E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
Atrial fibrillation (AF): a common and distressing cardiac arrhythmia. |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10003658 |
E.1.2 | Term | Atrial fibrillation |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate whether treatment with ISIS 329993 can reduce AF (Atrial Fibrillation) burden (percentage of time spent in AF as derived from continuous pacemaker monitoring) in subjects with paroxysmal AF |
|
E.2.2 | Secondary objectives of the trial |
1. To assess the effect of ISIS 329993 on the total number of AF (Atrial Fibrillation) episodes, average duration of AF per episode, average sinus rhythm duration, and atrial and ventricular rate during AF episodes derived from continuous pacemaker monitoring.
2. To assess the effect of ISIS 329993 on ventricular rate during sinus rhythm derived from continuous pacemaker monitoring.
3. To assess the effect of ISIS 329993 on PR, QRS, QT and QTc intervals derived from 12-lead ECG during periods of sinus rhythm.
4. To assess the effect of ISIS 329993 on measures of Quality of Life as assessed by SF 36, VAS, EHRA grade and AFSS questionnaires.
5. To assess whether treatment with ISIS 329993 reduces hsCRP in subjects with paroxysmal AF.
6. To assess the safety, tolerability, and pharmacokinetics (PK) of ISIS 329993 in subjects with paroxysmal AF.
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements
2. Males or females aged over 18 years old at the time of informed consent
3. Satisfy the following: a. Females: Non-pregnant and non-lactating; surgically sterile, post-menopausal, abstinent, or if engaged in sexual relations of child-bearing potential, subject is using an acceptable contraceptive method (refer to Section 6.3.1) from the time that the participant informed consent document is signed until 60 days after the last dose of Study Drug b. Males: Surgically sterile, abstinent or if engaged in sexual relations of child-bearing potential, subject is utilizing an acceptable contraceptive method (refer to Section 6.3.1) from the time that the participant informed consent document is signed until 60 days after the last dose of Study Drug
4. Dual chamber permanent pacemaker implanted at least 3 months prior to screening
5. Confirmed diagnosis of paroxysmal atrial fibrillation with an AF burden of 1 to 50% at screening, as derived from pacemaker diagnostic algorithms
6. Able to have pacemaker antiarrhythmic algorithms turned off for the duration of the study
7. Able to discontinue all Class I and III antiarrhythmic medication for the duration of the study
8. Therapeutically anticoagulated with Warfarin, and anticipated to be anticoagulated with Warfarin for the duration of the study
9. High sensitivity C-Reactive Protein (hsCRP) ≥2 mg/L and ≤10 mg/L at screening (2 measurements taken at least 1 week apart) unless pre-approved by Sponsor |
|
E.4 | Principal exclusion criteria |
1. Clinically significant abnormalities in medical history (e.g., acute coronary syndrome within six months of screening, major surgery within three months of screening) or physical examination
2. Screening laboratory results as follows, or any other clinically significant abnormalities in screening laboratory values that would render a subject unsuitable for inclusion: a) Renal Function: •Urine protein or blood persistently positive by dipstick •Estimated creatinine clearance calculated according to the formula of Cockcroft and Gault <60 mL/min b) Liver Function: •ALT or AST >1.5 x ULN •Total bilirubin >ULN c) Hematology: •Platelet count <LLN •Hemoglobin <10 mg/dL •Thyroid function tests indicative of hyperthyroidism
3. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1
4. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator
5. Known history of or positive test for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B
6. Malignancy within five years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated
7. NYHA class III/ IV heart failure
8. Impaired left ventricular function of less than 45% determined by echocardiography within 3 months of screening
9. Moderate or greater mitral regurgitation assessed by echocardiography within 3 months of screening
10. Permanent AF
11. Any episode of AF lasting greater than 1 week
12. Cardiac rhythm disorder other than AF
13. Endovascular intervention or cardioversion within 4 weeks prior to screening
14. Any planned major surgery, endovascular intervention or cardioversion within study period
15. Continuous Amiodarone therapy within 90 days prior to Study Day 1
16. Treatment with another Study Drug, biological agent, or device within one-month of screening, or five half-lives of study agent, whichever is longer
17. Treatment with an oligonucleotide within 9 months of screening. Subjects that have previously received only a single dose of an oligonucleotide as part of a clinical study may be included as long as a duration ≥5 half lives of the study oligonucleotide has elapsed since dosing
18. Use of systemic corticosteroids or other anti-inflammatory medications including non-steroidal anti-inflammatory drugs (NSAIDs)
19. Use of statins, ACE inhibitors or AT-receptor antagonists unless on a stable regimen for at least 3 months prior to dosing and will remain on a stable regimen for the duration of the study
20. Uncontrolled hypertension (BP >160/100)
21. History of bleeding diathesis or coagulopathy
22. Current or expected use of any anticoagulant apart from Warfarin
23. Regular use of alcohol within 6 months prior to screening (>7 drinks/week for females, >14 drinks/week for males, 1 drink= 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mLs) of hard liquor) or use of soft drugs (such as marijuana) within 3 months prior to screening or hard drugs (such as cocaine and phencyclidine [PCP]) within 1 year prior to screening, or positive urine drug screen at screening
24. Subjects must not have smoked tobacco within 6 months of screening and must be expected to not smoke for the duration of the study
25. Have any other conditions, which, in the opinion of the Investigator would make the subject unsuitable for inclusion, or could interfere with the subject participating in or completing the study |
|
E.5 End points |
E.5.1 | Primary end point(s) |
AF burden as assessed by the use of long term beat to beat pacemaker Holter monitoring |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
• Total number of AF episodes, average duration of AF per episode, average sinus rhythm duration and atrial and ventricular rate during AF episodes
• Ventricular rate during sinus rhythm
• Quality of life measures assessed by SF 36, VAS, EHRA grade and AFSS questionnaires
The effects of treatment with ISIS 329993 vs. Placebo on the following pharmacodynamic measures will be evaluated: • hsCRP and other markers of inflammation (for example erythrocyte sedimentation rate (ESR), serum amyloid A (SAA), IL-6, sTNF-R1 and –R2, fibrinogen).
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |