Clinical trial NCT05857163
Conditions: H.Pylori Infection
Sponsor: TenNor Therapeutics (Suzhou) Limited
Start date: 2023-05-18; Completion date: 2024-03-26
Enrollment: 700 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A multi-center, randomized, double-blind, bismuth-containing quadruple active comparator-controlled Phase 3 clinical study to evaluate the efficacy and safety of Rifasutenizol in combination with rabeprazole and amoxicillin in the primary treatment of participants with H. pylori infection using an adaptive design with sample size re-estimation.

Detailed description:
Subjects will be randomly assigned to test group or control group at a 1:1 ratio stratified by study site, and will receive Rifasutenizol capsules, rabeprazole sodium enteric-coated tablets, amoxicillin capsules combined with clarithromycin placebo tablets and bismuth potassium citrate placebo capsules (test group), or bismuth-containing quadruple regimen of amoxicillin capsules, clarithromycin tablets, rabeprazole sodium enteric-coated tablets and bismuth potassium citrate capsules combined with Rifasutenizol placebo capsules (control group) for 14 consecutive days.

carbon-13 (13C) UBT will be performed 4-6 weeks after the last dose to evaluate the eradication effect of H. pylori.

Arms: arm 1: Rifasutenizol capsules 400 mg + Rabeprazole sodium enteric-coated tablets 20 mg + Amoxicillin capsules 1 g + Bismuth potassium citrate placebo capsules + Clarithromycin placebo tablets, twice daily (BID) for 14 days arm 2: Amoxicillin capsules 1 g + Clarithromycin tablets 500 mg + Rabeprazole sodium enteric-coated tablets 20 mg + Bismuth potassium citrate capsules 240 mg + Rifasutenizol placebo capsules, BID for 14 days
Interventions: intervention 1: Rifasutenizol capsules intervention 2: Rabeprazole sodium enteric-coated tablets intervention 3: Amoxicillin Capsules intervention 4: Clarithromycin placebo tablets intervention 5: Bismuth potassium citrate placebo capsules intervention 6: Clarithromycin tablets intervention 7: Bismuth potassium citrate capsules intervention 8: Rifasutenizol placebo capsules
Intervention descriptions: intervention 1: 400 mg, BID, taken orally within half an hour after breakfast and dinner. intervention 2: 20 mg, BID, taken orally within half an hour before breakfast and dinner. intervention 3: 1 g, BID, taken orally within half an hour after breakfast and dinner. intervention 4: BID, taken orally within half an hour after breakfast and dinner. intervention 5: BID, taken orally within half an hour before breakfast and dinner. intervention 6: 500 mg, BID, taken orally within half an hour after breakfast and dinner. intervention 7: 240 mg, BID, taken orally within half an hour before breakfast and dinner. intervention 8: BID, taken orally within half an hour before breakfast and dinner.

Protocol documents:
Prot_SAP_000.pdf: 
 
A Multicenter, Randomized, Double-blind, Bismuth-containing Quadruple Active 
Comparator-controlled Phase 3 Clinical Trial to Evaluate the Efficacy and Safety of 
Rifasutenizol (TNP-2198) in Combination with Rabeprazole and Amoxicillin in Treatment-
Naïve Participants with H. pylori Infection 
 
 
 
 
 
Protocol Synopsis 
 
 
Protocol No.: TNP-2198-07 
 
 
Approval Date; 14 February 2023 
 
 
 


SYNOPSIS OF PROTOCOL 
Study Title: A Multicenter, Randomized, Double-blind, Bismuth-containing Quadruple Active Comparator-
controlled Phase 3 Clinical Trial to Evaluate the Efficacy and Safety of Rifasutenizol (TNP-2198) in 
Combination with Rabeprazole and Amoxicillin in Treatment-Naïve Participants with H. pylori Infection 
Indication: H. pylori infection 
Development Phase：Phase 3 
Study Objectives  
Primary objective 
 
