Common Variable Immunodeficiency, Hyperimmunoglobulin M Syndrome, Primary Immune Deficiency Disorders, X-linked Agammaglobulinaemia
Conditions
Keywords
Primary Immune Deficiency Disorders, Common Variable Immunodeficiency, X-linked agammaglobulinaemia, Hyper-IgM Syndrome, Subcutaneous, Immunoglobulins
Brief summary
The main objective of the study is to determine the pharmacokinetics profile of Subgam-VF. The secondary objectives are to assess the safety of Subgam-VF and refine the dose adjustment coefficient for Subgam-VF needed for subjects switching from prior intravenous immunoglobulin (IGIV) therapy.
Detailed description
This will be a Phase III, multicenter, open-label, non-randomized study. Following a screening period, eligible subjects will commence weekly Subgam-VF treatment; this is a 16% subcutaneous IgG product. Subjects will receive Subgam-VF for 26 weeks during which time safety will be assessed. After Week 21, PK sampling will commence. Follow-up visit (one week after the last Subgam-VF infusion, Week 27). All AEs will be monitored up to 28 days after the last Subgam-VF infusion by telephone contact (Week 30). Subgam-VF will be administered subcutaneously using infusion pumps. Subjects will be given diaries to record adverse event data as well as any infusions administered at home. In addition there will be a telephone follow up by an appropriately qualified site staff member on day 3 after each site administered and home administered infusion to check for any adverse reactions including infusion site reactions and remind subjects to document these in their subject study diary.
Interventions
BIOLOGICALSubgam
Subgam-VF dose will be given as 1.37 of the established IGIV dose (expressed in mg/kg/week) for 26 weeks (26 infusions) beginning one week after the last IGIV infusion. Dose of Subgam-VF will then be adjusted based on the ratio of the Immunoglobulin G (IgG) average concentration achieved with Subgam-VF compared to IGIV.
Sponsors
Bio Products Laboratory
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Aged between 2 and 75 years (at time of initial consent). 2. Body Mass Index (BMI) \< 46 for adults (aged 16 years & older), & BMI \< 28 for children. 3. Diagnosed with primary immunodeficiency disease e.g. common variable immunodeficiency, X-linked & autosomal forms of agammaglobulinaemia, hyper-IgM syndrome, Wiskott-Aldrich syndrome. 4. Currently receiving a licensed (or investigational stage III, IIIb) IGIV or SCIG and 1. IGIV dose is between 300 and 800 mg/kg/month. SCIG dose is between 110 & 300 mg/kg/week; 2. Dose is stable for at least the past three months (i.e. consistent mg/kg +/- 5%); 3. The infusion interval is every 21 or 28 days for IGIV & seven days for SCIG; 4. Has a documented trough level of ≥ 6 g/L (600 mg/dL) on current IgG therapy. If not available can be obtained at the screening visit, Visit 1 (Week 0). 5. Female subjects who are (or become) sexually active must practice contraception by using a method of proven reliability for the duration of the study. 6. Females of child-bearing potential, (defined from the onset of menstruation to one year post menopause), must have a negative result on a urine HCG-based pregnancy test. 7. Willing to comply with all aspects of the protocol, including blood sampling, for the duration of the study. 8. Signed an informed consent form. In the case of subjects under the legal age the parent/guardian will sign an informed consent form & where appropriate the subject will sign an assent form.
