Tolerability and Safety of Immune Globulin Subcutaneous Solution (IGSC) and rHuPH20 in PID

• ClinicalTrials.gov Identifier: NCT01175213
• Recruitment Status: Completed
• First Posted: August 4, 2010
• Results First Posted: May 26, 2016
• Last Update Posted: May 19, 2021
• Sponsor: Baxalta now part of Shire
• Information provided by (Responsible Party): Takeda ( Baxalta now part of Shire )

Study Description

Brief Summary:

The original purpose of the study is to assess the long-term safety, tolerability, and practicability of the subcutaneous (SC) treatment with Immune Globulin Subcutaneous Solution (IGSC), 10% facilitated with recombinant human hyaluronidase (rHuPH20) in participants with Primary Immunodeficiency Diseases (PID) who have completed Baxter Clinical Study Protocol No. 160603.

Following a discussion with the FDA, all participants still active in the study stopped treatment with rHuPH20 to assure safety of the participants participating in the study and went into a safety follow-up.

During this safety follow-up period, participants underwent either intravenous (IV) or SC treatment with IGSC, 10%. The IV or SC administration route was at the discretion of the participant and the investigator.

Condition or disease	Intervention/treatment	Phase
Primary Immunodeficiency Diseases (PID)	Biological: SC treatment with IGSC, 10% with rHuPH20 followed by SC/IGSC, 10% only (safety); Biological: SC treatment with IGSC, 10% with rHuPH20 followed by IV/IGSC, 10% only (safety); Biological: IV treatment with IGSC, 10%	Phase 3

Detailed Description:

IGSC, 10% is the same product as IMMUNE GLOBULIN INTRAVENOUS (HUMAN), 10% (IGIV, 10%) quoted in study 160603.

IGSC, 10% is abbreviated to IGI, 10% [IMMUNE GLOBULIN INFUSION (HUMAN), 10%]

In the US the product is licensed (trade name GAMMAGARD LIQUID) for the intravenous (IV) and SC replacement therapy of antibody deficiency in patients with PID.

In the EU this product is licensed (trade name KIOVIG)

IGSC, 10% with rHuPH20 established name is Innume Glubulin Infusion 10% (Human) with Recombinant Human Hyualuronidase.

US trade name is HYQVIA EU trade name is HyQvia

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 66 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Long-Term Tolerability and Safety of Immune Globulin Subcutaneous (IGSC) Solution Administered Subcutaneously Following Administration of Recombinant Human Hyaluronidase (rHuPH20) in Subjects With Primary Immunodeficiency Diseases
• Actual Study Start Date: July 28, 2010
• Actual Primary Completion Date: August 6, 2013
• Actual Study Completion Date: August 6, 2013

