Rapid Push vs Pump-Infused Subcutaneous Immunoglobulin Treatment: a Randomized Crossover Study of Quality of Life in Primary Immunodeficiency Patients

Rapid Push vs Pump-Infused Subcutaneous Immunoglobulin Treatment: a Randomized Crossover Study of... Purpose Subcutaneous immunoglobulin replacement therapy (IgRT) may be administered once a week with a pump or every other day with a syringe (rapid push). The objective of the study was to compare the impact of pump and rapid push infusions on patient’s life quality index (LQI). Methods This study was a randomized, crossover, multicenter, non-inferiority trial conducted in adults with primary immunode- ficiency (PID) accustomed to weekly infusions at home by pump. Patients used pump or rapid push for 3 months each according to the randomized sequence. Main criterion was PID-LQI factor I (treatment interference). Non-inferiority ratio was set at 90%. Results Thirty patients entered the study; 28 completed the two periods. IgRTexposure was similar during each period. At the end of each period, mean LQI factor 1 was 87.0 (IC95% [80.3; 94.3]) and 77.80 (IC95% [71.5; 84.7]) for pump and rapid push, respectively. There was a slightly larger effect of rapid push on treatment interference than with pump so that the primary endpoint could not be met. No difference was found on other LQI components, satisfaction (TSQM), or quality of life (SF36v2). Eight patients declared to prefer rapid push while 19 others preferred pump. Of rapid push infusions, 67.2% led to local reactions vs 71.8% of pump infusions (p = 0.11) illustrating its good tolerance. Rapid push and pump infusions achieved similar trough IgG levels with similar incidence of infections. Rapid push saved 70% of administration cost when compared to pump. Conclusions Since IgRT is a lifelong treatment in PID patients, individualization of treatment is of paramount importance. Rapid push is a new administration method in the physician’s armamentarium which is preferred by some patients and is cost-effective. ClinicalTrials.gov Identifier NCT02180763 Clinical Implications Self-administration of small volumes of immunoglobulins at home, every other day, using a syringe (rapid push) is a cost-effective alternative to administration of larger volumes by pump once a week. Capsule Summary This study compared subcutaneous infusions of immunoglobulins either weekly via a pump or every other day via a syringe (rapid push). Rapid push is preferred by some patients and is cost-effective, therefore completing a physician’s armamentarium. Boris Bienvenu and Grégoire Cozon contributed equally to this work. * Boris Bienvenu Jean-François Viallard bbienvenu@hopital-saint-joseph.fr jean-francois.viallard@chu-bordeaux.fr Grégoire Cozon Anne-Laure Fauchais gregoire.cozon@chu-lyon.fr anne-Laure.Fauchais@chu-limoges.fr Yves Mataix Pierre Clerson y.mataix@clinique-mutualiste-lyon.com pclerson@soladis.fr Cyrille Hoarau Jean-Charles Crave hoarauc@univ-tours.fr jean-charles.crave@octapharma.fr Eric Hachulla eric.hachulla@chru-lille.fr Extended author information available on the last page of the article 504 J Clin Immunol (2018) 38:503–512 . . . Keywords Primary immunodeficiency PID immunoglobulin replacement therapy home treatment rapid push Abbreviations SCIg. Further objectives included the comparison of other CI Confidence interval components of specific PID patients’ quality of life, generic Ig Immunoglobulin quality of life, burden of disease, and of IgRT and patient’s IgRT Immunoglobulin replacement therapy preference for pump or RP. In addition, the study aimed to IV IgIntravenous immunoglobulin describe the conditions of infusions and to provide details on PID Primary immunodeficiency costs. SCIg Subcutaneous immunoglobulin Study Design Introduction GAMEXPRESS was a prospective, interventional, non-infe- riority, longitudinal, randomized, crossover multicenter trial More than 50% of primary immunodeficiencies (PIDs) are conducted in France in adult patients with PID receiving characterized by an altered antibody production [1], exposing SCIg at home. Patients had to have a history of ongoing the patients to an increased risk of repeated and severe infec- home-based SCIg with gammanorm® 165 mg/mL tions [2]. Immunoglobulin replacement therapy (IgRT) restores (Octapharma AG, Lachen, Switzerland) by pump for at least sufficiently high serum levels of IgG, decreases the incidence of 1 month at the time of enrollment. Eligible patients were ran- infections [3], prevents complications such as bronchiectasis, domized (1:1) to pump and then RP or reverse sequence. Each and improves patient’s quality of life [4]. IgRT is administered crossover period lasted 3 months. Patients were free to switch intravenously (IVIg) or subcutaneously (SCIg). SCIg infusion from pump to RP and inversely at any time without being achieves IgG trough levels and an efficacy similar to those of dropped out. The dose of immunoglobulins could be adapted IVIg infusion but with lower incidence of general reactions [4], during the study as in routine care. better health-related quality of life, higher patient’s satisfaction [5–7], and faster functional recovery with less time off work [8, Immunoglobulins 9]. Local reactions, however, are more frequent although they tend to decrease with time and patient’sexperience [10]. SCIg High viscosity of some IgG solutions can make it difficult to products are often self-administered at home, therefore modest- handle the RP plunger by the patient, thus justifying the choice ly disturbing daily activities and reinforcing patient’s autonomy of a low-viscosity product. gammanorm® 165 mg/mL has the [6, 7]. Usually, patients use an infusion pump and self- lowest viscosity of all SCIg products available and is well administer SCIg once a week. SCIg by pump takes 1 to 2 h tolerated [13]. SCIg was to be administered around once a even with several catheters infusing several sites all at once. week during the pump period, and around every other day A new method for SCIg administration has recently been (three times a week) during the RP period. proposed [11, 12]. Rapid and manual administration of SCIg Patients were individually trained by the center. The first using a syringe, so-called rapid push (RP), would decrease the infusion of each period was performed in a hospital in the duration of administration (around 10 min per injection at one presence of an investigator and/or a nurse. Individual phone or two sites simultaneously) but imposes more frequent infu- contacts were set up to accompany the patients during the first sions. Replacing infusion pumps by RP would also reduce week of infusion(s) at home. The proposed maximum infusion material costs. Those data resulting from retrospective studies rate was set at 1–2 mL/min in order to allow fast diffusion of urged for a rigorous prospective controlled study to further the product, limit the risk of local untoward reactions, and determine the impact of RP in PID patients. To this end, this maintain the patient’s comfort. Patients were allowed to infuse randomized crossover multicenter study compared the feasi- several sites all at once. They were free to premedicate with bility, tolerability, and acceptance of RP and the current reg- painkillers, non-steroid anti-inflammatory drugs, or cortico- istered administration in adult PID patients. steroids before infusion. Methods Evaluations Objectives Patients were evaluated at enrollment (baseline values) andattheendofeach3-monthperiod.Atthe end of The main objective was to compare RP and pump administra- the study, the patients were asked which delivery device tion on interference on daily life in PID patients receiving they had preferred. J Clin Immunol (2018) 38:503–512 505 Impact of SCIg infusions on patient’sdaily life waseval- Statistics uated using the PID-specific life quality index (LQI) ques- tionnaire. The PID-LQI questionnaire involves 15 items rat- Results were expressed as mean ± standard deviation (m ± ed on a 7-point Likert scale ranging from “Extremely Good” SD) or median [first quartile; third quartile] and numbers (per- to “Extremely Poor.” Since costs for IgRT are entirely cov- centage). Percentages were calculated on the number of non- ered by the French Social Insurance System, two questions missing data. All analyses were performed on an intention-to- relatedtoeconomic concerns were deleted.The 13remaining treat basis. A sensitivity analysis was performed on a per- items are grouped into three subsets measuring the impact of protocol subset and provided very similar results (data not the treatment on patient quality of life: factor I (treatment shown). Calculation of LQI factors [18], derivation of interference), factor II (therapy-related problems), factor III TSQM dimensions [19], and calculation of standardized di- (therapy settings). Results range from 0 (maximal concern) mensions and summary components of the SF36v2 scale [15] to 100 (no concern). were performed as recommended by their authors. Costs were Satisfaction regarding SCIg infusion was evaluated by calculated based on public prices, VAT excluded. Costs for the “Treatment Satisfaction Questionnaire for Medication” nurses were based on the time in hours spent for the infusion (TSQM-11), a generic, self-administered, 11-item scale multiplied by 29.80 EUR [20]. Time spent for infusion by the [14] which evaluates efficacy, ease of use, and overall pa- patient was valued on the basis of the median income in tient satisfaction. In addition, patients rated their overall France (11.68 EUR/h) [21]. For premedication, we calculated satisfaction regarding IgRT at the end of each period, using a mean price for each type of treatment (for example, the mean a 7-point Likert scale. Quality of life was assessed by the cost for painkillers is the mean of public prices for all available SF36v2 scale [15]. The 36 items were grouped into eight painkillers) and costs were calculated by unit. Costs were dimensions and two summary scores, the physical compo- expressed on a monthly basis (30 days). nent summary score and the mental component summary Continuous variables were analyzed using a mixed score, were calculated. model with delivery device, period, and