Clinical Assessment of Pharmacokinetics, Efficacy, and Safety of 10% IVIg in PID Patients

Primary Immunodeficiency Disease Clinical Trial

— CARES10  

Official title:

A Phase III, Open-label, Prospective, Multicenter Study to Assess Efficacy, Safety and Pharmacokinetics of Kedrion Intravenous Immunoglobulin (IVIg) 10% in Primary Immunodeficiency Disease (PID) Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03961009
• Other study ID #: KIG10_US3_PID01
• Status: Completed
• Phase: Phase 3
• Start date: April 30, 2019
• Est. completion date: December 21, 2020

Study information

• Verified date: January 2022
• Source: Kedrion S.p.A.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study was to assess efficacy and safety of Kedrion Immunoglobulin 10% (KIg10) in participants with Primary Immunodeficiency (PID).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 47
• Est. completion date: December 21, 2020
• Est. primary completion date: December 21, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 70 Years

Eligibility

Inclusion Criteria:

• Written informed consent/assent obtained from participant/participant's parent(s) or legally acceptable representative indicating that they understand the purpose of and procedures required for the study and are willing to participate in it.

• Confirmed clinical diagnosis of a PID, requiring treatment with IVIg and have documented agammaglobulinemia (defined as the total absence of one or more classes of antibodies) or hypogammaglobulinemia (defined as low levels of one or more classes [that is at least 2 standard deviations under the mean level per age])

• Male or female, ages 2 to 70 years at screening

• Received 200 to 800 mg/kg of a commercially available IVIg therapy in the range of 21- or 28-day intervals (±3 days or ±4 days, respectively) for at least 3 infusion cycles prior to screening

• At least 2 documented IgG trough levels while receiving an IVIg, of greater than or equals to (>=) 6 gram per liter (g/L) obtained at 2 infusion cycles within 12 months (1 must be within 6 months) prior to Informed Consent Form (ICF) signature

• Participant is willing to comply all requirements of the protocol.

• Females of child-bearing potential with a negative urine pregnancy test and who agree to employ adequate birth control measures during the study

• Authorization to access personal health information

• Participant previously participating in a clinical trial with another experimental IVIg may be enrolled if they have received stable commercially available IVIg therapy for at least 3 infusion cycles (21 or 28 days) prior to screening

• Participant currently on treatment with any subcutaneous immunoglobulin (SCIG) can be enrolled if they are switched to stable commercially available IVIg therapy for at least 3 infusion cycles (21 or 28 days) prior to screening

Exclusion Criteria:

• Newly diagnosed PID and and naïve to IgG replacement therapy

• Dysgammaglobulinemia (defined as a deficiency in one or more classes of antibodies, but not severe enough to require substitutive therapy) or isolated IgG subclass deficiency or profound primary T-cell deficiency (defined as the absence or severe reduction of T lymphocytes [CD3+ <300 cells per cubic millimeter (cell/mm3)] and an absent or particularly low proliferative response [10% of the lower normal range] to phytohaemagglutinin P [PHA])

• Has history of severe or serious reactions or hypersensitivity to IVIg or other injectable forms of IgG

• Has history of thrombotic events (including deep vein thrombosis, cerebrovascular accident, pulmonary embolism, transient ischemic attacks, or myocardial infarction), as defined by at least 1 event in participant's lifetime

• Has IgA deficiency with documented antibodies to IgA

• Have received blood products that have not undergone viral inactivation measures within 12 months prior to Informed Consent Form (ICF) signature

• Has significant protein losing enteropathy, nephrotic syndrome, or lymphangiectasia

• Has an acute infection as documented by culture or diagnostic imaging and/or a body temperature >= 38 degree Celsius (°C) (>=100.4 degree Fahrenheit (°F) within 7 days prior to screening

• Has acquired immunodeficiency syndrome (AIDS) and/or hepatitis B/C active disease at ICF signature

• Has levels of Alanine aminotransferase (ALT) or aspartate aminotransferase (AST), 2.5 times of the upper limit of normal for the laboratory designated for the study

• Using an implanted venous access device

• Has profound anemia (haemoglobin less than10 gram per deciliter [g/dl]) or persistent severe neutropenia (<= 1000 neutrophils per millimeter cube (mm^3) or lymphopenia of less than 500 cells per microliter

