Trial Outcomes & Findings for A Study of Icatibant for Acute Attacks of Hereditary Angioedema in Japanese Participants (NCT NCT03888755)

NCT ID: NCT03888755

Last Updated: 2021-06-03

Results Overview

The TOSR was defined as a 50 percent (%) reduction from the pre-treatment score in the 3-symptom composite VAS score for non-laryngeal attacks and 5-symptom composite VAS score for laryngeal attacks. A VAS utilizes a scale consisting of a 100 millimeter (mm) horizontal line with extreme values at the beginning (0 mm = no symptom) and end (100 mm = worst possible symptom) of the line. The participant should draw a vertical line at the point along the scale that represents the current status of the measured symptom. Composite VAS scores were calculated as the average of VAS measurements for skin swelling, skin pain, and abdominal pain (3-symptom composite) for non-laryngeal attacks and for skin swelling, skin pain, abdominal pain, difficulty swallowing, and voice change (5-symptom composite) for laryngeal attacks.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 8 participants
• Primary outcome timeframe: Baseline up to 120 hours post-treatment
• Results posted on: 2021-06-03

Participant Flow

The study was conducted at 8 sites in Japan between 18 March 2015 (first participant first visit) and 12 February 2016 (last participant last visit).

A total of 8 Japanese participants were enrolled and included in the study treatment.

Participant milestones

Measure	Icatibant Participants with 1 acute non-laryngeal or laryngeal attack received a single icatibant 30 milligram (mg) subcutaneous (SC) injection in the abdominal area. A maximum of 3 SC injections (or 90 mg) of icatibant that were at least 6 hours apart were given for treatment of an attack if, within 48 hours of the initial treatment, there was insufficient relief or worsening of symptoms.
Overall Study STARTED	8
Overall Study COMPLETED	8
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A Study of Icatibant for Acute Attacks of Hereditary Angioedema in Japanese Participants

Baseline characteristics by cohort

Measure	Icatibant n=8 Participants Participants with 1 acute non-laryngeal or laryngeal attack received a single icatibant 30 milligram (mg) subcutaneous (SC) injection in the abdominal area. A maximum of 3 SC injections (or 90 mg) of icatibant that were at least 6 hours apart were given for treatment of an attack if, within 48 hours of the initial treatment, there was insufficient relief or worsening of symptoms.
Age, Continuous	45.5 Years STANDARD_DEVIATION 16.94 • n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	8 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline up to 120 hours post-treatment

Population: The treated population included all participants treated with icatibant

The TOSR was defined as a 50 percent (%) reduction from the pre-treatment score in the 3-symptom composite VAS score for non-laryngeal attacks and 5-symptom composite VAS score for laryngeal attacks. A VAS utilizes a scale consisting of a 100 millimeter (mm) horizontal line with extreme values at the beginning (0 mm = no symptom) and end (100 mm = worst possible symptom) of the line. The participant should draw a vertical line at the point along the scale that represents the current status of the measured symptom. Composite VAS scores were calculated as the average of VAS measurements for skin swelling, skin pain, and abdominal pain (3-symptom composite) for non-laryngeal attacks and for skin swelling, skin pain, abdominal pain, difficulty swallowing, and voice change (5-symptom composite) for laryngeal attacks.

Outcome measures

Measure

Icatibant n=8 Participants Participants with 1 acute non-laryngeal or laryngeal attack received a single icatibant 30 milligram (mg) subcutaneous (SC) injection in the abdominal area. A maximum of 3 SC injections (or 90 mg) of icatibant that were at least 6 hours apart were given for treatment of an attack if, within 48 hours of the initial treatment, there was insufficient relief or worsening of symptoms.

Time to Onset of Symptom Relief (TOSR)

1.75 Hours Interval 1.0 to 2.5

SECONDARY outcome

Timeframe: Baseline up to 120 hours post-treatment

Population: The treated population included all participants treated with icatibant

Primary symptom relief was based on the participant-assessed VAS score for a single primary symptom (determined by edema location) and corresponds to a reduction by 31 mm at a pretreatment VAS of 100 mm and by 21 mm at a pretreatment VAS of 30 mm. If the primary symptom pretreatment VAS less than (<) 30 mm, then primary symptom relief was defined as 68% reduction from pretreatment. A VAS utilizes a scale consisting of a 100 millimeter (mm) horizontal line with extreme values at the beginning (0 mm = no symptom) and end (100 mm = worst possible symptom) of the line. The TOSR-P was calculated from the time of icatibant administration to the onset of primary symptom relief.

Outcome measures

Measure

Icatibant n=8 Participants Participants with 1 acute non-laryngeal or laryngeal attack received a single icatibant 30 milligram (mg) subcutaneous (SC) injection in the abdominal area. A maximum of 3 SC injections (or 90 mg) of icatibant that were at least 6 hours apart were given for treatment of an attack if, within 48 hours of the initial treatment, there was insufficient relief or worsening of symptoms.

Time to Onset of Primary Symptom Relief (TOSR-P)

1.07 Hours Interval 1.0 to 2.0

SECONDARY outcome

Timeframe: Baseline, 2, 4 and 8 hours post-treatment

Population: The treated population included all participants treated with icatibant

A VAS utilizes a scale consisting of a 100 mm horizontal line with extreme values at the beginning (0 mm = no symptom) and end (100 mm = worst possible symptom) of the line. The participant should draw a vertical line at the point along the scale that represents the current status of the measured symptom. Composite VAS scores was calculated as the average of VAS measurements for skin swelling, skin pain, abdominal pain, difficulty swallowing, and voice change (5-symptom composite) for laryngeal attacks and as the average of VAS measurements for skin swelling, skin pain and abdominal pain (3-symptom composite) for non-laryngeal attacks. Change from baseline in the composite VAS score was reported.

Outcome measures

Measure	Icatibant n=8 Participants Participants with 1 acute non-laryngeal or laryngeal attack received a single icatibant 30 milligram (mg) subcutaneous (SC) injection in the abdominal area. A maximum of 3 SC injections (or 90 mg) of icatibant that were at least 6 hours apart were given for treatment of an attack if, within 48 hours of the initial treatment, there was insufficient relief or worsening of symptoms.
Change From Baseline in the Composite Visual Analog Scale (VAS) Score Baseline	30.78 Score on a scale Standard Deviation 13.465
Change From Baseline in the Composite Visual Analog Scale (VAS) Score 2 hours	-19.26 Score on a scale Standard Deviation 13.310
Change From Baseline in the Composite Visual Analog Scale (VAS) Score 4 hours	-24.57 Score on a scale Standard Deviation 13.367
Change From Baseline in the Composite Visual Analog Scale (VAS) Score 8 hours	-29.40 Score on a scale Standard Deviation 12.998

SECONDARY outcome

Timeframe: 8 hours post dose

Population: The treated population included all participants treated with icatibant

The investigator-assessed composite symptom score was calculated as an average of abdominal tenderness, nausea, vomiting, diarrhea, skin pain, erythema, skin irritation, and skin swelling (8 symptoms) for non-laryngeal attacks and the average of abdominal tenderness, nausea, vomiting, diarrhea, skin pain, erythema, skin irritation, skin swelling, dysphagia, voice change, breathing difficulties, stridor, and asphyxia (13 symptoms) for laryngeal attacks using the following 5-point scale 0 = none (absence of symptoms); 1 = mild (no to mild interference with daily activities); 2 = moderate (moderate interference with daily activities); 3 = severe (severe interference with daily activities); 4 = very severe (very severe interference with daily activities). Here the composite SS assessed by investigator was reported.

