A multicenter, prospective, randomized, placebo-controlled, double-blind, multi-arm, multi-stage clinical trial of Ivabradine for heart Rate control In Septic shock [IRISS]

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Virus Diseases [C02], Diseases [C] - Bacterial Infections and Mycoses [C01], Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutics [E02]

Trial duration

26 Feb 2021 → ongoing

Decision date (initial)

2024-12-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-515019-22-00

EudraCT number

2018-003801-24

ClinicalTrials.gov

NCT04031573

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

The primary objective is to assess the efficacy of ivabradine in controlling heart rate and improving 28-day survival in patients with septic shock. These objectives will be assessed via a two-stage trial: activity (focused on heart rate control) and efficacy (focused on mortality).

Conditions and MedDRA coding

Septic shock

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. 18 years of age or older
2. Proven or suspected site of infection
3. Proven or suspected site of infection, - Septic shock (defined as hypotension unresponsive to fluid resuscitation and requiring vasopressor treatment to maintain adequate blood pressure in the context of proven or suspected site of infection) for at least 2 hours and less than 24 hours (inclusion is possible before 2 hours in case of increasing doses of norepinephrine)
4. In sinus rhythm with heart rate ≥ 95 bpm at time of randomization
5. Informed consent obtained in accordance with local regulations
6. Affiliation to a social security regime

Exclusion criteria 17

1. Cardiac arythmia, conduction disorder, sinus syndrome ("sick sinus syndrome"), sino-atrial block; 3rd degree atrioventricular block
2. Cardiogenic shock or unstable or acute heart failure without proven or suspected infection
3. Acute myocardial infarction with angiographic documentation; CCS class ≥ II angina pectoris;
4. Septic shock requiring vasopressor treatment for more than 24 hours
5. Refractory shock with systolic arterial pressure <90 mm Hg) despite the use of high doses of vasopressors (norepinephrine BASE or epinephrine BASE > 2.4 µg/kg/min; these doses should be multiplied by two for noradrenaline salt (tartrate or bitartrate)
6. Co-treatment with drugs inducing bradycardia, QT lengthening or strong inhibition of CYP4503A4, pacemaker, defibrillator, kalemia <3 mM
7. Co-treatment with verapamil or diltiazem (which are moderate CYP4503A4 inhibitors with heart rate reducing properties)
8. Known pregnancy, breast feeding, women with childbearing potential will be tested for pregnancy and excluded if pregnant
9. Known allergy to ivabradine or to any of the excipients, retinitis pigmentosa, congenital galactosemia, lactase deficiency, glucose or galactose malabsorption
10. Severe chronic renal failure (creatinine clearance <15 ml/min) or hepatic failure (prothrombin time <20%)
11. Enteral feeding impossible, vomiting, congenital galactosemia, lactase deficiency, glucose-galactose malabsorption syndrome
12. Tachycardia due to hyperthyroidism, pheochromocytoma or severe anemia (<7 g/dL)
13. Prior enrolment in the trial, participation in another interventional study on septic shock
14. Known legal incapacity (patients under guardianship or curatorship)
15. Decision to limit full care taken before obtaining informed consent
16. Patient under AME (state emergency medical help)
17. Lack of affiliation to social security

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. There are 2 primary endpoints: i) for treatment selection at interim analysis: the percentage of patients with heart rate within the predefined threshold (80-94 bpm) at hour-48; in case of similar percentages, the percentage of time elapsed within the threshold between inclusion and hour-48 will be considered ii) for the final analysis: 28-day mortality.

Secondary endpoints 3

1. Determine the tolerance of ivabradine
2. Evaluate the impact of ivabradine-driven heart rate control on systemic hemodynamics, myocardial stress, organ dysfunction, morbidity, and intensive care mortality
3. Determine the pharmacokinetics of ivabradine

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr Armand MEKONTSO DESSAP

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Sophie THEVENIN

Locations

1 EU/EEA country · 28 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications