Clinical trial NCT00814320: Gammagard Liquid and rHuPH20 in PID
Official title: Efficacy, Tolerability and Pharmacokinetic Comparison of Immune Globulin Intravenous (Human), 10% (GAMMAGARD LIQUID/KIOVIG) Administered Intravenously or Subcutaneously Following Administration of Recombinant Human Hyaluronidase (rHuPH20) in Subjects With Primary Immunodeficiency Diseases
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Primary Immunodeficiency Diseases (PID)
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2008-12-24
Enrollment: 89
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of the study is to develop a subcutaneous treatment option for participants with Primary Immunodeficiency Diseases (PID) that allows an administration of Immune Globulin Intravenous (Human), 10% at the same frequency as IV administration.


Eligibility criteria: Inclusion Criteria:

* Participant is 2 years or older at the time of screening
* Written informed consent obtained from either the participant or the participant's legally acceptable representative prior to any study-related procedures and study product administration
* Participant has been diagnosed with a PID disorder requiring antibody replacement as defined by WHO criteria
* Participant has completed or is about to complete Baxter Clinical Study Protocol No. 160601 or has been receiving a regular IGIV-treatment at mean intervals of 21 ± 3 days or 28 ± 3 days, or SC at mean intervals of 5 to 16 days, over a period of at least 3 months prior to enrollment at a minimum dose of 300 mg/kg BW/4 weeks
* Participant has a serum trough level of IgG \> 4.5 g/L at the last documented determination
* If female of childbearing potential, participant presents with a negative urine pregnancy test and agrees to employ adequate birth control measures for the duration of the study
* Participant is willing and able to comply with the requirements of the protocol

Exclusion Criteria:

* Participant has a known history of or is positive at enrollment or screening for one or more of the following: Hepatitis B surface antigen (HbsAg), polymerase chain reaction (PCR) for Hepatitis C Virus (HCV), PCR for Human immunodeficiency virus (HIV) Type 1/2
* Participant has levels of alanine aminotransferase (ALT) or aspartate amino transferase (AST) \> 2.5 times the upper limit of normal for the testing laboratory
* Participant has persistent severe neutropenia (defined as an absolute neutrophil count \[ANC\] \<= 500/mm3)
* Participant has creatinine clearance (CLcr) values, calculated according to the formula below, which are \< 60% of normal for age and gender for males: CLcr = \[(140 - Age(years)) \* (body weight (kg))\] / \[72 \* (serum creatinine (mg/dL))\] for females: CLcr = \[(140 - Age(years)) \* (body weight(kg)) \* 0.85\] / \[72 \* (serum creatinine (mg/dL))\]
* Participant has been diagnosed with, or has a malignancy (other than adequately treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix) within the last 12 months prior to enrollment; participants treated with immunosuppressive chemotherapeutic agents during this period are excluded
* Participant has a history of thrombotic episodes (including deep vein thrombosis, myocardial infarction, cerebrovascular accident, pulmonary embolism) within the last 12 months
* Participant has abnormal protein loss (protein losing enteropathy, nephrotic syndrome)
* Participant has anemia that would preclude phlebotomy for laboratory studies
* Participant has received any blood or blood product other than an IGIV, SC immunoglobulin, immune serum globulin (ISG) preparation, or albumin within the 6 months prior to enrollment
* Participant has an ongoing history of hypersensitivity or persistent reactions (urticaria, breathing difficulty, severe hypotension, or anaphylaxis) following IGIV, SC immunoglobulin, and/or ISG infusions
* Participant has immunoglobulin A (IgA) deficiency and known anti IgA antibodies
* Participant is on preventative (prophylactic) antibiotics and cannot stop antibiotics at the time of enrollment
* Participant has active infection who started on antibiotic therapy for the treatment of infection within 7 days prior to screening
* Participant has a bleeding disorder or is on anti-coagulation therapy that results in a platelet count less than 20,000/μL or International Normalized Ration (INR) \> 2X control, or who, in the opinion of the investigator would be at significant risk of increased bleeding or bruising as a result of SC therapy
