Biomarker-Guided Early Clarithromycin Treatment To Prevent Sepsis Progression In Community-Acquired Pneumonia: The REACT Randomized Clinical Trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hellenic Institute For The Study Of Sepsis

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

12 Feb 2024 → ongoing

Decision date (initial)

2024-01-31

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacoeconomic

The primary objective of the REACT RCT is to optimize the clinical benefit from adjunctive clarithromycin treatment shown in the ACCESS trial and to provide evidence for the clinical benefit of early start of adjunctive oral clarithromycin guided by suPAR to prevent the progression into sepsis in patients with CAP at risk.

Secondary objectives 1

1. The secondary objectives of REACT are to investigate the impact of early adjunctive treatment with clarithromycin on the resolution of CAP at the test-of-cure (TOC) visit.

Conditions and MedDRA coding

Community-acquired pneumonia

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Age equal to or above 18 years
2. Male or female gender
3. In case of women of reproductive age, willingness to use dual contraceptive method during the study period
4. Written informed consent provided by the patient. For subjects without decision-making capacity, informed consent must be obtained from a legally designated representative following the national legislation
5. Presence of at least two of the following signs: i) cough; ii) purulent sputum expectoration; iii) dyspnea; and/or iv) pleuritic chest pain
6. Community-acquired pneumonia (CAP)
7. PCT ≥0.25 ng/ml
8. suPAR ≥6 ng/ml

Exclusion criteria 21

1. Age below 18 years
2. Denial of written informed consent
3. Any stage IV malignancy
4. Any do not resuscitate decision
5. Patients necessitating non-invasive ventilation or mechanical ventilation
6. Hospitalization in Intensive Care Unit
7. Infection by SARS-CoV-2
8. Oral or IV intake of corticosteroids at a daily dose equal to or greater than 0.4 mg/kg prednisone for a period greater than the last 15 days
9. Intake of any macrolide for the current episode of CAP under study
10. Known infection by the human immunodeficiency virus
11. Any chronic anti-cytokine treatment for more than two months
12. QTc interval at rest in the ECG ≥500 msec or history of know long QT syndrome
13. Medical history of allergy to macrolides
14. Concomitant oral intake of astemizole, cizapride, doperidone, pimozide, terfenadine, midazolam, ranolazine, ergot alkaloids (e.g. ergotamine and dihydroergotamine), lomitapide and colchicine; patients may be enrolled in the trial if they stop these drugs during trial participation.
15. Medical history of torsades de pointes arrhythmia
16. Concomitant intake of lovostatin or simvastatin; patients may be enrolled in the trial if they stop these drugs during trial participation.
17. Concomitant presence of end-stage liver failure and end-stage renal failure.
18. Severe hypokalemia or severe hypomagnesemia; a patient may be enrolled one any of these electrolyte disturbances are restored.
19. Any contradictions for macrolide uptake
20. Pregnancy or lactation. Women of child-bearing potential will be screened by a urine pregnancy test before inclusion in the study
21. Participation in any other interventional trial

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 5

1. This is defined on day 4 and it is a composite endpoint of three conditions. Only patients meeting ALL three conditions will be considered as succeeding the primary endpoint.
2. Condition A RSS i.e. the sum of scoring for the symptoms of cough, dyspnea, purulent sputum expectoration and pleuritic chest pain on visit 4 is decreased by at least 50% from the baseline score of day 1 without the development of any new symptom
3. Condition B SOFA score on visit 4 is decreased by at least 30% from the baseline SOFA score of day 1
4. Condition C Combination of: (Plasma PCT on visit 4 has decreased by at least 80% from baseline PCT on screening or it is below 0.25 ng/ml) AND ([plasma IL-10 on visit 4 has decreased by at least 25% from IL-10 of visit 1 or it is below the lower limit of detection] or [the IL-8 to IL-10 ratio of day 4 has decreased less than 15% from the IL- 8 to IL-10 ratio of visit 1]).
5. It is explicitly stated that patients dying prior to day 4 are considered failing the primary endpoint.

Secondary endpoints 12

1. Development of new organ dysfunctions until day 28
2. Progression into sepsis
3. Clinical success at the TOC visit; this is also analyzed separately for patients infected or colonized by clarithromycin-susceptible and clarithromycin-resistant S.pneumoniae
4. Need for up-escalation of the SoC administered antibiotics. This is considered as the change of the baseline administered SoC antibiotics into more broad-spectrum antibiotics.
5. Alive hospital discharge until day 28
6. Achievement of more than 50% decrease of baseline SOFA score at EOT visit
7. Score of improvement of CAP-associated immune dysregulation (see sections of Laboratory procedures) at the EOT visit
8. Change of cytokine production by PBMCs: IL -6, IL-8, IL-10, TNFα on day 4 from visit 1.
9. Association of 28-day mortality with the score of improvement of CAP-associated immune dysregulation
10. Association of 90-day mortality with score of improvement of CAP- associated immune dysregulation
11. Cost of hospital stay
12. Comparison of 28-day mortality between screening failure patients due to SuPAR <6 ng/ml and/or PCT <0.25 ng/ml, and patients randomized to the placebo group

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hellenic Institute For The Study Of Sepsis

Sponsor organisation

Hellenic Institute For The Study Of Sepsis

Address

Michalakopoulou 88

City

Athens

Postcode

115 28

Country

Greece

Scientific contact point

Organisation

Hellenic Institute For The Study Of Sepsis

Contact name

Clinical trial information desk

Public contact point

Organisation

Hellenic Institute For The Study Of Sepsis

Contact name

Clinical trial information desk

Third parties 1

Locations

1 EU/EEA country · 29 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 25 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