Safety and Pharmacokinetics of IGSC 20% in Subjects With Primary Immunodeficiency

• Sponsor: Grifols Therapeutics LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02604810
• Collaborator: (none)
• Enrollment: 53
• Locations: 25
• Arms: 2
• Actual Duration (Months): 23
• Patients Per Site: 2.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study was designed to determine a dose of weekly subcutaneously administered Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (Grifols) (IGSC 20%) that produces steady-state AUC of total IgG that was non-inferior to that of the regularly administered intravenous dose of Immune Globulin Injection (Human), 10% Caprylate/Chromatography Purified (Grifols) (IGIV-C 10%) in primary immunodeficiency subjects. This study was also designed to determine steady state trough total IgG levels after IGSC 20% infusion and after IGIV-C 10% infusion for comparison and to assess the safety and tolerability of IGSC 20%.

Condition or Disease	Intervention/Treatment	Phase
Primary Immunodeficiency	Biological: IGIV-C 10%; Biological: IGSC 20%	Phase 3

Detailed Description

This was a prospective, multi-center, open-label, single-sequence, 6-month, pharmacokinetic, safety and tolerability study of IGSC 20% in subjects with primary immunodeficiency. Approximately 50 subjects were to be enrolled in order to have approximately 30 adult subjects and 12 to 18 pediatric subjects (age 2-16 years) completing treatment with subcutaneously administered IGSC 20%.

This study included 3 treatment phases: Run-In Phase, IV Phase (IV administration of IGIV-C 10% treatment), and SC Phase (SC administration of IGSC 20%).

Subjects, depending on their current IgG treatment regimen, might be required to enter the Run-In Phase to receive IV IGIV-C 10% treatment (Sponsor provided) to achieve an approximately steady-state condition prior to entering the IV Phase. They then entered the IV Phase to determine the AUC profiles of IV infusions of IGIV-C 10%.

Subjects with a qualifying IV IGIV-C 10% treatment regimen (on stable IGIV-C 10% doses of 300-800 mg/kg) entered the IV Phase directly where they will receive IGIV-C 10%. In the IV Phase, steady-state IV PK assessments, including AUC, were to be performed.

After completing the IV Phase, subjects entered the SC Phase to receive weekly SC doses of IGSC 20% for at least 24 weeks.

The PK profiles of total IgG following administration of both IV (IGIV-C 10%) administration and SC (IGSC 20%) administration were determined and compared after reaching approximate steady-state conditions.

Study Design

• Study Type: Interventional
• Actual Enrollment: 53 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Multi-center Study to Evaluate the Safety and Pharmacokinetics of IGSC 20% Administered for 6 Months in Subjects With Primary Immunodeficiency
• Actual Study Start Date: Jan 1, 2016
• Actual Primary Completion Date: Sep 1, 2017
• Actual Study Completion Date: Dec 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: IGIV-C 10% IV dose of Immune Globulin Injection (Human), 10% Caprylate/Chromatography Purified (Grifols)	Biological: IGIV-C 10%; IGIV-C 10% infusions every 3 to 4 weeks based on previous IgG regimen; Other Names: Immune Globulin Injection 10% Caprylate/Chromatography
Experimental: IGSC 20% Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (Grifols)	Biological: IGSC 20%; IGSC 20% weekly infusions with dose calculated based on previous IgG regimen; Other Names: Immune Globulin Subcutaneous 20% Caprylate/Chromatography

Outcome Measures

Primary Outcome Measures

1. AUC in the IV Phase and SC Phases: Steady-state AUC of Total IgG Over a Regular Dosing Interval [For intravenous infusion, predose, 0,1,3-16 hours and 1,2,3,5,7,14,21 or 28 days (2, 7, 21, or 28 days for pediatric subjects) post-dose and for subcutaneous infusion, pre-dose,1,3,4,5,7 days (3 and 7 days for pediatric subjects) post-dose]

   The primary PK endpoint (steady-state AUC values) analysis was performed using analysis of variance (ANOVA) using PK data from a total of 49 subjects from the IV phase and 39 subjects from the SC phase.

Secondary Outcome Measures

1. Mean Steady-state Trough (Pre-dose) Concentration of Total IgG Following IV Administration of IGIV-C 10% or SC Administration of IGSC 20% [For intravenous infusion, pre-dose at Week 1 and Week 3 or Week 4 and for subcutaneous infusion, predose at Weeks 13, 14, 17, and 21]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Pre-existing diagnosis of primary immunodeficiency with features of hypogammaglobulinemia requiring IgG replacement therapy

• No serious bacterial infection within the last 3 months prior to or during Screening

• Currently on IgG replacement therapy (via IV or SC infusion) for ≥3 consecutive months. Subjects receiving IGIV must be receiving a dosage of 300 to 800 mg/kg per infusion

• Documented (at least once within previous 3 months) IgG trough level of ≥500 mg/dL on current IgG replacement therapy regimen

Exclusion Criteria:

• Known serious adverse reaction to immunoglobulin or any severe anaphylactic reaction to blood or any blood-derived product

• History of blistering skin disease, clinically significant thrombocytopenia, bleeding disorder, diffuse rash, recurrent skin infections, or other disorders where SC therapy would be contraindicated during the study

• Isolated IgG subclass deficiency, isolated specific antibody deficiency disorder, or transient hypogammaglobulinemia of infancy

• Nephrotic syndrome, and/or a history of acute renal failure and/or severe renal impairment, and/or on dialysis

• History (year prior to Screening or 2 episodes in lifetime ) of or current diagnosis of deep venous thrombosis or thromboembolism (eg, deep vein thrombosis, myocardial infarction, cerebrovascular accident or transient ischemic attack)

• Acquired medical condition known to cause secondary immune deficiency, such as chronic lymphocytic leukemia, lymphoma, multiple myeloma, chronic or recurrent neutropenia (absolute neutrophil count less than 1000/μL [1.0 x 10^9/L]), or human immunodeficiency virus infection/acquired immune deficiency syndrome

• Known previous infection with or clinical signs and symptoms consistent with current hepatitis B virus or hepatitis C virus infection

• Non-controlled arterial hypertension (systolic blood pressure >160 mmHg and/or diastolic blood pressure >100 mmHg in adult subjects)

• 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 of corticosteroids of not more than 10 days would not exclude a subject. Inhaled or topical corticosteroids are allowed.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA Medical Center	Los Angeles	California	United States	90095
2	AIRE Medical of Los Angeles	Santa Monica	California	United States	90404
3	National Jewish Health	Denver	Colorado	United States	80206
4	University of Miami - Batchelor Children's Research Institute	Miami	Florida	United States	33136
5	Allergy Associates of The Palm Beaches, PA	North Palm Beach	Florida	United States	33408
6	University of South Florida	Saint Petersburg	Florida	United States	33701
7	Emory Children's Center	Atlanta	Georgia	United States	30322
8	Rush University Medical Center	Chicago	Illinois	United States	60612
9	The South Bend Clinic	South Bend	Indiana	United States	46617
10	Children's Hospital of Michigan - Wayne State University	Detroit	Michigan	United States	48201
11	Midwest Immunology	Plymouth	Minnesota	United States	55446
12	Washington University Medical Center	Saint Louis	Missouri	United States	63110
13	Duke University Medical Center	Durham	North Carolina	United States	27710
14	Oklahoma Institute of Allergy and Asthma Clinical Research	Oklahoma City	Oklahoma	United States	73131
15	Vital Prospects Clinical Research Institute, PC	Tulsa	Oklahoma	United States	74136
16	Penn State University	Hershey	Pennsylvania	United States	17033
17	AARA Research Center	Dallas	Texas	United States	75231
18	Baylor Texas Children's Hospital	Houston	Texas	United States	77030
19	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
20	Children's Hospital of Richmond at VCU, VCU Medical Center	Richmond	Virginia	United States	23298
21	Ottawa Hospital, Division of Infectious Disease and Respirology	Ottawa	Ontario	Canada	K1H 8L6
22	CHU Sainte-Justine	Montreal	Quebec	Canada	H3T 1C4
23	McGill University Health Center	Montreal		Canada	H4A 3J1
24	Clinique d'asthme et d'allergie de Quebec	Quebec		Canada	G1V 4M6
25	The Hospital for Sick Children	Toronto		Canada	M5G 1X8

Sponsors and Collaborators

• Grifols Therapeutics LLC

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Mar 15, 2016
• Statistical Analysis Plan - Feb 9, 2018

More Information

Publications

None provided.

• Responsible Party: Grifols Therapeutics LLC
• ClinicalTrials.gov Identifier: NCT02604810
• Other Study ID Numbers: GTI1502
• First Posted: Nov 13, 2015
• Last Update Posted: Oct 4, 2019
• Last Verified: Sep 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Primary Immunodeficiency Diseases; Immunologic Deficiency Syndromes; Immunoglobulins; Antibodies; gamma-Globulins; Immunoglobulins, Intravenous; Rho(D) Immune Globulin; Immunoglobulin G

Study Results

Participant Flow

Recruitment Details	A total of 61 subjects were screened for participation in this study. Of these 61 subjects, 8 subjects were considered screen failures. A total of 20 investigators in the United States enrolled subjects in this study. The first subject was enrolled in this study on 04 Jan 2016 and the date of the last subject's last study visit was 14 Dec 2017.
Pre-assignment Detail	One subject was lost to follow-up before the IGIV-C Phase.

Arm/Group Title	IGIV-C 10% First, IGSC 20% Second
Arm/Group Description	IV dose of Immune Globulin Injection (Human), 10% Caprylate/Chromatography Purified (Grifols) IGIV-C 10%: IGIV-C 10% infusions every 3 to 4 weeks based on previous IgG regimen After completing the IGIV-C 10% infusions, subjects continued to receive IGSC 20% infusions. Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (Grifols) IGSC 20%: IGSC 20% weekly infusions with dose calculated based on previous IgG regimen
Period Title: IGIV-C 10%, 4-5 Weeks
STARTED	52
COMPLETED	49
NOT COMPLETED	3
Period Title: IGIV-C 10%, 4-5 Weeks
STARTED	49
COMPLETED	42
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	IGIV-C 10% First, IGSC 20% Second
Arm/Group Description	IV dose of Immune Globulin Injection (Human), 10% Caprylate/Chromatography Purified (Grifols) IGIV-C 10%: IGIV-C 10% infusions every 3 to 4 weeks based on previous IgG regimen After completing the IGIV-C 10% infusions, subjects continued to receive IGSC 20% infusions. Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (Grifols) IGSC 20%: IGSC 20% weekly infusions with dose calculated based on previous IgG regimen
Overall Participants	53
Age (Count of Participants)
<=18 years	15 28.3%
Between 18 and 65 years	33 62.3%
>=65 years	5 9.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.8 (21.36)
Sex: Female, Male (Count of Participants)
Female	26 49.1%
Male	27 50.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 9.4%
Not Hispanic or Latino	48 90.6%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 5.7%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 3.8%
White	48 90.6%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	AUC in the IV Phase and SC Phases: Steady-state AUC of Total IgG Over a Regular Dosing Interval
Description	The primary PK endpoint (steady-state AUC values) analysis was performed using analysis of variance (ANOVA) using PK data from a total of 49 subjects from the IV phase and 39 subjects from the SC phase.
Time Frame	For intravenous infusion, predose, 0,1,3-16 hours and 1,2,3,5,7,14,21 or 28 days (2, 7, 21, or 28 days for pediatric subjects) post-dose and for subcutaneous infusion, pre-dose,1,3,4,5,7 days (3 and 7 days for pediatric subjects) post-dose

Outcome Measure Data

Analysis Population Description

The PK population consisted of all subjects who received study drugs and had sufficient and valid total IgG concentration versus time data for either the IV or SC Phase to allow calculation of AUC0-τ,SC or AUC0-τ,IV (the primary PK endpoint).

Arm/Group Title	IGIV-C 10%	IGSC 20%
Arm/Group Description	IV dose of Immune Globulin Injection (Human), 10% Caprylate/Chromatography Purified (Grifols) IGIV-C 10%: IGIV-C 10% infusions every 3 to 4 weeks based on previous IgG regimen	Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (Grifols) IGSC 20%: IGSC 20% weekly infusions with dose calculated based on previous IgG regimen
Measure Participants	49	39
Geometric Mean (90% Confidence Interval) [h*mg/dL]	207921.5	213141.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IGIV-C 10%, IGSC 20%
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Method of estimation = least-squares means based on analysis of variance (ANOVA) with a mixed-effect model. The lower bound of the 90% confidence interval (CI) for the geometric LSM ratio (SC/IV) of the primary PK endpoint of steady state AUC0-7 days for the PK population should be above 0.80.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 90%; 1.00 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Mean Steady-state Trough (Pre-dose) Concentration of Total IgG Following IV Administration of IGIV-C 10% or SC Administration of IGSC 20%
Time Frame	For intravenous infusion, pre-dose at Week 1 and Week 3 or Week 4 and for subcutaneous infusion, predose at Weeks 13, 14, 17, and 21

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	IGIV-C 10%	IGSC 20%
Arm/Group Description	IV dose of Immune Globulin Injection (Human), 10% Caprylate/Chromatography Purified (Grifols) IGIV-C 10%: IGIV-C 10% infusions every 3 to 4 weeks based on previous IgG regimen	Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (Grifols) IGSC 20%: IGSC 20% weekly infusions with dose calculated based on previous IgG regimen
Measure Participants	51	44
Mean (Full Range) [mg/dL]	957.13	1244.84

Adverse Events

Time Frame	During the IV phase, the adverse event data were collected for 4 to 5 weeks. During the SC phase, the adverse event data were collected for 24 weeks.
Arm/Group Title	IGIV-C 10%		IGSC 20%
Arm/Group Description	IV dose of Immune Globulin Injection (Human), 10% Caprylate/Chromatography Purified (Grifols) IGIV-C 10%: IGIV-C 10% infusions every 3 to 4 weeks based on previous IgG regimen		Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (Grifols) IGSC 20%: IGSC 20% weekly infusions with dose calculated based on previous IgG regimen
All Cause Mortality
	IGIV-C 10%		IGSC 20%
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/52 (0%)		0/49 (0%)
Serious Adverse Events
	IGIV-C 10%		IGSC 20%
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/52 (1.9%)		2/49 (4.1%)
Infections and infestations
Pneumonia bacterial	1/52 (1.9%)	1	0/49 (0%)	0
Sepsis	1/52 (1.9%)	1	1/49 (2%)	1
Cellulitis	0/52 (0%)	0	1/49 (2%)	1
Injury, poisoning and procedural complications
Animal bite	0/52 (0%)	0	1/49 (2%)	1
Musculoskeletal and connective tissue disorders
Intervertebral disc	0/52 (0%)	0	1/49 (2%)	1
Other (Not Including Serious) Adverse Events
	IGIV-C 10%		IGSC 20%
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/52 (11.5%)		35/49 (71.4%)
Gastrointestinal disorders
Diarrhoea	0/52 (0%)	0	3/49 (6.1%)	3
General disorders
Infusion site bruising	0/52 (0%)	0	3/49 (6.1%)	3
Infusion site nodule	0/52 (0%)	0	6/49 (12.2%)	9
Infusion site pain	0/52 (0%)	0	3/49 (6.1%)	3
Infections and infestations
Sinusitis	3/52 (5.8%)	3	9/49 (18.4%)	10
Bronchitis	2/52 (3.8%)	2	3/49 (6.1%)	3
Pharyngitis streptococcal	0/52 (0%)	0	3/49 (6.1%)	3
Upper respiratory tract infection	0/52 (0%)	0	5/49 (10.2%)	6
Respiratory, thoracic and mediastinal disorders
Cough	1/52 (1.9%)	1	3/49 (6.1%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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