Hereditary Angioedema (HAE)
Conditions
Keywords
Crossover, C1 esterase inhibitor, Prevention, C1 inhibitor, Hereditary Angioedema, Subcutaneous, Recombinant human hyaluronidase
Brief summary
The primary objectives of the study are to evaluate the safety, tolerability, and efficacy of two doses of CINRYZE with recombinant human hyaluronidase (rHuPH20) administered by subcutaneous (SC) injection to prevent angioedema attacks.
Interventions
BIOLOGICALCINRYZE with rHuPH20
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Be ≥12 years of age. * Have a confirmed diagnosis of Hereditary Angioedema.
Exclusion criteria
* Receipt of any C1 inhibitor (C1 INH) therapy or any blood products for treatment or prevention of an angioedema attack within 7 days before the first dose of study drug. * Be receiving prophylactic intravenous CINRYZE that exceeds 1000 units every 3 or 4 days (maximum weekly dose 2000 units). * Have received any androgen therapy (e.g., danazol, oxandrolone, stanozolol, testosterone) within 7 days prior to the first dose of study drug. * If female, have started taking or changed the dose of any hormonal contraceptive regimen or hormone replacement therapy (i.e., estrogen/progestin containing products) within 3 months prior to the first dose of study drug. * History of allergic reaction to C1 INH products, including CINRYZE or other blood products. * History of abnormal blood clotting. * Have a known allergy to hyaluronidase or any other ingredient in the study formulation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Normalized Number of Angioedema Attacks During the Treatment Period | From Visit 1 (Week 1) up to Visit 16 (Week 8) 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. Participants who were dosed but did not have any attacks in the period were assigned a value of zero. The number of attacks was normalized for the number of days participants participated in a given period and expressed as the monthly frequency. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Attack-severity During the Treatment Period | From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period | Cumulative Attack-severity score was the sum of maximum symptom severity recorded for each angioedema attack, determined on the last day of symptoms and recorded as None=0, Mild=1, Moderate=2, and Severe=3 and summing over the unique attacks, yields a Cumulative Attack-severity score. None: no angioedema attack symptom; Mild: the angioedema attack symptom was noticeable to the participant but was easily tolerated and did not interfere with routine activities; Moderate: the angioedema attack symptom interfered with work/school or the ability to participate in family life and social activities; Severe: the angioedema attack symptom significantly limited the participant's ability to attend work/school or participate in family life and social activities. Cumulative attack-severity was normalized for the number of days participants participated in a given period and expressed as the monthly frequency. The scores ranged from 0 to 168 and higher scores represent worse symptoms. |
| Cumulative Daily-severity During the Treatment Period | From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period | Cumulative Daily-severity score was the sum of the severity scores recorded for every day of reported symptoms during the treatment period. Severity scores were recorded as None=0, Mild=1, Moderate=2, and Severe=3. None: no angioedema attack symptom; Mild: the angioedema attack symptom was noticeable to the participant but was easily tolerated and did not interfere with routine activities; Moderate: the angioedema attack symptom interfered with work/school or the ability to participate in family life and social activities; Severe: the angioedema attack symptom significantly limited the participant's ability to attend work/school or participate in family life and social activities. Cumulative daily severity was normalized for the number of days participants participated in a given period and expressed as the monthly frequency. The scores ranged from 0 to 168 and higher scores represent worse symptoms. |
| Cumulative Symptomatic Days During the Treatment Period | From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period | Cumulative symptomatic days was defined as the sum of the symptomatic days of each angioedema attack reported during the treatment period. Participants who were dosed but did not have any attacks in the period were assigned a value of zero. Cumulative symptomatic days was normalized for the number of days participants participated in a given period and expressed as the monthly frequency. |
| Number of Angioedema Attacks Requiring Acute Treatment During the Treatment Period | From Visit 1 (Week 1) up to Visit 16 (Week 8) 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. Participants who were dosed but did not have any attacks in the period were assigned a value of zero. The number of attacks was normalized for the number of days participants participated in a given period and expressed as the monthly frequency. |
Countries
Germany, Spain, Sweden, United States
Participant flow
Recruitment details
This study was conducted at 24 sites (United States=20, Europe=4) between 04 February 2013 (first participant dosed) and 13 September 2013 (last participant contact). Of 52 screened participants, 47 were randomized and treated. Screen failure reasons were consent withdrawn by 1 participant and violation of eligibility criteria by 4 participants.
Pre-assignment details
Due to emergence of, and unexpected incidence and titer of, non-neutralizing anti-rHuPH20 antibodies in some subjects after administration of CINRYZE+rHuPH20, sponsor decided to stop dosing subjects with rHuPH20 and thus close the study. However, the study was completed with collection of safety data as outlined in the protocol.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Included participants who received 1000 U CINRYZE with 24,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks (Treatment A) first and 2000 U CINRYZE with 48,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks (Treatment B) first. | 47 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention Period | Lost to Follow-up | 0 | 2 |
| First Intervention Period | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 39.0 years STANDARD_DEVIATION 14.6 |
| Sex: Female, Male Female | 33 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 42 / 44 | 46 / 46 |
| serious Total, serious adverse events | 0 / 44 | 0 / 46 |
Outcome results
Primary
Normalized Number of Angioedema Attacks During the 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. Participants who were dosed but did not have any attacks in the period were assigned a value of zero. The number of attacks was normalized for the number of days participants participated in a given period and expressed as the monthly frequency.
Time frame: From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period
Population: Intent-to-treat efficacy (ITT-E) population included all participants who completed both randomized treatment periods and fulfilled a priori defined evaluability criteria.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment A (1000 U CINRYZE + 24000 U rHuPH20) | Normalized Number of Angioedema Attacks During the Treatment Period | 1.58 angioedema attacks |
| Treatment B (2000 U CINRYZE + 48000 U rHuPH20) | Normalized Number of Angioedema Attacks During the Treatment Period | 0.97 angioedema attacks |
p-value: 0.052395% CI: [-1.23, 0.01]Paired t-test, 2 sided
Secondary
Cumulative Attack-severity During the Treatment Period
Cumulative Attack-severity score was the sum of maximum symptom severity recorded for each angioedema attack, determined on the last day of symptoms and recorded as None=0, Mild=1, Moderate=2, and Severe=3 and summing over the unique attacks, yields a Cumulative Attack-severity score. None: no angioedema attack symptom; Mild: the angioedema attack symptom was noticeable to the participant but was easily tolerated and did not interfere with routine activities; Moderate: the angioedema attack symptom interfered with work/school or the ability to participate in family life and social activities; Severe: the angioedema attack symptom significantly limited the participant's ability to attend work/school or participate in family life and social activities. Cumulative attack-severity was normalized for the number of days participants participated in a given period and expressed as the monthly frequency. The scores ranged from 0 to 168 and higher scores represent worse symptoms.
Time frame: From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period
Population: ITT-E population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A (1000 U CINRYZE + 24000 U rHuPH20) | Cumulative Attack-severity During the Treatment Period | 3.14 Score on a scale | Standard Deviation 3.79 |
| Treatment B (2000 U CINRYZE + 48000 U rHuPH20) | Cumulative Attack-severity During the Treatment Period | 1.81 Score on a scale | Standard Deviation 2.55 |
Secondary
Cumulative Daily-severity During the Treatment Period
Cumulative Daily-severity score was the sum of the severity scores recorded for every day of reported symptoms during the treatment period. Severity scores were recorded as None=0, Mild=1, Moderate=2, and Severe=3. None: no angioedema attack symptom; Mild: the angioedema attack symptom was noticeable to the participant but was easily tolerated and did not interfere with routine activities; Moderate: the angioedema attack symptom interfered with work/school or the ability to participate in family life and social activities; Severe: the angioedema attack symptom significantly limited the participant's ability to attend work/school or participate in family life and social activities. Cumulative daily severity was normalized for the number of days participants participated in a given period and expressed as the monthly frequency. The scores ranged from 0 to 168 and higher scores represent worse symptoms.
Time frame: From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period
Population: ITT-E population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A (1000 U CINRYZE + 24000 U rHuPH20) | Cumulative Daily-severity During the Treatment Period | 4.63 Score on a scale | Standard Deviation 5.79 |
| Treatment B (2000 U CINRYZE + 48000 U rHuPH20) | Cumulative Daily-severity During the Treatment Period | 2.81 Score on a scale | Standard Deviation 4.42 |
Secondary
Cumulative Symptomatic Days During the Treatment Period
Cumulative symptomatic days was defined as the sum of the symptomatic days of each angioedema attack reported during the treatment period. Participants who were dosed but did not have any attacks in the period were assigned a value of zero. Cumulative symptomatic days was normalized for the number of days participants participated in a given period and expressed as the monthly frequency.
Time frame: From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period
Population: ITT-E population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A (1000 U CINRYZE + 24000 U rHuPH20) | Cumulative Symptomatic Days During the Treatment Period | 3.06 days | Standard Deviation 3.51 |
| Treatment B (2000 U CINRYZE + 48000 U rHuPH20) | Cumulative Symptomatic Days During the Treatment Period | 2.14 days | Standard Deviation 3.3 |
Secondary
Number of Angioedema Attacks Requiring Acute Treatment During the 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. Participants who were dosed but did not have any attacks in the period were assigned a value of zero. The number of attacks was normalized for the number of days participants participated in a given period and expressed as the monthly frequency.
Time frame: From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period
Population: ITT-E population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A (1000 U CINRYZE + 24000 U rHuPH20) | Number of Angioedema Attacks Requiring Acute Treatment During the Treatment Period | 0.99 angioedema attacks | Standard Deviation 1.51 |
| Treatment B (2000 U CINRYZE + 48000 U rHuPH20) | Number of Angioedema Attacks Requiring Acute Treatment During the Treatment Period | 0.43 angioedema attacks | Standard Deviation 0.89 |