Primary Immunodeficiency
Conditions
Brief summary
Approximately 60 subjects will be enrolled in order to have approximately 20 adult subjects and 20 pediatric subjects treated with subcutaneously administered Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (IGSC 20%) who complete the entire study. This study will include 3 study stages: Screening/Previous Regimen Phase, IGSC 20% Treatment Stage 1 (13 IGSC 20% weekly doses), and IGSC 20% Treatment Stage 2 (39 IGSC 20% weekly doses). A total of 52 doses of IGSC 20% will be administered with a final follow-up visit 1 week after the last dose at Week 53. Subjects/caregivers will be trained on self-administration of IGSC 20% by the clinical site personnel.
Detailed description
This is a prospective, multi-center, open-label, single-arm, efficacy, PK, safety and tolerability study of IGSC 20% in subjects with PI. Approximately 60 subjects will be enrolled in order to have approximately 20 adult subjects and 20 pediatric subjects treated with subcutaneously administered IGSC 20% who complete the entire study. This study will include 3 study stages: Screening/Previous Regimen Phase, IGSC 20% Treatment Stage 1 (13 IGSC 20% weekly doses), and IGSC 20% Treatment Stage 2 (39 IGSC 20% weekly doses). Previous Regimen Phase: Subjects will be infused with their current ongoing (previous regimen) intravenous immune globulin/subcutaneous immune globulin (IVIG/SCIG) regimen (pIV/pSC) in the clinic to obtain 2 trough immunoglobulin G (IgG) levels (obtained prior to each pIV/pSC infusion) on each subject's previous regimen. 20% IGSC Treatment Stage 1: The first dose of IGSC 20% will be administered at the clinical site immediately after Baseline assessments are complete (SC#1). All subjects will receive 13 IGSC 20% infusions at weekly intervals. IgG trough blood levels will be measured at all (except SC#3) study visits All other doses of IGSC 20% may be infused at home (once properly trained) or in the clinic. The Treatment Stage 1 dose will continue into IGSC 20% Treatment Stage 2. IGSC 20% Treatment Stage 2: The IGSC 20% dose (mg/kg) will remain constant with no dose adjustment permitted in this phase, unless it is absolutely medically necessary. While all subjects will have a SC#17 clinic visit and standard assessments, serial pharmacokinetics (PK) sampling will only be performed in a subset of adult subjects:
Interventions
BIOLOGICALIGSC 20%
Weekly administration of IGSC 20% via intravenous infusion
Sponsors
Grifols Therapeutics LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Pre-existing diagnosis of PI with features of hypogammaglobulinemia requiring IgG replacement therapy * No serious bacterial infection within the 3 months prior to Screening and has no serious bacterial infections (SBIs) up to the time of the Baseline Visit * Currently on IgG replacement therapy (stable regimen \[dose and dosing interval\] via IV or SC infusion) for ≥ 3 consecutive months at a dosage of at least 200 mg/kg per infusion * Documented (within previous 3 months) of an IgG trough level of ≥ 500 mg/dL on current IgG replacement therapy regimen * Screening/pre-Baseline trough IgG levels must be ≥ 500 mg/dL.
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 is on dialysis * Known previous infection with or clinical signs and symptoms consistent with current hepatitis B virus or hepatitis C virus infection * History of (year prior to Screening or 2 episodes in lifetime) or current diagnosis of deep venous thrombosis or thromboembolism (e.g., 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 * HIV positive by nucleic acid amplification technology based on a Screening blood sample * Uncontrolled arterial hypertension (adult subjects: systolic blood pressure \> 160 mmHg and/or diastolic blood pressure \> 100 mmHg) * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Serious Bacterial Infection (SBI) Per Participant Per Year | IGSC 20% Treatment Stage 1: Week 1 to 13; IGSC 20% Treatment Stage 2: Week 14 to 53; IGSC 20% Overall: Week 1 to 53 | The rate of SBI events per participant per year during IGSC 20% treatment was calculated as the total number of SBI events divided by the total duration of exposure in years across all participants. The 2-sided 98% confidence interval (CI) was determined from a generalized linear model for poisson regression for the log-transformed number of events with log-transformed duration of exposure in years as an offset variable. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Trough Total IgG Concentration | Previous Regimen Phase: 2 timepoints pre-dose of pIV or pSC between Screening and Baseline (up to 8 weeks). IGSC 20% Phase: Pre-dose of IGSC 20% at Baseline (Week 1), Weeks 2, 5, 9, 13, 17, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Week 53 | Mean trough total IgG concentration during the previous regimen phase was calculated as the average of the trough concentrations at the previous IVIG (pIV)#1 and pIV#2 visits for participants entering the study on a previous IVIG regimen, or at the previous subcutaneous immune globulin (SCIG) (pSC)#1 and baseline/SC#1 visits for participants entering the study on a previous SCIG regimen. Mean trough total IgG concentration during the IGSC 20% phase was calculated as the average of all steady state trough concentrations measured during the IGSC 20% treatment stage 2 at the visits corresponding to Weeks 17, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 53. |
| Rate of Infection of Any Kind Per Participant Per Year | IGSC 20% Treatment Stage 1: Week 1 to 13; IGSC 20% Treatment Stage 2: Week 14 to 53; IGSC 20% Overall: Week 1 to 53 | The total number of infections of any kind (serious/non-serious including acute sinusitis, exacerbation of chronic sinusitis, acute otitis media, pneumonia, acute bronchitis, infectious diarrhea, etc.) as determined by the investigator were evaluated. The rate of infection events per participant per year during IGSC 20% treatment was calculated as the total number of infection events divided by the total duration of exposure in years across all participants. The 2-sided 95% CI was determined from a generalized linear model for poisson regression for the log-transformed number of events with log-transformed duration of exposure in years as an offset variable. |
| Rate of Days on Antibiotics Per Participants Per Year | IGSC 20% Treatment Stage 1: Week 1 to 13; IGSC 20% Treatment Stage 2: Week 14 to 53; IGSC 20% Overall: Week 1 to 53 | The rate of days on antibiotics per participants per year during IGSC 20% treatment was calculated as the total number of days on antibiotic divided by the total duration of exposure in years across all participants. The 2-sided 95% CI was determined from a generalized linear model for poisson regression for the log transformed number of days with log-transformed duration of exposure in years as an offset variable. |
| Rate of Hospitalization Due to Infection Per Participants Per Year | IGSC 20% Treatment Stage 1: Week 1 to 13; IGSC 20% Treatment Stage 2: Week 14 to 53; IGSC 20% Overall: Week 1 to 53 | The rate of hospitalization due to infection events per participant per year during IGSC 20% treatment was calculated as the total number of hospitalization due to infection events divided by the total duration of exposure in years across all participants. The 2-sided 95% CI was determined from a generalized linear model for poisson regression for the log-transformed number of events with log-transformed duration of exposure in years as an offset variable. |
| Rate of Days of Work/School/Daily Activities Missed Per Participants Per Year Due to Infections and Related Treatment | IGSC 20% Treatment Stage 1: Week 1 to 13; IGSC 20% Treatment Stage 2: Week 14 to 53; IGSC 20% Overall: Week 1 to 53 | The rate of days of work, school or daily activities missed per participant per year during IGSC 20% treatment was calculated as the total number of days of work/school/daily activities missed divided by the total duration of exposure in years across all participants. The 2-sided 95% CI was determined from a generalized linear model for poisson regression for the log-transformed number of days with log transformed duration of exposure in years as an offset variable. |
Countries
Australia, Czechia, France, Germany, Hungary, Poland, Spain, Sweden, United Kingdom
Participant flow
Recruitment details
Participants with primary immunodeficiency (PI) requiring IgG replacement were enrolled. Study has 3 stages: Screening/Previous Regimen Phase, Treatment Stage 1 and 2. Total 62 participants entered Previous Regimen Phase, of which 61 entered in Treatment Stage 1 to receive IGSC 20%. Study was conducted in 8 countries from June 2016 to May 2019.
Pre-assignment details
Participants had no SBI within last 3 months prior to screening and were on immunoglobulin G (IgG) replacement therapy (stable regimen via intravenous \[IV\] or subcutaneous \[SC\] infusion) for ≥3 consecutive months prior to screening. Participants receiving IVIG prior to study entry must have received a dosage of ≥200 mg/kg per infusion.