• Have severe chronic condition such as renal failure (creatinine concentration > 2.0 times the upper limit of normal) with proteinuria, congestive heart failure (New York Heart Association III/IV), cardiomyopathy, cardiac arrhythmia associated with thromboembolic events (e.g., atrial fibrillation), unstable or advanced ischemic heart disease, hyper viscosity, or any other condition that the Investigator believes is likely to interfere with evaluation of the study drug or with satisfactory conduct of the trial. Normal values for serum creatinine are the following: a) Female (18+ years): 45 - 84 micromole per liter (mcmol/L) or 0.51 - 0.95 milligrams per deciliter (mg/dl); b) Male (18+ years): 59 - 103 mcmol/L or 0.67 - 1.17 mg/dl

• Has history of a malignant disease other than properly treated carcinoma in situ of the cervix or basal cell or squamous cell carcinoma of the skin within 24 months prior to ICF signature

• Has history of pharmacoresistant epilepsy or multiple episodes of migraine (defined as at least 1 episode within 6 months of ICF signature) not completely controlled by medication

• Participants must not be receiving steroids (oral or parenteral daily dose of >= 0.15 milligram per kilogram per day (mg/kg/day) of prednisone or equivalent) or other immunosuppressive drugs or chemotherapy

• Females who are pregnant, breast feeding or planning a pregnancy during the course of the study. Women who become pregnant during the study will be withdrawn from the study

• Has participated in another clinical study within 3 weeks prior to study ICF signature

• Has history of drug or alcohol abuse within the 6 months before screening

• Has Employed or a direct relative of an employee of the CRO, the study site, or the Sponsor

• Previously treated under this protocol

• Unable to provide informed consent or provide informed consent by a legally authorized representative

Related Conditions & MeSH terms

• Immunologic Deficiency Syndromes
• Primary Immunodeficiency Disease
• Primary Immunodeficiency Diseases

Intervention

Biological:
• Kedrion IVIG 10%
Kedrion intravenous immunoglobulin (IVIg) 10%

Locations

Country	Name	City	State
United States	University of Buffalo	Buffalo	New York
United States	Rush University Medical Center	Chicago	Illinois
United States	Optimed Research	Columbus	Ohio
United States	AARA Research Center	Dallas	Texas
United States	Allergy Partners of North Texas Research	Dallas	Texas
United States	Allergy and Immunology Associates	Little Silver	New Jersey
United States	Ohio Clinical Research Associates, Inc.	Mayfield Heights	Ohio
United States	Allergy Associates of the Palm Beaches	North Palm Beach	Florida
United States	Dr. Henry J. Kanarek - Allergy, Asthma & Immunology	Overland Park	Kansas
United States	Midwest Immunology Clinic and Infusion Center	Plymouth	Minnesota
United States	Toledo Institute of Clinical Research Inc	Toledo	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
Kedrion S.p.A.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence Rate of Acute Serious Bacterial Infections (ABSIs)	Incidence rate was defined as the mean number of acute serious bacterial infections (bacterial pneumonia, bacteremia/sepsis, bacterial meningitis, visceral abscess, osteomyelitis/septic arthritis) per participant-year according to pre-specified criteria.	Baseline up to Week 51 (21-day dosing schedule) and Week 52 (28-day dosing schedule)
Secondary	Serum Immunoglobulin G (IgG) Trough Levels	The serum IgG trough levels were collected and analyzed at a central laboratory.	At baseline, Week 51 (21-day dosing schedule) and Week 52 (28-day dosing schedule)
Secondary	Immunoglobulin G (IgG) Subclasses Levels (IgG1, IgG2, IgG3, IgG4)	IgG subclasses levels (IgG1, IgG2, IgG3, IgG4) were collected and analyzed at a central laboratory.	At baseline, Weeks 16, 32 and 48 (28-day dosing schedule); Weeks 18, 30, 48 (21-day dosing schedule)
Secondary	Number of Participants With Total Immunoglobulin G (IgG) Trough Levels Less Than or Equal to (<=) 6 Grams/Liter (g/L) Criteria	Number of participants with Total IgG trough levels <= 6 g/L criteria were reported.	Up to 12 months
Secondary	Anti-Tetanus Toxoid Antibody Levels	The anti-tetanus toxoid antibody levels were collected and analyzed at a central laboratory. This antibody level was measured in international units per milliliter (IU/mL).	Baseline, Weeks 16, 32 and 48 (28-day dosing schedule); Weeks 18, 30, 48 (21-day dosing schedule)
Secondary	Anti-Pneumococcal Capsular Polysaccharide Antibody Levels	Anti-pneumococcal capsular polysaccharide antibody levels for serotype 1, serotype 12, serotype 14, serotype 17, serotype 19, serotype 2, serotype 20, serotype 22, serotype 23, serotype 26, serotype 3, serotype 4, serotype 34, serotype 43, serotype 5, serotype 51, serotype 54, serotype 56, serotype 57, serotype 68, serotype 70, serotype 8 and serotype 9 were collected and analyzed at a central laboratory.	Baseline, Weeks 16, 32 and 48 (28-day dosing schedule); Weeks 18, 30, 48 (21-day dosing schedule)
Secondary	Anti-Measles Antibody Levels	The anti-measles antibody levels were collected and analyzed at a central laboratory.	Baseline, Weeks 16, 32 and 48 (28-day dosing schedule); Weeks 18, 30, 48 (21-day dosing schedule)
Secondary	Anti-Haemophilus Influenza Type B Antibody Levels	The anti-haemophilus influenza type B antibody levels were collected and analyzed at central laboratory.	Baseline, Weeks 16, 32 and 48 (28 -day dosing schedule); Weeks 18, 30, 48 (21-day dosing schedule)
Secondary	Incidence Rate of Any Infection Other Than Acute Serious Bacterial Infections	Incidence rate was defined as the mean number of any infection other than acute serious bacterial infections (bacterial pneumonia, bacteraemia/sepsis, bacterial meningitis, visceral abscess, osteomyelitis/septic arthritis) per participant-year. Incidence rate of any infection other than acute bacterial serious infections collected by the participant/participants parent(s)/legal guardian(s) in the participant diary or during clinic visit was reported.	Baseline up to Week 51 (21-day dosing schedule) and Week 52 (28-day dosing schedule)
Secondary	Duration of Any Infection Other Than Acute Serious Bacterial Infections	Duration of any infection other than serious acute bacterial infections (in days) was calculated as date of stop of infection - date of start of infection + 1. Duration of any infection other than serious acute bacterial infections collected by the by the participant/participants parent(s)/legal guardian(s) in the participant diary or during clinic visit was reported.	Baseline up to Week 51 (21-day dosing schedule) and Week 52 (28-day dosing schedule)
Secondary	Incidence Rate of Fever Episodes	Incidence rate was defined as the mean number of fever episodes per participant-year. Incidence rate of fever episodes collected by the participant/participant's parent(s)/legal guardian(s) in the participant diary or during clinic visit were reported.	Baseline up to Week 51 (21-day dosing schedule) and Week 52 (28-day dosing schedule)
Secondary	Duration of Fever Episodes in Participants	Duration of fever episodes in participants was reported.	Baseline up to Week 51 (21-day dosing schedule) and Week 52 (28-day dosing schedule)
Secondary	Duration of Overall Participants Hospitalization	Duration of overall participants hospitalization was reported.	Baseline up to Week 51 (21-day dosing schedule) and Week 52 (28-day dosing schedule)
Secondary	Duration of Participants Hospitalization Due to Infection	Duration of participants hospitalization due to infection was reported.	Baseline up to Week 51 (21-day dosing schedule) and Week 52 (28-day dosing schedule)
Secondary	Incidence Rate of Antibiotics Episodes for Treatment of Any Kind of Infections	Incidence rate was defined as the mean number of antibiotics episodes per participant year. Incidence rate of participants on antibiotics for treatment of any kind of infections was reported.	Baseline up to Week 51 (21-day dosing schedule) and Week 52 (28-day dosing schedule)
Secondary	Duration of Participants on Antibiotics for Treatment of Any Kind of Infection	Duration of participants on antibiotics for treatment of any kind of infection was reported.	Baseline up to Week 51 (21-day dosing schedule) and Week 52 (28-day dosing schedule)
Secondary	Duration of Missed School/Work/Other Major Activities Due to Infections	Duration of missed school/work/other major activities due to infections was reported.	Baseline up to Week 51 (21-day dosing schedule) and Week 52 (28-day dosing schedule)
Secondary	Pediatric Quality of Life Inventory (PedsQL) Score	23-item PedsQL generic core scales was a modular approach to measure health-related Quality of Life (QoL) in healthy children, adolescents and those with acute and chronic health conditions. The total scale score (23 items) consisted of Physical Health Summary Score (8 items) and Psychosocial Health SummaryScore (15 items). Physical health summary included Physical Functioning (8 items) and Psychosocial health summary score included Emotional Functioning (5 items), Social Functioning (5 items) and School Functioning (5 items). Items were scored on a 5 point Likert-type response scale: 0=never a problem; 1=almost never a problem; 2=sometimes a problem; 3=often a problem; and 4=almost always a problem). Once scored, items were reverse scored and linearly transformed to a 0-100 scale, where higher scores indicated better QoL. The overall range for total PedsQL score (23 items) was 0 to 100, with higher score indicated better QoL. Data for 18-25 years and >25 years age group was reported.	Baseline, Week 24 (21-day dosing schedule and 28-day dosing schedule), Week 51 (21-day dosing schedule) and Week 52 (28-day dosing schedule)
Secondary	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs	An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a study drug which may or may not have a causal relationship with the study drug. A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life- threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. TEAE was defined as an AE with an onset that occurs after receiving study drug. Any TEAE included participants with both serious and non-serious TEAEs.	Baseline up to Week 51 (21-day dosing schedule) and Week 52 (28-day dosing schedule)
Secondary	Number of TEAEs and Serious TEAEs	An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a study drug which may or may not have a causal relationship with the study drug. A SAE was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life- threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. A TEAE was defined as an AE with an onset that occurs after receiving study drug. Number of TEAEs and Serious TEAEs were reported.	Baseline up to Week 51 (21-day dosing schedule) and Week 52 (28-day dosing schedule)
Secondary	Number of Drug Related Infusion Adverse Events (AEs)	An AE was defined as any untoward medical occurrence in a participant administered a study drug which may or may not have a causal relationship with the study drug. Number of drug related infusion AEs were reported.	Baseline up to Week 51 (21-day dosing schedule) and Week 52 (28-day dosing schedule)
Secondary	Percentage of Participants Who Experienced at Least One Drug Related Infusion Adverse Events (AEs)	Percentage of participants who experienced at least one drug related infusion AEs were reported.	Baseline up to Week 51 (21-day dosing schedule) and Week 52 (28-day dosing schedule)
Secondary	Number of Infusions With Decreased Infusion Rate Due to Adverse Events (AEs)	Number of infusions with decreased infusion rate due to AEs were reported.	Baseline up to Week 51 (21-day dosing schedule) and Week 52 (28-day dosing schedule)
Secondary	Number of Infusions With One or More Infusion Associated Adverse Events (AEs)	The number of infusions with one or more infusion associated AEs were reported collectively for 21 and 28-day dosing schedule up to Week 52.	Baseline up to Week 52
Secondary	Number of Participants With Clinically Significant Changes From Baseline in Vital Signs	Vital signs included body temperature, systolic and diastolic blood pressure, heart rate and weight. The systolic and diastolic blood pressure and pulse rate was measured after the participants have in a rested at least 3 minutes in seated position. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in vital signs were reported.	Baseline up to Week 51 (21-day dosing schedule) and Week 52 (28-day dosing schedule)
Secondary	Number of Participants With Clinically Significant Changes From Baseline in Physical Examinations	Physical examination included the examination of general appearance, skin, neck, eyes, ears, nose, throat, cardiovascular assessment including rhythm, and presence of other cardiac abnormalities (for example gallops, murmurs, cardiomegaly), respiratory system, gastrointestinal system, genitourinary system and musculoskeletal system. Clinical significance was decided by the investigator. The number of participants with clinically significant changes from baseline in physical examination were reported.	Baseline up to Week 51 (21-day dosing schedule) and Week 52 (28-day dosing schedule)
