SCIG03: Pharmacokinetics (PK) and Safety of Subgam-VF in Primary Immunodeficiency Diseases

• Sponsor: Bio Products Laboratory (Other)
• Overall Status: Completed
• CT.gov ID: NCT01884311
• Collaborator: (none)
• Enrollment: 38
• Locations: 16
• Arm: 1
• Actual Duration (Months): 21.2
• Patients Per Site: 2.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Primary Immune Deficiency Disorders; Common Variable Immunodeficiency; X-linked Agammaglobulinaemia; Hyperimmunoglobulin M Syndrome	Biological: Subgam	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Phase III, Multicenter, Open-Label Study to Evaluate the Pharmacokinetics and Safety of Subgam-VF in Primary Immunodeficiency Diseases
• Actual Study Start Date: Aug 20, 2015
• Actual Primary Completion Date: May 25, 2017
• Actual Study Completion Date: May 25, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Subgam-VF Subgam-VF is a 16% IgG and will be administered weekly, by subcutaneous infusion. The total duration of treatment will be for 26 weeks.	Biological: Subgam; 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.; Other Names: Subgam-VF

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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 Outcome Measures

1. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts 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

5. IGIV dose is between 300 and 800 mg/kg/month. SCIG dose is between 110 & 300 mg/kg/week;

6. Dose is stable for at least the past three months (i.e. consistent mg/kg +/- 5%);

7. The infusion interval is every 21 or 28 days for IGIV & seven days for SCIG;

8. 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).

9. Female subjects who are (or become) sexually active must practice contraception by using a method of proven reliability for the duration of the study.

10. 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.

11. Willing to comply with all aspects of the protocol, including blood sampling, for the duration of the study.

12. 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

1. 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)

1. 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.

2. Is known to abuse alcohol, opiates, psychotropic agents, or other chemicals or drugs, or has done so within the past 12 months.

3. Has a history of DVT, or thrombotic complications of IgG therapy, or a prior diagnosis of thrombophilia.

4. 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.

5. Has an acquired medical condition, such as chronic lymphocytic leukemia, lymphoma, multiple myeloma, chronic or recurrent neutropenia (ANC < 1 x 109/L).

6. 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

1. 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.

2. Has anemia (hemoglobin < 10 g/dL) at screening.

3. Has severe dermatitis that would preclude sites for safe product administration.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Allergy Associates	Chandler	Arizona	United States	85224
2	University of California, Irvine	Irvine	California	United States	92697
3	University of California San Diego-- Rady's Children's Hospital	San Diego	California	United States	92123
4	Immunoe International Research	Centennial	Colorado	United States	80112
5	Allergy Associate of the Palm Beaches	North Palm Beach	Florida	United States	33408
6	Ann and Robert H Lurie Children's Hospital	Chicago	Illinois	United States	60611
7	Cardinal Glennon Children's Medical Center	Minneapolis	Minnesota	United States	63104
8	Optimed Research	Columbus	Ohio	United States	43235
9	Oklahoma Institute of Allergy & Asthma Clinical Research, LLC	Oklahoma City	Oklahoma	United States	73131
10	Pennsylvania State University	Hershey	Pennsylvania	United States	174033
11	Dallas Allergy Immunology	Dallas	Texas	United States	75230
12	AARA Research Center	Dallas	Texas	United States	75231
13	University of Utah	Salt Lake City	Utah	United States	84112
14	O&O Alpan, LLC	Fairfax	Virginia	United States	22030
15	Bellingham Asthma Allergy Clinic	Bellingham	Washington	United States	98225
16	The Medical College of Wisconsin/Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Bio Products Laboratory

Investigators

• Study Director: Eric Wolford, Bio Products Laboratory Limited

Study Documents (Full-Text)

• Study Protocol - Mar 22, 2017
• Statistical Analysis Plan - Jan 12, 2017

More Information

Publications

None provided.

• Responsible Party: Bio Products Laboratory
• ClinicalTrials.gov Identifier: NCT01884311
• Other Study ID Numbers: SCIG03
• First Posted: Jun 24, 2013
• Last Update Posted: Sep 12, 2018
• Last Verified: Aug 1, 2018

• Keywords provided by Bio Products Laboratory: Primary Immune Deficiency Disorders; Common Variable Immunodeficiency; X-linked agammaglobulinaemia; Hyper-IgM Syndrome; Subcutaneous; Immunoglobulins
• Additional relevant MeSH terms: Agammaglobulinemia; Hyper-IgM Immunodeficiency Syndrome; Primary Immunodeficiency Diseases; Immunologic Deficiency Syndromes; Common Variable Immunodeficiency

Study Results

Participant Flow

Arm/Group Title	Subgam-VF
Arm/Group Description	Subgam-VF is a 16% IgG and will be administered weekly, by subcutaneous infusion over a period of 26 weeks.
Period Title: Overall Study
STARTED	38
COMPLETED	33
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Subgam-VF
Arm/Group Description	Subgam-VF is a 16% IgG and will be administered weekly, by subcutaneous infusion over a period of 26 weeks.
Overall Participants	38
Age, Customized (Count of Participants)
>=16 years	25 65.8%
< 16 years	13 34.2%
Sex: Female, Male (Count of Participants)
Female	22 57.9%
Male	16 42.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 5.3%
Not Hispanic or Latino	36 94.7%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 2.6%
Asian	1 2.6%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	35 92.1%
More than one race	1 2.6%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	38 100%

Outcome Measures

1. Primary Outcome

Title	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.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Subgam-VF and Gammaplex 5%
Arm/Group Description	Subgam-VF Subgam-VF is a 16% IgG and will be administered weekly, by subcutaneous infusion. The total duration of treatment will be for 26 weeks. The initial weekly dose of Subgam-VF administered will be calculated by taking the average weekly equivalent of the subject's IGIV dose (should be stable, as in same mg/kg +/- 5%), 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. This population included 50 Subjects from GMX01 (NCT00278954), 25 Subjects from GMX04 (NCT01289847) and 38 Subjects from SCIG03.
Measure Participants	113
Mean (90% Confidence Interval) [Ratio]	0.98

2. Secondary Outcome

Title	Number of Participants Who Experienced AEs Based on Treatment-emergent AEs (TEAEs)
Description	TEAEs defined as those events with onset date between the first infusion date and 28 days after the last infusion.
Time Frame	30 weeks

Outcome Measure Data

Analysis Population Description

The intent-to-treat population included all subjects who received at least 1 infusion of Subgam-VF.

Arm/Group Title	Subgam-VF
Arm/Group Description	Subgam-VF is a 16% IgG and will be administered weekly, by subcutaneous infusion for a total duration of 26 weeks.
Measure Participants	38
Any TEAE	36 94.7%
No TEAE	2 5.3%
Discontinued because of TEAEs	1 2.6%
Product Related TEAE	15 39.5%
No Product Related TEAEs	23 60.5%
SAE	0 0%

3. Secondary Outcome

Title	Dose Refinement in Switching From Gammaplex 5% IGIV to Subgam-VF
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Subgam-VF and Gammaplex 5%
Arm/Group Description	Subgam-VF is a 16% IgG and will be administered weekly, by subcutaneous infusion for a total duration of 26 weeks. This population included 23 Subjects from the Gammaplex PK Populations in GMX01 (NCT00278954) and 21 Subjects from GMX04 (NCT01289847), in addition included 20 Subjects from SCIG03.
Measure Participants	64
Geometric Mean (90% Confidence Interval) [Ratio]	1.33

4. Secondary Outcome

Title	Number of Infusion Site Reactions
Description	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

Outcome Measure Data

Analysis Population Description

Total number of participants was 38

Arm/Group Title	Subgam-VF
Arm/Group Description	Subgam-VF Subgam-VF is a 16% IgG and will be administered weekly, by subcutaneous infusion. The total duration of treatment will be for 26 weeks. The initial weekly dose of Subgam-VF administered will be calculated by taking the average weekly equivalent of the subject's IGIV dose (should be stable, as in same mg/kg +/- 5%), 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.
Measure Participants	38
Number [infusion site reactions]	447

5. Other Pre-specified Outcome

Title	Population PK Model for IgG in PID Patients for Alternative Dosing Schedules.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Subgam-VF
Arm/Group Description	Subgam-VF Subgam-VF is a 16% IgG and will be administered weekly, by subcutaneous infusion. The total duration of treatment will be for 26 weeks. The initial weekly dose of Subgam-VF administered will be calculated by taking the average weekly equivalent of the subject's IGIV dose (should be stable, as in same mg/kg +/- 5%), 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.
Measure Participants	113
Increase from IGIV to Weekly Subgam	31
Increase from IGIV to Biweekly Subgam	22
Decrease from Weekly Subgam to Biweekly Subgam	7
Increase from Weekly Subgam to twice weekly Subgam	2
Increase from Weekly Subgam to 3x weekly Subgam	3
Increase from weekly Subgam to 5x weekly Subgam	3
Increase from weekly Subgam to 7x weekly Subgam	3

Adverse Events

Time Frame	7 months
Adverse Event Reporting Description	Collected during 6 months of treatment and for 28 days after the last administration of Subgam-VF
Arm/Group Title	Subgam-VF
Arm/Group Description	Subgam-VF is a 16% IgG and will be administered weekly, by subcutaneous infusion for a total duration of 26 weeks.
All Cause Mortality
	Subgam-VF
	Affected / at Risk (%)	# Events
Total	0/38 (0%)
Serious Adverse Events
	Subgam-VF
	Affected / at Risk (%)	# Events
Total	0/38 (0%)
Other (Not Including Serious) Adverse Events
	Subgam-VF
	Affected / at Risk (%)	# Events
Total	36/38 (94.7%)
Gastrointestinal disorders
Abdominal Pain	2/38 (5.3%)	2
Abdominal Pain Upper	2/38 (5.3%)	2
Diarrhoea	8/38 (21.1%)	10
Vomiting	2/38 (5.3%)	2
General disorders
Chest Pain	2/38 (5.3%)	2
Fatigue	3/38 (7.9%)	4
Infusion Site Bruising	2/38 (5.3%)	3
Infusion Site Erythema	6/38 (15.8%)	12
Infusion Site Pain	6/38 (15.8%)	21
Infusion Site Pruritus	4/38 (10.5%)	5
Infusion Site Swelling	2/38 (5.3%)	6
Pain	3/38 (7.9%)	5
Pyrexia	6/38 (15.8%)	11
Infections and infestations
Acute Sinusitis	4/38 (10.5%)	6
Bronchitis	3/38 (7.9%)	3
Gastroenteritis	2/38 (5.3%)	3
Gastroenteritis Viral	3/38 (7.9%)	4
Nasopharyngitis	10/38 (26.3%)	15
Pharyngitis Streptococcal	3/38 (7.9%)	3
Rhinitis	2/38 (5.3%)	2
Sinusitis	4/38 (10.5%)	7
Upper Respiratory Tract Infection	3/38 (7.9%)	5
Urinary Tract Infection	4/38 (10.5%)	5
Viral Upper Respiratory Tract Infection	5/38 (13.2%)	6
Injury, poisoning and procedural complications
Ligament Sprain	2/38 (5.3%)	2
Tooth Fracture	2/38 (5.3%)	2
Investigations
Coombs Direct Test Positive	4/38 (10.5%)	5
Musculoskeletal and connective tissue disorders
Back Pain	2/38 (5.3%)	2
Osteoarthritis	2/38 (5.3%)	2
Pain in Extremity	3/38 (7.9%)	4
Tendonitis	2/38 (5.3%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal Cell Carcinoma	2/38 (5.3%)	2
Nervous system disorders
Headache	8/38 (21.1%)	12
Renal and urinary disorders
Haemosiderinuria	3/38 (7.9%)	3
Respiratory, thoracic and mediastinal disorders
Cough	5/38 (13.2%)	9
Nasal Congestion	3/38 (7.9%)	4
Oropharyngeal Pain	4/38 (10.5%)	5
Skin and subcutaneous tissue disorders
Dermatitis Contact	3/38 (7.9%)	3
Rash	2/38 (5.3%)	2
Surgical and medical procedures
Tooth Extraction	2/38 (5.3%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.