Stop of proton-pump inhibitor treatment in patients with liver cirrhosis – a doubleblind, placebo-controlled trial (STOPPIT)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

University Medical Center Hamburg-Eppendorf

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

29 Apr 2021 → ongoing

Decision date (initial)

2024-06-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2023-509863-26-00

EudraCT number

2019-005008-16

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

To determine the time to first unplanned re-hospitalization or death
(composite endpoint) in patients with liver cirrhosis who discontinue
long-term proton-pump inhibitor (PPI) therapy (intervention group) as
compared to patients who continue PPI therapy (control group) over a
period of 12 months (360 days).

Secondary objectives 3

1. To compare and assess the following endpoints in the two groups: a. Time to death and mortality (overall- and liver related). b. Time to and rate of unplanned re-hospitalizations. c. Overall infection rates and infection rates differentiated by site of infection, including spontaneous bacterial peritonitis (SBP), pneumonia, urinary tract infections, blood stream infections, Clostridium difficile-associated enterocolitis, Norovirus infections, Sars-CoV-2-infections. d. Rate of acute decompensation of cirrhosis and acute-onchronic liver failure (ACLF). e. Rate and sources of upper and lower gastrointestinal bleeding events.
2. To assess the changes in the intestinal microbiota in both groups and evaluate its effect on the primary endpoint.
3. To assess the potential pharmacoeconomic and socioeconomic impact of PPI discontinuation.

Conditions and MedDRA coding

Liver cirrhosis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Male or female adult (18 years) patient.
2. Liver cirrhosis (diagnosed either histologically or by a combination of clinical, laboratory and/or radiological signs).
3. Hospitalized or recently hospitalized (0 to 42 days before baseline) with complicated liver cirrhosis.
4. PPI treatment for at least 28 days prior to screening
5. PPI treatment with a single standard dose/day or less for a minimum of 7 days prior to screening.
6. Females/Males who agree to comply with the applicable contraceptive requirements of the protocol.
7. Non-pregnant, non-lactating females.
8. Ability to understand the patient information and to personally sign and date the informed consent to participate in the study, before completing any study related procedures.
9. The patient is co-operative and available for the entire study.
10. Provided written informed consent.

Exclusion criteria 11

1. Severe esophageal reflux disease (LA grade C or D) diagnosed by esophago-gastro-duodenoscopy (EGD) < 2 months prior to screening without PPI treatment for at least 8 weeks prior to screening.
2. Peptic ulcers diagnosed by EGD < 28 days prior to screening.
3. Endoscopic therapy for varices < 14 days prior to screening.
4. Life-expectancy < 1 year (at the discretion of the investigator) due to extrahepatic malignancies, metastasized hepatocellular carcinoma (HCC), or other severe extrahepatic-diseases. Importantly, HCC without extrahepatic metastases or a reduced life-expectancy < 1 year due to liver cirrhosis are not regarded as exclusion criteria.
5. Regular intake of non-steroidal anti-inflammatory drugs on a daily basis with the exemption of acetylsalicylic acid in a dosage of up to 100mg/day.
6. Patients with one or more of the following measurements at the time of screening or documented during 48 hours before screening: a. Body temperature > 38.5°C, or b. systolic blood pressure < 90 mmHg and tachycardia > 100 beats per minute, or c. ongoing catecholamine treatment higher than low dose norepinephrine ( 0.1 μg/kg/minute) (NB: terlipressin treatment for possible hepatorenal syndrome is not regarded as an exclusion criterion), or d. respiratory rate 22/minute.
7. Hypersensitivity or intolerance to esomeprazole, substituted benzimidazoles or other excipients of the investigational medicinal product (IMP; Nexium mups or Placebo).
8. Ongoing therapy with nelfinavir.
9. Participating in a clinical trial or use of an IMP within 30 days or five times the half-life of the IMP (whichever is longer) prior to receive the first dose within this study.
10. Positive urine pregnancy test at screening or positive serum pregnancy test before the first treatment or is breast feeding.
11. Patient is not willing to use adequate contraceptive precautions during the study or for up to 5 days after the last scheduled dose of IMP.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Time to first unplanned re-hospitalization* or death within 12 months after randomization (composite endpoint). *Exception: expected re-hospitalization for paracentesis in patients with a history of refractory ascites (without any other complication of cirrhosis) during a period of 30 days.

Secondary endpoints 6

1. Death (all-cause and liver-related).
2. Unplanned re-hospitalization.
3. Any Infection and differentiated by site of infection (SBP, pneumonia, urinary tract infection, blood stream infection, Clostridium difficile-associated enterocolitis, Norovirus infection, Sars-CoV-2-infection).
4. Acute hepatic decompensation and ACLF.
5. Upper and lower gastrointestinal bleeding event.
6. Experimental Endpoint: Changes of intestinal microbiota between baseline and day 90.

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

University Medical Center Hamburg-Eppendorf

Sponsor organisation

University Medical Center Hamburg-Eppendorf

Address

Martinistrasse 52, Eppendorf Eppendorf

City

Hamburg

Postcode

20251

Country

Germany

Scientific contact point

Organisation

University Medical Center Hamburg-Eppendorf

Contact name

Ansgar Lohse

Public contact point

Organisation

University Medical Center Hamburg-Eppendorf

Contact name

Ansgar Lohse

Third parties 1

Locations

1 EU/EEA country · 19 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 8 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