Clinical trial NCT04416581: Potassium-Competitive Acid Blocker Versus pROton-Pump Inhibitor for GastroproTECTion Strategies In Patients at High Gastro-Intestinal Bleeding Risk Receiving Antithrombotic Therapy
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Coronary Artery Disease
Percutaneous Coronary Intervention
Acute Coronary Syndrome
Myocardial Infarction
Keywords: gastroduodenal ulcer
gastrointestinal hemorrhage
peptic ulcer
acute coronary syndrome
coronary artery stent placement
antiplatelet
anticoagulant therapy
PPI
P-CAB
Proton-pump inhibitors
Potassium-Competitive Acid Blockers
Lead sponsor: Asan Medical Center
Sponsor class: OTHER
First posted: 2020-06-04
Enrollment: 3320
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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.

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).

Eligibility criteria: 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. Based on clinical guidelines, the use of P2Y12 inhibitor monotherapy (i.e. clopidogrel, ticagrelor, or prasugrel) is not considered in trial enrollment.
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. Patients with non-cardiac co-morbidities with a life expectancy of less than 12 months
17. Patients 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

Primary outcomes:
measure: The time from randomization to the first occurrence of a composite endpoint of upper GI clinical events, including during the treatment period
timeFrame: 12 months
Secondary outcomes:
measure: The event rate of overt upper gastrointestinal bleeding (confirmed by means of upper endoscopy or computed tomography)
timeFrame: 12 months
measure: The event rate of overt upper GI bleeding of unknown origin
timeFrame: 12 months
measure: 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
timeFrame: 12 months
measure: The event rate of symptomatic gastroduodenal ulcer(confirmed by means of endoscopy or computed tomography) without evidence of GI bleeding
timeFrame: 12 months
measure: 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)
timeFrame: 12 months
measure: The event rate of gastrointestinal obstruction
timeFrame: 12 months
measure: The event rate of gastrointestinal perforation
timeFrame: 12 months
measure: The time from randomization to discontinuation of study medication attributed to gastrointestinal signs or symptoms
timeFrame: 12 months
measure: The event rate of gastroesophageal reflux disease, as evidenced by symptomatic endoscopically confirmed erosive esophagitis
timeFrame: 12 months
measure: The event rate of composite cardiovascular safety endpoints
timeFrame: 12 months
measure: The event rate of death from cardiovascular causes
timeFrame: 12 months
measure: The event rate of myocardial infarction
timeFrame: 12 months
measure: The event rate of stroke
timeFrame: 12 months
measure: The event rate of any coronary or peripheral revascularization
timeFrame: 12 months
measure: The event rate of all-cause mortality
timeFrame: 12 months
measure: The event rate of any possible side effect of proton pump inhibitor (PPI) or Potassium-competitive acid blocker (PCAB)
timeFrame: 12 months
Other outcomes:
Locations:
city: Anyang
country: Korea, Republic of
facility: Hallym University Sacred Heart Hospital
city: Bucheon
country: Korea, Republic of
facility: Bucheon Sejong Hospital
city: Busan
country: Korea, Republic of
facility: Kosin University Gospel Hospital
city: Changwon
country: Korea, Republic of
facility: Gyeongsang National University Changwon Hospital
city: Changwon
country: Korea, Republic of
facility: Sungkyunkwan University Samsung Changwon Hospital
city: Cheonan
country: Korea, Republic of
facility: Dankook University Hospital
city: Cheonju
country: Korea, Republic of
facility: Chungbuk National University Hospital
city: Chuncheon
country: Korea, Republic of
facility: Gangwon National Univ. Hospital
city: Chuncheon
country: Korea, Republic of
facility: Hallym University Chuncheon Sacred Heart Hospital
city: Daegu
country: Korea, Republic of
facility: Keimyung University Dongsan Medical Center
city: Daegu
country: Korea, Republic of
facility: Yeungnam University Medical Center
city: Daejeon
country: Korea, Republic of
facility: Chungnam National University Hospital
city: Gangneung
country: Korea, Republic of
facility: Gangneung Asan Hospital
city: Guri
country: Korea, Republic of
facility: Hanyang University Guri Hospital
city: Gwangju
country: Korea, Republic of
facility: Chonnam National University Hospital
city: Ilsan
country: Korea, Republic of
facility: Inje University Ilsan Paik Hospital
city: Jeonju
country: Korea, Republic of
facility: Jeonbuk National University Hospital
city: Kwangju
country: Korea, Republic of
facility: Kwangju Christian Hospital
city: Pusan
country: Korea, Republic of
facility: Dong-A Medical Center
city: Pusan
country: Korea, Republic of
facility: Inje University Pusan Paik Hospital
city: Pusan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Sejong
country: Korea, Republic of
facility: Chungnam National University Sejong Hospital
city: Seongnam-si
country: Korea, Republic of
facility: Seoul university Bundang hospital
city: Seongnam
country: Korea, Republic of
facility: Bundang CHA Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Chung-Ang University Hospital
city: Seoul
country: Korea, Republic of
facility: Ewha Womans University Medical Center
city: Seoul
country: Korea, Republic of
facility: Hanyang University Seoul Hospital
city: Seoul
country: Korea, Republic of
facility: Kangbuk Samsung Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Kyung Hee University Hospital at Gangdong
city: Seoul
country: Korea, Republic of
facility: Kyung Hee University Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Seoul
country: Korea, Republic of
facility: SNU Boramae Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic Univ. of Korea Eunpyeong St. Mary's hospital
city: Seoul
country: Korea, Republic of
facility: The Catholic Univ. of Korea Seoul St. Mary's hospital
city: Suwon
country: Korea, Republic of
facility: Ajou University Hospital
city: Suwon
country: Korea, Republic of
facility: The Catholic University of Korea, ST. Vincent's Hospital
city: Ulsan
country: Korea, Republic of
facility: Ulsan University Hospital
city: Yangsan
country: Korea, Republic of
facility: Pusan National University Yangsan Hospital
Study officials:
References: