Clinical trial NCT02465359
Conditions: Chronic Inflammatory Demyelinating Polyneuropathy
Sponsor: University of South Florida
Start date: 2014-09-01; Completion date: 2021-05-01
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The investigators are using self administered subcutaneous immunoglobulin (SCIG) in patients with CIDP who require Intravenous immunoglobulin (IVIG). Safety, efficacy, and patient satisfaction will be examined.

Detailed description:
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune neurological disorder that causes limb weakness and numbness. Many patients require immunosuppressants and plasma exchange (PLEX) to control their symptoms. Intravenous immunoglobulin (IVIG) is also an effective treatment (Hughes et al, 2006 \& 2008; Hughes, 2009; Cocito et al, 2010), and the American Academy of Neurology (AAN) guideline recommended that it should be offered in the long-term treatment of CIDP (Patwa et al, 2012). While effective, IVIG causes systemic side effects in about 5% of patients. These side effects include rash, pruritus, myalgia, fever, chills, headache, low back pain, nausea, vomiting, changes in blood pressure or heart rate, renal failure, and aseptic meningitis (Berger, 2008). For many patients who are chronically treated with IVIG, venous access may be a problem over time. An alternative is the subcutaneous (SC) route, which has been in use since 1980 for primary immune deficiency disorders and is the treatment of choice for this condition in Scandinavia and England (Radinsky et al, 2003). As compared to intravenous (IV) route, SC route maintains higher trough levels of immunoglobulins, increases patient independence, reduces systemic side-effects, and is better tolerated in those who are pregnant or sensitized to Immunoglobulin A (IgA) (Radinsky et al, 2003). In a review of side effects associated with 33,168 SCIG infusions, no severe or anaphylactoid reactions occurred (Gardulf et al, 1995). Patients can self-administer medication, and hence, overall cost may be reduced. A retrospective study of 28 children with primary immunodeficiency in Canada showed that the mean difference in costs between IVIG and SCIG during the study period (1 year on IVIG and 1 year on SCIG) was $4,346 in favor of SCIG (Ducruet et al, 2011). A US$10,100 reduction in cost per year per patient associated with SCIG use was also reported by Gardulf et al (1995) in Sweden. Disadvantages of SCIG include more frequent infusions and local reactions at sites of infusion (transient swelling, soreness, redness, induration, local heat, and itching) in about 1% of patients.

Arms: arm 1: lmmune Globulin Subcutaneous(Human) 20% Liquid (Hizentra) will be given weekly
Interventions: intervention 1: Immune Globulin Subcutaneous (Human)
Intervention descriptions: intervention 1: Patients who have CIDP and are on IVIG will be allowed in the study to try subcutaneous immune Globulin (SCIG) as part of an open label study.

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
 
A study of subcutaneous immunoglobulin as chronic treatment for patients with chronic 
inflammatory demyelinating polyneuropathy 
NCT02465359 
Tuan H. Vu, M.D. – PI 
Lara Katzin, M.D. – Sub-I 
Brittany Harvey – Research Coordinator 
Natalie Tucker – Research Coordinator 
 
Version 12 
7/19/2016 
 
 


2 
 
 
BACKGROUND/RATIONALE 
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune neurological disorder that 
causes limb weakness and numbness.  Many patients require immunosuppressants and plasma exchange 
(PLEX) to control their symptoms.  Intravenous immunoglobulin (IVIG) is also an effective treatment (Hughes 
et al, 2006 & 2008; Hughes, 2009; Cocito et al, 2010), and the American Academy of Neurology (AAN) 
guideline recommended that it should be offered in the long-term treatment of CIDP (Patwa et al, 2012).  While 
effective, IVIG causes systemic side effects in about 5% of patients.  These side effects include rash, pruritus, 
myalgia, fever, chills, headache, low back pain, nausea, vomiting, changes in blood pressure or heart rate, renal 
failure, and aseptic meningitis (Berger, 2008).  For many patients who are chronically treated with IVIG, 
venous access may be a problem over time.  An alternative is the subcutaneous (SC) route, which has been in 
use since 1980 for primary immune deficiency disorders and is the treatment of choice for this condition in 
Scandinavia and England (Radinsky et al, 2003).  As compared to IV route, SC route maintains higher trough 
levels of immunoglobulins, increases patient independence, reduces systemic side-effects, and is better tolerated 
in those who are pregnant or sensitized to IgA (Radinsky et al, 2003).  In a review of side effects associated 
with 33,168 SCIG infusions, no severe or anaphylactoid reactions occurred (Gardulf et al, 1995).  Patients can 
self-administer medication, and hence, overall cost may be reduced.  A retrospective study of 28 children with 
primary immunodeficiency in Canada showed that the mean difference in costs between IVIG and SCIG during 
the study period (1 year on IVIG and 1 year on SCIG) was $4,346 in favor of SCIG (Ducruet et al, 2011).  
Gardulf et al (1995) also reported a reduction of US$10,100 in cost per year per patient with SCIG use in 
Sweden.  Similar cost savings were achieved in other countries as well (Lazzaro et al, 2014; Zbrozek, et al, 
2014).  Disadvantages of SCIG include more frequent infusions and local reactions at sites of infusion (transient 
swelling, soreness, redness, induration, local heat, and itching) in about 1% of patients.   
There are few reports of SCIG used in patients with CIDP (Koller et al, 2006; Lee et al, 2008; Cocito et al, 
2011). The data from these reports are summarized in table 1.  In general, SCIG was well tolerated and had 
similar clinical effects as IVIG.   
Table 1.Summary of reported use of SCIG in patients with CIDP.N/A = Data not reported; SE = side effects;  
 
