Long-term Safety and Efficacy Study of DX-2930 (SHP643) to Prevent Acute Angioedema Attacks in Patients With Type I and Type II HAE

HELP Study ExtensionTM: An Open-Label Study to Evaluate the Long-Term Safety and Efficacy of DX-2930 for Prevention Against Acute Attacks of Hereditary Angioedema (HAE)

This study is an open-label, long term safety and efficacy study to evaluate DX-2930 in preventing acute angioedema attacks in participants with Type I and Type II HAE.

Study Overview

• Status: Completed
• Conditions: Hereditary Angioedema (HAE)
• Intervention / Treatment: Drug: DX-2930; Drug: DX-2930

• Study Type: Interventional
• Enrollment (Actual): 212
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2V2
      • University of Alberta Hospital
  • Ontario
    • Ottawa, Ontario, Canada, K1G 6C6
      • Yang Medicine
    • Toronto, Ontario, Canada, M4V 1R2
      • Gordon Sussman Clinical Research, Inc.
  • Quebec
    • Quebec City, Quebec, Canada, G1V 4M6
      • Clinique Specialisee en Allergie de la Capitale
• Germany
  • Berlin, Germany, 10117
    • Charité - Universitätsmedizin Berlin
  • Frankfurt, Germany, 60596
    • Universitatsklinikum Frankfurt
  • Mainz, Germany, 55101
    • Hautklinik der Universitätsmedizin Mainz
  • Mörfelden-Walldorf, Germany, 64546
    • HZRM Hämophilie Zentrum Rhein Main GmbH
• Italy
  • Milan, Italy, 20157
    • University of Milan Luigi Sacco Hospital
• Jordan
  • Amman, Jordan, 11941
    • Triumpharma Clinical Evaluation Centre
• Puerto Rico
  • San Juan, Puerto Rico, 00918
    • Adler Medical Plaza
• United Kingdom
  • London, United Kingdom, E1 1BB
    • Royal London Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35209
      • Clinical Research Center of Alabama
  • Arizona
    • Scottsdale, Arizona, United States, 85251
      • Medical Research of Arizona
  • California
    • San Diego, California, United States, 92122
      • University of California San Diego
    • Santa Monica, California, United States, 90404
      • AIRE Medical of Los Angeles
    • Walnut Creek, California, United States, 94598
      • Allergy & Asthma Clinical Research
  • Colorado
    • Centennial, Colorado, United States, 80112
      • IMMUNOe Research Centers
    • Colorado Springs, Colorado, United States, 80907
      • Asthma and Allergy Associates, PC
  • Florida
    • Tampa, Florida, United States, 33613
      • University of South Florida
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Maryland
    • Chevy Chase, Maryland, United States, 20815
      • Institute Asthma and Allergy
  • Massachusetts
    • Boston, Massachusetts, United States, 02421
      • Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • University of Michigan
  • Minnesota
    • Plymouth, Minnesota, United States, 55446
      • Midwest Immunology Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New Jersey
    • Belleville, New Jersey, United States, 07109
      • Hudson-Essex Allergy, LLC
    • Ocean City, New Jersey, United States, 07712
      • Atlantic Research Center, LLC
  • New York
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
    • New York, New York, United States, 10029
      • Icahn School of Medicine At Mount Sinai
  • North Carolina
    • Charlotte, North Carolina, United States, 28277
      • Clinical Research Center of Charlotte
    • Durham, North Carolina, United States, 27705
      • Duke Asthma, Allergy, and Airway Center
  • Ohio
    • Cincinnati, Ohio, United States, 45231
      • Bernstein Clinical Research Center, LLC
    • Columbus, Ohio, United States, 43235
      • Optimed Research, Ltd.
    • Toledo, Ohio, United States, 43617
      • Toledo Institute of Clinical Research
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center
  • Texas
    • Austin, Texas, United States, 78731
      • Austin Regional Clinic
    • Dallas, Texas, United States, 75231
      • AARA Research Center
  • Utah
    • Draper, Utah, United States, 84020
      • Intermountain Clinical Research
    • Murray, Utah, United States, 84107
      • Allergy Associates of Utah
  • Virginia
    • Richmond, Virginia, United States, 23219
      • Virginia Commonwealth University
  • Washington
    • Spokane, Washington, United States, 99202
      • Premier Clinical Research
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin, Childrens Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and female HAE participants who are 12 years of age or older at the time of screening

• Documented diagnosis of HAE (Type I or II) based on

  1. Documented clinical history consistent with HAE (subcutaneous or mucosal, nonpruritic swelling episodes without accompanying urticaria).
  2. Diagnostic testing results obtained during screening (or a prior DX-2930 study) that confirm HAE Type I or II: C1 inhibitor (C1-INH) functional level less than (<) 40 percentage (%) of the normal level. Participants with functional C1-INH level 40-50% of the normal level may be enrolled if they also have a C4 level below the normal range. Participants may be retested if results are incongruent with clinical history or believed by the investigator to be confounded by long-term prophylactic (LTP) use. (It is understood that C1-INH therapy may alter the lab results of C1-INH assessments; therefore, the investigator's discretion in collaboration with Medical Monitor is advised for proper documentation of eligibility).
  3. At least one of the following: Age at reported onset of first angioedema symptoms less than or equal to (<=) 30 years, a family history consistent with HAE Type I or II, or C1q within normal range.
• A historical baseline HAE attack rate of at least 1 attack per 12 weeks
• Adult participants and caregivers of participants under the age of 18 are willing and able to read, understand, and sign an informed consent form. Participants age 12 to 17, whose caregiver has provided informed consent, are willing and able to read, understand and sign an assent form.

• Males and females who are fertile and sexually active must adhere to contraception requirements for the duration of the study as

  1. Females (NOTE: Female rollover participants (those who previously participated in Study DX-2930-03 [NCT02586805]) of childbearing potential may continue to use the birth control method used during Study DX-2930-03 (NCT02586805).) of childbearing potential must agree to be abstinent or it is recommended to use highly effective forms of contraception from the screening period through 30 days after the final study visit. This includes stable doses (for 3 months prior to study screening) of combined estrogen and progestin-containing hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable), progestin-only hormonal contraception associated with inhibition of ovulation, intra-uterine device (IUD, all types) or intrauterine hormone releasing systems (IUS). Notes: 1) A female whose male partner has had a vasectomy must agree to use one additional form of medically acceptable contraception. 2) Use of a male condom with or without spermicide or cervical cap, diaphragm or sponge with spermicide or a combination (double barrier methods) are not considered highly effective.
  2. Females of non-childbearing potential, defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months do not require contraception during the study.
  3. Males, including males who are surgically sterile (post vasectomy), with female partners of childbearing potential must agree to be abstinent or else use a medically acceptable form of contraception from the screening period through 60 days after the final study visit.

Exclusion Criteria:

• Discontinued from DX-2930-03 (NCT02586805) after enrollment for any reason.
• If rolling over from DX-2930-03 (NCT02586805), presence of important safety concerns that would preclude participation in this study.
• Concomitant diagnosis of another form of chronic, recurrent angioedema, such as acquired angioedema (AAE), HAE with normal C1 inhibitor (also known as HAE Type III), idiopathic angioedema, or recurrent angioedema associated with urticaria.
• Dosing with an investigational drug (not including DX-2930 or other HAE therapies) or exposure to an investigational device within 4 weeks prior to screening.
• Exposure to angiotensin-converting enzyme (ACE) inhibitors within 4 weeks prior to screening or any newly initiated or dose modification of estrogen-containing medications with systemic absorption (such as oral contraceptives or hormonal replacement therapy) 3 months prior to the screening visit.
• Unwilling to discontinue use of long-term prophylactic therapy for HAE (C1-INH, attenuated androgens, or anti-fibrinolytics) within 3 weeks after starting DX-2930 treatment.
• Any of the following liver function test abnormalities: alanine aminotransferase (ALT) > 3x upper limit of normal, or aspartate aminotransferase (AST) > 3x upper limit of normal, or total bilirubin > 2x upper limit of normal (unless the bilirubin elevation is a result of Gilbert's Syndrome).
• Pregnancy or breastfeeding.
• Participant has any condition that, in the opinion of the investigator or Sponsor, may compromise their safety or compliance, preclude successful conduct of the study, or interfere with interpretation of the results (eg, history of substance abuse or dependence, a significant pre-existing illness or other major comorbidity that the investigator considers may confound the interpretation of study results).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Rollover Participants; Participants who rollover from the DX-2930-03 study will receive 300 milligram (mg) DX-2930 subcutaneous injection at Day 0 followed by second dose following the first HAE attack and then once in every 2 weeks until the end of the treatment period (up to 924 days). A wash-out period of a minimum of 10 days and a maximum of 18 days is required between subsequent administrations.	Drug: DX-2930; Participants who rollover from the DX-2930-03 study will receive 300 milligram (mg) DX-2930 subcutaneous injection at Day 0 followed by second dose following the first HAE attack and then once in every 2 weeks until the end of the treatment period (up to 924 days). A wash-out period of a minimum of 10 days and a maximum of 18 days is required between subsequent administrations.; Drug: DX-2930; Participants who were not participants in DX-2930-03 will receive 300 milligram (mg) DX-2930 subcutaneous injection once in every 2 weeks until the end of the treatment period (up to 924 days).
EXPERIMENTAL: Non-rollover Participants; Participants who were not participants in DX-2930-03 will receive 300 milligram (mg) DX-2930 subcutaneous injection once in every 2 weeks until the end of the treatment period (up to 924 days).	Drug: DX-2930; Participants who rollover from the DX-2930-03 study will receive 300 milligram (mg) DX-2930 subcutaneous injection at Day 0 followed by second dose following the first HAE attack and then once in every 2 weeks until the end of the treatment period (up to 924 days). A wash-out period of a minimum of 10 days and a maximum of 18 days is required between subsequent administrations.; Drug: DX-2930; Participants who were not participants in DX-2930-03 will receive 300 milligram (mg) DX-2930 subcutaneous injection once in every 2 weeks until the end of the treatment period (up to 924 days).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An adverse event (AE) was any untoward medical occurrence in a clinical trial Participant whether or not it appeared to have a causal relationship with the treatment administered. Treatment-emergent AEs were defined as AEs with onset at the time of or following the first exposure to open-label DX-2930 in this study, or medical conditions present prior to the start of treatment but increasing in severity or relationship at the time of or following the start of treatment.	From start of the study up to follow-up (Day 952)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attacks During the Treatment Period	HAE attack was defined as a discrete episode during which the participant progressed from no angioedema to symptoms of angioedema. The treatment period investigator-confirmed HAE attack rate was calculated for each participant as the number of investigator-confirmed HAE attacks occurring during the treatment period (regular dosing stage of the treatment period for rollover participants) divided by the number of days the participant contributed to the treatment period multiplied by 28 days. Rate of investigator-confirmed HAE attacks during the treatment period was reported.	Up to Day 924
Rate of Investigator-Confirmed Hereditary Angioedema (HAE) Attacks Requiring Acute Treatment During the Treatment Period	HAE attack was defined as a discrete episode during which the participant progressed from no angioedema to symptoms of angioedema. Rate of investigator-confirmed HAE attacks requiring acute treatment for each participant as the number of investigator-confirmed HAE attacks occurring during the treatment period (regular dosing stage of the treatment period for rollover participants) divided by the number of days the participant contributed to the treatment period multiplied by 28 days. Rate of investigator-confirmed HAE attacks requiring acute treatment during the treatment period was reported.	Up to Day 924
Rate of Moderate or Severe Hereditary Angioedema (HAE) Attacks During the Treatment Period	HAE attack was defined as a discrete episode during which the participant progressed from no angioedema to symptoms of angioedema. Moderate and severe investigator-confirmed HAE attacks were the attacks that were moderate or severe as per the HAE attack assessment and reporting procedures (HAARP) defined severity. The overall severity of attack was determined by the investigator using following definitions: mild (transient or mild discomfort), moderate (mild to moderate limitation in activity), severe (marked limitation in activity). Rate of moderate or severe HAE attacks during the treatment period was reported.	Up to Day 924
Rate of High-Morbidity Hereditary Angioedema (HAE) Attacks During the Treatment Period	HAE attack was defined as a discrete episode during which the participant progressed from no angioedema to symptoms of angioedema. High-morbidity Hereditary Angioedema (HAE) attack was defined as any attack that had at least one of the following characteristics: severe, resulted in hospitalization (except hospitalization for observation lesser than [<] 24 hours), hemodynamically significant (systolic blood pressure <90 millimeter of mercury [mmHg], required intravenous hydration, or associated with syncope or near-syncope) or laryngeal edema. Number of high-morbidity HAE attacks during the treatment period was analyzed and reported using the methods for the overall number of investigator-confirmed HAE attacks with the exception of the monthly line graphs. Rate of high-morbidity HAE attacks during the treatment period was reported.	Up to Day 924
Time to First Investigator-Confirmed Hereditary Angioedema (HAE) Attacks in Rollover Participants	HAE attack was defined as a discrete episode during which the participant progressed from no angioedema to symptoms of angioedema. Time to first investigator-confirmed HAE attack was calculated from the time of first open-label dose to the start time of the first investigator-confirmed HAE attack. Time to the first investigator-confirmed HAE attack was analyzed and reported only in rollover safety population.	Up to Day 924

Collaborators and Investigators

• Sponsor: Shire

Publications and helpful links

General Publications

• Craig TJ, Zaragoza-Urdaz RH, Li HH, Yu M, Ren H, Juethner S, Anderson J; HELP and HELP OLE Study Investigators. Effectiveness and safety of lanadelumab in ethnic and racial minority subgroups of patients with hereditary angioedema: results from phase 3 studies. Allergy Asthma Clin Immunol. 2022 Sep 24;18(1):85. doi: 10.1186/s13223-022-00721-y.
• Banerji A, Bernstein JA, Johnston DT, Lumry WR, Magerl M, Maurer M, Martinez-Saguer I, Zanichelli A, Hao J, Inhaber N, Yu M, Riedl MA; HELP OLE Investigators. Long-term prevention of hereditary angioedema attacks with lanadelumab: The HELP OLE Study. Allergy. 2022 Mar;77(3):979-990. doi: 10.1111/all.15011. Epub 2021 Aug 13.
• Riedl MA, Bernstein JA, Craig T, Banerji A, Magerl M, Cicardi M, Longhurst HJ, Shennak MM, Yang WH, Schranz J, Baptista J, Busse PJ. An open-label study to evaluate the long-term safety and efficacy of lanadelumab for prevention of attacks in hereditary angioedema: design of the HELP study extension. Clin Transl Allergy. 2017 Oct 6;7:36. doi: 10.1186/s13601-017-0172-9. eCollection 2017.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 26, 2016
• Primary Completion (ACTUAL): October 31, 2019
• Study Completion (ACTUAL): October 31, 2019

Study Registration Dates

• First Submitted: April 8, 2016
• First Submitted That Met QC Criteria: April 15, 2016
• First Posted (ESTIMATE): April 18, 2016

Study Record Updates

• Last Update Posted (ACTUAL): June 8, 2021
• Last Update Submitted That Met QC Criteria: May 14, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Hereditary Angioedema; Dyax; DX-2930(SHP643)
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Hypersensitivity, Immediate; Genetic Diseases, Inborn; Skin Diseases, Vascular; Hypersensitivity; Urticaria; Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Angioedema; Angioedemas, Hereditary; Physiological Effects of Drugs; Immunologic Factors; Antibodies, Monoclonal
• Other Study ID Numbers: DX-2930-04; 2015-005255-27 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No