Clinical Trial Results:
A Phase 2 Study to Assess the Antiarrhythmic and Symptomatic Effect of the Second Generation Antisense Oligonucleotide ISIS 329993 Targeting CRP in Patients with Paroxysmal Atrial Fibrillation
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Summary
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EudraCT number |
2012-000833-38 |
Trial protocol |
GB |
Global end of trial date |
31 Mar 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
24 Jul 2019
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First version publication date |
24 Jul 2019
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Other versions |
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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 |
ISIS329993-CS6
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01710852 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Ionis Pharmaceuticals, Inc.
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Sponsor organisation address |
2855 Gazelle Court, Carlsbad, United States, CA 92010
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Public contact |
Ionis Pharmaceuticals, Inc., Ionis Pharmaceuticals, Inc., +1 800-679-4747, patients@ionisph.com
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Scientific contact |
Ionis Pharmaceuticals, Inc., Ionis Pharmaceuticals, Inc., +1 800-679-4747, patients@ionisph.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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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 |
31 Mar 2014
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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 |
31 Mar 2014
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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 |
The main objective of this study was to evaluate whether treatment with the antisense inhibitor of human C-reactive protein (CRP) (ISIS 329993) can reduce atrial fibrillation (AF) burden (percentage of time spent in AF as derived from continuous pacemaker monitoring) in subjects with paroxysmal AF.
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Protection of trial subjects |
Subjects were evaluated to determine their capacity to sign an informed consent form which was in English and easily understood by the subjects. The subjects were encouraged to complete the early termination study procedures and observations at the time of withdrawal.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
13 Feb 2013
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy, Scientific research | ||
Long term follow-up duration |
2 Months | ||
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 Kingdom: 7
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Worldwide total number of subjects |
7
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EEA total number of subjects |
7
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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) |
0
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Adults (18-64 years) |
1
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From 65 to 84 years |
6
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85 years and over |
0
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Recruitment
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Recruitment details |
Subjects were recruited at a single centre in the United Kingdom. | |||||||||
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Pre-assignment
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Screening details |
26 subjects with paroxysmal atrial fibrillation (AF) were screened and 7 were randomised to receive the treatment. | |||||||||
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Period 1
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Period 1 title |
Treatment Period 1
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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, Investigator, Monitor, Data analyst, Carer, Assessor | |||||||||
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Arms
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Are arms mutually exclusive |
No
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Arm title
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Placebo – ISIS 329993 400 mg | |||||||||
Arm description |
In Treatment Period 1, subjects received placebo subcutaneously (SC) followed by ISIS 329993 400 milligrams (mg) in Treatment Period 2. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
ISIS 329993
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Investigational medicinal product code |
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Other name |
CRPRx
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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 |
ISIS 329993 400 mg was administered SC
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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
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Arm title
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ISIS 329993 400 mg – Placebo | |||||||||
Arm description |
In Treatment Period 1 subjects received ISIS 329993 400 mg SC, followed by placebo SC, in Treatment Period 2. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
ISIS 329993
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Investigational medicinal product code |
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Other name |
CRPRx
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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 |
ISIS 329993 400 mg was administered SC
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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
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Period 2
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Period 2 title |
Treatment Period 2
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Is this the baseline period? |
No | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | |||||||||
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Arms
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Are arms mutually exclusive |
No
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Arm title
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Placebo – ISIS 329993 400 mg | |||||||||
Arm description |
In Treatment Period 1, subjects received placebo SC followed by ISIS 329993 400 mg SC in Treatment Period 2. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
ISIS 329993
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Investigational medicinal product code |
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Other name |
CRPRx
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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 |
ISIS 329993 400 mg was administered SC
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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
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Arm title
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ISIS 329993 400 mg – Placebo | |||||||||
Arm description |
In Treatment Period 1, subjects received ISIS 329993 400 mg SC followed by placebo SC in Treatment Period 2. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
ISIS 329993
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Investigational medicinal product code |
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Other name |
CRPRx
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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 |
ISIS 329993 400 mg was administered SC
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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
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Baseline characteristics reporting groups
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Reporting group title |
Placebo – ISIS 329993 400 mg
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Reporting group description |
In Treatment Period 1, subjects received placebo subcutaneously (SC) followed by ISIS 329993 400 milligrams (mg) in Treatment Period 2. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
ISIS 329993 400 mg – Placebo
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Reporting group description |
In Treatment Period 1 subjects received ISIS 329993 400 mg SC, followed by placebo SC, in Treatment Period 2. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo – ISIS 329993 400 mg
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Reporting group description |
In Treatment Period 1, subjects received placebo subcutaneously (SC) followed by ISIS 329993 400 milligrams (mg) in Treatment Period 2. | ||
Reporting group title |
ISIS 329993 400 mg – Placebo
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Reporting group description |
In Treatment Period 1 subjects received ISIS 329993 400 mg SC, followed by placebo SC, in Treatment Period 2. | ||
Reporting group title |
Placebo – ISIS 329993 400 mg
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Reporting group description |
In Treatment Period 1, subjects received placebo SC followed by ISIS 329993 400 mg SC in Treatment Period 2. | ||
Reporting group title |
ISIS 329993 400 mg – Placebo
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Reporting group description |
In Treatment Period 1, subjects received ISIS 329993 400 mg SC followed by placebo SC in Treatment Period 2. | ||
Subject analysis set title |
ISIS 329993 400 mg
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Three subjects received ISIS 329993 400 mg SC in Treatment period 1 and four in Treatment period 2.
