Comparison of Multigam IV (5% vs. 10%) as Substitution Therapy in Patients With an Immunodeficiency Secondary to a Hematological Disorder to Evaluate Infusion Time, Tolerance and Satisfaction. A Monocentric Observational Belgian Study
Conditions: Hematologic Diseases, Secondary Immune Deficiency
Sponsor: Universitaire Ziekenhuizen KU Leuven

 
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Full protocol title prospective observational study: 
 
“Comparative study of the use of Multigam IV (5% vs. 10%) as substitution therapy in patients with 
a secondary immunodeficiency due to a hematological disorder to evaluate infusion time, 
tolerability and satisfaction. A monocentric observational Belgian study.” 
 
Protocol acronym/short title: 
 
MULTISIM/Comparison of Multigam IV 5% and Multigam IV 10% in immunocompromised 
patients. 
 
Version and date of final protocol: 
Version 3 - 8 September 2017 
 
Sponsor: 
 
Name: UZLeuven 
Address: Herestraat 49, 3000 Leuven 
 
Principal investigator: 
 
Name: Professor Dr Delforge Michel 
Address: Herestraat 49, 3000 Leuven 
Email: michel.delforge@uzleuven.be 
 
 
 
 
 
 

 
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Signature 
 
 
 
_________________________ 
 
 
 
____________________ 
Principal Investigator 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Table of contents 
1. 
Study synopsis ................................................................................................................................. 5 
2. 
Background and rationale ............................................................................................................... 8 
3. 
Study objectives and design ............................................................................................................ 9 
3.1 Study objectives ........................................................................................................................ 9 
3.2 Primary endpoints ..................................................................................................................... 9 
3.3 Secondary endpoints ................................................................................................................. 9 
3.4 Study design .............................................................................................................................. 9 
3.5 Study diagram ............................................................................................................................ 9 
3.6 Study flowchart ....................................................................................................................... 10 
4. 
Selection and exclusion of participants ......................................................................................... 10 
4.1 Inclusion criteria ...................................................................................................................... 10 
4.2 Exclusion criteria ..................................................................................................................... 10 
4.3 Expected duration of study ..................................................................................................... 10 
5. 
Study actions per visit ................................................................................................................... 11 
5.1 Study visit 1 ............................................................................................................................. 11 
5.2 Study visit 2 ............................................................................................................................. 11 
6. 
Data collection ............................................................................................................................... 11 
7. 
Assessment of efficiency ............................................................................................................... 12 
8. 
Assessment of safety ..................................................................................................................... 12 
8.1 Specification, timing and registration of safety parameters ................................................... 12 
8.2 Procedures for registration and reporting of adverse events (AE) ......................................... 12 
9. 
Statistics ........................................................................................................................................ 15 
9.1 Sample size .............................................................................................................................. 15 
9.2 Analysis .................................................................................................................................... 15 
10. 
Direct access to source data and documents ............................................................................ 15 
11. 
Ethical and regulatory compliance ............................................................................................ 15 
12. 
Data handling and management ............................................................................................... 16 
13. 
Publication policy ...................................................................................................................... 16 
14. 
Insurance/compensation .......................................................................................................... 17 

 
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15. 
Financial aspects ........................................................................................................................ 17 
16. 
References ................................................................................................................................. 17 
17. 
Annex ......................................................................................................................................... 18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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1. Study synopsis 
Clinical trial title 
 
 
 
Comparative study of the use of Multigam IV (5% vs. 10%) 
as substitution therapy in patients with a secondary 
immunodeficiency due to a hematological disorder to 
evaluate infusion time, tolerability and satisfaction. A 
monocentric observational Belgian study. 
Protocol short title/Acronym 
 
 
MULTISIM/Comparison of Multigam IV 5% and Multigam 
IV 10% in immunocompromised patients. 
 
