Efficacy, Safety and Pharmacokinetics of Gammaplex in Primary Immunodeficiency Diseases.

• Sponsor: Bio Products Laboratory (Other)
• Overall Status: Completed
• CT.gov ID: NCT00278954
• Collaborator: (none)
• Enrollment: 50
• Locations: 7
• Arm: 1
• Duration (Months): 22
• Patients Per Site: 7.1
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The main objective of this study is to see if GAMMAPLEX is efficacious with respect to Food and Drug Administration (FDA) minimal requirements (no more than 1 serious, acute, bacterial infection per subject per year) in subjects with Primary Immunodeficiency Diseases (PID). The secondary objectives are to assess the safety and tolerability of GAMMAPLEX and to determine if GAMMAPLEX has a pharmacokinetic (PK) profile comparable with that of intact Immunoglobulin G (IgG) in subjects with PID.

Condition or Disease	Intervention/Treatment	Phase
Primary Immunodeficiency; Common Variable Hypogammaglobulinemia; X-linked Hypogammaglobulinemia; Hypogammaglobulinemia; Immunodeficiency With Hyper-IgM; Wiskott-Aldrich Syndrome	Biological: Gammaplex (Intravenous immunoglobulin)	Phase 3

Detailed Description

Primary Efficacy Variable The primary variable is the number of serious, acute, bacterial infections/subject/year, and it will be based on the total of all of the following events as defined by the FDA: bacterial Pneumonia, bacteremia/sepsis, osteomyelitis/septic arthritis, visceral abscess, and bacterial meningitis.

Secondary Efficacy Variables Secondary efficacy will be determined by using the following variables: number of days of work/school missed because of infection per subject year; number and days of hospitalizations because of infection per subject year; number of visits to physicians for acute problems and/or number of visits to hospital emergency rooms per subject year; other infections documented by fever or a positive result on a radiograph and/or culture; number of infectious episodes per subject per year; number of days on therapeutic antibiotics.These data will be entered into the subject diary, confirmed by the physician, and entered on the electronic-CRF (e-CRF).

Safety Variables. The variables used to assess safety will be the following: adverse events (AEs); vital signs; clinical laboratory tests and Direct Coombs' Test; transmission of viruses; physical examination.

Test product, dose/mode of administration, batch number(s): The GAMMAPLEX dose is 300-800 mg/kg/infusion (milligram per killgram per infusion) every 21 or 28 days, intravenously. At least 2 batches will be used in this study and no more than 1 batch in any given infusion.

Duration of treatment:

The total duration of treatment is 12 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III, Multicenter, Open-Label Study To Evaluate The Efficacy, Safety, and Pharmacokinetics of Gammaplex® in Primary Immunodeficiency Diseases
• Study Start Date: Jan 1, 2006
• Actual Primary Completion Date: Nov 1, 2007
• Actual Study Completion Date: Nov 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Other: Gammaplex Gammaplex	Biological: Gammaplex (Intravenous immunoglobulin); GAMMAPLEX 5g/100 mL, dose is 300-800 mg/kg/infusion every 21 or 28 days, intravenously for 12 months.

Outcome Measures

Primary Outcome Measures

1. Number of Serious, Acute, Bacterial Infections (SABIs) Per Subject Per Year in Subjects With Primary Immunodeficiency Disease. [12 months]

   By assessing the number of serious, acute, bacterial infections per subject per year in subjects with Primary Immunodeficiency disease.

Secondary Outcome Measures

1. The Pharmacokinetic (PK) Half-Life of Immunoglobulin G (IgG) [-5, 0, 60 minutes (min), 24, 48 hours (hrs), 4, 7, 14, 21 and 28 days]

   Blood samples for PK analysis were obtained and analysed at 10 different time points, i.e. -5, 0, 60 minutes (min), 24, 48 hours (hrs), 4, 7, 14, 21 and 28 days, at an infusion visit following 6 months of treatment.

2. The Pharmacokinetic (PK) Clearance of Immunoglobulin G (IgG) [-5, 0, 60 min, 24, 48 hrs, 4, 7, 14, 21 and 28 days]

   Blood samples for PK analysis were obtained and analysed at 10 different time points, i.e. -5, 0, 60 minutes (min), 24, 48 hours (hrs), 4, 7, 14, 21 and 28 days, at an infusion visit following 6 months of treatment.

3. The Pharmacokinetic (PK) Volume of Distribution (Vz)of Immunoglobulin G (IgG) [-5, 0, 60 min, 24, 48 hrs, 4, 7, 14, 21 and 28 days]

   Blood samples for PK analysis were obtained and analysed at 10 different time points, i.e. -5, 0, 60 minutes (min), 24, 48 hours (hrs), 4, 7, 14, 21 and 28 days, at an infusion visit following 6 months of treatment.

4. The Pharmacokinetic (PK) Mean Residence Time (MRT) for Inmuunoglobulin G (IgG) [-5, 0, 60 min, 24, 48 hrs, 4, 7, 14, 21 and 28 days]

   Blood samples for PK analysis were obtained and analysed at 10 different time points, i.e. -5, 0, 60 minutes (min), 24, 48 hours (hrs), 4, 7, 14, 21 and 28 days, at an infusion visit following 6 months of treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 1. The subject is 3 years of age or older, of either sex, belonging to any ethnic group, and above a minimum weight of 27.5 kg. This weight is based on the amount of blood required for testing. If subject is participating in the PK segment, the minimum weight required is 37 kg.

1. The subject has a primary immunodeficiency disease, which has as a significant component of hypogammaglobulinemia and/or antibody deficiency (e.g. (exempli gratia / for example), common variable immunodeficiency, X-linked and autosomal forms of agammaglobulinemia, hyper-immunoglobulin M (hyper-IgM) syndrome, Wiskott-Aldrich Syndrome). Isolated deficiency of a single IgG subclass, or of specific antibodies without hypogammaglobulinemia per se, does not qualify for inclusion.

2. The subject has been receiving licensed or investigational (Phase III or IIIb) immunoglobulin intravenous (IGIV) replacement therapy at a dose that has not changed by + 50% of the mean dose for at least 3 months before study entry and is between 300 and 800 mg/kg/infusion. The infusion interval must be between 21 and 28 days inclusive. The subject must have maintained a trough level at least 300 mg/dL (milligram per decilitre) above baseline serum IgG levels (defined as before initiation of any gamma globulin treatment for that subject). The trough level must be 600 mg/dL.

3. Trough levels of IgG and dose of IGIV, treatment intervals, and the trade name of the IGIV treatments used for the last 2 consecutive routine (licensed or investigational product) must be documented for each subject before the first infusion in this study can be administered.

4. If a subject is a female of child-bearing potential, she must have a negative result on an Human Chorionic Gonadotrophin (HCG)-based pregnancy test.

5. If a subject is a female who is or becomes sexually active, she must practice contraception by using a method of proven reliability for the duration of the study.

6. The subject is willing to comply with all aspects of the protocol, including blood sampling, for the duration of the study.

7. The subject has signed an informed consent form (if at least 18 years old) or the subject's parent or legal guardian has signed the informed consent form. If appropriate, the subject has signed a child assent form (See Section 12.3).

Exclusion Criteria:

• Subjects will be excluded if any of the following exclusion criteria are met:

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

2. The subject is known to be intolerant to any component of GAMMAPLEX, such as sorbitol (i.e.(id est / that is) , intolerance to fructose).

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

4. Subjects who have completed the study and subjects who have withdrawn cannot participate in the study for a second time.

5. The subject is currently receiving, or has received, any investigational agent, other than an immune serum globulin (ISG) preparation that is being evaluated in a Phase III or IIIb study, within the prior 3 months.

6. The subject has been exposed to blood or any blood product or derivative within the last 6 months, other than a commercially available IGIV or other forms of commercially available and licensed ISG or an ISG product that is in Phase III or IIIb studies.

7. The subject is pregnant or is nursing.

8. The subject is positive for any of the following at screening:

• Serological test for Human immunodeficiency virus (HIV) 1&2, Hepatitis C virus (HCV), or Hepatitis B surface antigen (HBsAg)

• Nucleic Acid test (NAT) for HCV

• NAT for HIV

1. The subject, at screening, has levels 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. The subject has a severe renal impairment (defined as serum creatinine greater than 2 times the upper limit of normal or Blood urea nitrogen (BUN) 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.

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

3. The subject has a history of deep vein thrombosis (DVT), or thrombotic complications of IGIV therapy.

4. 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, in the opinion of the investigator, may interfere with the conduct of the study.

5. The subject has an acquired medical condition, such as chronic lymphocytic leukemia, lymphoma, multiple myeloma, chronic or recurrent neutropenia (Absolute neutrophil count (ANC) < 1000 x 109/L).

6. The subject is receiving the following medication:

• Immunosuppressive drugs

• The subject is receiving the following medication: Steroids (long-term daily, >0.15 mg /kg/day of prednisone or prednisolone of equivalent dose of other corticosteroids) The requirement for burst or intermittent courses would not exclude the subject.

• Immunomodulatory drugs

1. The subject has non-controlled arterial hypertension (systolic blood pressure > 160 mmHg (millimeters of mercury) and/or diastolic blood pressure > 100 mmHg).

2. The subject has anemia (hemoglobin < 10 g/dL) at screening.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Allergy Associates of the Palm Beaches	North Palm Beach	Florida	United States	33408
2	Family Allergy and Asthma Center PC	Atlanta	Georgia	United States	30342
3	Rush University Medical Centre, University Consultants in Allergy & Immunology	Chicago	Illinois	United States	60612
4	Childrens Hospital at Buffalo, Allergy Division	Buffalo	New York	United States	14222
5	Allergy, Asthma & Immunology Clinic, P.A.	Irving	Texas	United States	75063
6	UCLA Medical Centre	Irving	Texas	United States	75063
7	University of Washington School of Medicine, Dept. of Pediatrics	Seattle	Washington	United States	989109-5235

Sponsors and Collaborators

• Bio Products Laboratory

Investigators

• Principal Investigator: Melvin Berger, MD, Rainbow Babies & Children's Hospital, Cleveland, Ohio

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Sponsor website

Publications

None provided.

• Responsible Party: Bio Products Laboratory
• ClinicalTrials.gov Identifier: NCT00278954
• Other Study ID Numbers: GMX01
• First Posted: Jan 19, 2006
• Last Update Posted: Jan 24, 2013
• Last Verified: Jan 1, 2013

• Keywords provided by Bio Products Laboratory: Primary Antibody Deficiency; Common variable hypogammaglobulinemia; X-linked hypogammaglobulinemia; Hypogammaglobulinemia; Immunodeficiency with hyper-IgM; Wiskott-Aldrich Syndrome
• Additional relevant MeSH terms: Wiskott-Aldrich Syndrome; Agammaglobulinemia; Hyper-IgM Immunodeficiency Syndrome; Primary Immunodeficiency Diseases; Immunologic Deficiency Syndromes; Common Variable Immunodeficiency; Immunoglobulins; Immunoglobulins, Intravenous; Antibodies; gamma-Globulins; Rho(D) Immune Globulin

Study Results

Participant Flow

Recruitment Details	First enrollment: 06 February 2006 Last subject completed: 06 November 2007 Seven investigative sites, all hospital clinics
Pre-assignment Detail	This was an open study. All enrolled subjects received study medication.

Arm/Group Title	Gammaplex
Arm/Group Description	All subjects received between 300 to 800 mg/kg/infusion of Gammaplex intravenously, every 21 day or 28 days.
Period Title: Overall Study
STARTED	50
COMPLETED	45
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Gammaplex
Arm/Group Description	All subjects received between 300 to 800 mg/kg/infusion of Gammaplex intravenously, every 21 day or 28 days.
Overall Participants	50
Age (Count of Participants)
<=18 years	6 12%
Between 18 and 65 years	37 74%
>=65 years	7 14%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.0 (19.10)
Sex: Female, Male (Count of Participants)
Female	24 48%
Male	26 52%
Region of Enrollment (participants) [Number]
United States	50 100%

Outcome Measures

1. Primary Outcome

Title	Number of Serious, Acute, Bacterial Infections (SABIs) Per Subject Per Year in Subjects With Primary Immunodeficiency Disease.
Description	By assessing the number of serious, acute, bacterial infections per subject per year in subjects with Primary Immunodeficiency disease.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT).

Arm/Group Title	Gammaplex
Arm/Group Description	All subjects received between 300 to 800 mg/kg/infusion of Gammaplex intravenously, every 21 day or 28 days.
Measure Participants	50
Number [SABIs/subject/year]	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gammaplex
	Comments	The estimated serious acute bacterial infection (SABI) rate was calculated by dividing no. of infections by no.of subject years. The exponential of the upper limit of the 98% 2-sided Confidence Interval (CI) gave the upper, 1-sided, 99% confidence bound, estimated using Poisson regression. The equivalent upper bound per subject year was obtained by dividing this figure by total subject years.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Poisson regression with log link
	Comments
Method of Estimation	Estimation Parameter	SABI per subject per year
	Estimated Value	0
	Confidence Interval	() 99%; 0 to 0.101
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean SABI rate = 0 per subject per year. 1-sided 99% upper confidence bound could not be calculated.

2. Secondary Outcome

Title	The Pharmacokinetic (PK) Half-Life of Immunoglobulin G (IgG)
Description	Blood samples for PK analysis were obtained and analysed at 10 different time points, i.e. -5, 0, 60 minutes (min), 24, 48 hours (hrs), 4, 7, 14, 21 and 28 days, at an infusion visit following 6 months of treatment.
Time Frame	-5, 0, 60 minutes (min), 24, 48 hours (hrs), 4, 7, 14, 21 and 28 days

Outcome Measure Data

Analysis Population Description

Only 24 of the 45 evaluable subjects participated in the Pharmacokinetic part of the protocol. No data imputation.

Arm/Group Title	Gammaplex
Arm/Group Description	All subjects received between 300 to 800 mg/kg/infusion of Gammaplex intravenously, every 21 day or 28 days.
Measure Participants	24
Mean (Standard Deviation) [Days]	41.19 (19.19)

3. Secondary Outcome

Title	The Pharmacokinetic (PK) Clearance of Immunoglobulin G (IgG)
Description	Blood samples for PK analysis were obtained and analysed at 10 different time points, i.e. -5, 0, 60 minutes (min), 24, 48 hours (hrs), 4, 7, 14, 21 and 28 days, at an infusion visit following 6 months of treatment.
Time Frame	-5, 0, 60 min, 24, 48 hrs, 4, 7, 14, 21 and 28 days

Outcome Measure Data

Analysis Population Description

Only 24 of the 45 evaluable subjects participated in the Pharmacokinetic part of the protocol. No data imputation.

Arm/Group Title	Gammaplex
Arm/Group Description	All subjects received between 300 to 800 mg/kg/infusion of Gammaplex intravenously, every 21 day or 28 days.
Measure Participants	24
Mean (Standard Deviation) [mL/day/kg]	0.585 (0.2508)

4. Secondary Outcome

Title	The Pharmacokinetic (PK) Volume of Distribution (Vz)of Immunoglobulin G (IgG)
Description	Blood samples for PK analysis were obtained and analysed at 10 different time points, i.e. -5, 0, 60 minutes (min), 24, 48 hours (hrs), 4, 7, 14, 21 and 28 days, at an infusion visit following 6 months of treatment.
Time Frame	-5, 0, 60 min, 24, 48 hrs, 4, 7, 14, 21 and 28 days

Outcome Measure Data

Analysis Population Description

Only 24 of the 45 evaluable subjects participated in the Pharmacokinetic part of the protocol. No data imputation.