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End point title |
Change from Baseline in Atrial Fibrillation (AF) Burden During Treatment with ISIS 329993 to End of Treatment [1] | ||||||||||||
End point description |
AF burden was defined as the percentage of time spent in AF as derived from continuous pacemaker monitoring. It was assessed using long-term, beat-to-beat pacemaker Holter monitoring. Per Protocol population included all subjects who were randomised and received at least 5 doses of ISIS 329993 and who did not have any clinically significant protocol deviations. Measurements were only compared from baseline and active treatment period.
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End point type |
Primary
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End point timeframe |
Baseline (Day 1) to End of Treatment (Day 29 for 3 subjects and Day 57 for 4 subjects)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics only. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change from Baseline in Total Number of AF Episodes to the End of Treatment | ||||||||||||
End point description |
AF episodes were derived from continuous pacemaker monitoring. Per Protocol population included all subjects who were randomised and received at least 5 doses of ISIS 329993 and who did not have any clinically significant protocol deviations. Measurements were only compared from baseline and active treatment period.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1) to End of Treatment (Day 29 for 3 subjects and Day 57 for 4 subjects)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change from Baseline in Average Duration of AF Per Episode to the End of Treatment | ||||||||||||
End point description |
The duration of AF episodes was derived from continuous pacemaker monitoring. The negative value indicated the decrease in the average duration of AF per episode. Per Protocol population included all subjects who were randomised and received at least 5 doses of ISIS 329993 and who did not have any clinically significant protocol deviations. Measurements were only compared from baseline and active treatment period.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1) to End of Treatment (Day 29 for 3 subjects and Day 57 for 4 subjects)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change from Baseline in Average Sinus Rhythm Duration to the End of Treatment | ||||||||||||
End point description |
Sinus rhythm duration was derived from continuous pacemaker monitoring. Per Protocol population included all subjects who were randomised and received at least 5 doses of ISIS 329993 and who did not have any clinically significant protocol deviations. Measurements were only compared from baseline and active treatment period.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1) to End of Treatment (Day 29 for 3 subjects and Day 57 for 4 subjects)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change from Baseline in Atrial and Ventricular Rate During AF episodes to the End of Treatment | ||||||||||||||||
End point description |
The atrial and ventricular rate during AF episodes were derived from continuous pacemaker monitoring. Per Protocol population included all subjects who were randomised and received at least 5 doses of ISIS 329993 and who did not have any clinically significant protocol deviations. Measurements were only compared from baseline and active treatment period.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1) to End of Treatment (Day 29 for 3 subjects and Day 57 for 4 subjects)
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Change from Baseline in Ventricular Rate During Sinus Rhythm to the End of Treatment | ||||||||||||
End point description |
Ventricular rate during sinus rhythm was derived from continuous pacemaker monitoring. Per Protocol population included all subjects who were randomised and received at least 5 doses of ISIS 329993 and who did not have any clinically significant protocol deviations. Measurements were only compared from baseline and active treatment period.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1) to End of Treatment (Day 29 for 3 subjects and Day 57 for 4 subjects)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change from Baseline in Measures of Health-Related Quality of Life as Assessed by Short-form (SF) 36 to the End of Treatment | ||||||||||||||||
End point description |
SF-36 investigates the standard of quality of life (QOL) through a general health assessment. It is a 36-item questionnaire measuring 8 domains (bodily pain [BP], general health [GH], mental health [MH], physical functioning [PF], role emotional [RE], role physical [RP], social functioning [SF], vitality [VT]). Two summary scale scores were computed based on weighted combinations of the 8 domain scores: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). Each domain score ranges from 0 (worst) to 100 (best), with higher scores reflecting better health-related functional status. Per Protocol population included all subjects who were randomised and received at least 5 doses of ISIS 329993 and who did not have any clinically significant protocol deviations. Measurements were only compared from baseline and active treatment period.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1) to End of Treatment (Day 29 for 3 subjects and Day 57 for 4 subjects)
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Change from Baseline in Measures of Health-Related Quality of Life as Assessed by Visual Analogue Scale (VAS) to the End of Treatment | ||||||||||||
End point description |
VAS QOL measurements were composed of 3 questions regarding overall health, daily activities, and mood. Per Protocol population included all subjects who were randomised and received at least 5 doses of ISIS 329993 and who did not have any clinically significant protocol deviations. Measurements were only compared from baseline and active treatment period.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1) to End of Treatment (Day 29 for 3 subjects and Day 57 for 4 subjects)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Health-Related Quality of Life as Assessed by European Heart Rhythm Association (EHRA) Grade to the End of Treatment | ||||||||||||||||||||||
End point description |
EHRA scores represented the severity of symptoms. The four levels reported were No symptoms (NS), Mild symptoms (MS), Severe symptoms (SS), Disabling symptoms (DS). Per Protocol population included all subjects who were randomised and received at least 5 doses of ISIS 329993 and who did not have any clinically significant protocol deviations. Measurements were only compared from baseline and active treatment period.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1) to End of Treatment (Day 29 for 3 subjects and Day 57 for 4 subjects)
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Change from Baseline in Measures of Health-Related Quality of Life as Assessed by Atrial Fibrillation Severity Score (AFSS) Questionnaire to the End of Treatment | ||||||||
End point description |
0 indicates that the summary was not calculated and the data is no longer available to generate. Measurements were only compared from baseline and active treatment period.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1) to End of Treatment (Day 29 for 3 subjects and Day 57 for 4 subjects)
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| No statistical analyses for this end point | |||||||||
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End point title |
Change from Baseline in High Sensitivity C-reactive Protein (hsCRP) in Subjects with Paroxysmal AF to the End of Treatment | ||||||||||||
End point description |
A negative sign indicated a reduction in hsCRP level. Per Protocol population included all subjects who were randomised and received at least 5 doses of ISIS 329993 and who did not have any clinically significant protocol deviations. Measurements were only compared from baseline and active treatment period.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1) to End of Treatment (Day 29 for 3 subjects and Day 57 for 4 subjects)
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Baseline (Day 1) to end of follow-up period (Day 113)
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Data from the placebo period (Study Days 1, 3, 5, 8, 15 and 22 for subjects who received placebo, SC in Treatment Period 1 and Study Days 29, 31, 33, 36, 43 and 50 for subjects who received placebo, SC in Treatment Period 2) are reported for this group, | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
ISIS 329993 400 mg
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Reporting group description |
Data from the ISIS 329993 400 mg, SC in the treatment period (Study Days 1, 3, 5, 8, 15 and 22 for subjects who received ISIS 329993 400 mg, SC in Treatment Period 1 and Study Days 29, 31, 33, 36, 43 and 50 for subjects who received ISIS 329993 400 mg, SC in Treatment period 2) are reported for this group. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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27 Apr 2012 |
Clarification provided for the use of concomitant medication whereby warfarin is the only anticoagulant permitted for use on study. |
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30 May 2012 |
Since plasma hsCRP levels may be elevated as a consequence of infection Exclusion Criterion 3 was amended to state that subjects with an active infection should complete systemic antiviral or antimicrobial treatment prior to the Screening Period. |
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13 Jul 2012 |
The rule for early crossover was changed to include any intolerable symptoms rather than just intolerable symptoms as a consequence of their AF. |
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17 Dec 2012 |
Direct thrombin antagonist dabigatran (PradaxaTM) was added to the list of allowed therapeutic anticoagulant medications and to Inclusion Criterion 8. Additional safety stopping rules for bleeding were added to the safety monitoring rules. |
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02 May 2013 |
Inclusion Criterion 8 was modified to clarify that the requirement for being on a stable dose of anticoagulant for ≥3 months was only applicable to subjects who received dabigatran and that the ≥3-month period of stable dosing for dabigatran was relative to Study Day 1. Since smoking increases CRP and impairs endothelial function, carbon monoxide breath testing throughout the duration of the study was added to the required study procedures for subjects that had been abstinent from smoking for ≤6 months prior to screening. Modified the wording of Inclusion Criteria 4 and 5, and Exclusion Criteria 2b, 6, 11, 18, and 24.
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16 Oct 2013 |
The maximum number of subjects enrolled was reduced from 20 to 25 subjects to 10 subjects because the target treatment effect had been increased from 35% to 50% reduction in AF burden. The interim safety analysis, which was to be performed after 10 subjects had completed the treatment period, was removed since the number of subjects required in the study had been reduced to 10 subjects. Inclusion Criterion 9, hsCRP ≥2 mg/L and ≤10 mg/L at Screening, was removed since there is no specific threshold for hsCRP at which subjects are deemed to be at increased risk for higher AF burden. Exclusion Criterion 24 was removed since there is no strong association between current smoking status and AF burden. |
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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 | |||
