A Phase 1 Randomized, Double-blind, Dose-Escalating Study to Assess the Safety, Tolerability, and Pharmacokinetics of MTX-439 in Healthy Adults and Adults With Diabetic Kidney Disease
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 88
- 试验地点
- 1
- 主要终点
- Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of MTX-439
研究概览
简要总结
This is a phase 1 randomized, double-blind, single ascending dose (SAD) and multiple ascending dose (MAD) study to assess the safety, tolerability, and Pharmacokinetics (PK) of single and multiple ascending doses of MTX-439 administered in healthy adults and adults with diabetic kidney disease (DKD)
详细描述
This is a randomized, double-blind, placebo-controlled, single-ascending dose (SAD) and multiple-ascending dose (MAD) study to assess the safety, tolerability, and PK of single- and multiple-ascending doses of MTX-439 administered in healthy adults and adults with DKD.
The SAD portion of the study with healthy participants will consist of 5 planned intravenous (IV) dosing cohorts, comprising 8 participants. Dosing will be weight based, and the starting dose will be 100 fold below the top of the safety window. Doses will then be increased, depending on the safety, tolerability and drug exposure levels, in subsequent Cohorts, with increases proceeding in either 2x or 3x increments. . Planned doses may be adjusted in response to the data. Additional participants and/or additional dosing cohorts may be added as needed based on the data. Within each HP cohort, participants will be randomly assigned to receive MTX-439 or matched placebo. The first 2 participants (sentinel participants) within each HP cohort will be randomized 1:1 to receive MTX-439 or placebo on Day 1. These participants will be monitored for 24 hours and, after review of the safety data from both participants and approval by the study Investigator, Medical Monitor, and Sponsor's Responsible Medical Officer (SRMO), the additional 6 participants will be randomized to study drug (n=5 MTX-439; n=1 placebo).
In addition, a minimum of 2 planned IV dosing cohorts comprising 8 DKD participants will receive MTX439 or matched placebo to assess the PK in patients vs healthy controls. DKD Cohort 1 may be dosed any time after the dose escalation meeting for HP Cohort 2 is completed, and the decision is made to dose escalate. The starting dose of study drug in DKD Cohort 1 will be the same as the dose for Cohort 1 in healthy volunteers. No dose can be administered to DKD participants until the same or higher dose has been safely administered to healthy participants. Participants in the DKD SAD portion of the study will be randomized 3:1 to receive MTX-439 or matched placebo on Day 1. Sentinel dosing will not be required in DKD cohorts.
The MAD portion of the study will consist of 4 planned IV dosing cohorts comprising 8 healthy participants (n=6 MTX-439; n=2 placebo).Dosing for each MAD cohort is planned for Day 1, Day 15 and Day 29. Cohort 1 of the MAD portion of the study can begin following completion of the SAD Cohort 2 safety meeting and once the study Investigator, Medical Monitor, and SRMO decide to proceed to HP SAD Cohort 3. Dose escalation will occur depending on the safety, tolerability and PK in previous cohorts.
Participants will be in the study will be followed for safety and be assessed for PK and immunogenicity. For SAD cohorts, participation will be 85 days and for MAD cohorts 113 days.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •All genders, ages 18 to 65 years, inclusive.
- •Able to read and understand the study and all related materials (including the ICF), and provide a signed, written informed consent.
- •Willing and able to complete all protocol-required study visits and procedures.
- •Consumption of no more than 5 cigarettes or other cotinine-containing products (including tobacco, nicotine gum, patches, nicotine pouches, and e-cigarettes) per week and agreement to abstain from all such products during inpatient stays.
- •Willing to refrain from marijuana- or cannabinol-containing products for 30 days before Screening and until the last study visit.
- •Agrees to not donate eggs (if applicable) from the time of the first infusion until 65 days after the final dose, or 125 days after the final dose for sperm (if applicable); additionally agrees to not donate blood from 56 days prior to the time of first infusion until 90 days after the last study visit or platelets/plasma from 14 days prior to the time of first infusion until 90 days after the last study visit.
- •Participants are required to follow specific contraception measures as follows:
- •Participants assigned male at birth must use a condom (even if vasectomised) at the time of Screening and for 125 days after the final dose.
