Hereditary Angioedema (HAE)
Conditions
Keywords
DX-2930(SHP643), Dyax, Hereditary Angioedema
Brief summary
This study is an open-label, long term safety and efficacy study to evaluate DX-2930 in preventing acute angioedema attacks in participants with Type I and Type II HAE.
Interventions
DRUGDX-2930
Participants who rollover from the DX-2930-03 study will receive 300 milligram (mg) DX-2930 subcutaneous injection at Day 0 followed by second dose following the first HAE attack and then once in every 2 weeks until the end of the treatment period (up to 924 days). A wash-out period of a minimum of 10 days and a maximum of 18 days is required between subsequent administrations.
Sponsors
Shire
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female HAE participants who are 12 years of age or older at the time of screening * Documented diagnosis of HAE (Type I or II) based on 1. Documented clinical history consistent with HAE (subcutaneous or mucosal, nonpruritic swelling episodes without accompanying urticaria). 2. Diagnostic testing results obtained during screening (or a prior DX-2930 study) that confirm HAE Type I or II: C1 inhibitor (C1-INH) functional level less than (\<) 40 percentage (%) of the normal level. Participants with functional C1-INH level 40-50% of the normal level may be enrolled if they also have a C4 level below the normal range. Participants may be retested if results are incongruent with clinical history or believed by the investigator to be confounded by long-term prophylactic (LTP) use. (It is understood that C1-INH therapy may alter the lab results of C1-INH assessments; therefore, the investigator's discretion in collaboration with Medical Monitor is advised for proper documentation of eligibility). 3. At least one of the following: Age at reported onset of first angioedema symptoms less than or equal to (\<=) 30 years, a family history consistent with HAE Type I or II, or C1q within normal range. * A historical baseline HAE attack rate of at least 1 attack per 12 weeks * Adult participants and caregivers of participants under the age of 18 are willing and able to read, understand, and sign an informed consent form. Participants age 12 to 17, whose caregiver has provided informed consent, are willing and able to read, understand and sign an assent form. * Males and females who are fertile and sexually active must adhere to contraception requirements for the duration of the study as 1. Females (NOTE: Female rollover participants (those who previously participated in Study DX-2930-03 \[NCT02586805\]) of childbearing potential may continue to use the birth control method used during Study DX-2930-03 (NCT02586805).) of childbearing potential must agree to be abstinent or it is recommended to use highly effective forms of contraception from the screening period through 30 days after the final study visit. This includes stable doses (for 3 months prior to study screening) of combined estrogen and progestin-containing hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable), progestin-only hormonal contraception associated with inhibition of ovulation, intra-uterine device (IUD, all types) or intrauterine hormone releasing systems (IUS). Notes: 1) A female whose male partner has had a vasectomy must agree to use one additional form of medically acceptable contraception. 2) Use of a male condom with or without spermicide or cervical cap, diaphragm or sponge with spermicide or a combination (double barrier methods) are not considered highly effective. 2. Females of non-childbearing potential, defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months do not require contraception during the study. 3. Males, including males who are surgically sterile (post vasectomy), with female partners of childbearing potential must agree to be abstinent or else use a medically acceptable form of contraception from the screening period through 60 days after the final study visit.
Exclusion criteria
* Discontinued from DX-2930-03 (NCT02586805) after enrollment for any reason. * If rolling over from DX-2930-03 (NCT02586805), presence of important safety concerns that would preclude participation in this study. * Concomitant diagnosis of another form of chronic, recurrent angioedema, such as acquired angioedema (AAE), HAE with normal C1 inhibitor (also known as HAE Type III), idiopathic angioedema, or recurrent angioedema associated with urticaria. * Dosing with an investigational drug (not including DX-2930 or other HAE therapies) or exposure to an investigational device within 4 weeks prior to screening. * Exposure to angiotensin-converting enzyme (ACE) inhibitors within 4 weeks prior to screening or any newly initiated or dose modification of estrogen-containing medications with systemic absorption (such as oral contraceptives or hormonal replacement therapy) 3 months prior to the screening visit. * Unwilling to discontinue use of long-term prophylactic therapy for HAE (C1-INH, attenuated androgens, or anti-fibrinolytics) within 3 weeks after starting DX-2930 treatment. * 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. * Participant has any condition that, in the opinion of the investigator or Sponsor, may compromise their safety or compliance, preclude successful conduct of the study, or interfere with interpretation of the results (eg, history of substance abuse or dependence, a significant pre-existing illness or other major comorbidity that the investigator considers may confound the interpretation of study results).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | From start of the study up to follow-up (Day 952) | An adverse event (AE) was any untoward medical occurrence in a clinical trial Participant whether or not it appeared to have a causal relationship with the treatment administered. Treatment-emergent AEs were defined as AEs with onset at the time of or following the first exposure to open-label DX-2930 in this study, or medical conditions present prior to the start of treatment but increasing in severity or relationship at the time of or following the start of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attacks During the Treatment Period | Up to Day 924 | HAE attack was defined as a discrete episode during which the participant progressed from no angioedema to symptoms of angioedema. The treatment period investigator-confirmed HAE attack rate was calculated for each participant as the number of investigator-confirmed HAE attacks occurring during the treatment period (regular dosing stage of the treatment period for rollover participants) divided by the number of days the participant contributed to the treatment period multiplied by 28 days. Rate of investigator-confirmed HAE attacks during the treatment period was reported. |