sequence as fixed PRISM (Pictorial Representation of Illness and Self- factors and patient within sequence as random factor. The Measure) quantitatively assessed the patient’s perception effect size associated to delivery device was estimated by of the burden he/she felt due to his/her illness [16, 17]. the ratio LQI − factor I /LQI − factor I .Results were RP pump This test is based on a non-verbal visualization technique: expressed after exponentiation of the geometric mean of a rectangular A4-size metal plate represents the life of the ratios with a two-sided 95% confidence interval (CI). The patient and a yellow disc located in the lower right corner lower limit of the CI was compared to the non-inferiority of the plate represents the patient. The investigator asked threshold of 0.90. Same methods were used for the other the patient to place a red disc on the plate so as to represent variables although not referring to a non-inferiority the disease in his/her life at the time of the test. The dis- threshold. tance between the centers of the discs quantifies the pa- The 3-month incidence of infections was estimated by a tient’s burden related to the intrusion of the disease in Poisson regression model using the natural logarithm of his/her life. The patients were asked to quantify separately follow-up duration (expressed as a multiple of 3 months) as the burden of the disease and that of IgRT, and provide offset term. The proportion of patients with IgG level < 6 g/L additional comments. Since the use of PRISM is not com- were described for each delivery device along with a two- mon practice, the investigators were trained prior to study sided 95% CI (Fisher’s exact method). Proportions of patients start. rating their satisfaction as rather good or extremely good re- Trough serum IgG levels and serum creatinine were mea- garding the P or RP were compared using Fisher’s exact test. sured at the end of each crossover period. Mild (not interfering Proportions of patients with local reactions, proportions of with daily activities), moderate (interfering with daily activi- infusions with local swelling, and proportions of infusions ties), or severe infections (including meningitis, pneumonia, with local pain were compared using two-proportion z test. sepsis, osteomyelitis, and visceral abscesses) were reported The analyses were performed using the SAS 9.4 software for each period. (SAS Institute, Cary, NC, USA). For each infusion, the patients reported the infused dose, the site(s) of infusion, and the number of pumps used (for the pump period), the duration, and the premedication they took Results before infusion. In parallel, the nurses who followed the pa- tients over the study were asked to report details on the mate- Patients rials that had been used for the infusions. Adverse events were collected by the investigator at each Thirty patients from six centers entered the study. Two pa- visit and patients reported local reactions on the diary. tients who prematurely withdrew for adverse events and did 506 J Clin Immunol (2018) 38:503–512 not complete the two periods of the study did not document Infusions the LQI scale and were excluded from the intention-to-treat population (Fig. 1). Patient exposure was similar during pump and RP period. A Patients were aged from 23 to 79 years. All but five total dose of 1101.3 ± 569.0 mg/kg was administered with were living in couple or family; around half of patients pump and 1101.2 ± 543.3 mg/kg with RP. In total, 355 infu- had a professional/school occupation (Table 1). Most fre- sions by pump and 989 infusions by RP have been document- quent PIDs were common variable immunodeficiency ed (Table 2). All infusions were self-administered, except the ( n = 17) and hypogammaglobulinemia ( n =8). first infusion of each period. Patients received a mean of 12.2 Agammaglobulinemia, severe combined variable immunode- ± 5.0 pump infusions and 38.0 ± 14.7 RP infusions. Mean ficiency, and selective deficiency of IgG subclasses were less interval between infusions was 6.6 ± 3.2 days (median frequent (one patient each). Median time since PID diagnosis 7.0 days) and 2.1 ± 1.1 days (median 2.0 days) with pump was 6.9 [interquartile range 3.8; 22.5] years. Patients had a and RP, respectively. The total dose administered per infusion mean history of ongoing home-based SCIg with was threefold lesser with RP (30.5 ± 14.2 mg/kg) than with gammanorm® 165 mg/mL via an infusion pump of 1.8 ± pump (94.8 ± 44.3 mg/kg) but patients received the same 2.4 years. amount of Ig over each period. Most infusions were done in Assessed for eligibility (n=31) Enrollment Excluded (n=1) Withdrew consent before administration (n=1) Randomized (n=30) Allocation Allocated to intervention (Pump - n=16) Allocated to intervention (Rapid Push - n=14) Received allocated intervention (n=16) Received allocated intervention (n=14) Allocated to intervention (Pump - n=14) Allocated to intervention (Rapid Push - n=16) Received allocated intervention (n=15) Received allocated intervention (n=14) Did not receive intervention Discontinued intervention for AEs (n=1) Did not receive intervention (n=1) st Prematurely withdrew during 1 sequence (n=1) Analysis Full analysis set (n=28) Excluded from analysis (n=2) No LQI at V2 and V3 (n=2) Fig. 1 CONSORT flowchart of the study J Clin Immunol (2018) 38:503–512 507 Table 1 Characteristics of patients 63 out of 86 (73.2%) infusions with RP associated with prior painkiller intake. Five patients took at least one painkiller prior Number of patients N =30 to infusion with P and two patients accounted for 23 out of 36 Age (years) 49.3 ± 17.8 (63.9%) infusions with P. One patient took painkillers for Male gender 7 (23.3%) 100% of infusions with P and 97.1% infusions with RP and Female gender 23 (73.7%) counted for 12 intakes during P period and 33 intakes during Weight (kg) 64.4 ± 16.5 RP period. Living alone 5 (16.7%) Professional/school occupation 14 (46.7%) Patient Satisfaction and Quality of Life Age at PID diagnosis (years)* 37.0 [24.0; 51.0] Continuous variables are summarized as mean ± SD unless otherwise The LQI factor I (treatment interference) was very high at specified; *median and interquartile range; categorical variables are de- baseline reflecting that daily life was only slightly altered by scribed as the number of non-missing data and percentage home-based SCIg infusion by pump (Table 3). At the end of each period, mean LQI factor 1 was 87.0 (IC95% [80.3; 94.3]) and 77.80 (IC95% [71.5; 84.7]) for pump and RP, respective- the abdomen. More than one site was used in 77% of pump ly. Ratio of least square means (Lsmeans) was 89.4% [80.9%; infusions but in less than 2% of RP infusions. On abdominal 99.9%], therefore under the non-inferiority threshold of 90% sites, median flow rate was 25 mL/h with pump and 60 mL/h (Fig. 2). LQI factors II and III were not impacted by the de- with RP. Smaller volumes and higher flow rates resulted in livery device. At enrollment, TSQM was 73.1 ± 15.4 and sat- quicker infusions with RP (range 2 to 70 min, mean 14.1 ± isfaction decreased during the study with poorer results during 7.9 min; median 10.0 min) than those with pump (up to the RP period than those during the pump period. However, 180min;mean81.3 ± 44.6min;median75.0min). the difference between devices did not reach statistical signif- Premedication with painkillers was reported in not more than icance. Quality of life was high at baseline. Apart from general 10% of infusions whatever the delivery device was. More health, other dimensions of SF36v2 were only slightly lower specifically, seven patients took at least one painkiller prior than those in the general population (norm-based values for to infusion during the RP period. Two patients accounted for healthy subjects are 50 for each dimension). The vitality Table 2 Characteristics of Infusions with pump Infusions with rapid push infusions N =355 N =989 Duration (min) 81.3 ± 44.6 14.1 ± 7.9 Dose administered per infusion (mg/kg) 94.8 ± 44.3 30.5 ± 14.2 Abdomen 310 (87.3%) 802 (81.1%) Thigh 23 (6.5%) 80 (8.1%) Other sites 1 (3.1%) 42 (4.2%) Unknown site 21 65 One site/2 sites/3 sites/4 sites/unknown 74/202/24/21/34 908/16/0/0/65 Volume (mL)* 32.6 ± 15.7 11.2 ± 4.4 40.0 [30.0; 50.0] 10.0 [10.0;10.0] Flow rate in abdomen (mL/h) 30.9 ± 20.9 54.0 ± 23.3 Flow rate in abdomen [0–15 mL/h] 33 (15.1%) 2 (0.3%) Flow rate in abdomen [15–25 mL/h] 85 (39.0%) 35 (4.9%) Flow rate in abdomen [25–35 mL/h] 32 (14.7%) 93 (13.1%) Flow rate in abdomen [> 35 mL/h] 68 (31.2%) 581 (81.7%) Flow rate in abdomen unknown 92 + 23 + 11 91 + 5 + 42 Time to perform infusions (min) 81.3 ± 44.6 14.1 ± 7.9 Premedication with painkillers 36 (10.1%) 86 (8.7%) Premedication with NSAIDs 14 (3.9%) 10 (1.0%) Continuous variables are summarized as mean ± SD unless otherwise specified; *median and interquartile range; categorical variables are described as the number of non-missing data and percentage; NSAIDs, non-steroid anti- inflammatory drugs 508 J Clin Immunol (2018) 38:503–512 Table 3 Patient’s satisfaction and Baseline Pump Rapid push Ratio* quality of life N =28 N =28 N =28 N =28 LQI factor I* 83.5 ± 12.4 87.0 [80.3; 94.3] 77.8 [71.5; 84.7] 89.4 [80.9; 99.9] LQI factor II 86.1 ± 12.9 83.6 [77.8; 89.8] 78.5 [72.8;84.7] 94.0 [86.6; 102.1] LQI factor III 94.1 ± 7.9 92.0 [87.3; 97.0] 88.0 [83.2; 93.1] 95.7 [88.6; 103.2] TSQM 73.1 ± 15.4 61.8 [49.6; 77.1] 53.4 [42.4; 67.2] 86.3 [64.2; 116.0] SF36v2: Physical functioning 50.0 ± 8.1 48.5 [44.5; 52.8] 49.9 [45.8; 54.4] 102.9 [98.1; 107.9] SF36v2: Role physical 47.1 ± 12.1 48.7 [44.6; 53.2] 50.0 [45.8; 54.7] 102.8 [98.0; 107.9] SF36v2: Bodily pain 49.6 ± 10.0 49.5 [45.5; 53.9] 49.0 [44.9; 53.5] 99.0 [93.2; 105.2] SF36v2: General health 40.3 ± 11.5 40.2 [36.2; 44.7] 40.1 [36.0; 44.7] 99.7 [92.7; 107.3] SF36v2: Vitality 49.1 ± 11.0 47.0 [43.0; 51.5] 50.9 [46.3; 55.8] 108.2 [100.6; 116.3] SF36v2: Social functioning 46.1 ± 11.6 47.0 [42.6; 51.8] 44.4 [40.1; 49.1] 94.3 [86.4; 103.0] SF36v2: Role emotional 45.9 ± 14.1 47.0 [40.9; 54.0] 43.7 [37.8; 50.5] 93.0 [81.0; 106.7] SF36v2: Mental health 48.9 ± 11.8 47.1 [42.6; 52.0] 47.6 [42.9; 52.9] 101.2 [93.5; 109.6] SF36v2: Physical component 47.5 ± 7.9 47.6 [44.2; 51.3] 48.0 [44.5; 51.7] 100.7 [97.5; 104.1] summary SF36: Mental component 46.7 ± 12.9 46.0 [41.1; 51.4] 45.7 [40.7; 51.3] 99.3 [90.5; 109.0] summary PRISM–Burden of disease 12.0 ± 7.5 9.5 [6.6; 13.7] 9.5 [6.6; 13.7] 100.7 [79.9; 127.1] PRISM–Burden of delivery 10.1 ± 5.6 10.2 [7.9; 13.3] 7.9 [6.1; 10.4] 77.5 [53.3; 112.5] device At baseline results are summarized as mean ± SD; at the end of each period, results are Lsmeans [95%CI]; ratios are calculated as Lsmeans syringe/Lsmeans pump. *For LQI factor I, the non-inferiority threshold was set at 90.0% dimension was higher during the RP period whereas no dif- were positive, 15 were negative, and 2 were neutral. As a ference was found on other dimensions (Fig. 3). No difference whole, negative statements regarding RP were related to the on burden of the disease or burden of IgRTwas found between higher frequency of injections while some patients reported devices. Since comments from patients were sometimes not in they had difficulties in pushing the plunger. On a 7-point line with the PRISM score, additional analyses were conduct- Likert scale, overall satisfaction was rated rather good, good, ed on the comments. In total, 27 patients gave a comment for or extremely good by 26 patients out of 28 (92.9%) when the pump. Among them, 14 were rather positive, 6 were rather using pump, and by 15 patients out of 28 when using RP negative, and 7 were neutral. For the RP, of 25 statements, 8 (53.6%, p = 0.002). Despite this, eight patients declared that Fig. 2 Life quality index (PID- LQI). Legend: dark bars, pump; clear bars, syringe. Values are Lsmeans derived from the mixed model with device, period and sequence as fixed factors, and patient within sequence as 70 random factor Treatment interference Therapy-related problems Therapy seng J Clin Immunol (2018) 38:503–512 509 Fig. 3 SF36v2 health domain scales and norm-based component scores. Legend: dark bars, pump; clear bars, syringe. Values are Lsmeans derived from the mixed model with device, period and sequence as fixed factors, and patient within sequence as random factor they preferred RP (19 preferred pump and one patient did for premedication, time lost for injections, and time for not answer). Patients who preferred RP did not differ from getting rid of infusion material (Table 4). those who preferred pump regarding age, gender, occupa- tion, or duration of IgRT before entry into the study. Safety However, they were more often living alone (4 of 8 who preferred RP versus 1 of 19 respectively who preferred Infusions of gammanorm® 165 mg/mL were well tolerated. pump, p = 0.02). In total, 17 patients (14 during the pump period and 9 during the RP period) reported a total of 55 adverse events (30 during Trough IgG Levels and Incidence Rate of Infections the pump period and 25 during the RP period). Two adverse events were related to the study drug. One patient experienced At the end of each period, patients achieved similar trough general reactions after pump infusion and dropped out from IgG levels (9.4 ± 2.3 g/L). Of note, 7 (16.7%) and 5 (11.9%) the study before the RP period. One patient reported local patients had an IgG level below 6 g/L at the end of the pump pruritus when using RP but did not have a reaction with the or RP period, respectively. Twenty-six infections were report- pump. He switched back to pump for a few days and then ed by 14 patients during the pump period, 25 of which were of withdrew from the study. All adverse events were of mild or mild intensity and 1 was moderate. During the RP period, 19 moderate intensity. At least one local reaction was self- infections were recorded in 9 patients, 15 of which were mild, reported after 67.2% of RP infusions and 71.8% of pump 3 were moderate, and 1 was of severe intensity (pneumonia). infusions (p = 0.11). Local swelling reactions were less fre- Six patients had infections during both periods. The overall 3- quent with RP (p = 0.003) whereas local pain was less fre- month incidence rate of infections was 1.00 [0.68; 1.47] for quent than with pump (p = 0.003; Table 5). More specifically, the pump period and 0.76 [0.49; 1.20] for the RP period. Eight ten patients experienced at least one infusion associated with patients during the pump period and 6 patients during the RP local pain during the RP period but three patients accounted period (out of 28 patients) received antibiotics at least once. for 80 out of 102 (78.4%) infusions with RP associated with Costs Table 4 Analysis of costs per month Pump Rapid push Total direct costs were 1681 ± 628 EUR for pump and 1320 ± 702 EUR for RP. After excluding costs related to Direct costs including costs for 1681 ± 628 1320 ± 702 gammanorm® 165 mg/mL, monthly direct costs for ad- gammanorm® 165 mg/mL ministration were 536 ± 176 EUR for pump and 164 ± (EUR per month) Direct costs excluding costs for 536 ± 176 164 ± 323 323 EUR for RP. Administration costs were mainly driven gammanorm® 165 mg/mL by the cost of pump rented by the healthcare service pro- (EUR per month) vider (990 EUR per pump for the 3-month period). No Indirect costs (EUR per month) 64 ± 42 69 ± 35 difference was found on indirect costs that included costs 510 J Clin Immunol (2018) 38:503–512 Table 5 Local reactions in patients receiving SCIg [22]. Here, 3-month incidence rate was estimated to be 1.00 [0.68; 1.47] for pump period and Pump Rapid push 0.76 [0.49; 1.20] for the RP period, which was relatively in 355 infusions 989 infusions line with previous results. Although data collection during Redness 141 (39.7%) 386 (39.0%) longer periods is warranted, our results supported the efficacy Swelling 221 (62.3%) 524 (53.0%) of RP infusions. Induration 86 (24.2%) 226 (22.9%) As expected, RP infusions were five- to sixfold faster but Pruritus 6 (1.7%) 11 (1.1%) more than threefold more frequent than pump infusions. Pain 18 (5.1%) 102 (10.3%) Despite not reaching statistical significance, the difference in At least one local reaction 255 (71.8%) 665 (67.2%) satisfaction as assessed by TSQM was lower with RP than that with pump. One could not rule out the possibility that higher frequency of infusions may have played a role in these results. local pain. Six patients experienced at least one infusion asso- It may also be possible that, as a manual procedure, RP re- ciated with local pain during the P period but one patient quired more effort to deliver SCIg. However, validated tools accounted for 11 out of 18 (61.1%) infusions with P associated used in this study could not specifically highlight these issues. with local pain. One patient experienced pain during 92% of Patient interviews may be more suited to capture such feed- infusions with P and 88% of infusions with RP. backs. A dedicated study may be warranted to qualitatively explore them. Furthermore, our patients were accustomed to using pumps for a fairly long time before enrollment. Discussion Therefore, switch to RP may have disrupted their well- established routine care. It is possible that new rituals would This randomized, open-label, crossover study compared the require a habituation period exceeding 3 months. subcutaneous administration of IgG by an infusion pump Unfortunately, the duration of each crossover period was lim- followed by manual RP, or vice versa in patients who had a ited to 3 months and we have no data that could suggest that long history of SCIg with pump. Our study was based on a satisfaction would increase with time. Shapiro et al. [11]have rigorous prospective and controlled design in which each pa- reported the results from 104 PID patients who started SCIg tient was exposed to both types of administration in a random- and were given the choice of pump or RP. Patients were free to ized order. The anticipated benefits of RP were higher flow switch to the alternative method at any time during the study. rates, shorter duration of infusions, and lower volumes per Among these patients with no previous experience with SCIg, infusion. On the other hand, the higher frequency of injections 74 initially chose RP and only 9 (12.2%) wished to switch to pump during the study. On the other hand, among 29 patients could be a matter of concern for some patients. As planned by the protocol, Ig exposure was similar during each period. who started with pump, 13 (44.8%) chose to switch to RP. In Therefore, periods differed only in the volume of each infu- contrast to our study which included only adult patients, two sion and frequency of infusions. This ensured that any thirds of patients in Shapiro’scohort wereless than 18 years highlighted difference could not originate from different treat- old. Maybe most importantly, given that they had no previous ment exposures. On one hand, treatment interference on daily experience with pump, RP did not disturb any established life (PID-LQI factor I) was higher with RP than the one with routine. In our study, no difference was found on LQI factor pump; the non-inferiority hypothesis had to be rejected. On II (therapy-related problems) suggesting that no peculiar ad- the other hand, no difference was found on other LQI factors ministration difficulty arose when using RP. As expected, LQI (treatment-related problems or therapy setting), global satis- factor III (therapy setting) did not vary since pumps and RP faction, quality of life, and burden of the disease or of IgRT were both used at home. Our results were consistent with a delivery. Moreover, despite the majority of patients preferring previous preliminary study on patients in the context of a the pump administration, 8 patients out of 28 (28.6%) declared dedicated Patient Support Program aiming at accompanying to prefer RP. Serum IgG levels resulting from RP infusions patients’ move from hospital care to home treatment [23]. were similar to those from pump infusions as previously ob- No difference on age, gender, and occupation was found served [11]. Overall, the 3-month incidence infection rate was between patients who preferred RP rather than pump and similar during pump and RP periods; although in the latter those who preferred pump. Half of patients with a preference case, it tended to lower but was associated with the occurrence for RP were living alone. Unfortunately, we did not collect of one severe infection. The study was not designed to com- details on occupation which might have suggested that some pare efficacy outcomes such as infection rate, especially in patients with frequent professional travels would prefer RP or patients already receiving IgRT. Interestingly, others have pump. evaluated efficacy data in patients receiving SCIg. Ochs et Infusions were well tolerated independently of the delivery al. reported an annual infection rate of 4.43 per patient-year device as suggested by the limited number of patients who J Clin Immunol (2018) 38:503–512 511 Acknowledgments The authors would like to thank Bastide Le Confort took painkillers or other premedication before infusions. Of Médical for the pump device logistics. abdominal infusions with RP, 81.7% were accomplished with a flow rate superior to 35 mL/h. Similar data were reported by Authorship Contribution B. Bienvenu, G. Cozon, C. Hoarau, JF. Shapiro et al. [11]. Good tolerability of high flow rates has Viallard; E. Hachulla, Y. Mataix, AL Fauchais were investigators in the present study. B. Bienvenu was the coordinating investigator of the pres- also been demonstrated with SCIg administration by pump ent study. [24]. RP allows administrating fairly high volumes in a short Clerson P and Fardini Y work as independent statisticians and earned time without deteriorating the patient comfort. Local reactions fees from Octapharma to draft the manuscript. All the authors reviewed with pump were in general as frequent as those with RP. The the data and approved the final manuscript. rate of infusions associated with local pain was higher with RP. This was not anticipated since patients have been Compliance with Ethical Standards instructed to adapt the flow rate to their own comfort. The study was conducted in accordance with the ethical principles of the Painkiller premedication and pain experience during infusion Declaration of Helsinki, and the International Conference on were limited to few patients suggesting that patient component Harmonization Guideline for Good Clinical Practice. A French Ethical seems to play a marked role. Review Board (Comité de Protection des Personnes Sud-Est II de Lyon) Home-based SCIg infusions have already been shown to be approved this study. The National Agency for Medicines and Health Products Safety authorized the study. Written evidence of free and in- more cost effective than hospital-based IVIg infusions [25]. formed patient consents was obtained prior to any study procedure. Furthermore, Martin et al. demonstrated that home-based RP was less expensive than hospital-based IVIg with a $5736 Conflict of Interest B. Bienvenu, G. Cozon, C. Hoarau, JF. Viallard, and saving over 3 years [26]. Here, we showed that after exclusion E. Hachulla take part in several scientific boards and/or take part in sev- of costs directly related to Ig, monthly costs were 70% less eral studies led by Octapharma. JC. Crave works at Octapharma. with RP than with pump. It should be highlighted that indirect Open Access This article is distributed under the terms of the Creative costs, which are mainly driven by the time spent by the pa- Commons Attribution 4.0 International License (http:// tients for infusion were similar between the two methods. creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appro- Shorter but more frequent infusions with RP require the same priate credit to the original author(s) and the source, provide a link to the amount of time per month than weekly pump infusions. Creative Commons license, and indicate if changes were made. Finally, an important part of direct costs during the pump period was driven by the costs of the device itself including fixed costs and monthly rental costs. Fixed costs have been amortized over the pump period. Had the study been longer, these costs would have been amortized on the longer time and References direct costs would have been decreased. It seems unlikely, however, that administration per pump could be competitive 1. Al-Herz W, Bousfiha A, Casanova JL, Chapel H, Conley ME, against RP. Cunningham-Rundles C, et al. Primary immunodeficiency dis- Our study has some limitations. Firstly, it has been con- eases: an update on the classification from the international union of immunological societies expert committee for primary immuno- ducted in only adult patients and satisfaction regarding RP deficiency. Front Immunol. 2011;2:54. might be different in younger or pediatric patients. Secondly, 2. Gardulf A. Immunoglobulin treatment for primary antibody defi- the sample size was calculated in order to warrant sufficient ciencies: advantages of the subcutaneous route. BioDrugs. power for the comparison of LQI factor I. Comparisons of 2007;21(2):105–16. other variables such as TSQM-11 or dimensions of SF36v2 3. Busse PJ, Razvi S, Cunningham-Rundles C. Efficacy of intrave- nous immunoglobulin in the prevention of pneumonia in patients may lack power. with common variable immunodeficiency. J Allergy Clin Immunol. Frequency, dose, route of administration, home or infusion- 2002;109(6):1001–4. center administration, and the use of self- or healthcare- 4. Gardulf A, Nicolay U. Replacement IgG therapy and self-therapy at professional-administered infusion can be tailored to suit in- home improve the health-related quality of life in patients with dividual patient needs and circumstances [27]. Here, RP primary antibody deficiencies. Curr Opin Allergy Clin Immunol. 2006;6(6):434–42. proved to be preferred by about one third of the patients and 5. GardulfA,BjorvellH,Andersen V, Bjorkander J, Ericson D, to be more cost-effective than pump infusion. Our results sug- Froland SS, et al. Lifelong treatment with gammaglobulin for gest that RP can be a valuable and well-accepted alternative primary antibody deficiencies: the patients' experiences of sub- for SC self-administration of gammanorm® 165 mg/mL at cutaneous self-infusions and home therapy. J Adv Nurs. 1995;21(5):917–27. home for many PID patients. Since IgRT is a lifelong treat- 6. Nicolay U, Kiessling P, Berger M, Gupta S, Yel L, Roifman CM, et ment in PID patients, individualization of treatment is of par- al. Health-related quality of life and treatment satisfaction in North amount importance. RP is a new, safe, and easy-to-learn meth- American patients with primary immunedeficiency diseases receiv- od that complements the physician’s armamentarium when ing subcutaneous IgG self-infusions at home. J Clin Immunol. prescribing IgRT. 2006;26(1):65–72. 512 J Clin Immunol (2018) 38:503–512 7. Gardulf A, Nicolay U, Math D, Asensio O, Bernatowska E, Bock immunodeficiency diseases receiving lifelong immunoglobulin re- placement therapy. Qual Life Res. 2005;14(7):1683–91. A, et al. Children and adults with primary antibody deficiencies gain quality of life by subcutaneous IgG self-infusions at home. J 19. Atkinson MJ, Sinha A, Hass SL, Colman SS, Kumar RN, Brod M, Allergy Clin Immunol. 2004;114(4):936–42. et al. Validation of a general measure of treatment satisfaction, the 8. Abolhassani H, Sadaghiani MS, Aghamohammadi A, Ochs HD, treatment satisfaction questionnaire for medication (TSQM), using Rezaei N. Home-based subcutaneous immunoglobulin versus a national panel study of chronic disease. Health Qual Life hospital-based intravenous immunoglobulin in treatment of prima- Outcomes. 2004;2:12. ry antibody deficiencies: systematic review and meta analysis. J 20. Direction générale de l’offre de soins. Guide pour le suivi de la Clin Immunol. 2012;32(6):1180–92. masse salariale. Ministère chargé de la santé. 2014 [cited 21/03/ 9. Shapiro RS. Why I use subcutaneous immunoglobulin (SCIG). J 2017]; Available from: http://social-sante.gouv.fr/IMG/pdf/dgos_ Clin Immunol. 2013;33(Suppl 2):S95–8. guide_suivi_masse_salariale_2014.pdf 10. Kobrynski L. Subcutaneous immunoglobulin therapy: a new option 21. Chaput H, Pinel C, Wilner L. Salaires dans le secteur privé et les for patients with primary immunodeficiency diseases. Biologics. entreprises publiques - En 2013, le salaire net moyen baisse de 0,3% 2012;6:277–87. en euros constants. Insee Première 2015 16/09/2015;1565. 11. Shapiro R. Subcutaneous immunoglobulin therapy by rapid push is 22. Ochs HD, Gupta S, Kiessling P, Nicolay U, Berger M. Safety and preferred to infusion by pump: a retrospective analysis. J Clin efficacy of self-administered subcutaneous immunoglobulin in pa- Immunol. 2010;30(2):301–7. tients with primary immunodeficiency diseases. J Clin Immunol. 12. Shapiro RS. Subcutaneous immunoglobulin: rapid push vs. infusion 2006;26(3):265–73. pump in pediatrics. Pediatr Allergy Immunol. 2013;24(1):49–53. 23. Reniers A, Heijmans C, Nols N, Rombaut B, Peche R. 13. Gardulf A. Clinical experiences in primary and secondary immu- Subcutaneous administration of gammanorm in immune-deficient nodeficiencies and immune-mediated conditions using patients by rapid push: report of the Belgian experience. J Clin gammanorm((R)). Immunotherapy. 2016;8(5):633–47. Immunol; 2014: SPRINGER/PLENUM PUBLISHERS 233 14. Bharmal M, Payne K, Atkinson MJ, Desrosiers MP, Morisky DE, SPRING ST, NEW YORK, NY 10013 USA; 2014. p. S507-S. Gemmen E. Validation of an abbreviated Treatment Satisfaction 24. Hansen S, Gustafson R, Smith CI, Gardulf A. Express subcutane- Questionnaire for Medication (TSQM-9) among patients on antihy- ous IgG infusions: decreased time of delivery with maintained safe- pertensive medications. Health Qual Life Outcomes. 2009;7:36. ty. Clin Immunol. 2002;104(3):237–41. 15. Ware JESK, Kosinski M. SF36 health survey. Manual and interpre- 25. Beaute J, Levy P, Millet V, Debre M, Dudoit Y, Le Mignot L, et al. tation guide. Lincoln: Quality-Metrics Inc.; 2000. Economic evaluation of immunoglobulin replacement in patients 16. Buchi S, Buddeberg C, Klaghofer R, Russi EW, Brandli O, with primary antibody deficiencies. Clin Exp Immunol. 2009;160: Schlosser C, et al. Preliminary validation of PRISM (pictorial rep- 240–5. resentation of illness and self measure)—a brief method to assess 26. Martin A, Lavoie L, Goetghebeur M, Schellenberg R. Economic suffering. Psychother Psychosom. 