Primary:- To compare the efficacy of AGN-151607 with placebo to prevent post-operative atrial fibrillation (POAF) in participants who are undergoing open chest cardiac surgerySecondary:- To compare the efficacy of AGN-151607 with placebo to reduce…
ID
Source
Brief title
Condition
- Heart failures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Percentage of participants with at least 1 continuous atrial fibrillation (AF)
episode >= 30 seconds during the first 30 days post surgery
Secondary outcome
- Percentage of time spent in AF (AF burden) during the first 30 days post
surgery
- Percentage of participants with at least 1 event of symptomatic AF during the
first 30 days post surgery
- Time to first occurrence of AF during the first 30 days post surgery
- Percentage of participants with at least 1 continuous AF episode >= 2 minutes
during the first 30 days post-surgery
- Percentage of participants with at least 1 continuous AF episode >= 5 minutes
during the first 30 days post-surgery
- Percentage of participants with at least 1 continuous AF episode >= 30 minutes
during the first 30 days post-surgery
- Percentage of participants with at least 1 continuous AF episode >= 1 hour
during the first 30 days post surgery
- Percentage of participants with at least 1 continuous AF episode >= 4 hours
during the first 30 days post surgery
- Percentage of participants with at least 1 continuous AF episode >= 24 hours
during the first 30 days post surgery
Safety:
- Adverse events (AEs), physical examination, clinical laboratory tests, vital
signs, electrocardiogram (ECGs), pulmonary function
- Potential immunogenicity response
Background summary
Post-Operative Atrial Fibrillation (POAF) is a serious condition, associated
with: recurrent AF, longer hospital stays (including in intensive-care
settings), increased healthcare costs (in-hospital and post-discharge), higher
risk of stroke, and increased mortality; all of which reflect an increased
clinical burden due to POAF, including the need for medical/procedural
interventions.
Current standard-of-care therapies have been unable to successfully prevent
POAF in cardiac surgery patients and most conventional therapies are applicable
only after AF occurs. Thus, there is an unmet need in this patient population
to prevent the occurrence of POAF. Non-clinical studies have demonstrated that
injections of botulinum toxin type A into discrete regions of the heart can
prevent AF and 2 clinical studies have demonstrated that botulinum toxin type A
injections can prevent POAF with no noted safety issues.
This Phase 2, placebo-controlled study will evaluate the efficacy and safety of
one time injections of AGN 151607-125U (25U per fat pad) and 250U (50U per fat
pad) distributed across each of the 5 major epicardial fat pads for the
prevention of POAF in participants undergoing open-chest cardiac surgery.
Injections will be administered during the open-chest cardiac surgery. Primary
and secondary efficacy will be assessed for 30 days post-surgery; participants
will be followed for additional efficacy and safety through Day 367 post
surgery.
The AE profile of AGN-151607 has not yet been fully characterized in humans.
However, extensive safety data are available from clinical studies and
post-marketing experience with BOTOX. BOTOX experience is considered relevant
to the current program, having a similar dose range and other similarities with
AGN-151607, as outlined in the Investigators Brochure.
Study objective
Primary:
- To compare the efficacy of AGN-151607 with placebo to prevent post-operative
atrial fibrillation (POAF) in participants who are undergoing open chest
cardiac surgery
Secondary:
- To compare the efficacy of AGN-151607 with placebo to reduce AF burden in
participants who are undergoing open-chest cardiac surgery
- To compare the efficacy of AGN-151607 with placebo to prevent POAF using
alternative definitions for AF in participants who are undergoing open-chest
cardiac surgery
Safety:
- To compare the safety of AGN-151607 with placebo in participants undergoing
open-chest cardiac surgery
Study design
This is a multi-center, randomized, double-blind, placebo-controlled, parallel
group, dose ranging study to evaluate the efficacy and safety of botulinum
toxin type A (AGN-151607) injections into the epicardial fat pads, foci of
ganglionic plexi, to prevent POAF in patients undergoing open-chest cardiac
surgery.
Intervention
One-time injections of AGN-151607 or Placeboduring scheduled cardiac surgery.
There are three study arms:
- 125 E (25 E per fat pad)
- 250 E (50 E per fat pad)
- Placebo
Study burden and risks
Subjects are asked to undergo procedures described on pages 10 - 12 of the
study protocol. These procedures include physical examination, blood draw,
vital signs, measurement of weight and abdominal circumference, ECG, pulmonary
function test, completion of questionnaires, answer questions of investigator
and study team and administration of study drug (during planned heart surgery).
Additionally, fertile subjects are asked to use contraceptives, and female
subjects of childbearing potential will have pregnancy tests.
The study medication as well performing the study-related procedures may cause
discomforts and risks. The risks associated with AGN-151607 are not well known.
