Bioequivalence Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Gammaplex® 10 and Gammaplex® 5% in Primary Immunodeficiency Diseases

Common Variable Immunodeficiency Clinical Trial

— GMX07  

Official title:

A Phase III, Multicenter, Open-label, Randomized, Two-Period, Crossover Bioequivalence Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Gammaplex® 10 and Gammaplex® 5% in Primary Immunodeficiency Diseases

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01963143
• Other study ID #: GMX07
• Status: Completed
• Phase: Phase 3
• First received: September 13, 2013
• Last updated: May 11, 2016
• Start date: February 2014
• Est. completion date: May 2016

Study information

• Verified date: May 2016
• Source: Bio Products Laboratory
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyHungary: National Institute for Quality and Organizational Development in Healthcare and Medicines
• Study type: Interventional

Clinical Trial Summary

The primary objective is to demonstrate the bioequivalence of Gammaplex® 10 intravenous immunoglobulin (IGIV) and Gammaplex® 5% IGIV with respect to area under the curve within a 28-day dosing interval (AUC0-28) in a cohort of adult subjects.

The secondary objectives are to demonstrate the bioequivalence of Gammaplex® 10 IGIV and Gammaplex® 5% IGIV with respect to area under the curve within a 21-day dosing interval (AUC0-21) in adult subjects; to assess the pharmacokinetics of Gammaplex 10 IGIV and Gammaplex 5% IGIV including Immunoglobulin G (IgG) trough levels and to investigate the safety and tolerability of Gammaplex 10 IGIV and Gammaplex 5% IGIV in adults subjects; to assess the pharmacokinetics of Gammaplex 10 IGIV including IgG trough levels and to investigate the safety and tolerability of Gammaplex 10 IGIV in pediatric subjects.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 48
• Est. completion date: May 2016
• Est. primary completion date: January 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 2 Years to 55 Years

Eligibility

Inclusion criteria:

1. Adult cohort: The subject is aged 16 to 55 years inclusive, is of either sex, and belongs to any ethnic group.

Pediatric cohort: The subject is aged 2 to 15 years inclusive, is of either sex, weighs at least 10 kg, and belongs to any ethnic group.

2. The subject has primary immunodeficiency disease, e.g. common variable immunodeficiency, X linked and autosomal forms of agammaglobulinemia, hyper IgM (Immunoglobulin M) syndrome. Isolated deficiency of a single IgG subclass or of specific antibodies without hypogammaglobulinemia per se, does not qualify for inclusion.

3. The subject is currently receiving a licensed IGIV (or investigational stage III, IIIb IGIV) at a dose that has not changed by ± 50% of the mean dose for at least three months before study entry and is between 300 and 800 mg/kg/infusion. The infusion interval must be either every 21 or every 28 days.

4. The subject must have a trough level = 6 g/L (600 mg/dL). At least one documented trough level must be available from the three months before Screening.

5. The subject must have documentation from the last three consecutive routine IGIV infusions for the following, before the first infusion in this study: dose of IGIV, treatment intervals, and trade name (or identity) of the IGIV treatment.

6. Female subjects of childbearing potential must have a negative result on an HCG (human chorionic gonadotropin) based pregnancy test at Screening.

7. Females who are or become sexually active must practice contraception using a method of proven reliability for the study duration.

8. The subject is willing to comply with all aspects of the protocol for the duration of the study.

9. The subject has signed an informed consent form and assent form (if applicable).

Exclusion criteria:

1. The subject has a history of any severe anaphylactic reaction to blood or any blood derived product.

2. The subject has selective IgA deficiency, history of reaction to products containing IgA (Immunoglobulin A), or has a history of antibodies to IgA.

3. The subject has cellular or innate impaired immunity (i.e. only subjects with humoral impaired immunity may be included).

4. The subject has evidence of an active infection at the time of enrolment.

5. The subject has previously completed or withdrawn from this study.

6. The subject is currently receiving, or has received, any investigational agent other than an IGIV within the prior three months.