Sponsor name 
 
 
UZ Leuven 
Principal investigator 
 
 
Professor dr. Delforge Michel 
Medical condition or ilness 
 
Secondary immune deficiencies in patients with an 
underlying hematological disorder. 
Purpose of the clinical trial 
 
 
Evaluation of infusion time, safety and tolerance of 
Multigam 10% compared to Multigam 5%. 
Primary objective 
 
 
Assess the administration of Multigam 10% compared to 
Multigam 5% to shorten the infusion time without 
additional side effects and loss of quality of care. 
Secondary objectives 
 
 
 Evaluate the tolerability and infusion related side 
effects. 
 Evaluate patient satisfaction. 
 Evaluate the number of care actions required. 
 Evaluate nursing staff satisfaction.  
Setup 
 
 
In this non-interventional, monocentric, observational 
study, the administration of Multigam 10% will be 
compared with the standard (Multigam 5%) in patients 
with a secondary immunodeficiency due to a 
hematological disorder. 
Patients who are being treated with Multigam because of 

 
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their secondary immunodeficiency will be evaluated for 
inclusion.  
The last administration of Multigam 5% will serve as a 
control. During this check, different parameters will be 
evaluated: 
-Infusion time (hours) 
-Hospitalization time at the oncological day clinic (hours) 
-Side effects (via CTCAE v4.03) 
-Nursing staff care actions  
Subsequently, an identical evaluation will take place at 
the first administration of Multigam 10% and the 
satisfaction of the patient and the nursing staff will also 
be assessed. The results will be analyzed and compared. 
Patients can then receive Multigam 10% or Multigam 5% 
according to their preference. 
 
Endpoints 
 
 
Primary: 
To compare the infusion time (hours) and tolerance of 
Multigam 10% and the standard administration of 
Multigam 5%. 
Screening
Multigam 5%
administration
Multigam 10%
administration
Final
evaluation
First evaluation

 
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Secondary: 
 Assess the tolerance and patient satisfaction of 
Multigam 5% vs. Multigam 10% via: 
- Patient questionnaire 
- Scoring of side effects via CTCAE v4.03 
 Assess nursing staff care actions 
 Assess the satisfaction of the nursing staff 
(questionnaire) 
 Patient characterization (age, gender, disorder) 
Population 
 
30 patients with a secondary immunodeficiency due to a 
hematological disorder. 
Inclusion criteria 
 
 
 Age ≥ 18 years 
 Secondary immunodeficiency due to a hematological 
disorder 
 Patient received at least 2x Multigam 5% 
 No side effects (grade 2 or higher according to CTCAE 
v4.03)  during their last 2 Multigam 5% infusions 
 Patient needs at least 2x Multigam 
 Signed informed consent form 
Exclusion criteria 
 
 Patient received less than 2x Multigam 5%  
 Side effects (grade 2 or higher according to CTCAE 
v4.03)  during their last 2 Multigam 5% infusions 
 Patient refuses to participate in the study 
Maximum duration of study/treatment 
 
 
2 months 
Version and date of final protocol 
 
Version 3 – 8 September 2017 
 
 
 
 
 
 
 
 

 
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2. Background and rationale 
Background 
The immune system ensures the detection and elimination of pathogens and even transformed cells. 
However, normal functioning can be disrupted by a variety of factors. Both primary and secondary 
causes can lead to an immune deficiency with increased vulnerability for infections (Cooper, et al. 
2003, Shinen & Shearer, 2008). 
Secondary immune deficiencies can be caused by various diseases (lymphoproliferative disorders, 
infections, 
...) 
and 
therapies 
(immunosuppressants, 
anti-inflammatory 
drugs, 
...). 
In 
lymphoproliferative disorders such as chronic lymphocytic leukemia (CLL) and multiple myeloma 
(MM), both treatment and the disease itself contribute to a secondary immunodeficiency. In order to 
strengthen the resistance in these patients, substitution therapy with immunoglobulins can be started 
in cases of recurrent infections (Friman, et al. 2016). Intravenous gamma globulins (IVIg) are 
reimbursed in Belgium for patients with CLL and MM with a secondary immunodeficiency that resulted 
in a life-threatening infection or in repeated episodes of clinically significant infections requiring 
antibiotics. The dose is 0.4 to 0.5 g / kg every 3 to 4 weeks. 
At the UZ Leuven Hematology department, Multigam is being used as standard IVIg substitution 
therapy. Multigam is an immunoglobulin preparation that is produced from the plasma of human 
donors. It exists in both 5% and 10% concentrated solution and is administered intravenously. 
Rationale 
The day clinic of the Hematology department at UZ Leuven is experiencing a yearly growth of about 
5% in the number of patient contacts. For this reason, we are constantly looking for ways to shorten 
the time spent at the day clinic to create additional capacity without causing a loss of quality in care. 
With the arrival of Multigam 10%, patients will be able to switch to this new immunoglobulin solution. 
This allows patients to be treated independently of the dose and their weight within a shorter period 
of time. 
With this study we want to quantify the transition from Multigam 5% to Multigam 10% in a scientific 
way. The rationale of this study is to compare and evaluate the administration of both solutions in 
terms of infusion time, infusion related side effects, patient satisfaction, number of care actions and 
satisfaction of the nursing staff, and this in about 30 patients. 
 

 
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3. Study objectives and design 
3.1 Study objectives 
With this study we want to evaluate the administration of Multigam 10% compared to the standard 
(Multigam 5%). We want to observe whether there are changes in infusion time and infusion related 
side effects. In addition, the patient satisfaction, the number of care actions and the satisfaction of the 
nursing staff will also be evaluated. 
3.2 Primary endpoints 
Comparing the infusion time (hours) and tolerance between Multigam 10% and the standard 
administration. 
3.3 Secondary endpoints 
 Assess the satisfaction and therapeutic tolerance of Multigam 5% vs. Multigam 10% via: 
-Patient questionnaire 
-CTCAE v4.03 
 Assess the care actions of the nursing staff 
 Assess the satisfaction of the nursing staff (questionnaire) 
 Patient characterization (age, gender, disorder) 
3.4 Study design 
Prospective - Observational 
3.5 Study diagram 
 
Screening
Multigam 5%
administration
Multigam 10%
administration
Final
evaluation
First evaluation

 
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3.6 Study flowchart 
 
Study visit 1  
(Multigam 5%) 
Study visit 2 
(Multigam 10%) 
Information and consent form 
X 
 
Physical examination 
AE scoring via CTCAE (v4.03) 
X 
X 
Patient questionnaire 
 
X 
Questionnaire concerning IVIg administration 
X 
X 
Nursing staff questionnaire 
 
X 
4. Selection and exclusion of participants 
4.1 Inclusion criteria 
- 
Age ≥ 18 years 
- 
Secondary immunodeficiency due to a hematological disorder 
- 
Patient received at least 2x Multigam 5% 
- 
No side effects during their last 2 Multigam 5% infusions 
- 
Patient needs at least 2x Multigam 
- 
Signed informed consent form 
4.2 Exclusion criteria 
- 
Patient received less than 2x Multigam 5% 
- 
Side effects/intolerance for Multigam 5% 
- 
Patient refuses to participate in the study 
4.3 Expected duration of study 
- 
Start-up: february 2017 
- 
Recruitment: 4 weeks 
- 
First participant: Q2 2017 
- 
EC submission: Q2 2017 
- 
Final reporting: december 2017 
 
 
 

 
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5. Study actions per visit 
5.1 Study visit 1 
- 
Sign information and consent form 
- 
Multigam 5% administration 
- 
Questionnaire concerning IVIg administration 
- 
CTCAE v4.03 scoring during and after infusion 
5.2 Study visit 2 
- 
Multigam 10% administration 
- 
Questionnaire concerning IVIg administration 
- 
CTCAE v4.03 scoring during and after infusion 
- 
Patient questionnaire 
- 
Nursing staff questionnaire 
6. Data collection 
The following data will be stored in the eCRF: 
-Patient characteristics (age, gender and disorder) 
 -Infusion time (hours) 
-Hospitalization time at the oncology day center (hours) 
 -Safety reporting (collect AEs en SA’s according to CTCAE v4.03 criteria) 
-Questionnaire concerning IVIg administration (both visits, annex 2) 
 -Patient satisfaction questionnaire (last visit; annex 1) 
-Nursing staff satisfaction questionnaire (last visit; annex 3) 
 
 
 
 
 
 
 
 
 

 
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7. Assessment of efficiency 
Primary endpoint: 
- 
Comparing the infusion time and tolerance 
Evaluate via time measurements, questioning and AE reporting during both treatments 
Secondary endpoints: 
- 
Satisfaction and therapeutic tolerance 
- 
Evaluation of satisfaction via questionnaire and tolerance via AE reporting   
- 
Safety 
- 
Evaluate AEs and SAEs via CTCAE v4.03 criteria 
- 
Care actions 
- 
Evaluate the number of nursing actions per patient 
- 
Satisfaction of nursing staff 
- 
Evaluation of satisfaction via questionnaire 
- 
Patient characterization 
- 
Characterization of patients (age, gender, disorder) 
8. Assessment of safety 
8.1 Specification, timing and registration of safety parameters 
Side effects due to Multigam 5% and Multigam 10% infusion will be reported by the responsible 
physician and will be registered in the electronic patient record. 
8.2 Procedures for registration and reporting of adverse events (AE) 
8.2.1 Adverse event reporting 
8.2.1.1 Adverse event definition 
An adverse event (AE) is any unfavorable medical event in a patient or subject of the treated group 
during an experiment or study and does not necessarily have a causal relationship with the treatment. 
It may therefore be, regardless of the cause, a new additional disease, a deterioration of a similar 
disease, an injury or any additional impairment of the patient's health (including laboratory values). 
Any deterioration (this is any clinically significant unfavorable change in the frequency or intensity of 
an already existing condition) must be considered an AE. 
8.2.1.2 Severity of the AE 
To describe and assess the severity of an AE, the National Cancer Institute - Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) version 4.03 is being used. For AEs that are not adequately 
described in the NCI-CTCAE version 4.03, the following scale is used: 

 
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Grade 1 
Mild 
Transient or mild discomfort; no restriction in physical activity; no 
medical intervention/therapy required 
Grade 2 
Moderate 
Mild to moderate limitation of activity; limited help may be 
necessary; no or minimal medical intervention/therapy required 
Grade 3 
Severe 
Noticeable limitation of activity; limited help usually needed; 
medical intervention/therapy required; hospitalization is possible 
Grade 4 
Life-
threatening 
Extreme limitation of activity; significant help required; significant 
medical intervention/therapy required; hospitalization or care in 
hospital probable 
Grade 5 
Death 
The event results in death.  
 
An AE or suspected adverse reaction (ADR) is "unexpected" if it does not appear in the list of the 
current Summary of Product Characteristics (SmPC) or if it is not listed on the specificity or severity 
observed. 
Abnormal laboratory values must be reported as AE if medical intervention (transfusion, hydration ...) 
is required or if the event is deemed clinically significant by the attending physician. 
8.2.1.3 Duration 
The start and stop date will be reported for all AEs. The start date is the first date when the patient / 
subject was aware of the AE and the end date is the date when the event was completely resolved or 
returned to baseline. 
8.2.1.4 Causality 
The investigator must determine the relationship between the administration of the immunoglobulin 
replacement therapy and the occurrence of an AE as Not suspected or Suspected via following 
definitions: 
Not suspected 
The temporal relationship between the adverse event and the administration of 
the immunoglobulin replacement therapy is not causal or small, or other 
medication, therapeutic interventions or underlying disorders provide sufficient 
explanation for the observed AE. 
Suspected 
The temporal relationship between the adverse event and the administration of 
the immunoglobulin replacement therapy is possibly causal and other medication, 

 
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therapeutic interventions or underlying disorders provide insufficient explanation 
for the observed AE. 
 
8.2.1.5 Reporting procedure 
All AEs are bundled into the eCRF starting from the patient having signed the information and consent 
form up to and including the last study visit. 
All AEs considered to be related to the substitution therapy and all SAEs independent of their 
relationship must be followed up until they recover, recover with consequences, non-recovery (death 
by other cause) or death (by the SAE). 
8.2.2 Serious Adverse Event reporting 
A serious adverse event (SAE) is any AE that meets one of the following criteria: 
- death 
- life-threatening (this is when, according to the researcher, the patient is exposed to a direct risk of 
dying from the AE) 
- requires hospitalization of patient or extension of existing hospitalization (hospitalization is defined 
as hospitalization of patient in hospital, regardless of length of stay) 
- results in persistence of significant incompetence (a substantial disruption in the patient's ability to 
perform normal life functions) 
- forms an important medical event 
Important medical events are defined as events that do not directly threaten the life of the patient or 
result in death, hospitalization or incompetence, but which do endanger the patient or require medical 
or surgical intervention to avoid one of the consequences above. 
Each SAE, independent of the causal link, that occurs after the patient has signed the information and 
consent form until the last study visit, must be reported to the sponsor. Each SAE report must be 
reported to the sponsor within 24 hours of awareness and also by using the Serious Adverse Event 
form in the eCRF. 
 
 

 
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9. Statistics 
 
9.1 Sample size 
For this descriptive, semi-quantitative study, the sample size is determined on 30 patients. Based on 
data in the package leaflet, we expect that the infusion time for Multigam 10% will be shorter than for 
Multigam 5%. This sample size will also be sufficient to correct for any variability as a result of nursing 
activities. A sample of 30 patients is sufficient to detect mild side effects. If, unexpectedly, more side 
effects occur with Multigam 10% administration, we will extend the sample size through an 
amendment and investigate this further. To evaluate the satisfaction of the patients and the nursing 
staff, 30 patients are also sufficient to correct for any missing values. 
9.2 Analysis 
The results are reported quantitatively (number of care actions, infusion and hospitalization time) and 
qualitatively (patient and nursing staff satisfaction). For the number of care actions, infusion time and 
hospitalization time, a T-test will examine whether both datasets (Multigam 5% and Multigam 10%) 
differ significantly from each other. The 95% confidence interval will also be determined and Cohen's 
d will be calculated to estimate the magnitude of the difference between the two variables (effect size, 
estimate the strength of the difference). For the satisfaction of patients and nursing staff, descriptive 
statistics will be used. 
10. 
Direct access to source data and documents 
 
The researcher / institution will provide direct access to source data and other documents. This access 
can consist of study-related monitoring, audits, EC review and statutory inspections. 
11. 
Ethical and regulatory compliance 
 
The research will be conducted in accordance with the principles of the Helsinki Declaration (current 
version), the principles of GCP and in accordance with the appropriate legal requirements. This 
protocol and all related documents will be submitted for review by the Ethics Committee. 
The research will be conducted in accordance with the principles of the Helsinki Declaration (current 
version), the principles of GCP and in accordance with the appropriate legal requirements. This 
protocol and all related documents will be submitted for review by the Ethics Committee. 
The study can and will only be conducted on the basis of prior consent, by the patient or the legal 
representative, to participate in the study. The participating site will obtain a signed informed consent 