More recently, Markvardsen and colleagues (2013) reported the effect of SCIG in 30 CIDP patients 
characterized as IVIG-responders by their treating physicians (see also abstract by Jacobsen et al, 2012).  The 
patients were randomized to receive either SCIG at a concentration of 1.6g/10cc or subcutaneous saline in a 
double-blinded fashion. Treatment with SCIG was demonstrated to be feasible, safe, and associated with 
improved strength, walking performance, and disability scores. 
Despite the potential advantages in terms of cost and scheduling conveniences, there are inherent barriers to the 
transition from IV to SC routes of administration.  First, self-administrating a large volume into the 
subcutaneous space may be unappealing to patients.  Second, the limb weakness caused by the disease may 
make it difficult to prepare the solution, operate the pump, and inserting the needles.  Third, many of the 
patients are elderly and may need considerable assistance to properly administer the medication.  However, in 
Pt No
Age
Gender IVIG dose
IVIG 
Duration
SCIG dose
Response
SE of SCIG
Preference
Reference
1
N/A
N/A
60 g/mo
2 yrs
60 g/mo
Same as IVIG
None
SCIG
Cocito et al, 2011
2
N/A
N/A
70 g/mo
6 yrs
70 g/mo
Same as IVIG
None
SCIG
Cocito et al, 2011
3
N/A
N/A
50 g/mo
16 yrs
50 g/mo
Same as IVIG
None
SCIG
Cocito et al, 2011
4
N/A
N/A
60 g/mo
3 yrs
60 g/mo
Same as IVIG
None
IVIG
Cocito et al, 2011
5
N/A
N/A
80 g/mo
13 yrs
80 g/mo
Same as IVIG
None
SCIG
Cocito et al, 2011
6
73
F
60 g/mo
18 mo
16 g/wk (64 g/mo)
Stable course
Mild skin rxn
N/A
Lee et al, 2008
7
53
M
200 g once One course
6.4 g/wk (25.6 g/mo)
Stable course ove Mild swelling
N/A
Lee et al, 2008
8
45
M
N/A
< 2 yrs
0.4 g/kg/mo
Stable
None
SCIG
Koller et al, 2006


3 
 
 
these patients, these obstacles may be overcome with assistance from a caregiver or a visiting nurse.  In 
additions, the impacts on quality of life (QOL) have not been fully assessed in this subset of patients. 
This study will survey the patients’ barriers to the transition from IV to the SC route of administration.  The 
results will form a basis for establishing a guideline for the use of SCIG. 
SPECIFIC AIMS 
As of October 2012, we identified more than 70 patients with the diagnosis of CIDP at the University of South 
Florida (USF) Neurology Clinic.  We estimated that at least 2/3 of these patients meet the Inflammatory 
Neuropathy Cause and Treatment (INCAT) Group diagnostic criteria (Sander & Latov, 2003).  Many of these 
patients still attend our clinic and many are dependent on IVIG to control symptoms.  Data are lacking in terms 
of tolerability, although our physicians are often contacted by patients or infusion centers for guidance 
regarding treatment of Ig infusion related side effects such as hypertension, flu-like symptoms, headaches, and 
joint pain.   
Specific Aim #1.This study will assess the QOL and adverse events experienced by patients on IVIG and 
whether patients currently treated with IVIG would be willing to try the SC route of administration.  This 
specific aim will be achieved via telephone or face-to-face survey.  The goal is to identify factors that may 
reduce the patients’ willingness to consider alternate drug delivery method. 
Specific Aim #2. For patients willing to switch to SCIG, this study will test the hypothesis that SCIG is safe and 
well tolerated and can be self-administered by patients with CIDP.  We will monitor patients’ adverse reactions 
via patient diary, questionnaires, examination, and laboratory studies.   
Specific Aim #3.  To test the hypothesis that SCIG is associated with better QOL, we will compare QOL 
measures pre- and post-treatment. 
Specific Aim #4.We will collect clinical data to test the hypothesis that SCIG is efficacious in controlling the 
symptoms of CIDP.  Patients will be followed with hand-held dynamometry (HHD) and 20-ft timed walk.  Pre- 
and post-treatment scores will be compared using appropriate statistical analysis. 
RESEARCH STRATEGY 
SIGNIFICANCE: 
We have a substantial number of CIDP patients who require frequent doses of IVIG.  Due to the side effects and 
time required by the IV route, these patients would potentially benefit from SCIG for the reasons discussed.  
The purpose of this pilot study is to determine whether SCIG is well tolerated, can be self-administered, 
improves QOL, and is efficacious in controlling CIDP symptoms.   
INNOVATION: 
Currently, most if not all CIDP patients who required Ig treatment are receiving it via the IV route.  If proven 
efficacious and better tolerated, SCIG would be an attractive alternative.  Additional benefits of SCIG include 
lesser cost and increased convenience to patients.   
APPROACH: 
This is a prospective, open label study of SCIG for the treatment of patients with CIDP who are dependent on 
IVIG for control of symptoms. 


4 
 
 
Participants:  Up to 30 patients with IVIG-dependent CIDP will be enrolled. To qualify, a patient must meet 
ALL of the inclusion criteria and NONE of the exclusion criteria. 
Inclusion Criteria: 
1) Confirmed diagnosis of CIDP (having 2 or more of the following): 
a) Weakness in any limb 
b) Motor fatigue significant enough to interfere with ADL’s or work 
c) Paresthesia of sufficient severity to require medication 
d) Sensory impairment 
e) Walking impairment 
2) Requires IVIG to control symptoms 
3) Male or female patient, older than 18 years of age 
4) Able to provide informed consent 
5) Able to be trained to provide self-injection 
6) Willing to be on birth control for the duration of the study (for women of reproductive potential) 
Exclusion Criteria:    
1) Thrombocytopenia or other bleeding disorders;  
2) Patients on anticoagulation therapy with an INR > 3.5;  
3) Severe or anaphylactoid reactions to IVIG;  
4) Cancer (active or currently treated);  
5) Pregnancy;  
6) Breast-feeding;  
7) Renal insufficiency (creatinine > 1.5 upper limit of normal) or failure;  
8) Congestive heart failure;  
9) Psychiatric illness that would interfere with ability to provide informed consent or adhere to protocol;  
10) Current IVIG doses greater than 2 g/kg per month;  
11) Subject with an IgA level < 5% lower limit of normal;  
12) History of active infection with HIV, Hepatitis B or Hepatitis C;  
13) Presence of any other medical condition, which in the opinion of the investigator might interfere with 
performance;  
14) Participation in a trial of an investigational medicinal product for CIDP in the past 12 weeks. 
 
Sample size and statistical analysis: Descriptive information for the rate of change, such as mean and standard 
deviation, will be calculated. Due to the small sample size and self-control used in this study, instead of using 
paired t-test, Wilcoxon paired ranked test will be used to compare the change of before and after from each 
patient.  Significance level is defined as 0.05 and all of the analyses will be carried by SAS (version 9.2).  
DESIGN: The study will be submitted to the USF IRB for approval.   
Specific Aim #1. We will assess QOL using the Medical Outcome Study 36-item short form health status scale 
(SF-36) and the Rasch-built Overall Disability Scale (R-ODS).  The scales have been validated in patients with 
CIDP (Merkies et al, 2002; van Nes et al, 2011).  We will also do a survey of side effects and satisfaction with 
treatment (using the Treatment Satisfaction Questionnaire for Medication, or TSQM) and CIP-PRO20 scale 
(used by permission from Dr. Ted Burns; see appendix 3).  No surveys will be completed until the patient signs 
the ICF. In addition, we will determine whether patients currently treated with IVIG would be willing to try the 
SC route of administration.  Reasons cited for unwillingness to switch will be collected.   


5 
 
 
Specific Aim #2.To test the safety and tolerability of SCIG and feasibility of self-administration in patients with 
CIDP. 
Patients will undergo baseline laboratory studies (CBC, CMP, TSH, quantitative IgG, PT/INR/PTT, pregnancy 
test for women of productive age), EKG, QOL questionnaires, treatment satisfaction and SE questionnaires, 
neurological and physical examination, and HHD measurements.  
The study will provide all study medications, pumps, and supplies.  
The first treatment of SCIG will start within 2 weeks after the last IVIG course (to maintain serum Ig levels).  
The first 2 weekly treatments will be done at USF Clinical Research Center (USF CRC).  Patients will be 
trained to perform their own infusions during these initial sessions and will receive additional training sessions 
if needed. Subjects will start self-administration at home after they feel comfortable and confident with the 
procedure. For each weekly treatment, 20% solution of human normal IgG (Hizentra, CSL Behring AG) will be 
infused subcutaneously in the abdomen, flanks, arms, or thighs. Simultaneous SC infusion at multiple sites will 
be done using a multi-needle administration set.  The volume at each infusion site will be 35 ml (7 g) or as 
tolerated, and administered via a syringe driver pump at a rate of 20-25 ml/hr/site or as tolerated.  For this study, 
we will use a 1:1 conversion ratio for IV to SC dosing.  The total SC dose weekly will be the patient’s current 
IVIG dose divided by 4 (0.25 g/kg – 0.5 g/kg, corresponding to 1 – 2 g/kg per month, which is usually our 
maintenance dose for CIDP patients).  Patients requiring > 2 g/kg of IVIG per month will be excluded from 
study. Weekly doses may be divided over the course of the week if needed (e.g., twice or three times a week).  
The SCIG will be given weekly for 24 weeks.  The dosing will be individualized to each patient depending on 
dose and patient response.  The regimen may be changed at any point as needed for patient comfort (e.g., a 
patient may increase his/her dosing schedule from 1 day to 2 or 3 days per week). After this period, the patients 
will be given a choice to discontinue treatment, continue with SCIG, or go back to IVIG.  Pregnancy screen will 
be performed monthly on women with reproductive potential while they are undergoing treatment.  If a subject 
becomes pregnant during the study, she will be withdrawn from treatment but will be monitored for the rest of 
the study.  Please see table 2 for schedule of study visits. Study subjects will be monitored for allergic reactions 
(rash, urticaria, facial edema, wheezing, dyspnea, hypotension, and tachycardia) and injection site reactions 
(transient swelling, soreness, redness, induration, local heat, and itching) while receiving their first infusion at 
USF CRC.  They will also keep a treatment log of injection site reactions for the duration of the study.  
Additional monitoring includes: 
1. CBC with differential count and platelet count will be done prior to treatment and once per month 
during treatment. 
2. Symptom monitoring will be done via phone and at scheduled visits at regular intervals.  Study visits 
will have a window of +/- 7 days.  Patients will have 24/7 access to investigators to report any 
symptoms that develop. 
3. Subjects will be provided with emergency contact number for questions relating to any symptoms during 
the study. 
4. In the event that the subject experiences a reaction at home, they will call us.  They will also be trained 
to call 911 in an emergency situation.  
Primary End-Points. 
1. Significant side-effects requiring withdrawal from study. 
2. Laboratory abnormalities requiring discontinuation of study. 
 