7. The subject is pregnant or is nursing.

8. The subject has positive results for any of the following at Screening:

• Serological test for HIV 1 and 2, HCV, or HBsAg

• NAT (Nucleic acid amplification technique)for HCV

• NAT for HIV

9. The subject has levels > 2.5 times the upper limit of normal, as defined at the central laboratory, of any of the following at Screening:

• Alanine amino transaminase

• Aspartate amino transaminase

10. The subject has severe renal impairment (defined as serum creatinine greater than two times the upper limit of normal or blood urea nitrogen greater than 2.5 times the upper limit of normal for the range of the laboratory doing the analysis); the subject is on dialysis; the subject has a history of acute renal failure.

11. The subject is known to abuse alcohol, opiates, psychotropic agents, or other chemicals or drugs, or has done so within the past 12 months.

12. The subject has a history of deep vein thrombosis or thrombotic complications of IGIV therapy.

13. The subject 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) that the Investigator feels may interfere with the conduct of the study.

14. The subject has an acquired immunodeficiency condition such as chronic* lymphocytic leukemia, lymphoma, multiple myeloma, or chronic or recurrent neutropenia (absolute neutrophil count < 1 × 109/L).

15. The subject is receiving the following medication:

• Steroids (long term daily, = 0.15 mg of prednisone equivalent/kg/day). Requirement for short or intermittent courses of steroids would not exclude a subject.

• Immunosuppressive drugs

• Immunomodulatory drugs

16. The subject has uncontrolled arterial hypertension (systolic blood pressure > 160 mm Hg and/or diastolic blood pressure > 100 mm Hg).

17. The subject has anemia (hemoglobin < 10 g/dL) at Screening.

18. The subject is known to be intolerant to any component of Gammaplex, such as sorbitol (i.e. hereditary intolerance to fructose) or glycine.

• Chronic conditions would be as per the Investigator's opinion however for this study the guidance is that the condition has been present for at least 6 months.

Study Design

Allocation: Randomized, Endpoint Classification: Bio-equivalence Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Agammaglobulinemia
• Common Variable Immunodeficiency
• Genetic Diseases, X-Linked
• Hyper-IgM Syndrome
• Immunologic Deficiency Syndromes
• Primary Immune Deficiency Disorders
• X-linked Agammaglobulinaemia

Intervention

Biological:
• Gammaplex (5%)

• Gammaplex 10

Locations

Country	Name	City	State
Hungary	Egyesitett Szent Istvan es Szent Laszlo Korhaz	Budapest
United Kingdom	University Hospital of Wales	Cardiff	Wales
United Kingdom	The Royal Free Hospital and Medical School	London
United States	Bellingham Asthma Allergy and Immunology Clinic	Bellingham	Washington
United States	IMMUNOe International Research Centers	Centennial	Colorado
United States	Arizona Allergy Associates	Chandler	Arizona
United States	Institute for Asthma and Allergy	Chevy Chase	Maryland
United States	Rush University Medical Center	Chicago	Illinois
United States	Dallas Allergy Immunology Research	Dallas	Texas
United States	O&O Alpan, LLC	Fairfax,	Virginia
United States	Joe DiMaggio Children's Hospital	Hollywood	Florida
United States	Miller Children's Hospital	Long Beach,	California
United States	Childrens Hospital Los Angeles	Los Angeles	California
United States	UCLA Medical Center	Los Angeles,	California
United States	Allergy Associates of the Palm Beaches, PA	N Palm Beach	Florida
United States	University of Utah Primary Children's Hospital	Salt Lake City	Utah
United States	Asthma and Allergy Center	Toledo	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
Bio Products Laboratory

Countries where clinical trial is conducted

United States,  Hungary,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Primary Bioequivalence analysis - area under the curve within a 28-day dosing interval (AUC0-28) in adult subjects		Week 15 or 20 and Week 30 or 40 at pre-infusion, 10 minutes before end of infusion, 1,3,6,24,48,84 hours, 14, 21 and 28 days post-infusion	No
Secondary	Secondary Bioequivalence analysis - IgG trough levels		Week 15 or 20 and Week 30 or 40 at pre-infusion, 10 minutes before end of infusion, 1,3,6,24,48,84 hours, 14, 21 and 28 days post-infusion	No
Secondary	Other pharmacokinetic parameters for IgG	AUC0-t - area under the concentration versus time curve within a dosing interval	Week 15 or 20 and Week 30 or 40 at pre-infusion, 10 minutes before end of infusion, 1,3,6,24,48,84 hours, 14, 21 and 28 days post-infusion	No
Secondary	Adverse events	The number and percent of infusions associated with one or more adverse events (AEs) (irrespective of causality) that begin during the infusion or within 72 hours after completion of the infusion will be calculated	Up to 10 months	Yes
Secondary	Adverse events - Thrombotic events	Number of thrombotic events	Up to 10 months	Yes
Secondary	Adverse events - product-related AEs	Nature, severity, and frequency of product-related AEs	Up to 10 months	Yes
Secondary	Adverse events - SUSARS	Number of Suspected unexpected serious adverse reactions (SUSARS)	Up to 10 months	Yes
Secondary	Vital signs	Clinically significant changes in vitals signs will be classified as adverse events	Screening and every 21 or 28 days during the study. Also 7 days after the first infusion in each treatment phase.	Yes
Secondary	Laboratory testing	Clinically significant changes in laboratory tests, hematology, clinical chemistry	Screening and every 21 or 28 days during the study. Also 7 days after the first infusion in each treatment phase.	Yes
Secondary	Viral transmission	Tests for Hepatitis B (HBV), Hepatitis C (HCV), Human immunodeficiency virus (HIV), and Parvovirus B19	Screening, Weeks 3 or 4, Weeks 4 or 5, Weeks 18 or 24, Weeks 19 or 25 and end of study (Weeks 34 or 44)	Yes
Secondary	Physical Examination	Physical examination will be recorded by body system. Clinically significant changes from baseline in any body system will be classified as adverse events.	Screening and every 21 or 28 days during the study. Also 7 days after the first infusion in each treatment phase.	Yes
Secondary	Tests for hemolysis	Direct Coombs' test	Weeks 3 or 4, Weeks 4 or 5, Weeks 6 or 8 and Weeks 18 or 24, Weeks 19 or 25, Weeks 21 or 28 and end of study (Week 34 or 44)	Yes
Secondary	Other pharmacokinetic parameters for IgG	Cmax - peak concentration in plasma tmax - time to reach the peak concentration in plasma	Week 15 or 20 and Week 30 or 40 at pre-infusion, 10 minutes before end of infusion, 1,3,6,24,48,84 hours, 14, 21 and 28 days post-infusion	No
Secondary	Other pharmacokinetic parameters for IgG	t1/2 - apparent terminal half-life	Week 15 or 20 and Week 30 or 40 at pre-infusion, 10 minutes before end of infusion, 1,3,6,24,48,84 hours, 14, 21 and 28 days post-infusion	No
Secondary	Other pharmacokinetic parameters for IgG	CL - systemic clearance	Week 15 or 20 and Week 30 or 40 at pre-infusion, 10 minutes before end of infusion, 1,3,6,24,48,84 hours, 14, 21 and 28 days post-infusion	No
Secondary	Tests for hemolysis	Tests for haptoglobin	Weeks 3 or 4, Weeks 4 or 5, Weeks 6 or 8 and Weeks 18 or 24, Weeks 19 or 25, Weeks 21 or 28 and end of study (Week 34 or 44)	Yes
Secondary	Tests for hemolysis	plasma free hemoglobin	Weeks 3 or 4, Weeks 4 or 5, Weeks 6 or 8 and Weeks 18 or 24, Weeks 19 or 25, Weeks 21 or 28 and end of study (Week 34 or 44)	Yes
Secondary	Tests for hemolysis	Urine hemosiderin	Weeks 3 or 4, Weeks 4 or 5, Weeks 6 or 8 and Weeks 18 or 24, Weeks 19 or 25, Weeks 21 or 28 and end of study (Week 34 or 44)	Yes