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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hereditary Angioedema (HAE)	Drug: C1 esterase inhibitor [human] liquid; Drug: Placebo	Phase 3

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	75 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Prevention
Official Title:	A Phase 3, Randomized, Double-blind, Placebo-controlled, Two-period, Three-sequence, Partial Crossover Study to Evaluate the Efficacy and Safety of Subcutaneous Administration of 2000 IU of C1 Esterase Inhibitor [Human] Liquid for Injection for the Prevention of Angioedema Attacks in Adolescents and Adults With Hereditary Angioedema
Actual Study Start Date :	November 1, 2015
Actual Primary Completion Date :	July 24, 2017
Actual Study Completion Date :	July 24, 2017

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Experimental/Placebo; Subjects will be randomized to receive C1 Esterase Inhibitor in the 1st Treatment period and then switch to Placebo in the 2nd treatment period.	Drug: C1 esterase inhibitor [human] liquid; C1 Esterase Inhibitor [Human] Liquid administered Subcutaneously as specified on specified days; Drug: Placebo; Placebo
Experimental: Placebo/Experimental; Subjects will be randomized to receive a placebo treatment in the 1st Treatment period and then switch to receive C1 Esterase Inhibitor in the 2nd treatment period.	Drug: C1 esterase inhibitor [human] liquid; C1 Esterase Inhibitor [Human] Liquid administered Subcutaneously as specified on specified days; Drug: Placebo; Placebo
Experimental: Experimental/ Experimental; Subjects will be randomized and receive C1 Esterase Inhibitor in both 1st as well as the 2nd treatment period	Drug: C1 esterase inhibitor [human] liquid; C1 Esterase Inhibitor [Human] Liquid administered Subcutaneously as specified on specified days

Outcome Measures

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Primary Outcome Measures :

1. Time-Normalized Number of Attacks (NNA) for Participants During a Treatment Period [ Time Frame: 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).

Secondary Outcome Measures :

1. 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. [ Time Frame: 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).
2. Time-Normalized Number of Attacks (NNA) for Participants During Each Treatment Period Excluding the First 2 Weeks. [ Time Frame: 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).
3. 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. [ Time Frame: 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).
4. 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. [ Time Frame: 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).
5. Cumulative Attack Severity [ Time Frame: 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 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 19.83 and higher scores represent worse symptoms.

6. Number of Attack-free Days [ Time Frame: Weeks 1 to 14 for treatment period 1 and 2 ]
   Attack free days were normalized per month.
7. Number of Angioedema Attacks Requiring Acute Treatment [ Time Frame: Weeks 1 to 14 for treatment period 1 and 2 ]
   Angioedema attacks were normalized per month.
8. Response to Icatibant When Administered for an Acute Attack [ Time Frame: 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.
9. Number of Patients With Adverse Events (AEs) [ Time Frame: 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.
10. Number of Participants With Injection Site Reactions [ Time Frame: 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.
11. Number of Patients With Positive Anti-C1 INH Antibodies [ Time Frame: Weeks 1 to 14 for treatment period 1 and 2 ]
    Anti-C1 INH antibodies were measured during study time.
12. PK Parameters: AUC (0-96) and AUC (0-t) for Functional C1 INH Binding Activity [ Time Frame: Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2. In addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2. ]
    AUC(0-96)=area under the plasma concentration-time curve from time zero to last measurable concentration; AUC(0-t)=area under the plasma concentration-time curve from time zero extrapolated to the end of the dosing interval tau, where tau is approximately 84 hours (ie, average of every 3 or 4 days) AUC(0-96) = AUC(0-tau).
13. PK Parameters: AUC (0-96) and AUC (0-t) for C1 INH Antigen Concentrations [ Time Frame: Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2. In addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2. ]
    AUC(0-96)=area under the plasma concentration-time curve from time zero to last measurable concentration; AUC(0-t)=area under the plasma concentration-time curve from time zero extrapolated to the end of the dosing interval tau, where tau is approximately 84 hours (ie, average of every 3 or 4 days) AUC(0-96) = AUC(0-tau).
14. PK Parameters: AUC (0-96) and AUC (0-t) for Complement C4 Concentrations (Treamtment C1 INH) [ Time Frame: Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2. In addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2. ]
    AUC(0-96)=area under the plasma concentration-time curve from time zero to last measurable concentration; AUC(0-t)=area under the plasma concentration-time curve from time zero extrapolated to the end of the dosing interval tau, where tau is approximately 84 hours (ie, average of every 3 or 4 days) AUC(0-96) = AUC(0-tau).
15. PK Parameters: AUC (0-96) and AUC (0-t) for Complement C4 Concentrations (Treatment Placebo) [ Time Frame: Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2. In addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2. ]
    AUC(0-96)=area under the plasma concentration-time curve from time zero to last measurable concentration; AUC(0-t)=area under the plasma concentration-time curve from time zero extrapolated to the end of the dosing interval tau, where tau is approximately 84 hours (ie, average of every 3 or 4 days) AUC(0-96) = AUC(0-tau). Participant wise data was reported for this outcome.
16. PK Parameters: Cmax and Cmin for Functional C1 INH Binding Activity [ Time Frame: Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2 and in addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2. ]
    Cmax=maximum observed plasma concentration and Cmin=minimum observed plasma concentration
17. PK Parameters: Cmax and Cmin for C1 INH Antigen Concentrations [ Time Frame: Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2 and in addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2 ]
    Cmax=maximum observed plasma concentration and Cmin=minimum observed plasma concentration
18. PK Parameters: Cmax and Cmin for Complement C4 Concentrations (Treatment C1 INH) [ Time Frame: Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2 and in addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2. ]
    Cmax=maximum observed plasma concentration and Cmin=minimum observed plasma concentration
19. PK Parameters: Cmax and Cmin for Complement C4 Concentrations (Treatment Placebo) [ Time Frame: Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2 and in addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2. ]

    Cmax=maximum observed plasma concentration and Cmin=minimum observed plasma concentration.

    Participant wise data was reported for this outcome.

20. PK Parameters: Tmax [ Time Frame: Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2 and in addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2. ]
    tmax=time of maximum observed plasma concentration
21. PK Parameters: Tmax for Complement C4 Concentrations (Placebo Group) [ Time Frame: Within 15 min prior dosing at week 1, week 2, week 8, week 16, week 24, week 27/28 and 48 (± 3) hours after dose in week 27/28 in period 1 and 2 and in addition 24 (±3) hours, 72 (±6) hours and 96 (±6) hours post dose in week 28 for period 2. ]
    tmax=time of maximum observed plasma concentration. Participant wise data was reported for this outcome.
22. Assess Disease Activity as Measured by the Angioedema Activity Score (AAS) Normalized Per Month [ Time Frame: Weeks 1 to 14 for treatment period 1 and 2 ]
    Disease activity was measured using a 98-day Angioedema Activity Score (AAS). The AAS collects information of disease activity in the last 24 hours. The following items are assessed: experience of swelling, severity of the swelling, timing of the swelling, extent of discomfort due to the swelling, extent that the swelling caused limitations in daily life, and feelings of being disfigured by the swelling. The instrument uses a binary response option for the first item and a three-point response scale for the 5 items thereafter. The daily AAS was the sum of the AAS items per day. Total daily ASS scores range between 0 and 15 points. Higher values stand for higher disease activity. The normalized 98-day AAS per month for a participant is calculated by (the sum of daily AAS within a treatment period/the number of days that a subject has AAS records within the treatment period)*30.4.
23. Participant Experience With Self-administration: Overall Experience With the Syringe [ Time Frame: Week 14 for treatment period 1 and 2 ]
    Self-administration survey with questions about the overall experience with the syringe was assessed in week 14 (visit 28 and 28b). Visit 28 summarizes treatment period 1 of the experimental/experimental arm and treatment periods 1 and 2 of the experimental/placebo arm and the placebo/experimental arm. Visit 28b summarizes treatment period 2 of the experimental/experimental arm.
24. Participant Experience With Self-administration: How Many Visits for Confidence With Self-administration [ Time Frame: Week 14 for treatment period 1 and 2 ]

    The self-administration survey includes the number of visits needed for participants to be able to self-administer investigational product with confidence and all participants could self-administer without supervision.