Participants by arm
| Arm | Count |
|---|---|
| IGSC 20% Following the previous regimen phase (screening), participants were enrolled to receive 13 IGSC 20% infusions at weekly intervals from baseline (Week 1) up to Week 13 in treatment stage 1. Participants were infused with IGSC 20% at a 1:1 dose-equivalent regimen from their previous regimen (or a minimum IGSC 20% dose of 100 mg/kg/week if the derived 1:1 dose from the previous regimen was lower) and followed by 39 IGSC 20% infusions at weekly intervals from Week 14 up to Week 52 in treatment stage 2. Dose adjustments were permitted per the study protocol and at the Investigator's discretion in the treatment stage 1. However, dose remained constant in treatment stage 2 unless it was absolutely medically necessary to change the dose, and such change required prior consultation with the Sponsor's Medical Monitor. A final follow-up visit occurred at Week 53. | 61 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Treatment Stage 1 | Adverse Event | 1 |
| Treatment Stage 2 | Adverse Event | 3 |
| Treatment Stage 2 | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | IGSC 20% |
|---|---|
| Age, Continuous | 27.3 years STANDARD_DEVIATION 19.97 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 49 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 Participants |
| Race/Ethnicity, Customized Unknown | 2 Participants |
| Race/Ethnicity, Customized White | 57 Participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 42 Participants |
| Subject Entry Status Entered on intravenous immune globulin (IVIG) | 40 Participants |
| Subject Entry Status Entered on subcutaneous immune globulin (SCIG) | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 61 |
| other Total, other adverse events | 49 / 61 |
| serious Total, serious adverse events | 7 / 61 |
Outcome results
Primary
Rate of Serious Bacterial Infection (SBI) Per Participant Per Year
The rate of SBI events per participant per year during IGSC 20% treatment was calculated as the total number of SBI events divided by the total duration of exposure in years across all participants. The 2-sided 98% confidence interval (CI) was determined from a generalized linear model for poisson regression for the log-transformed number of events with log-transformed duration of exposure in years as an offset variable.
Time frame: IGSC 20% Treatment Stage 1: Week 1 to 13; IGSC 20% Treatment Stage 2: Week 14 to 53; IGSC 20% Overall: Week 1 to 53
Population: Analysis was performed on the efficacy evaluable population which included all participants who received at least 1 dose of IGSC 20%.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IGSC 20% Treatment Stage 1 | Rate of Serious Bacterial Infection (SBI) Per Participant Per Year | 0 Rate of events per participant per year |
| IGSC 20% Treatment Stage 2 | Rate of Serious Bacterial Infection (SBI) Per Participant Per Year | 0.023 Rate of events per participant per year |
| IGSC 20% Overall | Rate of Serious Bacterial Infection (SBI) Per Participant Per Year | 0.017 Rate of events per participant per year |
Secondary
Mean Trough Total IgG Concentration
Mean trough total IgG concentration during the previous regimen phase was calculated as the average of the trough concentrations at the previous IVIG (pIV)#1 and pIV#2 visits for participants entering the study on a previous IVIG regimen, or at the previous subcutaneous immune globulin (SCIG) (pSC)#1 and baseline/SC#1 visits for participants entering the study on a previous SCIG regimen. Mean trough total IgG concentration during the IGSC 20% phase was calculated as the average of all steady state trough concentrations measured during the IGSC 20% treatment stage 2 at the visits corresponding to Weeks 17, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52 and 53.
Time frame: Previous Regimen Phase: 2 timepoints pre-dose of pIV or pSC between Screening and Baseline (up to 8 weeks). IGSC 20% Phase: Pre-dose of IGSC 20% at Baseline (Week 1), Weeks 2, 5, 9, 13, 17, 18, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Week 53
Population: Analysis was performed on the IgG population which consisted of all participants who received any amount of IGSC 20% and had total IgG concentration data to facilitate the comparison of mean trough IgG concentration during the IGSC 20% phase versus the pre-treatment phase.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IGSC 20% Treatment Stage 1 | Mean Trough Total IgG Concentration | 947.64 milligram per deciliter (mg/dL) | Standard Deviation 150.262 |
| IGSC 20% Treatment Stage 2 | Mean Trough Total IgG Concentration | 891.37 milligram per deciliter (mg/dL) | Standard Deviation 165.943 |
Secondary
Rate of Days of Work/School/Daily Activities Missed Per Participants Per Year Due to Infections and Related Treatment
The rate of days of work, school or daily activities missed per participant per year during IGSC 20% treatment was calculated as the total number of days of work/school/daily activities missed divided by the total duration of exposure in years across all participants. The 2-sided 95% CI was determined from a generalized linear model for poisson regression for the log-transformed number of days with log transformed duration of exposure in years as an offset variable.
Time frame: IGSC 20% Treatment Stage 1: Week 1 to 13; IGSC 20% Treatment Stage 2: Week 14 to 53; IGSC 20% Overall: Week 1 to 53
Population: Analysis was performed on the efficacy evaluable population which included all participants who received at least 1 dose of IGSC 20%.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IGSC 20% Treatment Stage 1 | Rate of Days of Work/School/Daily Activities Missed Per Participants Per Year Due to Infections and Related Treatment | 4.118 Rate of days missed per person per year |
| IGSC 20% Treatment Stage 2 | Rate of Days of Work/School/Daily Activities Missed Per Participants Per Year Due to Infections and Related Treatment | 5.283 Rate of days missed per person per year |
| IGSC 20% Overall | Rate of Days of Work/School/Daily Activities Missed Per Participants Per Year Due to Infections and Related Treatment | 4.983 Rate of days missed per person per year |
Secondary
Rate of Days on Antibiotics Per Participants Per Year
The rate of days on antibiotics per participants per year during IGSC 20% treatment was calculated as the total number of days on antibiotic divided by the total duration of exposure in years across all participants. The 2-sided 95% CI was determined from a generalized linear model for poisson regression for the log transformed number of days with log-transformed duration of exposure in years as an offset variable.
Time frame: IGSC 20% Treatment Stage 1: Week 1 to 13; IGSC 20% Treatment Stage 2: Week 14 to 53; IGSC 20% Overall: Week 1 to 53
Population: Analysis was performed on the efficacy evaluable population which included all participants who received at least 1 dose of IGSC 20%.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IGSC 20% Treatment Stage 1 | Rate of Days on Antibiotics Per Participants Per Year | Prophylactic Antibiotic | 43.240 Rate of days per participant per year |
| IGSC 20% Treatment Stage 1 | Rate of Days on Antibiotics Per Participants Per Year | Therapeutic Antibiotics | 13.085 Rate of days per participant per year |
| IGSC 20% Treatment Stage 2 | Rate of Days on Antibiotics Per Participants Per Year | Prophylactic Antibiotic | 44.846 Rate of days per participant per year |
| IGSC 20% Treatment Stage 2 | Rate of Days on Antibiotics Per Participants Per Year | Therapeutic Antibiotics | 7.451 Rate of days per participant per year |
| IGSC 20% Overall | Rate of Days on Antibiotics Per Participants Per Year | Prophylactic Antibiotic | 44.432 Rate of days per participant per year |
| IGSC 20% Overall | Rate of Days on Antibiotics Per Participants Per Year | Therapeutic Antibiotics | 8.904 Rate of days per participant per year |
Secondary
Rate of Hospitalization Due to Infection Per Participants Per Year
The rate of hospitalization due to infection events per participant per year during IGSC 20% treatment was calculated as the total number of hospitalization due to infection events divided by the total duration of exposure in years across all participants. The 2-sided 95% CI was determined from a generalized linear model for poisson regression for the log-transformed number of events with log-transformed duration of exposure in years as an offset variable.
Time frame: IGSC 20% Treatment Stage 1: Week 1 to 13; IGSC 20% Treatment Stage 2: Week 14 to 53; IGSC 20% Overall: Week 1 to 53
Population: Analysis was performed on the efficacy evaluable population which included all participants who received at least 1 dose of IGSC 20%.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IGSC 20% Treatment Stage 1 | Rate of Hospitalization Due to Infection Per Participants Per Year | 0 Rate of events per person per year |
| IGSC 20% Treatment Stage 2 | Rate of Hospitalization Due to Infection Per Participants Per Year | 0.023 Rate of events per person per year |
| IGSC 20% Overall | Rate of Hospitalization Due to Infection Per Participants Per Year | 0.017 Rate of events per person per year |
Secondary
Rate of Infection of Any Kind Per Participant Per Year
The total number of infections of any kind (serious/non-serious including acute sinusitis, exacerbation of chronic sinusitis, acute otitis media, pneumonia, acute bronchitis, infectious diarrhea, etc.) as determined by the investigator were evaluated. The rate of infection events per participant per year during IGSC 20% treatment was calculated as the total number of infection events divided by the total duration of exposure in years across all participants. The 2-sided 95% CI was determined from a generalized linear model for poisson regression for the log-transformed number of events with log-transformed duration of exposure in years as an offset variable.
Time frame: IGSC 20% Treatment Stage 1: Week 1 to 13; IGSC 20% Treatment Stage 2: Week 14 to 53; IGSC 20% Overall: Week 1 to 53
Population: Analysis was performed on the efficacy evaluable population which included all participants who received at least 1 dose of IGSC 20%.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IGSC 20% Treatment Stage 1 | Rate of Infection of Any Kind Per Participant Per Year | 2.524 Rate of events per participant per year |
| IGSC 20% Treatment Stage 2 | Rate of Infection of Any Kind Per Participant Per Year | 2.353 Rate of events per participant per year |
| IGSC 20% Overall | Rate of Infection of Any Kind Per Participant Per Year | 2.397 Rate of events per participant per year |