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This Phase I/II clinical trial is designed to evaluate, through a single-dose Phase I segment and a multiple-dose Phase II segment, the safety/tolerability, pharmacokinetic (PK) profile, and pharmacodynamic (PD) characteristics of BEBT-701 administered by subcutaneous injection in patients with mild to moderate hypertension and elevated LDL-C , and to explore its preliminary efficacy.
This study employs an integrated Phase I/II seamless adaptive design. Stage 1 is a single-dose Phase I component, randomized, double-blind, and placebo-controlled, with five pre-specified dose cohorts starting at 100 mg. Its primary objectives are to characterize the safety, tolerability, PK, PD, and preliminary efficacy of single-dose BEBT-701 across the planned dose range, thereby providing critical input for dose and dosing-interval selection for Stage 2.
After a 2- to 4-week observation period following the last Phase I cohort, three doses (preliminary) will be selected from the accumulated data to initiate Stage 2, a multiple-dose Phase II segment. This stage is a randomized, double-blind, parallel-group comparison of three active dose levels versus placebo. Placebo recipients will crossover to active treatment at Week 12 after the second dose; active-arm subjects will enter a double-blind extension after completing the 24-week post-second-dose visit, enabling collection of longer-term safety and efficacy data.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Phase I Single-Dose Cohorts (BEBT-701) | Experimental | Phase I: Five predefined dose cohorts are planned. In each cohort, the first two subjects (randomized 1:1 to active drug or placebo) are dosed in a sentinel fashion. Only after these two subjects have completed at least 48 h of safety observation and the investigator has confirmed acceptable tolerability will the remaining six subjects be enrolled and dosed at a 5:1 ratio (active drug : placebo). Enrollment and dosing of the next higher dose cohort will begin only after every subject in the preceding cohort has completed a minimum 2-week safety observation period and the safety data are judged acceptable. |
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| Phase I Single-Dose Cohorts (Placebo) | Placebo Comparator | Phase I: Five predefined dose cohorts are planned. In each cohort, the first two subjects (randomized 1:1 to active drug or placebo) are dosed in a sentinel fashion. Only after these two subjects have completed at least 48 h of safety observation and the investigator has confirmed acceptable tolerability will the remaining six subjects be enrolled and dosed at a 5:1 ratio (active drug : placebo). Enrollment and dosing of the next higher dose cohort will begin only after every subject in the preceding cohort has completed a minimum 2-week safety observation period and the safety data are judged acceptable. |
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| Phase II Multiple-Dose Cohorts (BEBT-701) | Experimental | Phase II: Based on the preliminary safety, PK, and PD data from the Phase I single-dose study, three dose levels will be selected for further evaluation. Eligible subjects will be randomized in a 1:1:1:1 ratio to one of the three pre-specified active doses or to placebo. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| BEBT-701 Injection | Drug | Phase I: The starting dose of BEBT-701 injection is 100 mg; the single subcutaneous doses are 100 mg, 200 mg, 400 mg, 800 mg, and 1200 mg. Phase II: Based on the preliminary Phase I findings, three dose levels will be selected for the Phase II study, with BEBT-701 injection administered subcutaneously on Day 1 and Day 85. |
| Measure | Description | Time Frame |
|---|---|---|
| Occurrence of Adverse Events (AEs) | Occurrence of AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE V5.0). | Up to 36 months |
| Low-Density Lipoprotein Cholesterol(LDL-C) | Percentage change from baseline in LDL-C after dosing. | Up to 24 weeks |
| 24hour-Ambulatory Blood Pressure Monitoring(24h-ABPM) | Change from baseline in mean 24h-ABPM systolic blood pressure (SBP) after dosing. | Up to 24weeks |
| Measure | Description | Time Frame |
|---|---|---|
| AUC0-∞ | The area under the plasma concentration-time curve from time zero to infinity. | Phase I:From pre-dose to 72 h post-dose on Day 1; Phase II:From pre-dose to 72 h post-dose on Day 1and Day 85. |
| Cmax |
| Measure | Description | Time Frame |
|---|---|---|
| Immunogenicity parameters | Anti-drug antibodies(ADA), interleukin-2(IL-2), interleukin-4(IL-4), interleukin-6(IL-6), interleukin-10(IL-10), interferon-gamma(IFN-γ), tumor necrosis factor-alpha(TNF-α), complement 3(C3)and complement 4(C4). | Up to 36 weeks |
Inclusion Criteria:
Male or female aged 18 to 60 years (inclusive).
Subjects with essential hypertension who are either treatment-naive or have remained off any antihypertensive medication for ≥ 30 days prior to screening and in whom the investigator deems no additional antihypertensive therapy necessary during the study period.
Body-mass index (BMI) 18.6-30kg/m² (inclusive); body weight ≥ 50 kg for men and ≥ 45 kg for women.
Has maintained a stable diet for at least 4 weeks before screening and has no plan to make a clinically significant change in diet or body weight during the study (a change > 10 % is considered significant).
Agrees to use a highly effective method of contraception and to avoid becoming a parent from enrollment until 12 months after the last dose.
Able to understand the study requirements, willing to comply, and provides written informed consent.
Phase I subjects must simultaneously meet the following criteria:
At screening and within 24 h before randomization, the 24-h ambulatory blood-pressure monitoring shows mean systolic blood pressure (SBP) > 130 mmHg and < 150 mmHg.
At screening and baseline, fasting serum LDL-C is ≥ 100 mg/dL (2.6 mmol/L) and < 190 mg/dL (4.9 mmol/L) in subjects who are either lipid-lowering-therapy-naive or have not received any lipid-lowering drug within 30 days before screening and whom the investigator judges will not require any additional lipid-lowering therapy during the study.
Phase II subjects must simultaneously meet the following criteria:
At screening and within 24h before randomization, 24-h ambulatory blood-pressure monitoring must show mean SBP > 130 mmHg and < 160 mmHg.
At screening and baseline, fasting serum LDL-C ≥ 100 mg/dL (2.6 mmol/L). Subjects already on statin therapy must have been on a stable statin dose and regimen for at least 30 days prior to screening and must have no planned changes to their statin treatment during the study.
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Kegang Jiang, Master | Contact | +86-18664786382 | kjiang@bebettermed.com |
| Name | Affiliation | Role |
|---|---|---|
| Hong Yuan, Ph.D | The Third Xiangya Hospital of Central South University | Principal Investigator |
| Guoping Yang, Ph.D | The Third Xiangya Hospital of Central South University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Third Xiangya Hospital of Central South University | Changsha | Hunan | 410013 | China |
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| Phase II Multiple-Dose Cohorts (Placebo) | Placebo Comparator | Phase II: Based on the preliminary safety, PK, and PD data from the Phase I single-dose study, three dose levels will be selected for further evaluation. Eligible subjects will be randomized in a 1:1:1:1 ratio to one of the three pre-specified active doses or to placebo. |
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| BEBT-701 Injection Placebo(0.9% Sodium Chloride Injection) | Drug | Phase I:BEBT-701 injection placebo, administered as a single subcutaneous dose. Phase II:BEBT-701 injection placebo administered subcutaneously on Day 1 and Day 85. |
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The maximum plasma drug concentration
| Phase I:From pre-dose to 72 h post-dose on Day 1; Phase II:From pre-dose to 72 h post-dose on Day 1and Day 85. |
| Tmax | The time to reach maximum plasma drug concentration | Phase I:From pre-dose to 72 h post-dose on Day 1; Phase II:From pre-dose to 72 h post-dose on Day 1and Day 85. |
| t1/2 | The time for plasma drug concentration to halve | Phase I:From pre-dose to 72 h post-dose on Day 1; Phase II:From pre-dose to 72 h post-dose on Day 1and Day 85. |
| Blood pressure-related parameters | Percentage change from baseline in mean 24-h ABPM SBP; Change from baseline in mean 24-h ABPM SBP; Change from baseline and percentage change from baseline in mean 24-h ABPM DBP,standard daytime mean SBP and DBP (6 a.m.-10 p.m.), standard nighttime mean SBP and DBP (10 p.m.-6 a.m.); Change from baseline and percentage change from baseline in office seated SBP, DBP, and mean arterial pressure (MAP). | Up to 24 weeks |
| Lipid-related parameters | Percentage change from baseline in LDL-C;Change from baseline and percentage change from baseline in total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), non-high-density-lipoprotein cholesterol (non-HDL-C), very-low-density-lipoprotein cholesterol (VLDL-C), apolipoprotein B, apolipoprotein A1, triglycerides, and lipoprotein(a). | Up to 24 weeks |
| Angiotensinogen(AGT) | Change from baseline and percentage change from baseline in AGT. | Up to 36 weeks |
| Proprotein convertase subtilisin/kexin type 9 (PCSK9) | Change from baseline and percentage change from baseline in PCSK9. | Up to 36 weeks |