    Visit 28 summarizes treatment period 1 of the experimental/experimental arm and treatment periods 1 and 2 of the experimental/placebo arm and the placebo/experimental arm. Visit 28b summarizes treatment period 2 of the experimental/experimental arm.

25. Participant Experience With Self-administration: Better Long-term Option and Preferred Administration [ Time Frame: Week 14 for treatment period 1 and 2 ]

    The self-administration survey includes the number of visits needed for participants to be able to self-administer investigational product with confidence and all participants could self-administer without supervision.

    Visit 28 summarizes treatment period 1 of the experimental/experimental arm and treatment periods 1 and 2 of the experimental/placebo arm and the placebo/experimental arm. Visit 28b summarizes treatment period 2 of the experimental/experimental arm.

26. Mean Change in Angioedema Quality of Life Questionnaire Scores From Baseline to Week 13 [ Time Frame: Baseline to week 13 for treatment period 1 and 2 ]
    The AE-QoL is a questionnaire on the quality of life of patients suffering from recurrent angioedema. It consists of 17 specific questions that are associated with work, physical activity, free time, social relations, and food. Each of the 17 questions has a five-point response scale ranging from 1 (Never) to 5 (Very Often). The AE-QoL consists of 4 dimensions (functioning=4 questions(qns) fatigue/mood=5 qns, fears/shame=6 qns, nutrition=2 qns) and a total score (all 17 questions).All scores were calculated by using the following formula: (Σ items - min Σ items / max Σ items - min Σ items) x 100. Σ items=sum of response by participant, min Σ items=minimum response possible, max Σ items=maximum response possible. Scores range from 0 to 100 , with higher scores indicating greater impairment. Absolute change calculated as visit score at week 13 minus score at baseline per period.

Eligibility Criteria

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Ages Eligible for Study:	12 Years and older (Child, Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

The maximum duration of participation is approximately 9 months. Patients will complete a screening period of up to 21 days. Following screening, eligible patients will be randomly assigned to 1 of 3 treatment sequences. Each patient will undergo 2 14-week treatment periods for a total of 28 weeks (Treatment Period 1 and Treatment Period 2). After completing the 2 treatment periods, patients will enter a 1-month follow-up period.

Contacts and Locations

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Sponsors and Collaborators

Shire

Investigators

Study Director:	Shire Physician	Shire

  Study Documents (Full-Text)

Documents provided by Shire:

Study Protocol: Protocol  [PDF] May 28, 2015

Study Protocol: Amendment1  [PDF] July 22, 2015

Study Protocol: Amendment2  [PDF] September 3, 2015

Study Protocol: Amendment3  [PDF] January 11, 2016

Study Protocol: Amendment4  [PDF] February 8, 2017

Statistical Analysis Plan  [PDF] August 17, 2017

More Information

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Responsible Party:	Shire
ClinicalTrials.gov Identifier:	NCT02584959 History of Changes
Other Study ID Numbers:	SHP616-300
First Posted:	October 23, 2015
Results First Posted:	November 28, 2018
Last Update Posted:	November 28, 2018
Last Verified:	November 2018

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; Complement C1s; Complement C1 Inhibitor Protein; Complement C1 Inactivator Proteins; Immunologic Factors; Physiological Effects of Drugs; Complement Inactivating Agents; Immunosuppressive Agents