- •Participants assigned female at birth must be of nonchildbearing potential (defined as either at least 6 months surgically sterilised or at least 1 year postmenopausal and confirmed by follicle-stimulating hormone [FSH] level > 40 U/L) OR, if of childbearing potential (defined as not sterilised via bilateral oophorectomy or hysterectomy; still menstruating; or < 1 year has passed since the last menses, if menopausal), must use a combination of 1 highly effective method of contraception and 1 effective method of contraception. This contraceptive practice should begin at least 28 days before the first dose of study drug, continue during the study, and persist for 65 days after the final dose of study drug, if applicable.
- •Male participants agree to ensure that their female partners who are of childbearing potential will use a highly effective method of contraception..
- •Vital signs within the following ranges:
- •Systolic blood pressure: 90-140 mmHg
- •Diastolic blood pressure: < 90 mmHg
- •Pulse rate: 55-100 bpm
- •Respiration rate: 10-16 respirations per minute
- •DKD participants:
- •All of the above.
- •Well-controlled diabetes requiring minimal dose adjustments of antidiabetic medications in the past 3 months and no adjustments within 30 days of Screening.
- •Haemoglobin A1C < 9.5%.
- •Estimated glomerular filtration rate (eGFR) between 30 and 60.
排除标准
- •Any active medical condition determined clinically significant by the Investigator, except for DKD (for DKD participants).
- •Body mass index (BMI) > 32 kg/m2 for healthy participants; > 40 kg/m2 for DKD participants.
- •Use of any systemic immunosuppressant medications, medications to treat diabetes (except DKD participants), antipsychotics, anticoagulants, or other prescription medications other than contraceptives within 90 days of Screening that, as determined by the Investigator, could confound their participation in the study.
- •Received a vaccine within 30 days of Screening.
- •Cancer or a history of cancer or lymphoproliferative disorder within 5 years of Screening except for adequately treated non-melanoma cancers of the skin and cervical carcinoma in situ.
- •Current infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) as evidenced by a positive hepatitis B surface antigen (HbsAg) test at Screening or a positive HIV test at Screening. For hepatitis C, a positive hepatitis C antibody (antiHCV) test is exclusionary unless the participant has previously been treated for hepatitis C, in which case they would be eligible with a negative HCV ribonucleic (RNA) test.
- •Currently pregnant, lactating, or planning to conceive or contribute to pregnancy during the trial and up to 65 days (for participants of childbearing potential) or 125 days (for males) after the participant's last dose of study drug, if applicable.
- •History of severe depression, psychosis, or suicidal ideation, as determined by the Investigator, within 5 years of Screening.
- •History of anaphylaxis or other significant allergies in the opinion of the Investigator.
- •History of substance use disorder as specified in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, within 1 year of Screening.
- •Positive screen for drugs of abuse or alcohol at Screening or admission to the CRU (Day -1).
- •Donation of blood within 28 days of Screening.
- •Any clinically significant disease or laboratory abnormality detected at Screening, including diabetes mellitus, that might interfere with a participant's ability to complete the study, on-study evaluations, or participant safety, including the following:
- •Haemoglobin < 115 g/L (female) or < 135 g/L (male); > 160 g/L (female) or > 180 g/L (male)
- •Absolute neutrophils < 2.0 × 109/L or > 7.5 × 109/L
- •White blood cells < 4.0 × 109/L or > 11.0 × 109/L
- •Platelet count < 150 × 109/L or > 450 × 109/L
- •Any clinically significant abnormality on any of the Screening ECGs
- •Alanine aminotransferase or aspartate aminotransferase greater than 1.2 times the upper limit of normal.
- •Any surgical procedure, including planned procedures within 12 weeks of Screening.
- •Known allergy to MTX-439 or any of its excipients.
- •Participation in another research study of an investigational agent within 30 days of Screening or 5 half-lives of the agent, whichever is longer.
研究组 & 干预措施
MTX-439
MTX-439
干预措施: MTX-439 (Biological)
Placebo
Placebo
干预措施: Placebo (Other)
结局指标
主要结局
Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of MTX-439
时间窗: From first dose up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-∞) of MTX-439. Unit of Measure: Nanogram·hour per milliliter (ng·h/mL)
Area Under the Plasma Concentration-Time Curve Over the Dosing Interval (AUC0-tau) of MTX-439
时间窗: From first dose up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Area under the plasma concentration-time curve over the dosing interval (AUC0-tau) of MTX-439 at steady state, where applicable Unit of Measure: Nanogram·hour per milliliter (ng·h/mL)
Time to Maximum Plasma Concentration (Tmax) of MTX-439
时间窗: From first dose up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Time to reach maximum observed plasma concentration (Tmax) of MTX-439 following dosing. Unit of Measure: Hours (h)
Terminal Elimination Half-Life (t1/2) of MTX-439
时间窗: From first dose up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Terminal elimination half-life (t1/2) of MTX-439 following dosing. Unit of Measure: Hours (h)
Incidence of Dose-Limiting Toxicities (DLTs)
时间窗: From first dose up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Number and percentage of participants who experience a dose-limiting toxicity (DLT) as defined in the protocol. Unit of Measure: Number of participants; Percentage of participants (%)
Incidence of Treatment-Emergent Adverse Events (TEAEs)
时间窗: From first dose up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Number and percentage of participants with at least one treatment-emergent adverse event (TEAE). TEAEs will be summarized by seriousness and maximum severity according to protocol-defined criteria Unit of Measure: Number of participants; Percentage of participants (%)
Incidence of Treatment-Related Adverse Events (TRAEs)
时间窗: From first dose up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Number and percentage of participants with at least one adverse event considered related to study intervention by the investigator. Unit of Measure: Number of participants; Percentage of participants (%)
Incidence of Dose Modifications Due to Adverse Events
时间窗: From first dose up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Number and percentage of participants requiring dose interruption, dose reduction, or permanent discontinuation of study intervention due to adverse events. Unit of Measure: Number of participants; Percentage of participants (%)
Clinically Significant Changes in Physical Examination Findings
时间窗: Baseline up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Number and percentage of participants with clinically significant abnormalities in physical examination findings. Unit of Measure: Number of participants; Percentage of participants (%)
Clinically Significant Changes in Vital Signs
时间窗: Baseline up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Number and percentage of participants with clinically significant changes from baseline in vital signs measurements (including blood pressure, heart rate, respiratory rate, temperature, and pulse oximetry). Unit of Measure: Number of participants; Percentage of participants (%)
Clinically Significant Changes in Electrocardiogram (ECG) Parameters
时间窗: Baseline up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Number and percentage of participants with clinically significant abnormalities in ECG parameters (including but not limited to PR interval, QRS duration, and QT/QTc interval). Unit of Measure: Number of participants; Percentage of participants (%)
Clinically Significant Changes in Clinical Laboratory Parameters
时间窗: Baseline up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Number and percentage of participants with clinically significant changes from baseline in hematology, clinical chemistry, urinalysis, and other protocol-specified laboratory parameters. Unit of Measure: Number of participants; Percentage of participants (%)
Maximum Observed Plasma Concentration (Cmax) of MTX-439
时间窗: From first dose up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Maximum observed plasma concentration (Cmax) of MTX-439 following single and multiple ascending doses. Unit of Measure: Nanograms per milliliter (ng/mL)
Area Under the Plasma Concentration-Time Curve From Time Zero to Time t (AUC0-t) of MTX-439
时间窗: From first dose up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC0-t) of MTX-439. Unit of Measure: Nanogram·hour per milliliter (ng·h/mL)
Incidence and Characterization of Anti-Drug Antibodies (ADA)
时间窗: From first dose up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts
Number and percentage of participants with detectable anti-drug antibodies (ADA), including ADA titer and assessment of the impact of ADA on PK and safety, if applicable. Unit of Measure: Number of participants; Percentage of participants (%); Titer (unitless dilution factor)
次要结局
- Change From Baseline in Total SMOC2 Levels(Baseline up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts)
- Change From Baseline in Free SMOC2 Levels(Baseline up to Day 85 for SAD cohorts and up to Day 113 for MAD cohorts)