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Children and adults with primary antibody deficiencies gain quality of life by subcutaneous IgG self-infusions at home

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A large number of children and adults with primary antibody deficiencies need lifelong IgG replacement therapy. It is mostly unknown what effect the choice of replacement therapy has on the patients' health-related quality of life (HRQOL) and treatment satisfaction (TS). To investigate whether a switch from hospital-based intravenous IgG (IVIG) to home-based subcutaneous IgG (SCIG) therapy would improve the HRQOL and TS. Fifteen children (<14 years; hospital-based IVIG therapy at enrollment) and 32 adults (> or =14 years; 22 on hospital-based IVIG and 10 on home-based SCIG therapy at enrollment) were included. Questionnaires were completed at baseline and at 6 and 10 months: the Child Health Questionnaire-Parental Form 50 (children) or Short Form 36 (adults), the Life Quality Index, and questions regarding therapy preferences. The SCIG home therapy was reported to give better health (P=.001) and improved school/social functioning (P=.02) for the children, reduced emotional distress (P=.02) and limitations on personal time for the parents (P=.004), and fewer limitations on family activities (P=.002). Adults switching therapy reported improved vitality (P=.04), mental health ( P=.05), and social functioning ( P=.01). Adults already on SCIG home therapy at enrollment retained high HRQOL and TS scores. The SCIG home therapy improved TS because it led to greater independence and better therapy convenience ( P <.05). The patients preferred the SCIG administration route and having the treatment at home. Home-based SCIG therapy improves several important aspects of HRQOL and provides the patients with primary antibody deficiencies and their families with greater independence and better control of the therapy situation and daily life. SCIG home therapy is an appreciated therapeutic alternative for adults and children in need of lifelong IgG replacement therapy.
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Original article
Children and adults with primary antibody
deficiencies gain quality of life by
subcutaneous IgG self-infusions at home
Ann Gardulf, RN, PhD,
a
Uwe Nicolay, Dipl Math,
a
Oscar Asensio, MD,
b
Ewa
Bernatowska, MD, PhD,
c
Andreas Bo¨ ck, MD,
d
Beatriz T. Costa-Carvalho, MD,
e
Carl
Granert, MD, PhD,
f
Stefan Haag, MD, PhD,
g
Dolores Herna
´ndez, MD, PhD,
h
Peter
Kiessling, PhD,
g
Jan Kus, MD, PhD,
i
Nuria Matamoros, MD, PhD,
j
Tim Niehues, MD,
PhD,
k
Sigune Schmidt, MD,
l
Ilka Schulze, MD, PhD,
m
and Michael Borte, MD, PhD
n
Stockholm, Sweden, Sabadell, Valencia, and Palma de Mallorca, Spain, Warsaw, Poland, Vienna,
Austria, Sa˜ o Paolo, Brazil, and Marburg, Du¨ sseldorf, Freiburg, Berlin, and Leipzig, Germany
Background: A large number of children and adults with
primary antibody deficiencies need lifelong IgG replacement
therapy. It is mostly unknown what effect the choice of
replacement therapy has on the patients’ health-related quality
of life (HRQOL) and treatment satisfaction (TS).
Objective: To investigate whether a switch from hospital-based
intravenous IgG (IVIG) to home-based subcutaneous IgG
(SCIG) therapy would improve the HRQOL and TS.
Methods: Fifteen children (<14 years; hospital-based IVIG
therapy at enrollment) and 32 adults (14 years; 22 on
hospital-based IVIG and 10 on home-based SCIG therapy at
enrollment) were included. Questionnaires were completed at
baseline and at 6 and 10 months: the Child Health
Questionnaire–Parental Form 50 (children) or Short Form 36
(adults), the Life Quality Index, and questions regarding
therapy preferences.
Results: The SCIG home therapy was reported to give better
health (P= .001) and improved school/social functioning
(P= .02) for the children, reduced emotional distress (P= .02)
and limitations on personal time for the parents (P= .004), and
fewer limitations on family activities (P= .002). Adults
switching therapy reported improved vitality (P= .04), mental
health (P= .05), and social functioning (P= .01). Adults already
on SCIG home therapy at enrollment retained high HRQOL
and TS scores. The SCIG home therapy improved TS because it
led to greater independence and better therapy convenience
(P< .05). The patients preferred the SCIG administration
route and having the treatment at home.
Conclusions: Home-based SCIG therapy improves several
important aspects of HRQOL and provides the patients with
primary antibody deficiencies and their families with greater
independence and better control of the therapy situation and
daily life. SCIG home therapy is an appreciated therapeutic
alternative for adults and children in need of lifelong
IgG replacement therapy. (J Allergy Clin Immunol
2004;114:936-42.)
Key words: Primary immunodeficiencies, subcutaneous IgG ther-
apy, intravenous IgG therapy, quality of life, home care, patient
satisfaction, self-care, nursing
Primary immunodeficiency diseases result from inborn
defects of the immune system. Most of these diseases
include a defective antibody formation (primary antibody
deficiency [PAD]), which leads to increased susceptibility
to bacterial infections of the mucous membranes, notably
of the sinopulmonary tract.
1
Many children and adults
with PAD need lifelong replacement therapy with IgG.
Rapid subcutaneous IgG (SCIG) infusions have been
shown to be easy to learn for both adult patients
2,3
and
children/parents
4,5
and to be safe, with no or few sys-
temic adverse reactions
2-10
and with no transmission of
the hepatitis C virus.
3
It results in normalized serum
From
a
the Swedish Centre for Immunodeficiencies, Division of Clinical
Immunology at the Department of Laboratory Medicine, Karolinska
Institutet at Karolinska University Hospital, Stockholm;
b
Servicio de
Immunologicia Clinica, Consorcio Hospitalari del Parc Tauli, Sabadell;
c
Children’s Memorial Health Institute, Department of Immunology,
Warsaw;
d
Universita¨tsklinik fu¨ r Kinder- und Jugendheilkunde, Vienna;
e
Department of Pediatrics, Division of Allergy, Clinical Immunology and
Rheumatology, Federal University of Sa˜o Paolo;
f
the Immunodeficiency
Unit, Section of Clinical Immunology, Karolinska University Hospital,
Stockholm;
g
ZLB Behring GmbH, Marburg;
h
Department of Allergy,
Hospital Universitario La Fe, Valencia;
i
National Research Institute of
Tuberculosis and Lung Diseases, Warsaw;
j
Servicio de Immunologia,
Hospital Universitario Son Dureta, Palma de Mallorca;
k
Universita¨tsklinikum Du¨ sseldorf Heinrich-Heine-University, Klinik fu¨r
Kinder-Onkologie, -Ha¨matologie und -Immunologie, Du¨ sseldorf;
l
Medizinische Universita¨tsklinik, Abteilung Rheumatologie und Klinische
Immunologie, Freiburg;
m
Charite´ Berlin, Humboldt-Universita¨ t, Klinik fu¨r
Pa¨diatrie mit Schwerpunkt Pneumologie/Immunologie, Berlin; and
n
Klinik
fu¨r Kinder- und Jugendmedizin am Sta¨ dtischen Klinikum "St Georg"
Leipzig, Akademisches Lehrkrankenhaus der Universita¨t Leipzig, Leipzig.
Supported by ZLB Behring GmbH, Marburg, Germany (formerly Aventis
Behring GmbH).
Disclosure of potential conflict of interest: The local study coordinators
received honoraria and/or travel grants from Aventis Behring GmbH,
Marburg, Germany. At the time of the study, U. Nicolay, S. Haag, and P.
Kiessling were employed by Aventis Behring GmbH.
Received for publication December 20, 2003; revised June 13, 2004; accepted
for publication June 29, 2004.
Reprint requests: Ann Gardulf, Karolinska University Hospital, Huddinge,
M96, SE-141 86 Stockholm, Sweden. E-mail: ann.gardulf@labmed.ki.se.
0091-6749/$30.00
Ó2004 American Academy of Allergy, Asthma and Immunology
doi:10.1016/j.jaci.2004.06.053
936
Basic and clinical immunology
Abbreviations used
CHQ-PF50: Child Health Questionnaire–Parental Form 50
HRQOL: Health-related quality of life
IVIG: Intravenous IgG
LQI: Life Quality Index
PAD: Primary antibody deficiency
SCIG: Subcutaneous IgG
SF-36: Short Form 36
TS: Treatment satisfaction
IgG concentrations
2-6,10
corresponding to those seen in
intravenous IgG (IVIG) replacement therapy and with as
few infections as during IVIG therapy.
7
Data regarding self-reported outcomes in the health-
related quality of life (HRQOL) due to PAD and its
replacement therapy are rare in adults
11
and lacking in
children and their families. The aims of the study were
therefore to describe self-reported HRQOL and treatment
satisfaction (TS) in children and adults with PAD and to
investigate whether the introduction of SCIG replacement
therapy as self-infusions at home would improve the
HRQOL and TS.
METHODS
Patients
The inclusion criteria were a diagnosis of PAD according to
definition,
1
age between 2 and 75 years, IVIG or SCIG replacement
therapy for at least 6 months, stable serum IgG trough levels (5g/L)
before enrollment, no other major chronic diseases, and an ability and
willingnessto answer questionnaires. Sixty eligible patientsat 12 study
sites in 6 countries were invited, and 58 agreed to participate. The
participants were divided into 2 groups—those younger than 14 years
(referred to as children; n = 17 at enrollment) and those 14 years or
older (adults; n = 41)—according to recommendations from the au-
thors of the 2 generic HRQOL questionnaires used for the study.
12,13
Medical data regarding the participants are shown in Table I.Thirty-
seven patients received hospital-based IVIG at enrollment, and 10
patients already used SCIGself-infusions at home. The mainreason for
including patients already receiving SCIG was that these patients, who
had a long experience with self-administered SCIG therapy at home,
served as controls to gauge the study-specific effects. The mean IgG
trough leveldirectly before the study start was 7.9 g/L (range, 5.5-11.9
g/L) for the children. For the adults, the corresponding figures were 8.3
g/L (range, 5.9-15.8 g/L) for those on IVIG therapy at enrollment and
9.0 g/L (range, 6.6-14.2 g/L) for those on SCIG therapy at enrollment.
The participants answered the questionnaires thrice: at baseline
and after 6 and 10 months. Not all the participants filled in all the
questionnaires. However, in no case was the failure to complete the
questionnaires attributed to the health of the participants (Table I).
SCIG therapy
The IgG was given as weekly infusions by using a technique
described previously.
2-7,9,10
Each participant completed 43 infusions
(10 months) with a liquid pasteurized polyvalent human 16% (160
mg/mL) IgG preparation intended for subcutaneous use (ZLB
Behring GmbH, Marburg, Germany [formerly Aventis Behring
GmbH, Marburg, Germany]). The patients continued with a dosage
equivalent to the dosage during the previous IgG replacement therapy.
Weekly dosages ranged between 50 and 150 mg/kg body weight.
Home therapy
All participants were trained and supervised once per week at the
local hospital for 4 to 6 training sessions and had to show practical
skill, knowledge, and confidence in the SCIG administration route
before being transferred to self-infusions at home. The parents gave
the infusions to their children or supervised the treatment. The
participants visited their clinic every fourth week for medical and
nursing follow-ups and to verify that the infusion technique was
correct.
Questionnaires: HRQOL
The Child Health Questionnaire–Parental Form 50 (CHQ-PF50)
12
was used for the children and answered by the parents. It focuses on
the physical and psychosocial functioning and well-being of the child
and his or her family and aggregates to 15 concepts in total (Table II).
For this study, the 1 stand-alone global item ‘‘change in health’’ was
not used because it has a 1-year recall period. Higher scores indicate
a better HRQOL.
Short Form 36 (SF-36) was used for the adults. It consists of 35
items forming 8 subscales: physical function (10 items), role-physical
(4 items), bodily pain (2 items), general health (5 items), vitality (4
items), social function (2 items), role-emotional (3 items), and mental
health (5 items).
13,14
As in the CHQ-PF50, the 1-year comparison of
health was excluded. Higher scores indicate a better HRQOL.
TABLE I. Demographic and medical patient data
Variable
Children
(<14 y)
Adults
(14 y)
No. patients enrolled 17 41
No. evaluable patients 15*32à§k
Sex (male/female) 15/0 20/12
Age (y)
Median 7 33.5
Range 3-13 14-74
Diagnosis (No. patients)
CVID 3 25
IgG subclass deficiency 2 0
Other hypo- or
gamma globulinemia
10 7
IgG therapy at enrollment
(No. patients)
Intravenous IgG 15 22
Subcutaneous IgG 0 10
Serum IgG trough levels
before study, mean (range)
7.9
(5.5-11.9)
8.3
(5.9-15.8)
9.0
(6.6-14.2){
CVID, Common variable immunodeficiency.
*Two children were excluded from the final evaluation because of belated
assessments (baseline, n = 1; 6 months, n = 1).
Study sites and number of patients evaluated: Brazil, children n = 0/adults
n = 3; Germany, n = 6/n = 13; Poland, n = 9/n = 4; Spain, n = 0/n = 2;
Sweden, n = 0/n = 10.
àFive adults were excluded from final evaluation because of belated
assessments (baseline, n = 1; 6 months, n = 2; 10 months, n = 2).
§Three adults prematurely discontinued the study before the 6-month
assessment (1 protocol violation [ie, a patient with renal failure was
wrongly included], 1 suspected systemic adverse reaction in a patient with
a history of such reactions during IVIG infusions, and, in 1 case, missed
follow-ups because of a long stay abroad).
kOne adult did not complete the questionnaires at the 10-month
assessment.