Arm/Group Title	Gammaplex
Arm/Group Description	All subjects received between 300 to 800 mg/kg/infusion of Gammaplex intravenously, every 21 day or 28 days.
Measure Participants	24
Mean (Standard Deviation) [dL/kg]	0.297 (0.0539)

5. Secondary Outcome

Title	The Pharmacokinetic (PK) Mean Residence Time (MRT) for Inmuunoglobulin G (IgG)
Description	Blood samples for PK analysis were obtained and analysed at 10 different time points, i.e. -5, 0, 60 minutes (min), 24, 48 hours (hrs), 4, 7, 14, 21 and 28 days, at an infusion visit following 6 months of treatment.
Time Frame	-5, 0, 60 min, 24, 48 hrs, 4, 7, 14, 21 and 28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gammaplex
Arm/Group Description	All subjects received between 300 to 800 mg/kg/infusion of Gammaplex intravenously, every 21 day or 28 days.
Measure Participants	50
Mean (Standard Deviation) [Days]	56.1 (23.06)

Adverse Events

Time Frame	An event was only included in the analysis of Adverse Events (AEs) if it had an onset date between the first Gammaplex infusion and 30 days after the last Gammaplex infusion, inclusive.
Arm/Group Title	Gammaplex
Arm/Group Description	All subjects received between 300 to 800 mg/kg/infusion of Gammaplex intravenously, every 21 day or 28 days.
All Cause Mortality
	Gammaplex
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Gammaplex
	Affected / at Risk (%)	# Events
Total	6/50 (12%)
General disorders
Chest Pain	1/50 (2%)	1
Infections and infestations
Gastroenteritis viral	1/50 (2%)	1
Pneumonia bacterial	1/50 (2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/50 (2%)	1
Squamous cell carcinoma	1/50 (2%)	1
Nervous system disorders
Syncope vasovagal	1/50 (2%)	1
Pregnancy, puerperium and perinatal conditions
Pregnancy	1/50 (2%)	1
Vascular disorders
Thrombosis	1/50 (2%)	1
Other (Not Including Serious) Adverse Events
	Gammaplex
	Affected / at Risk (%)	# Events
Total	47/50 (94%)
Eye disorders
Conjunctivitis	4/50 (8%)	5
Gastrointestinal disorders
Diarrhea	10/50 (20%)	13
Nausea	9/50 (18%)	12
Upper abdominal pain	5/50 (10%)	5
Vomiting	3/50 (6%)	3
General disorders
Chest pain	3/50 (6%)	3
Chills	4/50 (8%)	7
Fatigue	7/50 (14%)	22
Pain	5/50 (10%)	10
Pyrexia	15/50 (30%)	26
Infections and infestations
Bronchitis	6/50 (12%)	7
Bronchitis acute	4/50 (8%)	5
Cystitis	3/50 (6%)	3
Gastroenteritis viral	6/50 (12%)	8
Influenza	3/50 (6%)	4
Nasopharyngitis	7/50 (14%)	15
Sinusitis	17/50 (34%)	26
Upper respiratory tract infection	13/50 (26%)	19
Urinary tract infection	4/50 (8%)	4
Injury, poisoning and procedural complications
Contusion	3/50 (6%)	3
Musculoskeletal and connective tissue disorders
Athralgia	3/50 (6%)	5
Back pain	5/50 (10%)	6
Muscle spasms	3/50 (6%)	4
Myalgia	5/50 (10%)	7
Nervous system disorders
Headache	18/50 (36%)	97
Sinus headache	3/50 (6%)	4
Psychiatric disorders
Insomnia	3/50 (6%)	5
Respiratory, thoracic and mediastinal disorders
Asthma	4/50 (8%)	19
Cough	3/50 (6%)	5
Nasal congestion	6/50 (12%)	7
Pharyngolaryngeal pain	7/50 (14%)	11
Sinus congestion	4/50 (8%)	7
Wheezing	3/50 (6%)	5
Skin and subcutaneous tissue disorders
Rash	5/50 (10%)	6
Vascular disorders
Hypertension	3/50 (6%)	10

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Publication of the Study results will be allowed only with prior written approval from Sponsor, said consent not to be unreasonably withheld. At the request of Sponsor, the Institution and/or Investigator shall delete any Confidential Information pertaining to Sponsor's Inventions from any proposed publications prior to submitting or presenting the materials. Any and all publications will give appropriate recognition of any support received from Sponsor.