Secondary	Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters	Laboratory parameters included chemistry, hematology and urinalysis. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in laboratory parameters were reported.	Baseline up to Week 51 (21-day dosing schedule) and Week 52 (28-day dosing schedule)
Secondary	Number of Participants With Positive Coomb's Test at Week 16 (28-day Dosing Schedule) and Week 18 (21-day Dosing Schedule)	Intravascular hemolysis testing was performed by using coomb's test. The coomb's assessment was performed at a central laboratory.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule)
Secondary	Number of Participants With Positive Urine Hemosiderin Test	Number of participants with positive urine hemosiderin test were reported.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule)
Secondary	Number of Participants With Abnormal Plasma-free Haemoglobin Level	Number of participants with plasma-free haemoglobin level more than or equal to (>=) 69 milligrams per deciliter (mg/dL) were consisdered as abormal and were reported.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule)
Secondary	Number of Participants With Abnormal Serum Haptoglobin Level	Number of participants with abnormal serum haptoglobin level were reported.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule)
Secondary	Maximum Observed Serum Concentration (Cmax) of Total Immunoglobulin G (IgG)	Cmax was obtained directly from the concentration versus time curve. Both baseline corrected and un-corrected data was reported.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Elimination Half-Life (t1/2) of Total IgG	t1/2 was the time measured for the concentration to decrease by one half. t1/2 was calculated by natural log 2 divided by Kel. Kel was the elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase. Both baseline corrected and un-corrected data was reported.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Area Under the Serum Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of Total IgG	Area under the serum concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule. Both baseline corrected and un-corrected data was reported.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Area Under the Serum Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Total IgG	AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Kel, where Clast pred was the calculated serum concentration at the last sampling time point at which the measured serum concentration is at or above the Lower Limit of quantification (LLOQ) and Kel was the elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase. Both baseline corrected and un-corrected data was reported.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Area Under the Serum Concentration-Time Curve During a Dosing Interval (AUCtau) of Total IgG	AUCtau was defined as area under the serum concentration-time curve from time zero to the end of the dosing interval (tau). AUCtau was calculated using the mixed log linear trapezoidal rule. Both baseline corrected and un-corrected data was reported.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Volume of Distribution (Vd) of Total IgG	Vd was defined as the the theoretical volume in which the total amount of total IgG would need to be uniformly distributed to produce the desired blood concentration of a total IgG. Both baseline corrected and un-corrected data was reported.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Steady State Clearance (CLss) of Total IgG	Clearance of a total IgG was a measure of the rate at which a total IgG is metabolized or eliminated by normal biological processes. CLss of total IgG was measured in milliliters per hour per kilogram (mL/hr/kg). Both baseline corrected and un-corrected data was reported.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Minimum Observed Serum Concentration (Cmin) of Total IgG	Cmin was minimum observed serum concentration obtained directly from the concentration versus time curve. Both baseline corrected and un-corrected data was reported.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Time to Reach the Maximum Serum Concentration (Tmax) of Total IgG	Tmax was obtained directly from the concentration versus time curve. Both baseline corrected and un-corrected data was reported.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Elimination Rate Constant (Kel) of Total IgG	Kel was the elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase. Both baseline corrected and un-corrected data was reported.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Average Concentration of Total IgG Over the Dosing Interval (Cavg)	Average concentration of total IgG over the dosing interval (Cavg) was reported. Both baseline corrected and un-corrected data was reported.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Percentage Peak Trough Fluctuation of Total IgG	The peak trough fluctuation within complete dosing interval at steady state of total IgG was reported. Both baseline corrected and un-corrected data was reported.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Maximum Observed Serum Concentration (Cmax) of Antigen-Specific Tetanus Toxoid Antibodies	Cmax was obtained directly from the concentration versus time curve.