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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Myocardial Infarction; Coronary Artery Disease; Acute Coronary Syndrome; Percutaneous Coronary Intervention
• Intervention / Treatment: Drug: P-CAB 50; Drug: PPI

Detailed 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).

• Study Type: Interventional
• Enrollment (Estimated): 3100
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jeong-youn Bae, RN; Phone Number: 82230107259; Email: cvcrc10@amc.seoul.kr

Study Locations

• Korea, Republic of
  • Anyang, Korea, Republic of
    • Not yet recruiting
    • Hallym University Sacred Heart Hospital
    • Principal Investigator: Kyoung-ha Park, MD
    • Contact: Kyoung-ha Park, MD; Email: pkhmd@naver.com
  • Bucheon, Korea, Republic of
    • Not yet recruiting
    • Bucheon Sejong Hospital
    • Contact: Young-jin Choi, MD
    • Principal Investigator: Young-jin Choi, MD
  • Busan, Korea, Republic of
    • Not yet recruiting
    • Kosin University Gospel Hospital
    • Contact: Jung-ho Heo, MD
    • Principal Investigator: Jung-ho Heo, MD
  • Changwon, Korea, Republic of
    • Not yet recruiting
    • Gyeongsang National University Changwon Hospital
    • Contact: Yong-hwi Park, MD
    • Principal Investigator: Yong-hwi Park, MD
  • Changwon, Korea, Republic of
    • Not yet recruiting
    • Sungkyunkwan University Samsung Changwon Hospital
    • Contact: Yong-Hwan Park, MD
    • Principal Investigator: Yong-Hwan Park, MD
  • Cheonan, Korea, Republic of
    • Not yet recruiting
    • Dankook University Hospital
    • Contact: Sung-hoon Lim, MD
    • Principal Investigator: Sung-hoon Lim, MD
  • Cheonju, Korea, Republic of
    • Not yet recruiting
    • Chungbuk National University Hospital
    • Contact: jang-hwan Bae, MD
    • Principal Investigator: Jang-hwan Bae, MD
  • Chuncheon, Korea, Republic of
    • Not yet recruiting
    • Gangwon National Univ. Hospital
    • Contact: Bong-Ki Lee, MD
    • Principal Investigator: Bong-Ki Lee, MD
  • Chuncheon, Korea, Republic of
    • Not yet recruiting
    • Hallym University Chuncheon Sacred Heart Hospital
    • Contact: Hyun-hee Choi, MD
    • Principal Investigator: Hyun-hee Choi, MD
  • Daegu, Korea, Republic of
    • Not yet recruiting
    • Keimyung University Dongsan Medical Center
    • Contact: Chang-wook Nam, MD
    • Principal Investigator: Chang-wook Nam, MD
  • Daegu, Korea, Republic of
    • Not yet recruiting
    • Yeungnam University Medical Center
    • Principal Investigator: Woong Kim, MD
    • Contact: Woong Kim, MD
  • Daejeon, Korea, Republic of
    • Not yet recruiting
    • Chungnam National University Hospital
    • Contact: Jin-ok Jeong, MD
    • Principal Investigator: Jin-ok Jeong, MD
  • Gangneung, Korea, Republic of
    • Not yet recruiting
    • Gangneung Asan Hospital
    • Contact: Han-bit Park, MD
    • Principal Investigator: Han-bit Park, MD
  • Guri, Korea, Republic of
    • Recruiting
    • Hanyang University Guri Hospital
    • Contact: Hwan-cheol Park, MD
    • Principal Investigator: Hwan-cheol Park, MD
  • Gwangju, Korea, Republic of
    • Not yet recruiting
    • Chonnam National University Hospital
    • Contact: Young-joon Hong, MD
    • Principal Investigator: Young-joon Hong, MD
  • Ilsan, Korea, Republic of
    • Not yet recruiting
    • Inje University Ilsan Paik Hospital
    • Contact: Joon-hyung Do, MD
    • Principal Investigator: Joon-hyung Do, MD
  • Jeonju, Korea, Republic of
    • Not yet recruiting
    • Jeonbuk National University Hospital
    • Contact: Sang-rok Lee, MD
    • Principal Investigator: Sang-rok Lee, MD
  • Kwangju, Korea, Republic of
    • Not yet recruiting
    • Kwangju Christian Hospital
    • Contact: Seung-wook Lee, MD
    • Principal Investigator: Seung-wook Lee, MD
  • Pusan, Korea, Republic of
    • Not yet recruiting
    • Pusan National University Hospital
    • Contact: Han-cheol Lee, MD
    • Principal Investigator: Han-cheol Lee, MD
  • Pusan, Korea, Republic of
    • Not yet recruiting
    • Inje University Pusan Paik Hospital
    • Contact: Tae-hyun Yang, MD
    • Principal Investigator: Tae-hyun Yang, MD
  • Pusan, Korea, Republic of
    • Not yet recruiting
    • Dong-A Medical Center
    • Principal Investigator: Moo-hyun Kim, MD
    • Contact: Moo-hyun Kim, MD; Email: kmh60@damc.or.kr
  • Sejong, Korea, Republic of
    • Not yet recruiting
    • Chungnam National University Sejong Hospital
    • Contact: Yong-hoon Yoon, MD
    • Principal Investigator: Yong-hoon Yoon, MD
  • Seongnam, Korea, Republic of
    • Recruiting
    • Bundang CHA Hospital
    • Contact: Se-hun Kang, MD
    • Principal Investigator: Se-hun Kang, MD
  • Seongnam-si, Korea, Republic of
    • Not yet recruiting
    • Seoul university Bundang hospital
    • Principal Investigator: Jung-won Suh, MD
    • Contact: Jung-won Suh, MD
  • Seoul, Korea, Republic of
    • Recruiting
    • Asan Medical Center
    • Contact: Duk-woo Park, MD; Email: dwpark@amc.seoul.kr
    • Principal Investigator: Duk-woo Park, MD
  • Seoul, Korea, Republic of
    • Recruiting
    • Severance Hospital
    • Contact: Byoung-keuk Kim, MD
    • Principal Investigator: Byoung-keuk Kim, MD
  • Seoul, Korea, Republic of
    • Not yet recruiting
    • Seoul National University Hospital
    • Contact: Eui-keun Choi, MD
    • Principal Investigator: Eui-keun Choi, MD
  • Seoul, Korea, Republic of
    • Not yet recruiting
    • Kangdong Sacred Heart Hospital
    • Contact: Eun-seon Jin, MD
    • Principal Investigator: Eun-seon Jin, MD
  • Seoul, Korea, Republic of
    • Recruiting
    • Kangbuk Samsung Hospital
    • Principal Investigator: Jong-young Lee, MD
    • Contact: Jong-young Lee, MD
  • Seoul, Korea, Republic of
    • Recruiting
    • Chung-Ang University Hospital
    • Contact: Wang-soo Lee, MD
    • Principal Investigator: Wang-soo Lee, MD
  • Seoul, Korea, Republic of
    • Not yet recruiting
    • Korea University Anam Hospital
    • Contact: Soon-jun Hong, MD
    • Principal Investigator: Soon-jun Hong, MD
  • Seoul, Korea, Republic of
    • Not yet recruiting
    • Hanyang University Seoul Hospital
    • Contact: Young-Hyo Lim, MD
    • Principal Investigator: Young-hyo Lim, MD
  • Seoul, Korea, Republic of
    • Not yet recruiting
    • The Catholic Univ. of Korea Seoul St. Mary's Hospital
    • Contact: Byung-hee Hwang, MD
    • Principal Investigator: Byung-hee Hwang, MD
  • Seoul, Korea, Republic of
    • Recruiting
    • Kyung Hee University Medical Center
    • Contact: Won Kim, MD
    • Principal Investigator: Won Kim, MD
  • Seoul, Korea, Republic of
    • Not yet recruiting
    • Ewha womans university medical center
    • Contact: Woo-jin Jang, MD
    • Principal Investigator: Woo-jin Jang, MD
  • Seoul, Korea, Republic of
    • Not yet recruiting
    • The Catholic Univ. of Korea Eunpyeong St. Mary's Hospital
    • Contact: Jeong-hoon Lee, MD
    • Principal Investigator: Jeong-hoon Lee, MD
  • Seoul, Korea, Republic of
    • Not yet recruiting
    • SNU Boramae Medical Center
    • Contact: Sang-hyun Kim, MD
    • Principal Investigator: Sang-hyun Kim, MD
  • Suwon, Korea, Republic of
    • Not yet recruiting
    • Ajou University Hospital
    • Contact: Myoung-ho Yoon, MD
    • Principal Investigator: Myoung-ho Yoon, MD
  • Suwon, Korea, Republic of
    • Not yet recruiting
    • The Catholic University of Korea, St. Mary's Hospital
    • Contact: Sung-ho Her, MD
    • Principal Investigator: Sung-ho Her, MD
  • Ulsan, Korea, Republic of
    • Not yet recruiting
    • Ulsan University Hospital
    • Contact: Eun-seok Shin, MD
    • Principal Investigator: Eun-seok Shin, MD
  • Yangsan, Korea, Republic of
    • Not yet recruiting
    • Pusan National University Yangsan Hospital
    • Contact: Jung-soo Kim, MD
    • Principal Investigator: Jung-soo Kim, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: P-CAB 50mg group; tegoprazan 50 mg + rabeprazole 20mg placebo, once daily.	Drug: P-CAB 50; tegoprazan 50 mg + rabeprazole 20mg placebo, once daily.
Active Comparator: PPI group; rabeprazole 20mg + tegoprazan 50 mg placebo, once daily.	Drug: PPI; rabeprazole 20mg + tegoprazan 50 mg placebo, once daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
The event rate of overt upper gastrointestinal bleeding (confirmed by means of upper endoscopy or computed tomography)		12 months
The event rate of overt upper GI bleeding of unknown origin		12 months
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
The event rate of symptomatic gastroduodenal ulcer(confirmed by means of endoscopy or computed tomography) without evidence of GI bleeding		12 months
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
The event rate of gastrointestinal obstruction		12 months
The event rate of gastrointestinal perforation		12 months
The time from randomization to discontinuation of study medication attributed to gastrointestinal signs or symptoms		12 months
The event rate of gastroesophageal reflux disease, as evidenced by symptomatic endoscopically confirmed erosive esophagitis		12 months
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
The event rate of death from cardiovascular causes		12 months
The event rate of myocardial infarction		12 months
The event rate of stroke		12 months
The event rate of any coronary or peripheral revascularization		12 months
The event rate of all-cause mortality		12 months

Collaborators and Investigators

• Sponsor: Duk-Woo Park, MD

Study record dates

Study Major Dates

• Study Start (Actual): May 12, 2021
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: May 28, 2020
• First Submitted That Met QC Criteria: June 1, 2020
• First Posted (Actual): June 4, 2020

Study Record Updates

• Last Update Posted (Estimated): March 1, 2024
• Last Update Submitted That Met QC Criteria: February 29, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: peptic ulcer; acute coronary syndrome; PPI; antiplatelet; anticoagulant therapy; Proton-pump inhibitors; gastroduodenal ulcer; gastrointestinal hemorrhage; coronary artery stent placement; P-CAB; Potassium-Competitive Acid Blockers
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Myocardial Infarction; Infarction; Coronary Artery Disease; Acute Coronary Syndrome
• Other Study ID Numbers: AMCCV2020-05

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No