To evaluate whether the eradication rate of Rifasutenizol (TNP-2198) in combination with rabeprazole 
sodium and amoxicillin is non-inferior to bismuth quadruple regimen in treatment-naïve participants 
with Helicobacter pylori infection (if non-inferiority conclusion is established, it will be further assessed 
whether it is superior to bismuth quadruple regimen). 
Secondary objectives 
 
To evaluate the efficacy of Rifasutenizol (TNP-2198) in combination with rabeprazole and amoxicillin  
in treatment-naïve participants with H. pylori infection based on the results of H. pylori culture and drug 
susceptibility testing. 
 
To evaluate the safety of Rifasutenizol (TNP-2198) in combination with rabeprazole and amoxicillin in 
treatment-naïve participants with H. pylori infection. 
 
To evaluate the pharmacokinetic profile of Rifasutenizol (TNP-2198) when administered in combination 
with rabeprazole and amoxicillin. 
Study Endpoints 
Primary endpoint: 
 
Eradication rate of H. pylori (based on the test results of 13C-UBT) 4-6 weeks after the last dose of the 
study drugs. 
Secondary endpoints: 
 
Safety: incidence of adverse events during the study, relationship with the study drugs and severity, 
laboratory tests (blood chemistry, hematology, and urinalysis), vital signs, electrocardiogram (ECG), 
physical examination. 
 
Pharmacokinetic (PK): PK parameters of Rifasutenizol (TNP-2198): 
- 
PK parameters of the first dose: Tmax, Cmax, t1/2, AUC0-tau, AUC0-∞, Vd/F, and CL/F; 
- 
PK parameters of the multiple-dose: Tmax, ss; Cmax, ss; t1/2, ss; AUC0-tau, ss; AUC0-∞, ss; Vd/Fss; CL/Fss; 
and Rac. 
Methodology/Study Design 
This is a multi-center, randomized, double-blind, bismuth-containing quadruple active comparator-controlled 
Phase 3 clinical study to evaluate the efficacy and safety of Rifasutenizol (RSZ, formally known as TNP-
2198) in combination with rabeprazole and amoxicillin in treatment-naïve participants with H. pylori 
infection using an adaptive design with sample size re-estimation. The status of H. pylori infection during the 
Screening Period is determined by 13C-urea breath test (13C-UBT) and confirmed by gastroscopic biopsy 
histology. 
Eligible subjects will be randomly assigned to test group or control group at a 1:1 ratio stratified by study 
site, and will receive RSZ capsules, rabeprazole sodium enteric-coated tablets, amoxicillin capsules 
combined with clarithromycin placebo tablets and bismuth potassium citrate placebo capsules (test group), or 
bismuth-containing quadruple regimen of amoxicillin capsules, clarithromycin tablets, rabeprazole sodium 
enteric-coated tablets and bismuth potassium citrate capsules combined with RSZ placebo capsules (control 
group) for 14 consecutive days. 13C-UBT will be performed 4-6 weeks after the last dose to evaluate the 
eradication effect of H. pylori. 


This study will also conduct a PK study at one study site to evaluate the PK profile of RSZ when 
administered in combination with rabeprazole and amoxicillin. A minimum of 20 subjects and a maximum 
of 40 subjects will be enrolled in the PK study at this study site, and randomly assigned to the test group 
and  the control group in a 1:1 ratio. For the enrolled subjects, PK blood samples will be collected before and 
after the morning administration on Day 1 (D1) and D14 (1-3 day(s) earlier if necessary). 
Number of Subjects 
According to the study results of clinical trials for H. pylori eradication in China and abroad, it is estimated 
that the eradication rate of H. pylori with 14-day bismuth-containing quadruple therapy (amoxicillin, 
clarithromycin, rabeprazole and bismuth potassium citrate) is about 85%. If the eradication rates of H. pylori 
in the test group and the control group are both 85%, Type I error is 0.025 (one-sided), power is 90%, a 
non-inferiority margin is -10%, and a dropout rate is about 15%, the required sample size is 
about 700 subjects (350 and 350 subjects in the test group and the control group, respectively, including the 
subjects participating in the PK study). Considering the uncertainty of the treatment effect, an adaptive 
design with sample size re-estimation is planned in this trial. One interim analysis is planned will be 
performed by an independent data monitoring committee (IDMC) when the primary endpoint data of 50% of 
the subjects are obtained. If the eradication rate of H. pylori observed in the test group is less than 10% in the 
control group, the trial can be terminated due to futility. In addition, sample size re-estimation will be 
performed during the interim analysis, and the re-estimation of sample size will be based on the Promising-
Zone method (2011). The actual sample size will depend on the effect size or p-value observed during the 
interim analysis. Up to 1200 subjects are planned to be enrolled in this study. If the eradication rate of H. 
pylori in the test group 4-6 weeks after the end of treatment is non-inferior to that in the control group, the 
superiority comparison between the test group and the control group will be further performed. 
A Promising-Zone method is used for sample size re-estimation and power calculation to strictly control the 
Type I error. Statistical simulation results indicate that the adaptive design will provide 97.3% power to test 
non-inferiority if the efficacy (eradication rate of H. pylori) is 85% in the test group and 85% in the control 
group at a non-inferiority margin of -10%. If the efficacy is 82% in the test group and still 85% in the control 
group, the adaptive design will provide 77.1% power to test for non-inferiority. If the efficacy of the test 
group is higher than the estimated value, such as 90% eradication rate in the test group and 83% eradication 
rate in the control group, the design will provide approximately 78% power to test for superiority. If the 
eradication rate is 90% in the test group and 84% in the control group, the design will still provide 
approximately 66.1% power to test for superiority. 
Inclusion and Exclusion Criteria 
All of the following criteria must be met for inclusion: 
1) 
Voluntarily sign the informed consent form. 
2) 
Age 18-65 years (inclusive), male or female. 
3) 
The result of 13C-UBT is positive (≥ 4 Delta Over Baseline), and the infection of H. pylori are 
confirmed by gastroscopic biopsy histology. 
4) 
Subjects agree to refrain from taking any antibiotics or traditional Chinese medicines with antibacterial 
effect, bismuth, and antacids (such as PPI, H2 receptor blocker, P-CAB) other than the study drugs 
during the Screening Period until the end of the study (Visit 5, i.e., Efficacy Evaluation Visit). 
5) 
Subjects and their heterosexual partners must agree to have no pregnancy plan and voluntarily take 
effective contraceptive measures during the trial and for at least 6 months after the end of the study 
medication. 
6) 
Willing to follow and able to complete all trial procedures. 
Subjects will not be enrolled in the study if they meet any of the following exclusion criteria: 
1) 
Allergy to any of the study drugs (rabeprazole, amoxicillin, clarithromycin, bismuth potassium citrate), 
allergic constitution (multiple drug and food allergies); or any contraindication to the use of rifamycin, 
nitroimidazoles or study drugs. 
2) 
History of H. pylori eradication therapy (including participation in other clinical trials for H. pylori 
eradication). 
3) 
Subjects with confirmed tuberculosis (TB) or Mycobacterium avium complex (MAC) infection or a 
history of TB or MAC infection. 
4) 
History of dysphagia or any gastrointestinal disorder affecting drug absorption. 