Outcome measures

Measure

Icatibant n=8 Participants Participants with 1 acute non-laryngeal or laryngeal attack received a single icatibant 30 milligram (mg) subcutaneous (SC) injection in the abdominal area. A maximum of 3 SC injections (or 90 mg) of icatibant that were at least 6 hours apart were given for treatment of an attack if, within 48 hours of the initial treatment, there was insufficient relief or worsening of symptoms.

Composite Symptom Score (SS) Assessed by Investigator

0.12 Score on a scale Standard Deviation 0.18

SECONDARY outcome

Timeframe: 8 hours post dose

Population: The treated population included all participants treated with icatibant

The participant-assessed composite symptom score was calculated as an average of abdominal pain, nausea, vomiting, diarrhea, skin pain, erythema, skin irritation, and skin swelling (8 symptoms) for non-laryngeal attacks and the average of abdominal pain, nausea, vomiting, diarrhea, skin pain, erythema,skin irritation, skin swelling, dysphagia and voice change (10 symptoms) for laryngeal attacks using the following 5-point scale 0 = none (absence of symptoms); 1 = mild (no to mild interference with daily activities); 2 = moderate (moderate interference with daily activities); 3 = severe (severe interference with daily activities); 4 = very severe (very severe interference with daily activities). Here the composite SS assessed by participant was reported.

Outcome measures

Measure

Icatibant n=8 Participants Participants with 1 acute non-laryngeal or laryngeal attack received a single icatibant 30 milligram (mg) subcutaneous (SC) injection in the abdominal area. A maximum of 3 SC injections (or 90 mg) of icatibant that were at least 6 hours apart were given for treatment of an attack if, within 48 hours of the initial treatment, there was insufficient relief or worsening of symptoms.

Composite Symptom Score (SS) Assessed by Participant

0.14 Score on a scale Standard Deviation 0.16

SECONDARY outcome

Timeframe: 2, 4 and 8 hours post dose

Population: The treated population included all participants who received one dose of icatibant.

The investigator was made a global assessment (that is [i.e.] consideration of all abdominal symptoms combined, all cutaneous symptoms combined and/or all laryngeal symptoms combined) using the following 5-point scale, where the symptoms were scored from 0 for "absence of symptoms" to 4 for "very severe": 0 = none (absence of symptoms); 1 = mild (no to mild interference with daily activities); 2 = moderate (moderate interference with daily activities); 3 = severe (severe interference with daily activities); 4 = very severe (very severe interference with daily activities).

Outcome measures

Measure	Icatibant n=8 Participants Participants with 1 acute non-laryngeal or laryngeal attack received a single icatibant 30 milligram (mg) subcutaneous (SC) injection in the abdominal area. A maximum of 3 SC injections (or 90 mg) of icatibant that were at least 6 hours apart were given for treatment of an attack if, within 48 hours of the initial treatment, there was insufficient relief or worsening of symptoms.
Investigator Global Assessment Cutaneous Symptoms: 2 hours (h) post dose	0.9 Score on a scale Standard Deviation 0.99
Investigator Global Assessment Cutaneous Symptoms: 4 h post dose	0.6 Score on a scale Standard Deviation 0.52
Investigator Global Assessment Cutaneous Symptoms: 8 h post dose	0.5 Score on a scale Standard Deviation 0.53
Investigator Global Assessment Abdominal Symptoms: 2 h post dose	0.1 Score on a scale Standard Deviation 0.35
Investigator Global Assessment Abdominal Symptoms: 4 h post dose	0.0 Score on a scale Standard Deviation 0.00
Investigator Global Assessment Abdominal Symptoms: 8 h post dose	0.0 Score on a scale Standard Deviation 0.00
Investigator Global Assessment Laryngeal Symptoms: 2 h post dose	0.0 Score on a scale Standard Deviation 0.00
Investigator Global Assessment Laryngeal Symptoms: 4 h post dose	0.0 Score on a scale Standard Deviation 0.00
Investigator Global Assessment Laryngeal Symptoms: 8 h post dose	0.0 Score on a scale Standard Deviation 0.00

SECONDARY outcome

Timeframe: Baseline up to 120 hours post-treatment

Population: The treated population included all participants treated with icatibant

Time to initial symptom improvement was evaluated by the investigator; each were asked to record the time at which they perceived initial improvement of symptoms. Time to initial symptom improvement was calculated from the time of icatibant administration to the time reported by the investigator of initial improvement of symptoms.

