Hereditary Angioedema (HAE)Phase 3NCT02052141
Safety and Efficacy Study of CINRYZE for Prevention of Angioedema Attacks in Children Ages 6-11 With Hereditary Angioedema
A Phase 3 study testing CINRYZE 500 and CINRYZE 1000 in people with Hereditary Angioedema (HAE), run by Shire at 8 sites in 5 countries.
Trial summary
Primary Objective - To assess the relative efficacy of two dose levels of CINRYZE (500 Units and 1000 Units) administered by intravenous (IV) injection every 3 or 4 days to prevent angioedema attacks in children 6 to 11 years of age with hereditary angioedema (HAE). Read more about this study
- Who is it for?
- Ages 6 to 11 years
- Conditions the study is for
- Hereditary Angioedema (HAE)
- What is being tested?
- CINRYZE 500 and CINRYZE 1000
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 8 sitesin 5 countries
- Study dates
- 20 Mar 2014to 4 May 2017
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 to 11 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Diagnosis of Type I or Type II HAE.
- History of angioedema attacks.
Who cannot join
- History of bleeding or clotting abnormality.
- Diagnosis of acquired angioedema or known to have C1 INH antibodies.
- History of allergic reaction to C1 esterase inhibitor or other blood products.
- Receipt of any experimental agents other than those required for prevention or treatment of angioedema attacks within 30 days prior to screening.
Trial locations and contacts
8 sites in 5 countries.
8 sites in 5 countries
United States3 sites
Asthma and Allergy Associates, P.C
Colorado Springs, Colorado, 80907
Oregon Allergy Associates
Eugene, Oregon, 97401
Nevada Access to Research and Education Society
Las Vegas, Nevada, 89106
Germany2 sites
Klinikum der J.W. Goethe Universitat
Frankfurt, 60590
HZRM Hamophilie Zentrum Rhein Main GmbH
Mörfelden-Walldorf, 64546
About this study
Official title: A Phase 3, Multicenter, Randomized, Single-Blind, Dose-Ranging, Crossover Study to Evaluate the Safety and Efficacy of Intravenous Administration of CINRYZE® (C1 Esterase Inhibitor [Human]) for the Prevention of Angioedema Attacks in Children 6 to 11 Years of Age With Hereditary Angioedema
Primary Objective - To assess the relative efficacy of two dose levels of CINRYZE (500 Units and 1000 Units) administered by intravenous (IV) injection every 3 or 4 days to prevent angioedema attacks in children 6 to 11 years of age with hereditary angioedema (HAE).
Secondary Objectives - To assess the safety and tolerability, characterize the pharmacokinetics (PK) and pharmacodynamics (PD), and assess the immunogenicity of two dose levels of CINRYZE administered by IV injection in children 6 to 11 years of age with HAE.
- Conditions
- Hereditary Angioedema (HAE)
- Being tested
- CINRYZE 500, CINRYZE 1000
- Keywords
- Pediatric, C1 inhibitor, HAE, Cinryze, C1 INH, Prevention
- Medical subject headings
- Angioedemas, Hereditary
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CINRYZE 500Biological
500 Units of CINRYZE administered by IV injection
CINRYZE 1000Biological
1000 Units of CINRYZE administered by IV injection
| Study group | Role | What they receive |
|---|---|---|
| 500/1000 | Experimental | 500 Units of CINRYZE administered by IV injection twice per week for 12 weeks followed by 1000 Units of CINRYZE administered by IV injection twice per week for 12 weeks Receives: Biological: CINRYZE 500; Biological: CINRYZE 1000 |
| 1000/500 | Experimental | 1000 Units of CINRYZE administered by IV injection twice per week for 12 weeks followed by 500 Units of CINRYZE administered by IV injection twice per week for 12 weeks Receives: Biological: CINRYZE 500; Biological: CINRYZE 1000 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Normalized Number of Angioedema Attacks Per Month in a Treatment Period
Angioedema attack was defined as the participant-reported indication of symptoms or signs such as swelling or pain at any location following a report of no swelling or pain on the previous day. Manifestations of an attack that progress from one site to another, prior to complete resolution, was considered a single attack. Attacks that began to regress and then worsened before complete resolution was also considered one attack. Attacks that began then appeared to resolve and then reappeared without a symptom-free calendar day reported after the appearance of resolution were considered 1 attack. Any events of swelling due to trauma or symmetrical nonpainful swelling of the lower extremities were not considered an angioedema attack. The number of attacks was normalized for the number of days participants participated in a given period and expressed as the monthly frequency.
Measured: From start of treatment up to 12 weeks during each treatment period
Secondary outcomes (8)
Cumulative Attack-severity Score of Angioedema Attacks Normalized Per Month in a Treatment Period
Severity of the angioedema attack sign/symptom was characterized as None: no symptom; Mild: noticeable symptom but easily tolerated by the participant and did not interfere with routine activities; Moderate: symptom interfered with the participant's ability to attend school or participate in family life and social/recreational activities; Severe: symptom significantly limited the participant's ability to attend school or participate in family life and social/recreational activities. Symptom severity score was assigned as Mild = 1, Moderate = 2 and Severe = 3. Cumulative attack severity score was the sum of the maximum symptom severity scores recorded for each angioedema attack in a treatment period. Cumulative attack-severity score normalized per month [(raw score/number of days of participation in that treatment period)*30.4] was reported here. Cumulative attack-severity score normalized per month ranged from 0 to 10.4 and higher scores represent worse symptoms.
Measured: From start of treatment up to 12 weeks during each treatment period
Cumulative Daily-severity Score of Angioedema Attacks Normalized Per Month in a Treatment Period
Severity of the angioedema attack sign/symptom was characterized as None: no symptom; Mild: noticeable but easily tolerated by the participant and did not interfere with routine activities; Moderate: interfered with the participant's ability to attend school or participate in family life and social/recreational activities; Severe: significantly limited the participant's ability to attend school or participate in family life and social/recreational activities. Symptom severity score was assigned as Mild = 1, Moderate = 2 and Severe = 3. Cumulative daily-severity score was the sum of the severity scores recorded for every day of reported symptoms in a treatment period. Cumulative daily-severity score normalized per month [(raw score/number of days of participation in that treatment period)*30.4] was reported here. Cumulative daily-severity score normalized per month ranged from 0 to 15.6 and higher scores represent worse symptoms.
Measured: From start of treatment up to 12 weeks during each intervention period
Normalized Number of Angioedema Attacks Per Month Requiring Acute Treatment in a Treatment Period
Angioedema attack was defined as the participant-reported indication of symptoms or signs such as swelling or pain at any location following a report of no swelling or pain on the previous day. Manifestations of an attack that progress from one site to another, prior to complete resolution, was considered a single attack. Attacks that began to regress and then worsened before complete resolution was also considered one attack. Attacks that began then appeared to resolve and then reappeared without a symptom-free calendar day reported after the appearance of resolution were considered 1 attack. Any events of swelling due to trauma or symmetrical nonpainful swelling of the lower extremities were not considered an angioedema attack. The number of attacks requiring acute treatment was normalized for the number of days participants participated in a given period and expressed as the monthly frequency.
Measured: From start of treatment up to 12 weeks during each intervention period
Number of Participants With Treatment-emergent Adverse Events (TEAEs) by Dose Group
An adverse event (AE) was any untoward, undesired, unplanned clinical event in the form of signs, symptoms, disease, or laboratory or physiological observations occurring in a participant participating in a clinical study with the sponsor's product, regardless of causal relationship. TEAEs were defined as events that started or worsened on or after the date and time of the first dose of investigational product and up to 7 days after the last dose of investigational product.
Measured: From start of study treatment up to 25 weeks
Plasma Concentration of C1 Esterase Inhibitor (C1 INH) Antigen
C1 INH antigen concentration in plasma was determined using an automated nephelometric assay.
Measured: Pre-dose and 1 hour (h) post-dose at Week 1 (Dose 1) and Week 6 (Dose 12); Pre-dose, 1, 2, 4 and 8 h post-dose at Week 12 (Dose 24) of each intervention period
C1 Esterase Inhibitor (C1 INH) Functional Activity in Plasma
The functional activity of C1 INH in plasma samples was determined by a chromogenic assay.
Measured: Pre-dose and 1 h post-dose at Week 1 (Dose 1) and Week 6 (Dose 12); Pre-dose, 1, 2, 4 and 8 h post-dose at Week 12 (Dose 24) of each intervention period
Plasma Concentration of Complement C4
Concentration of Complement C4 in plasma was determined using an automated nephelometric assay.
Measured: Pre-dose and 1 h post-dose at Week 1 (Dose 1) and Week 6 (Dose 12); Pre-dose, 1, 2, 4 and 8 h post-dose at Week 12 (Dose 24) of each intervention period
Number of Participants With C1 Esterase Inhibitor (C1 INH) Antibodies in Plasma
The presence of C1 INH antibodies in plasma samples was determined using a proprietary enzyme-linked-immunosorbent-assay. Number of participants with C1 INH Antibodies was reported.