However, the risks associated with BOTOX (another botulinum toxin type A) are
well known and subjects may experience them after receiving AGN-151607. Side
effects and discomfort that have been observed with other botulinum toxin type
A (treatments similar to AGN-151607) when used to treat other diseases (i.e.,
not prevention of post-operative atrial fibrillation) include the following:
Shortness of breath; respiratory depression and/or respiratory failure;
breathing of food, saliva, liquids or vomit into the lungs; slurred or slow
speech; hoarse voice; dry mouth, dry eye, blurred vision, visual disturbance,
cross eyed, abdominal pain, diarrhea, nausea, vomiting, fever, loss of
appetite, partial loss of hearing, ringing in the ear, sensation of feeling off
balance, weakness of the facial muscles, loss of facial movement, pins and
needles, weakness, numbness and pain (usually in hands and feet), lack of
movement and lack of feeling in the arm and shoulder, pinched nerve, painting,
reduced sense of touch, general feeling of discomfort, illness or uneasiness
(malaise); general bodily weakness or discomfort, weakness in the skeletal
muscles, which are responsible for breathing and moving parts of the body,
including the arms and leg; rash, rash that appears as red, target-shaped
("bulls-eye") patches; itching, itchy, red and inflamed skin rash; excessive
sweating, hair loss including in the eyebrows and eyelashes.
For botulinum toxin type A such as BOTOX, serious and/or immediate
intolerance(hypersensitivity reactions such as anaphylaxis and serum sickness)
have been reported, as well as other manifestations of intolerance
(hypersensitivity) including hives (urticaria), soft tissue swelling (edema),
and shortness of breath (dyspnea).
People with certain muscle-weakening neurological conditions (such as Lou
Gehrig*s disease/amyotrophic lateral sclerosis, myasthenia gravis,
Lambert-Eaton syndrome, or motor neuropathy) or unrecognized neurological
conditions (neuromuscular junction disorders) can be extra-sensitive to the
effects of botulinum toxin and could develop problems such as severe difficulty
swallowing or breathing. In some cases, these problems may last for several
months and feeding tubes may be required.
Side effects have been reported hours to weeks after dosing with drugs in the
botulinum toxin class, which includes BOTOX. Spread of the study drug away from
the injection site may cause effects in other areas of the body, including:
muscle weakness, eyelid drooping (ptosis), double vision (diplopia), blurred
vision, facial weakness, difficulty swallowing (dysphagia), speech disorders,
constipation, pneumonia, difficulty breathing and slow and ineffective
breathing (respiratory depression).
Swallowing and breathing difficulties can be life-threatening, and death has
been reported. It is not known if botulinum toxin type A actually caused these
problems.
There have also been reports of heart problems (including abnormal heart rhythm
and heart attack, some leading to death) after injection with botulinum toxin
type A. However, it is not known if botulinum toxin type A actually caused
these problems; some of these people were already at risk for heart disease.
New onset or recurrent seizures have been reported, typically in people who are
predisposed to experiencing these events. It is not known if botulinum toxin
type A actually caused the seizures.
Risks of study procedures:
Epicardial Fat Pad Injection: There is a risk that the injection of the study
treatment in the surrounding structures of the heart (the epicardial fat pads)
result in piercing of the epicardium or bleeding. This may lead to surgical
complications.
Blood samples: Taking blood may cause faintness and/or swelling, pain, redness,
bruising, bleeding at the collection site, or infection (infection rarely
happens) at the site where the needle is inserted.
Electrocardiogram (ECG): Skin irritation is rare but could occur during an ECG
from the electrode patches or gel that is used.
Self-Adhesive Patch Risk: Subjects may experience an allergic reaction to the
adhesive used on the patch (the patch adhesive is hydrogel). This may result in
local irritation and skin redness.
Pulmonary Function Tests Risks: This involves some breathing and rapid
breathing, which may cause temporary shortness of breath and lightheadedness or
transient pain in the upper chest right after the tests.
Washout Risks: If subjects are taking antiarrhythmic medications (medications
to treat pre-existing abnormalities of the heart rhythm - also known as Atrial
Fibrillation), they may be asked to stop some or all of these medications
before the study treatment injection. During this time, the symptoms of any
pre-existing AF may get worse.
This Phase 2, placebo-controlled study will evaluate the efficacy and safety of
one time injections of AGN 151607-125U (25U per fat pad) and 250U (50U per fat
pad) distributed across each of the 5 major epicardial fat pads for the
prevention of POAF in participants undergoing open-chest cardiac surgery.
Injections will be administered during the open-chest cardiac surgery. Primary
and secondary efficacy will be assessed for 30 days post-surgery; participants
will be followed for additional efficacy and safety through Day 367 post
surgery.
The AE profile of AGN-151607 has not yet been fully characterized in humans.
However, extensive safety data are available from clinical studies and
post-marketing experience with BOTOX. BOTOX experience is considered relevant
to the current program, having a similar
dose range and other similarities with AGN-151607.
Marlow International, Parkway 1st floor
Marlow, Buckinghamshire SL7 1YL
GB
Marlow International, Parkway 1st floor
Marlow, Buckinghamshire SL7 1YL
GB
Listed location countries
Age
Inclusion criteria
1.01- Participants must be 55 to 90 years of age, inclusive, at the time of
signing the informed consent.
2.01- Participants who are scheduled to undergo open-chest cardiac surgery.
Includes: coronary artery bypass graft (CABG) and/or valve repair/replacement.
3.01- Male or female
4.01- Male participants willing to minimize the risk of inducing pregnancy up
to Day 60.
A male participant must agree to use contraception as detailed in Appendix 7,
Section 10.7 of this protocol until Day 60 and refrain from donating sperm
during this period.
4.02- Female participants willing to minimize the risk of inducing pregnancy up
to Day 60.
A female participant is eligible to participate if she is not pregnant (has a
negative urine pregnancy result prior to randomization) not breastfeeding, and
at least 1 of the following conditions applies:
a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 7,
Section 10.7
• OR
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 7,
Section 10.7 of this protocol until after Day 60.
5.01- Capable of giving signed informed consent as described in Appendix 1,
Section 10.1, which includes compliance with the requirements and restrictions
listed in the informed consent form (ICF) and in this protocol.
5.02- Written informed consent from the participant has been obtained prior to
any study related procedures.
5.03- Written documentation has been obtained in accordance with the relevant
country and local privacy requirements, where applicable (eg, Written
Authorization for Use and Release of Health and Research Study Information [US
sites] and written Data Protection consent (European Union [EU] sites).
6.01- In sinus rhythm for the last 48 hours prior to surgery (prior history of
paroxysmal atrial fibrillation (AF) is acceptable).
6.02- Willing to wear an electrocardiogram (ECG) patch for 30 days post-surgery
and for 7 days after each study visit
6.03- Able, as assessed by the investigator, and willing to follow study
instructions and likely to complete required study visit.
Exclusion criteria
1.01- Any uncontrolled clinically significant medical condition other than the
one under study that, in the investigator*s opinion, would put the participant
at an unacceptable risk with exposure to botulinum toxin type A.
1.02- Any medical condition that may put the participant at increased risk with
exposure to botulinum toxin type A, including diagnosed muscular dystrophy (eg,
Duchenne*s muscular dystrophy), myasthenia gravis, Eaton-Lambert syndrome,
amyotrophic lateral sclerosis, mitochondrial disease, or any other significant
disease which might interfere with neuromuscular function.
1.03- Participants with presence or history of any of the following within 3
months prior to the Day 1 visit that may indicate a vulnerable respiratory
state per the investigator*s clinical judgment: aspiration pneumonia, lower
respiratory tract infections, uncontrolled asthma, severe chronic obstructive
pulmonary disease, or otherwise compromised respiratory function.
1.04- Permanent/persistent atrial fibrillation (AF)
1.05- Has a known allergy or sensitivity to any botulinum toxin type A
preparation.
1.06- Has a known allergy or sensitivity to medical adhesive (eg, ECG patch
adhesive; hydrogel-based adhesive).
1.07- Severe (> 55mm) atrial enlargement
1.08- Left ventricular ejection fraction (LVEF) < 25%
1.09- Presence or history of symptomatic atrioventricular block > 1st degree
within the last 30 days
2.01- Class I or III antiarrhythmic drugs unless proper washout was documented
(Section 6.5.1)
2.02- Botulinum toxin type A (of any serotype) use within 6 months of
randomization
2.03- Has been immunized for any botulinum toxin type A serotype as determined
by participant medical history
2.04- Preoperative need for inotropes/vasopressors or intra-aortic balloon pump
2.05- Prior cardiac surgery
2.06- History of ablation for AF
2.07- Planned ablation procedure for AF at the time of surgery
2.08- Emergency surgery
3.01- Current enrollment in an investigational drug or device study or
participation in such a study within 30 days of entry into this study
4.01- Participants have diagnostic assessments which in the opinion of the
investigator prevent participation in the study.
4.02- Impaired prognosis defined as EuroSCORE II greater than 7% perioperative
mortality
5.01- Females who are pregnant, nursing, or planning a pregnancy during the
study
5.02- The participant has a condition or is in a situation which, in the
investigator*s opinion, may put the participant at significant risk, may
confound the study results, or may interfere significantly with the
participant*s participation in the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | 135000 |
| EudraCT | EUCTR2017-004399-68-NL |
| CCMO | NL67919.018.19 |