Hereditary Angioedema (HAE)
Conditions
Keywords
HAE
Brief summary
The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics (PK) profile of multiple subcutaneous administrations of DX-2930 across a range of doses in HAE participants.
Interventions
DRUGDX-2930
Participants will receive SC injection of DX-2930 (a recombinant, Chinese hamster ovary \[CHO\] cell expressed, fully human immunoglobulin IgG1, kappa light chain, monoclonal antibody) once and followed by the second dose after 2 week into the upper arm.
DRUGPlacebo
Participants will receive matching placebo subcutaneously.
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* At least 18 years of age at the time of screening * Documented diagnosis of HAE (Type I or II) * Experiencing ≥2 HAE attacks per year, with at least 1 attack in the past 6 months reported by the participant * Willing and able to read, understand, and sign an informed consent form * Females of childbearing potential must agree to be abstinent or else use acceptable forms of contraception throughout study * Males with female partners of childbearing potential must agree to be abstinent or use a medically acceptable form of contraception throughout study
Exclusion criteria
* Exposure to an investigational drug or device within 90 days prior to study * History of exposure within the past 5 years to a monoclonal antibody or recombinant protein bearing an Fc domain * Concomitant diagnosis of another form of chronic angioedema * Use of long-term prophylaxis for HAE within 90 days prior to study * Use of C1-INH that exceeds a total of 30 days within the past 90 days prior to study; any use of C1-INH within 7 days prior to study * Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systemic absorption within 90 days prior to study * Exposure to androgens within 90 days prior to study * Presence of an indwelling catheter * Diagnosis of HIV * Active liver disease or liver function test abnormalities * History of substance abuse or dependence * Pregnancy or breastfeeding * Any condition that, in the opinion of the Investigator, may compromise their safety or compliance, preclude successful conduct of the study, or interfere with interpretation of the results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious Adverse Events (SAE) and Treatment-Emergent Adverse Events (TEAE) | From Day 1 up to final follow-up (Day 123) | A SAE was any adverse experience occurring at any dose that resulted in any of the following outcomes: Death, Life-threatening experience, required inpatient hospitalization or prolongation of existing hospitalization. Resulted in persistent or significant disability or incapacity. Was a congenital anomaly or birth defect. Was considered to be an important medical event. An AE was considered treatment-emergent if the onset time was after administration of study drug through the Day 120 post-dose final follow-up visit or, in the event that onset time preceded study drug administration, the AE increased in severity during the 120-day post-dose follow-up period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Maximum Plasma Concentration (Tmax) | Days 1, 2, 4, 8, 15, 16, 18, 22, 29, 36, 50, 64, 92, and 120 | PK parameter Tmax data were reported. |
| Area Under the Plasma Concentration-Time Curve (AUC) | Days 1, 2, 4, 8, 15, 16, 18, 22, 29, 36, 50, 64, 92, and 120 | PK paramenter AUC data were reported. |
| Apparent Clearance (CL/F) | Days 1, 2, 4, 8, 15, 16, 18, 22, 29, 36, 50, 64, 92, and 120 | PK parameter CL/F data were reported. |
| Apparent Volume of Distribution (Vd/F) | Days 1, 2, 4, 8, 15, 16, 18, 22, 29, 36, 50, 64, 92, and 120 | PK parameter Vd/F data were reported. |
| Terminal Elimination Half-Life (t1/2) | Days 1, 2, 4, 8, 15, 16, 18, 22, 29, 36, 50, 64, 92, and 120 | PK parameter t(1/2) data were reported. |
| Maximum Plasma Concentration (Cmax) | Days 1, 2, 4, 8, 15, 16, 18, 22, 29, 36, 50, 64, 92, and 120 | Pharmacokinetic (PK) parameter Cmax data were reported. |
Other
| Measure | Time frame | Description |
|---|---|---|
| HAE Attacks Per Week From Day 8 to Day 64 | Day 8 to Day 64 | This endpoint analysis was based on participants in the 300 mg, 400 mg, and placebo dose groups with a historical baseline attack rate of at least 2 attacks over the last 3 months prior to enrollment. The result is based on General Estimating Equation (GEE) analysis of repeated counts per week during the prespecified assessment period (Day 8 to Day 64 predicted to correspond to a period of notable drug exposure). Baseline HAE attack rate per week is a covariate, treatment group is a fixed effect, and participant is a random effect in the GEE model with independence working correlation structure. |
