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A multicenter, Phase II, randomized, double-blind, single ascending dose (SAD) and multiple ascending dose (MAD), as well as single-arm clinical study evaluating the long-term efficacy and safety of MT1013 in hemodialysis subjects with secondary hyperparathyroidism. The SAD study consists of five cohorts at doses of 5, 10, 20, 40, and 60 mg. The MAD study consists of three cohorts at doses of 5, 10, and 20 mg. In both the SAD and MAD studies, each cohort includes 8 subjects (6 subjects receive the active investigational drug, and 2 subjects receive matching placebo), and the cohorts are conducted sequentially. In the long-term dosing cohort, all subjects will undergo regular hemodialysis three times per week, receiving the drug once after each hemodialysis session for a total duration of 52 weeks
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| MT1013 for SAD | Experimental | Single ascending doses of MT1013 |
|
| Placebo for SAD | Placebo Comparator | Placebo comparator for SAD |
|
| MT1013 for MAD | Experimental | Multiple ascending doses of MT1013 |
|
| Placebo for MAD | Placebo Comparator | Placebo comparator for MAD |
|
| Long-term Dosing Cohort | Experimental | Dose titration period covers the first 10 weeks , followed by maintenance dosing period, for a total treatment duration of 52 weeks |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Long-term Dosing Cohort | Drug | All subjects will undergo regular hemodialysis three times per week. Administration of MT1013occurs once after each hemodialysis session and will continue for 52 weeks. The first 10 weeks constitute the dose-titration period, during which the drug dose is titrated every 3 weeks based on iPTH and serum corrected calcium levels. During the maintenance dosing period, doses is adjusted based on iPTH and serum corrected calcium levels. |
| Measure | Description | Time Frame |
|---|---|---|
| SAD/MAD :Percentage of treatment-emergent adverse events (TEAEs) | To investigate the safety and tolerability of MT1013 by assessing the incidence and severity of TEAEs in Single Ascending Dose (SAD Cohort) and Multiple Ascending Doses (MAD Cohort) | SAD:on Day 8±1. MAD:on Day 16+2 or 30+2 and Day 21±2 or 35±2 |
| Long-term Dosing Cohort: Proportion of subjects with > 30% reduction in serum iPTH compared to baseline level. | Proportion of subjects achieving a >30% reduction in serum iPTH from baseline at Week 14. | 14 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Change in the mean serum intact parathyroid hormone (iPTH) from baseline | Change in serum intact parathyroid hormone (iPTH) from baseline at each visit | SAD:on Day 8±1. MAD:on Day 16+2 or 30+2 and Day 21±2 or 35±2. Long-term Dosing Cohort: 52 weeks |
| Proportion of subjects achieving a >30% reduction in serum iPTH from baseline |
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Inclusion Criteria (Subjects must meet all of the following criteria to participate in the trial):
Postmenopausal is defined as:
Age ≥55 years & amenorrhea for ≥12 months;
Or Age <55 years but no spontaneous menses for at least 2 years;
Or Age <55 years with spontaneous menses within the past 1 year, but currently amenorrheic, and with postmenopausal gonadotropin levels (luteinizing hormone and follicle-stimulating hormone levels >40 IU/L) or postmenopausal estradiol levels (<5.3 pmol/L or 5 ng/dL) or meeting the laboratory's definition of "postmenopausal range";Having undergone bilateral oophorectomy.
Exclusion Criteria (Subjects meeting any of the following criteria will be excluded from the study):
1 .History of severe ventricular arrhythmia or symptomatic ventricular arrhythmia at screening, or QTc >470 ms for males or >480 ms for females at screening;
2. Subjects with heart failure symptoms,class III or IV by New York Heart Association (NYHA) , at screening;
3. History of myocardial infarction, coronary angioplasty, or coronary artery bypass graft within the past 6 months;
4. History of seizures or having received treatment for seizures;
5. Prior parathyroidectomy;
6. Serum transaminases (alanine aminotransferase, aspartate aminotransferase) >3 times the upper limit of normal at screening; or serum albumin <30 g/L;
7.History of organ transplant (excluding being on the kidney transplant waiting list), hematopoietic stem cell transplant, or bone marrow transplant; or patients planning to undergo organ transplantation;
8.Severe uncontrolled hypertension, defined as systolic blood pressure >180 mmHg and diastolic blood pressure >100 mmHg despite optimal medical therapy before enrollment;
9.Known malignancy or other comorbidities with a life expectancy of <3 months (except for patients disease-free for ≥5 years, or disease-free for ≥5 years after the last dose of chemotherapy );
10.Known alcohol or illicit drug abuse within 12 months prior to screening, unwillingness or inability to abstain from alcohol for 24 hours prior to each study visit, or unwillingness or inability to limit alcohol consumption to a maximum of 2 drinks per day during the study (one drink is equivalent to 360 mL of regular beer, 150 mL of wine, or 45 mL of 40% alcohol spirits);
11.Positive for human immunodeficiency virus (HIV) or known diagnosis of acquired immunodeficiency syndrome (AIDS) at screening;
12.Subjects positive for hepatitis B surface antigen (HBsAg) at screening (indicative of chronic hepatitis B) AND with serum transaminases (alanine aminotransferase, aspartate aminotransferase) >2 times the upper limit of normal;
13.Positive for hepatitis C virus ribonucleic acid (RNA) by polymerase chain reaction (PCR) at screening (indicative of active hepatitis C - usually screened via hepatitis C antibody [HCV-Ab], with PCR for HCV RNA if HCV-Ab positive);
14.Patients with known hypersensitivity to the investigational product and/or its components;
15.Patients who have participated in another clinical trial and received an investigational drug within 8 weeks prior to the first dose or within 5 half-lives of the investigational drug (whichever is longer);
16. Patients who have previously received MT1013;
17. Subjects who have received cinacalcet treatment within 8 days prior to the first dose;
18. Pregnant or potentially pregnant women or lactating women;
19. Inability to fully comply with the study protocol;
20.Any other medical or psychiatric condition that, in the investigator's opinion, precludes participation in the study;
21. Subjects with active gastrointestinal bleeding or a high risk of astrointestinal bleeding tendency at screening.
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| First Affiliated Hospital College of Medicine, Zhejiang University | Hangzhou | Zhejiang | 310003 | China |
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This study consists of the following three cohorts:
SAD Cohort: All subjects will receive a single dose only after a single hemodialysis session and will be followed up on Day 8±1.
MAD Cohort: All subjects will undergo regular hemodialysis three times per week. Dosing will occur once after each hemodialysis session, continuing for either 2 or 4 weeks (treatment period). Subjects will undergo safety follow-up on Day 16+2 or 30+2 and Day 21±2 or 35±2.
Long-term Dosing Cohort: All subjects will undergo hemodialysis three times per week. Dosing will occur once after each hemodialysis session and will continue for 52 weeks. The first 10 weeks constitute the dose titration period, during which the drug dose is titrated every 3 weeks based on iPTH and serum corrected calcium levels. During other treatment periods, the drug dose may be adjusted based on iPTH and serum corrected calcium levels.
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|
| Single ascending doses of MT1013 | Drug | All subjects will receive a single dose (MT1013 or placebo) only after a single hemodialysis session |
|
| Multiple ascending doses of MT1013 | Drug | All subjects will undergo hemodialysis three times per week. Dosing (MT1013 or placebo) will occur once after each hemodialysis session, continuing for either 2 or 4 weeks (treatment period). |
|
Proportion of subjects achieving a >30% reduction in serum iPTH from baseline at each visit |
| SAD:on Day 8±1. MAD:on Day 16+2 or 30+2 and Day 21±2 or 35±2. Long-term Dosing Cohort: 52 weeks |
| Change from baseline in corrected Ca | Change in corrected calcium from baseline at each visit | SAD:on Day 8±1. MAD:on Day 16+2 or 30+2 and Day 21±2 or 35±2. Long-term Dosing Cohort: 52 weeks |
| Change from baseline in ionized calcium | Change in ionized calcium from baseline at each visit | SAD:on Day 8±1. MAD:on Day 16+2 or 30+2 and Day 21±2 or 35±2 |
| Change in DXA-measured bone mineral density (BMD) at the femoral neck and lumbar spine from baseline | Change in DXA-measured bone mineral density (BMD) at the femoral neck and lumbar spine from baseline at each visit | Long-term Dosing Cohort: 52 weeks |
| Incidence and severity of treatment-emergent adverse events (TEAEs) | Incidence and severity of adverse events occurred during the study period | Long-term Dosing Cohort: 52 weeks |
| Change from baseline in serum phosphorus | Change in serum phosphorus from baseline at each visit | SAD:on Day 8±1. MAD:on Day 16+2 or 30+2 and Day 21±2 or 35±2 |
| Change from baseline in the mean corrected calcium-phosphorus product | Change in the mean corrected calcium-phosphorus product from baseline at each visit | SAD:on Day 8±1. MAD:on Day 16+2 or 30+2 and Day 21±2 or 35±2 |
| Assessment change of Bone Turnover Markers - Change from Baseline | Change in PINP from baseline at each visit | SAD:on Day 8±1. MAD:on Day 16+2 or 30+2 and Day 21±2 or 35±2. Long-term Dosing Cohort: 52 weeks |
| Assessment change of Bone Turnover Markers - Change from Baseline | Change in CTX from baseline at each visit | SAD:on Day 8±1. MAD:on Day 16+2 or 30+2 and Day 21±2 or 35±2. Long-term Dosing Cohort: 52 weeks |
| Assessment change of Bone Turnover Markers - Change from Baseline | Change in OC from baseline at each visit | SAD:on Day 8±1. MAD:on Day 16+2 or 30+2 and Day 21±2 or 35±2. Long-term Dosing Cohort: 52 weeks |
| Assessment change of Bone Turnover Markers - Change from Baseline | Change in b-ALP from baseline at each visit | SAD:on Day 8±1. MAD:on Day 16+2 or 30+2 and Day 21±2 or 35±2. Long-term Dosing Cohort: 52 weeks |
| Assessment change of Bone Turnover Markers - Change from Baseline | Change in TRAP-5b from baseline at each visit | SAD:on Day 8±1. MAD:on Day 16+2 or 30+2 and Day 21±2 or 35±2. Long-term Dosing Cohort: 52 weeks |
| Cmax of MT1013 | Cmax - Maximum plasma concentration | SAD:on Day 8±1. MAD:on Day 16+2 or 30+2 and Day 21±2 or 35±2 |
| Tmax of MT1013 | Tmax - Time to reach Cmax | SAD:on Day 8±1. MAD:on Day 16+2 or 30+2 and Day 21±2 or 35±2 |
| T1/2 of MT1013 | T1/2 - Elimination half-life | SAD:on Day 8±1. MAD:on Day 16+2 or 30+2 and Day 21±2 or 35±2 |
| AUC0-tau of MT1013 | AUC0-tau - Area under the plasma concentration-time curve during one dosing interval | SAD:on Day 8±1. MAD:on Day 16+2 or 30+2 and Day 21±2 or 35±2 |
| AUC0-t of MT1013 | AUC0-t - Area under the plasma concentration-time curve from time zero to the last measurable concentration | SAD:on Day 8±1. MAD:on Day 16+2 or 30+2 and Day 21±2 or 35±2 |
| ID | Term |
|---|---|
| D006962 | Hyperparathyroidism, Secondary |
| ID | Term |
|---|---|
| D006961 | Hyperparathyroidism |
| D010279 | Parathyroid Diseases |
| D004700 | Endocrine System Diseases |
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