Phase 2/3 Study of IGSC, 20% in PIDD

Baxalta now part of Shire86 enrolled

Overview

The purpose of this study is to develop a 20% subcutaneous (SC) immunoglobulin preparation for the treatment of patients with primary immunodeficiency diseases (PIDD).

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Primary Immunodeficiency Diseases (PID)

Interventions

Immune Globulin Intravenous (Human), 10% SolutionBIOLOGICAL

Intravenous infusion with IGIV, 10%

Immune Globulin Subcutaneous (Human), 20% SolutionDRUG

Subcutaneous infusion with IGSC, 20%

Eligibility

Sex: ALLMin age: 2 Years

Medical Language ↔ Plain English

Main Inclusion Criteria: * Documented diagnosis of a form of primary humoral immunodeficiency involving defective antibody formation and requiring gammaglobulin replacement as defined according to the IUIS Scientific Committee, 2011 and by diagnostic criteria according to Conley et al. (1999). The diagnosis must be confirmed by the Medical Director prior to first treatment with the investigational product (IP) in the study. * Participant is 2 years or older at the time of screening, and has a minimum body weight of 13 kg. * Written informed consent has been obtained from either the participant or the participant's legally authorized representative prior to any study-related procedures and study product administration * Participant has been receiving a stable monthly equivalent dose of IgG at an average minimum dose equivalent to 300 mg/kg bodyweight (BW)/4 weeks and a maximum dose equivalent to 1.0 gram/kg BW/4 weeks, for a minimum of 12 weeks prior to first treatment with the IP in the study. * Serum trough level of IgG \> 500 mg/dL at screening * Participant is willing and able to comply with the requirements of the protocol Main Exclusion Criteria: * Participant has known history of or is positive at 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 * Abnormal laboratory values at screening meeting any one of the following criteria (abnormal tests may be repeated once to determine if they are persistent): * Persistent alanine aminotransferase (ALT) and aspartate amino transferase(AST) \> 2.5 times the upper limit of normal for the testing laboratory * Persistent severe neutropenia (defined as an absolute neutrophil count \[ANC\] ≤500/mm\^3) * Creatinine clearance (CLcr) value that is \< 60% of normal for age and gender either measured, or calculated according to the Cockcroft-Gault formula * Malignancy (other than adequately treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix), unless the disease-free period prior to screening exceeds 5 years * Participant is receiving anti-coagulation therapy (low dose aspirin at ≤325 mg/day is permitted) or has a history of thrombotic episodes (including deep vein thrombosis, myocardial infarction, cerebrovascular accident, pulmonary embolism) or sickle cell disease with crisis within 12 months prior to screening or a history of thrombophilia * Abnormal protein loss (protein losing enteropathy, nephrotic syndrome) * Anemia that would preclude phlebotomy for laboratory studies according to standard practice at the site * Acute serious bacterial infection within 3 months prior to screening * Ongoing history of hypersensitivity or persistent reactions (urticaria, breathing difficulty, severe hypotension, or anaphylaxis) following intravenous immunoglobulin, subcutaneous immunoglobulin, and/or Immune Serum Globulin (ISG) infusions * Severe immunoglobulin A (IgA) deficiency (less than 0.07g/L) with known anti-IgA antibodies and a history of hypersensitivity * Participant is on continuous systemic antibacterial antibiotics at doses sufficient to treat or prevent bacterial infections, and, in the opinion of the investigator, cannot stop these for the duration of the study without putting the patient at risk of increased infections * Participant has active infection and is receiving antibiotic therapy for the treatment of infection at the time of screening * Bleeding disorder or thrombocytopenia with a platelet count less than 20,000/μL, or who, in the opinion of the investigator, would be at significant risk of increased bleeding or bruising as a result of subcutaneous therapy * Total protein \> 9 g/dL or myeloma or macroglobulinemia (IgM) or paraproteinemia * Severe dermatitis that would preclude adequate sites for safe product administration * Women of childbearing potential meeting any one of the following criteria: * Participant presents with a positive pregnancy test * Participant is breast feeding * Participant intends to begin nursing during the course of the study * Participant does not agree to employ adequate birth-control measures (e.g. intrauterine device, diaphragm or condom \[for male partner\] with spermicidal jelly or foam, or birth control pills/patches) throughout the course of the study * Participation in another clinical study and exposure to an investigational product or device within 30 days prior to study enrollment (exception: treatment in a previous Baxter immunoglobulin study) * Participant is scheduled to participate in another (non-Baxter) non-observational (interventional) clinical study involving an investigational product or device during the course of the study