| HAE Attack Rate Per Week From Day 1 to Day 50 | Day 1 to Day 50 | This endpoint analysis was based on participants in the 300 mg, 400 mg, and placebo dose groups with a historical baseline attack rate of at least 2 attacks over the last 3 months prior to enrollment. The result is based on General Estimating Equation (GEE) analysis of repeated counts per week during the prespecified assessment period (Day 1 to Day 50 predicted to correspond to a period of notable drug exposure). Baseline HAE attack rate per week is a covariate, treatment group is a fixed effect, and participant is a random effect in the GEE model with independence working correlation structure. |
| HAE Attacks Per Week From Day 8 to Day 92 | Day 8 to Day 92 | This endpoint analysis was based on participants in the 300 mg, 400 mg, and placebo dose groups with a historical baseline attack rate of at least 2 attacks over the last 3 months prior to enrollment. The result is based on General Estimating Equation (GEE) analysis of repeated counts per week during the prespecified assessment period (Day 8 to Day 92 predicted to correspond to a period of notable drug exposure). Baseline HAE attack rate per week is a covariate, treatment group is a fixed effect, and participant is a random effect in the GEE model with independence working correlation structure. |
| HAE Attack Rate Per Week From Day 8 to Day 50 | Day 8 to Day 50 | Analysis of this outcome measure was based on participants in the 300 mg, 400 mg, and placebo dose groups with a historical baseline attack rate of at least 2 attacks over the last 3 months prior to enrollment. The result is based on General Estimating Equation (GEE) analysis of repeated counts per week during the pre-specified assessment period (Days 8 to 50; predicted to correspond to a period of notable drug exposure). Baseline HAE attack rate per week was a covariate, treatment group is a fixed effect, and participant was a random effect in the GEE model with independence working correlation structure. |
Countries
Italy, Jordan, United States
Participant flow
Recruitment details
Participants were recruited in United States, Italy, and Jordan between 14 May 2014 (first participant first visit) and 18 May 2015 (last participant last visit).
Pre-assignment details
A total of 38 participants were randomized and 37 participants were treated out of them 36 participants completed the study.
Participants by arm
| Arm | Count |
|---|---|
| DX-2930, Cohort 1 Participants received 30 mg dose of DX-2930 subcutaneous (SC) injection once and followed by the second dose after 2 week into the upper arm. | 4 |
| DX-2930, Cohort 2 Participants received 100 mg dose of DX-2930 subcutaneous (SC) injection once and followed by the second dose after 2 week into the upper arm. | 4 |
| DX-2930, Cohort 3 Participants received 300 mg dose of DX-2930 subcutaneous (SC) injection once and followed by the second dose after 2 week into the upper arm. | 5 |
| DX-2930, Cohort 4 Participants received 400 mg dose of DX-2930 subcutaneous (SC) injection once and followed by the second dose after 2 week into the upper arm. | 11 |
| Placebo Participants received placebo matched to 30, 100, 300 and 400 mg dose of DX-2930 subcutaneous (SC) injection once and followed by the second dose after 2 week into the upper arm. | 13 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Screen failure after randomization | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | DX-2930, Cohort 1 | DX-2930, Cohort 2 | DX-2930, Cohort 3 | DX-2930, Cohort 4 | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Customized <18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized >65 years | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Age, Customized Between 18 and 65 years | 4 Participants | 4 Participants | 5 Participants | 10 Participants | 12 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 4 Participants | 5 Participants | 10 Participants | 13 Participants | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 4 Participants | 5 Participants | 11 Participants | 13 Participants | 37 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 1 Participants | 9 Participants | 7 Participants | 23 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 4 Participants | 2 Participants | 6 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 4 | 0 / 5 | 0 / 11 | 0 / 13 |
| other Total, other adverse events | 1 / 4 | 3 / 4 | 2 / 5 | 8 / 11 | 10 / 13 |
| serious Total, serious adverse events | 0 / 4 | 0 / 4 | 0 / 5 | 0 / 11 | 1 / 13 |
Outcome results
Primary
Number of Participants With Serious Adverse Events (SAE) and Treatment-Emergent Adverse Events (TEAE)
A SAE was any adverse experience occurring at any dose that resulted in any of the following outcomes: Death, Life-threatening experience, required inpatient hospitalization or prolongation of existing hospitalization. Resulted in persistent or significant disability or incapacity. Was a congenital anomaly or birth defect. Was considered to be an important medical event. An AE was considered treatment-emergent if the onset time was after administration of study drug through the Day 120 post-dose final follow-up visit or, in the event that onset time preceded study drug administration, the AE increased in severity during the 120-day post-dose follow-up period.
