 7 days after treatment of a laryngeal attack were considered related to the study drug. Of the 267 laryngeal attacks documented in the four studies, in only one attack did the subject require intubation after being treated. Notably, this attack was not treated with C1 INH-nf until 14.5 hours after the onset of symptoms. Throughout this subject’s participation in the study, he was treated for a total of six laryngeal angioedema attacks outside the protocol-defined window of 4 hours from onset of symptoms. For all attacks in the open-label treatment study,11 none of the treatmentemergent SAEs were attributed to the study drug. Of the nonserious adverse events, two events (injection site pain and rash) were possibly related to the study drug, but were of mild or moderate intensity. The subjects in this study tolerated C1 INH-nf infusions well. A limitation of this post hoc analysis is that the development program was not specifically designed to evaluate laryngeal angioedema attacks. In fact, subjects presenting with laryngeal attacks were not eligible to be randomized in the pivotal treatment study. In a lifethreatening indication such as laryngeal edema, it would have been unethical to perform a placebo-controlled trial. Although patients enrolled in this development program received open-label C1 INH-nf for laryngeal edema, data compiled from these studies provide valuable information on the effectiveness of C1 INH-nf for treating laryngeal attacks of HAE.
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T
O C
CONCLUSIONS Results from this subset analysis of HAE patients with laryngeal edema treated in a clinical trial setting indicate that C1 INH-nf is generally well tolerated and is a clinically effective therapy for laryngeal angioedema attacks.
ACKNOWLEDGMENTS Grace H. Lee, Pharm.D., of Scientific Therapeutics Information, Inc. (Madison, NJ) provided writing and editorial assistance in the preparation of the article but did not meet the criteria for authorship.
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