Locations (18)

University of California, Irvine

Irvine, California, United States

IMMUNOe International Research Centers

Outcomes

Primary Outcomes

Rate of Acute Serious Bacterial Infections Per Year (ASBI)

Annual rate of validated acute serious bacterial infections was calculated using a Poisson model to account for the different lengths of observation per participant. The observation period for each participant starts with the day of the first subcutaneous (SC) infusion in Study Epoch 2 and ends with the day of the End of Study visit.

Time frame: 1 year

Secondary Outcomes

Annual Rate of All Infections Per Participant

Time frame: 1 year

Annual Rate of Sinus Infections Per Participant

Time frame: 1 year

Annual Rate of Fever Episodes Per Participant

Time frame: 1 year

Annual Rate of Days Off School/Work or Days Unable to Perform Normal Daily Activities Due to Illness or Infection Per Participant

Time frame: 1 year

Annual Rate of Days on Antibiotics Per Participant

Time frame: 1 year

Annual Rate of Hospitalizations for Illness or Infection Per Participant

Time frame: 1 year

Annual Rate of Days of Hospitalizations for Illness or Infection Per Participant

Time frame: 1 year

Annual Rate of Acute (Urgent or Unscheduled) Physician Visits, or Visits to the Emergency Room for Illness or Infection Per Participant

Time frame: 1 year

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Centennial, Colorado, United States

Allergy Associates of the Palm Beaches

North Palm Beach, Florida, United States

Emory University

Atlanta, Georgia, United States

Rush University Medical Center

Chicago, Illinois, United States

Family Allergy and Asthma Research Institute

Louisville, Kentucky, United States

Children's Hospital New Orleans- LSUHSC School of Medicine

New Orleans, Louisiana, United States

Midwest Immunology Clinical and Infusion Center

Plymouth, Minnesota, United States

SSM Cardinal Glennon Children's Medical Center

St Louis, Missouri, United States

Montefiore Medical Center Division of Allergy/Immunology

The Bronx, New York, United States

...and 8 more locations

Bioavailability of IGSC, 20% as Measured by the Ratio of the Geometric Means of Immunoglobulin G (IgG) AUCSC (Epoch 4) to IgG AUCIV,0-τ (Standardized to 1 Week) (Epoch 1) Adjusted for Dose and Dosing Frequency (Participants ≥12 Years Old)

IGSC, 20% = Immune Globulin Subcutaneous (Human), 20% Solution; AUCSC = area under the concentration-time curve following subcutaneous administration; AUCIV,0-τ = area under the concentration-time curve following intravenous administration over a dosing interval

Time frame: Epoch 1: 3 week IV administration interval: Week 10, 11, 12, 13. Epoch 1: 4 week IV interval: Week 9, 10, 11, 12, 13. Epoch 4 Subcutaneous administration weeks 17, 18

Trough Levels of IgG (Total), and IgG Subclasses at the End of the Treatment Intervals

Time frame: Epoch 1: 3 week IV interval- weeks 0, 1, 4, 7, 10, 13. Epoch 1: 4 week IV interval- weeks 0, 1, 5, 9, 13. Epochs 2 & 3: Subcutaneous (SC) weeks 5, 9. Epoch 4: SC weeks 1, 9, 17, 29, 40 (week dependent on time to establish "Adjusted Dose" in Epoch 2)

Trough Levels of Anti-Tetanus Antibody

Time frame: Epoch 1: 3 week IV interval- weeks 1, 4, 7, 10, 13. Epoch 1: 4 week IV interval- weeks 1, 5, 9, 13. Epochs 2 & 3: Subcutaneous (SC) weeks 5, 9. Epoch 4: SC weeks 1, 9, 17, 29, 40 (week dependent on time to establish "Adjusted Dose" in Epoch 2)