Exclusion criteria
1. Has a history of any severe anaphylactic reaction to blood or any blood-derived product. 2. Has selective IgA deficiency or has a history of antibodies to IgA. 3. Has clinically significant impairment of cellular or innate immunity at the discretion of the Investigator 4. Has evidence of an active infection at the time of enrolment (i.e. on day of first infusion). Subjects who are asymptomatic but have not completed their course of antibiotics are eligible. 5. Has previously completed or withdrawn from this study. 6. Is currently receiving, or has received, any investigational agent within the prior three months, unless it is an investigational stage III, IIIb IGIV or SCIG. 7. Is pregnant (confirmed by a positive result on an HCG-based pregnancy test) or is nursing. 8. Is positive for any of the following at screening: • Serological test for HIV 1&2, HCV, or HBsAg 9. Has levels at screening greater than 2.5 times the upper limit of normal as defined at the central laboratory of any of the following: * Alanine transaminase (ALT) * Aspartate transaminase (AST) 10. Has severe renal impairment (defined as serum creatinine greater than two times the upper limit of normal or BUN greater than two times the upper limit of normal for the range of the laboratory doing the analysis); the subject is on dialysis; or has a history of acute renal failure. 11. Is known to abuse alcohol, opiates, psychotropic agents, or other chemicals or drugs, or has done so within the past 12 months. 12. Has a history of DVT, or thrombotic complications of IgG therapy, or a prior diagnosis of thrombophilia. 13. Suffers from any acute or chronic medical condition, (e.g. renal disease or predisposing conditions for renal disease, coronary artery disease, or protein losing state, proteinuria) that the Investigator feels may interfere with the conduct of the study. 14. Has an acquired medical condition, such as chronic lymphocytic leukemia, lymphoma, multiple myeloma, chronic or recurrent neutropenia (ANC \< 1 x 109/L). 15. Is receiving the following medication: * Steroids (long-term daily, \> 0.15 mg of prednisone equivalent/kg/day). Requirement for short or intermittent courses of \> 0.15mg/kg/day would not exclude a subject. * Immunosuppressive drugs * Immunomodulatory drugs 16. If ≥ 18 years of age, has non-controlled arterial hypertension (systolic blood pressure \> 160 mmHg &/or diastolic blood pressure \> 100 mmHg). For younger subjects refer to current guidelines for diagnosis of blood pressure1. 17. Has anemia (hemoglobin \< 10 g/dL) at screening. 18. Has severe dermatitis that would preclude sites for safe product administration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Data (Derived From Absolute Concentration) Were Pooled With Historical Data and a Treatment Variable Defined (Subgam-VF or Gammaplex 5% IGIV). Outcome Measure Defined as Log Transformed sAUC0-t Standardized to One Week. | 1 week | Log transformed sAUC0-t, (AUC0-t standardized to one week) were analysed using a multiple linear regression model fitted including treatment, allowing for variability between treatment groups. The mean difference (Subgam-VF or Gammaplex IGIV 5%) between treatments with 90% Confidence Interval (CI) were back transformed to give an estimate of the ratio (Subgam-VF/ Gammaplex 5% IGIV) of sAUC(0-t). Data was collected at the following timepoints after week 21 of the clinical trial over a period of 1 week: Pre-dose on Day 0 and post-dose at days 1, 2, 3, 5 and 7. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced AEs Based on Treatment-emergent AEs (TEAEs) | 30 weeks | TEAEs defined as those events with onset date between the first infusion date and 28 days after the last infusion. |
| Dose Refinement in Switching From Gammaplex 5% IGIV to Subgam-VF | Week 26 | The initial weekly dose of Subgam-VF administered was calculated by taking the average weekly equivalent of the subject's IGIV dose, divided by the average dosing interval in weeks (i.e. 3 or 4), multiplied by 1.37, a dose adjustment coefficient based on other licensed subcutaneous IgG products. If the subject was already receiving a weekly SCIG IgG there will be no dose adjustment. A refined dose adjustment was estimated as 1.37/the ratio (Subgam-VF/ Gammaplex 5% IGIV) of geometric means for sAUC0-t and presented with 90% CI. |
