Acute-On-Chronic Liver Failure (ACLF) at High Risk of Hospital Mortality

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Instituto Grifols S.A.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

11 Apr 2019 → 15 Apr 2025

Decision date (initial)

2024-04-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2022-502187-20-00

EudraCT number

2016-001787-10

ClinicalTrials.gov

NCT03702920

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

To evaluate the effect of standard medical treatment (SMT) plus PE-A 5% (SMT+PE-A 5%) on 90-day overall survival

Secondary objectives 2

1. To evaluate the effect of SMT+PE-A 5% on 90-day transplant-free survival
2. To evaluate the effect of SMT+PE-A 5% on 28-day overall survival

Conditions and MedDRA coding

Subjects with cirrhosis with ACLF-1b, ACLF-2, or ACLF-3a detected either at admission or during hospitalization

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Male or female cirrhotic subjects between 18 and 79 years of age.
2. Subjects with ACLF-1b, ACLF-2, or ACLF-3a detected either at admission or during hospitalization (must be ACLF-1b, -2, or -3a within the Screening Period [a maximum of 10 days])
3. Willing and able to provide written informed consent or have an authorized representative able to provide written informed consent on behalf of the subject in accordance with local law and institutional policy
4. In case of hepatic encephalopathy, informed consent will be provided by a relative or a legally authorized representative if the subject is considered incompetent to consent.

Exclusion criteria 24

1. Subjects without ACLF
2. Subjects with ACLF-1a or ACLF-3b after the Screening Period
3. Subjects fulfilling inclusion criteria that improve to no ACLF or to ACLF-1a or worsen to ACLF-3b during the Screening Period (between initial evaluation and time of randomization)
4. Subjects with ACLF for more than 10 days prior to randomization
5. Subjects with acute or subacute liver failure without underlying cirrhosis
6. Subjects with septic shock requiring use of norepinephrine (> 0.3 mcg/kg/min) or need for a second vasopressor (including terlipressin)
7. Subjects with active bacterial or fungal infection: who have received less than 24h of appropriate antibiotic treatment
8. Subjects with severe respiratory failure with PaO2/FiO2 ≤200
9. Subjects with active or recent bleeding (unless controlled for >48 hours)
10. Subjects with severe thrombocytopenia (≤20×109/L) (based on local laboratory assessment)
11. Subjects with chronic renal failure and currently receiving hemodialysis
12. Evidence of current locally advanced or metastatic malignancy. Subjects with hepatocellular carcinoma within the Milan criteria (1 nodule ≤5 cm or 3 nodules ≤3 cm, non-melanocytic skin cancer, and controlled breast or prostate cancer can be included)
13. Subjects with severe chronic heart failure (New York Heart Association [NYHA] class III or IV
14. Subjects with severe pulmonary disease (Global Obstructive Lung Disease [GOLD] stage III or IV)
15. Subjects with severe myopathy as defined clinically
16. Subjects with a known infection with human immunodeficiency virus (HIV) or have clinical signs and symptoms consistent with current HIV infection
17. Females who are pregnant, breastfeeding, or if of childbearing potential, unwilling to practice a highly effective method of contraception (oral, injectable, or implanted hormonal methods of contraception, placement of an intrauterine device or intrauterine system, condom, or occlusive cap with spermicidal foam/gel/cream/suppository, male sterilization, or true abstinence*) throughout the study. * True abstinence: When this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods], declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception)
18. Subjects with previous liver transplantation.
19. Subjects receiving anti-platelet or anti-coagulant therapy (low molecular weight heparin [LMWH] for deep vein thrombosis [DVT] prophylaxis is allowed)
20. Participation in another clinical study within at least 30 days prior to screening
21. Subjects with active drug addiction (exceptions: active alcoholism or marijuana)
22. Subjects with a do-not-resuscitate order
23. In the opinion of the investigator, the subject may have compliance problems with the protocol and the procedures of the protocol
24. Subjects with current infection of COVID19, those who are less than 14 days post recovery or those who have clinical signs and symptoms consistent with COVID19 infection.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary efficacy endpoint is to is to compare the 90-day overall survival in the intent-to-treat (ITT) population between the SMT+PE-A 5% treatment group and the SMT control group.

Secondary endpoints 1

1. The secondary efficacy endpoints are to assess the effects of PE-A 5% on: 1) 90-day transplant-free survival and 2) 28-day overall survival versus SMT alone.

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Instituto Grifols S.A.

Sponsor organisation

Instituto Grifols S.A.

Address

Calle De Can Guasch 2, Poligono Industrial Llevant Poligono Industrial Llevant

City

Parets Del Valles

Postcode

08150

Country

Spain

Scientific contact point

Organisation

Instituto Grifols S.A.

Contact name

Clinical and Pharmacovigilance

Public contact point

Organisation

Instituto Grifols S.A.

Contact name

Clinical and Pharmacovigilance

Third parties 6

Locations

11 EU/EEA countries · 34 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 104 files

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

Application history

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