 
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document (ICD) for each patient before registering patients and taking part in the study in accordance 
with the prevailing legislation, regulations and, if necessary, the approval of the (local) Ethics 
Committee. The participating site will retain the ICDs in accordance with the requirements of the 
relevant regulatory bodies and laws. 
The researcher and the participating site will treat all information and data related to the study as 
confidential and will not disclose such information to third parties or use the information for any other 
purpose than the execution of the study. The collection, processing and disclosure of personal data, 
such as the health of patients and medical information, is subject to compliance with the prevailing 
protection and processing of personal data (Directive 95/46 / EC and Belgian law of December 8, 1992 
on the protection of Secrecy in connection with the Processing of Personal Data). 
With coded data, a link remains between the data and the individual who provided the information. 
The research team is obliged to protect the data against disclosure outside the research in accordance 
with the terms of the research protocol and the informed consent document. The patient name or 
other items that can be used for identification must be stored separately from the research data and 
replaced with a unique code to create a new identity for the patient. Note that encrypted data is not 
anonymous. 
12. 
Data handling and management 
 
As part of the responsibilities associated with participation in the study, the researcher agrees to 
maintain accurate eCRFs and source documents. The researcher or delegate must enter all results 
collected during the study into eCRFs. 
13. 
Publication policy 
 
The results of this study will be published as an abstract or article in which a co-authorship is offered 
to everyone who has made a significant contribution to the writing of the protocol, the execution of 
the study and the processing and interpretation of the results. The principal investigator has final 
responsibility concerning the publication. 
 
 
 

 
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14. 
Insurance/compensation 
 
In accordance with the Belgian legislation on experiments on human persons of May 7, 2004, the 
Sponsor will without fault assume the responsibility of any damage to a study patient, both directly 
and indirectly related to participation in the study, and will compensate provide through their own 
insurance. 
15. 
Financial aspects 
 
Both Multigam 5% and Multigam 10% are commercially available and are prescribed according to the 
formulary. 
16. 
References 
 
Chinen, J. and Shearer, W. (2008) ‘6. Secondary immunodeficiencies, including HIV infection’,Journal 
of Allergy and Clinical Immunology, 121(2), pp. S388–S392. doi: 10.1016/j.jaci.2007.06.003. 
Cooper, M.D. (2003) ‘Immunodeficiency disorders’, Hematology, 2003(1), pp. 314–330. doi: 
10.1182/asheducation-2003.1.314. 
Friman, V., Winqvist, O., Blimark, C., Langerbeins, P., Chapel, H. and Dhalla, F. (2016) ‘Secondary 
immunodeficiency in lymphoproliferative malignancies’, Hematological Oncology, 34(3), pp. 121–
132. doi: 10.1002/hon.2323. 
 
 
 
 
 
 
 

 
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17. 
Annex 
Annex 1: Patient questionnaire 
 
Strongly 
disagree (1) 
Disagree (2) 
Neutral (3) 
Agree (4) 
Strongly 
agree (5) 
I experienced fewer side 
effects with Multigam 10% 
 
 
 
 
 
I experienced time gain with  
Multigam 10% 
 
 
 
 
 
I will therefore have a more 
productive day 
 
 
 
 
 
For my own situation I am in 
favor of using Multigam 10% 
 
 
 
 
 
 
Annex 2: Questionnaire concerning IVIg administration (to be filled in by nursing staff) 
 
Multigam 5% 
Infusion time 
(..hour..minutes) 
Start: …… h …… min 
Stop: …… h …… min 
Number of care actions 
 
 
Multigam 10% 
Infusion time 
(..hour..minutes) 
Start: …… h …… min 
Stop: …… h …... min 
Number of care actions 
 
Care action means both the increase or decrease of infusion rate and any other intervention due to 
intolerance / complication. 

 
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Annex 3: Nursing staff questionnaire 
 
Strongly 
disagree (1) 
Disagree (2) 
Neutral (3) 
Agree (4) 
Strongly 
agree (5) 
I have been able to plan 
patients more efficiently 
with Multigam 10% 
 
 
 
 
 
I have experienced time 
gain with Multigam 10% 
 
 
 
 
 
I am in favor of using 
Multigam 10%