Potassium-Competitive Acid Blocker Versus pROton-Pump Inhibitor for GastroproTECTion Strategies In Patients at High Gastro-Intestinal Bleeding Risk Receiving Antithrombotic Therapy

Coronary Artery Disease Clinical Trial

— PROTECT-HBR  

Official title:

A Multi-centre, Randomized, Double-Blind, Double-Dummy, Parallel-Group, Phase 4 Efficacy and Safety Study of P-CAB (Tegoprazan 50 mg Once Daily) Compared With PPI (Rabeprazole 20 mg Once Daily) to Reduce Upper Gastrointestinal Events Including Bleeding and Symptomatic Ulcer Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04416581
• Other study ID #: AMCCV2020-05
• Status: Recruiting
• Phase: Phase 4
• Start date: May 12, 2021
• Est. completion date: December 31, 2027

Study information

• Verified date: June 2024
• Source: Asan Medical Center
• Contact: Jeong-youn Bae, RN
• Phone: 82230107259
• Email: cvcrc10[@]amc.seoul.kr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary aim of this study is to evaluate the efficacy and safety of novel P-CAB (tegoprazan 50 mg once daily) as compared with standard PPI (rabeprazole 20 mg once daily) for protection of GI events in patients with known cardiac and vascular disease receiving chronic use of antithrombotic drugs (either antiplatelets, OAC, and its combinations) who are at high GI bleeding risk. The primary hypothesis is that P-CAB (experimental arm) would non-inferior to PPI (standard arm) with respect to the rate of the primary composite end point of GI events at 12 months after randomization.

Description:

Before randomization phase, one lead-in subject (N = 300 patients) will be enrolled to perform safety surveillance of standard-dose tegoprazan (50 mg for 6 months) and to ensure the safety of tegoprazan (safety surveillance phase). Data on lead-in subjects will not be included in the data set used for primary analyses.

The safety of tegoprazan will be estimated SIAEs(Special Interest Adverse Events) as follows; Composite Event

1. liver function abnormalities

2. hypergastrinemia, or

3. enteric infection

Definitions

• liver function abnormality: defined as AST or ALT>3× upper limit of normal or two consecutive measurements of total bilirubin >2 x upper limit of normal

• hypergastrinemia

• enteric infection including C.difficile infection

If there are any new tegoprazan-related findings, it will be considered in the estimation.

If there is no safety concern during safety surveillance phase, investigator-driven, randomized, double-blind, double-dummy, active-controlled, clinical trial (N =3,100 patients) will be subsequently performed (randomization phase).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 3100
• Est. completion date: December 31, 2027
• Est. primary completion date: September 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years and older

Eligibility

Inclusion Criteria:

1. Patients 19 years of age or older with known cardiac and vascular disease who are receiving chronic use of antithrombotic drugs (either antiplatelets, oral anticoagulant (OAC), and its combinations). Specific clinical conditions that may confer a need for long-term antithrombotic therapy may include documented coronary artery disease (stable or unstable angina, acute coronary syndrome, a history of myocardial infarction, or any coronary revascularization), documented cerebrovascular disease (stroke or transient ischemic attack), known peripheral arterial disease or a history of peripheral arterial revascularization, atrial fibrillation, or valvular heart disease requiring interventions (transcatheter aortic valve replacement or transcatheter mitral-valve repair). Concomitant use of a proton pump inhibitor is strongly recommended in patients receiving aspirin monotherapy, DAPT (dual antiplatelet therapy; aspirin plus any P2Y12 inhibitors), DAT (dual antithrombotic therapy; antiplatelet drug plus OAC), TAT (triple antithrombotic therapy; DAPT plus OAC), or OAC monotherapy (warfarin or direct oral anticoagulants) who are at high risk of GI bleeding in order to reduce the risk of gastric bleed or GI events.

2. On the basis of clinical guidelines and expert consensus documents, we defined a study population with an increased risk of gastrointestinal bleeding if they had a least 1 or more criteria of the following characteristics. Eligible patients for randomization must meet at least 1 characteristic of these criteria:

*Definition of patients who are at high risk of gastrointestinal bleeding

1. Age =65 years

2. Concomitant use of OAC and any antiplatelet therapy (mono or DAPT) (i.e., DAT or TAT)

3. Long-term use of oral NSAIDs (non-steroidal anti-inflammatory drugs) or steroids or high-dose NSAID therapy even during a relatively short-term period.