| Number of Infusion Site Reactions | 30 weeks | Infusion site reactions are defined as those events with onset date between the first infusion date and 28 days after the last infusion. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Population PK Model for IgG in PID Patients for Alternative Dosing Schedules. | 30 months | Develop a population pharmacokinetic (PK) model for IgG in PID patients following IV (Gammaplex 5%) or SC (Subgam-VF) administration; * Conduct a formal covariate analysis to assess the impact of patient demographics, and disease-related factors on the PK of IgG following IV or SC administration and to identify those patient covariates which may be utilized in or require dose adjustment; * Use the final population PK model to simulate serum IgG concentration-time profiles in a population of PID patients in order to: * Assess switching from various IgG IV and SC dosing regimens; and * Derive the weight-adjusted dose increment required to achieve a specified difference in serum IgG trough levels when Subgam-VF is administered either weekly or biweekly |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Subgam-VF Subgam-VF is a 16% IgG and will be administered weekly, by subcutaneous infusion over a period of 26 weeks. | 38 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Precautionary measure | 1 |
| Overall Study | Withdrawal by Subject | 3 |
| Overall Study | withdrew consent due to AEs | 1 |
Baseline characteristics
| Characteristic | Subgam-VF |
|---|---|
| Age, Customized < 16 years | 13 Participants |
| Age, Customized >=16 years | 25 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 35 Participants |
| Region of Enrollment United States | 38 Participants |
| Sex: Female, Male Female | 22 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 38 |
| other Total, other adverse events | 36 / 38 |
| serious Total, serious adverse events | 0 / 38 |
Outcome results
Primary
Data (Derived From Absolute Concentration) Were Pooled With Historical Data and a Treatment Variable Defined (Subgam-VF or Gammaplex 5% IGIV). Outcome Measure Defined as Log Transformed sAUC0-t Standardized to One Week.
Log transformed sAUC0-t, (AUC0-t standardized to one week) were analysed using a multiple linear regression model fitted including treatment, allowing for variability between treatment groups. The mean difference (Subgam-VF or Gammaplex IGIV 5%) between treatments with 90% Confidence Interval (CI) were back transformed to give an estimate of the ratio (Subgam-VF/ Gammaplex 5% IGIV) of sAUC(0-t). Data was collected at the following timepoints after week 21 of the clinical trial over a period of 1 week: Pre-dose on Day 0 and post-dose at days 1, 2, 3, 5 and 7.
Time frame: 1 week
Population: Subgam PK Population was defined as all subjects in the ITT population who had a pre-dose sample at steady state and at least 4 post-dose samples at steady state, 1 of which should have been the Day 7 PK sample.~Population included 50 Subjects from GMX01 (NCT00278954), 25 Subjects from GMX04 (NCT01289847) and 38 Subjects from SCIG03.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Subgam-VF and Gammaplex 5% | Data (Derived From Absolute Concentration) Were Pooled With Historical Data and a Treatment Variable Defined (Subgam-VF or Gammaplex 5% IGIV). Outcome Measure Defined as Log Transformed sAUC0-t Standardized to One Week. | 0.98 Ratio |
Secondary
Dose Refinement in Switching From Gammaplex 5% IGIV to Subgam-VF
The initial weekly dose of Subgam-VF administered was calculated by taking the average weekly equivalent of the subject's IGIV dose, divided by the average dosing interval in weeks (i.e. 3 or 4), multiplied by 1.37, a dose adjustment coefficient based on other licensed subcutaneous IgG products. If the subject was already receiving a weekly SCIG IgG there will be no dose adjustment. A refined dose adjustment was estimated as 1.37/the ratio (Subgam-VF/ Gammaplex 5% IGIV) of geometric means for sAUC0-t and presented with 90% CI.
Time frame: Week 26
Population: The PK Dose-Adjustment population included all those in the Subgam PK population who had previous treatment with IGIV and those in the Gammaplex 5% PK population. This population was analysed to estimate a refined dose adjustment factor.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Subgam-VF and Gammaplex 5% | Dose Refinement in Switching From Gammaplex 5% IGIV to Subgam-VF | 1.33 Ratio |
Secondary
Number of Infusion Site Reactions
Infusion site reactions are defined as those events with onset date between the first infusion date and 28 days after the last infusion.
Time frame: 30 weeks
Population: Total number of participants was 38
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Subgam-VF and Gammaplex 5% | Number of Infusion Site Reactions | 447 infusion site reactions |
Secondary
Number of Participants Who Experienced AEs Based on Treatment-emergent AEs (TEAEs)
TEAEs defined as those events with onset date between the first infusion date and 28 days after the last infusion.
