Phase IIa Clinical Study to Assess the Safety and Efficacy of CN128 Tablets in the Treatment of Iron Overload in Transfusion Dependent Thalassemia Patients Aged 16 and Above
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Change in Auditory Function From Baseline Over Time
研究概览
简要总结
- Primary objectives:
• To evaluate the safety and efficacy of long-term orally administration of CN128 in thalassaemia patients with blood transfusion dependent and aged 16 and above. 2. Design:
- The study is designed as a single arm and opened phase IIa clinical trial, so as to investigate the safety and efficacy of CN128.
- A total of 50 eligible subjects are planned to be enrolled, and orally administration of CN128 for 24 weeks or 48 weeks according to the administration plan. The treatment period is from day 0 to 24 weeks, and the extended treatment period was from 25 weeks to 96 weeks.
- Subjects' medication status, uncomfortable symptoms, concomitant medication or non-drug therapy were recorded daily.
- Subject inclusion criteria:
- Thalassemia patients.
- The number of blood transfusion per month ≥1. Or hemoglobin can not be maintained at 90g/L above, if blood transfusions is less than once per month.
- Serum ferritin ≥ 500 µg/L
- Patients aged 16 and above
- Volunteer for the trial and sign the informed consent.
- Subject exclusion criteria:
- Active hepatitis B (HBsAg positive, HBsAb negative) or hepatitis C (HCV antibody positive, detectable HCV RNA, and alanine transaminase (ALT) beyond normal range)
- Active gastrointestinal disease history (including: gastric ulcer, duodenal ulcer, stomach or esophageal varices, ulcerative colitis, Crohn's disease, gastrointestinal cancer, familial genetic multiple intestinal polyps), and History of gastrointestinal perforation, gastrointestinal surgery that influence drug absorption, and other potential intestinal complications considered by researchers;
- ALT or Aspartate transaminase (AST) > 2.5 × Upper limit of normal (ULN), or serum creatinine > 1.5 × ULN;
- Neutropenia patient (neutrophil count < 1.5 × 109 / L);
- Active infection uncontrolled;
- The patients who are currently taking CYP3A strong inducer or strong inhibitor drugs, or the drug that may extend the QT interval, or the drug that may decrease neutrophil count, but can not temporarily interrupt the use of such drugs;
- Congenital long QT syndrome or known family history of long QT syndrome; QTc > 480 ms; clinically significant ventricular or atrial fast arrhythmia;
- The patients who can not accept MRI as detection means, such as claustrophobic for MRI, pacemaker, and those using ferromagnetic metal implants.
- Birth planner (including male subjects) within or within 3 months after the end of the trial;
- Participated in other clinical trials in the three months before taking the test preparation, except for non-interventional studies;
- Pregnant or lactating women;
- Unsuitable to participate in the trial considered by the researchers.
- Usage:
- All subjects will be given the lower (10 mg/kg bw, bid) or higher dose (15 mg/kg bw, bid) for 24 or 48 weeks, according to the administration plan.
- All subjects will be given the lower (15 mg/kg bw, bid) or higher dose (20 mg/kg bw, bid) for 49 or 96 weeks, according to the administration plan.
- Safety assessments:
Safety evaluations include adverse events, adverse reactions, severe adverse events, and severe adverse reactions; growth (weight, height); total and free testosterone in men, follicle-generating hormone and luteinizing hormone in women; vital signs and electrocardiogram; hearing, laboratory tests (blood routine analytes, blood biochemistry, coagulation function, thyroid and para-thyroid function, urine routine analytes.), urine pregnancy test (women of childbearing age),Levels of drug exposure during the study. 7. Efficacy assessments:
Efficacy evaluations include serum ferritin, liver iron content (MRI R2) and cardiac iron content (MRI T2*). 8. Statistics:
- Subject characteristic distribution Demographic characteristics, general conditions, and baseline conditions (pre-treatment) of enrolled subjects were analyzed.The measurement data are described by means, standard deviation, minimum value and maximum value, while the qualitative data list frequency and percentage.
- Safety analysis Descriptive statistical analysis was used for safety endpoints.
- Effectiveness analysis Mean, standard deviation, median, minimum and maximum values were described and 95% confidence intervals were calculated. Paired T-test was used to compare each time point with the baseline if necessary. The 95% confidence interval was calculated by using Clopper-Pearson method for the proportion of patients.
详细描述
Clinical Trial - IIa - Study Description - Detailed Description
- Primary objectives:
- To evaluate the adverse events, adverse reactions, severe adverse events and severe adverse reactions during the study period, so as to investigate the safety;
- To evaluate the changes of serum ferritin over time after orally administration of CN128 in thalassaemia patients with blood transfusion dependent and aged 16 and above, so as to investigate the efficacy;
- To evaluate the effect on iron excretion in liver after orally administration of CN128 for 12, 24 weeks in thalassaemia patients with blood transfusion dependent and aged 16 and above, so as to investigate the efficacy;
- To evaluate the effect on iron excretion in heart after orally administration of CN128 for 12, 24 weeks in thalassaemia patients with blood transfusion dependent and aged 16 and above, so as to investigate the efficacy;
- To evaluate the proportion of patients with decreased or unchanged liver iron content after orally administration of CN128 for 12, 24 weeks in thalassaemia patients with blood transfusion dependent and aged 16 and above, so as to investigate the efficacy;
- To evaluate the safety and efficacy of long-term orally administration of CN128 in thalassaemia patients with blood transfusion dependent and aged 16 and above.
- Design:
- The study is designed as a single arm and opened phase IIa clinical trial, so as to investigate the safety and efficacy of CN128.
- A total of 50 eligible subjects are planned to be enrolled, and orally administration of CN128 for 24 weeks or 48 weeks according to the administration plan. The treatment period is from day 0 to 24 weeks, and the extended treatment period was from 25 weeks to 96 weeks.
- Administration plan:
(1)0 day~48 weeks： The trial will start with the lower dose of CN128 (10 mg/kg body weight [bw], bid) for two weeks, then the subjects will return to the study center. If no unacceptable toxicity associated with CN128 is found, the subjects will be given the higher dose (15 mg/kg body weight [bw], bid). If unacceptable toxicity associated with CN128 is found, the subjects will be suspended or stopped administration. If the adverse event turns to normal or abnormal but no clinical significance after suspension administration, the subjects will be given the lower dose of CN128 (10 mg/kg body weight [bw], bid).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 16 Years 至 60 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Thalassemia patients.
- •The number of blood transfusion per month ≥
- •Or hemoglobin can not be maintained at 90g/L above, if blood transfusions is less than once per month.
- •Serum ferritin ≥ 500 µg/L
- •Patients aged 16 and above
- •Volunteer for the trial and sign the informed consent.
排除标准
- •Active hepatitis B (HBsAg positive, HBsAb negative) or hepatitis C (HCV antibody positive, detectable HCV RNA, and ALT beyond normal range)
- •Active gastrointestinal disease history (including: gastric ulcer, duodenal ulcer, stomach or esophageal varices, ulcerative colitis, Crohn's disease, gastrointestinal cancer, familial genetic multiple intestinal polyps), and History of gastrointestinal perforation, gastrointestinal surgery that influence drug absorption, and other potential intestinal complications considered by researchers;
- •ALT or AST > 2.5 × ULN, or serum creatinine > 1.5 × ULN;
- •Neutropenia patient (neutrophil count < 1.5 × 109 / L);
- •Active infection uncontrolled;
- •The patients who are currently taking CYP3A strong inducer or strong inhibitor drugs, or the drug that may extend the QT interval, or the drug that may decrease neutrophil count, but can not temporarily interrupt the use of such drugs;
- •The patients who are allergic or contraindicated to the main ingredients or excipients of CN128 tablets;
- •Congenital long QT syndrome or known family history of long QT syndrome; QTc > 480 ms; clinically significant ventricular or atrial fast arrhythmia;
- •The patients who can not accept MRI as detection means, such as claustrophobic for MRI, pacemaker, and those using ferromagnetic metal implants;
- •Birth planner (including male subjects) within or within 3 months after the end of the trial;
- •Participated in other clinical trials in the three months before taking the test preparation, except for non-interventional studies;
- •Pregnant or lactating women;
- •Unsuitable to participate in the trial considered by the researchers.
研究组 & 干预措施
CN128 Group
All subjects will be given the lower (10 mg/kg bw, bid) or higher dose (15 mg/kg bw, bid) for 24 or 48 weeks, according to the administration plan.
All subjects will be given the lower (15 mg/kg bw, bid) or higher dose (20 mg/kg bw, bid) for 49 or 96 weeks, according to the administration plan.
The dosage form is tablets.
干预措施: CN128 Tablets (Drug)
结局指标
主要结局
Change in Auditory Function From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's auditory function will be determined by otorhinolaryngology.
Absolute Change in Temperature (Unit: ℃）From Baseline Over Time
时间窗: Baseline, 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's temperature will be determined, and it's one kind of vital signs checks.
Absolute Change in Blood pressure (Unit: mmHg ) From Baseline Over Time
时间窗: Baseline, 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
Both patient's systolic and diastolic blood pressure will be measured, and it's one kind of vital signs checks.
Absolute Change in Basophilic Count (Unit: 10E9/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's basophilic count will be determined, and it's one kind of laboratory test.
Absolute Change in Neutrophil Count (Unit: 10E9/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's neutrophil count will be determined, and it's one kind of laboratory test.
Absolute Change in Monocyte Count (Unit: 10E9/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's monocyte count will be determined, and it's one kind of laboratory test.
Absolute Change in Lymphocyte Count (Unit: 10E9/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's lymphocyte count will be determined, and it's one kind of laboratory test.
Absolute Change in Eosinophilic Count (Unit: 10E9/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's eosinophilic count will be determined, and it's one kind of laboratory test.
Number of participants with adverse events, adverse reactions, severe adverse events and severe adverse reactions as a measure of safety and tolerability during the study period
时间窗: up to 96 weeks
To determine the incidence, type and severity of adverse events, adverse reactions, severe adverse events and severe adverse reactions in patients up to 96 weeks.
Absolute Change in Weight (Unit: kg) From Baseline Over Time
时间窗: Baseline, 24, 48, 72 and 96 weeks.
The patient's weight will be determined, and it's one kind of Physical examination.
Absolute Change in Height (Unit: m) From Baseline Over Time
时间窗: Baseline,24, 48, 72 and 96 weeks.
The patient's height will be determined, and it's one kind of Physical examination.
Absolute Change in Hormon (total and free testosterone in men, follicle-generating hormone and luteinizing hormon in women) From Baseline Over Time
时间窗: Baseline, 24, 48, 72 and 96 weeks.
Hormon will be determined, and it's one kind of laboratory test.
Absolute Change in Heart rate (Unit: bpm) From Baseline Over Time
时间窗: Baseline, 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's heart rate will be determined, and it's one kind of vital signs checks.
Absolute Change in Respiration (Unit: bpm) From Baseline Over Time
时间窗: Baseline, 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's respiration will be determined, and it's one kind of vital signs checks.
Absolute Change in Electrocardiogram (P-R (Unit: ms), QRS (Unit: ms), QTc (Unit: ms), etc) From Baseline Over Time
时间窗: Baseline, 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's electrocardiogram will be measured, and it's one kind of laboratory test.
Absolute Change in White Blood Count (Unit: 10E9/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's white blood count will be determined, and it's one kind of laboratory test.
Absolute Change in Red Blood Count (Unit: 10E9/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's red blood count will be determined, and it's one kind of laboratory test.
Absolute Change in Hemoglobin (Unit: g/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's hemoglobin will be determined, and it's one kind of laboratory test.
Absolute Change in Thrombocytocrit (Unit: %) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's thrombocytocrit will be determined, and it's one kind of laboratory test.
Absolute Change in Globulin (Unit: g/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's globulin will be determined, and it's one kind of laboratory test.
Absolute Change in Blood Platelet Count (Unit: 10E9/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's blood platelet count will be determined, and it's one kind of laboratory test.
Absolute Change in Alanine Aminotransferase (Unit: U/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's alanine aminotransferase will be determined, and it's one kind of laboratory test.
Absolute Change in Total Bilirubin (Unit:µmol/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's total bilirubin will be determined, and it's one kind of laboratory test.
Absolute Change in Total Protein (Unit:g/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's total protein will be determined, and it's one kind of laboratory test.
Absolute Change in Albumin (Unit: g/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's albumin will be determined, and it's one kind of laboratory test.
Absolute Change in Sodium (Unit: mmol/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's sodium will be determined, and it's one kind of laboratory test.
Absolute Change in Activated Partial Thromboplastin Time (APTT, Unit: s) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's APTT will be determined, and it's one kind of laboratory test.
Absolute Change in Thyroid and para-gland function (Serum total thyroxine, parathyroid hormone, total triiodothyronine and thyrotropin) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's thyroid and para-gland function will be determined, and it's one kind of laboratory test.
Absolute Change in Urine Glucose (Unit: mmol/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's urine glucose will be determined, and it's one kind of laboratory test.
Absolute Change in Urine Protein (Unit: g/L)) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's urine protein will be determined, and it's one kind of laboratory test.
Duration of Administration during the study period
时间窗: Up to 96 weeks
The duration of administration will be investigated up to 96 weeks.
Absolute Change in Hematocrit (Unit:%) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's hematocrit will be determined, and it's one kind of laboratory test.
Absolute Change in Alkaline Phosphatase (Unit: U/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's alkaline phosphatase will be determined, and it's one kind of laboratory test.
Absolute Change in Lactate Dehydrogenase (Unit: IU/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's lactate dehydrogenase will be determined, and it's one kind of laboratory test.
Absolute Change in Urea (Unit: mmol/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's urea will be determined, and it's one kind of laboratory test.
Absolute Change in Dosage（mg/kg）during the study period
时间窗: Up to 96 weeks
The dosages will be investigated up to 96 weeks.
Absolute Change in Serum ferritin (Unit: µg/L) From Baseline Over Time
时间窗: Baseline, 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
Serum ferritin will be determined, and it's one kind of laboratory test.
Absolute Change in Heart iron content (MRI T2*) From Baseline Over Time
时间窗: Baseline, 12, 24, 48, 72 and 96 weeks.
Heart iron content will be determined by cardio magnetic resonance.
Absolute Change in Liver iron content (MRI R2) From Baseline Over Time
时间窗: Baseline, 12, 24, 48, 72 and 96 weeks.
Liver iron content will be determined by liver magnetic resonance.
Absolute Change in Creatinine (Unit:µmol/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's creatinine will be determined, and it's one kind of laboratory test.
Absolute Change in Glucose (Unit: mmol/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's glucose will be determined, and it's one kind of laboratory test.
Absolute Change in Potassium (Unit: mmol/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's potassium will be determined, and it's one kind of laboratory test.
Absolute Change in Chlorine (Unit: mmol/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's chlorine will be determined, and it's one kind of laboratory test.
Absolute Change in Calcium (Unit: mmol/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's calcium will be determined, and it's one kind of laboratory test.
Absolute Change in Aspartate Aminotransferase (Unit: U/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's aspartate aminotransferase will be determined, and it's one kind of laboratory test.
Absolute Change in Fibrinogen (Unit: g/L) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's fibrinogen will be determined, and it's one kind of laboratory test.
Absolute Change in Prothrombin time (Unit: s) From Baseline Over Time
时间窗: Baseline, 2, 12, 24, 32, 40, 48, 60, 72, 84 and 96 weeks.
The patient's prothrombin time will be determined, and it's one kind of laboratory test.
Number of Participants during the study period
时间窗: Up to 96 weeks
The number of participants will be investigated up to 96 weeks.
次要结局
未报告次要终点