4. History of prior GI bleeding events at any time

5. History of a previously complicated ulcer

6. History of peptic ulcer disease or a previously uncomplicated ulcer

7. Documented Helicobacter pylori infection

3. Patients who voluntarily participated in the written agreement

Exclusion Criteria:

1. Active bleeding at the time of inclusion or a history of hereditary or acquired hemostatic disorder

2. Any clinical contraindication to using of antithrombotic therapies (antiplatelet agents or OAC)

3. Concurrent use of PPI or P-CAB within 4 weeks before randomization

4. Hemodynamically unstable conditions at the time of inclusion: cardiogenic shock at the time of randomization, refractory ventricular arrhythmias, or congestive heart failure (New York Heart Association class IV).

5. Baseline severe anemia (Hgb <8 g/dl at baseline) or transfusion within 4 weeks before randomization

6. Baseline severe thrombocytopenia (platelet count <50,000/mm3)

7. Renal failure dependent on dialysis or severe renal insufficiency (creatinine clearance <15 ml/min)

8. Severe chronic liver disease (defined as variceal haemorrhage, ascites, hepatic encephalopathy, or jaundice)

9. Hypersensitivity or contraindication to PPI, P-CAB, any of the product components, or substituted benzimidazoles

10. Use of clarithromycin and hypersensitivity to macrolide antibiotics for Helicobacter pylori eradication

11. Concomitant use of clarithromycin with terfenadine, cisapride, astemizole, or pimozide for Helicobacter pylori eradication

12. Systemic treatment with strong CYP 3A4 and p-glycoprotein (P-GP) inhibitors (e.g., systemic azole antimycotics, such as ketoconazole, and human immunodeficiency virus [HIV]-protease inhibitors, such as ritonavir)

13. Patients who take atazanavir, nelfinavir, or rilpivirine-containing products (see Drug-Drug interaction section)

14. Clinically significant laboratory abnormality at screening (estimated glomerular filtration rate (eGFR) <15 mL/min or elevated liver enzyme [AST, ALT, ALP, total bilirubin] > 3 times upper normal limit [UNL] or any other condition that, in the opinion of the Investigator, precludes participation in the study

15. Any known or suspected malignancy

16. Subjects with non-cardiac co-morbidities with a life expectancy of less than 12 months

17. Subjects with active treatment for H-pylori infection

18. Women who are pregnant or breastfeeding or female subjects, premenopausal who are not surgically sterile, or, if sexually active not practicing an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double-barrier method, contraceptive patch, male partner sterilization) before entry and throughout the study; and, for those of childbearing potential, who have a positive pregnancy test at screening

19. Participation in another clinical study within 12 months. However, where at least one or more conditions are satisfied, it could be an exception according to an investigator's discretion;

1. Participated in the observational study expected no effect on the safety and/or effectiveness evaluation of this trial

2. Screening failed before any interventional factor is involved

3. Participated in academic trials like strategic or medical device comparison studies conducted under standard therapy provided that there is no additional risk or a specific procedure to a subject and no interference between this trial and other studies

Related Conditions & MeSH terms

• Acute Coronary Syndrome
• Coronary Artery Disease
• Infarction
• Myocardial Infarction
• Percutaneous Coronary Intervention

Intervention

Drug:
• PPI
rabeprazole 20mg + tegoprazan 50 mg placebo, once daily.
• P-CAB 50
tegoprazan 50 mg + rabeprazole 20mg placebo, once daily.

Locations

Country	Name	City	State
Korea, Republic of	Hallym University Sacred Heart Hospital	Anyang
Korea, Republic of	Bucheon Sejong Hospital	Bucheon
Korea, Republic of	Kosin University Gospel Hospital	Busan
Korea, Republic of	Gyeongsang National University Changwon Hospital	Changwon
Korea, Republic of	Sungkyunkwan University Samsung Changwon Hospital	Changwon
Korea, Republic of	Dankook University Hospital	Cheonan
Korea, Republic of	Chungbuk National University Hospital	Cheonju
Korea, Republic of	Gangwon National Univ. Hospital	Chuncheon
Korea, Republic of	Hallym University Chuncheon Sacred Heart Hospital	Chuncheon
Korea, Republic of	Keimyung University Dongsan Medical Center	Daegu
Korea, Republic of	Yeungnam University Medical Center	Daegu
Korea, Republic of	Chungnam National University Hospital	Daejeon
Korea, Republic of	Gangneung Asan Hospital	Gangneung
Korea, Republic of	Hanyang University Guri Hospital	Guri
Korea, Republic of	Chonnam National University Hospital	Gwangju
Korea, Republic of	Inje University Ilsan Paik Hospital	Ilsan
Korea, Republic of	Jeonbuk National University Hospital	Jeonju
Korea, Republic of	Kwangju Christian Hospital	Kwangju
Korea, Republic of	Dong-A Medical Center	Pusan
Korea, Republic of	Inje University Pusan Paik Hospital	Pusan
Korea, Republic of	Pusan National University Hospital	Pusan
Korea, Republic of	Chungnam National University Sejong Hospital	Sejong
Korea, Republic of	Bundang CHA Hospital	Seongnam
Korea, Republic of	Seoul university Bundang hospital	Seongnam-si
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Chung-Ang University Hospital	Seoul
Korea, Republic of	Ewha Womans University Medical Center	Seoul
Korea, Republic of	Hanyang University Seoul Hospital	Seoul
Korea, Republic of	Kangbuk Samsung Hospital	Seoul
Korea, Republic of	Kangdong Sacred Heart Hospital	Seoul
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	Kyung Hee University Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital	Seoul
Korea, Republic of	SNU Boramae Medical Center	Seoul
Korea, Republic of	The Catholic Univ. of Korea Eunpyeong St. Mary's hospital	Seoul
Korea, Republic of	The Catholic Univ. of Korea Seoul St. Mary's hospital	Seoul
Korea, Republic of	Ajou University Hospital	Suwon
Korea, Republic of	The Catholic University of Korea, ST. Mary's Hospital	Suwon
Korea, Republic of	Ulsan University Hospital	Ulsan
Korea, Republic of	Pusan National University Yangsan Hospital	Yangsan

Sponsors (1)

Lead Sponsor	Collaborator
Duk-Woo Park, MD

Country where clinical trial is conducted

Korea, Republic of, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The time from randomization to the first occurrence of a composite endpoint of upper GI clinical events, including during the treatment period	This composite outcome included: Overt upper gastrointestinal bleeding (confirmed by means of upper endoscopy or computed tomography); Overt upper gastrointestinal bleeding of unknown origin; Bleeding of presumed occult gastrointestinal origin with a documented decrease in haemoglobin of = 2 g/dL or decrease in hematocrit = 10% from baseline; Symptomatic gastroduodenal ulcer (confirmed by means of endoscopy or computed tomography) without evidence of gastrointestinal bleeding; Persistent pain of presumed gastrointestinal origin (duration = 3 days) with underlying multiple erosive disease (5 or more gastroduodenal erosions confirmed by means of endoscopy); Obstruction; or; Perforation.; A composite endpoint is an endpoint that is a combination of multiple clinical endpoints. An event is considered to have occurred if any of several different events is observed.	12 months
Secondary	The event rate of overt upper gastrointestinal bleeding (confirmed by means of upper endoscopy or computed tomography)		12 months
Secondary	The event rate of overt upper GI bleeding of unknown origin		12 months
Secondary	The event rate of bleeding of presumed occult GI origin with the documented decrease in Hgb of=2g/dL or decrease in hematocrit=10% from baseline		12 months
Secondary	The event rate of symptomatic gastroduodenal ulcer(confirmed by means of endoscopy or computed tomography) without evidence of GI bleeding		12 months
Secondary	The event rate of the existence of persistent pain of presumed GI origin(duration = 3 days) with underlying multiple erosive diseases (5 or more gastroduodenal erosions confirmed by means of endoscopy)		12 months
Secondary	The event rate of gastrointestinal obstruction		12 months
Secondary	The event rate of gastrointestinal perforation		12 months
Secondary	The time from randomization to discontinuation of study medication attributed to gastrointestinal signs or symptoms		12 months
Secondary	The event rate of gastroesophageal reflux disease, as evidenced by symptomatic endoscopically confirmed erosive esophagitis		12 months
Secondary	The event rate of composite cardiovascular safety endpoints	composite cardiovascular safety endpoints including: death from cardiovascular causes; myocardial infarction; or; stroke; A composite endpoint is an endpoint that is a combination of multiple clinical endpoints. An event that is considered to have occurred if any one of several different events is observed.	12 months
Secondary	The event rate of death from cardiovascular causes		12 months
Secondary	The event rate of myocardial infarction		12 months
Secondary	The event rate of stroke		12 months
Secondary	The event rate of any coronary or peripheral revascularization		12 months
Secondary	The event rate of all-cause mortality		12 months