A Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Immune Globulin (Human) 10% (Gamunex-C) PEG Process (IVIG-PEG) Compared to Gamunex-C in Participants With Primary Humoral Immunodeficiency

A Phase 3, Multicenter, Open-label, Single-sequence, Cross-over, Bioequivalence Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of IVIG-PEG Compared to Gamunex-C in Subjects With Primary Humoral Immunodeficiency

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04561115

Enrollment

Registered

2020-09-23

Start date

2020-09-02

Completion date

2022-03-28

Last updated

2023-06-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Primary Immunodeficiency

Brief summary

The purpose of this study is to demonstrate bioequivalence of IVIG-PEG with Gamunex-C (IVIG-C) at steady-state as determined by comparing total Immunoglobulin G (IgG) area under the concentration-time curve during the defined dosing interval (\[AUC0-τ\] either every 3 weeks \[AUC0-21 days\] or every 4 weeks \[AUC0-28 days\]) and maximum concentration in a dosing interval (Cmax) in participants diagnosed with primary humoral immunodeficiency (PI) currently receiving chronic IVIG replacement treatment.

Interventions

BIOLOGICALGamunex-C

Intravenous infusion.

BIOLOGICALIVIG-PEG

Intravenous infusion.

Study design

Allocation

NON_RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

NONE

Intervention model description

The study model for this is Single-Sequence crossover.

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

Inclusion criteria

* Male or female between 18 and 75 years of age (inclusive) at Screening * Documented and confirmed pre-existing diagnosis of PI with features of hypogammaglobulinemia requiring IV IgG replacement therapy including but not limited to the following humoral-based immunodeficiency syndromes (example, X-linked agammaglobulinemia, common variable immunodeficiency), and combined immunodeficiency syndromes without lymphocytopenia (example, hyper immunoglobulin M \[IgM\] immunodeficiency syndrome). * IgG trough level ≥500 milligrams per deciliter (mg/dL) at screening visit. Note: Patients entering Group 1 must additionally have trough levels ≥500 mg/dL documented within the previous year. For patients entering Group 2, if Screening trough levels are not ≥500 mg/dL, the subject will be a Screen Failure, but may be rescreened following dose adjustment of their original IV IgG replacement therapy regimen and recording an IgG trough level ≥500 mg/dL * Has not had an SBI within the last 6 months prior to screening or during the screening. * Medical records are available to document diagnosis, previous infections, and treatment. * Willing to comply with all aspects of the study protocol, including blood sampling, for the duration of the study. * Signed and dated a written informed consent form (ICF) confirming his or her willingness to participate in study GC1902.

Exclusion criteria

* Has an acquired medical condition that is known to cause secondary immune deficiency such as chronic lymphocytic leukemia, lymphoma, multiple myeloma, chronic or recurrent neutropenia (absolute neutrophil count less than 1000per microliters (1000/μL) \[1.0 x 10\^9/L\]), or human immunodeficiency virus (HIV) infection/acquired immune deficiency syndrome (AIDS). * Has known selective Immunoglobulin A (IgA) deficiency (with or without antibodies to IgA). (Note: exclusion is for the specific diagnostic entity. It does not exclude other forms of primary humoral immunodeficiency which have decreased IgA in addition to decreased IgG requiring IgG replacement). * Has isolated IgG subclass deficiency or an isolated specific antibody deficiency disorder, or transient hypogammaglobulinemia of infancy * The subject has had a known serious adverse reaction to immunoglobulin or any severe anaphylactic reaction to blood or any blood-derived product. * Has a history of thrombotic complications following IVIG therapy. * Has a history of or current diagnosis of deep venous thrombosis (DVT) or thromboembolism (e.g., myocardial infarction, cerebrovascular accident or transient ischemic attack); history refers to an incident in the year prior to the Screening Visit or 2 episodes over lifetime or has thrombosis risk factors (e.g., prolonged immobilization, use of estrogens, indwelling central vascular catheters). * Has a known hyperviscosity syndrome or hypercoagulable states. * Has liver enzyme levels (alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\], gammaglutamyl transferase \[GGT\], or lactate dehydrogenase \[LDH\]) greater than 2.5 times the upper limit of normal (ULN) at the screening visit as defined by the testing laboratory. * Has pre-existing renal impairment (defined by serum creatinine greater than 1.5 times the ULN or blood urea nitrogen \[BUN\] greater than 2.5 times the ULN, or any subject who is on dialysis) at the screening visit or any history of acute renal injury. * Has clinically significant history of drug or alcohol abuse or dependence in the opinion of the Investigator (must be within the past 12 months and noted in the subject's medical records or documented at screening). * Clinical evidence of any significant acute or chronic medical condition (e.g., renal disease or predisposing conditions for renal disease, coronary artery disease, or protein losing state) that, in the opinion of the Investigator, may interfere with the conduct of the study or may place the subject at undue medical risk. * Females of childbearing potential who are pregnant, have a positive pregnancy test at Screening (human chorionic gonadotropin \[HCG\]-based assay), are breastfeeding, or unwilling to practice a highly effective method of contraception (eg, oral, injectable or implanted hormonal methods of contraception, placement of an intrauterine device \[IUD\] or intrauterine system \[IUS\], condom or occlusive cap with spermicidal foam/gel/film/cream/suppository, male sterilization, or true abstinence) throughout the study. Note: True abstinence: When this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, postovulation methods\], declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception). * Receiving any of the following medications: (a) immunosuppressants including chemotherapeutic agents, (b) immunomodulators, (c) long-term systemic corticosteroids defined as daily dose \>1 mg of prednisone equivalent/kg/day for \>30 days. Note: Intermittent courses not exceeding \>1mg of prednisone equivalent/kg/day for \>30 days would not exclude the subject. Inhaled or topical corticosteroids are allowed. * Has uncontrolled arterial hypertension (systolic blood pressure \[SBP\] \>160 mm Hg and/or diastolic blood pressure \[DBP\] \>100 mm Hg) * Has hemoglobin \<11 g/dL at the Screening Visit * Unable or unwilling to provide a storage serum sample at the Screening Visit. Note: A pre-treatment serum sample to be stored at -94°F (-70ºC) for possible future testing is required. * Received any live virus vaccine within 5 months prior to the Screening Visit and not willing to postpone receiving any live virus vaccines until 6 months after completing study treatment * Has a known previous infection with or clinical signs and symptoms consistent with current hepatitis B virus (HBV) or hepatitis C virus (HCV) infection * Has participated in another clinical trial within 30 days prior to Screening or has received any investigational product, with the exception of other IgG products, within the previous 3 months prior to the Screening Visit

Design outcomes

Primary

Measure	Time frame	Description
AUC (0-7): Area Under the Concentration Time Curve Over a Dosing Interval of Either Every 3 Weeks [AUC0-21 Days] or Every 4 Weeks [AUC0-28 Days] for Total Immunoglobulin G (IgG)	Pre-dose, within 10 minutes of last infusion completion, at 1, 3, 6, 24, 48 hours and 4, 7, 14 and 21 days (up to 3 weeks), and 28 days (up to 4 weeks - only for subjects on a 4-week dosing schedule) post-infusion	AUC (0-7 days) is calculated as AUC (0-21 days)/3 for subjects with a dosing frequency of every 3 weeks and as AUC(0-28 days)/4 for subjects with a dosing frequency of every 4 weeks.
Cmax: Maximum Concentration in a Dosing Interval for Total IgG	Pre-dose, within 10 minutes of last infusion completion, at 1, 3, 6, 24, 48 hours, and 4, 7, 14, 21 and 28 days post-infusion (up to 4 weeks)	—

Secondary

Measure	Time frame	Description
Rate of Days Per Person Per Year That Participants Were on Antibiotics	Baseline up to 6 months for each period, i.e., overall GC treatment phase and overall IVIG-PEG treatment phase with an aggregate duration of up to 12 months	Rate of days per person per year is calculated as the total number of days divided by the total duration of exposure in years across all participants. Antibiotics included prophylactic and therapeutic.
Rate of Serious Bacterial Infections (SBIs)	Baseline up to 6 months for each period, i.e., overall GC treatment phase and overall IVIG-PEG treatment phase with an aggregate duration of up to 12 months	The rate of SBI events per participant per year during treatment was calculated as the total number of SBI events divided by the total duration of exposure in years across all participants. The 2-sided 98% confidence interval (CI) was determined from a generalized linear model for Poisson regression for the log-transformed number of events with log-transformed duration of exposure in years as an offset variable.
Rate of Days of Work/School/Daily Activities Missed Per Participant Due to Infections and Their Treatment	Baseline up to 6 months for each period, i.e., overall GC treatment phase and overall IVIG-PEG treatment phase with an aggregate duration of up to 12 months	Rate of days per person per year is calculated as the total number of days divided by the total duration of exposure in years across all participants.
Number of Participants Hospitalized Due to Infection	Baseline up to 6 months for each period, i.e., overall GC treatment phase and overall IVIG-PEG treatment phase with an aggregate duration of up to 12 months	Hospitalization was considered only in cases of hospital admission (including emergency room stay) for equal or more than 24 hours.
Rate of Events Per Participant Per Year in Participants With Any Kind of Infection	Baseline up to 6 months for each period, i.e., overall GC treatment phase and overall IVIG-PEG treatment phase with an aggregate duration of up to 12 months	Rate of events per participant per year is calculated as the total number of events divided by the total duration of exposure in years across all participants. Any kind of infections included serious/nonserious including acute sinusitis, exacerbation of chronic sinusitis, acute otitis media, pneumonia, acute bronchitis, infectious diarrhea etc.) as determined by the Investigator.

Countries

United States

Participant flow

Recruitment details

Participants were enrolled at 10 investigative sites in the United States from 02 September 2020 (first participant enrolled to receive the study drug) to 28 March 2022 (last participant completed).

Pre-assignment details

A total of 43 participants were screened, of which 33 participants received study treatment. 22 participants entered the Gamunex-C (GC) Run-in Phase and received GC treatment to achieve an approximate steady-state condition prior to entering the GC pharmacokinetic (PK) Phase as per investigators discretion. Eleven (11) participants directly entered into the GC PK phase.

Participants by arm

Arm	Count
Gamunex-C Participants received GC by means of an infusion pump at a dose of 200 to 800 mg/kg per infusion at an infusion rate of 1 mg/kg/min or up to 8 mg/kg/min depending on participant tolerance. The participant's usual mg/kg dose (given on either a 3 or 4 week repeating schedule) was the same mg/kg dose and schedule that the participant was receiving prior to entering screening. This mg/kg dose and schedule were used throughout the study duration. GC was administered every 3 weeks (±4 days) or 4 weeks (±4 days), depending on the participant's prior IVIG dosing schedule. The duration of GC treatment included the GC PK Phase (up to 4 weeks) plus the additional GC Run-in Phase (up to 4.5 months) for participants not receiving GC or not on a stable dose of GC upon entering the trial. The approximate maximum duration was up to 6 months.	33
Total	33

Arm

Count

Gamunex-C

Participants received GC by means of an infusion pump at a dose of 200 to 800 mg/kg per infusion at an infusion rate of 1 mg/kg/min or up to 8 mg/kg/min depending on participant tolerance. The participant's usual mg/kg dose (given on either a 3 or 4 week repeating schedule) was the same mg/kg dose and schedule that the participant was receiving prior to entering screening. This mg/kg dose and schedule were used throughout the study duration. GC was administered every 3 weeks (±4 days) or 4 weeks (±4 days), depending on the participant's prior IVIG dosing schedule. The duration of GC treatment included the GC PK Phase (up to 4 weeks) plus the additional GC Run-in Phase (up to 4.5 months) for participants not receiving GC or not on a stable dose of GC upon entering the trial. The approximate maximum duration was up to 6 months.

Total

Withdrawals & dropouts

Period	Reason	FG000	FG001
GC Run-In + PK Phase (Up to 6 Months)	Withdrawal by Subject	1	0
IVIG-PEG + PK Phase (Up to 6 Months)	The Dose Changed Back and Forth 800-600 Mg/Kg During GC Phase Fulfilling Discontinuation Criteria	0	1
IVIG-PEG Treatment (Up to 4.5 Months)	The Dose Changed Back and Forth 800-600 Mg/Kg During GC Phase Fulfilling Discontinuation Criteria	0	1

Baseline characteristics

Characteristic	Gamunex-C
Age, Continuous	53.5 years STANDARD_DEVIATION 14.02
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	32 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	0 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	33 Participants
Sex: Female, Male Female	16 Participants
Sex: Female, Male Male	17 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 33	0 / 32
other Total, other adverse events	20 / 33	23 / 32
serious Total, serious adverse events	1 / 33	0 / 32

Outcome results

Primary

AUC (0-7): Area Under the Concentration Time Curve Over a Dosing Interval of Either Every 3 Weeks [AUC0-21 Days] or Every 4 Weeks [AUC0-28 Days] for Total Immunoglobulin G (IgG)

AUC (0-7 days) is calculated as AUC (0-21 days)/3 for subjects with a dosing frequency of every 3 weeks and as AUC(0-28 days)/4 for subjects with a dosing frequency of every 4 weeks.

Time frame: Pre-dose, within 10 minutes of last infusion completion, at 1, 3, 6, 24, 48 hours and 4, 7, 14 and 21 days (up to 3 weeks), and 28 days (up to 4 weeks - only for subjects on a 4-week dosing schedule) post-infusion

Population: The PK population consisted of all participants who received study drug and had sufficient and valid total IgG concentration versus time data for either the IVIG-PEG PK Phase or GC PK Phase to allow calculation of AUC0-τ. Overall number analyzed are the number of participants with data available for analysis.

Arm	Measure	Value (MEAN)	Dispersion
Gamunex-C	AUC (0-7): Area Under the Concentration Time Curve Over a Dosing Interval of Either Every 3 Weeks [AUC0-21 Days] or Every 4 Weeks [AUC0-28 Days] for Total Immunoglobulin G (IgG)	232088.8 hourmilligrams per decilitres (hmg/dL)	Standard Deviation 32848.46
IVIG-PEG	AUC (0-7): Area Under the Concentration Time Curve Over a Dosing Interval of Either Every 3 Weeks [AUC0-21 Days] or Every 4 Weeks [AUC0-28 Days] for Total Immunoglobulin G (IgG)	219149.9 hourmilligrams per decilitres (hmg/dL)	Standard Deviation 36894.29

90% CI: [0.926, 0.972]

Primary

Cmax: Maximum Concentration in a Dosing Interval for Total IgG

Time frame: Pre-dose, within 10 minutes of last infusion completion, at 1, 3, 6, 24, 48 hours, and 4, 7, 14, 21 and 28 days post-infusion (up to 4 weeks)

Arm	Measure	Value (MEAN)	Dispersion
Gamunex-C	Cmax: Maximum Concentration in a Dosing Interval for Total IgG	2328.8 milligrams per decilitre (mg/dL)	Standard Deviation 426.73
IVIG-PEG	Cmax: Maximum Concentration in a Dosing Interval for Total IgG	2330.4 milligrams per decilitre (mg/dL)	Standard Deviation 660.99

90% CI: [0.937, 1.021]

Secondary

Number of Participants Hospitalized Due to Infection

Hospitalization was considered only in cases of hospital admission (including emergency room stay) for equal or more than 24 hours.