Measured: Pre-dose, 1 week post treatment (Week 13, Week 25) and 1 month post treatment follow-up (Week 28)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Jan 2014 (estimated)
- Study start20 Mar 2014
- Primary completion4 May 2017
- Study completion4 May 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Hereditary Angioedema (HAE)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- Shire
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Study Director, Study director, Takeda
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02052141
- Sponsor's protocol ID
- 0624-301
- Other IDs
- 2013-002453-29, SHP616-301
- Status last verified
- May 2021
- First submitted
- 30 Jan 2014
- Last updated
- 3 Jun 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- Yes: 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.
Publications
Aygoren-Pursun E, Soteres D, Moldovan D, Christensen J, Van Leerberghe A, Hao J, Schranz J, Jacobson KW, Martinez-Saguer I. Preventing Hereditary Angioedema Attacks in Children Using Cinryze(R): Interim Efficacy and Safety Phase 3 Findings. Int Arch Allergy Immunol. 2017;173(2):114-119. doi: 10.1159/000477541. Epub 2017 Jun 30.
PubMed 28662509Beard N, Frese M, Smertina E, Mere P, Katelaris C, Mills K. Interventions for the long-term prevention of hereditary angioedema attacks. Cochrane Database Syst Rev. 2022 Nov 3;11(11):CD013403. doi: 10.1002/14651858.CD013403.pub2.
PubMed 36326435Aygoren-Pursun E, Soteres DF, Nieto-Martinez SA, Christensen J, Jacobson KW, Moldovan D, Van Leerberghe A, Tang Y, Lu P, Vardi M, Schranz J, Martinez-Saguer I. A randomized trial of human C1 inhibitor prophylaxis in children with hereditary angioedema. Pediatr Allergy Immunol. 2019 Aug;30(5):553-561. doi: 10.1111/pai.13060. Epub 2019 May 29.
PubMed 30968444
Study at a glance
From the registry record, last updated by the sponsor on 3 Jun 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 3, Multicenter, Randomized, Single-Blind, Dose-Ranging, Crossover Study to Evaluate the Safety and Efficacy of Intravenous Administration of CINRYZE® (C1 Esterase Inhibitor [Human]) for the Prevention of Angioedema Attacks in Children 6 to 11 Years of Age With Hereditary Angioedema
- ClinicalTrials.gov ID
- NCT02052141
- Acronym / sponsor ID
- 0624-301
- Conditions
- Hereditary Angioedema (HAE)
- Keywords
- Pediatric, C1 inhibitor, HAE, Cinryze, C1 INH, Prevention
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- ShireIndustry (pharma, biotech, devices)
- Study start
- 20 Mar 2014 (actual)
- Primary completion
- 4 May 2017 (actual)
- Study completion
- 4 May 2017 (actual)
- First posted
- 31 Jan 2014 (estimated)
- Results
- Posted 28 Aug 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Primary Objective - To assess the relative efficacy of two dose levels of CINRYZE (500 Units and 1000 Units) administered by intravenous (IV) injection every 3 or 4 days to prevent angioedema attacks in children 6 to 11 years of age with hereditary angioedema (HAE).
Secondary Objectives - To assess the safety and tolerability, characterize the pharmacokinetics (PK) and pharmacodynamics (PD), and assess the immunogenicity of two dose levels of CINRYZE administered by IV injection in children 6 to 11 years of age with HAE.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (participant)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 500/1000 | Experimental | Biological: CINRYZE 500, Biological: CINRYZE 1000500 Units of CINRYZE administered by IV injection twice per week for 12 weeks followed by 1000 Units of CINRYZE administered by IV injection twice per week for 12 weeks |
| 1000/500 | Experimental | Biological: CINRYZE 500, Biological: CINRYZE 10001000 Units of CINRYZE administered by IV injection twice per week for 12 weeks followed by 500 Units of CINRYZE administered by IV injection twice per week for 12 weeks |
Who may qualify
- Ages
- 6 to 11 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (2 listed)
- Diagnosis of Type I or Type II HAE.
- History of angioedema attacks.
Key exclusion criteria (4 listed)
- History of bleeding or clotting abnormality.
- Diagnosis of acquired angioedema or known to have C1 INH antibodies.
- History of allergic reaction to C1 esterase inhibitor or other blood products.
- Receipt of any experimental agents other than those required for prevention or treatment of angioedema attacks within 30 days prior to screening.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CINRYZE 500500 Units of CINRYZE administered by IV injection | Biological | 1000/500, 500/1000 |
| CINRYZE 10001000 Units of CINRYZE administered by IV injection | Biological | 1000/500, 500/1000 |
Primary outcome
Normalized Number of Angioedema Attacks Per Month in a Treatment Period
Time frame: From start of treatment up to 12 weeks during each treatment period
Angioedema attack was defined as the participant-reported indication of symptoms or signs such as swelling or pain at any location following a report of no swelling or pain on the previous day. Manifestations of an attack that progress from one site to another, prior to complete resolution, was considered a single attack. Attacks that began to regress and then worsened before complete resolution was also considered one attack. Attacks that began then appeared to resolve and then reappeared without a symptom-free calendar day reported after the appearance of resolution were considered 1 attack. Any events of swelling due to trauma or symmetrical nonpainful swelling of the lower extremities were not considered an angioedema attack. The number of attacks was normalized for the number of days participants participated in a given period and expressed as the monthly frequency.
8 secondary outcomes
Cumulative Attack-severity Score of Angioedema Attacks Normalized Per Month in a Treatment Period
Time frame: From start of treatment up to 12 weeks during each treatment period
Cumulative Daily-severity Score of Angioedema Attacks Normalized Per Month in a Treatment Period
Time frame: From start of treatment up to 12 weeks during each intervention period
Normalized Number of Angioedema Attacks Per Month Requiring Acute Treatment in a Treatment Period
Time frame: From start of treatment up to 12 weeks during each intervention period
Number of Participants With Treatment-emergent Adverse Events (TEAEs) by Dose Group
Time frame: From start of study treatment up to 25 weeks
Plasma Concentration of C1 Esterase Inhibitor (C1 INH) Antigen
Time frame: Pre-dose and 1 hour (h) post-dose at Week 1 (Dose 1) and Week 6 (Dose 12); Pre-dose, 1, 2, 4 and 8 h post-dose at Week 12 (Dose 24) of each intervention period
C1 Esterase Inhibitor (C1 INH) Functional Activity in Plasma
Time frame: Pre-dose and 1 h post-dose at Week 1 (Dose 1) and Week 6 (Dose 12); Pre-dose, 1, 2, 4 and 8 h post-dose at Week 12 (Dose 24) of each intervention period
Plasma Concentration of Complement C4
Time frame: Pre-dose and 1 h post-dose at Week 1 (Dose 1) and Week 6 (Dose 12); Pre-dose, 1, 2, 4 and 8 h post-dose at Week 12 (Dose 24) of each intervention period
Number of Participants With C1 Esterase Inhibitor (C1 INH) Antibodies in Plasma
Time frame: Pre-dose, 1 week post treatment (Week 13, Week 25) and 1 month post treatment follow-up (Week 28)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Jun 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 28662509Aygoren-Pursun E, Soteres D, Moldovan D, Christensen J, Van Leerberghe A, Hao J, Schranz J, Jacobson KW, Martinez-Saguer I. Preventing Hereditary Angioedema Attacks in Children Using Cinryze(R): Interim Efficacy and Safety Phase 3 Findings. Int Arch Allergy Immunol. 2017;173(2):114-119. doi: 10.1159/000477541. Epub 2017 Jun 30.
- Derived from this study: PubMed 36326435Beard N, Frese M, Smertina E, Mere P, Katelaris C, Mills K. Interventions for the long-term prevention of hereditary angioedema attacks. Cochrane Database Syst Rev. 2022 Nov 3;11(11):CD013403. doi: 10.1002/14651858.CD013403.pub2.
- Derived from this study: PubMed 30968444Aygoren-Pursun E, Soteres DF, Nieto-Martinez SA, Christensen J, Jacobson KW, Moldovan D, Van Leerberghe A, Tang Y, Lu P, Vardi M, Schranz J, Martinez-Saguer I. A randomized trial of human C1 inhibitor prophylaxis in children with hereditary angioedema. Pediatr Allergy Immunol. 2019 Aug;30(5):553-561. doi: 10.1111/pai.13060. Epub 2019 May 29.
- Individual participant dataSharing planned: Yes. 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Study Director study director
Takeda
8 sites in 5 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing CINRYZE 500 and CINRYZE 1000 in people with Hereditary Angioedema (HAE), run by Shire at 8 sites in 5 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Jun 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in United States, Germany, Israel, Mexico, Romania. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 28 Aug 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Normalized Number of Angioedema Attacks Per Month in a Treatment Period (time frame: From start of treatment up to 12 weeks during each treatment period). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02052141, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Jun 2021.