Clinical Trial Results:
A Phase 3 Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of ISIS 721744 in Patients With Hereditary Angioedema (HAE)
Summary
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EudraCT number |
2021-002571-19 |
Trial protocol |
FR IT ES NL DE BE BG DK PL |
Global end of trial date |
08 Nov 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
22 Dec 2024
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First version publication date |
22 Dec 2024
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ISIS721744-CS5
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT05139810 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Ionis Pharmaceuticals, Inc.
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Sponsor organisation address |
2855 Gazelle Court, Carlsbad, United States, 92010
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Public contact |
Ionis Clinical Trial Information, Ionis Pharmaceuticals, Inc., Ionis Pharmaceuticals, Inc., 1 760-603-2346, globalregulatoryaffairs@ionis.com
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Scientific contact |
Ionis Clinical Trial Information, Ionis Pharmaceuticals, Inc., Ionis Pharmaceuticals, Inc., 1 760-603-2346, globalregulatoryaffairs@ionis.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-003112-PIP01-21 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
08 Nov 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
08 Nov 2023
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the safety and efficacy of donidalorsen in subjects with Hereditary Angioedema (HAE) and effect of donidalorsen on the quality and pattern of HAE attacks and their impact on quality of life (QoL).
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Protection of trial subjects |
Each subject, or legally acceptable representative, signed an informed consent form before participating in the study.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
03 Dec 2021
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 18
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Country: Number of subjects enrolled |
Türkiye: 20
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Country: Number of subjects enrolled |
Italy: 9
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Country: Number of subjects enrolled |
Netherlands: 8
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Country: Number of subjects enrolled |
Spain: 6
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Country: Number of subjects enrolled |
Israel: 5
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Country: Number of subjects enrolled |
Poland: 5
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Country: Number of subjects enrolled |
United Kingdom: 5
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Country: Number of subjects enrolled |
Germany: 4
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Country: Number of subjects enrolled |
Bulgaria: 3
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Country: Number of subjects enrolled |
Canada: 3
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Country: Number of subjects enrolled |
France: 3
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Country: Number of subjects enrolled |
Belgium: 1
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Worldwide total number of subjects |
90
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EEA total number of subjects |
39
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
7
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Adults (18-64 years) |
81
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From 65 to 84 years |
2
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85 years and over |
0
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Recruitment
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Recruitment details |
Subjects took part in the study at 39 investigative sites from 03 December 2021 to 09 November 2023. | ||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 91 subjects were enrolled and randomized in study. Out of 91, 1 subject randomized to Cohort A, withdrew consent prior to receiving study drug. As pre-specified in protocol/statistical analysis plan, for purposes of analysis data for placebo subjects, from Cohort A and Cohort B was pooled for comparison to donidalorsen treated subjects. | ||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||
Roles blinded |
Subject, Carer, Investigator, Assessor | ||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Pooled Placebo | ||||||||||||||||||||||||||||
Arm description |
Subjects with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17). | ||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Placebo was administered SC either every 4 weeks or 8 weeks.
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Arm title
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Cohort 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, 13, 17, and 21. | ||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Donidalorsen 80 mg
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Investigational medicinal product code |
ISIS 721744
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Donidalorsen, 80 mg, administered SC, every 4 weeks.
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Arm title
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Cohort B: Donidalorsen 80 mg | ||||||||||||||||||||||||||||
Arm description |
Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17. | ||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Donidalorsen 80 mg
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Investigational medicinal product code |
ISIS 721744
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Donidalorsen, 80 mg, administered SC, every 8 weeks.
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Baseline characteristics reporting groups
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Reporting group title |
Pooled Placebo
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Reporting group description |
Subjects with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cohort A: Donidalorsen 80 mg
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Reporting group description |
Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cohort B: Donidalorsen 80 mg
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Reporting group description |
Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Pooled Placebo
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Reporting group description |
Subjects with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17). | ||
Reporting group title |
Cohort A: Donidalorsen 80 mg
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Reporting group description |
Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21. | ||
Reporting group title |
Cohort B: Donidalorsen 80 mg
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Reporting group description |
Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17. |
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End point title |
Time-Normalized Investigator-Confirmed (IC) HAE Attack Rate (Per Month) From Week 1 to Week 25 | ||||||||||||||||
End point description |
The time-adjusted HAE attack rate was calculated as number of IC HAE attacks occurring from Week 1 to Week 25, 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 full analysis set (FAS) included all randomized subjects who received at least 1 dose of the study drug (donidalorsen or placebo). As given in protocol/SAP, data for placebo subjects from Cohort A and Cohort B was pooled for comparison to donidalorsen treated subjects.