2002;71(6):333–41. benefits of subcutaneous rapid push versus intravenous immuno- 17. Buchi S, Sensky TPRISM. Pictorial representation of illness and globulin infusion therapy in adult patients with primary immune self measure. A brief nonverbal measure of illness impact and ther- deficiency. Transfus Med. 2013;23(1):55–60. apeutic aid in psychosomatic medicine. Psychosomatics. 27. Jolles S, Orange JS, Gardulf A, Stein MR, Shapiro R, Borte M, et 1999;40(4):314–20. al. Current treatment options with immunoglobulin G for the indi- 18. Nicolay U, Haag S, Eichmann F, Herget S, Spruck D, Gardulf A. vidualization of care in patients with primary immunodeficiency Measuring treatment satisfaction in patients with primary disease. Clin Exp Immunol. 2015;179(2):146–60. Affiliations 1,2 3 4 4 1 5 Boris Bienvenu & Grégoire Cozon & Yves Mataix & Dominique Lachaud & Antoine Alix & Cyrille Hoarau & 5 6 6 7 7 8 Daniel Antier & Eric Hachulla & Sylvie Brice & Jean-François Viallard & Stéphanie Tamisier & Anne-Laure Fauchais & 8 9 9 10 3 Françoise Renon-Carron & Pierre Clerson & Yann Fardini & Jean-Charles Crave & Pierre Miossec 1 6 Hôpital Côte de Nacre, CHU Caen, Caen, France Hôpital Claude Huriez, CHRU Lille, Lille, France 2 7 Hôpital Saint Joseph, Marseille, France Hôpital Haut-Lévêque, CHU Bordeaux, Bordeaux, France 3 8 Centre Hospitalier Edouard Herriot, Lyon, France Hôpital Dupuytren, CHU Limoges, Limoges, France 4 9 Clinique Mutualiste, Lyon, France Soladis Clinical Studies, Roubaix, France 5 10 Hôpital Bretonneau, CHRU Tours, Tours, France Octapharma France, Boulogne-Billancourt, France http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Immunology Springer Journals
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Biomedicine; Immunology; Infectious Diseases; Internal Medicine; Medical Microbiology
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Abstract

Purpose Subcutaneous immunoglobulin replacement therapy (IgRT) may be administered once a week with a pump or every other day with a syringe (rapid push). The objective of the study was to compare the impact of pump and rapid push infusions on patient’s life quality index (LQI). Methods This study was a randomized, crossover, multicenter, non-inferiority trial conducted in adults with primary immunode- ficiency (PID) accustomed to weekly infusions at home by pump. Patients used pump or rapid push for 3 months each according to the randomized sequence. Main criterion was PID-LQI factor I (treatment interference). Non-inferiority ratio was set at 90%. Results Thirty patients entered the study; 28 completed the two periods. IgRTexposure was similar during each period. At the end of each period, mean LQI factor 1 was 87.0 (IC95% [80.3; 94.3]) and 77.80 (IC95% [71.5; 84.7]) for pump and rapid push, respectively. There was a slightly larger effect of rapid push on treatment interference than with pump so that the primary endpoint could not be met. No difference was found on other LQI components, satisfaction (TSQM), or quality of life (SF36v2). Eight patients declared to prefer rapid push while 19 others preferred pump. Of rapid push infusions, 67.2% led to local reactions vs 71.8% of pump infusions (p = 0.11) illustrating its good tolerance. Rapid push and pump infusions achieved similar trough IgG levels with similar incidence of infections. Rapid push saved 70% of administration cost when compared to pump. Conclusions Since IgRT is a lifelong treatment in PID patients, individualization of treatment is of paramount importance. Rapid push is a new administration method in the physician’s armamentarium which is preferred by some patients and is cost-effective. ClinicalTrials.gov Identifier NCT02180763 Clinical Implications Self-administration of small volumes of immunoglobulins at home, every other day, using a syringe (rapid push) is a cost-effective alternative to administration of larger volumes by pump once a week. Capsule Summary This study compared subcutaneous infusions of immunoglobulins either weekly via a pump or every other day via a syringe (rapid push). Rapid push is preferred by some patients and is cost-effective, therefore completing a physician’s armamentarium. Boris Bienvenu and Grégoire Cozon contributed equally to this work. * Boris Bienvenu Jean-François Viallard bbienvenu@hopital-saint-joseph.fr jean-francois.viallard@chu-bordeaux.fr Grégoire Cozon Anne-Laure Fauchais gregoire.cozon@chu-lyon.fr anne-Laure.Fauchais@chu-limoges.fr Yves Mataix Pierre Clerson y.mataix@clinique-mutualiste-lyon.com pclerson@soladis.fr Cyrille Hoarau Jean-Charles Crave hoarauc@univ-tours.fr jean-charles.crave@octapharma.fr Eric Hachulla eric.hachulla@chru-lille.fr Extended author information available on the last page of the article 504 J Clin Immunol (2018) 38:503–512 . . . Keywords Primary immunodeficiency PID immunoglobulin replacement therapy home treatment rapid push Abbreviations SCIg. Further objectives included the comparison of other CI Confidence interval components of specific PID patients’ quality of life, generic Ig Immunoglobulin quality of life, burden of disease, and of IgRT and patient’s IgRT Immunoglobulin replacement therapy preference for pump or RP. In addition, the study aimed to IV IgIntravenous immunoglobulin describe the conditions of infusions and to provide details on PID Primary immunodeficiency costs. SCIg Subcutaneous immunoglobulin Study Design Introduction GAMEXPRESS was a prospective, interventional, non-infe- riority, longitudinal, randomized, crossover multicenter trial More than 50% of primary immunodeficiencies (PIDs) are conducted in France in adult patients with PID receiving characterized by an altered antibody production [1], exposing SCIg at home. Patients had to have a history of ongoing the patients to an increased risk of repeated and severe infec- home-based SCIg with gammanorm® 165 mg/mL tions [2]. Immunoglobulin replacement therapy (IgRT) restores (Octapharma AG, Lachen, Switzerland) by pump for at least sufficiently high serum levels of IgG, decreases the incidence of 1 month at the time of enrollment. Eligible patients were ran- infections [3], prevents complications such as bronchiectasis, domized (1:1) to pump and then RP or reverse sequence. Each and improves patient’s quality of life [4]. IgRT is administered crossover period lasted 3 months. Patients were free to switch intravenously (IVIg) or subcutaneously (SCIg). SCIg infusion from pump to RP and inversely at any time without being achieves IgG trough levels and an efficacy similar to those of dropped out. The dose of immunoglobulins could be adapted IVIg infusion but with lower incidence of general reactions [4], during the study as in routine care. better health-related quality of life, higher patient’s satisfaction [5–7], and faster functional recovery with less time off work [8, Immunoglobulins 9]. Local reactions, however, are more frequent although they tend to decrease with time and patient’sexperience [10]. SCIg High viscosity of some IgG solutions can make it difficult to products are often self-administered at home, therefore modest- handle the RP plunger by the patient, thus justifying the choice ly disturbing daily activities and reinforcing patient’s autonomy of a low-viscosity product. gammanorm® 165 mg/mL has the [6, 7]. Usually, patients use an infusion pump and self- lowest viscosity of all SCIg products available and is well administer SCIg once a week. SCIg by pump takes 1 to 2 h tolerated [13]. SCIg was to be administered around once a even with several catheters infusing several sites all at once. week during the pump period, and around every other day A new method for SCIg administration has recently been (three times a week) during the RP period. proposed [11, 12]. Rapid and manual administration of SCIg Patients were individually trained by the center. The first using a syringe, so-called rapid push (RP), would decrease the infusion of each period was performed in a hospital in the duration of administration (around 10 min per injection at one presence of an investigator and/or a nurse. Individual phone or two sites simultaneously) but imposes more frequent infu- contacts were set up to accompany the patients during the first sions. Replacing infusion pumps by RP would also reduce week of infusion(s) at home. The proposed maximum infusion material costs. Those data resulting from retrospective studies rate was set at 1–2 mL/min in order to allow fast diffusion of urged for a rigorous prospective controlled study to further the product, limit the risk of local untoward reactions, and determine the impact of RP in PID patients. To this end, this maintain the patient’s comfort. Patients were allowed to infuse randomized crossover multicenter study compared the feasi- several sites all at once. They were free to premedicate with bility, tolerability, and acceptance of RP and the current reg- painkillers, non-steroid anti-inflammatory drugs, or cortico- istered administration in adult PID patients. steroids before infusion. Methods Evaluations Objectives Patients were evaluated at enrollment (baseline values) andattheendofeach3-monthperiod.Atthe end of The main objective was to compare RP and pump administra- the study, the patients were asked which delivery device tion on interference on daily life in PID patients receiving they had preferred. J Clin Immunol (2018) 38:503–512 505 Impact of SCIg infusions on patient’sdaily life waseval- Statistics uated using the PID-specific life quality index (LQI) ques- tionnaire. The PID-LQI questionnaire involves 15 items rat- Results were expressed as mean ± standard deviation (m ± ed on a 7-point Likert scale ranging from “Extremely Good” SD) or median [first quartile; third quartile] and numbers (per- to “Extremely Poor.” Since costs for IgRT are entirely cov- centage). Percentages were calculated on the number of non- ered by the French Social Insurance System, two questions missing data. All analyses were performed on an intention-to- relatedtoeconomic concerns were deleted.The 13remaining treat basis. A sensitivity analysis was performed on a per- items are grouped into three subsets measuring the impact of protocol subset and provided very similar results (data not the treatment on patient quality of life: factor I (treatment