| Rate of Investigator-Confirmed Hereditary Angioedema (HAE) Attacks Requiring Acute Treatment During the Treatment Period | Up to Day 924 | 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 requiring acute treatment for each participant as the number of investigator-confirmed HAE attacks occurring during the treatment period (regular dosing stage of the treatment period for rollover participants) divided by the number of days the participant contributed to the treatment period multiplied by 28 days. Rate of investigator-confirmed HAE attacks requiring acute treatment during the treatment period was reported. |
| Rate of Moderate or Severe Hereditary Angioedema (HAE) Attacks During the Treatment Period | Up to Day 924 | 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 HAE attacks during the treatment period was reported. |
| Rate of High-Morbidity Hereditary Angioedema (HAE) Attacks During the Treatment Period | Up to Day 924 | HAE attack was defined as a discrete episode during which the participant progressed from no angioedema to symptoms of angioedema. High-morbidity Hereditary Angioedema (HAE) attack was defined as any attack that had at least one of the following characteristics: severe, resulted in hospitalization (except hospitalization for observation lesser than \[\<\] 24 hours), hemodynamically significant (systolic blood pressure \<90 millimeter of mercury \[mmHg\], required intravenous hydration, or associated with syncope or near-syncope) or laryngeal edema. Number of high-morbidity HAE attacks during the treatment period was analyzed and reported using the methods for the overall number of investigator-confirmed HAE attacks with the exception of the monthly line graphs. Rate of high-morbidity HAE attacks during the treatment period was reported. |
| Time to First Investigator-Confirmed Hereditary Angioedema (HAE) Attacks in Rollover Participants | Up to Day 924 | HAE attack was defined as a discrete episode during which the participant progressed from no angioedema to symptoms of angioedema. Time to first investigator-confirmed HAE attack was calculated from the time of first open-label dose to the start time of the first investigator-confirmed HAE attack. Time to the first investigator-confirmed HAE attack was analyzed and reported only in rollover safety population. |
Countries
Canada, Germany, Italy, Jordan, Puerto Rico, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 43 sites across United States, Canada, Europe and Jorden between 26 May 2016 (first participant first visit) and 31 October 2019 (last participant last visit).
Pre-assignment details
A total of 212 participants were enrolled and received treatment in two groups (Rollover participants \[109\] and Non-rollover participants \[103\]). Participants who rolled from the DX-2930-03 (NCT02586805) study were in Rollover group and participants who were directly enrolled into this DX-2930-04 study were in Non-rollover group.
Participants by arm
| Arm | Count |
|---|---|
| Rollover Participants Participants who rolled from the DX-2930-03 (NCT02586805) study received 300 milligrams (mg) of DX-2930 subcutaneous (SC) injection on Day 0 followed by a second dose after participants reported their first HAE attack and continued to receive repeated SC administrations of 300 mg DX-2930 every 2 weeks (q2wks) throughout the treatment period (up to 924 days). A wash-out period of a minimum of 10 days and a maximum of 18 days were required between subsequent administrations. | 109 |
| Non-rollover Participants Participants who directly entered in to this DX-2930-04 study received 300 mg of DX-2930 SC injection on Day 0 and continued to receive SC administrations of 300 mg DX-2930 every 2 weeks throughout the treatment period (up to 924 days). | 103 |
| Total | 212 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 5 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Other (Unspecified) | 0 | 3 |
| Overall Study | Physician Decision | 2 | 1 |
| Overall Study | Pregnancy | 3 | 1 |
| Overall Study | Subject withdrawn-Other | 17 | 4 |
| Overall Study | Subject withdrawn-to commercial product | 54 | 63 |
Baseline characteristics
| Characteristic | Non-rollover Participants | Total | Rollover Participants |
|---|---|---|---|
| Age, Continuous | 39.5 Years STANDARD_DEVIATION 16.71 | 40.7 Years STANDARD_DEVIATION 15.73 | 41.9 Years STANDARD_DEVIATION 14.74 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 13 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 97 Participants | 198 Participants | 101 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 10 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 99 Participants | 198 Participants | 99 Participants |
| Sex: Female, Male Female | 68 Participants | 143 Participants | 75 Participants |
| Sex: Female, Male Male | 35 Participants | 69 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 109 | 0 / 103 |
| other Total, other adverse events | 100 / 109 | 96 / 103 |
| serious Total, serious adverse events | 12 / 109 | 9 / 103 |
Outcome results
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) was any untoward medical occurrence in a clinical trial Participant whether or not it appeared to have a causal relationship with the treatment administered. Treatment-emergent AEs were defined as AEs with onset at the time of or following the first exposure to open-label DX-2930 in this study, or medical conditions present prior to the start of treatment but increasing in severity or relationship at the time of or following the start of treatment.
Time frame: From start of the study up to follow-up (Day 952)
Population: Safety population included all participants who received any study drug after entering the DX-2930-04 study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rollover Participants | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 105 Participants |
| Non-rollover Participants | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 101 Participants |
Secondary
Rate of High-Morbidity Hereditary Angioedema (HAE) Attacks During the Treatment Period
HAE attack was defined as a discrete episode during which the participant progressed from no angioedema to symptoms of angioedema. High-morbidity Hereditary Angioedema (HAE) attack was defined as any attack that had at least one of the following characteristics: severe, resulted in hospitalization (except hospitalization for observation lesser than \[\<\] 24 hours), hemodynamically significant (systolic blood pressure \<90 millimeter of mercury \[mmHg\], required intravenous hydration, or associated with syncope or near-syncope) or laryngeal edema. Number of high-morbidity HAE attacks during the treatment period was analyzed and reported using the methods for the overall number of investigator-confirmed HAE attacks with the exception of the monthly line graphs. Rate of high-morbidity HAE attacks during the treatment period was reported.
Time frame: Up to Day 924
Population: Safety population included all participants who received any study drug after entering the DX-2930-04 study. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rollover Participants | Rate of High-Morbidity Hereditary Angioedema (HAE) Attacks During the Treatment Period | 0.03 Attacks per month | Standard Deviation 0.085 |
| Non-rollover Participants | Rate of High-Morbidity Hereditary Angioedema (HAE) Attacks During the Treatment Period | 0.04 Attacks per month | Standard Deviation 0.103 |
Secondary
Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attacks During the Treatment Period
HAE attack was defined as a discrete episode during which the participant progressed from no angioedema to symptoms of angioedema. The treatment period investigator-confirmed HAE attack rate was calculated for each participant as the number of investigator-confirmed HAE attacks occurring during the treatment period (regular dosing stage of the treatment period for rollover participants) divided by the number of days the participant contributed to the treatment period multiplied by 28 days. Rate of investigator-confirmed HAE attacks during the treatment period was reported.
Time frame: Up to Day 924
Population: Safety population included all participants who received any study drug after entering the DX-2930-04 study. Here, the number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rollover Participants | Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attacks During the Treatment Period | 0.27 Attacks per month | Standard Deviation 0.581 |
| Non-rollover Participants | Rate of Investigator Confirmed Hereditary Angioedema (HAE) Attacks During the Treatment Period | 0.22 Attacks per month | Standard Deviation 0.521 |
Secondary
Rate of Investigator-Confirmed Hereditary Angioedema (HAE) Attacks Requiring Acute Treatment During the 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 requiring acute treatment for each participant as the number of investigator-confirmed HAE attacks occurring during the treatment period (regular dosing stage of the treatment period for rollover participants) divided by the number of days the participant contributed to the treatment period multiplied by 28 days. Rate of investigator-confirmed HAE attacks requiring acute treatment during the treatment period was reported.
Time frame: Up to Day 924
Population: Safety population was analyzed, which included all participants who received any study drug after entering the DX-2930-04 study. Here, the number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rollover Participants | Rate of Investigator-Confirmed Hereditary Angioedema (HAE) Attacks Requiring Acute Treatment During the Treatment Period | 0.20 Attacks per month | Standard Deviation 0.43 |
| Non-rollover Participants | Rate of Investigator-Confirmed Hereditary Angioedema (HAE) Attacks Requiring Acute Treatment During the Treatment Period | 0.21 Attacks per month | Standard Deviation 0.517 |
Secondary
Rate of Moderate or Severe Hereditary Angioedema (HAE) Attacks During the Treatment Period
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 HAE attacks during the treatment period was reported.
Time frame: Up to Day 924
Population: Safety population included all participants who received any study drug after entering the DX-2930-04 study. Here, the number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rollover Participants | Rate of Moderate or Severe Hereditary Angioedema (HAE) Attacks During the Treatment Period | 0.21 Attacks per month | Standard Deviation 0.479 |
| Non-rollover Participants | Rate of Moderate or Severe Hereditary Angioedema (HAE) Attacks During the Treatment Period | 0.19 Attacks per month | Standard Deviation 0.512 |
Secondary
Time to First Investigator-Confirmed Hereditary Angioedema (HAE) Attacks in Rollover Participants
HAE attack was defined as a discrete episode during which the participant progressed from no angioedema to symptoms of angioedema. Time to first investigator-confirmed HAE attack was calculated from the time of first open-label dose to the start time of the first investigator-confirmed HAE attack. Time to the first investigator-confirmed HAE attack was analyzed and reported only in rollover safety population.
Time frame: Up to Day 924
Population: Rollover Safety Population included subset of participants who participated in the DX-2930-03 (NCT02586805) study and received any study drug after entering the DX-2930-04 study (that is any exposure to open-label DX-2930). Here, data was not planned to be collected and analyzed for Non-rollover participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rollover Participants | Time to First Investigator-Confirmed Hereditary Angioedema (HAE) Attacks in Rollover Participants | 43 Days |