Time frame: From Day 1 up to final follow-up (Day 123)
Population: Safety Population included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DX-2930, Cohort 1 | Number of Participants With Serious Adverse Events (SAE) and Treatment-Emergent Adverse Events (TEAE) | Serious Adverse Events | 0 Participants |
| DX-2930, Cohort 1 | Number of Participants With Serious Adverse Events (SAE) and Treatment-Emergent Adverse Events (TEAE) | Treatment Emergent Adverse Events | 1 Participants |
| DX-2930, Cohort 2 | Number of Participants With Serious Adverse Events (SAE) and Treatment-Emergent Adverse Events (TEAE) | Serious Adverse Events | 0 Participants |
| DX-2930, Cohort 2 | Number of Participants With Serious Adverse Events (SAE) and Treatment-Emergent Adverse Events (TEAE) | Treatment Emergent Adverse Events | 3 Participants |
| DX-2930, Cohort 3 | Number of Participants With Serious Adverse Events (SAE) and Treatment-Emergent Adverse Events (TEAE) | Serious Adverse Events | 0 Participants |
| DX-2930, Cohort 3 | Number of Participants With Serious Adverse Events (SAE) and Treatment-Emergent Adverse Events (TEAE) | Treatment Emergent Adverse Events | 2 Participants |
| DX-2930, Cohort 4 | Number of Participants With Serious Adverse Events (SAE) and Treatment-Emergent Adverse Events (TEAE) | Treatment Emergent Adverse Events | 8 Participants |
| DX-2930, Cohort 4 | Number of Participants With Serious Adverse Events (SAE) and Treatment-Emergent Adverse Events (TEAE) | Serious Adverse Events | 0 Participants |
| Placebo | Number of Participants With Serious Adverse Events (SAE) and Treatment-Emergent Adverse Events (TEAE) | Serious Adverse Events | 1 Participants |
| Placebo | Number of Participants With Serious Adverse Events (SAE) and Treatment-Emergent Adverse Events (TEAE) | Treatment Emergent Adverse Events | 10 Participants |
Secondary
Apparent Clearance (CL/F)
PK parameter CL/F data were reported.
Time frame: Days 1, 2, 4, 8, 15, 16, 18, 22, 29, 36, 50, 64, 92, and 120
Population: Pharmacokinectic (PK) population included all randomized HAE participants in the safety population who had sufficient blood samples to obtain a plasma concentration versus time profile.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DX-2930, Cohort 1 | Apparent Clearance (CL/F) | 0.5720 Liter per day (L/day) | Standard Deviation 0.26829 |
| DX-2930, Cohort 2 | Apparent Clearance (CL/F) | 0.8110 Liter per day (L/day) | Standard Deviation 0.28258 |
| DX-2930, Cohort 3 | Apparent Clearance (CL/F) | 1.0036 Liter per day (L/day) | Standard Deviation 0.9087 |
| DX-2930, Cohort 4 | Apparent Clearance (CL/F) | 0.5514 Liter per day (L/day) | Standard Deviation 0.14318 |
Secondary
Apparent Volume of Distribution (Vd/F)
PK parameter Vd/F data were reported.
Time frame: Days 1, 2, 4, 8, 15, 16, 18, 22, 29, 36, 50, 64, 92, and 120
Population: Pharmacokinectic (PK) population included all randomized HAE participants in the safety population who had sufficient blood samples to obtain a plasma concentration versus time profile.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DX-2930, Cohort 1 | Apparent Volume of Distribution (Vd/F) | 11.553 Liter (L) | Standard Deviation 4.9218 |
| DX-2930, Cohort 2 | Apparent Volume of Distribution (Vd/F) | 16.125 Liter (L) | Standard Deviation 2.6949 |
| DX-2930, Cohort 3 | Apparent Volume of Distribution (Vd/F) | 17.436 Liter (L) | Standard Deviation 10.5609 |
| DX-2930, Cohort 4 | Apparent Volume of Distribution (Vd/F) | 11.696 Liter (L) | Standard Deviation 2.76 |
Secondary
Area Under the Plasma Concentration-Time Curve (AUC)
PK paramenter AUC data were reported.