Table 2. Schedule of Study Events and Visits.  


6 
 
 
   
 
 
Specific Aim #3.  To test the hypothesis SCIG is associated with better QOL.   
 
At baseline (pretreatment of SCIG, while subjects are being treated with IVIG), QOL and treatment satisfaction 
questionnaires (SF-36, CIP-PRO20, R-ODS, and TSQM) will be done.  These measures will be repeated 
monthly during the course of the study.  Data from pretreatment and treatment with SCIG phase will be 
compared using appropriate statistical methods with correction for multiple comparisons.   
Specific Aim #4.  To test the hypothesis that SCIG is efficacious in controlling the symptoms of CIDP.   
Clinical response to SCIG will be monitored using HHD and 20-ft timed walk.  Data from pretreatment and 
SCIG treatment phase will be compared.  The HHD will measure force generated by the following muscle 
groups:  Shoulder flexion, elbow flexion, elbow extension, wrist extension, first dorsal interosseous (hand), hip 
flexion, knee extension, knee flexion, ankle dorsiflexion.  Measurement will be done bilaterally in duplicates.  
For the primary efficacy endpoint, HHD muscle strength measured at Week 24 will be compared to HHD 
muscle strength measured at baseline (pretreatment) 
 
Secondary End-Point. 
1. Progression of symptoms requiring reversion to IVIG, initiation of PLEX or other medications, or 
hospitalization. 
Screening
Day 1
Week 1
Week 2* Week 3*
Week 4 
(Month 1)
Week 8 
(Month 2)
Week 12 
(Month 3)
Week 16 
(Month 4)
Week 20 
(Month 5)
Week 24 
EOS/ET 
(Month 6)
Follow-Up
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
Informed Consent
x
Inclusion/Exclusion Review
x
x
Medical History
x
x
x
Vital Signs Monitoring
x
x
x
x
x
x
x
x
 
x
x
Physical/Neuro Exam
x
x
x
x
x
x
x
x
x
x
TSQM
x
x
x
x
x
x
x
x
x
CIP-PRO20
x
x
x
x
x
x
x
x
x
R-ODS
x
x
x
x
x
x
x
x
x
SF-36
x
x
x
x
x
x
x
x
x
Hand-held Dynamometry
x
x
x
x
x
x
x
x
x
20-ft Timed Walk
x
x
x
x
x
x
x
x
x
Electrocardiogram (ECG)
x
PT/INR, PTT
x
TSH
x
Quantitative IgA, IgG, IgM
x
x
x
x
x
x
x
x
Hematology, blood chemistry
x
x
x
x
x
x
x
x
x
Urine Pregnancy Test
x
x
x
x
x
x
x
x
x
Subcutaneous Drug Administration Training
x
x
x
x
Subcutaneous Drug Administration 
x
x
x
x
Drug Diary Training
x
x
Drug Diary Review
x
x
x
x
x
x
x
x
Drug Dispensation
x
x
x
x
x
x
x
x
x
x
Drug Accountability
x
x
x
x
x
* optional for additional administration training (can be completed at home)


7 
 
 
Study Timeline and Feasibility: Participants will be recruited from the USF Neuromuscular Clinic. This Clinic 
is the tertiary referral center for the west coast of Florida, with a population of more than 4 million in the Tampa 
Bay region alone. We estimated that we have more than 70 patients with CIDP.  In addition, we see an average 
of 2 new CIDP patients per month.  Thus, there are enough patients for a 3 to 1 screening to enrollment ratio.  
Planned recruitment is an average of 1 patient every 1.5 months, for a total of 22.5 months. This schedule will 
place the final recruit completing the trial during month 30 and afford time during the final 6 months of the 
study for analyzing and preparing data for publication. This planned recruitment timeline is feasible given the 
size, established referral patterns, and historical recruitment experience of this clinic.  
 