* Participant has total protein \> 9 g/dL and participants with myeloma, macroglobulinemia (IgM) and paraproteinemia
* Participant has a known allergy to hyaluronidase
* If female, participant is pregnant or lactating at the time of study enrollment
* Participant has participated in another clinical study involving an investigational product (IP) or device within 30 days prior to study enrollment or is scheduled to participate in another clinical study involving an IP or device during the course of this study; exception: Baxter Study No. 160601
* Severe dermatitis that would preclude adequate sites for safe product administration

Primary outcomes:
measure: Validated Acute Serious Bacterial Infection (VASBI) Rate
timeFrame: Throughout the study period (17 months)
Secondary outcomes:
measure: Bioavailability (AUC) of IgG After Administration of IGIV, 10% Given Via IV or SC With rHuPH20 in Participants ≥12 Years
timeFrame: PK AUC evaluations: (IV: before infusion #4 [for 3-week treatment interval] or infusion #3 [for 4-week treatment interval];SC: before last SC infusion) 60 minutes pre-infusion up to 28 days (+/-2 days) post-infusion
measure: Bioavailability (Trough Levels) of IgG After Administration of IGIV, 10% Given Via IV or SC With rHuPH20 in Participants Aged 2 to < 12 Years
timeFrame: IgG trough levels measured at baseline and on day of each 3- or 4-week infusion for infusion for IV and SC (except during ramp-up for SC) and at end of study visit
measure: Bioavailability (AUC) of IgG After SC Administration of IGIV, 10%, Given With and Without rHuPH20
timeFrame: PK: 160603 (IV: before infusion (inf.) #4 [3-week treatment interval] or inf. #3 [4-week treatment interval];SC: before last SC inf.) 1 hour pre-inf. ≤28 days (+/-2 days) post-inf.; 160601- 1 hour pre-inf. (before inf. #8) ≤7 days (+/-1 day) post-inf.
measure: Annual Rate of All Infections Per Participant
timeFrame: Throughout the study period (17 months)
measure: Trough Levels of IgG After Administration of IGIV, 10% Given Via IV or SC With rHuPH20
timeFrame: IgG trough levels measured at baseline and on day of each 3- or 4-week infusion for IV and SC (except during ramp up for SC) and at end of study visit.
measure: Trough Levels of IgG Subclasses After Administration of IGIV, 10% Given Via IV or SC With rHuPH20
timeFrame: IgG subclasses (1-4) trough levels measured at baseline and on day of each 3- or 4-week infusion for infusion for IV and SC (except during ramp up for SC) and at end of study visit
measure: Antibody Levels to Tetanus (Clostridium Tetani Toxoid)
timeFrame: IV: At baseline; SC/rHuPH20: at baseline then at infusion #1 at ramp-up and at infusions #5, 9, 13 (for 3-week treatment interval) and infusions #4, 7, 10 (for 4-week treatment interval), SC: end of SC treatment and at end of study visit
measure: Antibody Levels to Haemophilus Influenzae
timeFrame: IV: At baseline; SC/rHuPH20: at baseline then at infusion #1 at ramp-up and at infusions #5, 9, 13 (for 3-week treatment interval) and infusions #4, 7, 10 (for 4-week treatment interval), SC: end of SC treatment and at end of study visit
measure: Antibody Levels to Measles
timeFrame: IV: At baseline; SC/rHuPH20: at baseline then at infusion #1 at ramp-up and at infusions #5, 9, 13 (for 3-week treatment interval) and infusions #4, 7, 10 (for 4-week treatment interval), SC: end of SC treatment and at end of study visit
measure: Antibody Levels to Hepatitis B
timeFrame: IV: At baseline; SC/rHuPH20: at baseline then at infusion #1 at ramp-up and at infusions #5, 9, 13 (for 3-week treatment interval) and infusions #4, 7, 10 (for 4-week treatment interval), SC: end of SC treatment and at end of study visit
measure: IgG Minimum Plasma Concentration (C_min) for Participants Aged 12 Years and Older
timeFrame: PK evaluations: (IV: before infusion #4 [for 3-week treatment interval] or infusion #3 [for 4-week treatment interval]; SC: before last SC infusion) 60 minutes pre-infusion up to 28 days (+/-2 days) post-infusion
measure: IgG Area Under the Curve (AUC)/Week for Participants Aged 12 Years and Older
timeFrame: PK evaluations: (IV: before infusion #4 [for 3-week treatment interval] or infusion #3 [for 4-week treatment interval];SC: before last SC infusion) 60 minutes pre-infusion up to 28 days (+/-2 days) post-infusion.