5) 
History of obstruction pyloric; or excessive gastric acid secretion (such as Zollinger-Ellison syndrome). 
6) 
History of gastric cancer. 
7) 
History of neoplasm malignant within 5 years prior to screening, with the exception of basal cell 
carcinoma or carcinoma cervix in situ treated without evidence of recurrence. 
8) 
History of esophageal or gastric surgery, except for simple repair of the perforated ulcer. 
9) 
History of substance abuse or drug use within 5 years prior to screening. 
10) Alcohol abuse or a history of alcohol abuse within 5 years prior to screening (average weekly 
consumption of ≥ 14 units of alcohol: 1 unit = 285 mL of beer, or 25 mL of spirits, or 100 mL of 
wine/Chinese rice wine/rice wine); 
11) Presence of active gastric and/or duodenal ulcer. 
12) Anticoagulant therapy or long-term treatment with nonsteroidal anti-inflammatory drugs. 
13) Treatment with any other investigational new drugs within 4 weeks prior to the Screening Period. 
14) Any prohibited medications or non-drug therapies as specified in the protocol. 
15) White blood cell count or neutrophil count below the lower limit of normal range. 
16) Anemia (hemoglobin < 90 g/L). 
17) Aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, or serum creatinine 
above the upper limit of normal range. 
18) Test positive for hepatitis B surface antigen, hepatitis C antibody, AIDS antibody, or microspironema 
pallidum antibody. 
19) Abnormal ECG with clinical significance. 
20) Female subjects who are pregnant, lactating, or have a positive urine pregnancy result during the 
Screening Period. 
21) Inability to communicate with the Investigator and to comply with the study requirements. 
22) Other conditions considered inappropriate to participate in this study by the Investigator, e.g., the 
subject has a history of severe central nervous system, cardiovascular, pulmonary, hepatic, renal, 
metabolic, gastrointestinal, urological, endocrine, or hematological diseases, or has clinical 
manifestations of these diseases. 
Study Drug, Dose, Dosage Form and Mode of Administration 
Test group 
Administered for 14 consecutive days as follows: 
 
RSZ capsules, 400 mg, BID, taken orally within half an hour after breakfast and dinner 
 
Rabeprazole sodium enteric-coated tablets, 20 mg, BID, taken orally within half an hour before breakfast 
and dinner 
 
Amoxicillin capsules, 1 g, BID, taken orally within half an hour after breakfast and dinner 
 
Clarithromycin placebo tablets, BID, taken orally within half an hour after breakfast and dinner 
 
Bismuth potassium citrate placebo capsules, BID, taken orally within half an hour before breakfast and 
dinner 
Control Group 
Administered for 14 consecutive days as follows: 
 
Amoxicillin capsules, 1 g, BID, taken orally within half an hour after breakfast and dinner 
 
Clarithromycin tablets, 500 mg, BID, taken orally within half an hour after breakfast and dinner 
 
Rabeprazole sodium enteric-coated tablets, 20 mg, BID, taken orally within half an hour before breakfast 
and dinner 
 
Bismuth potassium citrate capsules, 240 mg, BID, taken orally within half an hour before breakfast and 
dinner 
 
RSZ placebo capsules, BID, taken orally within half an hour after breakfast and dinner 
Duration of Subject Participation in the Study 


Planned total duration of study participation: up to approximately 70 days, i.e., 14 days of Screening, 14 days 
Treatment Period, and up to 42 days of Follow-up. 
Analysis Population 
Intention-to-treat (ITT): includes all randomized subjects and will be analyzed according to scheduled 
treatment groups. 
Modified intention-to-treat (mITT): includes all subjects in the ITT who received at least one dose of study 
drugs and will be analyzed according to scheduled treatment groups. 
Micro-ITT: includes all subjects in the mITT set who have a positive pre-dose H. pylori culture and a drug 
susceptibility testing result and will be analyzed according to scheduled treatment groups. 
Per-protocol (PP): includes all subjects without major protocol violations affecting efficacy analysis, who are 
randomized and receive more than 75% (including 75%) of the total amount of each study drugs and have 
13C-UBT performed 4-6 weeks after the last dose of study drugs and will be analyzed according to scheduled 
treatment groups. 
Safety set (SS): includes all randomized subjects who received at least one dose of study drug and will be 
analyzed according to actual treatment groups. 
Pharmacokinetic concentration set (PKCS): includes all randomized subjects who have received RSZ 
capsules and have at least one valid observed PK concentration data and will be analyzed according to actual 
treatment groups. 
Pharmacokinetic parameter set (PKPS): includes all randomized subjects who have received RSZ capsules 
and have at least one valid PK parameter data and will be analyzed according to actual treatment groups. 
Efficacy Evaluation 
Efficacy analysis and estimands: 
The efficacy endpoint of the study is the eradication rate of H. pylori 4-6 weeks after the last dose of the 
study drug, and the analysis of the mITT population is the primary analysis of the study. 
Depending on the study objectives and study design, the following primary estimands are specified: 
 
Primary estimand 
Population 
Treatment-naïve participants with H. pylori infection who meet the inclusion and 
exclusion criteria 
Variable 
Eradication of H. pylori (based on the test results of 13C-UBT) 4-6 weeks after the end of 
treatment 
Treatment 
RSZ capsules (400 mg) administered BID in combination with rabeprazole sodium enteric-
coated tablets (20 mg), amoxicillin capsules (1 g), clarithromycin placebo tablets, and 
bismuth potassium citrate placebo capsules, or bismuth-containing quadruple regimen plus 
RSZ placebo capsules; Continuous treatment for 14 days 
Intercurrent 
events 
Intercurrent events affecting the assessment of the primary endpoint include, but are not 
limited to: 
 
Discontinuation of study treatment 
 
Events of concomitant medications and non-drug therapy during the study that may 
affect the test results of the post-treatment 13C-UBT 
Detailed descriptions of intercurrent events, missing data, related to the estimands will be 
provided in the statistical analysis plan. 
Population level 
summary 
Eradication rate of H. pylori at 4-6 weeks after the end of treatment in the test group and the 
control group 
 
In addition, subgroup analysis of efficacy endpoints will also be performed based on drug susceptibility 
testing results: based on the baseline H. pylori culture and drug susceptibility testing results, the patients will 
be grouped according to the resistance status (resistant or sensitive) to rifabutin, amoxicillin, clarithromycin, 
metronidazole, tetracycline, furazolidone and levofloxacin, and the eradication rates of H. pylori at 4-6 weeks 
after the last dose of the test group and the control group in each subgroup will be analyzed. 
Safety Evaluation 


Safety endpoints: incidence of adverse events (AEs) during the study, relationship with the study drugs and 
severity, laboratory tests (hematology, urinalysis, blood chemistry), vital signs, ECG, physical examination. 
Pharmacokinetics (PK) 
For subjects participating in the PK study, PK blood samples (4 mL each) will be collected in the 
ethylenediamine tetraacetic acid (EDTA) anticoagulant tubes within 30 minutes before the first study drugs 
administration in the morning and 1, 2, 3, 4, 5, 6, 7, 8, 10, and 12 hours (before the second RSZ 
capsules/placebo administration on the same day) after RSZ capsules/placebo administration on D1 and D14 
(1-3 day(s) earlier if necessary). The allowable time window for blood sampling is ± 0. 5 hours.  
 
PK parameters of the first dose include: Tmax, Cmax, t1/2, AUC0-tau, AUC0-∞, Vd/F, and CL/F.  
 
PK parameters of the multiple-dose include: Tmax, ss; Cmax, ss; t1/2, ss; AUC0-tau, ss; AUC0-∞, ss; Vd/Fss; CL/Fss; 
and Rac. 
Statistical Method 
Demographical analysis 
Demographic analysis is conducted based on the ITT. Descriptive statistics will be performed for all 
demographic (age, sex, weight, height, ethnicity, etc.) and baseline characteristics, taking the last valid 
measurement before the administration of the study drugs as the baseline. 
Efficacy analysis 
Efficacy analysis is mainly based on the test results of 13C-UBT at 4-6 weeks after the last dose of study 
drugs to evaluate the effect of H. pylori eradication. Analysis will be mainly based on mITT set, and 
sensitivity analysis or supplementary analysis will be performed for the primary endpoints based on other 
efficacy analysis sets (ITT, Micro-ITT, and PP). Descriptive analysis is performed using frequency 
(percentage) according to 13C-UBT test results (negative or positive) in different groups. Farrington-Manning 
test is used as the primary analysis for non-inferiority comparison between the test group and the control 
group, with non-inferiority margin of -10%; If the non-inferiority test is statistically significant, the 
Farrington-Manning method is continued to be used for superiority test (null hypothesis is that the difference 
in eradication rate of H. pylori between the test group and the control group is ≤ 0, and alternative hypothesis 
is that the difference in eradication rate of H. pylori between the test group and the control group is > 0). As a 
supportive analysis, the point estimate and two-sided 95% confidence interval (CI) of the difference in 
eradication rate of H. pylori between the test group and the control group will be calculated using the 
Miettinen-Nurminen method. If the lower limit of the 95% CI is greater than -10%, the eradication rate of H. 
pylori in the test group is considered to be non-inferior to that in the control group. If the test group is non-
inferior to the control group and the lower limit of 95% CI is > 0, the eradication rate of H. pylori in the test 
group is considered superior to that in the control group. In addition, the efficacy of RSZ in combination with 
rabeprazole and amoxicillin in treatment-naïve participants with H. pylori infection is evaluated in a 
subgroup analysis based on the results of H. pylori culture and drug susceptibility testing. 
Safety analysis 
The evaluation and analysis of safety and tolerability are mainly based on descriptive statistics. Aes, 
treatment-emergent adverse events (TEAE), serious adverse events (SAE), drug-related TEAE, and TEAE 
leading to withdrawal from the trial will be summarized. 
The number and incidence of TEAE will be summarized and described by system organ class and preferred 
term in each group. 
The number and incidence of TEAE will be summarized and described by system organ class, preferred 
term, and severity in each group. 
The number and incidence of drug-related TEAE will be summarized and described by system organ class 
and preferred term in each group. 
Vital signs (blood pressure, respiration, pulse, and body temperature), laboratory tests and ECG results and 
changes from baseline will be summarized and described in each group, and clinically significant abnormal 
results and all test results post-baseline will be listed. 
SAE, TEAE leading to discontinuation of study treatment, and TEAE leading to premature withdrawal from 
the study will be presented separately. 
Pharmacokinetic analysis 


Pharmacokinetic parameters (non-compartmental models) will be estimated and analyzed for plasma 
concentration data using Phoenix WinNonlin software, and the main pharmacokinetic parameters will be 
calculated using PKPS data. 
PK concentration data will be statistically summarized and tabulated for RSZ at each sampling time point as 
defined in the protocol. Mean and median drug concentration-time profiles (linear and semi-logarithmic 
plots) will also be plotted by planned sampling time for each subject. The PK concentration data for 
individual subjects will be used to plot the drug concentration-time curve (linear and semi-logarithmic plots) 
based on the actual sampling time. 
For samples with concentrations below the quantification limit, samples sampled before Cmax should be 
calculated as zero and samples sampled after Cmax should be calculated as not detectable when performing 
pharmacokinetic analysis. According to the treatment groups, the analysis results of main pharmacokinetic 
parameters are summarized and displayed by sample size, arithmetic mean, standard deviation, coefficient of 
variation, median, minimum, maximum, geometric mean, and geometric coefficient of variation.  
PK parameters of the first dose include: Tmax, Cmax, t1/2, AUC0-tau, AUC0-∞, Vd/F, and CL/F. PK parameters of 
the multiple-dose include: Tmax, ss; Cmax, ss; t1/2, ss; AUC0-tau, ss; AUC0-∞, ss; Vd/Fss; CL/Fss; and Rac. For subjects 
with AUC_% Extrap > 20%, descriptive statistical analysis will not be performed for AUC0-∞, t1/2, CL/F, Vd/F, 
and AUC_% Extrap. 
The statistical analysis method and plan are detailed in the statistical analysis plan.