Rescue protocol: If a subject worsens (or “relapses”) during the study, we will institute a rescue protocol.  
Relapse is defined as a 20% decrease in force (as detected on HHD) in more than 50% of the muscles tested 
when compared to baseline. In case of relapse, we will quantify the serum Ig levels, give IVIG 1 g/kg boost 
followed by SCIG at 2 g/kg per month.  If the subject is already on 2 g/kg per month of SCIG, we will switch 
the patients back to IV administration and/or institute other treatment options (steroids, PLEX).  Please see 
algorithm in Appendix 2. We will also switch back to IVIG if, at any point during the study: 
a. The subject requests the switch due to treatment failure, adverse events or patient preference. 
b. The investigators consider it to be in the best interest of the subject (i.e., due to intolerable 
side-effects, pregnancy, or noncompliance). 
Potential Pitfalls and Alternative Strategies: There is the potential that some patients may lose interest or 
become too reticent in performing self-administration. Since compliance may be an issue with self-
administration of an injectable medication, serum IgG levels will be done to monitor patient’s adherence to 
protocol.  The use of a home journal for recording therapy and a weekly telephone call will encourage 
compliance. In the scenario where there is concern with patient compliance, a weekly home therapy visit will be 
done. Attrition is also expected during the course of the study. If a participant becomes a ‘drop out,’ his or her 
data will be used in the analysis using an intention to treat protocol. Finally, while recruitment can be an issue in 
clinical trials, our planned enrollment rate of an average of 1 patient per 1.5 months is feasible.  Furthermore, 
we already identified several patients who are appropriate for this trial.  With an average of 2 new CIDP 
patients seen per month in the USF Neuromuscular Clinic, we should be able to recruit the remaining patients in 
the proposed timeline.  Furthermore, there are many more CIDP patients in the greater Tampa region who are 
not being seen at USF.  Thus, there is an untapped pool of subjects available.  In the unanticipated scenario that 
we fall behind on subject recruitment, we have incorporated 6 additional months in our timeline for analysis and 
manuscript preparation that could be utilized for subject recruitment and treatment.   
Data Management and Quality Control: Physiologic and questionnaire data will be collected across two time 
points (pre- and SCIG treatment phase) by the PI and coordinator who are all proficient in these testing 
methods. To ensure participant confidentiality, data will be coded to remove patient identifiers into a password-
protected database (Excel) on a central computer system that is backed up daily. Data accuracy will be verified 
by double data entry. All original paper questionnaires will be locked in the PI’s office with only coded 
identifying information. There will be an interim analysis done after 8 patients have completed the study. 
 
Safety Monitoring and Adverse Events Reporting:  Patients will be closely monitored for safety and any adverse 
events. This monitoring of treatment tolerability will be achieved through weekly telephone contact and 
monthly visit. During the study visits, subjects will be seen by a member of the research staff and will complete 
all study instruments, undergo clinical assessment, and have blood drawn for safety and compliance monitoring.  
At all study visits, concomitant medications, symptoms and side effects will be reviewed.  Participants will also 
be provided with the Study Agent Intake and Symptom log which they will be required to complete. Adverse 


8 
 
 
Events will be reported to sponsor, USF IRB and regulatory agency, by investigators in a timely manner as 
required. 
 
Dose and Toxicity Management:  
A patient’s treatment will be suspended in any of the following circumstances:  
 
1. Allergic reaction to product  
2. Request of patient or patient’s physician;  
3. Unusual symptoms reported during telephone follow-up or other unusual symptoms or blood work results 
observed during the study period 
4. Pregnancy; or 
5. Worsening symptoms requiring hospitalization or PLEX.  
 
Any side effects associated or possibly associated with SCIG will be managed according to standard medical 
practice.  
 
 
 
 
 
 
 
 
 
REFERENCES 
Berger, M. Subcutaneous administration of IgG.Immunol Allergy Clin N Am 2008;28:779-802. 
Cocit D, Paolasso I, Antonini G, Benedetti L, Briani C, Comi C, et al. A nationwide retrospective analysis on 
the effect of immune therapies in patients with chronic inflammatory demyelinating 
polyradiculoneuropathy.Eur J Neurol 2010 Feb;17(2):289-94. 
Cocito D, Serra G, Falcone Y, Paolasso I. The efficacy of subcutaneous immunoglobulin administration in 
chronic inflammatory demyelinating polyneuropathy responders to intravenous immunoglobulin.  J 
PeripherNerv Syst. 2011 Jun;16(2):150-2. 
Gardulf A, Andersen V, Björkander J, Ericson D, Frøland SS, Gustafson R, et al. Subcutaneous 
immunoglobulin replacement in patients with primary antibody deficiencies: safety and costs. Lancet. 1995 Feb 
11;345(8946):365-9. 