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Elimination Half-Life (t1/2) of Antigen-Specific Tetanus Toxoid Antibodies	t1/2 was the time measured for the concentration to decrease by one half. t1/2 was calculated by natural log 2 divided by Kel. Kel was the elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Area Under the Serum Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of Antigen-Specific Tetanus Toxoid Antibodies	Area under the serum concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule. The AUC0-t of antigen-specific tetanus toxoid antibodies was measured in hour*international units per milliliter (hr*IU/mL).	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Area Under the Serum Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Antigen-Specific Tetanus Toxoid Antibodies	AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Kel, where Clast pred was the calculated serum concentration at the last sampling time point at which the measured serum concentration is at or above the Lower Limit of quantification (LLOQ) and Kel was the elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Area Under the Serum Concentration-Time Curve During a Dosing Interval (AUCtau) of Antigen-Specific Tetanus Toxoid Antibodies	AUCtau was defined as area under the serum concentration-time curve from time zero to the end of the dosing interval (tau). AUCtau was calculated using the mixed log linear trapezoidal rule.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Volume of Distribution (Vd) of Antigen-Specific Tetanus Toxoid Antibodies	Vd was defined as the the theoretical volume in which the total amount of antigen-specific tetanus toxoid antibodies would need to be uniformly distributed to produce the desired blood concentration of antigen-specific tetanus toxoid antibodies. The Vd of antigen-specific tetanus toxoid antibodies was measured in milligrams*milliliter per international unit*kilogram (mg*mL/IU*kg).	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Steady State Clearance (CLss) of Antigen-Specific Tetanus Toxoid Antibodies	Clearance of a antigen-specific tetanus toxoid antibodies was a measure of the rate at which a antigen-specific tetanus toxoid antibodies are metabolized or eliminated by normal biological processes. The CLss of antigen-specific tetanus toxoid antibodies was reported. The CLss of antigen-specific tetanus toxoid antibodies was measured in milligrams*milliliter per hour*international unit*kilogram (mg*mL/hr*IU*kg).	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Minimum Observed Serum Concentration (Cmin) of Antigen-Specific Tetanus Toxoid Antibodies	Cmin was minimum observed serum concentration obtained directly from the concentration versus time curve.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Time to Reach the Maximum Serum Concentration (Tmax) of Antigen-Specific Tetanus Toxoid Antibodies	Tmax was obtained directly from the concentration versus time curve.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Elimination Rate Constant (Kel) of Antigen-Specific Tetanus Toxoid Antibodies	Kel was the elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Average Concentration of Antigen-Specific Tetanus Toxoid Antibodies Over the Dosing Interval (Cavg)	Average concentration of antigen-specific tetanus toxoid antibodies over the dosing interval (Cavg) was reported.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Percentage Peak Trough Fluctuation of Antigen-Specific Tetanus Toxoid Antibodies	The peak trough fluctuation within complete dosing interval at steady state of antigen-specific tetanus toxoid antibodies was reported.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Maximum Observed Serum Concentration (Cmax) of Antigen-Specific Haemophilus Influenza Type B Antibodies	Cmax was obtained directly from the concentration versus time curve.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Elimination Half-Life (t1/2) of Antigen-Specific Haemophilus Influenza Type B Antibodies	t1/2 was the time measured for the concentration to decrease by one half. t1/2 was calculated by natural log 2 divided by Kel. Kel was the elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Area Under the Serum Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of Antigen-Specific Haemophilus Influenza Type B Antibodies	Area under the serum concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule. AUC0-t of antigen-specific haemophilus influenza Type B Antibodies was measured in hour*microgram per milliliter (hr*mcg/mL).	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Area Under the Serum Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Antigen-Specific Haemophilus Influenza Type B Antibodies	AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Kel, where Clast pred was the calculated serum concentration at the last sampling time point at which the measured serum concentration is at or above the Lower Limit of quantification (LLOQ) and Kel was the elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Area Under the Serum Concentration-Time Curve During a Dosing Interval (AUCtau) of Antigen-Specific Haemophilus Influenza Type B Antibodies	AUCtau was defined as area under the serum concentration-time curve from time zero to the end of the dosing interval (tau). AUCtau was calculated using the mixed log linear trapezoidal rule.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Volume of Distribution (Vd) of Antigen-Specific Haemophilus Influenza Type B Antibodies	Vd was defined as the the theoretical volume in which the total amount of antigen-specific haemophilus influenza type B antibodies would need to be uniformly distributed to produce the desired blood concentration of a antigen-specific haemophilus influenza type B antibodies.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Steady State Clearance (CLss) of Antigen-Specific Haemophilus Influenza Type B Antibodies	Clearance of antigen-specific haemophilus influenza type B antibodies was a measure of the rate at which antigen-specific haemophilus influenza type B antibodies were metabolized or eliminated by normal biological processes. CLss of antigen-specific haemophilus influenza type B antibodies was measured in milliliter per hour per kilogram (mL/hr/kg).	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Minimum Observed Serum Concentration (Cmin) of Antigen-Specific Haemophilus Influenza Type B Antibodies	Cmin was minimum observed serum concentration obtained directly from the concentration versus time curve.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Time to Reach the Maximum Serum Concentration (Tmax) of Antigen-Specific Haemophilus Influenza Type B Antibodies	Tmax was obtained directly from the concentration versus time curve.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Elimination Rate Constant (Kel) of Antigen-Specific Haemophilus Influenza Type B Antibodies	Kel was the elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Average Concentration of Antigen-Specific Haemophilus Influenza Type B Antibodies Over the Dosing Interval (Cavg)	Average concentration of antigen-specific haemophilus influenza type B antibodies over the dosing interval (Cavg) was reported.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Percentage Peak Trough Fluctuation of Antigen-Specific Haemophilus Influenza Type B Antibodies	The peak trough fluctuation within complete dosing interval at steady state of antigen-specific haemophilus influenza type B antibodies was reported.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Maximum Observed Serum Concentration (Cmax) of Anti-pneumococcal Capsular Polysaccharide (Overall SP Serotypes)	Cmax was obtained directly from the concentration versus time curve. The Cmax for serotype 1, serotype 12, serotype 14, serotype 17, serotype 19, serotype 2, serotype 20, serotype 22, serotype 23, serotype 26, serotype 3, serotype 4, serotype 34, serotype 43, serotype 5, serotype 51, serotype 54, serotype 56, serotype 57, serotype 68, serotype 70, serotype 8, serotype 9 was reported at Week 16 during 28-day dosing schedule and at Week 18 during 21-day dosing schedule.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Elimination Half-Life (t1/2) of Anti-pneumococcal Capsular Polysaccharide (Overall SP Serotypes)	t1/2 was the time measured for the concentration to decrease by one half. t1/2 was calculated by natural log 2 divided by Kel. Kel was the elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase.Kel was the elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase. The t1/2 for serotype 1, serotype 12, serotype 14, serotype 17, serotype 19, serotype 2, serotype 20, serotype 22, serotype 23, serotype 26, serotype 3, serotype 4, serotype 34, serotype 43, serotype 5, serotype 51, serotype 54, serotype 56, serotype 57, serotype 68, serotype 70, serotype 8 and serotype 9 was reported at Week 16 during 28-day dosing schedule and at Week 18 during 21-day dosing schedule.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Area Under the Serum Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of Anti-pneumococcal Capsular Polysaccharide (Overall SP Serotypes)	Area under the serum concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule. AUC0-t of antigen-pneumococcal capsular polysaccharide was measured in hour*microgram per milliliter (hr*mcg/mL). The AUC0-t for serotype 1, serotype 12, serotype 14, serotype 17, serotype 19, serotype 2, serotype 20, serotype 22, serotype 23, serotype 26, serotype 3, serotype 4, serotype 34, serotype 43, serotype 5, serotype 51, serotype 54, serotype 56, serotype 57, serotype 68, serotype 70, serotype 8 and serotype 9 was reported at Week 16 during 28-day dosing schedule and at Week 18 during 21-day dosing schedule.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Area Under the Serum Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Anti-pneumococcal Capsular Polysaccharide (Overall SP Serotypes)	AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Kel, where Clast pred was the calculated serum concentration at the last sampling time point at which the measured serum concentration is at or above the Lower Limit of quantification (LLOQ) and Kel was the elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase. The AUC0-inf for serotype 1, serotype 12, serotype 14, serotype 17, serotype 19, serotype 2, serotype 20 serotype 22, serotype 23, serotype 26, serotype 3, serotype 4, serotype 34, serotype 43, serotype 5, serotype 51, serotype 54, serotype 56, serotype 57, serotype 68, serotype 70, serotype 8 and serotype 9 was reported at Week 16 during 28-day dosing schedule and at Week 18 during 21-day dosing schedule.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Area Under the Serum Concentration-Time Curve During a Dosing Interval (AUCtau) of Anti-pneumococcal Capsular Polysaccharide (Overall SP Serotypes)	AUCtau was defined as area under the serum concentration-time curve from time zero to the end of the dosing interval (tau). AUCtau was calculated using the mixed log linear trapezoidal rule. The AUCtau for serotype 1, serotype 12, serotype 14, serotype 17, serotype 19, serotype 2, serotype 20, serotype 22, serotype 23, serotype 26, serotype 3, serotype 4, serotype 34, serotype 43, serotype 5, serotype 51, serotype 54, serotype 56, serotype 57, serotype 68, serotype 70, serotype 8 and serotype 9 was reported at Week 16 during 28-day dosing schedule and at Week 18 during 21-day dosing schedule.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Volume of Distribution (Vd) of of Anti-pneumococcal Capsular Polysaccharide (Overall SP Serotypes)	Vd was defined as the the theoretical volume in which the total amount of anti-pneumococcal capsular polysaccharide would need to be uniformly distributed to produce the desired blood concentration of a anti-pneumococcal capsular polysaccharide. The Vd for serotype 1, serotype 12, serotype 14, serotype 17, serotype 19, serotype 2, serotype 20, serotype 22, serotype 23, serotype 26, serotype 3, serotype 4, serotype 34, serotype 43, serotype 5, serotype 51, serotype 54, serotype 56, serotype 57, serotype 68, serotype 70, serotype 8 and serotype 9 was reported at Week 16 during 28-day dosing schedule and at Week 18 during 21-day dosing schedule.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Steady State Clearance (CLss) of Anti-pneumococcal Capsular Polysaccharide Antibodies (Overall SP Serotypes)	Clearance of a anti-pneumococcal capsular polysaccharide antibodies was a measure of the rate at which a anti-pneumococcal capsular polysaccharide antibodies are metabolized or eliminated by normal biological processes. The CLss of anti-pneumococcal capsular polysaccharide antibodies was reported. The CLss of anti-pneumococcal capsular polysaccharide antibodies was measured in milligrams*milliliter per hour*international unit*kilogram (mg*mL/hr*IU*kg). The CLss for serotype 1, serotype 12, serotype 14, serotype 17, serotype 19, serotype 2, serotype 20, serotype 22, serotype 23, serotype 26, serotype 3, serotype 4, serotype 34, serotype 43, serotype 5, serotype 51, serotype 54, serotype 56, serotype 57, serotype 68, serotype 70, serotype 8 and serotype 9 was reported at Week 16 during 28-day dosing schedule and at Week 18 during 21-day dosing schedule.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Minimum Observed Serum Concentration (Cmin) of Anti-pneumococcal Capsular Polysaccharide (Overall SP Serotypes)	Cmin was minimum observed serum concentration obtained directly from the concentration versus time curve. The Cmin for serotype 1, serotype 12, serotype 14, serotype 17, serotype 19, serotype 2, serotype 20, serotype 22, serotype 23, serotype 26, serotype 3, serotype 4, serotype 34, serotype 43, serotype 5, serotype 51, serotype 54, serotype 56, serotype 57, serotype 68, serotype 70, serotype 8 and serotype 9 was reported at Week 16 during 28-day dosing schedule and at Week 18 during 21-day dosing schedule.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Time to Reach the Maximum Serum Concentration (Tmax) of Anti-pneumococcal Capsular Polysaccharide (Overall SP Serotypes)	Tmax was obtained directly from the concentration versus time curve. The Tmax for serotype 1, serotype 12, serotype 14, serotype 17, serotype 19, serotype 2, serotype 20, serotype 22, serotype 23, serotype 26, serotype 3, serotype 4, serotype 34, serotype 43, serotype 5, serotype 51, serotype 54, serotype 56, serotype 57, serotype 68, serotype 70, serotype 8 and serotype 9 was reported at Week 16 during 28-day dosing schedule and at Week 18 during 21-day dosing schedule.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Elimination Rate Constant (Kel) of Anti-pneumococcal Capsular Polysaccharide (Overall SP Serotypes)	Kel was the elimination rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase. The Kel for serotype 1, serotype 12, serotype 14, serotype 17, serotype 19, serotype 2, serotype 20 serotype 22, serotype 23, serotype 26, serotype 3, serotype 4, serotype 34, serotype 43, serotype 5, serotype 51, serotype 54, serotype 56, serotype 57, serotype 68, serotype 70, serotype 8 and serotype 9 was reported at Week 16 during 28-day dosing schedule and at Week 18 during 21-day dosing schedule.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Average Concentration of Anti-pneumococcal Capsular Polysaccharide the Dosing Interval (Cavg) (Overall SP Serotypes)	Average concentration of anti-pneumococcal capsular polysaccharide over the dosing interval (Cavg) was reported. The Cavg for serotype 1, serotype 12, serotype 14, serotype 17, serotype 19, serotype 2, serotype 20, serotype 22, serotype 23, serotype 26, serotype 3, serotype 4, serotype 34, serotype 43, serotype 5, serotype 51, serotype 54, serotype 56, serotype 57, serotype 68, serotype 70, serotype 8 and serotype 9 was reported at Week 16 during 28-day dosing schedule and at Week 18 during 21-day dosing schedule.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion
Secondary	Percentage Peak Trough Fluctuation of Anti-pneumococcal Capsular Polysaccharide (Overall SP Serotypes)	The peak trough fluctuation within complete dosing interval at steady state of anti-pneumococcal capsular polysaccharide was reported. The peak trough fluctuation for serotype 1, serotype 12, serotype 14, serotype 17, serotype 19, serotype 2, serotype 20, serotype 22, serotype 23, serotype 26, serotype 3, serotype 4, serotype 34, serotype 43, serotype 5, serotype 51, serotype 54, serotype 56, serotype 57, serotype 68, serotype 70, serotype 8 and serotype 9 was reported at Week 16 during 28-day dosing schedule and at Week 18 during 21-day dosing schedule.	At Week 16 (28-day dosing schedule) and Week 18 (21-day dosing schedule), 10 to 30 minutes pre-infusion, 30 minutes, 2, 24, 72, 168, 336, 504, 672 hours post infusion