Arms and Interventions

Arm	Intervention/treatment
Experimental: SC/IGSC, 10% with rHuPH20 followed by SC of IGSC, 10% (safety); Efficacy and safety of subcutaneous (SC) administration of Immune Globulin Subcutaneous Solution (IGSC), 10% after SC administration of recombinant human hyaluronidase (rHuPH20) followed by Safety of SC of IGSC, 10% only (safety follow-up)	Biological: SC treatment with IGSC, 10% with rHuPH20 followed by SC/IGSC, 10% only (safety); Participants are to continue on the same doses and treatment intervals of IGSC, 10% adjusted for body weight, and rHuPH20 that were used for the last infusions in Study epoch 2 of Study 160603 (NCT00814320). After 3 infusions, participants are to change treatment to a 2-week interval, if agreed with participant and investigator. During this safety follow-up period, participants are treated with IGSC, 10% via the SC route. Treatment occurred once every week. The dose was the weekly equivalent of the most recent IV dose (adjusted per body weight) and multiplied by 1.37.; Other Names: HYQVIA (IGSC; 10% with rHuPH20 [US]); 10% with rHuPH20 [EU]); GAMMAGARD LIQUID (IGSC; 10% [US]); KIOVIG (IGSC; 10% [EU])
Experimental: SC/IGSC, 10% with rHuPH20 followed by IV of IGSC, 10% (safety; Efficacy and safety of subcutaneous (SC) administration of Immune Globulin Subcutaneous Solution (IGSC), 10% after SC administration of recombinant human hyaluronidase (rHuPH20) followed by Safety of intravenous (IV) administration of IGSC, 10% only (safety follow-up)	Biological: SC treatment with IGSC, 10% with rHuPH20 followed by IV/IGSC, 10% only (safety); Participants are to continue on the same doses and treatment intervals of IGSC, 10% adjusted for body weight, and rHuPH20 that were used for the last infusions in Study epoch 2 of Study 160603 (NCT00814320). After 3 infusions, participants are to change treatment to a 2-week interval, if agreed with participant and investigator. During this safety follow-up period, participants are treated with IGSC, 10% via the intravenous (IV) route. Treatment occurred once every 3-4 weeks. The weekly dose equivalent was 100% of the most recent IV dose.; Other Names: GAMMAGARD LIQUID (IGSC; 10% [US]); KIOVIG (IGSC; 10% [EU]); HyQvia (IGSC; 10% with rHuPH20 [EU]); 10% with rHuPH20 [US])
Experimental: IV treatment with IGSC, 10% only; Partial efficacy (trough levels of immunoglobulin G [IgG] only) and safety of intravenous (IV) administration of IGSC, 10% only. This was for participants enrolled in the study who had anti-rHuPH20 andibody titer from study160603	Biological: IV treatment with IGSC, 10%; During this safety follow-up period, participants are treated with IGSC, 10% via the intravenous (IV) route.; Other Names: GAMMAGARD LIQUID (US); KIOVIG (EU)

Outcome Measures

Primary Outcome Measures :

1. Annual Rate of Serious Bacterial Infections [ Time Frame: Throughout the efficacy period only (from 60 to 729 days) ]
   The point estimate of the annual rate of validated acute serious bacterial infections (VASBIs) per participant per year was provided during subcutaneous (SC) administration of Immune Globulin Subcutaneous Solution (IGSC), 10%, after SC administration of human recombinant hyaluronidase (rHuPH20). This efficacy outcome measure was only applicable prior to the safety follow-up i.e. before discontinuation of rHuPH20.
2. Annual Rate of All Infections [ Time Frame: Throughout the efficacy period only (from 60 to 729 days) ]
   Annualized rate of infections per participant as defined by MedDRA system organ class (SOC) "infections and infestations". The point estimate of the annual rate of all infections was provided during subcutaneous (SC) administration of Immune Globulin Subcutaneous Solution (IGSC), 10%, after SC administration of human recombinant hyaluronidase (rHuPH20). This efficacy outcome measure was only applicable prior to the safety follow-up i.e. before discontinuation of rHuPH20.
3. Trough Levels of IgG Maintained During the Study Period in Relation to Dose Frequency [ Time Frame: Throughout the efficacy period only (from 60 to 729 days) ]
   Immunoglobulin (IgG) steady state trough levels were measured in relation to dose frequency by measuring in relation to treatment interval (2-, 3- or 4-week intervals). Initially participants were administered subcutaneous (SC) infusions of Immune Globulin Subcutaneous Solution (IGSC), 10%, after SC administration of human recombinant hyaluronidase (rHuPH20) [or IV infusions of IGSC, 10% only] at the treatment intervals and dose determined by epoch 2 of study 160603 (3- or 4-week intervals). After 3 treatment intervals (either 3- or 4- week intervals), participants changed to a 2-week treatment interval, if agreed with participant and investigator, with the dose adjusted to 1/2 of the 4-week dose or 2/3 of the 3-week dose, whichever was applicable. The rHuPH20 dose was adjusted relative to the new IGSC, 10% dose in order to achieve a dose ratio of 75 U/g IgG. This efficacy outcome measure was only applicable prior to the safety follow-up i.e. before discontinuation of rHuPH20.

Secondary Outcome Measures :

1. The Annual Rate of Serious Adverse Events (SAEs), Related and Not Related to Study Drugs [ Time Frame: Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. ]
   Separated into age groups as described below and into related (related to either study drug) and not related (not related to either or both study drugs). Study drugs are Immune Globulin Subcutaneous Solution (IGSC), 10% and recombinant human hyaluronidase (rHuPH20).
2. Percentage of Infusions for Which the Infusion Rate Was Reduced and/or the Infusion Interrupted or Stopped for Tolerability Concerns or for AEs [ Time Frame: Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. ]
3. Percentage of Infusions Associated With One or More Moderate or Severe AEs (Including and Excluding Infections) That Begin During or Within 72 Hours of Completion of an Infusion [ Time Frame: Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. ]
4. Number of Participants Who Develop Antibodies and Neutralizing Antibodies to rHuPH20 [ Time Frame: Throughout entire study period for 160603 (1 year 11 months) and 160902 (2 years 11 months) ]
   Participants who develop binding antibodies and/or neutralizing antibodies to recombinant human hyaluronidase (rHuPH20) from study 160603 and/ or from this study (160902) are included here. This study (160902) is an extension of study 160603. Study 160603 was divided into 2 study epochs. In epoch 1 of study 160603 participants were treated with intravenous (IV) administration of Immune Globulin Subcutaneous Solution (IGSC), 10%. In epoch 2 of study 160603 participants were treated with subcutaneous (SC) administration of IGSC, 10% after SC administration of rHuPH20. Only participants who completed study 160603 were eligible to be screened and enrolled in this study (160902). In this study, participants started on same doses of IGSC, 10% and rHuPH20 that were used for the last infusions in epoch 2 of study 160603.
5. Percentage of Participants Who Develop Antibodies and Neutralizing Antibodies to rHuPH20 [ Time Frame: Throughout entire study period for 160603 (1 year 11 months) and 160902 (2 years 11 months) ]
   Participants who develop binding antibodies and/or neutralizing antibodies to recombinant human hyaluronidase (rHuPH20) from study 160603 and/ or from this study (160902) are included here. This study (160902) is an extension of study 160603. Study 160603 was divided into 2 study epochs. In epoch 1 of study 160603 participants were treated with intravenous (IV) administration of Immune Globulin Subcutaneous Solution (IGSC), 10%. In epoch 2 of study 160603 participants were treated with subcutaneous (SC) administration of IGSC, 10% after SC administration of rHuPH20. Only participants who completed study 160603 were eligible to be screened and enrolled in this study (160902). In this study, participants started on same doses of IGSC, 10% and rHuPH20 that were used for the last infusions in epoch 2 of study 160603.
6. Number of Participants With AEs Related to Anti-rHuPH20 Titers [ Time Frame: Throughout entire study period for 160603 (1 year 11 months) and 160902 (2 years 11 months) ]
7. Percentage of Participants With AEs Related to Anti-rHuPH20 Titers [ Time Frame: Throughout entire study period for 160603 (1 year 11 months) and 160902 (2 years 11 months) ]
8. Number of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Relatedness to the Study Drug, and Severity (A-F). [ Time Frame: Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. ]
   Categories presented as Preferred Term-Seriousness-Relatedness-Severity. The following codes are to be used: Seriousness: non-SAE-non-serious AE; SAE-serious AE Relatedness to study drug: R (related to either study drug); NR (not related to either or both study drugs). Study drugs are Immune Globulin Subcutaneous Solution, 10% (IGSC, 10%) and recombinant human hyaluronidase (rHuPH20) Severity: Mild; Mod (Moderate); Severe Preferred terms abbreviated: ADHD - Attention Deficit/Hyperactivity Disorder COPD - Chronic Obstructive Pulmonary Disease Other abbreviations: CPK - Creatinine Phosphokinase Inc. - Increased Dis - Disease Sml- small
9. Number of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Relatedness to the Study Drug, and Severity (G-M). [ Time Frame: Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. ]
   Categories presented as Preferred Term-Seriousness-Relatedness-Severity. The following codes are to be used: Seriousness: non-SAE-non-serious AE; SAE-serious AE Relatedness to study drug: R (related to either study drug); NR (not related to either or both study drugs). Study drugs are Immune Globulin Subcutaneous Solution, 10% (IGSC, 10%) and recombinant human hyaluronidase (rHuPH20) Severity: Mild; Mod (Moderate); Severe
10. Number of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Relatedness to the Study Drug, and Severity (N-Z). [ Time Frame: Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. ]
    Categories presented as Preferred Term-Seriousness, Relatedness, Severity. The following codes are to be used: Seriousness: non-SAE-non-serious AE; SAE-serious AE Relatedness to study drug: R (related to either study drug); NR (not related to either or both study drugs). Study drugs are Immune Globulin Subcutaneous Solution, 10% (IGSC, 10%) and recombinant human hyaluronidase (rHuPH20) Severity: Mild; Mod (Moderate); Severe Preferred terms abbreviated: Infection - Inf.
11. Rate of All AEs Per Participant Categorized by MedDRA Preferred Terms, Seriousness and Severity (A-F). [ Time Frame: Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. ]
    Categories presented as Preferred Term-Seriousness-Severity. The following codes are to be used: Seriousness: non-SAE-non-serious AE; SAE-serious AE Severity: Mild; Mod (Moderate); Sev (Severe) Preferred terms abbreviated: ADHD - Attention Deficit/Hyperactivity Disorder COPD - Chronic Obstructive Pulmonary Disease Other abbreviations: Inc. - Increased Dis. - Disease
12. Rate of All AEs Per Participant Categorized by MedDRA Preferred Terms, Seriousness and Severity (G-M). [ Time Frame: Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. ]
    Categories presented as Preferred term-Seriousness-Severity. The following codes are to be used: Seriousness: non-SAE-non-serious AE; SAE-serious AE Severity: Mild; Mod (Moderate); Sev (Severe)
13. Rate of All AEs Per Participant Categorized by MedDRA Preferred Terms, Seriousness and Severity (N-Z). [ Time Frame: Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. ]
    Categories presented as Preferred term-Seriousness-Severity. The following codes are to be used: Seriousness: non-SAE-non-serious AE; SAE-serious AE Severity: Mild; Mod (Moderate); Sev (Severe)
14. Rate of All AEs Per Infusion Categorized by MedDRA Preferred Terms, Seriousness and Severity (A-F). [ Time Frame: Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. ]
    Categories presented as Preferred term-Seriousness-Severity. The following codes are to be used: Seriousness: non-SAE-non-serious adverse event; SAE- serious adverse event Severity: Mild; Mod (Moderate); Sev (Severe) Preferred terms abbreviated: ADHD - Attention Deficit/Hyperactivity Disorder COPD - Chronic Obstructive Pulmonary Disease Other abbreviations: Inc. - Increased Dis. - Disease
15. Rate of All AEs Per Infusion Categorized by MedDRA Preferred Terms, Seriousness and Severity (G-M). [ Time Frame: Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. ]
    Categories presented as Preferred term-Seriousness-Severity. The following codes are to be used: Seriousness: non-SAE-non-serious AE; SAE-serious AE Severity: Mild; Mod (Moderate); Sev (Severe)
16. Rate of All AEs Per Infusion Categorized by MedDRA Preferred Terms, Seriousness and Severity (N-Z). [ Time Frame: Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. ]
    Categories presented as Preferred term-Seriousness-Severity. The following codes are to be used: Seriousness: non-SAE-non-serious AE; SAE-serious AE Severity: Mild; Mod (Moderate); Sev (Severe)
17. Rate of AEs Per Participant (Including and Excluding Infections) Determined by the Investigator to be Related to the Study Drug That Occur at Any Time During the Study ("Related") [ Time Frame: Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. ]
    Categories presented as adverse event (AE) type : Total, Local, Systemic including infections, Systemic excluding infections, and Severity (Mild, Moderate, Severe, Total). All of these adverse events are non-serious AEs.
18. Rate of AEs Per Infusion (Including and Excluding Infections) Determined by the Investigator to be Related to the Study Drug That Occur at Any Time During the Study ("Related") [ Time Frame: Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. ]
    Categories presented as adverse event (AE) type : Total, Local, Systemic including infections, Systemic excluding infections, and Severity (Mild, Moderate, Severe, Total). All of these adverse events are non-serious AEs.
19. Rate of AEs Per Participant (Including and Excluding Infections) Temporarily Associated With the Infusion [ Time Frame: Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. ]
    Categories presented as adverse event (AE) type : Total, Local, Systemic including infections, Systemic excluding infections, Seriousness: Serious AE (SAE), non-serious AE (nsAE) and Severity (Mild, Moderate, Severe, Total). All of these adverse events are non-serious AEs.
20. Rate of AEs Per Infusion (Including and Excluding Infections) Temporarily Associated With the Infusion [ Time Frame: Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. ]
    Categories presented as adverse event (AE) type : Total, Local, Systemic including infections, Systemic excluding infections, Seriousness: Serious AE (SAE), non-serious AE (non-SAE) and Severity (Mild, Moderate, Severe, Total). All of these adverse events are non-serious AEs.
21. Percentage of Infusions Associated With One or More Local AEs (Including and Excluding Infections), at Any Time During the Study [ Time Frame: Throughout entire study period (up to 3 years). Duration of participation for each participant is variable depending on date of enrollment and their anti-rHuPH20 binding antibody titer. ]

Eligibility Criteria

• Ages Eligible for Study: 2 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Participant has completed or is about to complete Baxter Clinical Study Protocol No. 160603. Participants who have discontinued rHuPH20 and reverted to intravenous or subcutaneous treatment due to an anti-rHuPH20 antibody also may enroll for long-term safety monitoring.
• Participant/caretaker has reviewed, signed and dated informed consent
• Participant is willing and able to comply with the requirements of the protocol

Exclusion Criteria:

• Participant has a serious medical condition such that the participant's safety or medical care would be impacted by participation in Study 160902
• Participant is scheduled to participate in another non-Baxter clinical study involving an investigational product or investigational device during the course of this study
• If female of childbearing potential, participant is pregnant or has a negative pregnancy test and does not agree to employ adequate birth control measures for the duration of the study

Contacts and Locations

Locations

United States, California

Cypress, California, United States

Irvine, California, United States

Los Angeles, California, United States

San Francisco, California, United States

United States, Colorado

Centennial, Colorado, United States

United States, Florida

North Palm Beach, Florida, United States

United States, Georgia

Atlanta, Georgia, United States

United States, Illinois

Hinsdale, Illinois, United States

United States, New York

Bronx, New York, United States

United States, Texas

Dallas, Texas, United States

Galveston, Texas, United States

Sponsors and Collaborators

Baxalta now part of Shire

Investigators

• Study Director: Study Director; Takeda

More Information

Publications of Results:

Wasserman RL, Melamed I, Stein MR, Engl W, Sharkhawy M, Leibl H, Puck J, Rubinstein A, Kobrynski L, Gupta S, Grant AJ, Ratnayake A, Richmond WG, Church J, Yel L, Gelmont D. Long-Term Tolerability, Safety, and Efficacy of Recombinant Human Hyaluronidase-Facilitated Subcutaneous Infusion of Human Immunoglobulin for Primary Immunodeficiency. J Clin Immunol. 2016 Aug;36(6):571-82. doi: 10.1007/s10875-016-0298-x. Epub 2016 May 25.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Wasserman RL, Gupta S, Stein M, Rabbat CJ, Engl W, Leibl H, Yel L. Infection rates and tolerability of three different immunoglobulin administration modalities in patients with primary immunodeficiency diseases. Immunotherapy. 2022 Mar;14(4):215-224. doi: 10.2217/imt-2021-0256. Epub 2021 Dec 21.

• Responsible Party: Baxalta now part of Shire
• ClinicalTrials.gov Identifier: NCT01175213
• Other Study ID Numbers: 160902
• First Posted: August 4, 2010
• Results First Posted: May 26, 2016
• Last Update Posted: May 19, 2021
• Last Verified: April 2021

Additional relevant MeSH terms:

Primary Immunodeficiency Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Genetic Diseases, Inborn; Immunoglobulins, Intravenous; gamma-Globulins; Rho(D) Immune Globulin; Immunologic Factors; Physiological Effects of Drugs