9 
 
 
Hughes AC, Bouche P, Cornblath DR, Evers E, Hadden RDM, Hhahn A, et al. Eur J Neurol. 2010 
Mar;17(3):356-63. 
Hughes RA, Donofrio P, Bril V, Dalakas MC, Deng C, Hanna K, et al. Intravenous immune globulin (10% 
caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating 
polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial. Lancet Neurol 2008 Feb;7(2):136-
44. 
Lazzaro C, Lopiano L, Cocito D.  Subcutaneous vs intravenous administration of immunoglobulin in chronic 
inflammatory demyelinating polyneuropathy:  an Italian cost-minimization analysis.  Neurol Sci 2014 35:1023-
1034. 
Jakobsen K, Markvardsen L, Harbo T, Sindrup S, Andersen H, Christiansen I, et al. A randomised, double-
blinded, placebo controlled trial of the effect of subcutaneous immunoglobulin on muscular performance in 
chronic inflammatory demyelinating polyneuropathy. Neurology 2012;78(1). 
Radinsky S, Bonagura VR. Subcutaneous immunoglobulin infusion as an alternative to intravenous 
immunoglobulin.J Allergy ClinImmunol 2003; 630-2. 
Köller H, Schroeter M, Feischen H, Hartung HP, Kieseier BC. Subcutaneous self-infusions of immunoglobulins 
as a potential therapeutic regimen in immune-mediated neuropathies. J Neurol 2006 Nov;253(11):1505-6.  
Lee DH, Linker RA, Paulus W, Schneider-Gold C, Chan A, Gold R. Subcutaneous immunoglobulin infusion: a 
new therapeutic option in chronic inflammatory demyelinating polyneuropathy. Muscle Nerve 2008 
Mar;37(3):406-9. 
Markvardsen LH, Debost JC, Harbo T, Sindrup SH, Andersen H, Christiansen I, Otto M, Olsen NK, Lassen LL, 
Jakobsen J, and the Danish CIDP and MMN Study Group.  Subcutaneous immunoglobulin in responders to 
intravenous therapy with chronic inflammatory demyelinating polyradiculoneuropathy.Eur J Neurol 2013:1-7. 
Merkies IS, Schmitz PI, van der Meché FG, Samijn JP, van Doorn PA, Inflammatory Neuropathy Cause and 
Treatment (INCAT) group. Quality of life complements traditional outcome measures in immune-mediated 
polyneuropathies. Neurology 2002 Jul 9;59(1):84-91. 
Patwa HS, Chaudhry V, Katzberg H, Rae-Grant AD, So YT. Evidence-based guideline: intravenous 
immunoglobulin in the treatment of neuromuscular disorders: report of the Therapeutics and Technology 
Assessment Subcommittee of the American Academy of Neurology. Neurology 2012 Mar 27;78(13):1009-15. 
Sander HW, Latov N. Research criteria for defining patients with CIDP.Neurology. 2003 Apr 1;60(8 Suppl 
3):S8-15. 
vanNes SI, Vanhoutte EK, van Doorn PA, Hermans M, Bakkers M, Kuitwaard K et al. Rasch-built Overall 
Disability Scale (R-ODS) for immune-mediated peripheral neuropathies. Neurology 2011 Jan 25;76(4):337-45. 
Zbrozek A, Berger M, Bullinger A.  Estimating the Economic Advantage of Subcutaneous Administration of 
IgG for Patients with Chronic Inflammatory Demyelinating Polyneuropathy (CIDP).  PNS Poster, 2014 
 
 


10 
 
 
APPENDIX – 1 
LIST OF ABBREVIATIONS 
AAN  
 
American Academy of Neurology 
CIDP  
 
Chronic Inflammatory Demyelinating Polyneuropathy 
CIP-PRO20 
 
Chronic Immune-mediated Polyneuropathy – Patient Reported Outcome Scale 
HHD  
 
Hand-held Dynamometry 
INCAT 
 
 
Inflammatory Neuropathy Cause and Treatment 
IVIG  
 
Intravenous Immunoglobulins 
PLEX  
 
Plasma Exchange 
QOL  
 
Quality of Life 
R-ODS 
 
 
Rasch-built Overall Disability Scale 
SC 
 
 
Subcutaneous 
SCIG  
 
Subcutaneous Immunoglobulins 
SE 
 
 
Side Effects 
SF-36  
 
Medical Outcome Study 36-item Short Form Health Status Scale 
TSQM  
 
Treatment Satisfaction Questionnaire for Medication 
USF 
 
 
University of South Florida 
USF CRC 
 
USF Clinical Research Center 
 
 
 
 
 


11 
 
 
APPENDIX – 2 
RELAPSE RESCUE PROTOCOL 
 
 
 
 
 


12 
 
 
APPENDIX – 3 
CIP-PRO20 Scale 2014 
 
 
 
Total Score: 
Completed by: 
Date:
I have trouble eating because of my neuropathy.
I have trouble doing activities around the house.
I am unable to do all the leisure activities that I 
want to do because of my neuropathy.
I am worn out because of my neuropathy.
I am falling because of my neuropathy.
I am preoccupied with my neuropathy.
I am dependent on others because of my 
neuropathy. 
I am depressed about my neuropathy.
I am bothered by limitations in performing my 
work (include work at home) because of my 
neuropathy.
I have trouble driving because of my neuropathy.
I have trouble getting dressed because of my 
neuropathy.
I have trouble sleeping because of my neuropathy.
I am bothered by pain from neuropathy.
I am off balance when walking because of my 
neuropathy.
Are you able to: 
0: Not at all
1: A little bit
2. A lot
I am furstrated by my neuropathy.
Protocol: A Study of Subcutaneous Immunoglobulin as Chronic Tratment 
for Paitents with Chronic Inflammatory Demyelinating Polyneuropathy
CIP-PRO 


13 
 
 
APPENDIX 4 
TSQM 
TSQM (Version II) 
 
Treatment Satisfaction Questionnaire for Medication 
 
Instructions:  Please take some time to think about your level of satisfaction or dissatisfaction 
with the medication you are taking in this clinical trial.  We are interested in your evaluation of 
the effectiveness, side effects, and convenience of the medication over the last two to three 
weeks, or since you last used it.  For each question, please place a single check mark next to 
the response that most closely corresponds to your own experiences. 
 