Time frame: 30 weeks
Population: The intent-to-treat population included all subjects who received at least 1 infusion of Subgam-VF.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Subgam-VF and Gammaplex 5% | Number of Participants Who Experienced AEs Based on Treatment-emergent AEs (TEAEs) | Any TEAE | 36 Participants |
| Subgam-VF and Gammaplex 5% | Number of Participants Who Experienced AEs Based on Treatment-emergent AEs (TEAEs) | No TEAE | 2 Participants |
| Subgam-VF and Gammaplex 5% | Number of Participants Who Experienced AEs Based on Treatment-emergent AEs (TEAEs) | Discontinued because of TEAEs | 1 Participants |
| Subgam-VF and Gammaplex 5% | Number of Participants Who Experienced AEs Based on Treatment-emergent AEs (TEAEs) | Product Related TEAE | 15 Participants |
| Subgam-VF and Gammaplex 5% | Number of Participants Who Experienced AEs Based on Treatment-emergent AEs (TEAEs) | No Product Related TEAEs | 23 Participants |
| Subgam-VF and Gammaplex 5% | Number of Participants Who Experienced AEs Based on Treatment-emergent AEs (TEAEs) | SAE | 0 Participants |
Other Pre-specified
Population PK Model for IgG in PID Patients for Alternative Dosing Schedules.
Develop a population pharmacokinetic (PK) model for IgG in PID patients following IV (Gammaplex 5%) or SC (Subgam-VF) administration; * Conduct a formal covariate analysis to assess the impact of patient demographics, and disease-related factors on the PK of IgG following IV or SC administration and to identify those patient covariates which may be utilized in or require dose adjustment; * Use the final population PK model to simulate serum IgG concentration-time profiles in a population of PID patients in order to: * Assess switching from various IgG IV and SC dosing regimens; and * Derive the weight-adjusted dose increment required to achieve a specified difference in serum IgG trough levels when Subgam-VF is administered either weekly or biweekly
Time frame: 30 months
Population: The analysis population included 50 Subjects from GMX01 (NCT00278954), 25 Subjects from GMX04 (NCT01289847) and 38 Subjects from SCIG03 Clinical Trials.~A measure type of 'number' has been used as this represents the predicted change in IgG trough levels when switching between Various IgG Dosing Regimens using a Dose Adjustment Factor of 1.37
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Subgam-VF and Gammaplex 5% | Population PK Model for IgG in PID Patients for Alternative Dosing Schedules. | Increase from IGIV to Weekly Subgam | 31 % of predicted change in IgG trough |
| Subgam-VF and Gammaplex 5% | Population PK Model for IgG in PID Patients for Alternative Dosing Schedules. | Increase from IGIV to Biweekly Subgam | 22 % of predicted change in IgG trough |
| Subgam-VF and Gammaplex 5% | Population PK Model for IgG in PID Patients for Alternative Dosing Schedules. | Decrease from Weekly Subgam to Biweekly Subgam | 7 % of predicted change in IgG trough |
| Subgam-VF and Gammaplex 5% | Population PK Model for IgG in PID Patients for Alternative Dosing Schedules. | Increase from Weekly Subgam to twice weekly Subgam | 2 % of predicted change in IgG trough |
| Subgam-VF and Gammaplex 5% | Population PK Model for IgG in PID Patients for Alternative Dosing Schedules. | Increase from Weekly Subgam to 3x weekly Subgam | 3 % of predicted change in IgG trough |
| Subgam-VF and Gammaplex 5% | Population PK Model for IgG in PID Patients for Alternative Dosing Schedules. | Increase from weekly Subgam to 5x weekly Subgam | 3 % of predicted change in IgG trough |
| Subgam-VF and Gammaplex 5% | Population PK Model for IgG in PID Patients for Alternative Dosing Schedules. | Increase from weekly Subgam to 7x weekly Subgam | 3 % of predicted change in IgG trough |