{Adults on subcutaneous IgG therapy at enrollment.
J ALLERGY CLIN IMMUNOL
VOLUME 114, NUMBER 4
Gardulf et al 937
Basic and clinical immunology
Treatment satisfaction
The Life Quality Index (LQI) was developed for a study regarding
PAD patients receiving IVIG infusion therapy at the clinic or at
home.
15
The LQI examines the respondent’s perceptions of the
impact of the IgG treatment on daily activities. The LQI is worded
without reference to home- or clinic-based setting. The original LQI
was slightly modified; ie, the wording ‘‘IVIG treatment’’ was
changed to ‘‘SCIG treatment.’’ Furthermore, in the version for the
parents, the statements were modified to ask for the perceptions of
the SCIG treatment in relation to ‘‘my child.’’ The LQI consists of
15 statements, each rated on a 7-point Likert response scale. A
maximum summary score of 105 indicates the highest possible
satisfaction with factors such as independence, therapy convenience,
social/school/work activities, and health and travel costs. In addition
to the LQI, 2 preference items were used: ‘‘Which IgG therapy do
you prefer?’’ (IVIG, SCIG, or no preference) and ‘‘Where do you
prefer to receive your IgG therapy?’’ (in the hospital/in the doctor’s
office, at home, or no preference).
Translation of the questionnaires
When available, linguistically validated translations of the instru-
ments were used. Where validated translations were not available, the
translation process followed the standard for the translation of
HRQOL instruments (forward-backward translation processes).
16
Assessments
The CHQ-PF50 or the SF-36, the LQI, and questions about
demographic background characteristics were completed at baseline.
At 6 and 10 months, the 2 ‘‘preference’’ items were added. The set of
questionnaires was answered at the hospitals by the adult patients
themselves or by the parents.
Statistical analysis
The primary analyses included the children (n = 15) and adults
(n = 32) who were fully compliant with the study protocol. However,
second-line analyses were also performed on the basis of the 2 entire
populations of children (n = 17) and adults (n = 41) to explore
whether the exclusion of noncompliant participants resulted in
a biased comparison. The comparisons of the data at 10 months with
baseline did not reveal relevant qualitative differences between the
entire and the final populations with regard to any of the question-
naires. Thus, restriction of the analyses to the compliant participant
populations did not lead to biased estimates.
The nonresponder rate to single items was very low (in total,
0.43%). Still, to handle missing data, 2 methods were used. If
less than 50% of the responses within a single scale were missing
for a respondent, item imputation was performed by mean value
substitution as described in the scoring manuals.
12,14
Otherwise,
values were predicted by using an explicit regression model
17
that
included the previously observed scores on the scale for the
individual as well as important covariates (age, country, route of
previous IgG treatment, and number of SCIG infusions).
Data were analyzedwith a repeated-measures model
18
that assumes
correlated assessments over time and normally distributed response
variables. Separately for children and adults, 6- and 10-month assess-
ments were compared with the patients’ baselines. Statistical analysis
was performed with SAS version 8.2 (SAS Institute Inc, Cary, NC).
TABLE II. Concepts measured in the CHQ-PF50
Concept Abbreviation No. items Definition
Physical functioning PF 6 Limitations in physical activities
Role/social–emotional, behavioral REB 3 Limitations in school, work, or social activities
because of emotional or behavioral problems
Role/social–physical RP 2 Limitations in school, work, or social activities
because of physical problems
Bodily pain BP 2 Intensity/frequency of pain/discomfort
Behavior BE 6*Ability to get along with others, behavioral
problems including aggression, delinquency,
impulsivity, and social withdrawal
Mental health MH 5 Positive and negative states including anxiety,
depression, and positive affect
Self-esteem SE 6 Satisfaction with school, athletic ability,
appearance, ability to get along with others
General health perceptions GH6*Perceptions of overall health and illness
Parental impact–emotional PE 3 Distress and worry experienced by parents
concerning child’s condition
Parental impact–time PT 3 Limitations in personal time experienced by
parents because of child’s condition
Family activities FA 6 Limitations and interruptions in usual family
activities and family tension as a result of the
child’s health
Family cohesion FC1 Ability of family members to get along with
one another
Global health GGH1*Overall health of the child
Global behavior GBE1*Overall behavior as compared with other children
of the same age
Change in health CHà1 Change in child’s health as compared with 1 y ago
*The subscale BE also includes the single-item scale GBE and the subscale GH the single-item scale GGH leading to a total of 52 items counted for the table.
A 4-week recall period was used for all concepts except for GH, FC, GGH, and GBE, for which ‘‘in general’’ is used instead.
àThe CH item was not used for this study.
J ALLERGY CLIN IMMUNOL
OCTOBER 2004
938 Gardulf et al
Basic and clinical immunology
Ethics
All adult patients and the children’s parents were given oral and
written information in their own languages, and written informed
consent was obtained from all study participants. The local ethics
committee at each participating hospital approved the study before
any patient was informed and enrolled.
RESULTS
HRQOL: CHQ-PF50
Significant improvements were found for 6 of the CHQ-
PF50 subscales at 10 months compared with baseline.
Between 47% and 87% of the 15 children showed an
improvement of at least 5 points with regard to these
scales. Four of these significant improvements were
already seen after 6 months (Table III).
HRQOL: SF-36
The 22 adults on IVIG at enrollment reported signifi-
cantly improved vitality (baseline mean, 62.8; 10-month
mean, 70.2; P= .04), mental health (baseline mean, 87.5;
10-month mean, 94.3; P= .05), and social functioning
(baseline mean, 77.7; 10-month mean, 83.2; P= .01) at 10
months. The proportion of IVIG adults with an improve-
ment of at least 5 points was 50%, 32%, and 32%,
respectively, for the 3 scales. The 10 adults on SCIG at
enrollment reported high SF-36 scores already at baseline,
and no significant changes were seen over time (data not
shown).
TS: LQI
For the children, the total mean summary LQI score
significantly improved from 73.4 613.4 at baseline to
94.9 68.7 at 10 months (P= .0001; Fig 1). For the adults
on IVIG therapy at enrollment, the total mean summary
LQI score improved from 82.2 615.0 to 93.7 69.0
(P= .0012). Sixty percent of the children and 50% of the
adults reported an increase of at least 10 points. The adults
on SCIG therapy at enrollment reported a high total mean
summary LQI score already at baseline (95.6 610.7), and
no significant change was seen over time (94.5 68.8 at 10
months; Fig 1).
Preference items
All children and their parents and all 10 adults on SCIG
therapy at enrollment reported that they preferred the
SCIG self-infusions at home. Sixteen (73%) of the 22
adults on IVIG at enrollment reported that they preferred
the SCIG self-infusions at home. Two reported that the
continuation of SCIG therapy was most important, but
they had no preference regarding setting. Two patients had
no preference regarding the IgG administration route but
wanted to continue with home therapy. One patient
reported no preference regarding either IgG administra-
tion route or setting, and 1 patient preferred IVIG therapy
at the hospital.
