Download PDF

Clinical Trial Results:
A Randomized, Double Blind, Placebo Controlled, Phase 2a Study to Assess the Clinical Efficacy of ISIS 721744, a Second Generation Ligand Conjugated Antisense Inhibitor of Prekallikrein, in Patients with Hereditary Angioedema

Summary
EudraCT number	2019-001044-22
Trial protocol	GB
Global end of trial date	01 Mar 2021

Results information
Results version number	v1(current)
This version publication date	22 Oct 2022
First version publication date	22 Oct 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

ISIS721744-CS2

ISRCTN number

US NCT number

NCT04030598

WHO universal trial number (UTN)

Sponsor organisation name

Ionis Pharmaceuticals, Inc.

Sponsor organisation address

2855 Gazelle Court, Carlsbad, United States, 92010

Public contact

Ionis Clinical Trial Information , Ionis Pharmaceuticals, Inc. , 1 760603-2387, ClinicalTrials@ionisph.com

Scientific contact

Ionis Clinical Trial Information , Ionis Pharmaceuticals, Inc. , 1 760603-2387, ClinicalTrials@ionisph.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

01 Mar 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

01 Mar 2021

Was the trial ended prematurely?

Main objective of the trial

To evaluate the clinical efficacy of antisense inhibitor of prekallikrein donidalorsen (IONIS PKK-LRx) in subjects with hereditary angioedema (HAE) type 1 (HAE-1), HAE type 2 (HAE-2), or HAE with normal C1-inhibitor (C1-INH).

Protection of trial subjects

Each subject, or legally acceptable representative, signed an informed consent form before participating in the study.

Background therapy

Evidence for comparator

Actual start date of recruitment

07 Jan 2020

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 15

Country: Number of subjects enrolled

Netherlands: 8

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

Subjects took part in the study at 7 investigative sites from 7 January 2020 to 1 March 2021.

Screening details

Subjects with hereditary angioedema were enrolled in Part A and B. In Part A, 20 subjects with hereditary angioedema type I/type II (HAE-1/HAE-2) were randomised in 2:1 ratio to receive donidalorsen/placebo for 13 weeks. In Part B, 3 subjects with HAE with normal C1-inhibitor (HAE-nC1-INH) received donidalorsen for 13 weeks after Part A.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Assessor

Are arms mutually exclusive

Yes

Part A: Placebo

Arm description

Subjects with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) every 4 weeks at Weeks 1, 5, 9, and 13.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo administered (SC) every 4 weeks.

Part A: Donidalorsen 80 mg

Arm description

Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.

Arm type

Experimental

Investigational medicinal product name

Donidalorsen 80 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Donidalorsen, 80 mg, administered SC, every 4 weeks

Part B: Donidalorsen 80 mg

Arm description

Subjects with hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.

Arm type

Experimental

Investigational medicinal product name

Donidalorsen 80 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Donidalorsen, 80 mg, administered SC, every 4 weeks.

Number of subjects in period 1	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Started	6	14	3
Completed	6	13	3
Not completed	0	1	0
Voluntary Withdrawal	-	1	-

Baseline characteristics

Top of page

Reporting group title

Part A: Placebo

Reporting group description

Subjects with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) every 4 weeks at Weeks 1, 5, 9, and 13.

Reporting group title

Part A: Donidalorsen 80 mg

Reporting group description

Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.

Reporting group title

Part B: Donidalorsen 80 mg

Reporting group description

Subjects with hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.

Reporting group values	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg	Total
Number of subjects	6	14	3	23
Age categorical
Units: Subjects
In utero				0
Preterm newborn infants (gestational age < 37 wks)				0
Newborns (0-27 days)				0
Infants and toddlers (28 days-23 months)				0
Children (2-11 years)				0
Adolescents (12-17 years)				0
Adults (18-64 years)				0
From 65-84 years				0
85 years and over				0
Age continuous
Units: years
arithmetic mean (full range (min-max))	40.0 (22 to 56)	37.8 (21 to 66)	34.0 (25 to 40)	-
Gender categorical
Units: Subjects
Female	4	9	3	16
Male	2	5	0	7
Ethnicity
Units: Subjects
Hispanic or Latino	0	1	0	1
Not Hispanic or Latino	6	13	3	22
Unknown or Not Reported	0	0	0	0
Race
Units: Subjects
Black or African American	1	0	0	1
White	5	14	3	22

End points

Top of page

Reporting group title

Part A: Placebo

Reporting group description

Subjects with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) every 4 weeks at Weeks 1, 5, 9, and 13.

Reporting group title

Part A: Donidalorsen 80 mg

Reporting group description

Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.

Reporting group title

Part B: Donidalorsen 80 mg

Reporting group description

Subjects with hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.

Primary: Time-normalised Number of HAE Attacks (Per Month) From Week 1 to Week 17

Top of page

End point title

Time-normalised Number of HAE Attacks (Per Month) From Week 1 to Week 17

End point description

The Week 1 to end of on-treatment period HAE attack rate was calculated for each subject as number of HAE attacks occurring from Week 1 to 28 days after the last dose date divided by the number of days the subject contributed to the period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). The intent-to-treat (ITT) population included all enrolled or randomised subjects.

End point type

Primary

End point timeframe

Week 1 to Week 17

End point values	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Number of subjects analysed	6	14	3
Units: HAE attacks per month
arithmetic mean (standard deviation)	2.21 ± 1.558	0.23 ± 0.268	1.52 ± 2.221

Statistical Analysis 1

Comparison groups

Part A: Placebo v Part A: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

< 0.001

Method

Wald Chi-Square

Parameter type

Percentage Difference

Point estimate

-90

Confidence interval

level

95%

sides

2-sided

lower limit

-96

upper limit

-76

Notes
[1] - The percentage difference in mean investigator-confirmed HAE attack rate between donidalorsen 80 mg and placebo was calculated as 100 percentage (%) × (mean rate ratio -1).

Secondary: Time-normalised Number of Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17

Top of page

End point title

Time-normalised Number of Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17

End point description

The Week 5 to end of on-treatment period HAE attack rate was calculated for each subject as number of HAE attacks occurring from Week 5 to 28 days after the last dose date divided by the number of days the subject contributed to the period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhoea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). ITT population included all enrolled or randomised subjects.

End point type

Secondary

End point timeframe

Week 5 to Week 17

End point values	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Number of subjects analysed	6	14	3
Units: HAE attacks per month
arithmetic mean (standard deviation)	2.06 ± 1.574	0.07 ± 0.267	1.78 ± 2.795

Statistical Analysis 1

Comparison groups

Part A: Donidalorsen 80 mg v Part A: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

= 0.003

Method

Wald Chi-Square

Parameter type

Percentage Difference

Point estimate

-97

Confidence interval

level

95%

sides

2-sided

lower limit

-100

upper limit

-69

Notes
[2] - The percentage difference in mean investigator-confirmed HAE attack rate between donidalorsen 80 mg and placebo was calculated as 100 percentage (%) × (mean rate ratio - 1).

Secondary: Time-normalised Number of Moderate or Severe Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17

Top of page

End point title

Time-normalised Number of Moderate or Severe Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17

End point description

Week 5 to end of on-treatment period HAE attack rate was calculated for each subject as number of moderate or severe HAE attacks occurring from Week 5 to 28 days after last dose date divided by number of days subject contributed to period multiplied by 28 days.HAE attack was defined as an event with signs/symptoms consistent with attack in at least 1 locations: peripheral angioedema (cutaneous swelling involving an extremity, face, neck, torso, genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhoea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). HAE attack severity: Mild: transient or mild discomfort, Moderate: mild to moderate limitation in activity, some assistance needed, and Severe: marked limitation in activity, assistance required. ITT population included all enrolled or randomised subjects.

End point type

Secondary

End point timeframe

Week 5 to Week 17

End point values	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Number of subjects analysed	6	14	3
Units: HAE attacks per month
arithmetic mean (standard deviation)	1.25 ± 1.208	0.05 ± 0.178	0.89 ± 1.540

Statistical Analysis 1

Comparison groups

Part A: Placebo v Part A: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.004

Method

Wald Chi-Square

Parameter type

Percentage Difference

Point estimate

-96

Confidence interval

level

95%

sides

2-sided

lower limit

-100

upper limit

-65

Notes
[3] - The percentage difference in mean investigator-confirmed HAE attack rate between donidalorsen 80 mg and placebo was calculated as 100 percentage (%) × (mean rate ratio -1).

Secondary: Number of Subjects With Clinical Response by Week 17

Top of page

End point title

Number of Subjects With Clinical Response by Week 17

End point description

Clinical response was defined as a ≥ 50%, ≥ 70%, or ≥ 90% reduction from Baseline in HAE attack rate from Week 5 to Week 17. HAE attack rate was calculated as number of investigator-confirmed HAE attacks occurring from Week 5 to 28 days after last dose administration, divided by the number of days the subject contributed to the period multiplied by 28 days. HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). ITT=all enrolled or randomised subjects. Subjects analysed=overall number of subjects with data available for analyses.

End point type

Secondary

End point timeframe

Week 5 to Week 17

End point values	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Number of subjects analysed	6	13	3
Units: subjects
≥ 50% Reduction	2	13	2
≥ 70% Reduction	1	12	2
≥ 90% Reduction	0	12	1

Statistical Analysis 1

Comparison groups

Part A: Placebo v Part A: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

= 0.004

Method

Fisher Exact

Parameter type

Risk Difference (RD)

Point estimate

66.7

Confidence interval

level

95%

sides

2-sided

lower limit

17.5

upper limit

95.7

Notes
[4] - For ≥ 50% reduction from Baseline in the HAE attack rate.

Statistical Analysis 2

Comparison groups

Part A: Placebo v Part A: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

= 0.003

Method

Fisher Exact

Parameter type

Risk Difference (RD)

Point estimate

75.6

Confidence interval

level

95%

sides

2-sided

lower limit

26.8

upper limit

96.5

Notes
[5] - For ≥ 70% reduction from Baseline in the HAE attack rate.

Statistical Analysis 3

Comparison groups

Part A: Placebo v Part A: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

P-value

< 0.001

Method

Fisher Exact

Parameter type

Risk Difference (RD)

Point estimate

92.3

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

99.8

Notes
[6] - For ≥ 90% reduction from Baseline in the HAE attack rate.

Secondary: Number of Investigator-confirmed HAE Attacks Requiring Acute Therapy From Week 5 to Week 17

Top of page

End point title

Number of Investigator-confirmed HAE Attacks Requiring Acute Therapy From Week 5 to Week 17

End point description

The Week 5 to end of on-treatment period HAE attack rate was calculated for each subject as number of HAE attacks requiring acute therapy occurring from Week 5 to 28 days after the last dose date divided by the number of days the subject contributed to the period multiplied by 28 days. An HAE attack was defined as an event with signs or symptoms consistent with an attack in at least 1 of the locations: peripheral angioedema (cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain, with or without abdominal distention, nausea, vomiting, or diarrhoea), laryngeal angioedema (stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx). HAE attacks requiring acute therapy included those attacks with medical intervention or hospitalization marked on the case report form (CRFs). ITT= all enrolled or randomised subjects.

End point type

Secondary

End point timeframe

Week 5 to Week 17

End point values	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Number of subjects analysed	6	14	3
Units: HAE attacks per month
arithmetic mean (standard deviation)	1.40 ± 1.727	0.07 ± 0.267	0.89 ± 1.540

Statistical Analysis 1

Comparison groups

Part A: Placebo v Part A: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

= 0.009

Method

Wald Chi-Square

Parameter type

Percentage Difference

Point estimate

-95

Confidence interval

level

95%

sides

2-sided

lower limit

-99

upper limit

-52

Notes
[7] - The percentage difference in mean investigator-confirmed HAE attack rate between donidalorsen 80 mg and placebo was calculated as 100 percentage (%) × (mean rate ratio -1).

Secondary: Percentage of Cleaved High Molecular Weight Kininogen (cHMWK) Levels at Weeks 9 and 17

Top of page

End point title

Percentage of Cleaved High Molecular Weight Kininogen (cHMWK) Levels at Weeks 9 and 17

End point description

High-molecular-weight kininogen (HMWK) is an abundant protein found in plasma and it has a critical role in acute attacks of HAE. During HAE attack plasma kallikrein cleaves HMWK producing cleaved HMWK (cHMWK) and bradykinin, the major biologic peptide that promotes the oedema, one of the characteristic traits of HAE. Percentage of cHMWK levels were assessed to evaluate pharmacodynamics of donidalorsen. ITT population included all enrolled or randomised subjects. n is number of subjects with data available for analysis at specified time point.

End point type

Secondary

End point timeframe

Weeks 9 and 17

End point values	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Number of subjects analysed	6	14	3
Units: percentage of cHMWK levels
arithmetic mean (standard deviation)
Week 9 (n=6, 14, 3)	5.62 ± 3.255	2.07 ± 1.241	1.03 ± 0.115
Week 17 (n=6, 13, 3)	7.00 ± 4.338	2.35 ± 1.353	2.13 ± 0.929

No statistical analyses for this end point

Secondary: Prekallikrein (PKK) Activity Levels at Weeks 9 and 17

Top of page

End point title

Prekallikrein (PKK) Activity Levels at Weeks 9 and 17

End point description

Prekallikrein (PKK) has a critical role in acute attacks of HAE. During HAE attack PKK is activated to form plasma kallikrein. Plasma kallikrein cleaves HMWK producing cleaved HMWK (cHMWK) and bradykinin, the major biologic peptide that promotes the edema, one of the characteristic traits of HAE. Prekallikrein levels were measured to assess pharmacodynamics of donidalorsen. ITT population included all enrolled or randomised subjects. n is number of subjects with data available for analysis at specified timepoint.

End point type

Secondary

End point timeframe

Weeks 9 and 17

End point values	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Number of subjects analysed	6	14	3
Units: milligram per liter (mg/L)
arithmetic mean (standard deviation)
Week 9 (n=6, 14, 3)	95.467 ± 23.7193	37.676 ± 14.5639	25.630 ± 19.2671
Week 17 (n=6, 13, 2)	98.600 ± 34.5944	37.795 ± 38.6618	28.615 ± 22.8042

No statistical analyses for this end point

Secondary: Number of Subjects Who Consumed On-demand Medication at Weeks 9 and 17

Top of page

End point title

Number of Subjects Who Consumed On-demand Medication at Weeks 9 and 17

End point description

Treatment options for HAE included on-demand treatment of attacks and prophylaxis. On-demand medication options included supplementation of C1-INH (either plasma-derived or recombinant C1-INH concentrate) and inhibition of BK2 receptor activation (BK2-receptor antagonist). The number of subjects who used on-demand medication at Week 9 (Day 57) and at Week 17 (end of the on-treatment period) were reported. ITT population included all enrolled or randomised subjects.

End point type

Secondary

End point timeframe

Weeks 9 and 17

End point values	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Number of subjects analysed	6	14	3
Units: subjects
Week 9	6	12	3
Week 17	6	11	3

Statistical Analysis 1

Statistical analysis description

Week 9

Comparison groups

Part A: Placebo v Part A: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 1

Method

Fisher exact

Parameter type

Risk Difference (RD)

Point estimate

-14.3

Confidence interval

level

95%

sides

2-sided

lower limit

-59.1

upper limit

33.9

Statistical Analysis 2

Statistical analysis description

Week 17

Comparison groups

Part A: Placebo v Part A: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.521

Method

Fisher exact

Parameter type

Risk Difference (RD)

Point estimate

-21.4

Confidence interval

level

95%

sides

2-sided

lower limit

-64.9

upper limit

27.1

Secondary: Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Weeks 9 and 17

Top of page

End point title

Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Weeks 9 and 17

End point description

AE-QoL was developed to measure health-related quality of life (HRQoL) impairment in subjects with recurrent angioedema.It is a self-administered questionnaire that can be completed in less than 5 minutes. It comprises 17 items across 4 domains: functioning, fatigue/mood, fears/shame, and food. Responses use a 5-point Likert scale ranging from '0 = never' to '4 = very often.' Per-subject scores for each domain were computed using the appropriate scoring algorithm applied to the question response scores for each domain. Per-subject total scores (including all 4 domains) were similarly computed using the question response scores for all 17 questions. Outputs from scoring algorithm were normalised on scale ranging from 0(less adverse impact) to 100(most adverse impact). Global total score ranges from 0 to 100, with higher scores indicating greater impairment. ITT=all enrolled or randomised subjects. n= number of subjects with data available at specified timepoints.

End point type

Secondary

End point timeframe

Baseline, Weeks 9 and 17

End point values	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Number of subjects analysed	6	14	3
Units: score on a scale
arithmetic mean (standard deviation)
Change from Baseline at Week 9 (n=6, 14, 3)	-5.51 ± 13.436	-25.84 ± 14.558	-33.58 ± 29.452
Change from Baseline at Week 17 (n=6, 13, 3)	-10.17 ± 5.331	-24.32 ± 19.201	-32.11 ± 17.652

Statistical Analysis 1

Statistical analysis description

Week 9

Comparison groups

Part A: Placebo v Part A: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mixed Effect Model Repeated Measure

Point estimate

-25.92

Confidence interval

level

95%

sides

2-sided

lower limit

-37.1

upper limit

-14.74

Statistical Analysis 2

Statistical analysis description

Week 17

Comparison groups

Part A: Placebo v Part A: Donidalorsen 80 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Mixed Effect Model Repeated Measure

Point estimate

-20.69

Confidence interval

level

95%

sides

2-sided

lower limit

-32.7

upper limit

-8.68

Adverse events

Top of page

Timeframe for reporting adverse events

From first dose of study drug up to end of the study (Up to Week 26)

Adverse event reporting additional description

The safety population included all enrolled subjects who received at least 1 dose of study drug (donidalorsen or placebo).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Part A: Placebo

Reporting group description

Subjects with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo SC every 4 weeks at Weeks 1, 5, 9, and 13.

Reporting group title

Part A: Donidalorsen 80 mg

Reporting group description

Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.

Reporting group title

Part B: Donidalorsen 80 mg

Reporting group description

Subjects with hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, and 13.

Serious adverse events	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 3 (0.00%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Part A: Placebo	Part A: Donidalorsen 80 mg	Part B: Donidalorsen 80 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 6 (50.00%)	2 / 14 (14.29%)	3 / 3 (100.00%)
Nervous system disorders
Headache
subjects affected / exposed	2 / 6 (33.33%)	2 / 14 (14.29%)	0 / 3 (0.00%)
occurrences all number	3	2	0
Lethargy
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	2
General disorders and administration site conditions
Application site rash
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Feeling hot
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Hyperhidrosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Gastrointestinal disorders
Nausea
subjects affected / exposed	1 / 6 (16.67%)	1 / 14 (7.14%)	0 / 3 (0.00%)
occurrences all number	1	1	0
Vomiting
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Respiratory, thoracic and mediastinal disorders
Chest pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Epistaxis
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	3
Nasal congestion
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Oropharyngeal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Renal and urinary disorders
Pollakiuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Musculoskeletal and connective tissue disorders
Myalgia
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Infections and infestations
Coronavirus infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Fungal infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1
Tooth abscess
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	2
Urinary tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

21 Oct 2019

The primary purpose of this amendment was to specify a minimal compliance level in the inclusion criteria for completion of the Angioedema Activity Score, during the screening period, as a requirement prior to randomization to treatment in Part A, or initiation of treatment in Part B, of the study. Broadened the exclusion criteria to include elevated partial thromboplastin time (PTT), history of coagulopathy or bleeding diathesis, and renal and hepatic diseases. Modified the exclusion criteria to allow for subjects who tested positive for hepatitis B or C enzyme but were non-reactive. Provided the definition of an HAE attack and delineated how discrete attacks would be counted. Designated adverse events of special interest (AESIs). In the Schedule of Procedures, added anti-drug antibody testing at Day 15 and Day 29 visits and removed the requirement for a physical examination from the day 15 visit.

29 Jan 2020

The primary purpose of this amendment was to update the established mutations in the plasminogen and angiopoietin genes from the legacy description to the Human Genome Variation Society description in the diagnostic report. The plasminogen gene was changed from c.9886A>G to 988A>G and the angiopoietin-1 gene from c.807G>T to 355G>T. Changed the duration of male and female contraceptive advice from at least 13 weeks to at least 24 weeks. This allowed for near-complete elimination of ISIS 721744 as 24 weeks encompassed approximately 5 half-lives of ISIS 721744 and 1 menstrual cycle (requested by the Medicines and Healthcare products Regulatory Agency (MHRA), to comply with Clinical Trial Facilitation Group guidance (Clinical Trial Facilitation Group 2014). Added language that subject who completed Study Visit Week 17 and met eligibility requirements could start the Treatment Period in the ISIS 721744-CS3 open label study (OLE) study any time after the Week 17 visit and discontinue participation in the CS2 Post-Treatment Evaluation Period at that time. Removed as secondary endpoints the time-normalised number of HAE attacks (per month) from Week 9 to Week 21 and the time-normalised number of moderate or severe HAE attacks (per month) from Week 9 to Week 21 because subject were allowed to rollover to the ISIS 721744-CS3 OLE study after the Week 17 visit. Removed the requirement that subject must fast before visits that required blood sampling because none of the laboratories required fasting and, therefore, fasting was an unnecessary burden for the subject.

05 May 2020

The primary purpose of this amendment was to adjust the length of time subjects must not have received lanadelumab prior to screening for ISIS 721744-CS2 from 6 months to 10 weeks (i.e., 5 times the ~14-day half-life for lanadelumab). To decrease the burden of site visits where feasible for subjects, added that Study Drug administration, assessments, and procedures may have been conducted by either a Home Healthcare professional (if available) or the Study Center, as arranged by the Study Center personnel, for visits as noted in the Schedule of Procedures. To decrease the burden of pharmacokinetic (PK) sampling for subjects, revised to only a subgroup of approximately 6 subjects (rather than all subjects) would have blood draws at pre-dose, 1, 2, 4, and 6 hours post-dose on Day 1 and Day 85. This, along with a pre-dose and a 2 hour post-dose blood collection on Day 1 and Day 85 in all subjects, would provide enough information to determine PK parameters.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Clinical trials

Clinical Trial Results:
A Randomized, Double Blind, Placebo Controlled, Phase 2a Study to Assess the Clinical Efficacy of ISIS 721744, a Second Generation Ligand Conjugated Antisense Inhibitor of Prekallikrein, in Patients with Hereditary Angioedema

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Time-normalised Number of HAE Attacks (Per Month) From Week 1 to Week 17

Primary: Time-normalised Number of HAE Attacks (Per Month) From Week 1 to Week 17

Secondary: Time-normalised Number of Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17

Secondary: Time-normalised Number of Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17

Secondary: Time-normalised Number of Moderate or Severe Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17

Secondary: Time-normalised Number of Moderate or Severe Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17

Secondary: Number of Subjects With Clinical Response by Week 17

Secondary: Number of Subjects With Clinical Response by Week 17

Secondary: Number of Investigator-confirmed HAE Attacks Requiring Acute Therapy From Week 5 to Week 17

Secondary: Number of Investigator-confirmed HAE Attacks Requiring Acute Therapy From Week 5 to Week 17

Secondary: Percentage of Cleaved High Molecular Weight Kininogen (cHMWK) Levels at Weeks 9 and 17

Secondary: Percentage of Cleaved High Molecular Weight Kininogen (cHMWK) Levels at Weeks 9 and 17

Secondary: Prekallikrein (PKK) Activity Levels at Weeks 9 and 17

Secondary: Prekallikrein (PKK) Activity Levels at Weeks 9 and 17

Secondary: Number of Subjects Who Consumed On-demand Medication at Weeks 9 and 17

Secondary: Number of Subjects Who Consumed On-demand Medication at Weeks 9 and 17

Secondary: Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Weeks 9 and 17

Secondary: Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Weeks 9 and 17

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Randomized, Double Blind, Placebo Controlled, Phase 2a Study to Assess the Clinical Efficacy of ISIS 721744, a Second Generation Ligand Conjugated Antisense Inhibitor of Prekallikrein, in Patients with Hereditary Angioedema

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Time-normalised Number of HAE Attacks (Per Month) From Week 1 to Week 17

Primary: Time-normalised Number of HAE Attacks (Per Month) From Week 1 to Week 17

Secondary: Time-normalised Number of Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17

Secondary: Time-normalised Number of Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17

Secondary: Time-normalised Number of Moderate or Severe Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17

Secondary: Time-normalised Number of Moderate or Severe Investigator-confirmed HAE Attacks (Per Month) From Week 5 to Week 17

Secondary: Number of Subjects With Clinical Response by Week 17

Secondary: Number of Subjects With Clinical Response by Week 17

Secondary: Number of Investigator-confirmed HAE Attacks Requiring Acute Therapy From Week 5 to Week 17

Secondary: Number of Investigator-confirmed HAE Attacks Requiring Acute Therapy From Week 5 to Week 17

Secondary: Percentage of Cleaved High Molecular Weight Kininogen (cHMWK) Levels at Weeks 9 and 17

Secondary: Percentage of Cleaved High Molecular Weight Kininogen (cHMWK) Levels at Weeks 9 and 17

Secondary: Prekallikrein (PKK) Activity Levels at Weeks 9 and 17

Secondary: Prekallikrein (PKK) Activity Levels at Weeks 9 and 17

Secondary: Number of Subjects Who Consumed On-demand Medication at Weeks 9 and 17

Secondary: Number of Subjects Who Consumed On-demand Medication at Weeks 9 and 17

Secondary: Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Weeks 9 and 17

Secondary: Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Weeks 9 and 17

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Randomized, Double Blind, Placebo Controlled, Phase 2a Study to Assess the Clinical Efficacy of ISIS 721744, a Second Generation Ligand Conjugated Antisense Inhibitor of Prekallikrein, in Patients with Hereditary Angioedema