Outcome measures

Measure

Icatibant n=8 Participants Participants with 1 acute non-laryngeal or laryngeal attack received a single icatibant 30 milligram (mg) subcutaneous (SC) injection in the abdominal area. A maximum of 3 SC injections (or 90 mg) of icatibant that were at least 6 hours apart were given for treatment of an attack if, within 48 hours of the initial treatment, there was insufficient relief or worsening of symptoms.

Time to Initial Symptom Improvement by Investigator

0.98 H Interval 0.3 to 2.0

SECONDARY outcome

Timeframe: Baseline up to 120 hours post-treatment

Population: The treated population included all participants treated with icatibant.

Time to initial symptom improvement was evaluated by the participants; each were asked to record the time at which they perceived initial improvement of symptoms. Time to initial symptom improvement was calculated from the time of icatibant administration to the time reported by the participant of initial improvement of symptoms.

Outcome measures

Measure

Icatibant n=8 Participants Participants with 1 acute non-laryngeal or laryngeal attack received a single icatibant 30 milligram (mg) subcutaneous (SC) injection in the abdominal area. A maximum of 3 SC injections (or 90 mg) of icatibant that were at least 6 hours apart were given for treatment of an attack if, within 48 hours of the initial treatment, there was insufficient relief or worsening of symptoms.

Time to Initial Symptom Improvement by Participants

1.04 h Interval 0.3 to 2.05

SECONDARY outcome

Timeframe: Baseline up to 120 hours post-treatment

Population: The treated population included all participants treated with icatibant

Time to almost complete symptom relief was calculated from the time of icatibant administration to almost complete symptom relief. Almost complete symptom relief was determined retrospectively as the earliest of three consecutive non-missing measurements for which all VAS scores < 10 mm. A VAS utilizes a scale consisting of a 100 millimeter (mm) horizontal line with extreme values at the beginning (0 mm = no symptom) and end (100 mm = worst possible symptom) of the line. The participant should draw a vertical line at the point along the scale that represents the current status of the measured symptom.

Outcome measures

Measure

Icatibant n=8 Participants Participants with 1 acute non-laryngeal or laryngeal attack received a single icatibant 30 milligram (mg) subcutaneous (SC) injection in the abdominal area. A maximum of 3 SC injections (or 90 mg) of icatibant that were at least 6 hours apart were given for treatment of an attack if, within 48 hours of the initial treatment, there was insufficient relief or worsening of symptoms.

Time to Almost Complete Symptom Relief As Assessed by Visual Analog Scale (VAS) Score

5.98 H Interval 2.27 to 8.0

SECONDARY outcome

Timeframe: Baseline, 0.75, 2 hours post-treatment

Population: The pharmacokinetic (PK) analysis population included all participants who received study drug and provided evaluable plasma drug concentrations.

The Cmax was estimated by a population PK modeling approach. The Cmax of icatibant was reported.

Outcome measures

Measure

Icatibant n=8 Participants Participants with 1 acute non-laryngeal or laryngeal attack received a single icatibant 30 milligram (mg) subcutaneous (SC) injection in the abdominal area. A maximum of 3 SC injections (or 90 mg) of icatibant that were at least 6 hours apart were given for treatment of an attack if, within 48 hours of the initial treatment, there was insufficient relief or worsening of symptoms.

Maximum Observed Plasma Concentration (Cmax) of Icatibant After a Single Subcutaneous (SC) Administration of Icatibant

405 Nano grams per milliliter (ng/mL) Standard Deviation 194

SECONDARY outcome

Timeframe: Baseline, 0.75, 2 hours post-treatment

Population: The PK analysis population included all participants who received study drug and provided evaluable plasma drug concentrations.

The AUC0-2 was estimated by a population PK modeling approach. The AUC0-2 of Icatibant was reported.

Outcome measures

Measure

Icatibant n=8 Participants Participants with 1 acute non-laryngeal or laryngeal attack received a single icatibant 30 milligram (mg) subcutaneous (SC) injection in the abdominal area. A maximum of 3 SC injections (or 90 mg) of icatibant that were at least 6 hours apart were given for treatment of an attack if, within 48 hours of the initial treatment, there was insufficient relief or worsening of symptoms.

Area Under the Concentration-time Curve From 0 to 2 Hours (AUC0-2) After a Single Subcutaneous (SC) Administration of Icatibant

611 Nanograms*hour per milliliter (ng•h/mL) Standard Deviation 338

SECONDARY outcome

Timeframe: Baseline, 0.75, 2 hours post-treatment

Population: The PK analysis population included all participants who received study drug and provided evaluable plasma drug concentrations.

The AUC0-4 was estimated by a population PK modeling approach. The AUC0-4 of Icatibant was reported.

Outcome measures

Measure

Icatibant n=8 Participants Participants with 1 acute non-laryngeal or laryngeal attack received a single icatibant 30 milligram (mg) subcutaneous (SC) injection in the abdominal area. A maximum of 3 SC injections (or 90 mg) of icatibant that were at least 6 hours apart were given for treatment of an attack if, within 48 hours of the initial treatment, there was insufficient relief or worsening of symptoms.

Area Under the Concentration-time Curve From 0 to 4 Hours (AUC0-4) After a Single Subcutaneous (SC) Administration of Icatibant

1198 ng•h/mL Standard Deviation 495

SECONDARY outcome

Timeframe: Baseline, 0.75, 2 hours post-treatment

Population: The PK analysis population included all participants who received study drug and provided evaluable plasma drug concentrations.

The AUC0-6 was estimated by a population PK modeling approach. The AUC0-6 of Icatibant was reported.

Outcome measures

Measure

Icatibant n=8 Participants Participants with 1 acute non-laryngeal or laryngeal attack received a single icatibant 30 milligram (mg) subcutaneous (SC) injection in the abdominal area. A maximum of 3 SC injections (or 90 mg) of icatibant that were at least 6 hours apart were given for treatment of an attack if, within 48 hours of the initial treatment, there was insufficient relief or worsening of symptoms.

Area Under the Concentration-time Curve From 0 to 6 Hours (AUC0-6) After a Single Subcutaneous (SC) Administration of Icatibant

1506 ng•h/mL Standard Deviation 509

SECONDARY outcome

Timeframe: From start of study drug administration to follow-up (up to 10 days)

Population: The treated population included all participants treated with icatibant

An AE was any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurred in any phase of a clinical study, whether or not considered investigational product related. The TEAEs were defined as all AEs occurred on or after the time of study drug administration.

Outcome measures

Measure

Icatibant n=8 Participants Participants with 1 acute non-laryngeal or laryngeal attack received a single icatibant 30 milligram (mg) subcutaneous (SC) injection in the abdominal area. A maximum of 3 SC injections (or 90 mg) of icatibant that were at least 6 hours apart were given for treatment of an attack if, within 48 hours of the initial treatment, there was insufficient relief or worsening of symptoms.

Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

3 Participants

SECONDARY outcome

Timeframe: From start of study drug administration to follow-up (up to 10 days)

Population: The treated population included all participants treated with icatibant

Number of participants with injection site reactions (erythema, swelling, cutaneous pain, burning sensation, itching/pruritus, and warm sensation) were reported.

Outcome measures

Measure	Icatibant n=8 Participants Participants with 1 acute non-laryngeal or laryngeal attack received a single icatibant 30 milligram (mg) subcutaneous (SC) injection in the abdominal area. A maximum of 3 SC injections (or 90 mg) of icatibant that were at least 6 hours apart were given for treatment of an attack if, within 48 hours of the initial treatment, there was insufficient relief or worsening of symptoms.
Number of Participants With Injection Site Reactions Reported as Adverse Event (AE) Any Reaction	7 Participants
Number of Participants With Injection Site Reactions Reported as Adverse Event (AE) Any Severe Reaction	1 Participants

SECONDARY outcome

Timeframe: From start of study drug administration to follow-up (up to 10 days)

Population: The treated population included all participants treated with icatibant

Clinical laboratory tests included serum chemistry, hematology, urinalysis and coagulation were assessed. Number of participants with clinically significant changes in clinical laboratory tests were reported.

Outcome measures

Measure

Icatibant n=8 Participants Participants with 1 acute non-laryngeal or laryngeal attack received a single icatibant 30 milligram (mg) subcutaneous (SC) injection in the abdominal area. A maximum of 3 SC injections (or 90 mg) of icatibant that were at least 6 hours apart were given for treatment of an attack if, within 48 hours of the initial treatment, there was insufficient relief or worsening of symptoms.

Number of Participants With Clinically Significant Changes in Clinical Laboratory Tests Reported as Adverse Event (AE)

0 Participants

SECONDARY outcome

Timeframe: From start of study drug administration to follow-up (up to 10 days)

Population: The treated population included all participants treated with icatibant

Vital signs included pulse rate, blood pressure, respiration rate, and temperature. The number of participants with clinically significant changes in vital signs were reported.

Outcome measures

Measure

Icatibant n=8 Participants Participants with 1 acute non-laryngeal or laryngeal attack received a single icatibant 30 milligram (mg) subcutaneous (SC) injection in the abdominal area. A maximum of 3 SC injections (or 90 mg) of icatibant that were at least 6 hours apart were given for treatment of an attack if, within 48 hours of the initial treatment, there was insufficient relief or worsening of symptoms.

Number of Participants With Clinically Significant Changes in Vital Signs Reported as Adverse Event (AE)

0 Participants

SECONDARY outcome

Timeframe: From start of study drug administration to follow-up (up to 10 days)

Population: The treated population included all participants treated with icatibant

A standard 12-lead ECG was performed. The number of participants who reported clinically significant changes in ECGs were reported.

Outcome measures

Measure

Icatibant n=8 Participants Participants with 1 acute non-laryngeal or laryngeal attack received a single icatibant 30 milligram (mg) subcutaneous (SC) injection in the abdominal area. A maximum of 3 SC injections (or 90 mg) of icatibant that were at least 6 hours apart were given for treatment of an attack if, within 48 hours of the initial treatment, there was insufficient relief or worsening of symptoms.

Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Reported as Adverse Event (AE)

0 Participants

Adverse Events

Icatibant

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Icatibant n=8 participants at risk Participants with 1 acute non-laryngeal or laryngeal attack received a single icatibant 30 milligram (mg) subcutaneous (SC) injection in the abdominal area. A maximum of 3 SC injections (or 90 mg) of icatibant that were at least 6 hours apart were given for treatment of an attack if, within 48 hours of the initial treatment, there was insufficient relief or worsening of symptoms.
Congenital, familial and genetic disorders HEREDITARY ANGIOEDEMA	25.0% 2/8 • Number of events 2 • From start of study drug administration to 10 days
Nervous system disorders HEADACHE	12.5% 1/8 • Number of events 1 • From start of study drug administration to 10 days

Additional Information

Study Director

Shire

Phone: +1 866 842 5335

Email: ClinicalTransparency@shire.com

Results disclosure agreements

• Principal investigator is a sponsor employee If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.
• Publication restrictions are in place

Restriction type: OTHER