Time frame: Days 1, 2, 4, 8, 15, 16, 18, 22, 29, 36, 50, 64, 92, and 120
Population: Pharmacokinectic (PK) population included all randomized HAE participants in the safety population who had sufficient blood samples to obtain a plasma concentration versus time profile.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DX-2930, Cohort 1 | Area Under the Plasma Concentration-Time Curve (AUC) | 64100.0 day*nanogram per milliliter (day*ng/mL) | Standard Deviation 34731.16 |
| DX-2930, Cohort 2 | Area Under the Plasma Concentration-Time Curve (AUC) | 135425.0 day*nanogram per milliliter (day*ng/mL) | Standard Deviation 48616.76 |
| DX-2930, Cohort 3 | Area Under the Plasma Concentration-Time Curve (AUC) | 451800.0 day*nanogram per milliliter (day*ng/mL) | Standard Deviation 226801.01 |
| DX-2930, Cohort 4 | Area Under the Plasma Concentration-Time Curve (AUC) | 762777.8 day*nanogram per milliliter (day*ng/mL) | Standard Deviation 166713.66 |
Secondary
Maximum Plasma Concentration (Cmax)
Pharmacokinetic (PK) parameter Cmax data were reported.
Time frame: Days 1, 2, 4, 8, 15, 16, 18, 22, 29, 36, 50, 64, 92, and 120
Population: Pharmacokinectic (PK) population included all randomized HAE participants in the safety population who had sufficient blood samples to obtain a plasma concentration versus time profile.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DX-2930, Cohort 1 | Maximum Plasma Concentration (Cmax) | 3895.0 Nanogram per milliliter (ng/mL) | Standard Deviation 2159.76 |
| DX-2930, Cohort 2 | Maximum Plasma Concentration (Cmax) | 7890.0 Nanogram per milliliter (ng/mL) | Standard Deviation 2058.43 |
| DX-2930, Cohort 3 | Maximum Plasma Concentration (Cmax) | 27460.0 Nanogram per milliliter (ng/mL) | Standard Deviation 14542.46 |
| DX-2930, Cohort 4 | Maximum Plasma Concentration (Cmax) | 45322.2 Nanogram per milliliter (ng/mL) | Standard Deviation 8704.56 |
Secondary
Terminal Elimination Half-Life (t1/2)
PK parameter t(1/2) data were reported.
Time frame: Days 1, 2, 4, 8, 15, 16, 18, 22, 29, 36, 50, 64, 92, and 120
Population: Pharmacokinectic (PK) population included all randomized HAE participants in the safety population who had sufficient blood samples to obtain a plasma concentration versus time profile.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DX-2930, Cohort 1 | Terminal Elimination Half-Life (t1/2) | 14.225 Day | Standard Deviation 0.8261 |
| DX-2930, Cohort 2 | Terminal Elimination Half-Life (t1/2) | 14.625 Day | Standard Deviation 3.4082 |
| DX-2930, Cohort 3 | Terminal Elimination Half-Life (t1/2) | 13.802 Day | Standard Deviation 3.2535 |
| DX-2930, Cohort 4 | Terminal Elimination Half-Life (t1/2) | 14.967 Day | Standard Deviation 2.4377 |
Secondary
Time to Maximum Plasma Concentration (Tmax)
PK parameter Tmax data were reported.
Time frame: Days 1, 2, 4, 8, 15, 16, 18, 22, 29, 36, 50, 64, 92, and 120
Population: Pharmacokinectic (PK) population included all randomized HAE participants in the safety population who had sufficient blood samples to obtain a plasma concentration versus time profile.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DX-2930, Cohort 1 | Time to Maximum Plasma Concentration (Tmax) | 17.930 Days | Standard Deviation 1.14 |
| DX-2930, Cohort 2 | Time to Maximum Plasma Concentration (Tmax) | 18.020 Days | Standard Deviation 0.4596 |
| DX-2930, Cohort 3 | Time to Maximum Plasma Concentration (Tmax) | 18.172 Days | Standard Deviation 1.4526 |
| DX-2930, Cohort 4 | Time to Maximum Plasma Concentration (Tmax) | 17.700 Days | Standard Deviation 0.9804 |
Other Pre-specified
HAE Attack Rate Per Week From Day 1 to Day 50
This endpoint analysis was based on participants in the 300 mg, 400 mg, and placebo dose groups with a historical baseline attack rate of at least 2 attacks over the last 3 months prior to enrollment. The result is based on General Estimating Equation (GEE) analysis of repeated counts per week during the prespecified assessment period (Day 1 to Day 50 predicted to correspond to a period of notable drug exposure). Baseline HAE attack rate per week is a covariate, treatment group is a fixed effect, and participant is a random effect in the GEE model with independence working correlation structure.
Time frame: Day 1 to Day 50
Population: All randomized participants in the 300 mg, 400 mg, and placebo groups who received at least 1 dose of study drug and who had a historical baseline attack rate of at least 2 attacks in the 3 months prior to enrollment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DX-2930, Cohort 1 | HAE Attack Rate Per Week From Day 1 to Day 50 | Mean baseline HAE attack rate (attacks/week) | 0.3269 HAE attacks per week | Standard Deviation 0.24627 |
| DX-2930, Cohort 1 | HAE Attack Rate Per Week From Day 1 to Day 50 | Estimated mean rate based on GEE (attacks/week) | 0 HAE attacks per week | — |
| DX-2930, Cohort 1 | HAE Attack Rate Per Week From Day 1 to Day 50 | Mean HAE attack rate, unadjusted (attacks/week) | 0 HAE attacks per week | — |
| DX-2930, Cohort 2 | HAE Attack Rate Per Week From Day 1 to Day 50 | Mean baseline HAE attack rate (attacks/week) | 0.5455 HAE attacks per week | Standard Deviation 0.17356 |
| DX-2930, Cohort 2 | HAE Attack Rate Per Week From Day 1 to Day 50 | Estimated mean rate based on GEE (attacks/week) | 0.0525 HAE attacks per week | Standard Deviation 0.03998 |
| DX-2930, Cohort 2 | HAE Attack Rate Per Week From Day 1 to Day 50 | Mean HAE attack rate, unadjusted (attacks/week) | 0.0541 HAE attacks per week | Standard Deviation 0.17634 |
| DX-2930, Cohort 3 | HAE Attack Rate Per Week From Day 1 to Day 50 | Mean HAE attack rate, unadjusted (attacks/week) | 0.0392 HAE attacks per week | Standard Deviation 0.15105 |
| DX-2930, Cohort 3 | HAE Attack Rate Per Week From Day 1 to Day 50 | Mean baseline HAE attack rate (attacks/week) | 0.4872 HAE attacks per week | Standard Deviation 0.211 |
| DX-2930, Cohort 3 | HAE Attack Rate Per Week From Day 1 to Day 50 | Estimated mean rate based on GEE (attacks/week) | 0.0382 HAE attacks per week | Standard Deviation 0.02898 |
| DX-2930, Cohort 4 | HAE Attack Rate Per Week From Day 1 to Day 50 | Mean baseline HAE attack rate (attacks/week) | 0.3916 HAE attacks per week | Standard Deviation 0.17694 |
| DX-2930, Cohort 4 | HAE Attack Rate Per Week From Day 1 to Day 50 | Estimated mean rate based on GEE (attacks/week) | 0.3588 HAE attacks per week | Standard Deviation 0.08864 |
| DX-2930, Cohort 4 | HAE Attack Rate Per Week From Day 1 to Day 50 | Mean HAE attack rate, unadjusted (attacks/week) | 0.3506 HAE attacks per week | Standard Deviation 0.32803 |
Comparison: The result was based on General Estimating Equation (GEE) analysis. Generalized Estimating Equation (GEE) approach with Poisson distribution assumption was applied to the repeated-measures mixed model with independence working correlation structure. The treatment group was a fixed effect and the number of baseline HAE attacks per week was included as a covariate in the GEE.p-value: <0.000195% CI: [-100, -100]Mixed Models Analysis
Comparison: The result was based on General Estimating Equation (GEE) analysis. Generalized Estimating Equation (GEE) approach with Poisson distribution assumption was applied to the repeated-measures mixed model with independence working correlation structure. The treatment group was a fixed effect and the number of baseline HAE attacks per week was included as a covariate in the GEE.p-value: 0.014195% CI: [-96.79, -32.03]Mixed Models Analysis
Comparison: The result was based on General Estimating Equation (GEE) analysis. Generalized Estimating Equation (GEE) approach with Poisson distribution assumption was applied to the repeated-measures mixed model with independence working correlation structure. The treatment group was a fixed effect and the number of baseline HAE attacks per week was included as a covariate in the GEE.p-value: 0.00495% CI: [-97.68, -51.13]Mixed Models Analysis
Other Pre-specified
HAE Attack Rate Per Week From Day 8 to Day 50
Analysis of this outcome measure was based on participants in the 300 mg, 400 mg, and placebo dose groups with a historical baseline attack rate of at least 2 attacks over the last 3 months prior to enrollment. The result is based on General Estimating Equation (GEE) analysis of repeated counts per week during the pre-specified assessment period (Days 8 to 50; predicted to correspond to a period of notable drug exposure). Baseline HAE attack rate per week was a covariate, treatment group is a fixed effect, and participant was a random effect in the GEE model with independence working correlation structure.
Time frame: Day 8 to Day 50
Population: All randomized participants in the 300 mg, 400 mg, and placebo groups who received at least 1 dose of study drug and who had a historical baseline attack rate of at least 2 attacks in the 3 months prior to enrollment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DX-2930, Cohort 1 | HAE Attack Rate Per Week From Day 8 to Day 50 | Mean baseline HAE attack rate (attacks/week) | 0.3269 HAE attacks per week | Standard Error 0.24627 |
| DX-2930, Cohort 1 | HAE Attack Rate Per Week From Day 8 to Day 50 | Estimated mean rate based on GEE (attacks/week) | 0 HAE attacks per week | — |
| DX-2930, Cohort 1 | HAE Attack Rate Per Week From Day 8 to Day 50 | Mean HAE attack rate, unadjusted (attacks/week) | 0 HAE attacks per week | — |
| DX-2930, Cohort 2 | HAE Attack Rate Per Week From Day 8 to Day 50 | Mean baseline HAE attack rate (attacks/week) | 0.5455 HAE attacks per week | Standard Error 0.17356 |
| DX-2930, Cohort 2 | HAE Attack Rate Per Week From Day 8 to Day 50 | Estimated mean rate based on GEE (attacks/week) | 0.0454 HAE attacks per week | Standard Error 0.03319 |
| DX-2930, Cohort 2 | HAE Attack Rate Per Week From Day 8 to Day 50 | Mean HAE attack rate, unadjusted (attacks/week) | 0.0476 HAE attacks per week | Standard Error 0.1504 |
| DX-2930, Cohort 3 | HAE Attack Rate Per Week From Day 8 to Day 50 | Mean HAE attack rate, unadjusted (attacks/week) | 0.0345 HAE attacks per week | Standard Error 0.12894 |
| DX-2930, Cohort 3 | HAE Attack Rate Per Week From Day 8 to Day 50 | Mean baseline HAE attack rate (attacks/week) | 0.4872 HAE attacks per week | Standard Error 0.211 |
| DX-2930, Cohort 3 | HAE Attack Rate Per Week From Day 8 to Day 50 | Estimated mean rate based on GEE (attacks/week) | 0.0333 HAE attacks per week | Standard Error 0.02404 |
| DX-2930, Cohort 4 | HAE Attack Rate Per Week From Day 8 to Day 50 | Mean baseline HAE attack rate (attacks/week) | 0.3916 HAE attacks per week | Standard Error 0.17694 |
| DX-2930, Cohort 4 | HAE Attack Rate Per Week From Day 8 to Day 50 | Estimated mean rate based on GEE (attacks/week) | 0.3712 HAE attacks per week | Standard Error 0.09596 |
| DX-2930, Cohort 4 | HAE Attack Rate Per Week From Day 8 to Day 50 | Mean HAE attack rate, unadjusted (attacks/week) | 0.3636 HAE attacks per week | Standard Error 0.36376 |
Comparison: The result was based on General Estimating Equation (GEE) analysis. Generalized Estimating Equation (GEE) approach with Poisson distribution assumption was applied to the repeated-measures mixed model with independence working correlation structure. The treatment group was a fixed effect and the number of baseline HAE attacks per week was included as a covariate in the GEE.p-value: <0.000195% CI: [-100, -100]Mixed Models Analysis
Comparison: The result was based on General Estimating Equation (GEE) analysis. Generalized Estimating Equation (GEE) approach with Poisson distribution assumption was applied to the repeated-measures mixed model with independence working correlation structure. The treatment group was a fixed effect and the number of baseline HAE attacks per week was included as a covariate in the GEE.p-value: 0.00595% CI: [-97.18, -46.9]Mixed Models Analysis
Comparison: The result was based on General Estimating Equation (GEE) analysis. Generalized Estimating Equation (GEE) approach with Poisson distribution assumption was applied to the repeated-measures mixed model with independence working correlation structure. The treatment group was a fixed effect and the number of baseline HAE attacks per week was included as a covariate in the GEE.p-value: 0.001295% CI: [-97.93, -61.57]Mixed Models Analysis
Other Pre-specified
HAE Attacks Per Week From Day 8 to Day 64
This endpoint analysis was based on participants in the 300 mg, 400 mg, and placebo dose groups with a historical baseline attack rate of at least 2 attacks over the last 3 months prior to enrollment. The result is based on General Estimating Equation (GEE) analysis of repeated counts per week during the prespecified assessment period (Day 8 to Day 64 predicted to correspond to a period of notable drug exposure). Baseline HAE attack rate per week is a covariate, treatment group is a fixed effect, and participant is a random effect in the GEE model with independence working correlation structure.
Time frame: Day 8 to Day 64
Population: All randomized participants in the 300 mg, 400 mg, and placebo groups who received at least 1 dose of study drug and who had a historical baseline attack rate of at least 2 attacks in the 3 months prior to enrollment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DX-2930, Cohort 1 | HAE Attacks Per Week From Day 8 to Day 64 | Mean baseline HAE attack rate | 0.3269 HAE Attacks per Week | Standard Deviation 0.24627 |
| DX-2930, Cohort 1 | HAE Attacks Per Week From Day 8 to Day 64 | Estimated mean rate based on GEE | 0 HAE Attacks per Week | — |
| DX-2930, Cohort 1 | HAE Attacks Per Week From Day 8 to Day 64 | Mean HAE attack rate, unadjusted | 0 HAE Attacks per Week | — |
| DX-2930, Cohort 2 | HAE Attacks Per Week From Day 8 to Day 64 | Mean baseline HAE attack rate | 0.5455 HAE Attacks per Week | Standard Deviation 0.17356 |
| DX-2930, Cohort 2 | HAE Attacks Per Week From Day 8 to Day 64 | Estimated mean rate based on GEE | 0.0661 HAE Attacks per Week | Standard Deviation 0.02759 |
| DX-2930, Cohort 2 | HAE Attacks Per Week From Day 8 to Day 64 | Mean HAE attack rate, unadjusted | 0.0723 HAE Attacks per Week | Standard Deviation 0.13227 |
| DX-2930, Cohort 3 | HAE Attacks Per Week From Day 8 to Day 64 | Mean HAE attack rate, unadjusted | 0.0522 HAE Attacks per Week | Standard Deviation 0.11651 |
| DX-2930, Cohort 3 | HAE Attacks Per Week From Day 8 to Day 64 | Mean baseline HAE attack rate | 0.4872 HAE Attacks per Week | Standard Deviation 0.211 |
| DX-2930, Cohort 3 | HAE Attacks Per Week From Day 8 to Day 64 | Estimated mean rate based on GEE | 0.0490 HAE Attacks per Week | Standard Deviation 0.02002 |
| DX-2930, Cohort 4 | HAE Attacks Per Week From Day 8 to Day 64 | Mean baseline HAE attack rate | 0.3916 HAE Attacks per Week | Standard Deviation 0.17694 |
| DX-2930, Cohort 4 | HAE Attacks Per Week From Day 8 to Day 64 | Estimated mean rate based on GEE | 0.3773 HAE Attacks per Week | Standard Deviation 0.09518 |
| DX-2930, Cohort 4 | HAE Attacks Per Week From Day 8 to Day 64 | Mean HAE attack rate, unadjusted | 0.3636 HAE Attacks per Week | Standard Deviation 0.33752 |
Comparison: The result was based on General Estimating Equation (GEE) analysis. Generalized Estimating Equation (GEE) approach with Poisson distribution assumption was applied to the repeated-measures mixed model with independence working correlation structure. The treatment group was a fixed effect and the number of baseline HAE attacks per week was included as a covariate in the GEE.p-value: <0.000195% CI: [-100, -100]Mixed Models Analysis
Comparison: The result was based on General Estimating Equation (GEE) analysis. Generalized Estimating Equation (GEE) approach with Poisson distribution assumption was applied to the repeated-measures mixed model with independence working correlation structure. The treatment group was a fixed effect and the number of baseline HAE attacks per week was included as a covariate in the GEE.p-value: <0.000195% CI: [-92.5, -58.64]Mixed Models Analysis
Comparison: The result was based on General Estimating Equation (GEE) analysis. Generalized Estimating Equation (GEE) approach with Poisson distribution assumption was applied to the repeated-measures mixed model with independence working correlation structure. The treatment group was a fixed effect and the number of baseline HAE attacks per week was included as a covariate in the GEE.p-value: <0.000195% CI: [-94.55, -69.06]Mixed Models Analysis
Other Pre-specified
HAE Attacks Per Week From Day 8 to Day 92
This endpoint analysis was based on participants in the 300 mg, 400 mg, and placebo dose groups with a historical baseline attack rate of at least 2 attacks over the last 3 months prior to enrollment. The result is based on General Estimating Equation (GEE) analysis of repeated counts per week during the prespecified assessment period (Day 8 to Day 92 predicted to correspond to a period of notable drug exposure). Baseline HAE attack rate per week is a covariate, treatment group is a fixed effect, and participant is a random effect in the GEE model with independence working correlation structure.