measure: IgG Clearance (CL) for Participants Aged 12 Years and Older
timeFrame: PK evaluations: (IV: before infusion #4 [for 3-week treatment interval] or infusion #3 [for 4-week treatment interval];SC: before last SC infusion) 60 minutes pre-infusion up to 28 days (+/-2 days) post-infusion.
measure: IgG Maximum Plasma Concentration (C_max) for Participants Aged 12 Years and Older
timeFrame: PK evaluations: (IV: before infusion #4 [for 3-week treatment interval] or infusion #3 [for 4-week treatment interval]; SC: before last SC infusion) 60 minutes pre-infusion up to 28 days (+/-2 days) post-infusion.
measure: IgG Terminal Half Life (T1/2) for Participants Aged 12 Years and Older
timeFrame: PK evaluations: (IV: before infusion #4 [for 3-week treatment interval] or infusion #3 [for 4-week treatment interval]; SC: before last SC infusion) 60 minutes pre-infusion up to 28 days (+/-2 days) post-infusion.
measure: Time to Maximum IgG Concentration (T-max) for Participants Aged 12 Years and Older
timeFrame: PK evaluations: (IV: before infusion #4 [for 3-week treatment interval] or infusion #3 [for 4-week treatment interval]; SC: before last SC infusion) 60 minutes pre-infusion up to 28 days (+/-2 days) post-infusion.
measure: Tetanus Antibody Minimum Plasma Concentration (C_min) for Participants Aged 12 Years and Older
timeFrame: PK evaluations: (IV: before infusion #4 [for 3-week treatment interval] or infusion #3 [for 4-week treatment interval]; SC: before last SC infusion) 60 minutes pre-infusion up to 28 days (+/-2 days) post-infusion.
measure: Tetanus Antibody Area Under the Curve (AUC)/Week for Participants Aged 12 Years and Older
timeFrame: PK evaluations: (IV: before infusion #4 [for 3-week treatment interval] or infusion #3 [for 4-week treatment interval];SC: before last SC infusion) 60 minutes pre-infusion up to 28 days (+/-2 days) post-infusion.
measure: Tetanus Antibody Clearance (CL) for Participants Aged 12 Years and Older
timeFrame: PK evaluations: (IV: before infusion #4 [for 3-week treatment interval] or infusion #3 [for 4-week treatment interval];SC: before last SC infusion) 60 minutes pre-infusion up to 28 days (+/-2 days) post-infusion.
measure: Tetanus Antibody Terminal Half Life (T1/2) for Participants Aged 12 Years and Older
timeFrame: PK evaluations: (IV: before infusion #4 [for 3-week treatment interval] or infusion #3 [for 4-week treatment interval]; SC: before last SC infusion) 60 minutes pre-infusion up to 28 days (+/-2 days) post-infusion.
measure: Tetanus Antibody Maximum Plasma Concentration (C_max) for Participants Aged 12 Years and Older
timeFrame: PK evaluations: (IV: before infusion #4 [for 3-week treatment interval] or infusion #3 [for 4-week treatment interval]; SC: before last SC infusion) 60 minutes pre-infusion up to 28 days (+/-2 days) post-infusion.
measure: Time to Maximum Tetanus Antibody Concentration (T-max) for Participants Aged 12 Years and Older
timeFrame: PK evaluations: (IV: before infusion #4 [for 3-week treatment interval] or infusion #3 [for 4-week treatment interval]; SC: before last SC infusion) 60 minutes pre-infusion up to 28 days (+/-2 days) post-infusion.
measure: H. Influenzae Antibody Minimum Plasma Concentration (C_min) for Participants Aged 12 Years and Older
timeFrame: PK evaluations: (IV: before infusion #4 [for 3-week treatment interval] or infusion #3 [for 4-week treatment interval]; SC: before last SC infusion) 60 minutes pre-infusion up to 28 days (+/-2 days) post-infusion.
measure: H. Influenzae Antibody Area Under the Curve (AUC)/Week for Participants Aged 12 Years and Older
timeFrame: PK evaluations: (IV: before infusion #4 [for 3-week treatment interval] or infusion #3 [for 4-week treatment interval];SC: before last SC infusion) 60 minutes pre-infusion up to 28 days (+/-2 days) post-infusion.
measure: H. Influenzae Antibody Clearance (CL) for Participants Aged 12 Years and Older
timeFrame: PK evaluations: (IV: before infusion #4 [for 3-week treatment interval] or infusion #3 [for 4-week treatment interval];SC: before last SC infusion) 60 minutes pre-infusion up to 28 days (+/-2 days) post-infusion.
measure: H. Influenzae Antibody Maximum Plasma Concentration (C_max) for Participants Aged 12 Years and Older
timeFrame: PK evaluations: (IV: before infusion #4 [for 3-week treatment interval] or infusion #3 [for 4-week treatment interval]; SC: before last SC infusion) 60 minutes pre-infusion up to 28 days (+/-2 days) post-infusion.
measure: H. Influenzae Antibody Terminal Half Life (T1/2) for Participants Aged 12 Years and Older
timeFrame: PK evaluations: (IV: before infusion #4 [for 3-week treatment interval] or infusion #3 [for 4-week treatment interval]; SC: before last SC infusion) 60 minutes pre-infusion up to 28 days (+/-2 days) post-infusion.
measure: Time to Maximum H. Influenzae Antibody Concentration (T-max) for Participants Aged 12 Years and Older
timeFrame: PK evaluations: (IV: before infusion #4 [for 3-week treatment interval] or infusion #3 [for 4-week treatment interval]; SC: before last SC infusion) 60 minutes pre-infusion up to 28 days (+/-2 days) post-infusion.
measure: Rate of Days Off School or Work
timeFrame: Monthly, for up to 17 months
measure: Rate of Days on Antibiotics
timeFrame: Monthly, for up to 17 months
measure: Rate of Acute Physician Visits
timeFrame: Monthly, for up to 17 months
measure: Rate of Days in Hospital
timeFrame: Monthly, for up to 17 months
measure: Percentage of Participants for Which the Infusion Rate Was Reduced and/or the Infusion Interrupted or Stopped for Tolerability Concerns or for Adverse Events (AEs)
timeFrame: Throughout the study period (17 months)
measure: Percentage of Infusions for Which the Infusion Rate Was Reduced and/or the Infusion Interrupted or Stopped for Tolerability Concerns or for Adverse Events (AEs)
timeFrame: Throughout the study period (17 months)
measure: Rate of Temporally Associated AEs Per Infusion
timeFrame: During infusion or within 72 hours of completion of infusion
measure: Percentage of Participants Reporting ≥1 Temporally Associated AEs
timeFrame: During infusion or within 72 hours of completion of infusion
measure: Percentage of Infusions Resulting in ≥1 Temporally Associated AEs
timeFrame: During infusion or within 72 hours of completion of infusion
measure: Percentage of Participants Reporting ≥1 Temporally Associated Moderate or Severe AEs
timeFrame: During infusion or within 72 hours of completion of infusion
measure: Percentage of Infusions Resulting in ≥1 Temporally Associated Moderate or Severe AEs Within 72 Hours of Completion of Infusion
timeFrame: During infusion or within 72 hours of completion of infusion
measure: Percentage of SC Doses of IGIV, 10% and rHuPH20 Tolerated at 1 Infusion Site
timeFrame: During infusion or within 60 minutes of completion of the infusion
measure: Percentage of Infusions Associated With ≥1 Systemic AE During Infusion or Within 72 Hours of Completion of Infusion
timeFrame: During infusion or within 72 hours of completion of infusion
measure: Percentage of Participants With ≥1 Systemic AE (Including and Excluding Infections) During Infusion or Within 72 Hours of Completion of Infusion
timeFrame: During infusion or within 72 hours of completion of infusion
measure: Percentage of Infusions Associated With ≥1 Local AE (Including and Excluding Infections) During Infusion or Within 72 Hours of Completion of Infusion
timeFrame: During infusion or within 72 hours of completion of infusion
measure: Percentage of Infusions Associated With ≥1 Local AE At Any Time During the Study
timeFrame: At any time during the study
measure: Percentage of Participants With ≥1 Local AE During Infusion or Within 72 Hours of Completion of Infusion
timeFrame: During infusion or within 72 hours of completion of infusion
measure: Percentage of Participants With ≥1 Local AE At Any Time During the Study
timeFrame: During infusion or within 72 hours of completion of infusion
measure: Rate of AEs Determined to be Related to the Study Drug by the Investigator Per Participant
timeFrame: Throughout the study period (17 months)
measure: Rate of AEs Determined to be Related to the Study Drug by the Investigator Per Infusion
timeFrame: Throughout the study period (17 months)
measure: Frequency of Dose Corrections (If IgG Trough Levels <4.5 g/L) for Each Study Epoch (IV and SC/rHuPH20 Treatment)
timeFrame: Throughout the study period (17 months)
measure: Number of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Relatedness to Study Drug, and Severity (A-F)
timeFrame: Throughout the study period (17 months)
measure: Number of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Relatedness to Study Drug, and Severity (G-M)
timeFrame: Throughout the study period (17 months)
measure: Number of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Relatedness to Study Drug, and Severity (N-Z)
timeFrame: Throughout the study period (17 months)
measure: Rate of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Relatedness to Study Drug, and Severity Per Infusion (A-F)
timeFrame: Throughout the study period (17 months)
measure: Rate of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Relatedness to Study Drug, and Severity Per Infusion (G-M)
timeFrame: Throughout the study period (17 months)
measure: Rate of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Relatedness to Study Drug, and Severity Per Infusion (N-Z)
timeFrame: Throughout the study period (17 months)
measure: Rate of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Relatedness to Study Drug, and Severity Per Participant (A-F)
timeFrame: Throughout the study period (17 months)
measure: Rate of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Relatedness to Study Drug, and Severity Per Participant (G-M)
timeFrame: Throughout the study period (17 months)
measure: Rate of All AEs Categorized by MedDRA Preferred Terms, Seriousness, Relatedness to Study Drug, and Severity Per Participant (N-Z)
timeFrame: Throughout the study period (17 months)
measure: Percentage of Infusions Associated With ≥1 AE Related to Either or Both Study Drugs
timeFrame: Throughout the study period (17 months)
measure: Percentage of Infusions Tolerated With IV and SC Administration at Dose Used in Study Epoch 2 (SC/rHuPH20 Treatment)
timeFrame: Throughout the study period (17 months)
measure: Median Rate of AEs Temporally Associated or Related to Study Drug Per Infusion
timeFrame: Throughout the study period (17 months)
measure: Number of Participants Who Developed Neutralizing Antibodies to Recombinant Human Hyaluronidase (rHuPH20)
timeFrame: Throughout the study period (17 months)
measure: Percentage of Participants Who Developed Neutralizing Antibodies to Recombinant Human Hyaluronidase (rHuPH20)
timeFrame: Throughout the study period (17 months)
measure: Number of Participants Who Experienced a Hemoglobin Drop of >2.0 g/dL, With Evidence of Hemolysis on Further Analysis
timeFrame: Throughout the study period (17 months)
measure: Percentage of Participants Who Experienced a Hemoglobin Drop of >2.0 g/dL, With Evidence of Hemolysis on Further Analysis
timeFrame: Throughout the study period (17 months)
Other outcomes:
Locations:
city: Cypress
country: United States
state: California
city: Irvine
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: San Francisco
country: United States
state: California
city: Centennial
country: United States
state: Colorado
city: North Palm Beach
country: United States
state: Florida
city: Atlanta
country: United States
state: Georgia
city: Hinsdale
country: United States
state: Illinois
city: Omaha
country: United States
state: Nebraska
city: Bronx
country: United States
state: New York
city: Dallas
country: United States
state: Texas
city: Galveston
country: United States
state: Texas
city: Milwaukee
country: United States
state: Wisconsin
city: Vancouver
country: Canada
state: British Columbia
Study officials:
affiliation: Shire
name: Study Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: Wasserman RL, Melamed I, Stein MR, Gupta S, Puck J, Engl W, Leibl H, McCoy B, Empson VG, Gelmont D, Schiff RI; IGSC, 10% with rHuPH20 Study Group. Recombinant human hyaluronidase-facilitated subcutaneous infusion of human immunoglobulins for primary immunodeficiency. J Allergy Clin Immunol. 2012 Oct;130(4):951-7.e11. doi: 10.1016/j.jaci.2012.06.021. Epub 2012 Jul 28.
citation: 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.