Hereditary Angioedema (HAE)
Conditions
Keywords
DX-2930, Hereditary Angioedema, Dyax
Brief summary
This is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of DX-2930 in preventing acute angioedema attacks in patients with Type I and Type II HAE.
Interventions
DRUGDX-2930 - 300mg/2wk
300 mg DX-2930 administered every 2 weeks by subcutaneous injection.
DRUGDX-2930 - 300mg/4wk
300 mg DX-2930 administered every 4 weeks by subcutaneous injection. To maintain the study blind, subjects will be given placebo injections every other 2 weeks when they are not receiving drug.
DRUGDX-2930 - 150mg/4wk
150 mg DX-2930 administered every 4 weeks by subcutaneous injection. To maintain the study blind, subjects will be given placebo injections every other 2 weeks when they are not receiving drug.
DRUGPlacebo
Placebo administered every 2 weeks by subcutaneous injection.
Sponsors
Dyax Corp.
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
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
* Males and females 12 years of age or older at time of screening * Documented diagnosis of HAE, Type I or II * Baseline rate of at least 1 Investigator-confirmed HAE attack per 4 weeks * Adult subjects and caregivers of subjects under the age of 18 are willing and able to read, understand, and sign an informed consent form. Subjects age 12 to 17, whose caregiver provides informed consent, are willing and able to read, understand an dsign an assent form. * Males and femailes who are fertile and sexually active must adhere to contraception requirements.
Exclusion criteria
* Concomitant diagnosis of another form of chronic, recurrent angioedema, such as acquired angioedema, idiopathic angioedema, or recurrent angioedema associated with urticaria. * Participation in a prior DX-2930 study * Treatment with any other investigational drug or exposure to an investigational device within 4 weeks prior screening * Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications within 4 weeks prior to screening. * Exposure to androgens within 2 weeks prior to entering the run-in period. * Use of long-term prophylactic therapy for HAE within 2 weeks prior to entering the run-in period. * Use of short-term prophylaxis for HAE within 7 days prior to entering the run-in period. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attacks During Treatment Period | From Day 0 to Day 182 | 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 was analyzed using a generalized linear model (GLM) for count data assuming a poisson distribution with a log link function and Pearson chi-square scaling of standard errors to account for potential overdispersion. The logarithm of time in days each subject was observed during the treatment period was used as an offset variable in the model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attack Requiring Acute Treatment | From Day 0 to Day 182 | 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 attack was analyzed using the GLM for count data assuming a poisson distribution with a log link function and Pearson chi-square scaling of standard errors to account for potential overdispersion. The logarithm of time in days each subject was observed during the treatment period was used as an offset variable in the model. |
| Rate of Moderate or Severe Investigator Confirmed Hereditary Angioedema (HAE) Attacks | From Day 0 to Day 182 | 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 investigator confirmed HAE attack was analyzed using the GLM for count data assuming a poisson distribution with a log link function and Pearson chi-square scaling of standard errors to account for potential overdispersion. The logarithm of time in days each subject was observed during the treatment period was used as an offset variable in the model. |
| Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attacks During Day 14 Through Day 182 | From Day 14 to Day 182 | 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 during day 14 after study drug administration through day 182 was analyzed by the same poisson regression model as in the primary endpoint analysis. |
Countries
Canada, Germany, Italy, Jordan, Puerto Rico, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 41 sites in the United States, United Kingdom, Italy, Germany, Canada and Jordan between 03 March 2016 (first participant first visit) and 13 April 2017 (last participant last visit).
Pre-assignment details
A total of 159 participants were screened and 126 participants were randomized in the ratio of 3:2:2:2 to the placebo versus DX-2930-03 arms. Of them, 125 participants were assigned to study treatment and one participant determined to be screen failure after randomization.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo matched to DX-2930 SC q2wks for 26 weeks. | 41 |
| Lanadelumab (DX-2930) 150 mg Every 4 Weeks Participants received 150 mg dose of DX-2930 SC q4wks and matched placebo SC q2wks between DX-2930 doses for 26 weeks. | 28 |
| Lanadelumab (DX-2930) 300 mg Every 4 Weeks Participants received 300 mg dose of DX-2930 SC q4wks and matched placebo SC q2wks between DX-2930 doses for 26 weeks. | 29 |
| Lanadelumab (DX-2930) 300 mg Every 2 Weeks Participants received 300 mg dose of DX-2930 SC q2wks for 26 weeks. | 27 |
| Total | 125 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 1 | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo | Lanadelumab (DX-2930) 150 mg Every 4 Weeks | Lanadelumab (DX-2930) 300 mg Every 4 Weeks | Lanadelumab (DX-2930) 300 mg Every 2 Weeks | Total |
|---|---|---|---|---|---|
| Age, Continuous | 40.1 Years STANDARD_DEVIATION 16.75 | 43.4 Years STANDARD_DEVIATION 14.91 | 39.5 Years STANDARD_DEVIATION 12.85 | 40.3 Years STANDARD_DEVIATION 13.35 | 40.7 Years STANDARD_DEVIATION 14.69 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 1 Participants | 2 Participants | 3 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 38 Participants | 27 Participants | 27 Participants | 23 Participants | 115 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 34 Participants | 20 Participants | 19 Participants | 15 Participants | 88 Participants |
| Sex: Female, Male Male | 7 Participants | 8 Participants | 10 Participants | 12 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 41 | 0 / 28 | 0 / 29 | 0 / 27 |
| other Total, other adverse events | 40 / 41 | 25 / 28 | 26 / 29 | 23 / 27 |
| serious Total, serious adverse events | 1 / 41 | 0 / 28 | 3 / 29 | 2 / 27 |
Outcome results
Primary
Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attacks During 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 was analyzed using a generalized linear model (GLM) for count data assuming a poisson distribution with a log link function and Pearson chi-square scaling of standard errors to account for potential overdispersion. The logarithm of time in days each subject was observed during the treatment period was used as an offset variable in the model.