Time frame: Day 8 to Day 92
Population: All randomized participants in the 300 mg, 400 mg, and placebo groups who received at least 1 dose of study drug and who had a historical baseline attack rate of at least 2 attacks in the 3 months prior to enrollment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DX-2930, Cohort 1 | HAE Attacks Per Week From Day 8 to Day 92 | Mean baseline HAE attack rate (attacks/week) | 0.3269 HAE Attacks per Week | Standard Deviation 0.24627 |
| DX-2930, Cohort 1 | HAE Attacks Per Week From Day 8 to Day 92 | Estimated mean rate based on GEE (attacks/week) | 0 HAE Attacks per Week | — |
| DX-2930, Cohort 1 | HAE Attacks Per Week From Day 8 to Day 92 | Mean HAE attack rate, unadjusted (attacks/week) | 0 HAE Attacks per Week | — |
| DX-2930, Cohort 2 | HAE Attacks Per Week From Day 8 to Day 92 | Mean baseline HAE attack rate (attacks/week) | 0.5455 HAE Attacks per Week | Standard Deviation 0.17356 |
| DX-2930, Cohort 2 | HAE Attacks Per Week From Day 8 to Day 92 | Estimated mean rate based on GEE (attacks/week) | 0.0603 HAE Attacks per Week | Standard Deviation 0.02438 |
| DX-2930, Cohort 2 | HAE Attacks Per Week From Day 8 to Day 92 | Mean HAE attack rate, unadjusted (attacks/week) | 0.0732 HAE Attacks per Week | Standard Deviation 0.12665 |
| DX-2930, Cohort 3 | HAE Attacks Per Week From Day 8 to Day 92 | Mean HAE attack rate, unadjusted (attacks/week) | 0.0526 HAE Attacks per Week | Standard Deviation 0.11206 |
| DX-2930, Cohort 3 | HAE Attacks Per Week From Day 8 to Day 92 | Mean baseline HAE attack rate (attacks/week) | 0.4872 HAE Attacks per Week | Standard Deviation 0.211 |
| DX-2930, Cohort 3 | HAE Attacks Per Week From Day 8 to Day 92 | Estimated mean rate based on GEE (attacks/week) | 0.0461 HAE Attacks per Week | Standard Deviation 0.01826 |
| DX-2930, Cohort 4 | HAE Attacks Per Week From Day 8 to Day 92 | Mean baseline HAE attack rate (attacks/week) | 0.3916 HAE Attacks per Week | Standard Deviation 0.17694 |
| DX-2930, Cohort 4 | HAE Attacks Per Week From Day 8 to Day 92 | Estimated mean rate based on GEE (attacks/week) | 0.3787 HAE Attacks per Week | Standard Deviation 0.10957 |
| DX-2930, Cohort 4 | HAE Attacks Per Week From Day 8 to Day 92 | Mean HAE attack rate, unadjusted (attacks/week) | 0.3636 HAE Attacks per Week | Standard Deviation 0.36945 |
Comparison: The result was based on General Estimating Equation (GEE) analysis. Generalized Estimating Equation (GEE) approach with Poisson distribution assumption was applied to the repeated-measures mixed model with independence working correlation structure. The treatment group was a fixed effect and the number of baseline HAE attacks per week was included as a covariate in the GEE.p-value: <0.000195% CI: [-100, -100]Mixed Models Analysis
Comparison: The result was based on General Estimating Equation (GEE) analysis. Generalized Estimating Equation (GEE) approach with Poisson distribution assumption was applied to the repeated-measures mixed model with independence working correlation structure. The treatment group was a fixed effect and the number of baseline HAE attacks per week was included as a covariate in the GEE.p-value: <0.000195% CI: [-93.07, -63.46]Mixed Models Analysis
Comparison: The result was based on General Estimating Equation (GEE) analysis. Generalized Estimating Equation (GEE) approach with Poisson distribution assumption was applied to the repeated-measures mixed model with independence working correlation structure. The treatment group was a fixed effect and the number of baseline HAE attacks per week was included as a covariate in the GEE.p-value: <0.000195% CI: [-94.81, -71.5]Mixed Models Analysis