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End point type |
Primary
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End point timeframe |
Week 1 to Week 25
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||||||
Statistical analysis description |
The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject was observed from Week 1 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion.
Model adjusted rate ratio from Poisson regression model.
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Comparison groups |
Pooled Placebo v Cohort A: Donidalorsen 80 mg
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Number of subjects included in analysis |
67
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||
Method |
Poisson regression model | ||||||||||||||||
Parameter type |
IC HAE attack rate ratio | ||||||||||||||||
Point estimate |
0.19
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.107 | ||||||||||||||||
upper limit |
0.351 | ||||||||||||||||
Statistical analysis title |
Statistical analysis 2 | ||||||||||||||||
Statistical analysis description |
The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject
was observed from Week 1 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson
regression model to account for potential overdispersion.
Model adjusted rate ratio from Poisson regression model.
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Comparison groups |
Pooled Placebo v Cohort B: Donidalorsen 80 mg
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Number of subjects included in analysis |
45
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.004 | ||||||||||||||||
Method |
Poisson regression model | ||||||||||||||||
Parameter type |
IC HAE attack rate ratio | ||||||||||||||||
Point estimate |
0.45
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.261 | ||||||||||||||||
upper limit |
0.777 |
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End point title |
Time-Normalized IC HAE Attack Rate (Per Month) From Week 5 to Week 25 | ||||||||||||||||
End point description |
The time-adjusted HAE attack rate was calculated as number of IC HAE attacks occurring from Week 5 to Week 25, 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 FAS included all randomized subjects who received at least 1 dose of the study drug (donidalorsen or placebo). As given in protocol/SAP, data for placebo subjects from Cohort A and Cohort B was pooled for comparison to donidalorsen treated subjects.
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End point type |
Secondary
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End point timeframe |
Week 5 to Week 25
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Statistical analysis title |
Statistical analysis 2 | ||||||||||||||||
Statistical analysis description |
The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion.
Model adjusted rate ratio from Poisson regression model.
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Comparison groups |
Pooled Placebo v Cohort B: Donidalorsen 80 mg
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Number of subjects included in analysis |
45
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.004 | ||||||||||||||||
Method |
Poisson regression model | ||||||||||||||||
Parameter type |
IC HAE attack rate ratio | ||||||||||||||||
Point estimate |
0.4
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.212 | ||||||||||||||||
upper limit |
0.748 | ||||||||||||||||
Statistical analysis title |
Statistical analysis 1 | ||||||||||||||||
Statistical analysis description |
The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion.
Model adjusted rate ratio from Poisson regression model.
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Comparison groups |
Pooled Placebo v Cohort A: Donidalorsen 80 mg
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Number of subjects included in analysis |
67
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||
Method |
Poisson regression model | ||||||||||||||||
Parameter type |
IC HAE attack rate ratio | ||||||||||||||||
Point estimate |
0.13
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.062 | ||||||||||||||||
upper limit |
0.281 |
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End point title |
Percentage of IC HAE Attack-Free Subjects From Week 5 to Week 25 | ||||||||||||||||
End point description |
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). Percentages are rounded off to the nearest decimal. The FAS included all randomized subjects who received at least 1 dose of the study drug (donidalorsen or placebo). As given in protocol/SAP, data for placebo subjects from Cohort A and Cohort B was pooled for comparison to donidalorsen treated subjects.
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End point type |
Secondary
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End point timeframe |
Week 5 to Week 25
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Statistical analysis title |
Statistical analysis 2 | ||||||||||||||||
Comparison groups |
Pooled Placebo v Cohort B: Donidalorsen 80 mg
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Number of subjects included in analysis |
45
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.24 [1] | ||||||||||||||||
Method |
Regression, Logistic | ||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||
Point estimate |
3.23
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.46 | ||||||||||||||||
upper limit |
22.85 | ||||||||||||||||
Notes [1] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate. |
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||||||
Comparison groups |
Pooled Placebo v Cohort A: Donidalorsen 80 mg
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Number of subjects included in analysis |
67
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.003 [2] | ||||||||||||||||
Method |
Regression, Logistic | ||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||
Point estimate |
11.79
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
2.34 | ||||||||||||||||
upper limit |
59.36 | ||||||||||||||||
Notes [2] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate. |
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End point title |
Time-Normalized Moderate or Severe IC HAE Attack Rate (Per Month) From Week 5 to Week 25 | ||||||||||||||||
End point description |
Time-adjusted HAE attack rate was calculated as number of IC moderate or severe HAE attacks occurring from Week 5 to Week 25, 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 tongue, palate, uvula, or larynx). The FAS included all randomized subjects who received at least 1 dose of the study drug (donidalorsen or placebo). As given in protocol/SAP, data for placebo subjects from Cohort A and Cohort B was pooled for comparison to donidalorsen treated subjects.
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End point type |
Secondary
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End point timeframe |
Week 5 to Week 25
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Statistical analysis title |
Statistical analysis 2 | ||||||||||||||||
Statistical analysis description |
The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject
was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson
regression model to account for potential over dispersion.
Model adjusted rate ratio from Poisson regression model.
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Comparison groups |
Pooled Placebo v Cohort B: Donidalorsen 80 mg
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Number of subjects included in analysis |
45
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.173 | ||||||||||||||||
Method |
Poisson regression model | ||||||||||||||||
Parameter type |
IC HAE attack rate ratio | ||||||||||||||||
Point estimate |
0.59
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Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.276 | ||||||||||||||||
upper limit |
1.26 | ||||||||||||||||
Statistical analysis title |
Statistical analysis 1 | ||||||||||||||||
Statistical analysis description |
The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject
was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson
regression model to account for potential over dispersion.
Model adjusted rate ratio from Poisson regression model.
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Comparison groups |
Pooled Placebo v Cohort A: Donidalorsen 80 mg
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Number of subjects included in analysis |
67
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||
Method |
Poisson regression model | ||||||||||||||||
Parameter type |
IC HAE attack rate ratio | ||||||||||||||||
Point estimate |
0.11
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.035 | ||||||||||||||||
upper limit |
0.339 |
|
|||||||||||||||||||||||||
End point title |
Number of Subjects With a Clinical Response From Week 5 to Week 25 | ||||||||||||||||||||||||
End point description |
Clinical response= ≥ 50%, ≥ 70%, or ≥ 90% reduction from Baseline in HAE attack rate from Week 5 to Week 25. HAE attack rate between Week 5 and Week 25 for each subject is calculated as number of HAE attacks (occurring from Week 5 to week 25)/number of days subject contributed to period*28 days. An HAE attack- an event with signs or symptoms consistent with an attack in at least 1 of locations: peripheral angioedema (cutaneous swelling involving an extremity, 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). Baseline= Run-in period which is period from screening to last day prior to Day 1. FAS. As per protocol/SAP, data for placebo subjects from Cohort A&B was pooled for comparison to donidalorsen treated subjects.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Week 5 to Week 25
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
Statistical analysis 1 | ||||||||||||||||||||||||
Statistical analysis description |
≥ 50% Reduction: The odds ratio and its 95% confidence interval were calculated based on a logistic regression with baseline (the time-normalized run-in period attack rate) and the treatment-by-baseline interaction as a covariate.
|
||||||||||||||||||||||||
Comparison groups |
Pooled Placebo v Cohort A: Donidalorsen 80 mg
|
||||||||||||||||||||||||
Number of subjects included in analysis |
67
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
< 0.001 [3] | ||||||||||||||||||||||||
Method |
Regression, Logistic | ||||||||||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||||||||||
Point estimate |
310.35
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
11.63 | ||||||||||||||||||||||||
upper limit |
8279.94 | ||||||||||||||||||||||||
Notes [3] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate. |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical analysis 2 | ||||||||||||||||||||||||
Statistical analysis description |
≥ 50% Reduction: The odds ratio and its 95% confidence interval were calculated based on a logistic regression with baseline (the time-normalized run-in period attack rate) and the treatment-by-baseline interaction as a covariate.
