Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04607122 |
| Other study ID # |
2019/10 |
| Secondary ID |
2019-004829-25 |
| Status |
Completed |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
January 27, 2021 |
| Est. completion date |
July 22, 2023 |
Study information
| Verified date |
August 2023 |
| Source |
CMC Ambroise Paré |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Postoperative atrial fibrillation (POAF) is a common complication that occurs in 30-50% of
patients after cardiac surgery and increases morbidity and mortality and hospital length of
stay. During the perioperative period, the discontinuation of beta-blocker treatment is known
to be a risk factor for developing POAF in patient undergoing cardiac surgery. Early
beta-blocker reintroduction is associated with lower incidence of POAF. Unfortunately, side
effects of currently available beta-blockers (including esmolol), such as low blood pressure
and excessive bradycardia and/or their extended duration of action, limit their use in the
post-operative period especially for prevention.
Landiolol, an ultra-short acting injectable beta-blocker, offers the advantage of
significantly limiting low blood pressure events while increasing therapeutic efficacy in the
treatment of POAF in cardiac and non-cardiac surgery. Landiolol, when used at low dose in the
postoperative period, has been showed to reduce the incidence of POAF with no increased
incidence of side effect as compared to standard of care. The limitation is that these
promising data come from single center studies with limited samples and conducted exclusively
in Japanese population. If landiolol is approved for use in the treatment of atrial
fibrillation in non-Asian patients, there are no data on the prevention of POAF in cardiac
surgery.
The objective of this multicenter, double-blind, randomized, placebo- controlled phase III
trial is to confirm that landiolol postoperative infusion is associated with lower incidence
of POAF without excess of adverse events as compared to standard of care in a non-Asian
population after cardiac surgery with sternotomy.
Description:
This is a multicenter, randomized, double-blind, parallel-group controlled, Landiolol vs
Placebo (saline), phase III trial assessing the efficacy and the safety of landiolol
postoperative treatment on POAF occurrence within 7 days of surgery in patients undergoing
cardiac surgery with sternotomy.
Subjects are randomly assigned in a 1:1 ratio to receive either Landiolol or Placebo
(saline). A stratification of the randomization is planned according to the hospital and the
age of the patient (65 ≤ age ≤ 70 and age > 70).
A preventive treatment is infused during at least the first 24 hours after surgery (in ICU)
to each patient included in the study until the optimal oral betablocker dose. Continuous
infusion of landiolol at 2 µg/kg/min (1.2 ml/h, for a 60 kg patient) in Landiolol group or
continuous infusion of saline (at 1.2 ml/h for a 60 kg patient) in Placebo group is
administrated until restoration of an effective oral beta-blocker treatment.
Treatment:
Treatment is initiated after the surgery, on arrival at the ICU (Day-0) in the absence of a
contraindication. The target of continuous intravenous infusion of landiolol is 2 µg/kg/min
(1.2 ml/h for a 60 kg patient), or placebo (saline) at the same infusion rate as landiolol.
The modalities for initiating the treatment are as follows:
- No bolus is performed,
- Continuous infusion starting at the lowest dosage (1 µg/kg/min),
- Increasing in increments every 10 to 15 minutes until 2 µg/kg/min by maintaining a MAP ≥
65 mmHg and HR ≥ 50/min.
Relay with oral betablocker treatment:
The relay with oral betablocker treatment, bisoprolol (1.25 mg x 2/day) for initial
introduction (target HR < 100/min) or with the patient's preoperative beta-blocker in case of
preoperative treatment, is resumed on Day-1 if possible or as soon as possible.
The dosage of landiolol can be reduced as follows:
- Within the first hour after the first dose of the alternative medicinal product has been
administered, the infusion rate of landiolol should be reduced by one-half (e.g. from 2
to 1 µg/kg/min).
- After administration of the second dose of the alternative medicinal product (12 hours
later), the patient's response should be supervised and if satisfactory control is
maintained for a least one hour, the landiolol infusion can be discontinued.
Maximal duration of continuous intravenous treatment before oral betablocker relay is 5 days,
exclusively administrated in ICU for safety reasons.
Precautions for patient safety:
The landiolol infusion should be decreased half and progressively re-increased every 15 min
by step of 0.5 µg/kg/min and/or discontinued temporarily or permanently in case of:
- Bradycardia defined by HR < 50 /mim
- Hypotension defined by SAP < 90 mmHg or MAP < 65 mmHg
- Atrioventricular conduction treated by pacing
- Norepinephrine increase > 50% after introduction of landiolol infusion
In case of POAF event:
Patients will benefit from the usual care:
- Intravenous magnesium sulfate injection: 3 g over 1 hour
- Intravenous or per os treatment with amiodarone depending on patient's condition:
- Intravenous: IV bolus of 300 mg over 1 hour; then IV infusion pump of 150-600 mg
per day
- Per os: loading dose with 4-6 tablets of 200 mg; then 2 tablets per day during one
week
- If AF persists, cardioversion
- Anticoagulant therapy if required Treatment with landiolol or placebo is continued and
the infusion rate is adjusted if needed as described above.
Primary endpoint: Continuous monitoring of heart rate is performed in ICU and POAF event > 5
minutes and/or requiring medical treatment and/or cardioversion is recorded during the ICU
stay and reported.