shown). Calculation of LQI factors [18], derivation of interference), factor II (therapy-related problems), factor III TSQM dimensions [19], and calculation of standardized di- (therapy settings). Results range from 0 (maximal concern) mensions and summary components of the SF36v2 scale [15] to 100 (no concern). were performed as recommended by their authors. Costs were Satisfaction regarding SCIg infusion was evaluated by calculated based on public prices, VAT excluded. Costs for the “Treatment Satisfaction Questionnaire for Medication” nurses were based on the time in hours spent for the infusion (TSQM-11), a generic, self-administered, 11-item scale multiplied by 29.80 EUR [20]. Time spent for infusion by the [14] which evaluates efficacy, ease of use, and overall pa- patient was valued on the basis of the median income in tient satisfaction. In addition, patients rated their overall France (11.68 EUR/h) [21]. For premedication, we calculated satisfaction regarding IgRT at the end of each period, using a mean price for each type of treatment (for example, the mean a 7-point Likert scale. Quality of life was assessed by the cost for painkillers is the mean of public prices for all available SF36v2 scale [15]. The 36 items were grouped into eight painkillers) and costs were calculated by unit. Costs were dimensions and two summary scores, the physical compo- expressed on a monthly basis (30 days). nent summary score and the mental component summary Continuous variables were analyzed using a mixed score, were calculated. model with delivery device, period, and sequence as fixed PRISM (Pictorial Representation of Illness and Self- factors and patient within sequence as random factor. The Measure) quantitatively assessed the patient’s perception effect size associated to delivery device was estimated by of the burden he/she felt due to his/her illness [16, 17]. the ratio LQI − factor I /LQI − factor I .Results were RP pump This test is based on a non-verbal visualization technique: expressed after exponentiation of the geometric mean of a rectangular A4-size metal plate represents the life of the ratios with a two-sided 95% confidence interval (CI). The patient and a yellow disc located in the lower right corner lower limit of the CI was compared to the non-inferiority of the plate represents the patient. The investigator asked threshold of 0.90. Same methods were used for the other the patient to place a red disc on the plate so as to represent variables although not referring to a non-inferiority the disease in his/her life at the time of the test. The dis- threshold. tance between the centers of the discs quantifies the pa- The 3-month incidence of infections was estimated by a tient’s burden related to the intrusion of the disease in Poisson regression model using the natural logarithm of his/her life. The patients were asked to quantify separately follow-up duration (expressed as a multiple of 3 months) as the burden of the disease and that of IgRT, and provide offset term. The proportion of patients with IgG level < 6 g/L additional comments. Since the use of PRISM is not com- were described for each delivery device along with a two- mon practice, the investigators were trained prior to study sided 95% CI (Fisher’s exact method). Proportions of patients start. rating their satisfaction as rather good or extremely good re- Trough serum IgG levels and serum creatinine were mea- garding the P or RP were compared using Fisher’s exact test. sured at the end of each crossover period. Mild (not interfering Proportions of patients with local reactions, proportions of with daily activities), moderate (interfering with daily activi- infusions with local swelling, and proportions of infusions ties), or severe infections (including meningitis, pneumonia, with local pain were compared using two-proportion z test. sepsis, osteomyelitis, and visceral abscesses) were reported The analyses were performed using the SAS 9.4 software for each period. (SAS Institute, Cary, NC, USA). For each infusion, the patients reported the infused dose, the site(s) of infusion, and the number of pumps used (for the pump period), the duration, and the premedication they took Results before infusion. In parallel, the nurses who followed the pa- tients over the study were asked to report details on the mate- Patients rials that had been used for the infusions. Adverse events were collected by the investigator at each Thirty patients from six centers entered the study. Two pa- visit and patients reported local reactions on the diary. tients who prematurely withdrew for adverse events and did 506 J Clin Immunol (2018) 38:503–512 not complete the two periods of the study did not document Infusions the LQI scale and were excluded from the intention-to-treat population (Fig. 1). Patient exposure was similar during pump and RP period. A Patients were aged from 23 to 79 years. All but five total dose of 1101.3 ± 569.0 mg/kg was administered with were living in couple or family; around half of patients pump and 1101.2 ± 543.3 mg/kg with RP. In total, 355 infu- had a professional/school occupation (Table 1). Most fre- sions by pump and 989 infusions by RP have been document- quent PIDs were common variable immunodeficiency ed (Table 2). All infusions were self-administered, except the ( n = 17) and hypogammaglobulinemia ( n =8). first infusion of each period. Patients received a mean of 12.2 Agammaglobulinemia, severe combined variable immunode- ± 5.0 pump infusions and 38.0 ± 14.7 RP infusions. Mean ficiency, and selective deficiency of IgG subclasses were less interval between infusions was 6.6 ± 3.2 days (median frequent (one patient each). Median time since PID diagnosis 7.0 days) and 2.1 ± 1.1 days (median 2.0 days) with pump was 6.9 [interquartile range 3.8; 22.5] years. Patients had a and RP, respectively. The total dose administered per infusion mean history of ongoing home-based SCIg with was threefold lesser with RP (30.5 ± 14.2 mg/kg) than with gammanorm® 165 mg/mL via an infusion pump of 1.8 ± pump (94.8 ± 44.3 mg/kg) but patients received the same 2.4 years. amount of Ig over each period. Most infusions were done in Assessed for eligibility (n=31) Enrollment Excluded (n=1) Withdrew consent before administration (n=1) Randomized (n=30) Allocation Allocated to intervention (Pump - n=16) Allocated to intervention (Rapid Push - n=14) Received allocated intervention (n=16) Received allocated intervention (n=14) Allocated to intervention (Pump - n=14) Allocated to intervention (Rapid Push - n=16) Received allocated intervention (n=15) Received allocated intervention (n=14) Did not receive intervention Discontinued intervention for AEs (n=1) Did not receive intervention (n=1) st Prematurely withdrew during 1 sequence (n=1) Analysis Full analysis set (n=28) Excluded from analysis (n=2) No LQI at V2 and V3 (n=2) Fig. 1 CONSORT flowchart of the study J Clin Immunol (2018) 38:503–512 507 Table 1 Characteristics of patients 63 out of 86 (73.2%) infusions with RP associated with prior painkiller intake. Five patients took at least one painkiller prior Number of patients N =30 to infusion with P and two patients accounted for 23 out of 36 Age (years) 49.3 ± 17.8 (63.9%) infusions with P. One patient took painkillers for Male gender 7 (23.3%) 100% of infusions with P and 97.1% infusions with RP and Female gender 23 (73.7%) counted for 12 intakes during P period and 33 intakes during Weight (kg) 64.4 ± 16.5 RP period. Living alone 5 (16.7%) Professional/school occupation 14 (46.7%) Patient Satisfaction and Quality of Life Age at PID diagnosis (years)* 37.0 [24.0; 51.0] Continuous variables are summarized as mean ± SD unless otherwise The LQI factor I (treatment interference) was very high at specified; *median and interquartile range; categorical variables are de- baseline reflecting that daily life was only slightly altered by scribed as the number of non-missing data and percentage home-based SCIg infusion by pump (Table 3). At the end of each period, mean LQI factor 1 was 87.0 (IC95% [80.3; 94.3]) and 77.80 (IC95% [71.5; 84.7]) for pump and RP, respective- the abdomen. More than one site was used in 77% of pump ly. Ratio of least square means (Lsmeans) was 89.4% [80.9%; infusions but in less than 2% of RP infusions. On abdominal 99.9%], therefore under the non-inferiority threshold of 90% sites, median flow rate was 25 mL/h with pump and 60 mL/h (Fig. 2). LQI factors II and III were not impacted by the de- with RP. Smaller volumes and higher flow rates resulted in livery device. At enrollment, TSQM was 73.1 ± 15.4 and sat- quicker infusions with RP (range 2 to 70 min, mean 14.1 ± isfaction decreased during the study with poorer results during 7.9 min; median 10.0 min) than those with pump (up to the RP period than those during the pump period. However, 180min;mean81.3 ± 44.6min;median75.0min). the difference between devices did not reach statistical signif- Premedication with painkillers was reported in not more than icance. Quality of life was high at baseline. Apart from general 10% of infusions whatever the delivery device was. More health, other dimensions of SF36v2 were only slightly lower specifically, seven patients took at least one painkiller prior than those in the general population (norm-based values for to infusion during the RP period. Two patients accounted for healthy subjects are 50 for each dimension). The vitality Table 2 Characteristics of Infusions with pump Infusions with rapid push infusions N =355 N =989 Duration (min) 81.3 ± 44.6 14.1 ± 7.9 Dose administered per infusion (mg/kg) 94.8 ± 44.3 30.5 ± 14.2 Abdomen 310 (87.3%) 802 (81.1%) Thigh 23 (6.5%) 80 (8.1%) Other sites 1 (3.1%) 42 (4.2%) Unknown site 21 65 One site/2 sites/3 sites/4 sites/unknown 74/202/24/21/34 908/16/0/0/65 Volume (mL)* 32.6 ± 15.7 11.2 ± 4.4 40.0 [30.0; 50.0] 10.0 [10.0;10.0] Flow rate in abdomen (mL/h) 30.9 ± 20.9 54.0 ± 23.3 Flow rate in abdomen [0–15 mL/h] 33 (15.1%) 2 (0.3%) Flow rate in abdomen [15–25 mL/h] 85 (39.0%) 35 (4.9%) Flow rate in abdomen [25–35 mL/h] 32 (14.7%) 93 (13.1%) Flow rate in abdomen [> 35 mL/h] 68 (31.2%) 581 (81.7%) Flow rate in abdomen unknown 92 + 23 + 11 91 + 5 + 42 Time to perform infusions (min) 81.3 ± 44.6 14.1 ± 7.9 Premedication with painkillers 36 (10.1%) 86 (8.7%) Premedication with NSAIDs 14 (3.9%) 10 (1.0%) Continuous variables are summarized as mean ± SD unless otherwise specified; *median and interquartile range; categorical variables are described as the number of non-missing data and percentage; NSAIDs, non-steroid anti- inflammatory drugs 508 J Clin Immunol (2018) 38:503–512 Table 3 Patient’s satisfaction and Baseline Pump Rapid push Ratio* quality of life N =28 N =28 N =28 N =28 LQI factor I* 83.5 ± 12.4 87.0 [80.3; 94.3] 77.8 [71.5; 84.7] 89.4 [80.9; 99.9] LQI factor II 86.1 ± 12.9 83.6 [77.8; 89.8] 78.5 [72.8;84.7] 94.0 [86.6; 102.1] LQI factor III 94.1 ± 7.9 92.0 [87.3; 97.0] 88.0 [83.2; 93.1] 95.7 [88.6; 103.2] TSQM 73.1 ± 15.4 61.8 [49.6; 77.1] 53.4 [42.4; 67.2] 86.3 [64.2; 116.0] SF36v2: Physical functioning 50.0 ± 8.1 48.5 [44.5; 52.8] 49.9 [45.8; 54.4] 102.9 [98.1; 107.9] SF36v2: Role physical 47.1 ± 12.1 48.7 [44.6; 53.2] 50.0 [45.8; 54.7] 102.8 [98.0; 107.9] SF36v2: Bodily pain 49.6 ± 10.0 49.5 [45.5; 53.9] 49.0 [44.9; 53.5] 99.0 [93.2; 105.2] SF36v2: General health 40.3 ± 11.5 40.2 [36.2; 44.7] 40.1 [36.0; 44.7] 99.7 [92.7; 107.3] SF36v2: Vitality 49.1 ± 11.0 47.0 [43.0; 51.5] 50.9 [46.3; 55.8] 108.2 [100.6; 116.3] SF36v2: Social functioning 46.1 ± 11.6 47.0 [42.6; 51.8] 44.4 [40.1; 49.1] 94.3 [86.4; 103.0] SF36v2: Role emotional 45.9 ± 14.1 47.0 [40.9; 54.0] 43.7 [37.8; 50.5] 93.0 [81.0; 106.7] SF36v2: Mental health 48.9 ± 11.8 47.1 [42.6; 52.0] 47.6 [42.9; 52.9] 101.2 [93.5; 109.6] SF36v2: Physical component 47.5 ± 7.9 47.6 [44.2; 51.3] 48.0 [44.5; 51.7] 100.7 [97.5; 104.1] summary SF36: Mental component 46.7 ± 12.9 46.0 [41.1; 51.4] 45.7 [40.7; 51.3] 99.3 [90.5; 109.0] summary PRISM–Burden of disease 12.0 ± 7.5 9.5 [6.6; 13.7] 9.5 [6.6; 13.7] 100.7 [79.9; 127.1] PRISM–Burden of delivery 10.1 ± 5.6 10.2 [7.9; 13.3] 7.9 [6.1; 10.4] 77.5 [53.3; 112.5] device At baseline results are summarized as mean ± SD; at the end of each period, results are Lsmeans [95%CI]; ratios are calculated as Lsmeans syringe/Lsmeans pump. *For LQI factor I, the non-inferiority threshold was set at 90.0% dimension was higher during the RP period whereas no dif- were positive, 15 were negative, and 2 were neutral. As a ference was found on other dimensions (Fig. 3). No difference whole, negative statements regarding RP were related to the on burden of the disease or burden of IgRTwas found between higher frequency of injections while some patients reported devices. Since comments from patients were sometimes not in they had difficulties in pushing the plunger. On a 7-point line with the PRISM score, additional analyses were conduct- Likert scale, overall satisfaction was rated rather good, good, ed on the comments. In total, 27 patients gave a comment for or extremely good by 26 patients out of 28 (92.9%) when the pump. Among them, 14 were rather positive, 6 were rather using pump, and by 15 patients out of 28 when using RP negative, and 7 were neutral. For the RP, of 25 statements, 8 (53.6%, p = 0.002). Despite this, eight patients declared that Fig. 2 Life quality index (PID- LQI). Legend: dark bars, pump; clear bars, syringe. Values are Lsmeans derived from the mixed model with device, period and sequence as fixed factors, and patient within sequence as 70 random factor Treatment interference Therapy-related problems Therapy seng J Clin Immunol (2018) 38:503–512 509 Fig. 3 SF36v2 health domain scales and norm-based component scores. Legend: dark bars, pump; clear bars, syringe. Values are Lsmeans derived from the mixed model with device, period and sequence as fixed factors, and patient within sequence as random factor they preferred RP (19 preferred pump and one patient did for premedication, time lost for injections, and time for not answer). Patients who preferred RP did not differ from getting rid of infusion material (Table 4). those who preferred pump regarding age, gender, occupa- tion, or duration of IgRT before entry into the study. Safety However, they were more often living alone (4 of 8 who preferred RP versus 1 of 19 respectively who preferred Infusions of gammanorm® 165 mg/mL were well tolerated. pump, p = 0.02). In total, 17 patients (14 during the pump period and 9 during the RP period) reported a total of 55 adverse events (30 during Trough IgG Levels and Incidence Rate of Infections the pump period and 25 during the RP period). Two adverse events were related to the study drug. One patient experienced At the end of each period, patients achieved similar trough general reactions after pump infusion and dropped out from IgG levels (9.4 ± 2.3 g/L). Of note, 7 (16.7%) and 5 (11.9%) the study before the RP period. One patient reported local patients had an IgG level below 6 g/L at the end of the pump pruritus when using RP but did not have a reaction with the or RP period, respectively. Twenty-six infections were report- pump. He switched back to pump for a few days and then ed by 14 patients during the pump period, 25 of which were of withdrew from the study. All adverse events were of mild or mild intensity and 1 was moderate. During the RP period, 19 moderate intensity. At least one local reaction was self- infections were recorded in 9 patients, 15 of which were mild, reported after 67.2% of RP infusions and 71.8% of pump 3 were moderate, and 1 was of severe intensity (pneumonia). infusions (p = 0.11). Local swelling reactions were less fre- Six patients had infections during both periods. The overall 3- quent with RP (p = 0.003) whereas local pain was less fre- month incidence rate of infections was 1.00 [0.68; 1.47] for quent than with pump (p = 0.003; Table 5). More specifically, the pump period and 0.76 [0.49; 1.20] for the RP period. Eight ten patients experienced at least one infusion associated with patients during the pump period and 6 patients during the RP local pain during the RP period but three patients accounted period (out of 28 patients) received antibiotics at least once. for 80 out of 102 (78.4%) infusions with RP associated with Costs Table 4 Analysis of costs per month Pump Rapid push Total direct costs were 1681 ± 628 EUR for pump and 1320 ± 702 EUR for RP. After excluding costs related to Direct costs including costs for 1681 ± 628 1320 ± 702 gammanorm® 165 mg/mL, monthly direct costs for ad- gammanorm® 165 mg/mL ministration were 536 ± 176 EUR for pump and 164 ± (EUR per month) Direct costs excluding costs for 536 ± 176 164 ± 323 323 EUR for RP. Administration costs were mainly driven gammanorm® 165 mg/mL by the cost of pump rented by the healthcare service pro- (EUR per month) vider (990 EUR per pump for the 3-month period). No Indirect costs (EUR per month) 64 ± 42 69 ± 35 difference was found on indirect costs that included costs 510 J Clin Immunol (2018) 38:503–512 Table 5 Local reactions in patients receiving SCIg [22]. Here, 3-month incidence rate was estimated to be 1.00 [0.68; 1.47] for pump period and Pump Rapid push 0.76 [0.49; 1.20] for the RP period, which was relatively in 355 infusions 989 infusions line with previous results. Although data collection during Redness 141 (39.7%) 386 (39.0%) longer periods is warranted, our results supported the efficacy Swelling 221 (62.3%) 524 (53.0%) of RP infusions. Induration 86 (24.2%) 226 (22.9%) As expected, RP infusions were five- to sixfold faster but Pruritus 6 (1.7%) 11 (1.1%) more than threefold more frequent than pump infusions. Pain 18 (5.1%) 102 (10.3%) Despite not reaching statistical significance, the difference in At least one local reaction 255 (71.8%) 665 (67.2%) satisfaction as assessed by TSQM was lower with RP than that with pump. One could not rule out the possibility that higher frequency of infusions may have played a role in these results. local pain. Six patients experienced at least one infusion asso- It may also be possible that, as a manual procedure, RP re- ciated with local pain during the P period but one patient quired more effort to deliver SCIg. However, validated tools accounted for 11 out of 18 (61.1%) infusions with P associated used in this study could not specifically highlight these issues. with local pain. One patient experienced pain during 92% of Patient interviews may be more suited to capture such feed- infusions with P and 88% of infusions with RP. backs. A dedicated study may be warranted to qualitatively explore them. Furthermore, our patients were accustomed to using pumps for a fairly long time before enrollment. Discussion Therefore, switch to RP may have disrupted their well- established routine care. It is possible that new rituals would This randomized, open-label, crossover study compared the require a habituation period exceeding 3 months. subcutaneous administration of IgG by an infusion pump Unfortunately, the duration of each crossover period was lim- followed by manual RP, or vice versa in patients who had a ited to 3 months and we have no data that could suggest that long history of SCIg with pump. Our study was based on a satisfaction would increase with time. Shapiro et al. [11]have rigorous prospective and controlled design in which each pa- reported the results from 104 PID patients who started SCIg tient was exposed to both types of administration in a random- and were given the choice of pump or RP. Patients were free to ized order. The anticipated benefits of RP were higher flow switch to the alternative method at any time during the study. rates, shorter duration of infusions, and lower volumes per Among these patients with no previous experience with SCIg, infusion. On the other hand, the higher frequency of injections 74 initially chose RP and only 9 (12.2%) wished to switch to pump during the study. On the other hand, among 29 patients could be a matter of concern for some patients. As planned by the protocol, Ig exposure was similar during each period. who started with pump, 13 (44.8%) chose to switch to RP. In Therefore, periods differed only in the volume of each infu- contrast to our study which included only adult patients, two sion and frequency of infusions. This ensured that any thirds of patients in Shapiro’scohort wereless than 18 years highlighted difference could not originate from different treat- old. Maybe most