1. How satisfied or dissatisfied are you with the ability of the medication to prevent or treat the condition?  
 □1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
2. How satisfied or dissatisfied are you with the way the medication relieves symptoms?  
 □1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
3.  As a result of taking this medication, do you experience any side effects at all? 
 □1   Yes 
□0   No 
 
4. How dissatisfied are you by side effects that interfere with your physical health and ability to function (e.g., 
strength, energy levels)? 
 □1   Extremely Dissatisfied 
□2   Very Dissatisfied 


14 
 
 
□3   Somewhat Dissatisfied 
□4   Slightly Dissatisfied 
□5   Not at all Dissatisfied 
□(5) Not Applicable 
5. How dissatisfied are you by side effects that interfere with your mental function (e.g., ability to think clearly, 
stay awake)? 
 □1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Somewhat Dissatisfied 
□4   Slightly Dissatisfied 
□5   Not at all Dissatisfied 
□(5) Not Applicable 
 
6. How dissatisfied are you by side effects that interfere with your mood or emotions (e.g., anxiety/fear, 
sadness, irritation/anger)? 
 □1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Somewhat Dissatisfied 
□4   Slightly Dissatisfied 
□5   Not at all Dissatisfied 
□(5) Not Applicable 
 
7. How satisfied or dissatisfied are you with how easy the medication is to use? 
 □1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
 
8. How satisfied or dissatisfied are you with how easy it is to plan when you will use the medication each time? 
 □1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 


15 
 
 
9. How satisfied or dissatisfied are you by how often you are expected to use/take the medication? 
 □1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
10. How satisfied are you that the good things about this medication outweigh the bad things? 
 □1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
11. Taking all things into account, how satisfied or dissatisfied are you with this medication? 
 □1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
 
 
 
 
 
 
 
 


16 
 
 
APPENDIX 5 
HAND HELD DYNAMOMETRY WORKSHEET 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes
No
□
Subject unable to perform task due to weakness
□
Other (specify)_______________________________
□
Subject unable to perform task due to weakness
□
Other (specify)_______________________________
□
Subject unable to perform task due to weakness
□
Other (specify)_______________________________
□
Subject unable to perform task due to weakness
□
Other (specify)_______________________________
□
Subject unable to perform task due to weakness
□
Other (specify)_______________________________
□
Subject unable to perform task due to weakness
□
Other (specify)_______________________________
□
Subject unable to perform task due to weakness
□
Other (specify)_______________________________
□
Subject unable to perform task due to weakness
□
Other (specify)_______________________________
□
Subject unable to perform task due to weakness
□
Other (specify)_______________________________
□
Subject unable to perform task due to weakness
□
Other (specify)_______________________________
□
Subject unable to perform task due to weakness
□
Other (specify)_______________________________
□
Subject unable to perform task due to weakness
□
Other (specify)_______________________________
□
Subject unable to perform task due to weakness
□
Other (specify)_______________________________
□
Subject unable to perform task due to weakness
□
Other (specify)_______________________________
□
Subject unable to perform task due to weakness
□
Other (specify)_______________________________
□
Subject unable to perform task due to weakness
□
Other (specify)_______________________________
□
Subject unable to perform task due to weakness
□
Other (specify)_______________________________
□
Subject unable to perform task due to weakness
□
Other (specify)_______________________________
Completed by: 
Date:
Protocol: A Study of Subcutaneous Immunoglobulin as Chronic Tratment 
for Paitents with Chronic Inflammatory Demyelinating Polyneuropathy
HHD
□
□
□
Right ankle 
dorsiflexion
□
□
□
Left ankle 
dorsiflexion
□
□
□
Right first 
dorsal 
interosseous
□
□
□
Left first 
dorsal 
interosseous
□
□
Right knee  
flexion
□
□
□
Left knee 
flexion
□
□
□
Right knee 
extension
□
□
□
Left knee 
extension
□
□
□
Right hip 
flexion
□
□
□
Left hip 
flexion
□
□
□
Right wrist 
extension
□
□
□
Left wrist 
extension
□
□
□
Right elbow 
extension
□
□
□
Left elbow 
extension
□
□
□
Right elbow 
flexion
□
□
□
Left elbow 
flexion
□
□
□
Right 
shoulder 
flexion
□
□
□
Left shoulder 
flexion
□
Not 
Tested
Muscle
Trial 1 
(lbs.)
Trial 2 
(lbs.)
Trial 3 
(lbs.)   
if 
needed
Able to break?
If not tested, please explain:


17 
 
 
APPENDIX 6 
R-ODS Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total Score: 
Completed by: 
Date:
Dance?
Stand for hours?
Walk outdoors < 1km?
Carry and put down a heavy object?
Run?
Go to a general practitioner?
Wash your lower body?
Move a chair?
Do the shopping?
Catch an object (e.g. ball)?
Take a shower?
Do the dishes?
Travel by public transport?
Walk and avoid obstacles?
Bend and pick up an object?
Walk 1 flight of stairs?
Make a sandwich?
Dress your upper body?
Brush your teeth?
Sit on a toilet?
Wash upper body?
Turn a key in a lock?
Read a newspaper/book?
Eat?
Protocol: A Study of Subcutaneous Immunoglobulin as Chronic Tratment 
for Paitents with Chronic Inflammatory Demyelinating Polyneuropathy
R-ODS
Are you able to: 
0: Impossible to 
perform
1: Performed 
with difficulty
2. Easily 
Performed


18 
 
 
APPENDIX 7 
Short Form-36 Questionnaire 
Protocol: A Study of Subcutaneous Immunoglobulin as Chronic 
Tratment for Paitents with Chronic Inflammatory Demyelinating 
Polyneuropathy 
SF-36 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. In general, would you say your health is:  
□ 
1 - Excellent 
□ 
2 - Very good 
□ 
3 - Good  
□ 
4 - Fair 
□ 
5 - Poor 
2. Compared to one year ago, how would you rate your 
health in general now? 
□ 
1 - Much better than one year ago 
□ 
2 - Somewhat better than one year ago 
□ 
3 - About the same as one year ago 
□ 
4 - Somewhat worse now than one year ago 
□ 
5 - Much worse now than one year ago 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
The following questions are about activities you might do during a typical day. 
Does your health now limit you in these activities? If so, how much? 
Response: 
  