Trough Levels of Anti-Haemophilus Influenza B Antibody

Trough Levels of Anti-Hepatitis B Antibody

Pharmacokinetics Parameters for Immunoglobulin G (IgG): Area Under the Curve (AUC)

The AUC between adjacent infusions will be calculated by the trapezoidal rule. Linear interpolation/extrapolation will be used to calculate the AUC for exact duration of the infusion intervals (21 or 28 days for IV administration and 7 days for SC administration). To allow for comparisons between Epochs 1, 2 and 4, AUC0-τ will be standardized for the infusion intervals (3 or 4 weeks vs. 1 week)

Time frame: Epoch 1: 3 week IV interval: Weeks 10-13. Epoch 1: 4 week IV interval: Weeks 9-13. Epoch 2: Subcutaneous (SC) weeks 9-10. Epoch 4: SC weeks 17-18

Pharmacokinetics Parameters for Immunoglobulin G (IgG): Dose Per Weight-adjusted Area Under the Curve (AUC)

Time frame: Epoch 1: 3 week IV interval: Weeks 10-13. Epoch 1: 4 week IV interval: Weeks 9-13. Epoch 2: Subcutaneous (SC) weeks 9-10. Epoch 4: SC weeks 17-18

Pharmacokinetics Parameters for Immunoglobulin G (IgG): Clearance (CL) for Immune Globulin Administered Intravenously (IGIV) and Apparent Clearance for Immune Globulin Administered Subcutaneously (IGSC)

Clearance (CL) or apparent clearance (CL/F) for IV and SC administration, respectively, will be determined by the formula: CL or CL/F = (Dose (mg/kg)) / (AUC 0-τ). (F= bioavailability)

Time frame: Epoch 1: 3 week IV interval: Weeks 10-13. Epoch 1: 4 week IV interval: Weeks 9-13. Epoch 2: Subcutaneous (SC) weeks 9-10. Epoch 4: SC weeks 17-18

Pharmacokinetics Parameters for Immunoglobulin G (IgG): Maximum Concentration (Cmax)

The maximum concentration (Cmax) following administration of study drug (either immune globulin administered intravenously (IGIV) or immune globulin administered subcutaneously (IGSC).

Time frame: Epoch 1: 3 week IV interval: Weeks 10-13. Epoch 1: 4 week IV interval: Weeks 9-13. Epoch 2: Subcutaneous (SC) weeks 9-10. Epoch 4: SC weeks 17-18

Pharmacokinetics Parameters for Immunoglobulin G (IgG): Time to Maximum Concentration (Tmax)

The minimum time (Tmax) to reach the maximum concentration (Cmax)

Time frame: Epoch 1: 3 week IV interval: Weeks 10-13. Epoch 1: 4 week IV interval: Weeks 9-13. Epoch 2: Subcutaneous (SC) weeks 9-10. Epoch 4: SC weeks 17-18

Pharmacokinetics Parameters for Immunoglobulin G (IgG): Minimum Concentration (Cmin)

The minimum concentration (Cmax) following administration of study drug (either immune globulin administered intravenously (IGIV) or immune globulin administered subcutaneously (IGSC).

Time frame: Epoch 1: 3 week IV interval: Weeks 10-13. Epoch 1: 4 week IV interval: Weeks 9-13. Epoch 2: Subcutaneous (SC) weeks 9-10. Epoch 4: SC weeks 17-18

Pharmacokinetics Parameters for Haemophilus Influenza B Antibody: Area Under the Curve (AUC)

The AUC between adjacent infusions will be calculated by the trapezoidal rule . Linear interpolation/extrapolation will be used to calculate the AUC for exact duration of the infusion intervals (21 or 28 days for IV administration and 7 days for SC administration). To allow for comparisons between Epochs 1, 2 and 4, AUC 0-τ will be standardized for the infusion intervals (3 or 4 weeks vs. 1 week )

Time frame: Epoch 1: 3 week IV interval: Weeks 10-13. Epoch 1: 4 week IV interval: Weeks 9-13. Epoch 2: Subcutaneous (SC) weeks 9-10. Epoch 4: SC weeks 17-18

Pharmacokinetics Parameters for Haemophilus Influenza B Antibody: Dose Per Weight-adjusted Area Under the Curve (AUC)

The AUC between adjacent infusions will be calculated by the trapezoidal rule . Linear interpolation/extrapolation will be used to calculate the AUC for exact duration of the infusion intervals (21 or 28 days for IV administration and 7 days for SC administration). To allow for comparisons between Epochs 1, 2 and 4, AUC 0-τ will be standardized for the infusion intervals (3 or 4 weeks vs. 1 week) adjusted for the dose per weight.

Time frame: Epoch 1: 3 week IV interval: Weeks 10-13. Epoch 1: 4 week IV interval: Weeks 9-13. Epoch 2: Subcutaneous (SC) weeks 9-10. Epoch 4: SC weeks 17-18

Pharmacokinetics Parameters for Haemophilus Influenza B Antibody: Clearance (CL) for Immune Globulin Administered Intravenously (IGIV) and Apparent Clearance (CL/F) for Immune Globulin Administered Subcutaneously

Clearance (CL) or apparent clearance (CL/F) for IV and SC administration, respectively, will be determined by the formula: CL or CL/F = (Dose (mg/kg)) / (AUC 0- τ). (F= bioavailability)

Time frame: Epoch 1: 3 week IV interval: Weeks 10-13. Epoch 1: 4 week IV interval: Weeks 9-13. Epoch 2: Subcutaneous (SC) weeks 9-10. Epoch 4: SC weeks 17-18

Pharmacokinetics Parameters for Haemophilus Influenza B Antibody: Maximum Concentration (Cmax)

The maximum concentration (Cmax) following administration of study drug (either immune globulin administered intravenously (IGIV) or immune globulin administered subcutaneously (IGSC).

Time frame: Epoch 1: 3 week IV interval: Weeks 10-13. Epoch 1: 4 week IV interval: Weeks 9-13. Epoch 2: Subcutaneous (SC) weeks 9-10. Epoch 4: SC weeks 17-18

Pharmacokinetics Parameters for Haemophilus Influenza B Antibody: Time to Maximum Concentration (Tmax)

The minimum time (Tmax) to reach the maximum concentration (Cmax)

Time frame: Epoch 1: 3 week IV interval: Weeks 10-13. Epoch 1: 4 week IV interval: Weeks 9-13. Epoch 2: Subcutaneous (SC) weeks 9-10. Epoch 4: SC weeks 17-18

Pharmacokinetics Parameters for Haemophilus Influenza B Antibody: Minimum Concentration (Cmin)

The minimum concentration (Cmax) following administration of study drug (either immune globulin administered intravenously (IGIV) or immune globulin administered subcutaneously (IGSC).

Time frame: Epoch 1: 3 week IV interval: Weeks 10-13. Epoch 1: 4 week IV interval: Weeks 9-13. Epoch 2: Subcutaneous (SC) weeks 9-10. Epoch 4: SC weeks 17-18

Correction Factor to Determine the Individually Adapted Dose in Study 170904 Epoch 4 (Dose Adjustment Table)

There is a high degree of variability in catabolism of immunoglobulin G (IgG) between individuals. To address this, trough levels immediately prior to the 9th weekly infusion in Epoch 3 were measured. The ratio of the measured trough levels on subcutaneous (SC) (Epoch 3) and intravenous (IV) administration (Epoch1) were compared to the expected trough level determined in Epoch 2. This was used to determine the Individually Adapted Dose to be used in Epoch 4. This was an interim study analysis.

Time frame: 29 weeks

Number of Serious (SAEs) and Non-serious Adverse Events (AEs) (Including and Excluding Infections) Deemed Related to the Investigational Product Per Participant

Number of related SAEs and AEs divided by number of participants

Time frame: Up to 20 months per subject (throughout entire study)

Number of Serious (SAEs) and Non-serious Adverse Events (AEs) (Including and Excluding Infections) Deemed Related to the Investigational Product Per Infusion

Number of related SAEs and AEs divided by number of subjects and divided by number of infusions

Time frame: Up to 20 months per subject (throughout entire study)

Number of Serious (SAEs) and Non-serious Adverse Events (AEs) (Including and Excluding Infections) Regardless of Relationship to the Investigational Product Per Participant

Number of all SAEs and AEs divided by number of participants

Time frame: Up to 20 months per subject (throughout entire study)

Number of Serious (SAEs) and Non-serious Adverse Events (AEs) (Including and Excluding Infections) Regardless of Relationship to the Investigational Product Per Infusion

Number of all SAEs and AEs divided by number of infusions

Time frame: Up to 20 months per subject (throughout entire study)

Number of Adverse Events (AEs) (Including and Excluding Infections) That Begin During or Within 72 Hours of Completion of Infusion Per Participant

Number of AEs that begin during or within 72 hours of completion of infusion divided by number of participants

Time frame: Within 72 hours of completion of infusion

Number of Adverse Events (AEs) (Including and Excluding Infections) That Begin During or Within 72 Hours of Completion of Infusion Per Infusion

Number of AEs that begin during or within 72 hours of completion of infusion divided by the number of infusions

Time frame: Within 72 hours of completion of infusion

Number of Adverse Events (AEs) (Including and Excluding Infections) That Begin During or Within 24 Hours of Completion of Infusion Per Participant

Number of AEs that begin during or within 24 hours of completion of infusion divided by number of participants

Time frame: Within 24 hours of completion of infusion

Number of Adverse Events (AEs) (Including and Excluding Infections) That Begin During or Within 24 Hours of Completion of Infusion Per Infusion

Number of AEs that begin during or within 24 hours of completion of infusion divided by number of infusions

Time frame: Within 24 hours of completion of infusion

Number of Adverse Events (AEs) (Including and Excluding Infections) That Begin During or Within 1 Hour of Completion of Infusion Per Participant

Number of AEs that begin during or within 1 hour of completion of infusion divided by number of participants

Time frame: Within 1 hour of completion of infusion

Number of Adverse Events (AEs) (Including and Excluding Infections) That Begin During or Within 1 Hour of Completion of Infusion

Number of AEs that begin during or within 1 hour of completion of infusion divided by number of infusions

Time frame: Within 1 hour of completion of infusion

Causally Related and/or Temporally Associated Adverse Events (AEs) Per Infusion

The total number of all AEs (including and excluding infections) that begin during infusion or within 72 hours of completion of an infusion ("temporally associated") plus the total number of AEs (including and excluding infections) starting more than 72 hours following the completion of an infusion determined by the investigator to be at least possibly related to the study drug("related"), divided by the total number of infusions

Time frame: Within 72 hours post infusion for Temporally Associated AEs; End of each Study Epoch (Epoch 1, Epoch 2, Epoch 3, and Epoch 4) for Causally Related AEs

Percentage of Infusions Associated With One or More Local Non-serious Adverse Events (Non-SAEs)

The number of infusions associated with local non-SAEs divided by the total number of infusions.

Time frame: Up to 20 months (throughout entire study)

Percentage of Participants Reporting One or More Local Non-serious Adverse Events (Non-SAEs)

Time frame: Up to 20 months (throughout entire study)

Number of Infusions for Which the Infusion Rate Was Reduced and/or the Infusion Was Interrupted or Stopped Due to Tolerability Concerns or AEs

Time frame: Up to 20 months (throughout entire study)

Percentage of Participants for Whom the Infusion Rate Was Reduced and/or the Infusion Was Interrupted or Stopped Due to Tolerability Concerns or AEs

Time frame: Up to 20 months (throughout entire study)

Percentage of Infusions Tolerated With Intravenous or Subcutaneous Administration

An infusion will be deemed as tolerated unless one of the following occurs: 1. Any serious related AE(s) 2. Any non-serious local or systemic related AE(s) that prevent(s) completion of infusion 3. Any severe non-serious local or systemic related AE(s) that occur within 60 minutes of completion of the infusion

Time frame: Up to 20 months (throughout entire study)

Short Term Tolerance - Change in Systolic Blood Pressure: Immune Globulin Administered Intravenously (Human), 10% (IV 10%), Infusion 1

Vital signs measured pre-infusion, during infusion, and post-infusion of Immune globulin administered intravenously (Human), 10% (IV 10%) was graded by the investigator and the sponsor using a 4-grade scale: mild (grade 1), moderate (grade 2), severe (grade 3) or life-threatening (grade 4) according to the U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research; Guidance for Industry - Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, September2007. \*Note 5th Grade (grade 0) added to scale to reflect within normal range.