SPARK: Safety and Pharmacokinetics of Alpha-1 Proteinase Inhibitor in Subjects With Alpha1-Antitrypsin Deficiency

• Sponsor: Grifols Therapeutics LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01213043
• Collaborator: (none)
• Enrollment: 30
• Locations: 5
• Arms: 2
• Duration (Months): 14
• Patients Per Site: 6
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This is a study to assess the safety and pharmacokinetics of weekly infusions of 120 mg/kg of Prolastin-C (alpha1-proteinase inhibitor [alpha1-PI] [Human]), compared to weekly infusions of 60 mg/kg of Prolastin-C in patients with alpha 1-antitrypsin deficiency (AATD).

Condition or Disease	Intervention/Treatment	Phase
Emphysema; Alpha 1-antitrypsin Deficiency (AATD)	Biological: Prolastin-C, 60 mg/kg; Biological: Prolastin-C, 120 mg/kg	Phase 2

Detailed Description

The question of whether higher doses of alpha1-PI (>60 mg/kg) are able to provide better protection to patients with alpha 1-antitrypsin deficiency is currently unknown. As a first step to address this question, the present study has been undertaken. This is a multi-center, randomized, double-blind, crossover study to assess the safety and pharmacokinetics of weekly infusions of 120 mg/kg of Prolastin-C, compared to weekly infusions of 60 mg/kg of Prolastin-C in patients with alpha 1-antitrypsin deficiency. This study is a crossover design with 2 treatment sequences:

Treatment Sequence 1: 60 mg/kg weekly infusion of Prolastin-C for 8 weeks followed by 120 mg/kg weekly infusion of Prolastin-C for 8 weeks (starting at Week 1) (total of 16 treatment weeks)

Treatment Sequence 2: 120 mg/kg weekly infusion of Prolastin-C for 8 weeks followed by 60 mg/kg weekly infusion of Prolastin-C for 8 weeks (starting at Week 11) (total of 16 treatment weeks)

Approximately 15 subjects are planned to be entered into each treatment sequence.

At Weeks 8 to 11 and Weeks 18 to 21, a total of 15 serial blood samples for each subject will be drawn for pharmacokinetic analysis. The expected duration of the study subject's participation will be approximately 25 weeks (which includes a 3-Week Screening Phase, 2-Week Washout Period [between different alpha-1 PI treatment doses], and a 4-Week Follow-up Period). The following safety parameters will be assessed: adverse events, pulmonary exacerbations, vital signs, pulmonary function tests, and clinical laboratory tests.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized Double-blind Crossover Study to Assess the Safety and Pharmacokinetics of Two Different Doses of Weekly Intravenous Administration of Alpha1-Proteinase Inhibitor (Human) Prolastin®-C in Subjects With Alpha1-Antitrypsin Deficiency
• Study Start Date: Nov 1, 2010
• Actual Primary Completion Date: Jan 1, 2012
• Actual Study Completion Date: Jan 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Prolastin-C, 60 mg/kg 60 mg/kg weekly infusion of Prolastin-C for 8 weeks. Subjects were infused with 60 mg/kg Prolastin-C by means of one of two possible treatment sequences: 1) 60 mg/kg weekly infusion of Prolastin-C for 8 weeks followed by 120 mg/kg Prolastin-C for 8 weeks, or 2) 120 mg/kg Prolastin-C for 8 weeks followed by 60 mg/kg weekly infusion of Prolastin-C for 8 weeks (total of 16 weeks).	Biological: Prolastin-C, 60 mg/kg; 60 mg/kg weekly infusion of Prolastin-C for 8 weeks; Other Names: Alpha1-Proteinase Inhibitor Alpha1-Proteinase Inhibitor (Human), Modified Process Alpha-1 MP
Experimental: Prolastin-C, 120 mg/kg 120 mg/kg weekly infusion of Prolastin-C for 8 weeks. Subjects were infused with 120 mg/kg Prolastin-C by means of one of two possible treatment sequences: 1) 60 mg/kg weekly infusion of Prolastin-C for 8 weeks followed by 120 mg/kg Prolastin-C for 8 weeks, or 2) 120 mg/kg Prolastin-C for 8 weeks followed by 60 mg/kg weekly infusion of Prolastin-C for 8 weeks (total of 16 weeks).	Biological: Prolastin-C, 120 mg/kg; 120 mg/kg weekly infusion of Prolastin-C for 8 weeks; Other Names: Alpha1-Proteinase Inhibitor Alpha1-Proteinase Inhibitor (Human), Modified Process Alpha-1 MP

Outcome Measures

Primary Outcome Measures

1. Subjects With Treatment-Emergent Adverse Events (TEAEs) [22 weeks]

   Number of subjects experiencing at least one TEAE. TEAEs were defined as any adverse event (AE) during the study that began on or after the date of first dose of investigational product (i.e., Prolastin-C).

2. Subjects With Drug-Related TEAE(s) [22 weeks]

   Number of subjects with at least one TEAE that was determined by the Investigator to be either "possibly related" or "related" to the investigational product (i.e., Prolastin-C).

3. Subjects With Treatment-Emergent Serious Adverse Events (SAEs) [22 weeks]

   Number of subjects who experienced at least one treatment-emergent SAE.

4. Subjects Withdrawn Due to an AE(s) [22 weeks]

   Number of subjects who were withdrawn from the study due to at least one AE.

5. Subjects With Treatment-Emergent Pulmonary Exacerbation(s) [22 weeks]

   Number of subjects with at least one treatment-emergent pulmonary exacerbation

6. Subjects With Severe TEAE(s) or Pulmonary Exacerbation(s) [22 weeks]

   Number of subjects who experienced at least one severe TEAE or pulmonary exacerbation.

7. Number of TEAEs [22 Weeks]

   Total number of TEAEs reported.

8. Number of Drug-related TEAEs [22 Weeks]

   Total number of drug-related TEAEs reported

9. Number of Treatment-Emergent Pulmonary Exacerbations [22 Weeks]

   Total number of treatment-emergent pulmonary exacerbations.

Secondary Outcome Measures

1. AUC0-7days [Week 8 and Week 18 at the following timepoints: 0 (pre-infusion), completion of first infusion bag, completion of 2nd infusion bag, and 15 min, 30 min, and 1, 2, 4, 8, 24, 48, 120, and 168 hours post-dose]

   Area Under the Alpha-1 PI Concentration-Time Curve from Day 0 to Day 7

2. Mean Trough [Single measurment immediately prior to infusion at Weeks 6, 7, 8, 9 and Weeks 16, 17, 18, 19]

   The average trough concentration at steady-state, calculated as the mean value using the four Trough measurements obtained at Weeks 6, 7, 8 and at 7 days (168 hours) post infusion at Week 8 for the first treatment period or prior to the start of the infusions at Weeks 16, 17, 18, and at 7 days (168 hours) post infusion at Week 18 for the second treatment period.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Be between 18 and 70 years of age

• Have a documented diagnosis of congenital AATD

• Have a post-bronchodilator Forced Expired Volume in 1 second (FEV1) of ≥30% and <80% and FEV1/forced vital capacity (FVC) <70%

• If receiving alpha-1 PI augmentation therapy, be willing to discontinue the treatment for the duration of the study

Exclusion Criteria:

• Had a moderate or severe pulmonary exacerbation during the 4 weeks before the study

• History of lung or liver transplant

• Any lung surgery during the past 2 years

• Confirmed liver cirrhosis

• Elevated liver enzymes

• Severe concurrent disease

• Females who are pregnant or breast-feeding or unwilling to practice effective contraception during the study

• Infection with hepatitis A, B, or C, human immunodeficiency or parvovirus B19

• Smoking during the past 6 months

• Use of systemic steroids within 4 weeks of the study

• Use of antibiotics for an exacerbation within 4 weeks of the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Florida College of Medicine	Gainesville	Florida	United States	32610-0225
2	University of Miami	Miami	Florida	United States	33136
3	Temple University Hosptial/Temple Lung Center	Philadelphia	Pennsylvania	United States	19140
4	Medical University of South Carolina, Division of Pulmonary and Critical Care Medicine	Charleston	South Carolina	United States	29425-6300
5	The University of Texas Health Science Center at Tyler	Tyler	Texas	United States	75708

Sponsors and Collaborators

• Grifols Therapeutics LLC

Investigators

• Principal Investigator: Mark Brantly, MD, University of Florida
• Principal Investigator: Michael Campos, MD, University of Miami
• Principal Investigator: Friedrich Kueppers, MD, Temple University Hospital/Temple Lung Center
• Principal Investigator: James Stocks, MD, The University of Texas Health Science Center at Tyler
• Principal Investigator: Charlie Strange, MD, Medical University of South Carolina, Division of Pulmonary and Critical Care Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

• Willis T, Wee K, Mohn G. A high-purity Alpha-1 proteinase inhibitor from human plasma, TAL6004. Proceeding of the 19th European Respiratory Society Annual Congress; 2009 Sep 12-16; Vienna, Austria. Abstracts;34:S53.

• Responsible Party: Grifols Therapeutics LLC
• ClinicalTrials.gov Identifier: NCT01213043
• Other Study ID Numbers: T6004-201/Version 2
• First Posted: Oct 1, 2010
• Last Update Posted: May 20, 2013
• Last Verified: Apr 1, 2013

• Keywords provided by Grifols Therapeutics LLC: emphysema; alpha 1-antitrypsin; alpha 1-antitrypsin deficiency (AATD); alpha 1-proteinase inhibitor (Alpha-1 PI)
• Additional relevant MeSH terms: Alpha 1-Antitrypsin Deficiency; Pulmonary Emphysema; Emphysema; Protease Inhibitors; Alpha 1-Antitrypsin

Study Results

Participant Flow

Pre-assignment Detail	Subjects entered a Screening Phase (up to 21 days in duration) to determine subject eligibility and for wash-out of prior alpha1-PI augmentation therapy, if applicable, prior to randomization to one of two treatment sequences.

Arm/Group Title	60 mg/kg - 120 mg/kg Prolastin-C Treatment Sequence	120 mg/kg - 60 mg/kg Prolastin-C Treatment Sequence
Arm/Group Description	Weekly infusions of 60 mg/kg Prolastin-C for 8 weeks followed by a 2-week off-treatment washout period followed by weekly infusions of 120 mg/kg Prolastin-C for 8 weeks (total of 16 treatment weeks)	Weekly infusions of 120 mg/kg Prolastin-C for 8 weeks followed by a 2-week off-treatment washout period followed by weekly infusions of 60 mg/kg Prolastin-C for 8 weeks (total of 16 treatment weeks)
Period Title: Treatment Period 1
STARTED	15	15
COMPLETED	15	15
NOT COMPLETED	0	0
Period Title: Treatment Period 1
STARTED	15	15
COMPLETED	15	15
NOT COMPLETED	0	0
Period Title: Treatment Period 1
STARTED	15	15
COMPLETED	15	15
NOT COMPLETED	0	0
Period Title: Treatment Period 1
STARTED	15	15
COMPLETED	15	15
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	60 mg/kg - 120 mg/kg Prolastin-C Treatment Sequence	120 mg/kg - 60 mg/kg Prolastin-C Treatment Sequence	Total
Arm/Group Description	Weekly infusions of 60 mg/kg Prolastin-C for 8 weeks followed by a 2-week off-treatment washout period followed by weekly infusions of 120 mg/kg Prolastin-C for 8 weeks (total of 16 treatment weeks)	Weekly infusions of 120 mg/kg Prolastin-C for 8 weeks followed by a 2-week off-treatment washout period followed by weekly infusions of 60 mg/kg Prolastin-C for 8 weeks (total of 16 treatment weeks)	Total of all reporting groups
Overall Participants	15	15	30
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.7 (6.89)	57.4 (6.34)	58.6 (6.62)
Sex: Female, Male (Count of Participants)
Female	8 53.3%	8 53.3%	16 53.3%
Male	7 46.7%	7 46.7%	14 46.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	15 100%	15 100%	30 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Subjects With Treatment-Emergent Adverse Events (TEAEs)
Description	Number of subjects experiencing at least one TEAE. TEAEs were defined as any adverse event (AE) during the study that began on or after the date of first dose of investigational product (i.e., Prolastin-C).
Time Frame	22 weeks

Outcome Measure Data

Analysis Population Description

All safety analyses were performed on the safety population, which comprised of all subjects who were randomized and received at least one dose of investigational product (Prolastin-C).

Arm/Group Title	60 mg/kg Prolastin-C	120 mg/kg Prolastin-C
Arm/Group Description
Measure Participants	30	30
Number [participants]	23 153.3%	18 120%

2. Secondary Outcome

Title	AUC0-7days
Description	Area Under the Alpha-1 PI Concentration-Time Curve from Day 0 to Day 7
Time Frame	Week 8 and Week 18 at the following timepoints: 0 (pre-infusion), completion of first infusion bag, completion of 2nd infusion bag, and 15 min, 30 min, and 1, 2, 4, 8, 24, 48, 120, and 168 hours post-dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Population, which consisted of all subjects who received investigational product (Prolastin-C) and had sufficient and valid serum concentration data to facilitate calculation of PK parameters.

Arm/Group Title	60 mg/kg Prolastin-C	120 mg/kg Prolastin-C
Arm/Group Description
Measure Participants	29	30
Mean (Standard Deviation) [h*mg/mL]	203.6 (20.48)	344.8 (46.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	60 mg/kg Prolastin-C, 120 mg/kg Prolastin-C
	Comments	Dose proportionality was analysed using an ANOVA model for the natural log-transformed AUC0-7days with treatment, period, and sequence as fixed effects and subject within sequence as a random effect. The treatment dose of 60 mg/kg was the reference treatment and 120 mg/kg was the test treatment. PK parameters in individual subjects for each treatment dose were dose normalized to 60mg/kg based on the actual dose administered at Week 8 or Week 18 (i.e., (AUC0-7days/Actual Dose in mg/kg)*60mg/kg).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Equivalence margin was: [0.80, 1.25]
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Geometric Least Square Means Ratio
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 90%; 0.83 to 0.88
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Subjects With Drug-Related TEAE(s)
Description	Number of subjects with at least one TEAE that was determined by the Investigator to be either "possibly related" or "related" to the investigational product (i.e., Prolastin-C).
Time Frame	22 weeks

Outcome Measure Data

Analysis Population Description

All safety analyses were performed on the safety population, which comprised of all subjects who were randomized and received at least one dose of investigational product (Prolastin-C).

Arm/Group Title	60 mg/kg Prolastin-C	120 mg/kg Prolastin-C
Arm/Group Description
Measure Participants	30	30
Number [participants]	3 20%	1 6.7%

4. Primary Outcome

Title	Subjects With Treatment-Emergent Serious Adverse Events (SAEs)
Description	Number of subjects who experienced at least one treatment-emergent SAE.
Time Frame	22 weeks

Outcome Measure Data

Analysis Population Description

All safety analyses were performed on the safety population, which comprised of all subjects who were randomized and received at least one dose of investigational product (Prolastin-C).

Arm/Group Title	60 mg/kg Prolastin-C	120 mg/kg Prolastin-C
Arm/Group Description
Measure Participants	30	30
Number [participants]	0 0%	0 0%

5. Primary Outcome

Title	Subjects Withdrawn Due to an AE(s)
Description	Number of subjects who were withdrawn from the study due to at least one AE.
Time Frame	22 weeks

Outcome Measure Data

Analysis Population Description

All safety analyses were performed on the safety population, which comprised of all subjects who were randomized and received at least one dose of investigational product (Prolastin-C).

Arm/Group Title	60 mg/kg Prolastin-C	120 mg/kg Prolastin-C
Arm/Group Description
Measure Participants	30	30
Number [participants]	0 0%	0 0%

6. Primary Outcome

Title	Subjects With Treatment-Emergent Pulmonary Exacerbation(s)
Description	Number of subjects with at least one treatment-emergent pulmonary exacerbation
Time Frame	22 weeks

Outcome Measure Data

Analysis Population Description

All safety analyses were performed on the safety population, which comprised of all subjects who were randomized and received at least one dose of investigational product (Prolastin-C).

Arm/Group Title	60 mg/kg Prolastin-C	120 mg/kg Prolastin-C
Arm/Group Description
Measure Participants	30	30
Number [participants]	7 46.7%	5 33.3%

7. Primary Outcome

Title	Subjects With Severe TEAE(s) or Pulmonary Exacerbation(s)
Description	Number of subjects who experienced at least one severe TEAE or pulmonary exacerbation.
Time Frame	22 weeks

Outcome Measure Data

Analysis Population Description

All safety analyses were performed on the safety population, which comprised of all subjects who were randomized and received at least one dose of investigational product (Prolastin-C).

