A Study to Evaluate IGSC 20% Biweekly Dosing in Treatment-Experienced Participants and Loading/Maintenance Dosing in Treatment-Naïve Participants With Primary Immunodeficiency

• ClinicalTrials.gov Identifier: NCT04566692
• Recruitment Status: Completed
• First Posted: September 28, 2020
• Results First Posted: August 7, 2023
• Last Update Posted: September 29, 2023
• Sponsor: Grifols Therapeutics LLC
• Information provided by (Responsible Party): Grifols Therapeutics LLC

Study Description

Brief Summary:

The purpose of the study is to determine whether biweekly (every 2 weeks) administration of Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (IGSC 20%) produces a steady-state area under the concentration versus time curve (AUC) of total Immunoglobulin G (IgG) that is non-inferior to that produced by weekly administration of IGSC 20% in treatment-experienced participants with primary immunodeficiency (PI).

Condition or disease	Intervention/treatment	Phase
Primary Immunodeficiency	Biological: IGSC 20%	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 33 participants
• Allocation: Non-Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Single sequence crossover design
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Single-Sequence, Open-label Study to Evaluate IGSC 20% Biweekly Dosing in Treatment-Experienced Subjects and Loading/Maintenance Dosing in Treatment-Naïve Subjects With Primary Immunodeficiency
• Actual Study Start Date: November 24, 2020
• Actual Primary Completion Date: July 18, 2022
• Actual Study Completion Date: July 25, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: IGSC 20%: Treatment-experienced Cohort; Participants first received 16 weekly doses of IGSC 20% using a subcutaneous (SC) infusion pump from Week 0 to Week 15. Participants entering study on intravenous immune globulin (IVIG), IGSC 20% was dosed at 1.37 times the equivalent weekly dose and participants entering on subcutaneous immunoglobulin (SCIG) received the same milligram/kilogram (mg/kg) equivalent weekly dose as given prior to study entry, without using a dose adjustment factor (DAF). Participants then received 9 biweekly doses of IGSC 20 % (i.e, IGSC 20% every 2 weeks) using an SC infusion pump, with the first IGSC 20% dose administered at Week 16 and the final dose given at Week 32.	Biological: IGSC 20%; SC infusion pump.; Other Name: Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified
Experimental: IGSC 20%: Treatment-naïve Cohort; Treatment-naïve participants received a loading dose of 150 mg/kg/day of IGSC 20% for 5 consecutive days (Week 0, Days 1 to 5) followed by weekly maintenance infusions of 150 mg/kg IGSC 20% starting Week 1 (Day 8) through Week 32. IGSC 20% infusion was administered using an SC infusion pump.	Biological: IGSC 20%; SC infusion pump.; Other Name: Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified

Outcome Measures

Primary Outcome Measures :

1. Treatment-experienced Cohort: AUC of IGSC 20% Administered Weekly Assessed as: Steady-State AUC of Total IgG Over a Regular Dosing Interval (τ) [ Time Frame: Predose and post dose at multiple time points after end of infusion up to Week 15 ]
   Area under the concentration vs. time curve at steady state over the dosing interval (from time 0 to τ), was calculated by a combination of linear and logarithmic trapezoidal methods. The linear trapezoidal method was used for all incremental trapezoids arising from increasing concentrations and the logarithmic trapezoidal method was used for those arising from decreasing concentrations. The dose interval τ was 7 days for participants on weekly IGSC 20% dosing. The data is reported for participants who received weekly dosing.
2. Treatment-experienced Cohort: AUC of IGSC 20% Administered Biweekly Assessed as Steady-State AUC of Total IgG Over a Biweekly Dosing Interval [ Time Frame: Predose and post dose at multiple timepoints after end of infusion up to Week 32 ]
   Area under the concentration vs. time curve at steady state over the dosing interval (from time 0 to τ), was calculated by a combination of linear and logarithmic trapezoidal methods. The linear trapezoidal method was used for all incremental trapezoids arising from increasing concentrations and the logarithmic trapezoidal method was used for those arising from decreasing concentrations. The dose interval τ was 14 days for participants on a biweekly IGSC 20% dosing. AUC (0-14 days) for the biweekly dosing were divided by 2 for comparison with AUC(0-7 days) for the weekly dosing prior to the statistical comparison. The data is reported for participants who received bi-weekly dosing.

Secondary Outcome Measures :

1. Treatment-experienced Cohort: Cmax of Total IgG at Steady State Following IGSC 20% Weekly and Biweekly Administration [ Time Frame: Predose and post dose at multiple timepoints after end of infusion up to Week 32 ]
   The observed maximum total IgG concentration following drug infusion obtained directly from the experimental data without interpolation. The data is reported for participants who received weekly and bi-weekly dosing
2. Treatment-experienced Cohort: Tmax of Total IgG at Steady State Given IGSC 20% Weekly and Biweekly [ Time Frame: Predose and post dose at multiple timepoints after end of infusion up to Week 32 ]
   The data is reported for participants who received weekly and bi-weekly dosing
3. Treatment-experienced Cohort: Steady-State Mean Trough Concentration of Total IgG Following IGSC 20% Weekly and Biweekly Administration [ Time Frame: Predose and post dose at multiple timepoints after end of infusion up to Week 32 ]
   Mean Trough was calculated as the average of the trough concentrations at Weeks 12, 14 Pre-infusion, and 16 for the Weekly Period; and at Weeks 28, 30 Pre-infusion, and 32 for the Biweekly Period. Mean Trough for a given period was not calculated if at least one trough measure was missing. The data is reported for participants who received weekly and bi-weekly dosing.
4. Treatment-experienced Cohort: Individual Trough Concentration of Total IgG Following IGSC 20% Weekly and Biweekly Administration [ Time Frame: Screening, IgG Trough 2, Weeks 0, 2, 4, 8, 12, 14 (pre-infusion), 15, 16, 20, 24, 28, 30 (pre-infusion) and 32 ]
   IgG Trough 2 = For treatment-experienced participants entering the study on IVIG or Immune Globulin Infusion 10% (Human) with Recombinant Human Hyaluronidase (HYQVIA), a second IgG trough level was obtained after screening; this was summarized in the visit designated as IgG Trough 2. Week 0 = Participants entering IVIG or HYQVIA, the first IGSC 20% dose was approximately 1 week post last IVIG/HYQVIA dose and so IgG at Week 0 for these participants represented a pre-dose value. For participants entering on all other forms of SCIG, the Week 0 value is true trough.
5. Treatment-naïve Cohorts: Individual Trough Concentration of Total IgG [ Time Frame: Screening, Weeks 0, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28 and 32 ]
   Week 0 = Participants entering IVIG or HYQVIA, the first IGSC 20% dose was approximately 1 week post last IVIG/HYQVIA dose and so IgG at Week 0 for these participants represented a pre-dose value. For participants entering on all other forms of SCIG, the Week 0 value is true trough.
6. Treatment-experienced and Treatment-naïve Cohorts: Number of Participants With Serious Bacterial Infection (SBI) [ Time Frame: From screening up to final follow up visit at Week 33 ]
7. Treatment-experienced and Treatment-naïve Cohorts: Rate of Events Per Participant Per Year With Infections of Any Kind as Determined by the Investigator [ Time Frame: From screening up to final follow up visit at Week 33 ]
   Rate of events per participant per year was calculated as the total number of events divided by the total duration of exposure in years across all participants. All infections of any kind included serious/nonserious including acute sinusitis, exacerbation of chronic sinusitis, acute otitis media, pneumonia, acute bronchitis, infectious diarrhea etc.) as determined by the investigator. The data is reported for participants in the treatment-naive cohort and the participants who received weekly and bi-weekly dosing.
8. Treatment-experienced and Treatment-naïve Cohorts: Rate of Events Per Participant Per Year With Validated Infections [ Time Frame: From screening up to final follow up visit at Week 33 ]
   Rate of events per participant per year was calculated as the total number of events divided by the total duration of exposure in years across all participants. A validated treatment-emergent infection was documented by positive radiograph, fever (>38°C oral or >39°C rectal), culture, or diagnostic testing for microorganisms e.g., bacterial, viral, fungal, or protozoal pathogens (e.g., rapid streptococcal antigen detection test). Treatment-emergent infection was defined as an infection with onset on or after first infusion start date/time. The data is reported for participants in the treatment-naive cohort and the participants who received weekly and bi-weekly dosing.
9. Treatment-experienced and Treatment-naïve Cohorts: Rate of Days Per Participant Per Year That Participants Were on Antibiotics [ Time Frame: From screening up to final follow up visit at Week 33 ]
   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. The data is reported for participants in the treatment-naive cohort and the participants who received weekly and bi-weekly dosing.
10. Treatment-experienced and Treatment-naïve Cohorts: Rate of Hospitalizations Per Participant Per Year Due to Infection [ Time Frame: From screening up to final follow up visit at Week 33 ]
    Rate of hospitalizations per participant per year was calculated as the total number of events divided by the total duration of exposure in years across all participants. Hospitalization was considered only in cases of hospital admission (including emergency room stay) for equal or more than 24 hours. The data is reported for participants in the treatment-naive cohort and the participants who received weekly and bi-weekly dosing.

Eligibility Criteria

• Ages Eligible for Study: 6 Years to 75 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

Inclusion Criteria only for Treatment-Experienced Participants

• Participants 18 years to 75 years (inclusive) at screening
• Participants with documented and confirmed pre-existing diagnosis of Primary Immunodeficiency (PI) with features of hypogammaglobulinemia requiring Immunoglobulin G (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 immunodeficiency syndrome).
• Participants have not had an Serious bacterial infection (SBI) or been hospitalized for infection of any etiology (example, viral, fungal, parasitic) within the last 3 months prior to screening or during screening.
• Participants currently receiving IgG replacement therapy for ≥3 months via Intravenous (IV) or SC infusion. Participants receiving IVIG prior to study must receive a dosage of at least 200 mg/kg per infusion.
• Participants whose screening IgG trough levels must be ≥500 milligram per deciliter (mg/dL).
• Participants have signed an informed consent form.

Inclusion Criteria only for Treatment-Naïve Participants

• Participants 6 years to 75 years (inclusive) at screening.
• Participants with documented and confirmed diagnosis of PI with features of hypogammaglobulinemia requiring 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 immunodeficiency syndrome).
• Participants have never received IgG replacement treatment (ie, no prior immune globulin replacement therapy).
• Participants whose screening IgG level must be ≤400 mg/dL.
• Participants do not have an SBI nor requires hospitalization for infection of any etiology (example, viral, fungal, parasitic) during screening or at baseline.
• Participants have signed an informed consent.

Exclusion Criteria:

• Participants with clinical evidence of any significant acute or chronic disease that, in the opinion of the investigator, may interfere with successful completion of the trial or place the participant at undue medical risk.
• Participants have had a known serious adverse reaction (AR) to immunoglobulin or any anaphylactic reaction to blood or any blood-derived product.
• Participants who have a 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.
• Participants have known isolated IgG subclass deficiency; isolated specific antibody deficiency (SAD) or selective IgG deficiency; or transient hypogammaglobulinemia of infancy.
• Participants have known Selective Immunoglobulin A (IgA) Deficiency (with or without antibodies to IgA).
• Participants have significant proteinuria (≥3+ or known urinary protein loss >1 gram g/24 hours or nephrotic syndrome), has acute renal failure, is on dialysis, and/or has severe renal impairment on Screening laboratory testing (blood urea nitrogen [BUN] or creatinine more than 2.5 times the upper limit of normal [ULN]).
• Participants have screening values of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels exceeding more than 2.5 times the ULN for the expected normal range for the testing laboratory.
• Participants have hemoglobin <9 gram per deciliter (g/dL) at screening.
• Participants have a history (either 1 episode within the year prior to the Screening Visit or 2 previous episodes over a lifetime) of or current diagnosis of thromboembolism (example, myocardial infarction, cerebrovascular accident or transient ischemic attack) or deep venous thrombosis.
• Participants are currently receiving anti-coagulation therapy which would make SC administration inadvisable (vitamin K antagonists, nonvitamin K antagonist oral anticoagulants [example, dabigatran etexilate targeting Factor IIa, rivaroxaban, edoxaban, and apixaban targeting Factor Xa], and parenteral anticoagulants [example, fondaparinux]).
• Participants currently have a known hyperviscosity syndrome.
• Participants have 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 1000/microliter (μL) [1.0 x10^9/L]), or human immunodeficiency virus infection/acquired immune deficiency syndrome.
• Participants have a known previous infection with or clinical signs and symptoms consistent with current hepatitis B virus or hepatitis C virus infection.
• Participants are 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 participant. Inhaled or topical corticosteroids are allowed.
• Participants (if <18 years of age) have non-controlled arterial hypertension at a level of greater than or equal to the 90th percentile blood pressure (either systolic or diastolic) for their age and height or the adult participant has non-controlled arterial hypertension (systolic blood pressure [SBP] >160 millimeter per mercury (mmHg) and/or diastolic blood pressure [DBP] >100 mmHg).

Contacts and Locations

Locations

United States, Alabama

Clinical Research Center of Alabama

Birmingham, Alabama, United States, 35209

United States, Arizona

Research Solutions of Arizona, PC

Litchfield Park, Arizona, United States, 85340

United States, Florida

Allergy Associates of The Palm Beaches

North Palm Beach, Florida, United States, 33408

United States, Georgia

Allergy & Asthma Clinics of Georgia, P.C.

Albany, Georgia, United States, 31707

United States, Maryland

Institute for Asthma and Allergy

Chevy Chase, Maryland, United States, 20815

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63141

United States, Ohio

Optimed Research LTD

Columbus, Ohio, United States, 43235

United States, Oklahoma

Allergy, Asthma and Clinical Research Center

Oklahoma City, Oklahoma, United States, 73120

Oklahoma Institute of Allergy and Asthma Clinical Research

Oklahoma City, Oklahoma, United States, 73131

Vital Prospect Clinical Research Institute

Tulsa, Oklahoma, United States, 74136

United States, Pennsylvania

Allergy and Clinical Immunology Associates

Pittsburgh, Pennsylvania, United States, 15241

United States, Texas

AARA Research Center

Dallas, Texas, United States, 75231

Sponsors and Collaborators

Grifols Therapeutics LLC

  Study Documents (Full-Text)

Documents provided by Grifols Therapeutics LLC:

Study Protocol  [PDF] March 17, 2020

Statistical Analysis Plan  [PDF] February 2, 2022

More Information

• Responsible Party: Grifols Therapeutics LLC
• ClinicalTrials.gov Identifier: NCT04566692
• Other Study ID Numbers: GC1906
• First Posted: September 28, 2020
• Results First Posted: August 7, 2023
• Last Update Posted: September 29, 2023
• Last Verified: September 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Grifols Therapeutics LLC:

Immunologic Deficiency Syndromes; Immune System Diseases; Immunoglobulins

Additional relevant MeSH terms:

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