Double-Blind, Multiple Ascending Dose Study to Assess Safety, Tolerability and Pharmacokinetics of DX-2930 in Hereditary Angioedema (HAE) Subjects

• ClinicalTrials.gov Identifier: NCT02093923
• Recruitment Status: Completed
• First Posted: March 21, 2014
• Results First Posted: August 1, 2016
• Last Update Posted: August 1, 2016
• Sponsor: Shire
• Information provided by (Responsible Party): Shire

Study Description

Brief Summary:

The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetic profile of multiple subcutaneous administrations of DX-2930 across a range of doses in Hereditary Angioedema subjects.

Condition or disease	Intervention/treatment	Phase
Hereditary Angioedema	Drug: DX-2930; Drug: Placebo	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 38 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 1b, Double-Blind, Multiple Ascending Dose Study to Assess Safety, Tolerability and Pharmacokinetics of DX-2930 in Hereditary Angioedema Subjects
• Study Start Date: April 2014
• Actual Primary Completion Date: May 2015
• Actual Study Completion Date: May 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: DX-2930, Dose level 1; 30 mg of DX-2930 administered twice, two weeks apart	Drug: DX-2930; DX-2930 is a recombinant, Chinese hamster ovary (CHO) cell expressed, fully human immunoglobulin IgG1, kappa light chain, monoclonal antibody; Drug: Placebo; Placebo
Experimental: DX-2930, Dose level 2; 100 mg of DX-2930 administered twice, two weeks apart	Drug: DX-2930; DX-2930 is a recombinant, Chinese hamster ovary (CHO) cell expressed, fully human immunoglobulin IgG1, kappa light chain, monoclonal antibody; Drug: Placebo; Placebo
Experimental: DX-2930, Dose level 3; 300 mg of DX-2930 administered twice, two weeks apart	Drug: DX-2930; DX-2930 is a recombinant, Chinese hamster ovary (CHO) cell expressed, fully human immunoglobulin IgG1, kappa light chain, monoclonal antibody; Drug: Placebo; Placebo
Experimental: DX-2930, Dose level 4; 400 mg of DX-2930 administered twice, two weeks apart	Drug: DX-2930; DX-2930 is a recombinant, Chinese hamster ovary (CHO) cell expressed, fully human immunoglobulin IgG1, kappa light chain, monoclonal antibody; Drug: Placebo; Placebo
Placebo Comparator: Placebo; Placebo administered twice, two weeks apart	Drug: Placebo; Placebo

Outcome Measures

Primary Outcome Measures :

1. Number of Patients With Treatment-Emergent Adverse Events (TEAE) [ Time Frame: through 4 months ]
   As per the DX-2930-02 clinical protocol, an AE was considered treatment-emergent if the onset time was after administration of study drug through the Day 120 post-dose final follow-up visit or, in the event that onset time preceded study drug administration, the AE increased in severity during the 120-day post-dose follow-up period.
2. Proportion of Patients With Treatment-Emergent Adverse Events (TEAE) [ Time Frame: through 4 months ]
   As per the DX-2930-02 clinical protocol, an AE was considered treatment-emergent if the onset time was after administration of study drug through the Day 120 post-dose final follow-up visit or, in the event that onset time preceded study drug administration, the AE increased in severity during the 120-day post-dose follow-up period.
3. Number of Patients With Serious Adverse Events (SAEs) [ Time Frame: through 4 months ]

   As per the DX-2930-02 clinical protocol, a SAE was any adverse experience occurring at any dose that resulted in any of the following outcomes:

   • Death
   • Life-threatening experience: "life-threatening" referred to a situation in which the subject was at risk of death at the time of the event, it did not refer to an event that might have caused death if it were more severe.
   • Required inpatient hospitalization or prolongation of existing hospitalization: this did not include hospitalization for observation with release within 24 hours. A scheduled hospitalization for a pre-existing condition that had not worsened during participation in the study did not meet this criterion. Pre-planned hospitalizations for an elective medical/surgical procedure or routine check-ups did not meet this criterion.
   • Resulted in persistent or significant disability or incapacity.
   • Was a congenital anomaly or birth defect.
   • Was considered to be an important medical event
4. Proportion of Patients With Serious Adverse Events [ Time Frame: through 4 months ]

   As per the DX-2930-02 clinical protocol, a SAE was any adverse experience occurring at any dose that resulted in any of the following outcomes:

   • Death
   • Life-threatening experience: "life-threatening" referred to a situation in which the subject was at risk of death at the time of the event, it did not refer to an event that might have caused death if it were more severe.
   • Required inpatient hospitalization or prolongation of existing hospitalization: this did not include hospitalization for observation with release within 24 hours. A scheduled hospitalization for a pre-existing condition that had not worsened during participation in the study did not meet this criterion. Pre-planned hospitalizations for an elective medical/surgical procedure or routine check-ups did not meet this criterion.
   • Resulted in persistent or significant disability or incapacity.
   • Was a congenital anomaly or birth defect.
   • Was considered to be an important medical event

Secondary Outcome Measures :

1. Maximum Plasma Concentration (Cmax) [ Time Frame: Pharmacokinetic samples were drawn on Days 1, 2, 4, 8, 15, 16, 18, 22, 29, 36, 50, 64, 92, and 120. ]
2. Time to Maximum Plasma Concentration (Tmax) [ Time Frame: Pharmacokinetic samples were drawn on Days 1, 2, 4, 8, 15, 16, 18, 22, 29, 36, 50, 64, 92, and 120. ]
3. Area Under the Plasma Concentration-time Curve (AUC) [ Time Frame: Pharmacokinetic samples were drawn on Days 1, 2, 4, 8, 15, 16, 18, 22, 29, 36, 50, 64, 92, and 120. ]
4. Apparent Clearance (CL/F) [ Time Frame: Pharmacokinetic samples were drawn on Days 1, 2, 4, 8, 15, 16, 18, 22, 29, 36, 50, 64, 92, and 120. ]
5. Apparent Volume of Distribution (Vd/F) [ Time Frame: Pharmacokinetic samples were drawn on Days 1, 2, 4, 8, 15, 16, 18, 22, 29, 36, 50, 64, 92, and 120. ]
6. Terminal Elimination Half-life (t1/2) [ Time Frame: Pharmacokinetic samples were drawn on Days 1, 2, 4, 8, 15, 16, 18, 22, 29, 36, 50, 64, 92, and 120. ]

Other Outcome Measures:

1. HAE Attack Rate Per Week [ Time Frame: Baseline, Day 8 to Day 50 ]
   The pre-specified, primary efficacy analysis was based on subjects in the 300 mg, 400 mg, and placebo dose groups with a historical baseline attack rate of at least 2 attacks over the last 3 months prior to enrollment. The result is based on General Estimating Equation (GEE) analysis of repeated counts per week during the prespecified assessment period (Days 8 to 50; predicted to correspond to a period of notable drug exposure). Baseline HAE attack rate per week is a covariate, treatment group is a fixed effect, and subject is a random effect in the GEE model with independence working correlation structure.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• At least 18 years of age at the time of screening.
• Documented diagnosis of HAE (Type I or II)
• Experiencing ≥2 HAE attacks per year, with at least 1 attack in the past 6 months reported by the subject.
• Willing and able to read, understand, and sign an informed consent form.
• Females of childbearing potential must agree to be abstinent or else use acceptable forms of contraception throughout study
• Males with female partners of childbearing potential must agree to be abstinent or use a medically acceptable form of contraception throughout study.

Exclusion Criteria:

• Exposure to an investigational drug or device within 90 days prior to study.
• History of exposure within the past 5 years to a monoclonal antibody or recombinant protein bearing an Fc domain.
• Concomitant diagnosis of another form of chronic angioedema
• Use of long-term prophylaxis for HAE within 90 days prior to study.
• Use of C1-INH that exceeds a total of 30 days within the past 90 days prior to study; any use of C1-INH within 7 days prior to study.
• Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systemic absorption within 90 days prior to study.
• Exposure to androgens within 90 days prior to study.
• Presence of an indwelling catheter.
• Diagnosis of HIV.
• Active liver disease or liver function test abnormalities
• History of substance abuse or dependence.
• Pregnancy or breastfeeding.
• Any condition that, in the opinion of the Investigator, may compromise their safety or compliance, preclude successful conduct of the study, or interfere with interpretation of the results

Contacts and Locations

Locations

United States, California

UC San Diego Health System - La Jolla

San Diego, California, United States, 92122

Allergy & Asthma Clinical Research

Walnut Creek, California, United States, 94598

United States, Florida

University of South Florida Asthma, Allergy or Immunology Clinical Research Unit

Tampa, Florida, United States, 33613

United States, Maryland

Institute for Asthma & Allergy, PC

Chevy Chase, Maryland, United States, 20815

United States, Massachusetts

Massachusetts General Hospital Allergy Associates

Boston, Massachusetts, United States, 02114

United States, Missouri

Washington University School of Medicine

St. Louis, Missouri, United States, 63110

United States, New York

Winthrop-University Hospital, Clinical Trials Center

Mineola, New York, United States, 11501

Icahn School of Medicine at Mount Sinai - The Mount Sinai Medical Center

New York, New York, United States, 10029

United States, Ohio

UC Physicians Company

Cincinnati, Ohio, United States, 45267

United States, Oregon

Baker Allergy, Asthma and Dermatology Research Center

Lake Oswego, Oregon, United States, 97035

United States, Pennsylvania

Penn State Hershey Medical Center

Hershey, Pennsylvania, United States, 17033

United States, Texas

AARA Research Center

Dallas, Texas, United States, 75231

Italy

Ospedale L. Sacco

Milano, MI, Italy, 20157

Jordan

Jordan University Hospital

Amman, Jordan, 11942

Sponsors and Collaborators

Shire

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Banerji A, Busse P, Shennak M, Lumry W, Davis-Lorton M, Wedner HJ, Jacobs J, Baker J, Bernstein JA, Lockey R, Li HH, Craig T, Cicardi M, Riedl M, Al-Ghazawi A, Soo C, Iarrobino R, Sexton DJ, TenHoor C, Kenniston JA, Faucette R, Still JG, Kushner H, Mensah R, Stevens C, Biedenkapp JC, Chyung Y, Adelman B. Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis. N Engl J Med. 2017 Feb 23;376(8):717-728. doi: 10.1056/NEJMoa1605767.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT02093923
• Other Study ID Numbers: DX-2930-02
• First Posted: March 21, 2014
• Results First Posted: August 1, 2016
• Last Update Posted: August 1, 2016
• Last Verified: June 2016

Keywords provided by Shire:

HAE

Additional relevant MeSH terms:

Angioedema; Angioedemas, Hereditary; Vascular Diseases; Cardiovascular Diseases; Urticaria; Skin Diseases, Vascular; Skin Diseases; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Genetic Diseases, Inborn