DISCUSSION
HRQOL is a subjective perception of the effect of
health status (including disease and treatment) on physi-
cal, psychological, and social functioning and well-
being.
19,20
Children and adults with PAD have a chronic
condition and in most cases are faced with the prospect
of lifelong IgG treatment. Surprisingly, only 1 study
11
using standardized, validated, generic HRQOL instru-
ments has been presented with patient-reported data
regarding HRQOL in adults. In this study, the HRQOL
and TS of children with PAD and their families have been
addressed for the first time.
TABLE III. Results of the CHQ-PF50 before and during SCIG self-infusions at home
Pvalues
Concept*Baseline (mean SD) 6 mo (mean SD) 10 mo (mean SD) 6 mo vs BL 10 mo vs BL
PF 90.4 611.4 91.5 625.8 90.4 616.1 NS NS
REB 79.5 625.6 83.0 632.8 95.6 610.1 NS .02
RP 85.6 623.5 86.7 630.3 92.2 618.8 NS NS
BP 80.0 623.9 78.0 622.7 88.7 617.3 NS NS
BE 67.3 616.2 69.0 620.0 72.4 616.5 NS NS
MH 70.8 619.4 71.3 620.0 76.3 613.9 NS NS
SE 80.5 611.0 77.2 616.2 82.2 615.4 NS NS
GH 36.1 613.4 51.3 615.3 53.7 611.5 .01 .001
PE 52.8 627.4 68.9 627.4 72.8 624.5 .05 .02
PT 64.4 628.8 71.9 626.8 81.5 620.9 NS .004
FA 68.1 620.1 77.8 621.2 85.6 616.4 .04 .002
FC 67.3 617.3 70.3 621.0 76.0 614.0 NS NS
GGH 55.0 623.6 77.8 611.3 78.7 614.6 .008 .01
GBE 69.7 616.6 69.0 622.8 69.7 621.9 NS NS
BL, Baseline; NS, not significant.
*Explanations of the abbreviations of the concepts are given in Table II. Higher scores indicate better physical or psychosocial functioning or less effect on the
family situation because of a disease.
J ALLERGY CLIN IMMUNOL
VOLUME 114, NUMBER 4
Gardulf et al 939
Basic and clinical immunology
The parents reported significant improvements for 6
of the 14 subscales in the CHQ-PF50. The improve-
ments were seen in areas related to the children’s social
functioning and health, the parents’ own life situation, and
family functioning. After the introduction of the SCIG
home-therapy regimen, the parents reported improved
school and social functioning for their child (subscale role/
social–emotional, behavioral) and improved overall
health (global health); they also reported that the child
now was as healthy as other children and that the child
had a better resistance against infections (general health
perceptions). Moreover, the parents had greater expect-
ations for a healthier life of the child in the future (general
health perceptions).
From this study, is it not possible to say whether the
reported improvements in the children’s health were
primarily related to the use of the SCIG therapy itself,
the switch to home therapy, or both. The main goal with
any IgG replacement therapy is to achieve normalized
serum IgG levels and, thereby, a reduced frequency and
severity of infections. One inclusion criterion for the study
was a serum IgG trough level of >5 g/L for at least
6 months before enrollment. In the children, the serum
IgG trough levels ranged between 5.5 and 11.9 g/L at
enrollment and remained high (data not shown). The
stable day-by-day serum IgG concentrations demonstrated
between SCIG infusions
21,22
may have contributed to
a better resistance against infections and, thereby, the
better health status of the children. The SCIG administra-
tion route also avoids unphysiologically high serum IgG
peak levels, as are commonly observed after IVIG
infusions; these are suspected to trigger systemic side
reactions such as headache. Another benefit from the
home-therapy regimen itself was the reduced number of
visits to the hospital for the PAD children and a decreased
risk for the children to acquire infections. This may
contribute to the reported improved health of the PAD
children and may also reduce the parents’ anxiety that their
child may become infected. Indeed, in this study it was
found that the introduction of the SCIG home therapy
made the parents feel less worried or concerned regarding
their child’s physical health and emotional well-being
(subscale parental impact–emotional).
The parents also reported that the introduction of the
home therapy resulted in less limitation in personal time
for their own needs (parental impact–time). Moreover, the
home-therapy regimen positively influenced the entire
family situation, eg, fewer restrictions and interruptions
in the usual family activities (family activities). Home
therapy has been considered especially important in pe-
diatric immunodeficiency care because it saves the
families the trips to the hospital,
4
and families have
reported that they prefer the shorter, more frequent
infusions at home to the more disruptive and lengthy
visits to a hospital every third to fourth week as required
by IVIG infusions.
5
For the adults on IVIG therapy at enrollment, improve-
ments in HRQOL as measured by the SF-36 were also
seen (vitality, mental health, and social functioning) after
the switch to SCIG home therapy. This was in contrast to
the adults already on SCIG home therapy, in whom high
scores for these 3 scales were already seen at enrollment.
The vitality scale captures the subjective well-being in
relation to energy level and fatigue, the mental health scale
captures different aspects of psychological well-being,
and the social functioning scale captures both the quantity
FIG 1. Life Quality Index scale (range, 15-105). A maximum summary score of 105 indicates the highest
possible satisfaction with the effect of any IgG replacement therapy on factors such as independence, therapy
convenience, social/school/work activities, and health and travel costs. Data are given as self-reported
summary scores for children and adults at baseline and at 6 and 10 months. *P<.05 (F test at 10 months vs
baseline).
J ALLERGY CLIN IMMUNOL
OCTOBER 2004
940 Gardulf et al
Basic and clinical immunology
and quality of social activities.
14
It has previously been
shown that adult patients with common variable immu-
nodeficiency who are not yet treated with IgG replace-
ment therapy report significantly pronounced fatigue,
restrictions in social and leisure activities, and poorer
psychological well-being compared with healthy individ-
uals.
11
Also, adults on hospital-based therapy with
adequate dosages of IVIG infusions or intramuscular
IgG injections reported significantly decreased physiolog-
ical well-being and pronounced fatigue compared with
healthy individuals. The introduction of SCIG home
therapy was, in both the untreated and the previously
IVIG-treated or intramuscular IgG–treated adults, found to
result in a significant improved HRQOL and decreased
fatigue.
11
It has been stated by the patients that the
introduction of home therapy leads to independence,
a sense of freedom and flexibility, and a reduced sense
of being sick or disabled.
23
Introduction of home therapy
programs seems to have a major beneficial effect on the
patients’ psychological well-being and vitality. This in
turn may lead to an increased courage for welcoming
social contacts and activities—something otherwise
avoided by PAD patients because of tiredness and fear
of acquiring infections.
11
The increased vitality reported in both this study and in
the previous HRQOL study
11
after the introduction of the
weekly SCIG therapy is of interest in relation to the
ongoing discussion regarding the possible benefit of the
stable between-infusion serum IgG levels seen during
SCIG therapy.
21,22
It is known that the use of monthly
IVIG therapy results in fluctuations in serum IgG con-
centrations,
24
and patients often complain of increased
tiredness and worsened well-being in the week before
the next infusion. The increased infusion frequency with
the weekly SCIG therapy has been found to result in
a trend to a higher IgG trough level
7
and a day-by-day
serum IgG curve that better corresponds to the normal
endogenous IgG production.
22
The stable serum IgG level
between weekly SCIG infusions may indeed be one
contributing factor to the improved vitality reported by
the patients.
The introduction of the home-therapy program also led
to increased TS, as measured by the LQI, for children and
adults switching from hospital-based to home-based
therapy. The adults on SCIG home therapy at enrollment
already reported a high total mean summary LQI score
at baseline. The LQI showed that home therapy resulted
in greater independence, with less disruption of daily
activities; less effect on school, work, and social activities;
freedom to travel; better therapy convenience; comfort;
treatment flexibility; and pleasantness of treatment atmo-
sphere. The concept of feeling able to control a treatment
is important for the patient because a sense of active
participation leads to greater compliance and improved
medical outcome.
15
Also, home-based IVIG therapy is a patient-appreciated
option in some countries. In a study from the United
States, it was shown that the switch from hospital-based
IVIG to home-based IVIG therapy improved the TS of the
included children and adults.
15
However, different patient
selection criteria must be used for IVIG self-infusions at
home, and this reduces the number of individuals who can
benefit from home therapy.
The home-therapy regimen, whether SCIG or IVIG, has
also a beneficial effect on the direct and indirect costs of
the society and of the individual patient and family. For the
families in this study, the child and at least 1 parent had to
visit the hospital for IVIG therapy an average of every
third week, ie, seventeen 1-day visits per year. For the 15
children in this study alone, the production loss for the
accompanying adults amounted to 225 days. The parents
may also have to take time off from work with salary
reductions and also pay for the travel costs and possible
fees at the hospital. Once in home therapy, no time off
from school for the child or work for the parent is needed.
Instead the infusion can be given at a suitable time for
the family, for example, during the evening when watch-
ing television, when the child is busy playing, or during
dinner. It has been shown that SCIG therapy at home
substantially reduces society and health-care costs
3
and
cuts the direct and indirect costs of the patients by half.
25
The study design was derived from the European
Committee for Proprietary Medicinal Products guidelines
for intravenous
26
and subcutaneous and intramuscular
27
use of immunoglobulins. Both guidelines recommend that
IgG replacement therapy be studied in a longitudinal
design for at least 6 months. To have more reliable data,
we expanded the European Union recommendation by
treating more patients and for 10 months with weekly
SCIG. The study was designed as an open prospective
evaluation that used each participant as his or her own
control in comparing baseline HRQOL data with the data
reported at the final evaluation after 10 months. The
follow-up time for this study was 10 months, and this must
be considered a short period in which to study the effect of
a treatment on HRQOL and daily activities. However,
already after 6 months the parents and the adult patients
reported significant improvements in HRQOL. We cannot
completely rule out the possibility that the improvements
in HRQOL and TS were, to some extent, results from
study effects. However, most likely, the reported changes
can be attributed to the switch from the hospital-based to
the home-based therapy; otherwise, the patients who had
already been on SCIG before enrollment in the study
should also have exhibited a further improvement with
regard to their HRQOL and TS, but this did not occur.
For children and adults with PAD, lifelong IgG re-
placement therapy aims at reducing the frequency and
severity of infections and the subsequent fatigue and lack
of energy. A successful IgG treatment and support should
provide the patient with a feeling of increased resistance to
infections and, thereby, the courage, strength, and will-
ingness to participate in social and family activities. In this
study, it was found that several aspects of the HRQOL and
the TS improved when children and adults with PAD
changed from a staff-run, hospital-based IVIG therapy
program to a staff-supported, patient- or parent-run, home-
therapy program with SCIG self-infusions. A successful
J ALLERGY CLIN IMMUNOL
VOLUME 114, NUMBER 4
Gardulf et al 941
Basic and clinical immunology
home-therapy regimen must be based on interactive
patient/family education programs and continuous sup-
port.
23,28,29
The easy SCIG administration technique gives
most adult patients and children or parents the opportunity
to manage their own IgG treatment. On the basis of the
results from this study and previous evaluations of the
SCIG administration route showing safety,
2-10
normalized
serum IgG trough levels,
2,3,6,7,10,21,22
protection against
infections,
7
patient preference for home therapy,
4,5,11,15,23
and the easy infusion technique, SCIG home therapy is
strongly advocated as a therapeutic alternative for adults
and children in need of lifelong IgG replacement therapy.
We are grateful to all the nurses at the local study centers who
helped with the study by training and supervising the patients and by
collecting blood samples and questionnaires. We sincerely thank
Sylvia Herget (data collection and database handling) and Dirk
Spruck (statistical analyses) at Covidence GmbH, Marburg,
Germany. We also thank Neil Tomkinson, Preston, England, for
his help with the language revision.
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Basic and clinical immunology
... Eighteen studies were identified that compared IV and SC infusion of immunoglobulin (IVIg or SCIg). [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][52][53][54] Of these, four studies were randomized controlled trials (RCTs); 14-17 six were non-randomized interventional studies; [18][19][20][21][22]52 four were observational studies; [23][24][25]53 and four were surveys. [26][27][28]54 The indication in the majority of included studies of SCIg (13 studies in total) was immunodeficiency, mostly primary immunodeficiency (PID). ...
... Eighteen studies were identified that compared IV and SC infusion of immunoglobulin (IVIg or SCIg). [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][52][53][54] Of these, four studies were randomized controlled trials (RCTs); 14-17 six were non-randomized interventional studies; [18][19][20][21][22]52 four were observational studies; [23][24][25]53 and four were surveys. [26][27][28]54 The indication in the majority of included studies of SCIg (13 studies in total) was immunodeficiency, mostly primary immunodeficiency (PID). ...
... [26][27][28]54 The indication in the majority of included studies of SCIg (13 studies in total) was immunodeficiency, mostly primary immunodeficiency (PID). 14,15,[18][19][20]23,24,[26][27][28][52][53][54] The remaining studies comprised four studies of patients with multifocal motor neuropathy (MMN) 16,21,22,25 and two studies of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) 17,25 (one study included both MMN and CIDP groups). 25 The remaining 31 studies compared administration routes for a range of non-immunoglobulin therapies, and described preferences for IV infusion or SC injection. ...
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Background: For many chronic immune system disorders, the available treatments provide several options for route of administration. The objective of this systematic literature review is to inform discussions about therapy choices for individual patients by summarizing the available evidence regarding the preferences of patients with chronic immune system disorders for intravenous (IV) or subcutaneous (SC) administration. Methods: Searches of the MEDLINE, Embase and Cochrane Library databases were conducted using terms designed to capture studies reporting patient preferences between IV and SC therapy published in English. Relevant studies were limited to those in which mode of administration, including treatment frequency and setting, was the main difference between comparators. Results: In total, 49 studies were included in the review. Among 18 studies that compared IV and SC immunoglobulin therapy, 16 found patients to prefer the SC administration route. The results of the 31 studies comparing IV infusion and SC injection of non-immunoglobulin therapies were mixed, with patients favoring SC administration in 20, IV infusion in seven, and having no overall preference in four. Patient experience had a strong effect on preferences, with treatment-experienced patients preferring their current administration route in most studies. Patients preferring SC administration tended also to prefer treatment at home, mainly due to the convenience and comfort of home treatment and the avoidance of having to attend hospital. By contrast, patients preferring IV infusion tended to cite the lower treatment frequency and a dislike of self-injecting, and preferred hospital treatment, mainly due to the presence of healthcare professionals and resulting feelings of safety. Conclusion: In general patients with chronic immune system disorders tend to be more likely to choose SC administration than IV infusion, but preferences may vary according among individuals. These findings may assist discussions around appropriate treatment choices for each patient.
... [8][9][10] It is an important concept because it may negatively affect adherence to treatment, quality of life, disease management and health care outcomes such as hospitalisations and survival. 11,12 Whilst there are numerous studies which have tried to measure the quality of life of patients with a PID, 1,5,[13][14][15][16][17][18][19][20][21][22] less attention has focused upon the burden of Ig treatment. A recent systematic review which synthesised the evidence regarding the potential burden of Ig treatment found that overall, PID patients reported little Ig treatment burden and appeared satisfied with IVIg and SCIg therapy. ...
... Our findings concurred with the results of the quantitative studies in this area. [13][14][15][16][17][18][19][20][21][22] We found the biggest burden of Ig therapy was in relation to time, with over two thirds of patients reporting this as a treatment burden. ...
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This paper describes the burden of receiving immunoglobulin (Ig) treatment from the perspective of patients diagnosed with a Primary Immunodeficiency (PID). Thirty semi-structured interviews with patients receiving intravenous (n=21) and subcutaneous immunoglobulin (n=9) therapy, either at home or in hospital were undertaken. Underpinned by a phenomenological theoretical framework, and using a qualitative, inductive thematic approach to prioritise patients’ concerns, we identified that Ig treatment requires considerable effort by the patient, particularly in relation to the amount of time, organization and planning that is needed. They also face numerous physical, social, relationship, emotional, role functioning, travelling, and financial challenges in their effort to undergo and maintain their infusions and care for their health. Some qualitative differences in treatment burden were noted between home and hospital settings which contributed to non-adherence to those regimes. Immunoglobulin treatment burden is complex and influenced by therapeutic mode and setting and the personal circumstances of the patient. As choice over treatment method appears to be mainly informed by lifestyle needs, PID patients may benefit from more information about these potential Ig lifestyle influences when selecting which form of treatment to take together with their health professional.
... All this on the condition of an adequate selection of suitable patients and careful training. Home therapy has been shown to be effective and comfortable in other therapeutic areas, such as rheumatology and hematology, many years before respiratory diseases, for treatments such as subcutaneous gamma globulin and etanercept [27]. In 2007, a pioneering study was conducted to demonstrate the hypothesis that self-administration can improve adherence to long-term therapy thanks also to the excellent safety profile of omalizumab, a mAb with a low risk of anaphylaxis [28]. ...
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Introduction: The advent of biologic therapies for severe asthma has profoundly changed the management of this pathology. The introduction of home administration is therefore an important innovation to optimize the patients' management, even if there are many aspects that need to be clarified and pointed out. Areas covered: This review summarizes the path that led to the possibility of self-administration of biologics, and what the pandemic has changed in the management of these patients. Expert opinion: The growing understanding of asthma phenotypes and endotypes is enabling the careful selection of patients suitable for biologics. In this context, the availability of reliable and simple self-injection devices is important in implementing self-administration. The transition to self-injection is also possible thanks to the high safety profile of biologics. With attention, most patients may potentially be suitable for self-administration. The transition process from hospital to home administration can therefore be carried out correctly by clinicians with adequate expertise in the field of severe asthma and biologic therapies, with the support of other health professionals, pharmacists, and general practitioners. Home administration is probably the best way to guarantee high adherence and high-level satisfaction of patients, even in the long term.
... Hence, products for SC delivery of immune globulin (SCIG) are effective in the prevention of infections in adults, adolescents, and children (≤ 12 years). SCIG also offers the possibility of administration in a home setting [5,[7][8][9][10][11][12][13][14][15][16]. The advantages of SCIG relative to IVIG-convenience, ease of adoption and use, and greater independence and autonomy [3,4,11,16]-have increased access to safe and effective IgG treatments for many patients with PI diseases [17][18][19][20][21][22][23][24]. ...
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Purpose The purpose of this phase 3 study was to evaluate the efficacy, pharmacokinetics (PK), and safety of Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (IGSC 20%) in patients with primary immunodeficiency (PI). Methods Immunoglobulin treatment-experienced subjects with PI received 52 weeks of IGSC 20% given weekly at the same dose as the subject’s previous IgG regimen (DAF 1:1); the minimum dose was 100 mg/kg/week. The primary endpoint was serious bacterial infections (SBIs [null vs alternative hypothesis: SBI rate per person per year ≥ 1 vs < 1]). IgG subclasses and specific pathogen antibody levels were also measured. Results Sixty-one subjects (19 children [≤ 12 years], 10 adolescents [> 12–16 years], and 32 adults) were enrolled. The rate of SBIs per person per year was 0.017. The 1-sided 99% upper confidence limit was 0.036 (< 1), and the null hypothesis was rejected. The rate of hospitalization due to infection per person per year was 0.017 (2-sided 95% confidence interval: 0.008–0.033) overall. The mean trough total IgG concentrations were comparable to the previous IgG replacement regimen. The average of the individual mean trough ratios (IGSC 20%:previous regimen) was 1.078 (range: 0.83–1.54). The average steady-state mean trough IgG concentrations were 947.64 and 891.37 mg/dL, respectively. Seven subjects had serious treatment-emergent adverse events (TEAEs); none was drug-related. The rate of all TEAEs, including local infusion site reactions, during 3045 IGSC 20% infusions was 0.135. Most TEAEs were mild or moderate. Conclusions IGSC 20% demonstrated efficacy and good safety and tolerability in subjects with PI.
... SCIG therapy affords several advantages, including positive effects of self-administration on quality of life in patients with limited access to healthcare services and/ or venous access problems and those who cannot tolerate IVIG therapy [24,28,30,31]. However, drawbacks include the frequency of infusions (weekly) and the need for several injections at multiple areas during a single infusion [32]. ...
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Purpose The aim was to review the compliance, side effects and effectiveness of subcutaneous immunoglobulin (SCIG) supplementation in patients with primary immunodeficiencies (PID) who had previously received intravenous immunoglobulin (IVIG) therapy and subsequently switched to SCIG, as well as to compare these parameters in patients while considering body weight. Methods Demographic data, clinical and laboratory findings, SCIG dose, and side effects of 87 patients were retrospectively obtained from patient files. In patients who first received IVIG and then SCIG, the monthly SCIG dose was calculated by multiplying the IVIG dose by 1.37. The total monthly SCIG dose was distributed via injection across three or four doses per month, thus every 7 or 10 days. Results Of the 87 patients aged between one and 22 years, 50 were male (57.5%) and 37 were female (42.5%). The serum IgG levels of the SCIG group were higher and more stable than those of the IVIG group. The number of hospitalizations and infections decreased significantly after initiation of SCIG. Thirteen patients (14.9%) had low body weight (LBW) for their age, seven of whom were male (53.8%). Serum IgG levels of the LBW cohort were significantly elevated and more stable during the SCIG period than the IVIG period. Mild, local side effects were detected in 153 administrations (3.3%) in 30 patients with normal body weight, while no local reactions were recorded in the patients with LBW. Conclusion SCIG supplementation is an effective treatment for pediatric patients with PID. The preliminary data from the present study suggest that such treatment is also safe for LBW children. The numbers of patient hospitalizations and family visits to clinics were reduced, allowing our patients and their parents to live more normal lives.
... Prospective clinical studies of the efficacy of SCIG in children and adolescents are scarce, even though this treatment has become the standard of care for children with PADs. A number of reports have examined HRQoL and treatment satisfaction in children [27][28][29][30], but dosing, efficacy and safety of SCIG in children have largely been extrapolated from studies of mixed populations of children and adults [11,31,32]. ...
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Background: Subcutaneous human immunoglobulin (16.5%; octanorm/cutaquig ® ) was efficacious and well tolerated in patients with primary immunodeficiencies in a Phase III study. A subanalysis of pediatric data is presented here. Materials & methods: Children (2–16 years) previously treated with intravenous human immunoglobulin received weekly subcutaneous human immunoglobulin infusions over 64 weeks. The main objective was to assess the efficacy of cutaquig in preventing serious bacterial infections. Results: 38 children received 2213 infusions of cutaquig. No serious bacterial infections developed during the study. The rate of other infections was 3.1 per person-year and the rate of adverse drug reactions was 0.083 per infusion. Higher immunoglobulin G trough levels were achieved with cutaquig compared with previous intravenous therapy. Conclusion: Once-weekly infusions of cutaquig were efficacious and well tolerated in children with primary immunodeficiencies.
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Introduction Hypogammaglobulinemia in the first months after allogeneic hematopoietic stem cell transplantation (HSCT) is common in paediatric patients. During this phase, replacement therapy with human immunoglobulin must be administered parenterally to prevent infections. In some cases, this hypogammaglobulinemia persists over time, which forces further treatment when the patient is usually no longer a carrier of a central line, making them ideal candidates for subcutaneous replacement therapy. There is little published literature describing the use of this method in paediatric patients undergoing HSCT, widely described in replacement treatment in children with primary immunodeficiencies with very good results. Patients and methods An observational, descriptive, longitudinal and retrospective study is carried out. During the years 2008–2019, we evaluated all paediatric patients undergoing HSCT in our center with persistent chronic hypogammaglobulinemia (for over a year). The treatment phase with intravenous immunoglobulin (Privigen®) and the first four years of treatment with subcutaneous immunoglobulin (Hizentra®) are evaluated using a questionnaire. Results During the years 2008–2019, 175 patients underwent HSCT, 143 (82%) of whom exceeded three months after transplantation. Three (2%) of them had persistent hypogammaglobulinemia. All three share factors described in the literature involved in immune reconstitution. After analysing the questionnaire, it is observed that switching from intravenous to subcutaneous gammaglobulin has involved a great improvement in their quality of life. Conclusions The origin of chronic hypogammaglobulinemia in our patients shows different factors and cannot be attributed to a single cause. Due to the limited number of patients no conclusions can be drawn at the population level. We have been able to observe that replacement treatment with Hizentra 20% has been as effective as the intravenous administration without evidence of an increase in bacterial infections. Furthermore, it has also led to an improvement in quality of life and increased comfort, as the patients themselves have stated.
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Home blood product transfusion has been utilized around the world in various forms over the past few decades. There is current interest in decentralizing hospital care to improve patient independence and convenience, minimize cost to the health service and to prevent nosocomial infection, especially with the recent COVID-19 pandemic. The transition to “hospital in the home” is occurring across the healthcare sector driven by aims to improve patient outcomes and patient satisfaction, capacity pressures in the acute care sector, and most recently due to concerns regarding infectious disease transmission in hospital settings. This review explores the published literature on home red cell and platelet transfusions, and where the literature is limited, also considered data from subcutaneous immunoglobulin studies. Current published experience on red cell and platelet transfusion at home has identified benefits to the patient and health service, with further studies needed to quantify improvement in quality of life and health related outcomes. Safety concerns may be a perceived barrier to implementation of home transfusion, however current published data suggests serious adverse reactions are rare. Cost effectiveness data for home transfusion are very limited and a key area for future research. Home transfusion has the potential to benefit from newer technologies, such as portable/remote monitoring and electronic patient identifiers.
Article
Resumen Introducción La hipogammaglobulinemia en los primeros meses postrasplante de progenitores hematopoyéticos (TPH) es común en pacientes pediátricos. Durante esta fase se debe administrar tratamiento sustitutivo con inmunoglobulina humana por vía parenteral para la prevención de infecciones. En algunos casos, esta hipogammaglobulinemia persiste en el tiempo, lo que obliga a prolongar el tratamiento cuando el paciente ya no suele ser portador de una vía central, por lo que son candidatos ideales para el tratamiento de reemplazo por vía subcutánea. Existe escasa bibliografía publicada que describa el uso de esta vía en pacientes pediátricos sometidos a TPH; sin embargo, está ampliamente descrita y con muy buenos resultados en el tratamiento de reemplazo en los niños con inmunodeficiencias primarias. Pacientes y métodos Se realiza un estudio observacional, descriptivo y longitudinal de carácter retrospectivo. Durante los años 2008-2019 se evalúan a todos los pacientes pediátricos sometidos a TPH en nuestro centro que presentan una hipogammaglobulinemia crónica persistente (superior a un año). Se evalúa la fase de tratamiento con inmunoglobulina intravenosa (Privigen®) y los primeros 4 años de tratamiento con inmunoglobulina subcutánea (Hizentra®) mediante un cuestionario. Resultados Durante los años 2008-2019 se han realizado en nuestro centro 175 trasplantes de precursores hematopoyéticos, de los cuáles 143 (82%) superaron los 3 meses postrasplante. De estos, 3 (2%) pacientes presentaron una hipogammaglobulinemia persistente. Los 3 comparten factores descritos en la bibliografía involucrados en la reconstitución inmune. Mediante el cuestionario se observa que el cambio de gammaglobulina intravenosa a subcutánea ha supuesto una gran mejoría en la calidad de vida de los pacientes. Conclusiones El origen de la hipogammaglobulinemia crónica de nuestros pacientes presenta diferentes factores, y no se puede atribuir a una sola causa. Debido al limitado número de pacientes no es posible establecer conclusiones a nivel poblacional. Hemos podido observar que el tratamiento de reemplazo con Hizentra® al 20% ha sido igual de eficaz que la vía intravenosa, sin evidenciarse un aumento en las infecciones bacterianas. Además, ha supuesto una mejoría de la calidad de vida y mayor comodidad expresada por los propios pacientes.
Article
Studies investigating the safety of IgPro10 (Privigen®, CSL Behring, King of Prussia, PA, USA) in Japanese patients with primary immunodeficiency (PID) are lacking. This study evaluated safety and tolerability of IgPro10 in Japanese patients with PID. In this prospective, open-label, single-arm, registrational study for Japan, IgPro10 was administered intravenously at pre-study doses of 138–556 mg/kg body weight per 3-/4-weekly dosing cycle for up to 4 months. Frequency and intensity of adverse events (AEs), their relationship to IgPro10 and AE rate per infusion (AERI) were evaluated. Of 11 enrolled patients, 10 completed the study. The median (range) total duration of exposure was 16.14 (4.1–16.3) weeks. Eight patients reported 19 AEs, none severe (based on maximum severity), giving an AERI of 0.442. One AE was deemed related to IgPro10 treatment. Three patients experienced temporally associated AEs. No serious AEs or deaths were reported. Nine patients (90%) who completed the study tolerated flow rates of ≥ 8 mg/kg/min; 5 tolerated 12 mg/kg/min (7.2 mL/kg/h), translating into a threefold decrease in mean infusion time. IgPro10 was well tolerated at a flow rate of up to 12 mg/kg/min. Safety and tolerability findings were consistent with previously reported studies in non-Japanese patients with PID.
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Design Principles and Analysis Techniques for HRQoL Clinical Trials SAS, R, and SPSS examples realistically show how to implement methods Focusing on longitudinal studies, Design and Analysis of Quality of Life Studies in Clinical Trials, Second Edition addresses design and analysis aspects in enough detail so that readers can apply statistical methods, such as mixed effect models, to their own studies. The author illustrates the implementation of the methods using the statistical software packages SAS, SPSS, and R. New to the Second Edition • Data sets available for download online, allowing readers to replicate the analyses presented in the text • New chapter on testing models that involve moderation and mediation • Revised discussions of multiple comparisons procedures that focus on the integration of health-related quality of life (HRQoL) outcomes with other study outcomes using gatekeeper strategies • Recent methodological developments for the analysis of trials with missing data • New chapter on quality adjusted life-years (QALYs) and QTWiST specific to clinical trials • Additional examples of the implementation of basic models and other selected applications in R and SPSS This edition continues to provide practical information for researchers directly involved in the design and analysis of HRQoL studies as well as for those who evaluate the design and interpret the results of HRQoL research. By following the examples in the book, readers will be able to apply the steps to their own trials.
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Preface to Second Edition. Mixed Model Notations. 1 Introduction. 1.1 The Use of Mixed Models. 1.2 Introductory Example. 1.3 A Multi-Centre Hypertension Trial. 1.4 Repeated Measures Data. 1.5 More aboutMixed Models. 1.6 Some Useful Definitions. 2 NormalMixed Models. 2.1 Model Definition. 2.2 Model Fitting Methods. 2.3 The Bayesian Approach. 2.4 Practical Application and Interpretation. 2.5 Example. 3 Generalised Linear MixedModels. 3.1 Generalised Linear Models. 3.2 Generalised Linear Mixed Models. 3.3 Practical Application and Interpretation. 3.4 Example. 4 Mixed Models for Categorical Data. 4.1 Ordinal Logistic Regression (Fixed Effects Model). 4.2 Mixed Ordinal Logistic Regression. 4.3 Mixed Models for Unordered Categorical Data. 4.4 Practical Application and Interpretation. 4.5 Example. 5 Multi-Centre Trials and Meta-Analyses. 5.1 Introduction to Multi-Centre Trials. 5.2 The Implications of using Different Analysis Models. 5.3 Example: A Multi-Centre Trial. 5.4 Practical Application and Interpretation. 5.5 Sample Size Estimation. 5.6 Meta-Analysis. 5.7 Example: Meta-analysis. 6 RepeatedMeasures Data. 6.1 Introduction. 6.2 Covariance Pattern Models. 6.3 Example: Covariance Pattern Models for Normal Data. 6.4 Example: Covariance Pattern Models for Count Data. 6.5 Random Coefficients Models. 6.6 Examples of Random Coefficients Models. 6.7 Sample Size Estimation. 7 Cross-Over Trials. 7.1 Introduction. 7.2 Advantages of Mixed Models in Cross-Over Trials. 7.3 The AB/BA Cross-Over Trial. 7.4 Higher Order Complete Block Designs. 7.5 Incomplete Block Designs. 7.6 Optimal Designs. 7.7 Covariance Pattern Models. 7.8 Analysis of Binary Data. 7.9 Analysis of Categorical Data. 7.10 Use of Results from Random Effects Models in Trial Design. 7.11 General Points. 8 Other Applications of MixedModels. 8.1 Trials with Repeated Measurements within Visits. 8.2 Multi-Centre Trials with Repeated Measurements. 8.3 Multi-Centre Cross-Over Trials. 8.4 Hierarchical Multi-Centre Trials and Meta-Analysis. 8.5 Matched Case-Control Studies. 8.6 Different Variances for Treatment Groups in a Simple Between-Patient Trial. 8.7 Estimating Variance Components in an Animal Physiology Trial. 8.8 Inter- and Intra-Observer Variation in Foetal Scan Measurements. 8.9 Components of Variation and Mean Estimates in a Cardiology Experiment. 8.10 Cluster Sample Surveys. 8.11 Small AreaMortality Estimates. 8.12 Estimating Surgeon Performance. 8.13 Event History Analysis. 8.14 A Laboratory Study Using aWithin-Subject 4 x 4 Factorial Design. 8.15 Bioequivalence Studies with Replicate Cross-Over Designs. 8.16 Cluster Randomised Trials. 9 Software for Fitting MixedModels. 9.1 Packages for Fitting Mixed Models. 9.2 Basic use of PROC MIXED. 9.3 Using SAS to Fit Mixed Models to Non-Normal Data. Glossary. References. Index.