ADRESS : Efficacy of the Alpha 2 agonist dexmedetomidine for sympathetic Deactivation in REfractory Septic Shock: a randomized, controlled trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hospices Civils De Lyon

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Not possible to specify

Decision date (initial)

2026-04-24

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

DGOS

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

Evaluate the impact of dexmedetomidine (DEX) as an adjunctive treatment for refractory septic shock on 30-day mortality in mechanically ventilated patients compared to standard care.

Secondary objectives 15

1. Evaluate the effect of dexmedetomidine (DEX) as an adjunctive treatment in addition to standard care in patients with septic shock resistant to vasopressors, compared to standard care, on 72-hour mortality.
2. Evaluate the effect of dexmedetomidine (DEX) as an adjunctive treatment in addition to standard care in patients with septic shock resistant to vasopressors, compared to standard care, on vasopressor doses during the first hours (6h, 12h, 24h) following randomization.
3. Evaluate the effect of dexmedetomidine (DEX) as an adjunctive treatment in addition to standard care in patients with septic shock resistant to vasopressors, compared to standard care, on the rate of use of rescue therapies.
4. Evaluate the effect of dexmedetomidine (DEX) as an adjunctive treatment in addition to standard care in patients with septic shock resistant to vasopressors, compared to standard care, on blood pressure changes during the first 24 hours following randomization.
5. Evaluate the effect of dexmedetomidine (DEX) as an adjunctive treatment in addition to standard care in patients with septic shock resistant to vasopressors, compared to standard care, on the duration of vasopressor dependence during the first 30 days following randomization.
6. Evaluate the effect of dexmedetomidine (DEX) as an adjunctive treatment in addition to standard care in patients with septic shock resistant to vasopressors, compared to standard care, on the duration of mechanical ventilation during the first 30 days following randomization.
7. Evaluate the effect of dexmedetomidine (DEX) as an adjunctive treatment in addition to standard care in patients with septic shock resistant to vasopressors, compared to standard care, on lactate clearance during the first hours (6h, 12h, 24h).
8. Evaluate the effect of dexmedetomidine (DEX) as an adjunctive treatment in addition to standard care in patients with septic shock resistant to vasopressors, compared to standard care, on the evolution of the SOFA score (Sepsis-related Organ Failure Assessment) 3 days after randomization.
9. Evaluate the effect of dexmedetomidine (DEX) as an adjunctive treatment in addition to standard care in patients with septic shock resistant to vasopressors, compared to standard care, on the evolution of daily fluid balance and the volume of resuscitation fluids during the first 5 days (Day 0 to Day 4) following randomization.
10. Evaluate the effect of dexmedetomidine (DEX) as an adjunctive treatment in addition to standard care in patients with septic shock resistant to vasopressors, compared to standard care, on the occurrence of new-onset or persistent atrial fibrillation within 14 days following randomization.
11. Evaluate the effect of dexmedetomidine (DEX) as an adjunctive treatment in addition to standard care in patients with septic shock resistant to vasopressors, compared to standard care, on ICU mortality and 90-day mortality.
12. Assess the tolerability of dexmedetomidine in this population based on the occurrence of bradycardia during the treatment period (including in case of treatment resumption).
13. Assess the tolerability of dexmedetomidine in this population regarding delayed awakening.
14. Assess the tolerability of dexmedetomidine in this population regarding the incidence of ICU delirium.
15. Ancillary study: Determine the impact of dexmedetomidine on sympathetic activity and the renin-angiotensin-aldosterone axis.

Conditions and MedDRA coding

Septic shock

Study design 1 period

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Age ≥ 18 years.
2. Septic shock, defined according to the ‘Sepsis-3’ criteria: Proven or suspected infection, with a SOFA score increase of ≥2 points ; Persistent hypotension requiring vasopressors to maintain a MAP >65 mmHg ; And a serum lactate level >2 mmol/L despite adequate fluid resuscitation.
3. Catecholamine resistance, defined as: The need for an equivalent dose of norepinephrine tartrate ≥0.5 µg/kg/min (according to the NEE vasopressor score, accounting for any concomitant administration of vasopressin, for example) for more than 2 consecutive hours AND Persistent circulatory failure with at least one of the following criteria present within the 2 hours preceding randomization: Hyperlactatemia >2 mmol/L And/or mottling (score ≥1) And/or oliguria (urine output <0.5 ml/kg/h over the last 2 hours).
4. Adequate fluid resuscitation: ≥30 ml/kg OR absence of preload dependence criteria (e.g., passive leg raise, pulse pressure variation).
5. Patient under invasive mechanical ventilation.
6. Patient affiliated with a social security scheme or equivalent.
7. Written consent obtained from the patient (or from the trusted person, family member, or relative if the patient is unable to sign/express consent), or emergency inclusion if the patient is unable to provide consent and neither the trusted person nor any family member or relative is present at the time of inclusion. In the context of refractory shock, the proposed therapeutic intervention cannot be delayed by more than one hour.
8. Continuation consent obtained from the patient as soon as they are able to provide consent (in cases where consent was initially signed by the trusted person, a family member, or a relative at inclusion) and, in the case of emergency inclusion: continuation consent from the relative obtained as soon as possible (if the trusted person, a family member, or a relative arrives at the hospital while the patient is still unable to consent).

Exclusion criteria 12

1. Cardiac index <2.2 L/min/m² after volume correction
2. Patient participating in another study with an ongoing exclusion period at inclusion
3. Pregnant woman (β-HCG ≥5 IU/L) or breastfeeding
4. Bradycardia <55 bpm (excluding treatment with β-blockers) or second- or third-degree AV block without pacing
5. Moribund patient or those for whom death appears imminent within 24 hours (according to investigator judgment)
6. Acute hepatocellular failure with PT and Factor V <50% in the absence of DIC (disseminated intravascular coagulation)
7. Contraindications to dexmedetomidine: Known hypersensitivity to dexmedetomidine or to any of its excipients, advanced heart block (grade 2 or 3) unless a pacemaker is present, uncontrolled hypotension, acute cerebrovascular conditions.
8. Patient receiving dexmedetomidine prior to randomization
9. Patient treated with iproniazid within 15 days prior to randomization
10. Patient for whom a decision to limit or withdraw life-sustaining treatments has been made
11. Patient under legal protection (guardianship or curatorship) or judicial safeguard
12. Contraindications to any of the adjunct medications — norepinephrine, midazolam, propofol, and hydrocortisone — according to their respective SmPCs.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Vital status at 30 days after randomization (Day 30).

Secondary endpoints 15

1. Efficacy criteria: Vital status at 72 hours after randomization.
2. Efficacy criteria: Cumulative dose and peak of vasopressors in norepinephrine equivalent (NEE score, Kotani et al. 2023) at 6h, 12h, and 24h after randomization.
3. Efficacy criteria: Rate of use of vasopressin (VP) or other rescue therapies during the 30 days following randomization (Day 0 → Day 30).
4. Efficacy criteria: Evolution of mean arterial pressure (MAP) and MAP/Neq ratio (Neq = norepinephrine equivalent) within the first 24 hours after randomization (H0, H+6, H+12, H+24).
5. Efficacy criteria: Number of vasopressor-free days during the 30 days following randomization (Day 0 → Day 30).
6. Efficacy criteria: Number of mechanical ventilation–free days during the 30 days following randomization (Day 0 → Day 30).
7. Efficacy Criteria: Lactate level at randomization, then at H+6, H+12, and H+24.
8. Efficacy Criteria: SOFA score at Day 0 and Day 3 after randomization.
9. Efficacy Criteria: Difference between total fluid intake (including IV infusions, enteral nutrition, blood products, flushes, and diluents) and total fluid losses (including urine output, drain outputs, and gastric tube losses) over 6 days (from Day 0 to Day 5).
10. Efficacy Criteria: Occurrence of new-onset or persistent atrial fibrillation within 14 days following randomization.
11. Efficacy Criteria: Vital status at ICU discharge and at 90 days after randomization.
12. Tolerance Criteria: Occurrence of bradycardia during the treatment period: heart rate (HR) < 50 bpm requiring therapeutic intervention (discontinuation of dexmedetomidine due to bradycardia, administration of atropine, adrenaline, isoprenaline, or external electrical pacing).
13. Tolerance Criteria: Number of coma-free days at Day 30 (or at ICU discharge if discharged before Day 30), defined as the number of days with a RASS score ≥ -3.
14. Tolerance Criteria: Occurrence of ICU delirium during the stay, screened daily using the CAM-ICU score (Appendix 2) until Day 30 (or ICU discharge if discharged before Day 30) in patients with a RASS score (Appendix 2) ≥ -3.
15. Ancillary Study Criteria: Serum electrolyte panel (Na⁺, K⁺, Cl⁻) at H0 (randomization), H+12, H+24, H+48, and Day 5; plasma measurements of endogenous catecholamines and plasma assays of the renin–angiotensin system (angiotensin I and II, aldosterone) at H0 (randomization), H+12, H+48, and Day 5. Urinary electrolyte panel (Na⁺, K⁺, Cl⁻) and urinary measurements of endogenous catecholamines and the renin–angiotensin system (angiotensin I and II, aldosterone) at H+24.

Investigational products

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

Test 1

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hospices Civils De Lyon

Sponsor organisation

Hospices Civils De Lyon

Address

3 Quai Des Celestins, Bp 2251 Bp 2251

City

Lyon Cedex 02

Postcode

69229

Country

France

Scientific contact point

Organisation

Hospices Civils De Lyon

Contact name

Dr Auguste DARGENT

Public contact point

Organisation

Hospices Civils De Lyon

Contact name

Dr Auguste DARGENT

Locations

1 EU/EEA country · 18 investigational sites

By country

Investigational sites

Results and documents

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

Documents 11 files

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

Application history

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