A Multi-center, Multi-dose Phase Ib/IIa Clinical Study Evaluating the Safety, Tolerability, Preliminary Efficacy, Pharmacokinetics, and Impact on Biomarkers of IPG11406 in Patients With Lupus Nephritis
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 24
- 试验地点
- 35
- 主要终点
- Evaluate the safety and tolerability via Heart rate of Vital Signs
研究概览
简要总结
A multi-center, multi-dose phase Ib/IIa clinical study evaluating the safety, tolerability, preliminary efficacy, pharmacokinetics, and impact on biomarkers of IPG11406 in patients with Lupus Nephritis
详细描述
This is a multi-center, multi-dose phase Ib/IIa study to evaluate the safety, tolerability, preliminary efficacy, pharmacokinetics, and impact on biomarkers of IPG11406 in patients with Lupus Nephritis.
This study has two parts.In Part A1, there will be 3 dose groups, 20 mg bid (Cohort 1), 40 mg bid (Cohort 2), 80 mg bid (Cohort 3).In Cohorts 1 to 3, there will be 3-6 participants in each cohort.In Part A2, dose expansion will be conducted at the proposed recommended Phase 2 dose (RP2D). All subjects will be screened within 28 days before administration, and eligible subjects will be administered and observed for 28 days after screening. In this part, it is planned to recruit about 36 patients with nephritis.
After each cohort has completed the 28-day dosing and evaluation, the safety monitoring committee (SMC) will evaluate the safety and tolerability of IPG11406 based on all accumulated safety data (including follow-up data) and available PK data. Based on the evaluation results of safety and tolerability, the SMC will decide whether to administer the next dose group.Part A1 will determine the recommended Phase 2 dose (RP2D) and maximum tolerated dose (MTD) of IPG11406.
The design of Part B will be finalized based on the results of Part A.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Criteria for Inclusion and Exclusion \
- •Aged 18-70 years (inclusive), male or female.
- •In line with the revised classification criteria of the American College of Rheumatology (ACR) 1997, adult subjects diagnosed with systemic lupus erythematosus prior to screening.
- •Confirmed disease activity during screening: SLEDAI-2K score ≥
- •The patient's 24-h urine protein-to-creatinine ratio (UPCR) is >0.5 g/g or 24-h urine protein is ≥0.5 g during the screening period, and the estimated glomerular filtration rate (eGFR) calculated using the MDRD formula is ≥60 mL/min/1.73 m^
- •The patient's baseline blood IFN-γ level exceeded the upper limit of normal (Part B only).
- •Patients with baseline peripheral blood Th1/Th2 ratio ≥14 (Part B only).
- •(1) Subjects who have not received induction therapy or have not received treatment in the past 2 months are allowed to be enrolled, but other treatments for systemic lupus erythematosus and lupus nephritis (including hormones, immunosuppressants, hydroxychloroquine sulfate, and biologics) are not allowed to be added during the study and follow-up period except for the study treatment.
- •(2) Subjects are allowed to be receiving any of the following standard treatment regimens at the time of enrollment: 1) Oral prednisone (or equivalent) monotherapy: a. Treatment duration: ≥ 2 weeks prior to screening and have a stable dose for ≥ 2 weeks prior to enrollment; b. Dose requirements: maximum daily dose: 1 mg/kg/day; 2) Immunosuppressants: a. Permitted medications include: antimalarials, azathioprine, cyclophosphamide, mycophenolate mofetil/mycophenolic acid, methotrexate, cyclosporine A, and tacrolimus; b. Treatment duration: ≥ 12 weeks prior to screening and have a stable dose for ≥ 8 weeks prior to enrollment; c. Dose requirements: hydroxychloroquine ≤ 400 mg/day, azathioprine ≤ 100 mg/day, cyclophosphamide ≤ 800 mg/4 weeks, mycophenolate mofetil/mycophenolic acid ≤ 2 g/day, oral, subcutaneous (SC), or intramuscular methotrexate ≤ 15 mg/week, cyclosporine A ≤ 3 mg/kg/day, tacrolimus ≤ 3 mg/day; 3) Oral prednisone (or equivalent) monotherapy ± hydroxychloroquine sulfate ± ≥ one immunosuppressant a. The above requirements for treatment duration and dose stability of oral corticosteroids (OCS) and immunosuppressants should be met; b. The maximum daily/weekly dose of each drug in 1) and 2) should not be exceeded.
- •8.Female subjects are required to be non-pregnant and non-lactating during the trial.
- •9.Subjects who do not have a pregnancy plan, voluntarily take effective contraceptive measures (see the Appendix for details), and have no sperm or egg donation plan from screening to 6 months after the end of the study.
- •The subject voluntarily participates in the study, is able to sign the informed consent form, and complies with the requirements on the informed consent form.
排除标准
- •Pregnant and lactating women.
- •Have participated in other clinical trials within 3 months before screening and/or are currently participating in other clinical trials (except for those who have not used the investigational product).
- •Active severe lupus nephritis with estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m^2 calculated using the MDRD formula.
- •Severe neuropsychiatric SLE includes, but is not limited to, the following: seizures, new or worsening impaired level of consciousness, psychosis, delirium or confusional state, aseptic meningitis, ascending or transverse myelitis, chorea, cerebellar ataxia, mononeuritis multiplex, demyelinating syndromes, or any condition that prevents the subject from fully understanding the ICF.
- •History or current diagnosis of clinically significant non-SLE-associated vasculitis syndrome or overlap with other connective tissue diseases.
- •Any active dermatologic disease other than SLE that may interfere with study assessments of SLE, including but not limited to psoriasis, dermatomyositis, systemic sclerosis, non-SLE cutaneous lupus manifestations (eg, cutaneous vascular disease, periungual telangiectasias, sclerodactyly, rheumatoid nodules, erythema multiforme, leg ulcers), or drug-induced lupus.
- •Those who have had or are currently suffering from malignant tumors in the past 5 years (except for skin squamous cell carcinoma in situ, basal cell carcinoma, papillary thyroid carcinoma, and cervical carcinoma in situ that have undergone radical treatment and do not have any evidence of recurrence).
- •Patients with uncontrolled anticardiolipin antibody syndrome (APS).
- •With a history of major organ transplantation (e.g., heart, lung, kidney, and liver) or hematopoietic stem cell/bone marrow transplantation.
- •Major surgical procedure (craniotomy, thoracotomy, or laparotomy), or unhealed wounds, ulcers, or fractures within 4 weeks prior to screening.
- •Have received a live/attenuated vaccine within 8 weeks before screening or plan to receive a live/attenuated vaccine during the trial.
- •Those who are allergic to the study drugs (including excipients), suffer from severe allergic diseases, or are allergic constitution (such as allergic to two or more drugs, food, or pollen), which may cause damage to the safety of the subjects as judged by the investigator.
- •Has any of the following cardiac impairment at screening: a. New York Heart Association (NYHA) Class III-IV; b. Uncontrolled angina, congestive heart failure, or myocardial infarction within 6 months prior to the first dose; c. QTcF prolongation calculated by Fridericia's formula (> 450 msec for males; > 470 msec for females); d. type II second degree atrioventricular (AV) block, third degree atrioventricular (AV) block or PR interval > 250 ms, etc.; e. various factors that may increase the risk of QTcF prolongation or arrhythmic events, such as heart failure, hypokalemia, congenital long QT syndrome, and unexplained sudden death before 40 years of age in first-degree relatives in family history; f. Left ventricular ejection fraction (LVEF) < 50%.
- •Has active or latent tuberculosis infection at screening.
- •Presence of serious herpes virus infections at screening, such as herpes encephalitis, disseminated herpes, and ophthalmic herpes.
- •Use of intravenous anti-infectives (including antivirals and antibiotics) for infections within 4 weeks prior to screening.
- •Has been hospitalized for an opportunistic infection within 3 months prior to screening.
- •Have been treated with Chinese patent medicines such as Tripterygium wilfordii within 4 weeks before screening.
- •HBsAg-positive in hepatitis B panel (HBsAg-negative but HBcAb-positive, additional HBV-DNA quantitative test is required; patients with HBV-DNA test results ≥ the upper limit of reference value at each site or requiring antiviral therapy are ineligible for study participation), hepatitis C antibody-positive (additional HCV-RNA test may be performed; if negative, the patient may be enrolled), Treponema pallidum antibody-positive (if Treponema pallidum antibody is positive, a further Treponema pallidum serological test should be performed; patients who have been infected with syphilis but have been cured as judged by the investigator are eligible), and HIV antibody-positive.
- •Subjects with significant abnormalities in liver and kidney functions and hematology at screening, including: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 2 × upper limit of normal (ULN), serum total bilirubin > 1.5 × ULN, hemoglobin < 90 g/L, white blood cell count < 3.0 × 10^9/L, platelet count (PLT) < 75 × 10^9/L, and neutrophil count < 1.0 × 10^9/L; other abnormal laboratory test results that, in the judgment of the investigator, may affect the subject's completion of the trial or interfere with the trial results.
- •have a history of drug abuse or substance abuse.
- •Subjects with acute diseases prior to the use of the investigational product. Other conditions judged by the investigator to be unsuitable for enrollment.
研究组 & 干预措施
Cohort 1 (20 mg, Bid)
3~6 subjects will be orally administered with IPD11406 20 mg twice a day. All subjects will undergo screening for 28 days before administration, and those who pass the screening will undergo 28 days of drug administration and observation.
干预措施: IPG11406 (Drug)
Cohort 2 (40 mg, Bid)
After cohort 1 complete 28 days of dosing and evaluation, the Safety Monitoring Committee (SMC) will assess the safety and tolerability of IPG11406 based on all accumulated safety data (including follow-up data) and available pharmacokinetic (PK) data. Based on SMC approval, 3~6 subjects will be orally administered 40 mg with IPD11406 twice a day. All subjects will undergo screening for 28 days before administration, and those who pass the screening will undergo 28 days of drug administration and observation.
干预措施: IPG11406 (Drug)
Cohort 3 (80 mg, Bid)
After cohort 2 complete 28 days of dosing and evaluation, the Safety Monitoring Committee (SMC) will assess the safety and tolerability of IPG11406 based on all accumulated safety data (including follow-up data) and available pharmacokinetic (PK) data. Based on SMC approval, 3~6 subjects will be orally administered 80 mg with IPD11406 twice a day. All subjects will undergo screening for 28 days before administration, and those who pass the screening will undergo 28 days of drug administration and observation.
干预措施: IPG11406 (Drug)
结局指标
主要结局
Evaluate the safety and tolerability via Heart rate of Vital Signs
时间窗: Up to 58 days
Changes from baseline， Heart rate in beats per minute
Evaluate the safety and tolerability via Blood pressure of Vital Signs
时间窗: Up to 58 days
Changes from baseline，Blood pressure in mmHg
Evaluating the safety and tolerability from Red blood cell count of Laboratory Examination
时间窗: Up to 58 days
Changes from baseline of Red blood cell count in whole blood is reported in the form of number.
Evaluating the safety and tolerability from ALT of Laboratory Examination
时间窗: Up to 58 days
Changes from baseline, Changes of ALT concentration (U/L) in serum will be recorded.
Evaluate the impact of oral administration of IPG11406 on 24-hour urine protein quantitation of proteinuria and renal function in patients with Lupus Nephritis
时间窗: Up to 58 days
Measure the changes in 24-hour urine protein quantitation before and after medication administration
Evaluate the safety and tolerability via assessment of Adverse events
时间窗: Up to 58 days
Grades of AE will be assessed according to CTCAE 5.0
Evaluating the safety and tolerability from Laboratory Examination
时间窗: Up to 58 days
Changes from baseline of Laboratory Examination (hematology, clinical chemistry, coagulation, urinalysis)
Evaluate the safety and tolerability via Respiration rate of Vital Signs
时间窗: Up to 58 days
Changes from baseline， Respiration rate in times per minute
Evaluating the safety and tolerability from Prothrombin time of Laboratory Examination
时间窗: Up to 58 days
Changes from baseline, Prothrombin time (PT) is a screening test for exogenous coagulation factors.
Evaluating the safety and tolerability from AST of Laboratory Examination
时间窗: Up to 58 days
Changes from baseline, Changes of AST concentration (U/L) in serum will be recorded.
Evaluate the safety and tolerability via Body temperature of Vital Signs
时间窗: Up to 58 days
Changes from baseline，Body temperature in Celsius degree
Evaluating the safety and tolerability from White blood cell of Laboratory Examination
时间窗: Up to 58 days
Changes from baseline of White blood cell count in whole blood is reported in the form of number.
Evaluating the safety and tolerability from lymphocyte count of Laboratory Examination
时间窗: Up to 58 days
Changes from baseline , Lymphocyte count in whole blood is reported in the form of number.
Evaluating the safety and tolerability from total bilirubin concentration of Laboratory Examination
时间窗: Up to 58 days
Changes from baseline, Changes of total bilirubin concentration (μmol/L) in serum will be recorded.
Evaluating the safety and tolerability from hemoglobin of Laboratory Examination
时间窗: Up to 58 days
Changes from baseline , Changes of hemoglobin concentration（g/dL）in whole blood will be recorded.
Evaluating the safety and tolerability from Activated partial thromboplastin time of Laboratory Examination
时间窗: Up to 58 days
Changes from baseline, Activated partial thromboplastin time (APTT) is a screening test for endogenous coagulation factors.
Evaluating the safety and tolerability from direct bilirubin concentratio of Laboratory Examination
时间窗: Up to 58 days
Changes from baseline, Changes of direct bilirubin concentration (μmol/L) in serum will be recorded.
Evaluating the safety and tolerability from creatinine concentration of Laboratory Examination
时间窗: Up to 58 days
Changes from baseline, Changes of creatinine concentration (μmol/L) in serum will be recorded.
Evaluating the safety and tolerability from triglyceridesconcentration of Laboratory Examination
时间窗: Up to 58 days
Changes from baseline, Changes of triglycerides (TG) concentration (mmol/L) in serum will be recorded.
Evaluating the safety and tolerability from QRS (ms) of Electrocardiogram
时间窗: Up to 58 days
Changes from Clinical Significant Changes in 12-Lead Electrocardiogram (ECG) findings for QRS (ms)
Evaluating the safety and tolerability from urine protein of Laboratory Examination
时间窗: Up to 58 days
Changes from baseline, Changes of urine protein will be examined by qualitative test
Evaluating the safety and tolerability from urine pH value of Laboratory Examination
时间窗: Up to 58 days
Changes from baseline, Changes of urine pH value will be recorded.
Evaluating the safety and tolerability from ventricular rate of Electrocardiogram
时间窗: Up to 58 days
Changes from Clinical Significant Changes in 12-Lead Electrocardiogram (ECG) findings for ventricular rate (beats/min)
Evaluating the safety and tolerability from PR interval of Electrocardiogram
时间窗: Up to 58 days
Changes from Clinical Significant Changes in 12-Lead Electrocardiogram (ECG) findings for PR interval (ms)
Evaluating the safety and tolerability from QTc of Electrocardiogram
时间窗: Up to 58 days
Changes from Clinical Significant Changes in 12-Lead Electrocardiogram (ECG) findings for QTc (ms),
Evaluate the impact of oral IPG11406 on biomarkers in patients with Lupus Nephritis
时间窗: Up to 58 days
Changes in biomarkers before and after medication administration in patients
Evaluate the impact of oral administration of IPG11406 on estimated glomerular filtration rate of proteinuria and renal function in patients with Lupus Nephritis
时间窗: Up to 58 days
Measure the changes in estimated glomerular filtration rate (eGFR) calculated using the MDRD formula before and after medication administration
Evaluate the impact of oral administration of IPG11406 on ratio of 24-hour urine protein to urine creatinine of proteinuria and renal function in patients with Lupus Nephritis
时间窗: Up to 58 days
Measure the changes in ratio of 24-hour urine protein to urine creatinine before and after medication administration
Evaluate the impact of oral administration of IPG11406 on proteinuria and renal function in patients with Lupus Nephritis
时间窗: Up to 58 days
Measure the changes in 24-hour urine protein quantitation, estimated glomerular filtration rate (eGFR) calculated using the MDRD formula, and the ratio of 24-hour urine protein to urine creatinine before and after medication administration
次要结局
- Evaluate the pharmacokinetics (PK) characteristics of oral IPG11406 in CL by plasma concentration of whole blood sample(Up to 28 days)
- Evaluate the preliminary efficacy of oral IPG11406 from Relative count of lymphocyte subsets(Up to 58 days)
- Evaluate the preliminary efficacy of oral IPG11406 from Routine immunological tests(Up to 58 days)
- Evaluate the preliminary efficacy of oral IPG11406 from tests from antiphospholipid antibodies(Up to 58 days)
- Evaluate the preliminary efficacy of oral IPG11406 from Serum ferritin(Up to 58 days)
- Evaluate the pharmacokinetics (PK) characteristics of oral IPG11406 in Area under the curve(Up to 28 days)
- Evaluate the pharmacokinetics (PK) characteristics of oral IPG11406 in Maximum Plasma Concentration(Up to 28 days)
- Evaluate the pharmacokinetics (PK) characteristics of oral IPG11406 from T1/2(Up to 28 days)
- Evaluate the pharmacokinetics (PK) characteristics of oral IPG11406 from clearance at steady state(Up to 28 days)
- Evaluate the preliminary efficacy of oral IPG11406 from cytokines(Up to 58 days)
- Evaluate the preliminary efficacy of oral IPG11406 from peripheral blood T lymphocyte counts and proportion(Up to 58 days)
- Evaluate the preliminary efficacy of oral IPG11406 from Autoantibodies(Up to 58 days)
- Evaluate the preliminary efficacy of oral IPG11406 from Th1/Th2 detection(Up to 58 days)
- Evaluate the preliminary efficacy of oral IPG11406 in patients with Lupus Nephritis(Up to 58 days)
- Evaluate the preliminary efficacy of oral IPG11406 from 24-hour urine protein test(Up to 58 days)
- Evaluate the preliminary efficacy of oral IPG11406 from Systemic Lupus Erythematosus Disease Activity Index 2000（SLEDAI-2K） score(Up to 58 days)