NCT02584959

Study to Evaluate the Clinical Efficacy and Safety of Subcutaneously Administered C1 Esterase Inhibitor for the Prevention of Angioedema Attacks in Adolescents and Adults With Hereditary Angioedema

Completed Phase 3 Results posted Last updated 8 June 2021

What this trial tests

Phase 3 trial testing C1 esterase inhibitor [human] liquid in Hereditary Angioedema (HAE) in 75 participants. Completed in 24 July 2017.

Timeline

1 November 2015

Primary endpoint
24 July 2017

24 July 2017

Quick facts

Lead sponsor	Shire
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	crossover
Masking	double
Primary purpose	prevention
Enrollment	75
Start date	1 November 2015
Primary completion	24 July 2017
Estimated completion	24 July 2017
Sites	27 locations across Israel, Germany, Hungary, Romania, Canada, United States, Spain

Drugs / interventions tested

• C1 esterase inhibitor [human] liquid — full drug profile →
• Placebo

Conditions studied

• Hereditary Angioedema (HAE) — all drugs for Hereditary Angioedema (HAE) →

Sponsor

Shire — full company profile →

Who can join

12 and older, any sex, with Hereditary Angioedema (HAE). Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Time-Normalized Number of Attacks (NNA) for Participants During a Treatment Period Primary · Weeks 1 to 14 for treatment period 1 and 2

The angioedema attacks were recorded in the electronic patient diary. The investigator completed a separate angioedema eCRF for each attack based on the review of the patients diary. Time-normalized number of angioedema attacks was expressed as the number of attacks per month (ie, 30.4 days) of exposure. NNA=30.4 \* (number of attacks during treatment period) / (days of treatment period).

Group	Value	95% CI
Treatment C1 INH	1.611	1.067 – 2.156
Treatment Placebo	3.931	3.391 – 4.471

Proportion of Participants Meeting at Least a 50% Reduction in NNA (Normalized Number of Angioedema Attacks) During the Experimental Injection Treatment Period Relative to the Placebo Period. Secondary · Weeks 1 to 14 for treatment period 1 and 2

The angioedema attacks were recorded in the electronic patient diary. The investigator completed a separate angioedema eCRF for each attack based on the review of the patients diary. Time-Normalized Number of Attacks was expressed as the number of attacks per month (ie, 30.4 days) of exposure. NNA = 30.4 x (number of attacks during treatment period) / (days of treatment period).

Group	Value	95% CI
Full Analysis Set	38

Time-Normalized Number of Attacks (NNA) for Participants During Each Treatment Period Excluding the First 2 Weeks. Secondary · Weeks 3 to 14 for treatment period 1 and 2

The angioedema attacks were recorded in the electronic patient diary. The investigator completed a separate angioedema eCRF for each attack based on the review of the patients diary. Time-normalized number of angioedema attacks was expressed as the number of attacks per month (ie, 30.4 days) of exposure. NNA=30.4 \* (number of attacks during treatment period) / (days of treatment period).

Group	Value	95% CI
Treatment C1 INH	1.524	0.912 – 2.136
Treatment Placebo	3.847	3.237 – 4.457

Proportion of Participants Meeting at Least a 50% Reduction in NNA (Normalized Number of Angioedema Attacks) During the Experimental Injection Treatment Period Relative to the Placebo Period Excluding the First 2 Weeks of Each Treatment Period. Secondary · Weeks 3 to 14 for treatment period 1 and 2

The angioedema attacks were recorded in the electronic patient diary. The investigator completed a separate angioedema eCRF for each attack based on the review of the patients diary. Time-Normalized Number of Attacks was expressed as the number of attacks per month (ie, 30.4 days) of exposure. NNA = 30.4 x (number of attacks during treatment period) / (days of treatment period).

Group	Value	95% CI
Full Analysis Data Set	36

Proportion of Participants Meeting at Least a 50% Reduction in NNA (Normalized Number of Angioedema Attacks) During the Experimental Injection Treatment Period Relative to the Pre-treatment Assessment. Secondary · Weeks 1 to 14 for treatment period 1 and 2

The angioedema attacks were recorded in the electronic patient diary. The investigator completed a separate angioedema eCRF for each attack based on the review of the patients diary. Time-Normalized Number of Attacks was expressed as the number of attacks per month (ie, 30.4 days) of exposure. NNA = 30.4 x (number of attacks during treatment period) / (days of treatment period).

Group	Value	95% CI
Treatment C1 INH	41
Treatment Placebo	13

Cumulative Attack Severity Secondary · Weeks 1 to 14 for treatment period 1 and 2

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 w

Group	Value	95% CI
Treatment C1 INH	3.159	1.856 – 4.463
Treatment Placebo	8.041	6.746 – 9.336

Number of Attack-free Days Secondary · Weeks 1 to 14 for treatment period 1 and 2

Attack free days were normalized per month.

Group	Value	95% CI
Treatment C1 INH	26.788	25.106 – 28.470
Treatment Placebo	21.353	19.681 – 23.025

Number of Angioedema Attacks Requiring Acute Treatment Secondary · Weeks 1 to 14 for treatment period 1 and 2

Angioedema attacks were normalized per month.

Group	Value	95% CI
Treatment C1 INH	1.454	0.906 – 2.002
Treatment Placebo	3.628	3.085 – 4.172

Response to Icatibant When Administered for an Acute Attack Secondary · Weeks 1 to 14 for treatment period 1 and 2

The number of Acute Hereditary Angioedema Attacks that required Icatibant as acute therapy is presented by the number of Icatibant injections.

Group	Value	95% CI
Treatment C1 INH	129
Treatment Placebo	306
Treatment C1 INH	38
Treatment Placebo	89
Treatment C1 INH	13
Treatment Placebo	30
Treatment C1 INH	1
Treatment Placebo	28

Number of Patients With Adverse Events (AEs) Secondary · Weeks 1 to 14 for treatment period 1 and 2

Treatment-emergent adverse events (TEAE) were counted by the treatment most recently taken when the event occurred. Participants were counted once per category per treatment.

Any TEAE

Group	Value	95% CI
Treatment C1 INH	42
Treatment Placebo	32

Serious TEAE

Group	Value	95% CI
Treatment C1 INH	2
Treatment Placebo	3

Severe TEAE

Group	Value	95% CI
Treatment C1 INH	4
Treatment Placebo	3

TEAE within 24 hours of IP administration

Group	Value	95% CI
Treatment C1 INH	10
Treatment Placebo	7

Serious TEAE within 24 hours of IP administration

Group	Value	95% CI
Treatment C1 INH	0
Treatment Placebo	0

Treatment-related TEAE within 24 hrs of IP admin.

Group	Value	95% CI
Treatment C1 INH	3
Treatment Placebo	2

Treatment-related SAE within 24 hrs of IP admin.

Group	Value	95% CI
Treatment C1 INH	0
Treatment Placebo	0

TEAE within 24 hrs IP admin. leading to withdrawal

Group	Value	95% CI
Treatment C1 INH	1
Treatment Placebo	0

Number of Participants With Injection Site Reactions Secondary · Weeks 1 to 14 for treatment period 1 and 2

Injection site reactions (Erythema, Swelling, Cutaneous pain, Burning sensation, Itching/Pruritus, Warm sensation) were recorded on a designated eCRF page by the site personnel who monitored the local reaction for 1 hour after IP administration 5 times during each treatment period.

Any injection site reaction

Group	Value	95% CI
Treatment C1 INH	42
Treatment Placebo	15

Any severe injection site reaction

Group	Value	95% CI
Treatment C1 INH	2
Treatment Placebo	0

Any mild injection site reaction

Group	Value	95% CI
Treatment C1 INH	42
Treatment Placebo	15

Any moderate injection site reaction

Group	Value	95% CI
Treatment C1 INH	14
Treatment Placebo	1

Number of Patients With Positive Anti-C1 INH Antibodies Secondary · Weeks 1 to 14 for treatment period 1 and 2

Anti-C1 INH antibodies were measured during study time.

Positive anti-C1 INH antibodies prior treatment

Group	Value	95% CI
Treatment C1 INH	0
Treatment Placebo	0

Positive anti-C1 INH antibodies developed

Group	Value	95% CI
Treatment C1 INH	0
Treatment Placebo	0

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse events were reported from the time the informed consent was signed through 7 days afer the last dose of investigational product was received (week 1 to 15 for treatment period 1 and 2).. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Treatment C1 INH

Serious: 2/71 (3%)

Deaths: 0/71

Treatment Placebo

Serious: 3/57 (5%)

Deaths: 0/57

Serious adverse events (5 terms)

Reaction	System	Treatment C1 INH	Treatment Placebo
Cardiac arrest	Cardiac disorders	—	—
Hereditary angioedema	Congenital, familial and genetic disorders	—	—
Cholelithiasis	Hepatobiliary disorders	—	—
Appendicitis	Infections and infestations	—	—
Staphylococcal infection	Infections and infestations	—	—

Other adverse events (4 terms — click to expand)

Reaction	System	Treatment C1 INH	Treatment Placebo
Viral upper respiratory tract infection	Infections and infestations	—	—
Upper respiratory tract infection	Infections and infestations	—	—
Headache	Nervous system disorders	—	—
Contusion	Injury, poisoning and procedural complications	—	—

Most-reported serious reactions: Cardiac arrest, Hereditary angioedema, Cholelithiasis, Appendicitis, Staphylococcal infection.

Data from ClinicalTrials.gov NCT02584959 adverse events section.

Sponsor's own description

The purpose of this study is to assess the efficacy and safety of subcutaneous administration of a liquid formulation of C1 esterase inhibitor for the prevention of angioedema attacks in adolescent and adult subjects with hereditary angioedema.

Publications & conference data

6 peer-reviewed publications reference this trial (live from Europe PMC):

1. Complement System: An Immunotherapy Target in Colorectal Cancer.
   Talaat IM, Elemam NM, Saber-Ayad M. · · 2022 · cited 38× · PMID 35173724 · DOI 10.3389/fimmu.2022.810993
2. Emerging Therapies in Hereditary Angioedema.
   Chen M, Riedl MA. · · 2017 · cited 21× · PMID 28687111 · DOI 10.1016/j.iac.2017.03.003
3. Content validation and psychometric evaluation of the Angioedema Quality of Life Questionnaire for hereditary angioedema.
   Vanya M, Watt M, Shahraz S, Kosmas CE, et al · · 2023 · cited 12× · PMID 37012445 · DOI 10.1186/s41687-023-00576-w
4. Self-administered C1 esterase inhibitor concentrates for the management of hereditary angioedema: usability and patient acceptance.
   Li HH. · · 2016 · cited 12× · PMID 27660422 · DOI 10.2147/ppa.s86379
5. Fixed-Dose Subcutaneous C1-Inhibitor Liquid for Prophylactic Treatment of C1-INH-HAE: SAHARA Randomized Study.
   Lumry WR, Martinez-Saguer I, Yang WH, Bernstein JA, et al · · 2019 · cited 10× · PMID 30682573 · DOI 10.1016/j.jaip.2019.01.021
6. Abstracts from the European Academy of Allergy and Clinical Immunology Congress, 26-30 May 2018, Munich, Germany.
   · 2018 · cited 3× · PMID 32745248 · DOI 10.1111/all.13539