importantly, given that they had no previous ment exposures. On one hand, treatment interference on daily experience with pump, RP did not disturb any established life (PID-LQI factor I) was higher with RP than the one with routine. In our study, no difference was found on LQI factor pump; the non-inferiority hypothesis had to be rejected. On II (therapy-related problems) suggesting that no peculiar ad- the other hand, no difference was found on other LQI factors ministration difficulty arose when using RP. As expected, LQI (treatment-related problems or therapy setting), global satis- factor III (therapy setting) did not vary since pumps and RP faction, quality of life, and burden of the disease or of IgRT were both used at home. Our results were consistent with a delivery. Moreover, despite the majority of patients preferring previous preliminary study on patients in the context of a the pump administration, 8 patients out of 28 (28.6%) declared dedicated Patient Support Program aiming at accompanying to prefer RP. Serum IgG levels resulting from RP infusions patients’ move from hospital care to home treatment [23]. were similar to those from pump infusions as previously ob- No difference on age, gender, and occupation was found served [11]. Overall, the 3-month incidence infection rate was between patients who preferred RP rather than pump and similar during pump and RP periods; although in the latter those who preferred pump. Half of patients with a preference case, it tended to lower but was associated with the occurrence for RP were living alone. Unfortunately, we did not collect of one severe infection. The study was not designed to com- details on occupation which might have suggested that some pare efficacy outcomes such as infection rate, especially in patients with frequent professional travels would prefer RP or patients already receiving IgRT. Interestingly, others have pump. evaluated efficacy data in patients receiving SCIg. Ochs et Infusions were well tolerated independently of the delivery al. reported an annual infection rate of 4.43 per patient-year device as suggested by the limited number of patients who J Clin Immunol (2018) 38:503–512 511 Acknowledgments The authors would like to thank Bastide Le Confort took painkillers or other premedication before infusions. Of Médical for the pump device logistics. abdominal infusions with RP, 81.7% were accomplished with a flow rate superior to 35 mL/h. Similar data were reported by Authorship Contribution B. Bienvenu, G. Cozon, C. Hoarau, JF. Shapiro et al. [11]. Good tolerability of high flow rates has Viallard; E. Hachulla, Y. Mataix, AL Fauchais were investigators in the present study. B. Bienvenu was the coordinating investigator of the pres- also been demonstrated with SCIg administration by pump ent study. [24]. RP allows administrating fairly high volumes in a short Clerson P and Fardini Y work as independent statisticians and earned time without deteriorating the patient comfort. Local reactions fees from Octapharma to draft the manuscript. All the authors reviewed with pump were in general as frequent as those with RP. The the data and approved the final manuscript. rate of infusions associated with local pain was higher with RP. This was not anticipated since patients have been Compliance with Ethical Standards instructed to adapt the flow rate to their own comfort. The study was conducted in accordance with the ethical principles of the Painkiller premedication and pain experience during infusion Declaration of Helsinki, and the International Conference on were limited to few patients suggesting that patient component Harmonization Guideline for Good Clinical Practice. A French Ethical seems to play a marked role. Review Board (Comité de Protection des Personnes Sud-Est II de Lyon) Home-based SCIg infusions have already been shown to be approved this study. The National Agency for Medicines and Health Products Safety authorized the study. Written evidence of free and in- more cost effective than hospital-based IVIg infusions [25]. formed patient consents was obtained prior to any study procedure. Furthermore, Martin et al. demonstrated that home-based RP was less expensive than hospital-based IVIg with a $5736 Conflict of Interest B. Bienvenu, G. Cozon, C. Hoarau, JF. Viallard, and saving over 3 years [26]. Here, we showed that after exclusion E. Hachulla take part in several scientific boards and/or take part in sev- of costs directly related to Ig, monthly costs were 70% less eral studies led by Octapharma. JC. Crave works at Octapharma. with RP than with pump. It should be highlighted that indirect Open Access This article is distributed under the terms of the Creative costs, which are mainly driven by the time spent by the pa- Commons Attribution 4.0 International License (http:// tients for infusion were similar between the two methods. creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appro- Shorter but more frequent infusions with RP require the same priate credit to the original author(s) and the source, provide a link to the amount of time per month than weekly pump infusions. Creative Commons license, and indicate if changes were made. Finally, an important part of direct costs during the pump period was driven by the costs of the device itself including fixed costs and monthly rental costs. Fixed costs have been amortized over the pump period. Had the study been longer, these costs would have been amortized on the longer time and References direct costs would have been decreased. It seems unlikely, however, that administration per pump could be competitive 1. Al-Herz W, Bousfiha A, Casanova JL, Chapel H, Conley ME, against RP. Cunningham-Rundles C, et al. Primary immunodeficiency dis- Our study has some limitations. Firstly, it has been con- eases: an update on the classification from the international union of immunological societies expert committee for primary immuno- ducted in only adult patients and satisfaction regarding RP deficiency. Front Immunol. 2011;2:54. might be different in younger or pediatric patients. Secondly, 2. Gardulf A. Immunoglobulin treatment for primary antibody defi- the sample size was calculated in order to warrant sufficient ciencies: advantages of the subcutaneous route. BioDrugs. power for the comparison of LQI factor I. 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Lifelong treatment with gammaglobulin for gest that RP can be a valuable and well-accepted alternative primary antibody deficiencies: the patients' experiences of sub- for SC self-administration of gammanorm® 165 mg/mL at cutaneous self-infusions and home therapy. J Adv Nurs. 1995;21(5):917–27. home for many PID patients. Since IgRT is a lifelong treat- 6. Nicolay U, Kiessling P, Berger M, Gupta S, Yel L, Roifman CM, et ment in PID patients, individualization of treatment is of par- al. Health-related quality of life and treatment satisfaction in North amount importance. RP is a new, safe, and easy-to-learn meth- American patients with primary immunedeficiency diseases receiv- od that complements the physician’s armamentarium when ing subcutaneous IgG self-infusions at home. J Clin Immunol. prescribing IgRT. 2006;26(1):65–72. 512 J Clin Immunol (2018) 38:503–512 7. Gardulf A, Nicolay U, Math D, Asensio O, Bernatowska E, Bock immunodeficiency diseases receiving lifelong immunoglobulin re- placement therapy. Qual Life Res. 2005;14(7):1683–91. A, et al. Children and adults with primary antibody deficiencies gain quality of life by subcutaneous IgG self-infusions at home. J 19. Atkinson MJ, Sinha A, Hass SL, Colman SS, Kumar RN, Brod M, Allergy Clin Immunol. 2004;114(4):936–42. et al. Validation of a general measure of treatment satisfaction, the 8. Abolhassani H, Sadaghiani MS, Aghamohammadi A, Ochs HD, treatment satisfaction questionnaire for medication (TSQM), using Rezaei N. Home-based subcutaneous immunoglobulin versus a national panel study of chronic disease. Health Qual Life hospital-based intravenous immunoglobulin in treatment of prima- Outcomes. 2004;2:12. ry antibody deficiencies: systematic review and meta analysis. J 20. Direction générale de l’offre de soins. Guide pour le suivi de la Clin Immunol. 2012;32(6):1180–92. masse salariale. Ministère chargé de la santé. 2014 [cited 21/03/ 9. Shapiro RS. Why I use subcutaneous immunoglobulin (SCIG). J 2017]; Available from: http://social-sante.gouv.fr/IMG/pdf/dgos_ Clin Immunol. 2013;33(Suppl 2):S95–8. guide_suivi_masse_salariale_2014.pdf 10. Kobrynski L. Subcutaneous immunoglobulin therapy: a new option 21. Chaput H, Pinel C, Wilner L. Salaires dans le secteur privé et les for patients with primary immunodeficiency diseases. Biologics. entreprises publiques - En 2013, le salaire net moyen baisse de 0,3% 2012;6:277–87. en euros constants. Insee Première 2015 16/09/2015;1565. 11. Shapiro R. Subcutaneous immunoglobulin therapy by rapid push is 22. Ochs HD, Gupta S, Kiessling P, Nicolay U, Berger M. Safety and preferred to infusion by pump: a retrospective analysis. J Clin efficacy of self-administered subcutaneous immunoglobulin in pa- Immunol. 2010;30(2):301–7. tients with primary immunodeficiency diseases. J Clin Immunol. 12. Shapiro RS. 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Affiliations 1,2 3 4 4 1 5 Boris Bienvenu & Grégoire Cozon & Yves Mataix & Dominique Lachaud & Antoine Alix & Cyrille Hoarau & 5 6 6 7 7 8 Daniel Antier & Eric Hachulla & Sylvie Brice & Jean-François Viallard & Stéphanie Tamisier & Anne-Laure Fauchais & 8 9 9 10 3 Françoise Renon-Carron & Pierre Clerson & Yann Fardini & Jean-Charles Crave & Pierre Miossec 1 6 Hôpital Côte de Nacre, CHU Caen, Caen, France Hôpital Claude Huriez, CHRU Lille, Lille, France 2 7 Hôpital Saint Joseph, Marseille, France Hôpital Haut-Lévêque, CHU Bordeaux, Bordeaux, France 3 8 Centre Hospitalier Edouard Herriot, Lyon, France Hôpital Dupuytren, CHU Limoges, Limoges, France 4 9 Clinique Mutualiste, Lyon, France Soladis Clinical Studies, Roubaix, France 5 10 Hôpital Bretonneau, CHRU Tours, Tours, France Octapharma France, Boulogne-Billancourt, France

Journal

Journal of Clinical ImmunologySpringer Journals

Published: May 31, 2018

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