|
||||||||||||||||||||||||
Comparison groups |
Pooled Placebo v Cohort B: Donidalorsen 80 mg
|
||||||||||||||||||||||||
Number of subjects included in analysis |
45
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
< 0.001 [4] | ||||||||||||||||||||||||
Method |
Regression, Logistic | ||||||||||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||||||||||
Point estimate |
14.8
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
3.15 | ||||||||||||||||||||||||
upper limit |
69.41 | ||||||||||||||||||||||||
Notes [4] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate. |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical analysis 3 | ||||||||||||||||||||||||
Statistical analysis description |
≥ 70% Reduction: The odds ratio and its 95% confidence interval were calculated based on a logistic regression with baseline (the time-normalized run-in period attack rate) and the treatment-by-baseline interaction as a covariate.
|
||||||||||||||||||||||||
Comparison groups |
Pooled Placebo v Cohort A: Donidalorsen 80 mg
|
||||||||||||||||||||||||
Number of subjects included in analysis |
67
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
< 0.001 [5] | ||||||||||||||||||||||||
Method |
Regression, Logistic | ||||||||||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||||||||||
Point estimate |
34.74
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
7.32 | ||||||||||||||||||||||||
upper limit |
164.87 | ||||||||||||||||||||||||
Notes [5] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate. |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical analysis 4 | ||||||||||||||||||||||||
Statistical analysis description |
≥ 70% Reduction: The odds ratio and its 95% confidence interval were calculated based on a logistic regression with baseline (the time-normalized run-in period attack rate) and the treatment-by-baseline interaction as a covariate.
|
||||||||||||||||||||||||
Comparison groups |
Pooled Placebo v Cohort B: Donidalorsen 80 mg
|
||||||||||||||||||||||||
Number of subjects included in analysis |
45
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.004 [6] | ||||||||||||||||||||||||
Method |
Regression, Logistic | ||||||||||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||||||||||
Point estimate |
9.17
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
2.05 | ||||||||||||||||||||||||
upper limit |
41.09 | ||||||||||||||||||||||||
Notes [6] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate. |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical analysis 5 | ||||||||||||||||||||||||
Statistical analysis description |
≥ 90% Reduction: The odds ratio and its 95% confidence interval were calculated based on a logistic regression with baseline (the time-normalized run-in period attack rate) and the treatment-by-baseline interaction as a covariate.
|
||||||||||||||||||||||||
Comparison groups |
Pooled Placebo v Cohort B: Donidalorsen 80 mg
|
||||||||||||||||||||||||
Number of subjects included in analysis |
45
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
< 0.001 [7] | ||||||||||||||||||||||||
Method |
Regression, Logistic | ||||||||||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||||||||||
Point estimate |
17.04
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
3.36 | ||||||||||||||||||||||||
upper limit |
86.42 | ||||||||||||||||||||||||
Notes [7] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate. |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical analysis 6 | ||||||||||||||||||||||||
Statistical analysis description |
≥ 90% Reduction: The odds ratio and its 95% confidence interval were calculated based on a logistic regression with baseline (the time-normalized run-in period attack rate) and the treatment-by-baseline interaction as a covariate.
|
||||||||||||||||||||||||
Comparison groups |
Pooled Placebo v Cohort B: Donidalorsen 80 mg
|
||||||||||||||||||||||||
Number of subjects included in analysis |
45
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.014 [8] | ||||||||||||||||||||||||
Method |
Regression, Logistic | ||||||||||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||||||||||
Point estimate |
8.7
|
||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||
lower limit |
1.56 | ||||||||||||||||||||||||
upper limit |
48.52 | ||||||||||||||||||||||||
Notes [8] - p-value was calculated based on logistic regression with baseline and the treatment-by-baseline interaction as a covariate. |
|
|||||||||||||||||
End point title |
IC HAE Attack Rate Requiring Acute HAE Therapy From Week 5 to Week 25 | ||||||||||||||||
End point description |
Time-adjusted HAE attack rate= number of investigator-confirmed HAE attacks requiring acute therapy occurring from Week 5 to Week 25, divided by number of days subject contributed to period multiplied by 28 days. HAE attack- event with signs or symptoms consistent with an attack in at least 1 of 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). ). HAE attacks requiring acute therapy included those attacks with following concomitant medications c1 esterase inhibitors (human and recombinant), plasma kallikrein inhibitor (human), and bradykinin antagonist. FAS. As per protocol/SAP, data for placebo subjects from Cohort A and Cohort B was pooled.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Week 5 to Week 25
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical analysis 1 | ||||||||||||||||
Statistical analysis description |
The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion.
Model adjusted rate ratio from Poisson regression model.
|
||||||||||||||||
Comparison groups |
Pooled Placebo v Cohort A: Donidalorsen 80 mg
|
||||||||||||||||
Number of subjects included in analysis |
67
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||
Method |
Poisson regression model | ||||||||||||||||
Parameter type |
IC HAE attack rate ratio | ||||||||||||||||
Point estimate |
0.08
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.03 | ||||||||||||||||
upper limit |
0.234 | ||||||||||||||||
Statistical analysis title |
Statistical analysis 2 | ||||||||||||||||
Statistical analysis description |
The Poisson regression model includes treatment groups, baseline (the run-in period HAE attack rate), the treatment-by-baseline interaction as a covariate, and the logarithm of time in every-4-week that each subject was observed from Week 5 to Week 25 used as an offset variable. Pearson chi-square scaling of standard errors was used in the Poisson regression model to account for potential over dispersion.
Model adjusted rate ratio from Poisson regression model.
|
||||||||||||||||
Comparison groups |
Pooled Placebo v Cohort B: Donidalorsen 80 mg
|
||||||||||||||||
Number of subjects included in analysis |
45
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.004 | ||||||||||||||||
Method |
Poisson regression model | ||||||||||||||||
Parameter type |
IC HAE attack rate ratio | ||||||||||||||||
Point estimate |
0.33
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.155 | ||||||||||||||||
upper limit |
0.706 |
|
|||||||||||||||||
End point title |
Percentage of Subjects Who Are Well Controlled on the Angioedema Control Test (AECT) at Week 25 | ||||||||||||||||
End point description |
AECT is a validated subject-reported outcome instrument to assess disease activity in subjects with recurrent angioedema. Questionnaire consists of 4 questions asking about the frequency and severity of angioedema experienced in last four weeks. Each question has 5 response choices with total score ranging from 0 to 16. AECT can be used to identify subjects with poorly controlled disease by working with a cutoff value of greater than or equal to 10 points. Subjects who score less than 10 points (0-9) in the AECT have poorly controlled disease whereas subjects with well-controlled disease score 10-16 points. Percentages are rounded off to the nearest decimal. FAS included all randomized subjects who received at least 1 dose of the study drug (donidalorsen or placebo). Subjects analyzed indicates the number of subjects with data available for analysis at the specified timepoint. As per protocol/SAP, data for placebo subjects from Cohort A and Cohort B was pooled.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Week 25
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Change From Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire Total Score at Week 25 | ||||||||||||||||
End point description |
AE-QoL: validated tool to assess symptom-specific health-related QOL impairment in subjects suffering from recurrent angioedema. It is a self-administered questionnaire comprising 17 questions across 4 domains: functioning, fatigue/mood, fears/shame, and food. The responses are scored from 0 to 4 where, 0=never, 1=rarely, 2=occasionally, 3=often, 4=very often. The AE-QoL domain scores and total score were calculated by using the following formula: (Sum score of all completed items) / (maximum sum score of all possible items) × 100. Total scores ranges from 0 to 100, with higher scores indicating greater impairment. Negative change from baseline indicates improvement. Calculated domain and total scores were not raw scores but linear transformations to a 0 to 100 scale. Baseline= score on Study Day 1. FAS. Subjects analyzed= number of subjects with data available for analysis at specified time point. As per protocol/SAP, data for placebo subjects from Cohort A and Cohort B was pooled.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Week 25
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical analysis 2 | ||||||||||||||||
Comparison groups |
Pooled Placebo v Cohort B: Donidalorsen 80 mg
|
||||||||||||||||
Number of subjects included in analysis |
40
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.01 | ||||||||||||||||
Method |
MMRM | ||||||||||||||||
Parameter type |
Treatment difference] | ||||||||||||||||
Point estimate |
-13.65
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-24.024 | ||||||||||||||||
upper limit |
-3.286 | ||||||||||||||||
Statistical analysis title |
Statistical analysis 1 | ||||||||||||||||
Comparison groups |
Pooled Placebo v Cohort A: Donidalorsen 80 mg
|
||||||||||||||||
Number of subjects included in analysis |
60
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.001 | ||||||||||||||||
Method |
Mixed model with repeated measures(MMRM) | ||||||||||||||||
Parameter type |
Treatment difference | ||||||||||||||||
Point estimate |
-18.56
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-27.673 | ||||||||||||||||
upper limit |
-9.454 |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Up to Week 38
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
The safety set included all randomized subjects who received at least 1 dose of the study drug (donidalorsen or placebo). As pre-specified in the protocol and statistical analysis plan, for purposes of analysis, data for placebo subjects from Cohort A and Cohort B was pooled for comparison to donidalorsen treated subjects.
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
26.1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Pooled Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects with hereditary angioedema type I/type II (HAE-1/HAE-2) received placebo subcutaneously (SC) either every 4 weeks (Week 1, 5, 9, 13,17, and 21) or 8 weeks (Week 1, 9, and 17). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cohort B: Donidalorsen 80 mg
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 8 weeks at Weeks 1, 9, and 17. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cohort A: Donidalorsen 80 mg
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Reporting group description |
Subjects with HAE-1/HAE-2 received donidalorsen, 80 mg, SC, every 4 weeks at Weeks 1, 5, 9, 13, 17, and 21. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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01 Oct 2021 |
Secondary and exploratory objectives were summarized into more cohesive objectives because details were already provided in the endpoints. Added the inclusion and rationale for of a second dosing Cohort with a dose frequency of per 8 weeks (donidalorsen 80 mg once per 8 weeks). Additional subjects were added to the study with a new dosing cohort (donidalorsen 80 mg every 8 weeks). A clarification was added to the collection of HAE attack details that confirmed HAE attacks were based on symptoms and Investigator diagnosis, not on presence of symptoms alone. Safety stopping rules for platelet count and actions in subjects with confirmed low platelet count were updated to increase monitoring frequency for platelets for counts between 100,000 /mm^3 and 125,000/mm^3 and added requirement for Sponsor approval for continued dosing when platelets were ≥ 75,000/mm^3 to ≤ 100,000/mm^3. Added a safety monitoring plan. The definition of clinically relevant non-major bleeding events was updated to the most current version. Updated the Safety and PK population definitions to include randomized subjects. The primary efficacy analysis was updated to reflect that the primary analysis was to compare between the 80 mg donidalorsen-4 group versus placebo group. The recall period for the work productivity and impairment (WPAI) questionnaire was 7 days. Therefore, this assessment was completed by the subject weekly throughout the entire study rather than intermittently as specified in the original protocol. Added directions to follow if urine pregnancy test was positive in Schedule of Procedures. Electrocardiogram (ECG)-related assessment changes were added to the Schedule of Procedures including predose and 2 hours after dose. Updated Schedule of Procedures by adding a physical exam at every visit to examine for
reactions due to study drug administration. Updated Schedule of Procedures and PK Sampling Schedule to reflect the new dosing groups. |
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01 Oct 2021 |
The time points for PK sampling were accidentally inverted in the original protocol. Study Drug administration did not occur at Week 25 and therefore, the time points for PK sampling at Weeks 21 and 25 were switched. Also added 2-hours post-dosing at Week 21 only for Cohort A and at Week 17 only for Cohort B. Added the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, Sept. 2007 to indicate how Adverse Events (AE) were graded. Exclusion criteria's were updated. |
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12 Jul 2022 |
Added a clarification on how many attacks were required for a subject to be randomized i.e., ≥ 2 HAE attacks. Changed inclusion criteria 6 and 7 and contraception requirements to include the use of acceptable instead of highly effective contraceptive methods. Added a clarification to the exclusion criteria to exclude subjects with alcohol or drug abuse. Added a clarification to contraception requirements to note that the exclusion of combined estrogen and progesterone hormonal contraception was intended for oral hormonal therapy, and not for intrauterine or intravaginal estrogens. Updated the urine protein-creatinine ratio (UPCR) to a more accurate lab measure: UPCR > 1000 mg/g confirmed a quantitative total urine protein measurement of >1.0 g/24 hours. Added a clarification that the final analysis was to be performed before the follow-up period was completed. Deleted reference that dose reductions were allowed from the protocol. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |