Efficacy and Safety of Human Intravenous Immunoglobulin 10% (Panzyga®) in Patients with Primary Immunodeficiency Diseases: a Two-Stage, Multicenter, Prospective, Open-Label Study

Efficacy and Safety of Human Intravenous Immunoglobulin 10% (Panzyga®) in Patients with Primary... J Clin Immunol (2017) 37:603–612 DOI 10.1007/s10875-017-0424-4 ORIGINAL ARTICLE Efficacy and Safety of Human Intravenous Immunoglobulin 10% (Panzyga®) in Patients with Primary Immunodeficiency Diseases: a Two-Stage, Multicenter, Prospective, Open-Label Study 1,2 3 4 5 Michael Borte & Isaac R. Melamed & Grazyna Pulka & Barbara Pyringer & 6 7 8 9 Alan P. Knutsen & Hans D. Ochs & Roger H. Kobayashi & Ai Lan Kobayashi & 10 11 12 13 Sudhir Gupta & Magdalena Strach & William Smits & Anna Pituch-Noworolska & James N. Moy Received: 14 March 2017 /Accepted: 18 July 2017 /Published online: 29 July 2017 The Author(s) 2017. This article is an open access publication Abstract ment was associated with a higher rate of upper respiratory Purpose To assess the efficacy and safety of panzyga® (intra- tract infections (RTIs), ear infections, and work/school ab- venous immunoglobulin 10%) in preventing serious bacterial sences, but a lower rate of lower RTIs and fever. Treatment infections (SBIs) in patients with primary immunodeficiency was generally well tolerated; no AE led to treatment with- diseases (PIDs), a prospective, open-label, multicenter, phase drawal or death. 3 study and an open-label extension study were undertaken. Conclusions Overall, the use of panzyga® in patients with Methods Initially, the study drug (infusion rate ≤0.08 mL/kg/ antibody-deficient PID was associated with a low rate of min) was administered at intervals of 3 or 4 weeks for AEs and was effective in preventing SBIs, exceeding US 12 months, followed by 3 months of panzyga® at infusion FDA and European Medicines Agency recommendations for rates increasing from 0.08 to 0.14 mL/kg/min. The primary efficacy. endpoint in the main study was the rate of SBIs per patient- year on treatment. Secondary outcomes included non-serious Keywords Primary immunodeficiency diseases intravenous . . infections, work/school absence, episodes of fever, quality of immunoglobulin panzyga® serious bacterial infections life, and adverse events (AEs). Results The main study enrolled 51 patients (35% female, mean age 26.8 years), with 21 participating in the extension Introduction study. The rate of SBIs per patient-year was 0.08 in the total population; there were four SBIs in the 4-weekly treatment Primary immunodeficiency diseases (PIDs) comprise a het- group (2/30 patients) and none in the 3-weekly group erogeneous group of disorders that have intrinsic defects in- (n = 21). Compared with 4-weekly treatment, 3-weekly treat- volving the development and function of the immune system * Michael Borte Saint Louis University, St. Louis, MO, USA Michael.Borte@sanktgeorg.de Department of Pediatrics, University of Washington and Seattle Children’s Research Institute, Seattle, WA, USA Klinik für Kinder- und Jugendmedizin, Klinikum St. Georg gGmbH, UCLA School of Medicine, Los Angeles, CA, USA Leipzig, Germany Papillion, NE, USA Immunodeficiency Centre Leipzig (IDCL), Hospital St. Georg University of California, Irvine, CA, USA gGmbH Leipzig, Delitzscher Strasse 141, 04129 Leipzig, Germany Jagiellonian University Medical College, Kraków, Poland IMMUNOe Research Center Centennial, Centennial, CO, USA The Allergy and Asthma Center, Fort Wayne, IN, USA Klinika Alergologii Collegium Medicum, Uniwersytetu Jagiellońskiego, Kraków, Poland University Children Hospital, Kraków, Poland 5 14 Clinical Research and Development Department, Octapharma Division of Pediatric Allergy/Immunology, Stroger Hospital of Cook Pharmazeutika Produktionsges.m.b.H, Vienna, Austria County, Chicago, IL, USA 604 J Clin Immunol (2017) 37:603–612 [1]. To date, >300 molecularly defined disorders have been weight every 21–28 days for at least six infusion intervals, and identified with new PIDs still being added and classification evidence of an IgG trough level of ≥550 mg/dL at the previous ongoing [2]. Children and adults with PID and predominant two infusions before enrolment. Female patients of childbear- antibody deficiency have an increased risk of severe bacterial, ing potential had to have a negative pregnancy test and use a viral, and fungal infections, and present with infections that reliable contraceptive method during the study. A minimum typically involve the upper and lower respiratory tracts, the weight requirement was based on the blood test volumes gastrointestinal system, skin, and other organs [3]. needed for the study. Furthermore, patients with PID are at greater risk of develop- The main exclusion criteria were (1) requirement for rou- ing malignancies [4] and autoimmune disorders [5]. Because tine premedication for IVIG infusion, (2) severe impairment most of these antibody deficiencies cannot be cured, affected of liver function, (3) abnormal renal function, (4) congestive patients require lifelong infusions with intravenous or subcu- heart failure or uncontrolled arterial hypertension, (5) a posi- taneous immunoglobulin G (IVIG or SCIG) [6]. Replacement tive screening test for HIV and/or hepatitis B or C infection, therapy with IVIG or SCIG provides patients with predomi- (6) treatment with immunosuppressive or immunomodulatory nant antibody deficiency with specific antibodies, thus drugs, and (7) pregnant or nursing women. preventing serious bacterial and viral infections and reducing This study was designed in accordance with the US Food the number and duration of hospitalizations, as well as the loss and Drug Administration (FDA) and European Medicines of school/work days [6, 7]. Agency (EMA) guidelines on the clinical investigation of hu- This report describes the results of a phase 3 study of 12- man IVIG [8, 9]. month duration and its 3-month extension; the main study objective was to assess efficacy and safety of two treatment Extension Study schedules of 10% IVIG (panzyga®; Octapharma AG, Lachen, Switzerland) in preventing serious bacterial infections (SBIs), Patients in the USA who had completed the main study and while the extension study provided data on the tolerability of were 6 years or older were eligible to enroll in the extension panzyga® administered at high infusion rates. study (ClinicalTrials.gov record NCT01313507). A further inclusion criterion was administration of the maximum infusion rate (0.08 mL/kg/min; 480 mg/kg/h) for the last Methods three infusions of the main study, without need for premedication. Exclusion criteria were any condition or The protocols for both studies were reviewed and approved by circumstance that would result in exclusion from the main each study site’s Independent Ethics Committee or study, administration of any immunoglobulin apart from panzyga® between the conclusion of the main study and Institutional Review Board before the study commenced. The studies were conducted in accordance with the ethical start of the extension study, and any deviation in the principles of the Declaration of Helsinki and the patient’s treatment interval of >7 days between the last International Conference on Harmonization guideline E6: infusion in the main study and the first infusion in the Good Clinical Practice. Adult patients provided written in- extension study. formed consent; for minors, both written informed assent (as applicable for the study site) and consent from the patient and Study Medication the patient’s parent/legal guardian, respectively, were required. Panzyga® is a ready-to-use, sterile, glycine-stabilized 10% liquid preparation of polyvalent human immunoglobulin G Study Design (IgG) for intravenous administration with physiologic osmo- lality (240–310 mosmol/kg). Virus safety is achieved through Main Study a combination of various process steps, including S/D treat- ment, ion-exchange chromatography, and nanofiltration This prospective, open-label, non-controlled, non-random- (20 nm). ized, multicenter phase 3 study examined two panzyga® in- fusion regimens administered every 3 or 4 weeks for Main Study 12 months in patients with PID from the USA and Europe (ClinicalTrials.gov record NCT01012323). Each enrolled patient received 200–800 mg/kg body weight of Inclusion criteria were age 2–75 years, confirmed diagnosis study drug every 21 (±3) or 28 (±3) days for 12 months, unless of common variable immunodeficiency disorders (CVIDs) or medical conditions or other circumstances resulted in the pa- X-linked agammaglobulinemia (XLA), previous treatment tient’s withdrawal from the study. Individual treatment doses and intervals were dependent upon the patient’sprevious with a commercial IVIG at a dose of 200–800 mg/kg body J Clin Immunol (2017) 37:603–612 605 IVIG dose and dosing frequency before entry into the study. activity with required assistance; medical intervention/therapy Patients received treatment using an infusion pump at the fol- required). AEs were identified as serious (SAEs) if they re- lowing rates: 0.01 mL/kg/min for the first 30 min, followed by sulted in death or persistent or significant disability/incapacity, 0.02 mL/kg/min for the second 30 min; infusion rates were were life-threatening, required hospitalization or prolongation then increased every 30 min using predefined patterns with of existing hospitalization, or other important medical event. maximum rates of 0.04 mL/kg/min (first and second infusion), 0.06 mL/kg/min (third and fourth infusion), 0.07 mL/kg/min Extension Study (fifth and sixth infusion), and 0.08 mL/kg/min (all subsequent infusions). Rate increases were only made if the lower infu- The primary endpoint was occurrence of AEs causally and/or sion rate was tolerated. Patients receiving treatment every temporally related to panzyga® given at infusion rates of up to 3 weeks had a total of 17 infusions, and those receiving treat- 0.14 mL/kg/min. The safety parameters assessed were the ment every 4 weeks had a total of 13 infusions. same as those in the main study. Extension Study Statistical Analysis The dose and infusion schedule remained unchanged from the The statistical software package used in both studies was SAS, main study. Patients received panzyga® using an infusion version 9.1 or higher. pump at the following rates: 0.01 mL/kg/min for the first 30 min, followed by 0.03 mL/kg/min for 15 min; infusion Main Study rates were then increased every 15 min using predefined pat- terns with maximum rates of 0.10 mL/kg/min (first infusion), The full analysis set (FAS) included all patients who received 0.12 mL/kg/min (second infusion), and 0.14 mL/kg/min (all ≥1 complete treatment and had available data on infections subsequent infusions). Rate increases were only made if the from ≥1 post-treatment diary. The per-protocol (PP) set prior infusion rate was tolerated. Patients receiving treatment consisted of those patients in the FAS with no major protocol every 3 weeks had a total of five infusions, and those receiving violations. The safety set included all patients who had re- treatment every 4 weeks had a total of four infusions. ceived at least one infusion. The rate of SBI/year for each patient was presented as point estimates of the rate along with Treatment Outcomes a 99% confidence interval (CI) and was calculated as r =(total number of SBIs) / (patient-years on panzyga® treatment). The Main Study null hypothesis was to be rejected if the upper one-sided con- fidence limit for SBI rate per patient-year was less than 1.0, The primary efficacy endpoint was the rate of SBIs (defined as tested at the 1% significance level. The planned sample size bacteremia/sepsis, bacterial meningitis, osteomyelitis/septic was 50 patients, based on an SBI frequency of <0.5/year in arthritis, bacterial pneumonia, and visceral abscess) per patients receiving regular IVIG [8], and accounting for an patient-year on treatment. Secondary endpoints included the overall dropout rate of 15%. number of episodes per patient-year of other infections; the type, severity, and time to resolution of other infections; num- Extension Study ber of days of use of antibiotics per patient-year on treatment and type and dose; number of days of absence from school or The planned number of patients for the extension study was 20– work per patient-year on treatment; hospitalizations due to 35, based on the number of patients enrolled in the main study infection and number of days of hospitalization per patient- from US study sites who completed the study at the maximum year on treatment; reason for hospitalization; and number of infusion rate and without the need for premedication and did episodes of fever per patient-year on treatment. These data not meet the exclusion criteria for the extension study. were collected from patient diaries which were checked by the investigator at each visit. Safety assessments included type and frequency of adverse Results events (AEs), laboratory parameters (hematology, biochemis- try, direct Coombs test, urinalysis, and viral markers), vital Patient Characteristics signs, and physical examination. The severity of AEs was described as mild (no significant discomfort to patient or Main Study change in routine activities), moderate (limitation in activity with possible need for some assistance; no or minimal medical In total, 51 patients (13 children [≥2 to <12 years], 12 adoles- intervention/therapy required), or severe (marked limitation in cents [≥12 to <16], and 26 adults [≥16 to ≤75]) were enrolled 606 J Clin Immunol (2017) 37:603–612 from 11 study centers, seven in the USA and four in Europe. The rate of SBIs per patient-year was less than 1.0 in all The patient disposition through the study is outlined in Fig. 1. treatment groups (Table 2). This result was confirmed in the One patient with bronchiectasis on a 4-week schedule was PP set, from which one patient with an SBI was excluded, removed from the study after nine infusions at the investiga- with a rate of SBI per patient-year for all patients of 0.061 tor’s discretion, in order to increase the IVIG dose to 800 mg/ (99% CI 0.0060–0.6246); of note, the excluded patient who kg following exacerbation of the lung disease. All patients experienced an SBI missed two infusion visits and was late for enrolled in the study received at least nine infusions and pro- others and had low IgG levels during the study (≤500 mg/dL). vided data on infections by at least nine post-treatment diaries, so all 51 patients were included in the FAS. One patient on the Secondary Endpoints 4-week infusion schedule was excluded from the PP set for major protocol violations, including missing two infusion For both treatment schedules, trough levels of serum IgG were visits. The remaining patients (n = 50) comprised the PP anal- almost constant throughout the study. Patients on a 4-week ysis set. infusion schedule had median IgG trough levels of 810– There were no substantial differences in baseline character- 870 mg/dL, while patients on a 3-week schedule had median istics between the two treatment groups (Table 1). Briefly, the levels of 1100–1220 mg/dL. Over 75% of patients reported a mean age of the total population was 26.8 years (range 2– non-serious infection (Table 3). Infections occurring in >25% 65 years), 35% were female; 14% of all patients were of of the total population included lower (LRTI) and upper respi- Hispanic or Latino ethnicity. Twenty-one patients (41%) were ratory tract infections (URTIs) and infections of the gastrointes- treated with 3-weekly infusions, and 30 patients (59%) with 4- tinal tract. Patients in the 3-weekly group reported more URTIs weekly infusions (Table 1). Of the 51 patients enrolled in the and ear infections than the 4-weekly group and fewer LRTIs study, 43 patients (84.3%) were diagnosed with CVID and (Table 3). The rate of other infections per patient-year was 3.68 eight patients (15.7%) with XLA. in the total patient group, with a higher rate for patients in the 3- The mean duration of treatment was 360 days. Overall, weekly schedule (4.19) than in the 4-weekly schedule (3.33). there were 740 infusions with an actual mean IgG dose of The mean time to resolution of infection was 14.3 days for 417 g (range 104–1224 g) per patient, and a mean dose per SBIs and 18.4 days for other infections. The time to resolution infusion of 485 mg/kg body weight. The mean duration of of non-serious infections was higher in the 4-weekly group vs each infusion was 2.2 h (range 1.4–4.3 h). Of the high-rate the 3-weekly group (21.4 vs 14.9 days), but high standard infusions, 90.1% were administered at the maximum rate of deviations were seen in both groups (data not shown). 0.08 mL/kg/min. Antibiotics were used by 82.4% of patients during the course of the study of which 86.0% were for therapeutic rea- Extension Study sons, while the rest were prophylactic use. The percentage of patients using antibiotics was similar between treatment The extension study enrolled 21 patients (eight children groups (data not shown). [age ≥ 6 years to <12], three adolescents [≥12 to <16 years], Overall, 49.0% of patients in the study had a total number and ten adults [≥16 to ≤75]) from six US centers. All patients of 68 absences from work or school due to infections; the completed the study. Thirty-eight percent of patients were percentage of patients taking absences and the number of ab- female and the mean age of the patient cohort was 23.8 years sences were higher in the 3-weekly group (13 of 21 patients (range 6–62 years). Hispanic or Latino ethnicity was reported [61.9%] and 37 absences) than in the 4-weekly group (12 of by 19% of patients. Most patients (76.2%) had CVID, while 30 patients [40.0%] and 31 absences). There were 183 days the remainder had XLA. missed from work/school during the study, and the mean num- The mean treatment duration was 107 days. Patients had a ber of days missed per patient-year was 3.64. total of 96 infusions. The actual mean dose of IgG per infusion Only one patient treated at 4-week intervals was hospital- was 29.8 g or 542 mg/kg body weight. The mean duration of ized due to infections (for bacterial pneumonia; total duration each infusion was 1.5 h (range 1.2–2.0 h), and 85.2% of the of hospital stay 4 days; overall rate of days in hospital per high rate infusions were administered at the maximum rate of patient-year 0.080). Fourteen episodes of fever occurred in 0.14 mL/kg/min. 11 patients (Table 4). Efficacy Safety Primary Endpoint Main Study In the FAS, all SBIs reported were bacterial pneumonia, and Of the 51 patients in the safety set, 48 (94.1%) experienced ≥1 occurred in patients receiving 4-weekly infusions (Table 2). AE during the study. No AEs led to study withdrawal or death. J Clin Immunol (2017) 37:603–612 607 Fig. 1 Patient disposition through the main study Table 1 Baseline characteristics Parameter 3-weekly IVIG schedule 4-weekly IVIG schedule Total and demographics of the main (n =21) (n =30) (n =51) study population Gender, n (%) Female 7 (33.3) 11 (36.7) 18 (35.3) Male 14 (66.7) 19 (63.3) 33 (64.7) Age (years) Mean ± SD 26.2 ± 21.2 27.2 ± 18.2 26.8 ± 19.3 Min, max 2, 65 5, 63 2, 65 Race, n (%) White 21 (100.0) 30 (100.0) 51 (100.0) Ethnicity, n (%) Hispanic or Latino 3 (14.3) 4 (13.3) 7 (13.7) Not Hispanic or 18 (85.7) 25 (83.3) 43 (84.3) Latino Not reported 0 (0.0) 1 (3.3) 1 (2.0) Height (cm) Mean ± SD 156.3 ± 25.3 156.7 ± 23.6 156.5 ± 24.1 Min, max 90, 191 108, 186 90, 191 Weight (kg) Mean ± SD 59.7 ± 31.4 57.9 ± 23.0 58.7 ± 26.5 Min, max 13, 145 18, 100 13, 145 BMI (kg/m ) Mean ± SD 22.8 ± 8.6 22.3 ± 4.6 22.5 ± 6.5 Min, max 15, 52 15, 32 15, 52 BMI body mass index, IVIG intravenous immunoglobulin, SD standard deviation 608 J Clin Immunol (2017) 37:603–612 Table 2 Serious bacterial SBI 3-weekly IVIG schedule 4-weekly IVIG schedule Total infections (SBIs) per patient-year (n =21) (n =30) (n =51) in the main study population Total no. of SBI, n 044 Bacterial pneumonia 0 4 4 Total no. of patients with SBI, 0 (0.0) 2 (6.7) 2 (3.9) n (%) Bacterial pneumonia 0 (0.0) 2 (6.7) 2 (3.9) Number of patient years 20.5 29.7 50.2 exposure Rate of SBI per patient-year na 0.135 0.080 One sided 99% CI, upper limit na 0.849 0.503 CI confidence interval, IVIG intravenous immunoglobulin, na not applicable, no. number Serious (SAEs) and severe AEs occurred in five (9.8%) and group), 25.0% of adolescents (12.5% 3-weekly; 50.0% seven patients (13.7%), respectively. No children had SAE, 4-weekly group), and 15.4% of children (none 3-weekly; but four adults (15.4%) and one adolescent (8.3%) had seven 25.0% 4-weekly group). The most common events in SAEs, all considered unrelated (gout, pneumonia, bronchiec- adults were headache (26.9%), nausea (11.5%), and tasis [twice], bronchospasm, septoplasty, and thrombocytope- vomiting, upper abdominal pain, and pyrexia (7.7% each), nia). Table 5 lists AEs experienced by >10% and related AEs while in adolescents, the most common were headache, experienced by >3% of treated patients. Patients in the 4- pyrexia, fatigue, and chills (8.3% each) and in children weekly group had a higher incidence of SAEs (13 vs 5%). abdominal pain (15.4%) and chills, headache, nausea, In contrast, more patients in the 3-weekly treatment group and ear pain each in one case (7.7%). Only two patients had severe AEs than patients in the 4-weekly group (24 vs received premedication (3.9%) for three infusions (0.4%). 7%). The maximum infusion rate of 0.08 mL/kg/min was used During the course of this study, treatment-emergent in 90.1% of infusions after the seventh infusion. Study AEs that were classified by the investigator to be related medication-related (possible or probable) treatment- to the study medication occurred in 16 patients (31.4%); emergent AEs occurred during 38 infusions (5.1%: 2.7% six patients (28.6%) enrolled in the 3-weekly treatment in children, 2.2% in adolescent, and 7.8% in adult infu- schedule and ten patients (33.3%) in the 4-weekly treat- sions). Study medication-related headache was the most ment schedule. The age distribution was as follows: abundant and noted in 22 infusions (3.0%). Most of these 42.3% of adults (62.5% 3-weekly; 33.3% 4-weekly (35/38) occurred within 72 h after end of infusion. Table 3 Number of patients with Other infections 3-weekly IVIG schedule 4-weekly IVIG schedule Total other infections, rate of other (n =21) (n =30) (n =51) infections per patient-year, main study population Total no. of patients with other 18 (85.7) 21 (70.0) 39 (76.5) infections, n (%) Ear infections 5 (23.8) 4 (13.3) 9 (17.6) Eye infections 1 (4.8) 2 (6.7) 3 (5.9) GI tract infections 7 (33.3) 10 (33.3) 17 (33.3) Genitourinary tract infections 2 (9.5) 3 (10.0) 5 (9.8) URTI 14 (66.7) 14 (46.7) 28 (54.9) LRTI 4 (19.0) 9 (30.0) 13 (25.5) Skin infections 2 (9.5) 2 (6.7) 4 (7.8) Infections not classified elsewhere 4 (19.0) 6 (20.0) 10 (19.6) Total number of other infections, n 86 99 185 Number of patient-year exposure 20.5 29.7 50.2 Rate of other infections per 4.19 3.33 3.68 patient-year One sided 95% CI, upper limit 6.89 5.17 5.12 CI confidence interval, GI gastrointestinal, IVIG intravenous immunoglobulin, LRTI lower respiratory tract infection, URTI upper respiratory tract infection J Clin Immunol (2017) 37:603–612 609 Table 4 Total number of episodes of fever in the main study population patients had hematological AEs; one patient had leukopenia (no treatment was required), one had thrombocytopenia, and Episodes of Children Adolescents Adults Total one had anemia (both resolved due to effective treatment). No fever ≥2 years, ≥12 years, ≥16 years, (n =51) <12 years <16 years ≤75 years change to the study medication administration schedule was (n =13) (n =12) (n =26) required in these patients. No. of patients 5 (38.5) 1 (8.3) 5 (19.2) 11 with fever, (21.- Extension Study n (%) 6) Total no. of 62 6 14 Of the 21 patients in the safety set, 17 (81.0%) experienced at episodes of fever, n least one AE during the study which were generally mild to Rate of 0.463 0.174 0.233 0.279 moderate in intensity with only one patient having severe AEs episodes of (4.8%). No AEs led to study withdrawal or death. No SAEs fever per were reported. Table 6 lists AEs experienced by at least two patient-year (9.5%) and the related AEs experienced by >3% of treated no. number patients. There was a higher overall incidence of AEs in pa- As determined by the investigator tients receiving the 3-week treatment schedule than the 4- week schedule (91.7 vs 66.7%), as well as a higher incidence Only 13 infusions had clinically significant abnormal of related AEs (25.0 vs 11.1%) and severe AEs (8.3 vs 0%). values in hematology parameters or urinalysis, and none was AEs were considered treatment-related in four patients present in three or more infusions. There were no abnormali- (19.0%); two children had a total of three related AEs (abdom- ties in direct Coombs test, biochemical assessments, viral inal pain, headache, and vascular procedure complication each markers, vital signs, and physical examinations. Three 12.5%) and two adults had a total of six related AEs (nausea Table 5 Display of all adverse Adverse event All AEs, n (%) Related AEs, n (%) events (AEs; frequency >10% of the 51 total patients) and study Infections and infestations 40 (78.4) 0 (0.0) medication-related AEs (frequen- cy >3%) by MedDRA System Upper respiratory tract infection 15 (29.4) Organ Class and Preferred Term Nasopharyngitis 13 (25.5) in the main study population Sinusitis 13 (25.5) Bronchitis 8 (15.7) Gastroenteritis 8 (15.7) Otitis media 7 (13.7) Influenza 6 (11.8) Pharyngitis 6 (11.8) Gastrointestinal disorders 27 (52.9) 7 (13.7) Abdominal pain 11 (21.6) 5 (9.8) Nausea 7 (13.7) 4 (7.8) Vomiting 7 (13.7) 2 (3.9) General disorders and administration site conditions 27 (52.9) 8 (15.7) Pyrexia 11 (21.6) 3 (5.9) Fatigue 10 (19.6) 2 (3.9) Chills 2 (3.9) Nervous system disorders 20 (39.2) 9 (17.6) Headache 14 (27.5) 9 (17.6) Respiratory, thoracic and mediastinal disorders 20 (39.2) 1 (2.0) Cough 7 (13.7) 1 (2.0) Musculoskeletal and connective tissue disorders 14 (27.5) 1 (2.0) Pain in extremity 6 (11.8) Injury, poisoning and procedural complication 9 (17.6) 0 (0.0) Skin and subcutaneous tissue disorders 9 (17.6) 0 (0.0) Metabolism and nutrition disorders 6 (11.8) 0 (0.0) 610 J Clin Immunol (2017) 37:603–612 Table 6 Display of all adverse Adverse event All AEs, n (%) Related AEs, n (%) events (AEs) and study medication-related AEs (frequen- Infections and infestations 9 (42.9) 0 (0.0) cy at least two [all AEs] or one [related AEs] of the total 21 pa- Sinusitis 4 (19.0) tients) by MedDRA System Nasopharyngitis 2 (9.5) Organ Class and Preferred Term Gastrointestinal disorders 7 (33.3) 3 (14.3) in the extension study population Nausea 3 (14.3) 2 (9.5) Vomiting 3 (14.3) 0 (0.0) Abdominal pain 2 (9.5) 1 (4.8) Diarrhea 2 (9.5) 0 (0.0) General disorders and administration site conditions 1 (4.8) Chest pain 4 (19.0) 1 (4.8) Pyrexia 2 (9.5) 0 (0.0) Nervous system disorders 2 (9.5) 2 (9.5) Headache 2 (9.5) 2 (9.5) Respiratory, thoracic and mediastinal disorders 5 (23.8) 0 (0.0) Musculoskeletal and connective tissue disorders 2 (9.5) 2 (9.5) Arthralgia <2 1 (4.8) Musculoskeletal pain <2 1 (4.8) Injury, poisoning and procedural complication 6 (28.6) 1 (4.8) Contusion 2 (9.5) 0 (0.0) Vascular procedure complication <2 1 (4.8) Skin and subcutaneous tissue disorders 2 (9.5) 0 (0.0) 20%; arthralgia, musculoskeletal pain, headache, and chest core summary of product characteristics. Serum IgG trough pain, each 10%). levels were nearly constant for both treatment schedules dur- No patients received premedication. The maximum infu- ing the course of the study and exceeded the trough level of sion rate of 0.14 mL/kg/min was used in 19/21 patients. Study 600 mg/dL recommended by EMA [10]. medication-related (possible or probable) treatment-emergent The results from the present study are consistent with other AEs were observed with six infusions (6.3%), 8.3% in chil- clinical trials investigating the efficacy of IVIG in patients dren, none in adolescent, and 6.7% in adult infusions. with antibody-deficient PID. A study of 80 adults and children Headache was the most abundant event during the extension with CVID or XLA treated with Privigen® 10% at a dose of study and noted in three infusions (3.1%). 200–888 mg/kg every 3 or 4 weeks for 12 months had an There were no clinically significant changes in laboratory annual SBI rate of 0.08 (upper one-sided 97.5% CI 0.182), parameters and no prominent results from vital signs or phys- while the annual rate of all infections was 3.55 [11], similar ical examination during the extension period. rates to those seen in the present study. The average annual rate of missed school or work days was 7.94 days/patient [11], a higher rate than what was seen with panzyga®. In another Discussion study of 22 patients with PID receiving 300–450 mg/kg Kiovig 10% every 3 weeks, no episodes of severe infection Both the FDA and EMA recommend that a finding of a seri- were reported, and the median monthly rate of mild or mod- ous infection rate per patient-year of <1.0 is adequate evidence erate infection episodes was 0.48. The rate of days off work/ school per month ranged from 0 to 1.58 in the observational of efficacy of IVIG as substitution therapy [8, 9]. The current study meets this requirement, with a rate of SBI as low as 0.08 period [12]. Other clinical trials include a 46-patient study of octagam® overall, confirming the efficacy of panzyga® in preventing the occurrence of SBIs in patients with PID. This low rate of SBIs 5% IVIG (400 or 600 mg/kg every 28 days or 300–450 mg/kg every 21 days) for 12 months, in which the estimated infection as well as the low rate of other infections (3.7 per patient/year) further confirms that the dosing and corresponding trough rate was 0.1 SBIs/patient/year (98% CI 0.033–0.279) and mean number of days of work or school missed was 5 during levels observed in this study were adequate. The average dose calculated by body weight at each infusion was 485 mg/kg the course of the study; both outcomes were similar to those in the present study [13]. A study with Flebogamma® 10% DIF body weight, which is in line with doses recommended in the J Clin Immunol (2017) 37:603–612 611 infused at a dose of 300–600 mg/kg every 3 or 4 weeks for very low level of SBIs and a low rate of related AEs, even 12 months in 46 PID patients reported that the overall rate of when infusion rates were increased up to 0.14 mL/kg/min. acute SBIs/patient/year was 0.025 (98% CI 0.001–0.133) and the overall mean rate of all infections was 2.2/patient/year, Acknowledgements The authors would like to thank Sheridan with 43% patients reporting missing at least 1 day of Henness, PhD, of Springer Healthcare Communications for the medical writing assistance; this assistance was funded by Octapharma AG. The work/school/usual activities, with the mean number of days authors would also like to thank Dr. Stefan Wietek and Dr. Ursula lost being 3.0 [14]. A 12-month study of Bivigam® 300– Konheiser from Octapharma Vienna, Austria and Lachen, Switzerland, 800 mg/kg infused every 3 or 4 weeks into 63 patients with respectively, for their assistance with preparation of the manuscript. PID demonstrated a SBI rate of 0.035/patient/year, and a gen- Thanks also go to the patients who took part in this study, and the mem- bers of the data monitoring committee: Prof. Volker Wahn, Prof. Deborah eral infection rate of 2.6/patient/year. Days off work or school Kado, and Prof. Luc Mouthon. were 2.28/patient/year [15], results again similar to our study. Authorship Contributions Dr. Borte, Dr. Melamed, Dr. Pulka, Dr. In the present study, the proportion of patients who expe- Knutsen, Dr. Moy, Dr. Ochs, Dr. RH Kobayashi, Dr. AL Kobayashi, rienced infections other than SBIs was greater and the rate of Dr. Gupta, Dr. Strach, Dr. Smits, and Dr. Pituch-Noworolska recruited patients for the trial and were responsible for the supervision of the trial at URTIs was higher in the 3-weekly group than in the 4-weekly their respective sites; they also participated in the editing of the manu- group. This could have been a chance occurrence that may script. Barbara Pyringer was involved in the planning, management, and have taken place in any random grouping of patients, as the reporting of the study, as well as in the preparation of the manuscript. patients continued with their treatment schedule and dose that they had received before enrolment into this study. Compliance with Ethical Standards Alternatively, it is possible that patients who were placed on a 3-weekly schedule for IVIG treatment were likely to have a Conflict of Interest MBorte’s institution has received research grant more compromised immune system and, therefore, be at support from CSL Behring, Octapharma, and Baxalta, and he has partic- ipated in advisory boards for CSL Behring and Octapharma. IR Melamed greater risk of developing such infections. has received research grant support from CSL Behring, Octapharma, The majority of AEs were assessed as mild; none led to Baxalta, and Bio Products Laboratories. B. Pyringer is an employee of study withdrawal or death. None of the patients in the study Octapharma, Vienna, Austria. AP Knutsen has acted as a consultant for exhibited signs of hemolysis. As expected, the most frequent Baxalta, CSL, and Octapharma. HD Ochs has acted as consultant for Baxalta, CSL Behring, and Octapharma. RH Kobayashi has acted as a related AE observed was headache. The tolerability and safety consultant for Baxalta, CSL, ADMA, and Octapharma. AL Kobayashi profile was excellent at high infusion rates. Indeed, panzyga® received grant support from Baxalta and Octapharma. JN Moy has re- could be safely administered at infusion speeds that were ceived fees as a consultant for Grifols, Prometic, Octapharma, equal [16] or considerably higher than used in most clinical MacroCure, and Baxalta. G Pulka, S Gupta, M Strach, W Smits, and A Pituch-Noworolska have no conflicts of interest to declare. Open Access trials treating antibody-deficient patients with IVIG, exceed- for this Article was funded by Octapharma. ing the maximum approved rates for most IVIG preparations [11, 17, 18]. Most patients (>90%) in the extension study Open Access This article is distributed under the terms of the Creative tolerated the highest infusion speed of 0.14 mL/kg/min Commons Attribution 4.0 International License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted use, (840 mg/kg/h), without any associated increase in rates of distribution, and reproduction in any medium, provided you give appro- AEs. In fact, there was a decrease in the related AE rate from priate credit to the original author(s) and the source, provide a link to the 31.4% in the main study to 19.0% in the extension study. Creative Commons license, and indicate if changes were made. The strengths of the study include its multicenter, interna- tional design, and the wide age range of the patients, which makes the results applicable to an extended population. The high proportion of patients (96%) completing the study with- References out any major protocol violation is an additional strength. Limitations of the study include the lack of a comparator 1. Parvaneh N, Casanova JL, Notarangelo LD, Conley ME. Primary group and a lack of blinding, although it should be noted that immunodeficiencies: a rapidly evolving story. J Allergy Clin this study was designed in accordance with the study design Immunol. 2013;131(2):314–23. doi:10.1016/j.jaci.2012.11.051. 2. Picard C, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley recommendations of the FDA and the EMA for studies of ME, et al. Primary immunodeficiency diseases: an update on the IVIG in the treatment of PID [8, 9]. classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J Clin Immunol. 2015;35(8):696–726. doi:10.1007/s10875-015- 0201-1. Conclusion 3. Berger M, Murphy E, Riley P, Bergman GE. Improved quality of life, immunoglobulin G levels, and infection rates in patients with These results demonstrate that treatment with panzyga® is primary immunodeficiency diseases during self-treatment with sub- highly effective in PID patients with predominant antibody cutaneous immunoglobulin G. South Med J. 2010;103(9):856–63. doi:10.1097/SMJ.0b013e3181eba6ea. deficiency and has excellent tolerability; patients exhibited a 612 J Clin Immunol (2017) 37:603–612 4. Kersey JH, Spector BD, Good RA. Primary immunodeficiency 11. Stein MR,NelsonRP, Church JA,Wasserman RL,Borte M, Vermylen C, et al. Safety and efficacy of Privigen, a novel 10% diseases and cancer: the immunodeficiency-cancer registry. Int J Cancer. 1973;12(2):333–47. liquid immunoglobulin preparation for intravenous use, in patients 5. Westerberg LS, Klein C, Snapper SB. Breakdown of T cell toler- with primary immunodeficiencies. J Clin Immunol. 2009;29(1): ance and autoimmunity in primary immunodeficiency—lessons 137–44. doi:10.1007/s10875-008-9231-2. learned from monogenic disorders in mice and men. Curr Opin 12. Bjorkander J, Nikoskelainen J, Leibl H, Lanbeck P, Wallvik J, Immunol. 2008;20(6):646–54. doi:10.1016/j.coi.2008.10.004. Lumio JT, et al. Prospective open-label study of pharmacokinetics, 6. Cunningham-Rundles C. Key aspects for successful immunoglob- efficacy and safety of a new 10% liquid intravenous immunoglob- ulin therapy of primary immunodeficiencies. Clin Exp Immunol. ulin in patients with hypo- or agammaglobulinemia. Vox Sang. 2011;164(Suppl 2):16–9. doi:10.1111/j.1365-2249.2011.04390.x. 2006;90(4):286–93. doi:10.1111/j.1423-0410.2006.00764.x. 7. Yong PL, Boyle J, Ballow M, Boyle M, Berger M, Bleesing J, et al. 13. Ochs HD, Pinciaro PJ. Octagam 5%, an intravenous IgG product, is Use of intravenous immunoglobulin and adjunctive therapies in the efficacious and well tolerated in subjects with primary immunode- treatment of primary immunodeficiencies: a working group report ficiency diseases. J Clin Immunol. 2004;24(3):309–14. doi:10. of and study by the Primary Immunodeficiency Committee of the 1023/B:JOCI.0000025453.23817.3f. American Academy of Allergy Asthma and Immunology. Clin 14. Berger M, Pinciaro PJ, Althaus A, Ballow M, Chouksey A, Moy J, Immunol. 2010;135(2):255–63. doi:10.1016/j.clim.2009.10.003. et al. Efficacy, pharmacokinetics, safety, and tolerability of 8. US Food and Drug Administration. Guidance for industry: safety, Flebogamma 10% DIF, a high-purity human intravenous immuno- efficacy, and pharmacokinetic studies to support marketing of im- globulin, in primary immunodeficiency. J Clin Immunol. mune globulin intravenous (human) as replacement therapy for pri- 2010;30(2):321–9. doi:10.1007/s10875-009-9348-y. mary humoral immunodeficiency. 2008. http://www.fda.gov/ 15. Wasserman RL, Church JA, Stein M, Moy J, White M, Strausbaugh downloads/BiologicsBloodV acci n e s/ S, et al. Safety, efficacy and pharmacokinetics of a new 10% liquid GuidanceComplianceRegulatoryInformation/Guidances/Blood/ intravenous immunoglobulin (IVIG) in patients with primary im- ucm078526.pdf. Accessed 27 February 2015. munodeficiency. J Clin Immunol. 2012;32(4):663–9. doi:10.1007/ 9. European Medicines Agency. Guideline on the clinical investiga- s10875-012-9656-5. tion of human normal immunoglobulin for intravenous administra- 16. Gelfand EW, Hanna K. Safety and tolerability of increased rate of tion (IVIg). EMA/CHMP/BPWP/94033/2007 rev. 2. 2010. http:// infusion of intravenous immunoglobulin G, 10% in antibody- www.ema.europa.eu/docs/en_GB/document_library/Scientific_ deficient patients. J Clin Immunol. 2006;26(3):284–90. doi:10. guideline/2009/10/WC500004766.pdf. Accessed 20 December 1007/s10875-006-9014-6. 2016. 17. Ochs HD, Buckley RH, Pirofsky B, Fischer SH, Rousell RH, 10. European Medicines Agency. Guideline on core SmPC for human Anderson CJ, et al. Safety and patient acceptability of intravenous normal immunoglobulin for intravenous administration (IVIg). immune globulin in 10% maltose. Lancet. 1980;2(8205):1158–9. EMA/CHMP/BPWP/94038/2007 Rev. 5. 2016. http://www.ema. 18. Ochs HD, Lee ML, Fischer SH, Kingdon HS, Wedgwood RJ. europa.eu/docs/en_GB/document_library/Scientific_guideline/ Efficacy of a new intravenous immunoglobulin preparation in pri- 2016/12/WC500219036.pdf. Accessed 13 January 2017. mary immunodeficient patients. Clin Ther. 1987;9(5):512–22. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Immunology Springer Journals

Efficacy and Safety of Human Intravenous Immunoglobulin 10% (Panzyga®) in Patients with Primary Immunodeficiency Diseases: a Two-Stage, Multicenter, Prospective, Open-Label Study

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J Clin Immunol (2017) 37:603–612 DOI 10.1007/s10875-017-0424-4 ORIGINAL ARTICLE Efficacy and Safety of Human Intravenous Immunoglobulin 10% (Panzyga®) in Patients with Primary Immunodeficiency Diseases: a Two-Stage, Multicenter, Prospective, Open-Label Study 1,2 3 4 5 Michael Borte & Isaac R. Melamed & Grazyna Pulka & Barbara Pyringer & 6 7 8 9 Alan P. Knutsen & Hans D. Ochs & Roger H. Kobayashi & Ai Lan Kobayashi & 10 11 12 13 Sudhir Gupta & Magdalena Strach & William Smits & Anna Pituch-Noworolska & James N. Moy Received: 14 March 2017 /Accepted: 18 July 2017 /Published online: 29 July 2017 The Author(s) 2017. This article is an open access publication Abstract ment was associated with a higher rate of upper respiratory Purpose To assess the efficacy and safety of panzyga® (intra- tract infections (RTIs), ear infections, and work/school ab- venous immunoglobulin 10%) in preventing serious bacterial sences, but a lower rate of lower RTIs and fever. Treatment infections (SBIs) in patients with primary immunodeficiency was generally well tolerated; no AE led to treatment with- diseases (PIDs), a prospective, open-label, multicenter, phase drawal or death. 3 study and an open-label extension study were undertaken. Conclusions Overall, the use of panzyga® in patients with Methods Initially, the study drug (infusion rate ≤0.08 mL/kg/ antibody-deficient PID was associated with a low rate of min) was administered at intervals of 3 or 4 weeks for AEs and was effective in preventing SBIs, exceeding US 12 months, followed by 3 months of panzyga® at infusion FDA and European Medicines Agency recommendations for rates increasing from 0.08 to 0.14 mL/kg/min. The primary efficacy. endpoint in the main study was the rate of SBIs per patient- year on treatment. Secondary outcomes included non-serious Keywords Primary immunodeficiency diseases intravenous . . infections, work/school absence, episodes of fever, quality of immunoglobulin panzyga® serious bacterial infections life, and adverse events (AEs). Results The main study enrolled 51 patients (35% female, mean age 26.8 years), with 21 participating in the extension Introduction study. The rate of SBIs per patient-year was 0.08 in the total population; there were four SBIs in the 4-weekly treatment Primary immunodeficiency diseases (PIDs) comprise a het- group (2/30 patients) and none in the 3-weekly group erogeneous group of disorders that have intrinsic defects in- (n = 21). Compared with 4-weekly treatment, 3-weekly treat- volving the development and function of the immune system * Michael Borte Saint Louis University, St. Louis, MO, USA Michael.Borte@sanktgeorg.de Department of Pediatrics, University of Washington and Seattle Children’s Research Institute, Seattle, WA, USA Klinik für Kinder- und Jugendmedizin, Klinikum St. Georg gGmbH, UCLA School of Medicine, Los Angeles, CA, USA Leipzig, Germany Papillion, NE, USA Immunodeficiency Centre Leipzig (IDCL), Hospital St. Georg University of California, Irvine, CA, USA gGmbH Leipzig, Delitzscher Strasse 141, 04129 Leipzig, Germany Jagiellonian University Medical College, Kraków, Poland IMMUNOe Research Center Centennial, Centennial, CO, USA The Allergy and Asthma Center, Fort Wayne, IN, USA Klinika Alergologii Collegium Medicum, Uniwersytetu Jagiellońskiego, Kraków, Poland University Children Hospital, Kraków, Poland 5 14 Clinical Research and Development Department, Octapharma Division of Pediatric Allergy/Immunology, Stroger Hospital of Cook Pharmazeutika Produktionsges.m.b.H, Vienna, Austria County, Chicago, IL, USA 604 J Clin Immunol (2017) 37:603–612 [1]. To date, >300 molecularly defined disorders have been weight every 21–28 days for at least six infusion intervals, and identified with new PIDs still being added and classification evidence of an IgG trough level of ≥550 mg/dL at the previous ongoing [2]. Children and adults with PID and predominant two infusions before enrolment. Female patients of childbear- antibody deficiency have an increased risk of severe bacterial, ing potential had to have a negative pregnancy test and use a viral, and fungal infections, and present with infections that reliable contraceptive method during the study. A minimum typically involve the upper and lower respiratory tracts, the weight requirement was based on the blood test volumes gastrointestinal system, skin, and other organs [3]. needed for the study. Furthermore, patients with PID are at greater risk of develop- The main exclusion criteria were (1) requirement for rou- ing malignancies [4] and autoimmune disorders [5]. Because tine premedication for IVIG infusion, (2) severe impairment most of these antibody deficiencies cannot be cured, affected of liver function, (3) abnormal renal function, (4) congestive patients require lifelong infusions with intravenous or subcu- heart failure or uncontrolled arterial hypertension, (5) a posi- taneous immunoglobulin G (IVIG or SCIG) [6]. Replacement tive screening test for HIV and/or hepatitis B or C infection, therapy with IVIG or SCIG provides patients with predomi- (6) treatment with immunosuppressive or immunomodulatory nant antibody deficiency with specific antibodies, thus drugs, and (7) pregnant or nursing women. preventing serious bacterial and viral infections and reducing This study was designed in accordance with the US Food the number and duration of hospitalizations, as well as the loss and Drug Administration (FDA) and European Medicines of school/work days [6, 7]. Agency (EMA) guidelines on the clinical investigation of hu- This report describes the results of a phase 3 study of 12- man IVIG [8, 9]. month duration and its 3-month extension; the main study objective was to assess efficacy and safety of two treatment Extension Study schedules of 10% IVIG (panzyga®; Octapharma AG, Lachen, Switzerland) in preventing serious bacterial infections (SBIs), Patients in the USA who had completed the main study and while the extension study provided data on the tolerability of were 6 years or older were eligible to enroll in the extension panzyga® administered at high infusion rates. study (ClinicalTrials.gov record NCT01313507). A further inclusion criterion was administration of the maximum infusion rate (0.08 mL/kg/min; 480 mg/kg/h) for the last Methods three infusions of the main study, without need for premedication. Exclusion criteria were any condition or The protocols for both studies were reviewed and approved by circumstance that would result in exclusion from the main each study site’s Independent Ethics Committee or study, administration of any immunoglobulin apart from panzyga® between the conclusion of the main study and Institutional Review Board before the study commenced. The studies were conducted in accordance with the ethical start of the extension study, and any deviation in the principles of the Declaration of Helsinki and the patient’s treatment interval of >7 days between the last International Conference on Harmonization guideline E6: infusion in the main study and the first infusion in the Good Clinical Practice. Adult patients provided written in- extension study. formed consent; for minors, both written informed assent (as applicable for the study site) and consent from the patient and Study Medication the patient’s parent/legal guardian, respectively, were required. Panzyga® is a ready-to-use, sterile, glycine-stabilized 10% liquid preparation of polyvalent human immunoglobulin G Study Design (IgG) for intravenous administration with physiologic osmo- lality (240–310 mosmol/kg). Virus safety is achieved through Main Study a combination of various process steps, including S/D treat- ment, ion-exchange chromatography, and nanofiltration This prospective, open-label, non-controlled, non-random- (20 nm). ized, multicenter phase 3 study examined two panzyga® in- fusion regimens administered every 3 or 4 weeks for Main Study 12 months in patients with PID from the USA and Europe (ClinicalTrials.gov record NCT01012323). Each enrolled patient received 200–800 mg/kg body weight of Inclusion criteria were age 2–75 years, confirmed diagnosis study drug every 21 (±3) or 28 (±3) days for 12 months, unless of common variable immunodeficiency disorders (CVIDs) or medical conditions or other circumstances resulted in the pa- X-linked agammaglobulinemia (XLA), previous treatment tient’s withdrawal from the study. Individual treatment doses and intervals were dependent upon the patient’sprevious with a commercial IVIG at a dose of 200–800 mg/kg body J Clin Immunol (2017) 37:603–612 605 IVIG dose and dosing frequency before entry into the study. activity with required assistance; medical intervention/therapy Patients received treatment using an infusion pump at the fol- required). AEs were identified as serious (SAEs) if they re- lowing rates: 0.01 mL/kg/min for the first 30 min, followed by sulted in death or persistent or significant disability/incapacity, 0.02 mL/kg/min for the second 30 min; infusion rates were were life-threatening, required hospitalization or prolongation then increased every 30 min using predefined patterns with of existing hospitalization, or other important medical event. maximum rates of 0.04 mL/kg/min (first and second infusion), 0.06 mL/kg/min (third and fourth infusion), 0.07 mL/kg/min Extension Study (fifth and sixth infusion), and 0.08 mL/kg/min (all subsequent infusions). Rate increases were only made if the lower infu- The primary endpoint was occurrence of AEs causally and/or sion rate was tolerated. Patients receiving treatment every temporally related to panzyga® given at infusion rates of up to 3 weeks had a total of 17 infusions, and those receiving treat- 0.14 mL/kg/min. The safety parameters assessed were the ment every 4 weeks had a total of 13 infusions. same as those in the main study. Extension Study Statistical Analysis The dose and infusion schedule remained unchanged from the The statistical software package used in both studies was SAS, main study. Patients received panzyga® using an infusion version 9.1 or higher. pump at the following rates: 0.01 mL/kg/min for the first 30 min, followed by 0.03 mL/kg/min for 15 min; infusion Main Study rates were then increased every 15 min using predefined pat- terns with maximum rates of 0.10 mL/kg/min (first infusion), The full analysis set (FAS) included all patients who received 0.12 mL/kg/min (second infusion), and 0.14 mL/kg/min (all ≥1 complete treatment and had available data on infections subsequent infusions). Rate increases were only made if the from ≥1 post-treatment diary. The per-protocol (PP) set prior infusion rate was tolerated. Patients receiving treatment consisted of those patients in the FAS with no major protocol every 3 weeks had a total of five infusions, and those receiving violations. The safety set included all patients who had re- treatment every 4 weeks had a total of four infusions. ceived at least one infusion. The rate of SBI/year for each patient was presented as point estimates of the rate along with Treatment Outcomes a 99% confidence interval (CI) and was calculated as r =(total number of SBIs) / (patient-years on panzyga® treatment). The Main Study null hypothesis was to be rejected if the upper one-sided con- fidence limit for SBI rate per patient-year was less than 1.0, The primary efficacy endpoint was the rate of SBIs (defined as tested at the 1% significance level. The planned sample size bacteremia/sepsis, bacterial meningitis, osteomyelitis/septic was 50 patients, based on an SBI frequency of <0.5/year in arthritis, bacterial pneumonia, and visceral abscess) per patients receiving regular IVIG [8], and accounting for an patient-year on treatment. Secondary endpoints included the overall dropout rate of 15%. number of episodes per patient-year of other infections; the type, severity, and time to resolution of other infections; num- Extension Study ber of days of use of antibiotics per patient-year on treatment and type and dose; number of days of absence from school or The planned number of patients for the extension study was 20– work per patient-year on treatment; hospitalizations due to 35, based on the number of patients enrolled in the main study infection and number of days of hospitalization per patient- from US study sites who completed the study at the maximum year on treatment; reason for hospitalization; and number of infusion rate and without the need for premedication and did episodes of fever per patient-year on treatment. These data not meet the exclusion criteria for the extension study. were collected from patient diaries which were checked by the investigator at each visit. Safety assessments included type and frequency of adverse Results events (AEs), laboratory parameters (hematology, biochemis- try, direct Coombs test, urinalysis, and viral markers), vital Patient Characteristics signs, and physical examination. The severity of AEs was described as mild (no significant discomfort to patient or Main Study change in routine activities), moderate (limitation in activity with possible need for some assistance; no or minimal medical In total, 51 patients (13 children [≥2 to <12 years], 12 adoles- intervention/therapy required), or severe (marked limitation in cents [≥12 to <16], and 26 adults [≥16 to ≤75]) were enrolled 606 J Clin Immunol (2017) 37:603–612 from 11 study centers, seven in the USA and four in Europe. The rate of SBIs per patient-year was less than 1.0 in all The patient disposition through the study is outlined in Fig. 1. treatment groups (Table 2). This result was confirmed in the One patient with bronchiectasis on a 4-week schedule was PP set, from which one patient with an SBI was excluded, removed from the study after nine infusions at the investiga- with a rate of SBI per patient-year for all patients of 0.061 tor’s discretion, in order to increase the IVIG dose to 800 mg/ (99% CI 0.0060–0.6246); of note, the excluded patient who kg following exacerbation of the lung disease. All patients experienced an SBI missed two infusion visits and was late for enrolled in the study received at least nine infusions and pro- others and had low IgG levels during the study (≤500 mg/dL). vided data on infections by at least nine post-treatment diaries, so all 51 patients were included in the FAS. One patient on the Secondary Endpoints 4-week infusion schedule was excluded from the PP set for major protocol violations, including missing two infusion For both treatment schedules, trough levels of serum IgG were visits. The remaining patients (n = 50) comprised the PP anal- almost constant throughout the study. Patients on a 4-week ysis set. infusion schedule had median IgG trough levels of 810– There were no substantial differences in baseline character- 870 mg/dL, while patients on a 3-week schedule had median istics between the two treatment groups (Table 1). Briefly, the levels of 1100–1220 mg/dL. Over 75% of patients reported a mean age of the total population was 26.8 years (range 2– non-serious infection (Table 3). Infections occurring in >25% 65 years), 35% were female; 14% of all patients were of of the total population included lower (LRTI) and upper respi- Hispanic or Latino ethnicity. Twenty-one patients (41%) were ratory tract infections (URTIs) and infections of the gastrointes- treated with 3-weekly infusions, and 30 patients (59%) with 4- tinal tract. Patients in the 3-weekly group reported more URTIs weekly infusions (Table 1). Of the 51 patients enrolled in the and ear infections than the 4-weekly group and fewer LRTIs study, 43 patients (84.3%) were diagnosed with CVID and (Table 3). The rate of other infections per patient-year was 3.68 eight patients (15.7%) with XLA. in the total patient group, with a higher rate for patients in the 3- The mean duration of treatment was 360 days. Overall, weekly schedule (4.19) than in the 4-weekly schedule (3.33). there were 740 infusions with an actual mean IgG dose of The mean time to resolution of infection was 14.3 days for 417 g (range 104–1224 g) per patient, and a mean dose per SBIs and 18.4 days for other infections. The time to resolution infusion of 485 mg/kg body weight. The mean duration of of non-serious infections was higher in the 4-weekly group vs each infusion was 2.2 h (range 1.4–4.3 h). Of the high-rate the 3-weekly group (21.4 vs 14.9 days), but high standard infusions, 90.1% were administered at the maximum rate of deviations were seen in both groups (data not shown). 0.08 mL/kg/min. Antibiotics were used by 82.4% of patients during the course of the study of which 86.0% were for therapeutic rea- Extension Study sons, while the rest were prophylactic use. The percentage of patients using antibiotics was similar between treatment The extension study enrolled 21 patients (eight children groups (data not shown). [age ≥ 6 years to <12], three adolescents [≥12 to <16 years], Overall, 49.0% of patients in the study had a total number and ten adults [≥16 to ≤75]) from six US centers. All patients of 68 absences from work or school due to infections; the completed the study. Thirty-eight percent of patients were percentage of patients taking absences and the number of ab- female and the mean age of the patient cohort was 23.8 years sences were higher in the 3-weekly group (13 of 21 patients (range 6–62 years). Hispanic or Latino ethnicity was reported [61.9%] and 37 absences) than in the 4-weekly group (12 of by 19% of patients. Most patients (76.2%) had CVID, while 30 patients [40.0%] and 31 absences). There were 183 days the remainder had XLA. missed from work/school during the study, and the mean num- The mean treatment duration was 107 days. Patients had a ber of days missed per patient-year was 3.64. total of 96 infusions. The actual mean dose of IgG per infusion Only one patient treated at 4-week intervals was hospital- was 29.8 g or 542 mg/kg body weight. The mean duration of ized due to infections (for bacterial pneumonia; total duration each infusion was 1.5 h (range 1.2–2.0 h), and 85.2% of the of hospital stay 4 days; overall rate of days in hospital per high rate infusions were administered at the maximum rate of patient-year 0.080). Fourteen episodes of fever occurred in 0.14 mL/kg/min. 11 patients (Table 4). Efficacy Safety Primary Endpoint Main Study In the FAS, all SBIs reported were bacterial pneumonia, and Of the 51 patients in the safety set, 48 (94.1%) experienced ≥1 occurred in patients receiving 4-weekly infusions (Table 2). AE during the study. No AEs led to study withdrawal or death. J Clin Immunol (2017) 37:603–612 607 Fig. 1 Patient disposition through the main study Table 1 Baseline characteristics Parameter 3-weekly IVIG schedule 4-weekly IVIG schedule Total and demographics of the main (n =21) (n =30) (n =51) study population Gender, n (%) Female 7 (33.3) 11 (36.7) 18 (35.3) Male 14 (66.7) 19 (63.3) 33 (64.7) Age (years) Mean ± SD 26.2 ± 21.2 27.2 ± 18.2 26.8 ± 19.3 Min, max 2, 65 5, 63 2, 65 Race, n (%) White 21 (100.0) 30 (100.0) 51 (100.0) Ethnicity, n (%) Hispanic or Latino 3 (14.3) 4 (13.3) 7 (13.7) Not Hispanic or 18 (85.7) 25 (83.3) 43 (84.3) Latino Not reported 0 (0.0) 1 (3.3) 1 (2.0) Height (cm) Mean ± SD 156.3 ± 25.3 156.7 ± 23.6 156.5 ± 24.1 Min, max 90, 191 108, 186 90, 191 Weight (kg) Mean ± SD 59.7 ± 31.4 57.9 ± 23.0 58.7 ± 26.5 Min, max 13, 145 18, 100 13, 145 BMI (kg/m ) Mean ± SD 22.8 ± 8.6 22.3 ± 4.6 22.5 ± 6.5 Min, max 15, 52 15, 32 15, 52 BMI body mass index, IVIG intravenous immunoglobulin, SD standard deviation 608 J Clin Immunol (2017) 37:603–612 Table 2 Serious bacterial SBI 3-weekly IVIG schedule 4-weekly IVIG schedule Total infections (SBIs) per patient-year (n =21) (n =30) (n =51) in the main study population Total no. of SBI, n 044 Bacterial pneumonia 0 4 4 Total no. of patients with SBI, 0 (0.0) 2 (6.7) 2 (3.9) n (%) Bacterial pneumonia 0 (0.0) 2 (6.7) 2 (3.9) Number of patient years 20.5 29.7 50.2 exposure Rate of SBI per patient-year na 0.135 0.080 One sided 99% CI, upper limit na 0.849 0.503 CI confidence interval, IVIG intravenous immunoglobulin, na not applicable, no. number Serious (SAEs) and severe AEs occurred in five (9.8%) and group), 25.0% of adolescents (12.5% 3-weekly; 50.0% seven patients (13.7%), respectively. No children had SAE, 4-weekly group), and 15.4% of children (none 3-weekly; but four adults (15.4%) and one adolescent (8.3%) had seven 25.0% 4-weekly group). The most common events in SAEs, all considered unrelated (gout, pneumonia, bronchiec- adults were headache (26.9%), nausea (11.5%), and tasis [twice], bronchospasm, septoplasty, and thrombocytope- vomiting, upper abdominal pain, and pyrexia (7.7% each), nia). Table 5 lists AEs experienced by >10% and related AEs while in adolescents, the most common were headache, experienced by >3% of treated patients. Patients in the 4- pyrexia, fatigue, and chills (8.3% each) and in children weekly group had a higher incidence of SAEs (13 vs 5%). abdominal pain (15.4%) and chills, headache, nausea, In contrast, more patients in the 3-weekly treatment group and ear pain each in one case (7.7%). Only two patients had severe AEs than patients in the 4-weekly group (24 vs received premedication (3.9%) for three infusions (0.4%). 7%). The maximum infusion rate of 0.08 mL/kg/min was used During the course of this study, treatment-emergent in 90.1% of infusions after the seventh infusion. Study AEs that were classified by the investigator to be related medication-related (possible or probable) treatment- to the study medication occurred in 16 patients (31.4%); emergent AEs occurred during 38 infusions (5.1%: 2.7% six patients (28.6%) enrolled in the 3-weekly treatment in children, 2.2% in adolescent, and 7.8% in adult infu- schedule and ten patients (33.3%) in the 4-weekly treat- sions). Study medication-related headache was the most ment schedule. The age distribution was as follows: abundant and noted in 22 infusions (3.0%). Most of these 42.3% of adults (62.5% 3-weekly; 33.3% 4-weekly (35/38) occurred within 72 h after end of infusion. Table 3 Number of patients with Other infections 3-weekly IVIG schedule 4-weekly IVIG schedule Total other infections, rate of other (n =21) (n =30) (n =51) infections per patient-year, main study population Total no. of patients with other 18 (85.7) 21 (70.0) 39 (76.5) infections, n (%) Ear infections 5 (23.8) 4 (13.3) 9 (17.6) Eye infections 1 (4.8) 2 (6.7) 3 (5.9) GI tract infections 7 (33.3) 10 (33.3) 17 (33.3) Genitourinary tract infections 2 (9.5) 3 (10.0) 5 (9.8) URTI 14 (66.7) 14 (46.7) 28 (54.9) LRTI 4 (19.0) 9 (30.0) 13 (25.5) Skin infections 2 (9.5) 2 (6.7) 4 (7.8) Infections not classified elsewhere 4 (19.0) 6 (20.0) 10 (19.6) Total number of other infections, n 86 99 185 Number of patient-year exposure 20.5 29.7 50.2 Rate of other infections per 4.19 3.33 3.68 patient-year One sided 95% CI, upper limit 6.89 5.17 5.12 CI confidence interval, GI gastrointestinal, IVIG intravenous immunoglobulin, LRTI lower respiratory tract infection, URTI upper respiratory tract infection J Clin Immunol (2017) 37:603–612 609 Table 4 Total number of episodes of fever in the main study population patients had hematological AEs; one patient had leukopenia (no treatment was required), one had thrombocytopenia, and Episodes of Children Adolescents Adults Total one had anemia (both resolved due to effective treatment). No fever ≥2 years, ≥12 years, ≥16 years, (n =51) <12 years <16 years ≤75 years change to the study medication administration schedule was (n =13) (n =12) (n =26) required in these patients. No. of patients 5 (38.5) 1 (8.3) 5 (19.2) 11 with fever, (21.- Extension Study n (%) 6) Total no. of 62 6 14 Of the 21 patients in the safety set, 17 (81.0%) experienced at episodes of fever, n least one AE during the study which were generally mild to Rate of 0.463 0.174 0.233 0.279 moderate in intensity with only one patient having severe AEs episodes of (4.8%). No AEs led to study withdrawal or death. No SAEs fever per were reported. Table 6 lists AEs experienced by at least two patient-year (9.5%) and the related AEs experienced by >3% of treated no. number patients. There was a higher overall incidence of AEs in pa- As determined by the investigator tients receiving the 3-week treatment schedule than the 4- week schedule (91.7 vs 66.7%), as well as a higher incidence Only 13 infusions had clinically significant abnormal of related AEs (25.0 vs 11.1%) and severe AEs (8.3 vs 0%). values in hematology parameters or urinalysis, and none was AEs were considered treatment-related in four patients present in three or more infusions. There were no abnormali- (19.0%); two children had a total of three related AEs (abdom- ties in direct Coombs test, biochemical assessments, viral inal pain, headache, and vascular procedure complication each markers, vital signs, and physical examinations. Three 12.5%) and two adults had a total of six related AEs (nausea Table 5 Display of all adverse Adverse event All AEs, n (%) Related AEs, n (%) events (AEs; frequency >10% of the 51 total patients) and study Infections and infestations 40 (78.4) 0 (0.0) medication-related AEs (frequen- cy >3%) by MedDRA System Upper respiratory tract infection 15 (29.4) Organ Class and Preferred Term Nasopharyngitis 13 (25.5) in the main study population Sinusitis 13 (25.5) Bronchitis 8 (15.7) Gastroenteritis 8 (15.7) Otitis media 7 (13.7) Influenza 6 (11.8) Pharyngitis 6 (11.8) Gastrointestinal disorders 27 (52.9) 7 (13.7) Abdominal pain 11 (21.6) 5 (9.8) Nausea 7 (13.7) 4 (7.8) Vomiting 7 (13.7) 2 (3.9) General disorders and administration site conditions 27 (52.9) 8 (15.7) Pyrexia 11 (21.6) 3 (5.9) Fatigue 10 (19.6) 2 (3.9) Chills 2 (3.9) Nervous system disorders 20 (39.2) 9 (17.6) Headache 14 (27.5) 9 (17.6) Respiratory, thoracic and mediastinal disorders 20 (39.2) 1 (2.0) Cough 7 (13.7) 1 (2.0) Musculoskeletal and connective tissue disorders 14 (27.5) 1 (2.0) Pain in extremity 6 (11.8) Injury, poisoning and procedural complication 9 (17.6) 0 (0.0) Skin and subcutaneous tissue disorders 9 (17.6) 0 (0.0) Metabolism and nutrition disorders 6 (11.8) 0 (0.0) 610 J Clin Immunol (2017) 37:603–612 Table 6 Display of all adverse Adverse event All AEs, n (%) Related AEs, n (%) events (AEs) and study medication-related AEs (frequen- Infections and infestations 9 (42.9) 0 (0.0) cy at least two [all AEs] or one [related AEs] of the total 21 pa- Sinusitis 4 (19.0) tients) by MedDRA System Nasopharyngitis 2 (9.5) Organ Class and Preferred Term Gastrointestinal disorders 7 (33.3) 3 (14.3) in the extension study population Nausea 3 (14.3) 2 (9.5) Vomiting 3 (14.3) 0 (0.0) Abdominal pain 2 (9.5) 1 (4.8) Diarrhea 2 (9.5) 0 (0.0) General disorders and administration site conditions 1 (4.8) Chest pain 4 (19.0) 1 (4.8) Pyrexia 2 (9.5) 0 (0.0) Nervous system disorders 2 (9.5) 2 (9.5) Headache 2 (9.5) 2 (9.5) Respiratory, thoracic and mediastinal disorders 5 (23.8) 0 (0.0) Musculoskeletal and connective tissue disorders 2 (9.5) 2 (9.5) Arthralgia <2 1 (4.8) Musculoskeletal pain <2 1 (4.8) Injury, poisoning and procedural complication 6 (28.6) 1 (4.8) Contusion 2 (9.5) 0 (0.0) Vascular procedure complication <2 1 (4.8) Skin and subcutaneous tissue disorders 2 (9.5) 0 (0.0) 20%; arthralgia, musculoskeletal pain, headache, and chest core summary of product characteristics. Serum IgG trough pain, each 10%). levels were nearly constant for both treatment schedules dur- No patients received premedication. The maximum infu- ing the course of the study and exceeded the trough level of sion rate of 0.14 mL/kg/min was used in 19/21 patients. Study 600 mg/dL recommended by EMA [10]. medication-related (possible or probable) treatment-emergent The results from the present study are consistent with other AEs were observed with six infusions (6.3%), 8.3% in chil- clinical trials investigating the efficacy of IVIG in patients dren, none in adolescent, and 6.7% in adult infusions. with antibody-deficient PID. A study of 80 adults and children Headache was the most abundant event during the extension with CVID or XLA treated with Privigen® 10% at a dose of study and noted in three infusions (3.1%). 200–888 mg/kg every 3 or 4 weeks for 12 months had an There were no clinically significant changes in laboratory annual SBI rate of 0.08 (upper one-sided 97.5% CI 0.182), parameters and no prominent results from vital signs or phys- while the annual rate of all infections was 3.55 [11], similar ical examination during the extension period. rates to those seen in the present study. The average annual rate of missed school or work days was 7.94 days/patient [11], a higher rate than what was seen with panzyga®. In another Discussion study of 22 patients with PID receiving 300–450 mg/kg Kiovig 10% every 3 weeks, no episodes of severe infection Both the FDA and EMA recommend that a finding of a seri- were reported, and the median monthly rate of mild or mod- ous infection rate per patient-year of <1.0 is adequate evidence erate infection episodes was 0.48. The rate of days off work/ school per month ranged from 0 to 1.58 in the observational of efficacy of IVIG as substitution therapy [8, 9]. The current study meets this requirement, with a rate of SBI as low as 0.08 period [12]. Other clinical trials include a 46-patient study of octagam® overall, confirming the efficacy of panzyga® in preventing the occurrence of SBIs in patients with PID. This low rate of SBIs 5% IVIG (400 or 600 mg/kg every 28 days or 300–450 mg/kg every 21 days) for 12 months, in which the estimated infection as well as the low rate of other infections (3.7 per patient/year) further confirms that the dosing and corresponding trough rate was 0.1 SBIs/patient/year (98% CI 0.033–0.279) and mean number of days of work or school missed was 5 during levels observed in this study were adequate. The average dose calculated by body weight at each infusion was 485 mg/kg the course of the study; both outcomes were similar to those in the present study [13]. A study with Flebogamma® 10% DIF body weight, which is in line with doses recommended in the J Clin Immunol (2017) 37:603–612 611 infused at a dose of 300–600 mg/kg every 3 or 4 weeks for very low level of SBIs and a low rate of related AEs, even 12 months in 46 PID patients reported that the overall rate of when infusion rates were increased up to 0.14 mL/kg/min. acute SBIs/patient/year was 0.025 (98% CI 0.001–0.133) and the overall mean rate of all infections was 2.2/patient/year, Acknowledgements The authors would like to thank Sheridan with 43% patients reporting missing at least 1 day of Henness, PhD, of Springer Healthcare Communications for the medical writing assistance; this assistance was funded by Octapharma AG. The work/school/usual activities, with the mean number of days authors would also like to thank Dr. Stefan Wietek and Dr. Ursula lost being 3.0 [14]. A 12-month study of Bivigam® 300– Konheiser from Octapharma Vienna, Austria and Lachen, Switzerland, 800 mg/kg infused every 3 or 4 weeks into 63 patients with respectively, for their assistance with preparation of the manuscript. PID demonstrated a SBI rate of 0.035/patient/year, and a gen- Thanks also go to the patients who took part in this study, and the mem- bers of the data monitoring committee: Prof. Volker Wahn, Prof. Deborah eral infection rate of 2.6/patient/year. Days off work or school Kado, and Prof. Luc Mouthon. were 2.28/patient/year [15], results again similar to our study. Authorship Contributions Dr. Borte, Dr. Melamed, Dr. Pulka, Dr. In the present study, the proportion of patients who expe- Knutsen, Dr. Moy, Dr. Ochs, Dr. RH Kobayashi, Dr. AL Kobayashi, rienced infections other than SBIs was greater and the rate of Dr. Gupta, Dr. Strach, Dr. Smits, and Dr. Pituch-Noworolska recruited patients for the trial and were responsible for the supervision of the trial at URTIs was higher in the 3-weekly group than in the 4-weekly their respective sites; they also participated in the editing of the manu- group. This could have been a chance occurrence that may script. Barbara Pyringer was involved in the planning, management, and have taken place in any random grouping of patients, as the reporting of the study, as well as in the preparation of the manuscript. patients continued with their treatment schedule and dose that they had received before enrolment into this study. Compliance with Ethical Standards Alternatively, it is possible that patients who were placed on a 3-weekly schedule for IVIG treatment were likely to have a Conflict of Interest MBorte’s institution has received research grant more compromised immune system and, therefore, be at support from CSL Behring, Octapharma, and Baxalta, and he has partic- ipated in advisory boards for CSL Behring and Octapharma. IR Melamed greater risk of developing such infections. has received research grant support from CSL Behring, Octapharma, The majority of AEs were assessed as mild; none led to Baxalta, and Bio Products Laboratories. B. Pyringer is an employee of study withdrawal or death. None of the patients in the study Octapharma, Vienna, Austria. AP Knutsen has acted as a consultant for exhibited signs of hemolysis. As expected, the most frequent Baxalta, CSL, and Octapharma. HD Ochs has acted as consultant for Baxalta, CSL Behring, and Octapharma. RH Kobayashi has acted as a related AE observed was headache. The tolerability and safety consultant for Baxalta, CSL, ADMA, and Octapharma. AL Kobayashi profile was excellent at high infusion rates. Indeed, panzyga® received grant support from Baxalta and Octapharma. JN Moy has re- could be safely administered at infusion speeds that were ceived fees as a consultant for Grifols, Prometic, Octapharma, equal [16] or considerably higher than used in most clinical MacroCure, and Baxalta. G Pulka, S Gupta, M Strach, W Smits, and A Pituch-Noworolska have no conflicts of interest to declare. Open Access trials treating antibody-deficient patients with IVIG, exceed- for this Article was funded by Octapharma. ing the maximum approved rates for most IVIG preparations [11, 17, 18]. Most patients (>90%) in the extension study Open Access This article is distributed under the terms of the Creative tolerated the highest infusion speed of 0.14 mL/kg/min Commons Attribution 4.0 International License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted use, (840 mg/kg/h), without any associated increase in rates of distribution, and reproduction in any medium, provided you give appro- AEs. In fact, there was a decrease in the related AE rate from priate credit to the original author(s) and the source, provide a link to the 31.4% in the main study to 19.0% in the extension study. Creative Commons license, and indicate if changes were made. The strengths of the study include its multicenter, interna- tional design, and the wide age range of the patients, which makes the results applicable to an extended population. The high proportion of patients (96%) completing the study with- References out any major protocol violation is an additional strength. 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Journal of Clinical ImmunologySpringer Journals

Published: Jul 29, 2017

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