Arm/Group Title	60 mg/kg Prolastin-C	120 mg/kg Prolastin-C
Arm/Group Description
Measure Participants	30	30
Number [participants]	0 0%	0 0%

8. Secondary Outcome

Title	Mean Trough
Description	The average trough concentration at steady-state, calculated as the mean value using the four Trough measurements obtained at Weeks 6, 7, 8 and at 7 days (168 hours) post infusion at Week 8 for the first treatment period or prior to the start of the infusions at Weeks 16, 17, 18, and at 7 days (168 hours) post infusion at Week 18 for the second treatment period.
Time Frame	Single measurment immediately prior to infusion at Weeks 6, 7, 8, 9 and Weeks 16, 17, 18, 19

Outcome Measure Data

Analysis Population Description

PK Population, which consisted of all subjects who received investigational product (Prolastin-C) and had sufficient and valid serum concentration data to facilitate calculation of PK parameters.

Arm/Group Title	60 mg/kg Prolastin-C	120 mg/kg Prolastin-C
Arm/Group Description
Measure Participants	30	30
Mean (Standard Deviation) [μM]	17.3 (2.36)	27.7 (3.75)

9. Primary Outcome

Title	Number of TEAEs
Description	Total number of TEAEs reported.
Time Frame	22 Weeks

Outcome Measure Data

Analysis Population Description

All safety analyses were performed on the safety population, which comprised of all subjects who were randomized and received at least one dose of investigational product (Prolastin-C).

Arm/Group Title	60 mg/kg Prolastin-C	120 mg/kg Prolastin-C
Arm/Group Description
Measure Participants	30	30
Number [Events]	69	43

10. Primary Outcome

Title	Number of Drug-related TEAEs
Description	Total number of drug-related TEAEs reported
Time Frame	22 Weeks

Outcome Measure Data

Analysis Population Description

All safety analyses were performed on the safety population, which comprised of all subjects who were randomized and received at least one dose of investigational product (Prolastin-C).

Arm/Group Title	60 mg/kg Prolastin-C	120 mg/kg Prolastin-C
Arm/Group Description
Measure Participants	30	30
Number [Events]	5	1

11. Primary Outcome

Title	Number of Treatment-Emergent Pulmonary Exacerbations
Description	Total number of treatment-emergent pulmonary exacerbations.
Time Frame	22 Weeks

Outcome Measure Data

Analysis Population Description

All safety analyses were performed on the safety population, which comprised of all subjects who were randomized and received at least one dose of investigational product (Prolastin-C).

Arm/Group Title	60 mg/kg Prolastin-C	120 mg/kg Prolastin-C
Arm/Group Description
Measure Participants	30	30
Number [Events]	9	6

Adverse Events

Time Frame	Adverse events were assessed from the time of informed consent through the end of study visit; thus, AEs were assessed for up to 25 weeks.
Adverse Event Reporting Description	Assessment of AEs were performed by questioning the subject at each scheduled study visit. Treatment Emergent adverse events were defined as any AE during the study that began on or after the date of first dose of investigational product (i.e., Prolastin-C).
Arm/Group Title	60 mg/kg Prolastin-C		120 mg/kg Prolastin-C
Arm/Group Description
All Cause Mortality
	60 mg/kg Prolastin-C		120 mg/kg Prolastin-C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	60 mg/kg Prolastin-C		120 mg/kg Prolastin-C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/30 (0%)
Other (Not Including Serious) Adverse Events
	60 mg/kg Prolastin-C		120 mg/kg Prolastin-C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/30 (50%)		10/30 (33.3%)
Blood and lymphatic system disorders
Thrombocytopenia	2/30 (6.7%)	2	0/30 (0%)	0
Infections and infestations
Urinary Tract Infection	3/30 (10%)	4	0/30 (0%)	0
Injury, poisoning and procedural complications
Contusion	1/30 (3.3%)	1	2/30 (6.7%)	2
Investigations
Blood Creatinine Increased	0/30 (0%)	0	2/30 (6.7%)	2
Blood Glucose Increased	0/30 (0%)	0	2/30 (6.7%)	2
Renal and urinary disorders
Proteinuria	2/30 (6.7%)	2	1/30 (3.3%)	1
Respiratory, thoracic and mediastinal disorders
COPD Exacerbation	7/30 (23.3%)	9	5/30 (16.7%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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