  
 1 - Yes, limited a lot 
  
 2 - Yes, limited a little 
 3 - No, not limited at all 
3. Vigorous activities, such as running, lifting heavy objects, participating in strenuous 
sports. 
□ 1 
□ 2 
□ 3 
4. Moderate activities, such as moving a table, pushing a vacuum cleaner, bowling or 
playing golf 
□ 1 
□ 2 
□ 3 
5. Lifting or carrying groceries 
  
  
□ 1 
□ 2 
□ 3 
  
  
6. Climbing several flights of stairs 
  
  
□ 1 
□ 2 
□ 3 
  
  
7. Climbing one flight of stairs 
  
  
□ 1 
□ 2 
□ 3 
  
  
8. Bending, kneeling or stooping 
  
  
□ 1 
□ 2 
□ 3 
  
  
9. Walking more than a mile 
  
  
□ 1 
□ 2 
□ 3 
  
  
10. Walking several blocks 
  
  
□ 1 
□ 2 
□ 3 
  
  
11. Walking one block 
  
  
□ 1 
□ 2 
□ 3 
  
  
12. Bathing or dressing yourself 
  
  
□ 1 
□ 2 
□ 3 
  
  
Response: 


19 
 
 
During the past 4 weeks, have you had any of the following problems with your work or other regular 
daily activities as a result of your physical health? 
  
1 - 
Yes 
  
2 - 
No 
13. Cut down on the amount of time you spent on work or other activities 
□ 1 
□ 2 
14. Accomplished less than you would like 
□ 1 
□ 2 
15. Were limited in the kind of work or other activities 
□ 1 
□ 2 
16. had difficulty performing the work or other activities (took extra effort) 
□ 1 
□ 2 
During the past 4 weeks, have you had any of the following problems with your work or other regular 
daily activities as a result of any emotional problems (such as feeling depressed or anxious)? 
Response: 
  
1 - 
Yes 
  
2 - 
No 
17. Cut down the amount of time you spent on work or other activities 
□ 1 
□ 2 
18. Accomplished less than you would like 
□ 1 
□ 2 
19. Didn't do work or other activities as carefully as usual 
□ 1 
□ 2 
20. During the past 4 weeks, to what extent has your physical health or 
emotional problems interfered with your normal social activities with 
family, friends, neighbors or groups? 
□ 
1 - Not at all 
  
  
□ 
2 - Slightly 
  
  
□ 
3 - Moderately 
  
□ 
4 - Quite a bit 
  
  
□ 
5 - Extremely 
  
  
21. How much bodily pain have you had during the past 4 weeks? 
□ 
1 - None 
  
  
□ 
2 - Very Mild 
  
  
□ 
3 - Mild 
  
  
□ 
4 - Moderate 
  
  


20 
 
 
□ 
5 - Severe 
  
  
□ 
6 - Very severe 
  
22. During the past 4 weeks, how much did pain interfere with your 
normal work (including both work outside the home and housework)? 
□ 
1 - Not at all 
  
  
□ 
2 - A little bit 
  
  
□ 
3 - Moderately 
  
□ 
4 - Quite a bit 
  
  
□ 
5 - Extremely 
  
  
These questions are about how your feel and how things have 
been with you during the past 4 weeks. For each question, please 
give the one answer than comes closest to the way you have been 
feeling, how much of the time during the past 4 weeks 
Response: 
  
  
  
  
  
1 - All of the time 
  
  
  
2 - Most of the time 
  
  
  
3 - A good bit of the time 
  
  
4 - Some of the time 
  
  
  
5 - A little of the time 
  
  
  
6 -None of the time 
  
  
23. Did you feel full of pep? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
□ 6 
24.  Have you been a very nervous person? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
□ 6 
25. Have you felt so down in the dumps that nothing could cheer 
you up? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
□ 6 
26.  Have you felt calm and peaceful? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
□ 6 
27.  Did you have a lot of energy? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
□ 6 
28.  Have you felt downhearted and blue? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
□ 6 
29. Did you feel worn out? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
□ 6 
30.  Have you been a happy person? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
□ 6 
31.  Did you feel tired? 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
□ 6 


21 
 
 
32. During the past 4 weeks, how much of the time has your physical 
health or emotional problems interfered with your social activities (like 
visiting friends, relatives, etc.)? 
□ 
1 - All of the time 
  
□ 
2 - Most of the time 
  
□ 
3 - Some of the time 
  
□ 
4 - A little of the time 
  
□ 
5 - None of the time 
  
How TRUE or FALSE is each of the following statements for you? 
Response: 
  
  
  
  
1 - Definitely true 
  
  
2 - Mostly true 
  
  
3 - Don't know 
  
  
4 - Mostly false 
  
  
5 - Definitely 
false 
  
  
33. I seem to get sick a little easier than other people 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
34. I am as healthy as anybody I know 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
35. I expect my health to get worse 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
36. My health is excellent. 
□ 1 
□ 2 
□ 3 
□ 4 
□ 5 
Total Score:  
  
  
Completed by:  
  
  
  
  
  
  
  
Date: