Study to Assess Rifaximin Soluble Solid Dispersion (SSD) for the Delay of Encephalopathy Decompensation in Cirrhosis (RED-C-3132)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Salix Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

23 Apr 2024 → 27 Oct 2025

Decision date (initial)

2023-08-16

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Salix Pharmaceuticals, Inc. an affiliate of Bausch Health US, LLC

External identifiers

EU CT number

2022-502899-23-00

ClinicalTrials.gov

NCT05297448

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacokinetic

The primary objective of this study is to assess the efficacy of rifaximin SSD-40IR versus placebo to delay the occurrence of HE-related hospitalization.

Secondary objectives 2

1. The secondary objective of this study is to assess the effects of treatment with rifaximin SSD-40IR on hospitalization rates.
2. The safety objective of this study is to assess the safety of rifaximin SSD-40IR following a treatment regimen of 72 weeks.

Conditions and MedDRA coding

Hepatic Encephalopathy (OHE)

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, Medicines Evaluation Board

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. A participant will be eligible for inclusion in this study if he/she meets all of the following criteria: 1. Participant has a diagnosis of liver cirrhosis with medically controlled ascites (> 30 days). Cirrhosis diagnosis can be made using any of the following: o Histopathological evidence of cirrhosis o Magnetic resonance imaging (MRI) o Computed tomography (CT) o Fibroscan (Transient Elastography) o Imaging (sonographic or cross-sectional) o Presence of esophageal varices o Thrombocytopenia (<150,000/μL) in participants with CLD Medically controlled ascites (>30 days) includes: o Ascites that is controlled by diet and/or medication for over 30 days and that does not require recurring therapeutic paracentesis (could have had paracentesis in the past).
2. Participant has a Conn (West Haven Criteria [WHC]) score of < 2.
3. Participant has a Mini-Mental State Examination (MMSE) score > 24 at screening.
4. Participant is ≥ 18 and ≤ 85 years of age.
5. Females of childbearing (reproductive) potential must have a negative serum or urine pregnancy test at screening. All participants must agree to use highly effective methods of contraception throughout their participation in the study.
6. Participant must be able to independently read, fully understand and provide written informed consent on the Institutional Review Board (IRB)/Ethics Committee (EC) approved informed consent form (ICF) without additional support and provide authorization as appropriate per local privacy regulations.

Exclusion criteria 26

1. Participant has an active COVID-19 infection that is unresolved or, in the opinion of the investigator, may affect evaluation of the study drug or might place the subject at undue risk.
2. Participant has a history of anaphylaxis or hypersensitivity to rifaximin, rifampin, rifamycin antimicrobial agents, or any of the components of rifaximin.
3. Participant has a history of documented SBP by diagnostic paracentesis, EVB within 6 months, or AKI-HRS within 6 months. • SBP diagnostic criteria: polymorphonuclear cell (PMN) count in the ascitic fluid is ≥ 250 cells/mm3 and secondary causes of peritonitis are excluded. • AKI-HRS diagnostic criteria: ≥ Stage 2 acute kidney injury (AKI); no improvement of serum creatinine after ≥ 48 hours of diuretic withdrawal and volume expansion with albumin at a dose of 1 g/kg of body weight, up to a maximum of 100 g daily; absence of hypovolemic shock or infection that require vasoactive drugs to support blood pressure; no current or recent use of nephrotoxic drugs; proteinuria < 500 mg/day, and hematuria < 50 RBC/high power field.
4. Participant has a documented history of an OHE episode (Conn score ≥ 2). b. Participant has a history of rifaximin 550 mg and lactulose use for suspected OHE episode. Short-course (< 2 weeks) of rifaximin for non-OHE indications (e.g., traveler’s diarrhea or irritable bowel syndrome with diarrhea indications), > 90 days prior to screening is allowed. Prior occasional and intermittent use of lactulose (≤ 2 weeks) for non-OHE indications (e.g., constipation or for testing purposes, like lactulose breath test), > 30 days prior to screening is allowed.
5. Participant has other uncontrolled neurological or psychiatric conditions which may confound the assessment of cognitive function (e.g., dementia, schizophrenia, etc.). Participants with generalized seizure within 30 days prior to screening are excluded.
6. Participants with focal neurological deficits due to a neurological event such as cerebrovascular accident.
7. Participants with Wernicke’s or Wernicke-Korsakoff encephalopathy
8. Participant has pseudomembranous colitis, abdominal abscess, or clinically significant strictures and fistulas of the gastrointestinal tract.
9. Participant consumes more than moderate amounts of alcohol, defined as 1 standard drink per day for women and 2 standard drinks per day for men.
10. Participant has a history of substance abuse < 6 months prior to signing the ICF and cannot refrain from substance abuse during the study period. For alcohol abuse, participants undergoing alcohol use counselling or receiving Alcohol Use Disorder pharmacotherapy, can be considered for inclusion.
11. Participants on antipsychotic medications should be excluded irrespective of indication or dose. Participants who discontinue psychoactive medications with a washout period of 30 days before providing consent are allowed. Benzodiazepine, psychoactive medicine, and opioid use are excluded, with the exception of: a. Participants on stable dose psychoactive medicines may be included. b. Participants are allowed to remain on opioids, if on a stable opioid dose for at least 30 days.
12. Participant has been diagnosed with an uncontrolled infection < 4 weeks prior to screening.
13. Participant has been diagnosed with an upper gastrointestinal bleed from non-variceal sources < 6 weeks prior to screening.
14. Participant shows presence of intestinal obstruction or has inflammatory bowel disease.
15. Participant has undergone bariatric surgery or intestinal resection. Limited segmental resection of colon (e.g., adenomatous polyp) > 2 years prior is allowed.
16. Participant has a history of an acute portal vein thrombosis that requires anticoagulants within the past 3 months, a history of a TIPS procedure, or plans to undergo a TIPS procedure.
17. Participant has a history of shunt surgery or direct intrahepatic portocaval shunt (DIPS) procedure for portal hypertension or plans to undergo a DIPS procedure.
18. Participant requires peritoneal dialysis or hemodialysis.
19. Participant has undergone prophylactic variceal banding within 2 weeks of screening (Note: participants with previous prophylactic variceal banding will be allowed to participate in the study).
20. Participant has Type 1 or Type 2 diabetes that is not adequately controlled in the opinion of the investigator.
21. Participant with a life expectancy < 18 months.
22. Participant has active malignancy (except basal carcinoma of the skin), including active hepatocellular carcinoma (HCC). Participants with resections or ablations of squamous cell carcinoma of the skin, or in situ carcinoma of the cervix, that occurred greater than 6 months prior to screening and are considered disease free are eligible for enrollment.
23. Evidence of HCC or a probable HCC lesion within 6 months on ultrasound or contrast multiphase MRI or CT. If there is a lesion suspicious for HCC and this imaging is not available, or if alpha-fetoprotein (AFP) is ≥ 20 ng/mL at screening, participants should undergo standard of care diagnostic procedures with their physician to rule out HCC during the screening period.
24. Participant has any condition or circumstance that adversely affects the participant, could cause noncompliance with treatment or visits, may impact the interpretation of clinical data, could cause bias, or may otherwise contraindicate the participant’s participation in the study.
25. Participant used any investigational product or device within 30 days or 5 half-lives of the investigational product (whichever comes first) of providing consent.
26. Chronic antibiotic use throughout the study is prohibited. A short-course of antibiotic therapy (≤ 14 days; non-rifamycin only) to treat non-cirrhosis-related conditions such as sinusitis, dental therapy prophylaxis, urinary tract infections, etc. is permitted. Longer courses of therapy will require sponsor’s permission.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Time to first event of OHE requiring hospitalization. • A thorough evaluation of the patient will be carried out to confirm the diagnosis of OHE, which will be made by a trained medical professional (e.g., MD, DO) using American Association for the Study of Liver Disease Guidelines. • Every OHE diagnosis will be evaluated and confirmed to meet endpoint definitions by the Clinical Event Adjudication Committee (CEAC).

Secondary endpoints 3

1. Time to first Conn score ≥ 2
2. Time to all-cause hospitalization
3. Time to first event of OHE that requires hospitalization, or all-cause death

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Salix Pharmaceuticals Inc.

Sponsor organisation

Salix Pharmaceuticals Inc.

Address

8510 Colonnade Center Drive

City

Raleigh

Postcode

27615-5860

Country

United States

Scientific contact point

Organisation

Salix Pharmaceuticals Inc.

Contact name

Clinical trial information desk

Public contact point

Organisation

Salix Pharmaceuticals Inc.

Contact name

Clinical trial information desk

Third parties 9

Locations

8 EU/EEA countries · 68 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 260 files

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

Application history

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