Time frame: From Day 0 to Day 182
Population: ITT population included all randomized participants who received any exposure to the investigational product.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attacks During Treatment Period | 1.967 Attacks per 4 weeks |
| Lanadelumab (DX-2930) 150 mg Every 4 Weeks | Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attacks During Treatment Period | 0.480 Attacks per 4 weeks |
| Lanadelumab (DX-2930) 300 mg Every 4 Weeks | Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attacks During Treatment Period | 0.526 Attacks per 4 weeks |
| Lanadelumab (DX-2930) 300 mg Every 2 Weeks | Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attacks During Treatment Period | 0.257 Attacks per 4 weeks |
p-value: <0.00195% CI: [-84.65, -61.243]Chi-squared
p-value: <0.00195% CI: [-82.379, -59.456]Chi-squared
p-value: <0.00195% CI: [-92.828, -76.15]Chi-squared
Secondary
Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attack Requiring Acute Treatment
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 attack was analyzed using the GLM for count data assuming a poisson distribution with a log link function and Pearson chi-square scaling of standard errors to account for potential overdispersion. The logarithm of time in days each subject was observed during the treatment period was used as an offset variable in the model.
Time frame: From Day 0 to Day 182
Population: ITT population included all randomized participants who received any exposure to the investigational product.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attack Requiring Acute Treatment | 1.637 Attacks per 4 weeks |
| Lanadelumab (DX-2930) 150 mg Every 4 Weeks | Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attack Requiring Acute Treatment | 0.314 Attacks per 4 weeks |
| Lanadelumab (DX-2930) 300 mg Every 4 Weeks | Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attack Requiring Acute Treatment | 0.423 Attacks per 4 weeks |
| Lanadelumab (DX-2930) 300 mg Every 2 Weeks | Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attack Requiring Acute Treatment | 0.208 Attacks per 4 weeks |
p-value: <0.00195% CI: [-89.169, -66.114]Chi-squared
p-value: <0.00195% CI: [-83.733, -58.983]Chi-squared
p-value: <0.00195% CI: [-93.494, -75.204]Chi-squared
Secondary
Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attacks During Day 14 Through Day 182
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 during day 14 after study drug administration through day 182 was analyzed by the same poisson regression model as in the primary endpoint analysis.
Time frame: From Day 14 to Day 182
Population: ITT population included all randomized participants who received any exposure to the investigational product.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attacks During Day 14 Through Day 182 | 1.988 Attacks per 4 weeks |
| Lanadelumab (DX-2930) 150 mg Every 4 Weeks | Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attacks During Day 14 Through Day 182 | 0.445 Attacks per 4 weeks |
| Lanadelumab (DX-2930) 300 mg Every 4 Weeks | Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attacks During Day 14 Through Day 182 | 0.489 Attacks per 4 weeks |
| Lanadelumab (DX-2930) 300 mg Every 2 Weeks | Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attacks During Day 14 Through Day 182 | 0.218 Attacks per 4 weeks |
p-value: <0.00195% CI: [-86.253, -63.572]Chi-squared
p-value: <0.00195% CI: [-84.115, -61.833]Chi-squared
p-value: <0.00195% CI: [-94.325, -78.707]Chi-squared
Secondary
Rate of Moderate or Severe Investigator Confirmed Hereditary Angioedema (HAE) Attacks
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 investigator confirmed HAE attack was analyzed using the GLM for count data assuming a poisson distribution with a log link function and Pearson chi-square scaling of standard errors to account for potential overdispersion. The logarithm of time in days each subject was observed during the treatment period was used as an offset variable in the model.
Time frame: From Day 0 to Day 182
Population: ITT population included all randomized participants who received any exposure to the investigational product.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Rate of Moderate or Severe Investigator Confirmed Hereditary Angioedema (HAE) Attacks | 1.216 Attacks per 4 weeks |
| Lanadelumab (DX-2930) 150 mg Every 4 Weeks | Rate of Moderate or Severe Investigator Confirmed Hereditary Angioedema (HAE) Attacks | 0.359 Attacks per 4 weeks |
| Lanadelumab (DX-2930) 300 mg Every 4 Weeks | Rate of Moderate or Severe Investigator Confirmed Hereditary Angioedema (HAE) Attacks | 0.325 Attacks per 4 weeks |
| Lanadelumab (DX-2930) 300 mg Every 2 Weeks | Rate of Moderate or Severe Investigator Confirmed Hereditary Angioedema (HAE) Attacks | 0.202 Attacks per 4 weeks |
p-value: <0.00195% CI: [-82.696, -49.699]Chi-squared
p-value: <0.00195% CI: [-84.316, -54.496]Chi-squared
p-value: <0.00195% CI: [-91.618, -67.099]Chi-squared