Patient case: 19-year-old female with long QT syndrome; genetic feature: KCNH2

Clinical trial: Short-term Clinical Study of CN128 in Thalassemia Patients

Summary: 1. Primary objectives:
  -  To explore the tolerability and safety of CN128 in thalassemia patients.
  -  To explore the pharmacokinetics of CN128 in thalassemia patients.
  2. Design:
  The study is designed as a safety, tolerability and pharmacokinetic parameters study, phase Ib trial.
  The study is consisted of: safety and tolerability of administeation; pharmacokinetic parameters.
  3. Subject inclusion criteria:
  -  Thalassemia patients, serum ferritin ≥ 500 µg/L
  -  Patients aged 16 and above
  -  HB≥80 g/L before administration
  -  Volunteer for the trial and sign the informed consent.
  4. Subject exclusion criteria:
  -  Hematology screening for HIV antibodies or HBV surface antigen or HCV antibody or TP antibody positive, or hepatitis B core antibody (HbcAb) and HBV-DNA positive;
  -  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, and other potential intestinal complications considered by researchers;
  -  Patients with abnormal liver function (ALT /AST> 2.5 × ULN) or those with abnormal renal function (serum creatinine> 1.5 × ULN);
  -  Active infection uncontrolled;
  -  The patients who are currently taking CYP3A strong inducer or strong inhibitor drugs or the drug may extend the QT interval , but can not temporarily interrupt the use of such drugs, and can not use other drugs to replace;
  -  ect.
  5. Usage:
  All subjects fasted prior to administration of study drug using 240 ml warm water. The people can not drink water within 1h before administration.
  6. Pharmacokinetic assessment of CN128 administration:
  The PK data of CN128 (AUC 0-t, AUC 0-∞, Cmax, Tmax, t1/2, CL/F, Vd/ F, MRT ,Css-av, Css-min, Css-max, Accumulation rate, Fluctuation index, etc.
  7. Safety and tolerability assessments:
  Safety evaluations included adverse events, termination information, laboratory test results and vital signs.
  8. Statistics

Detailed description: 1. Primary objectives:
  -  To explore the tolerability and safety of CN128 in thalassemia patients aged 16 and above after repeated administration.
  -  To explore the pharmacokinetics of CN128 in thalassemia patients aged 16 and above after repeated administration.
  2. Design:
  The study is designed as a safety, tolerability and pharmacokinetic parameters study, phase Ib trial.
  The study is consisted of:
  -  The trial will start with the lower dose of CN128 given to 8 subjects (20 mg/kg body weight [bw], bid).The dose of second group is 15 mg/kg bw, bid (n=8).
  -  Pharmacokinetic parameters: AUC 0-t, AUC 0-∞, Cmax, Tmax, t1/2, CL/F, Vd/ F, MRT ,Css-av, Css-min, Css-max, Accumulation rate, Fluctuation index, etc.
  3. Subject inclusion criteria:
  -  Thalassemia patients, serum ferritin ≥ 500 µg/L
  -  Patients aged 16 and above
  -  HB≥80 g/L before administration
  -  Volunteer for the trial and sign the informed consent.
  4. Subject exclusion criteria:
  -  Hematology screening for HIV antibodies or HBV surface antigen or HCV antibody or TP antibody positive, or hepatitis B core antibody (HbcAb) and HBV-DNA positive;
  -  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, and other potential intestinal complications considered by researchers;
  -  Patients with abnormal liver function (ALT /AST> 2.5 × ULN) or those with abnormal renal function (serum creatinine> 1.5 × ULN);
  -  Active infection uncontrolled;
  -  The patients who are currently taking CYP3A strong inducer or strong inhibitor drugs or the drug may extend the QT interval , but can not temporarily interrupt the use of such drugs, and can not use other drugs to replace;
  -  Allergic constitution: Allergy or contraindications to the main ingredients or excipients of CN128 tablets (microcrystalline cellulose, croscarmellose sodium, silica, sodium stearyl fumarate, Opadry);
  -  ECG abnormalities have clinical significance: congenital long QT syndrome or known family history of long QT syndrome; QTc> 450ms (male) or QTc> 470 ms (female); clinically significant ventricular or atrial Fast arrhythmia;
  -  Birth planner (including male subjects) within or within 3 months after the end of the trial;
  -  Blood donation in the last 3 month;
  -  Have a history of addictions (more than 5 cigarettes / day or use a considerable amount of nicotine products), alcoholism history (more than 14 alcohol consumption per week: 1 alcohol unit equal to 10mL or 8g pure alcohol, 25mL 40% white wine, 330mL 5 % Beer, 175mL 12% of the wine, respectively, about 1.0,1.5,2.0 alcohol units), drug abuse history, history of drug abuse;
  -  Smoking within 48 hours before applying the drug or using any food or drink (including chocolate, tea, coffee or cola drinks, etc.) containing alcohol, xanthine or grapefruit;
  -  Participated in other clinical trials in the three months before taking the test preparation, except for non-interventional studies;
  -  Nicotine, urine screening results were positive;
  -  Blood collection difficulties;
  -  Blood test for pregnancy was positive;
  -  Unsuitable to participate in the trial considered by the researchers (such as Poor health, poor compliance, unwillingness or inability to comply with treatment plan, including failure to visit on time).
  5. Usage:
  All subjects fasted prior to administration of study drug using 240 ml warm water. The people can not drink water within 1h before administration.
  6. Pharmacokinetic assessment of CN128 administration:
  The PK data of CN128 (AUC 0-t, AUC 0-∞, Cmax, Tmax, t1/2, CL/F, Vd/ F, MRT ,Css-av, Css-min, Css-max, Accumulation rate, Fluctuation index, etc.)
  7. Safety and tolerability assessments:
  Safety evaluations included adverse events, termination information, laboratory test results and vital signs.
  8. Statistics:
  By adopting the method of statistical description.Measurement data lists the mean, standard deviation, median, maximum, minimum, count data and rank list frequency (constituent ratio), probability and confidence interval.

Eligibility: Inclusion Criteria:
  -  Thalassemia patients, serum ferritin ≥ 500 µg/L
  -  Patients aged 16 and above
  -  HB≥80 g/L before administration
  -  Volunteer for the trial and sign the informed consent.
  Exclusion Criteria:
  -  Hematology screening for HIV antibodies or HBV surface antigen or HCV antibody or TP antibody positive, or hepatitis B core antibody (HbcAb) and HBV-DNA positive;
  -  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, and other potential intestinal complications considered by researchers;
  -  Patients with abnormal liver function (ALT /AST> 2.5 × ULN) or those with abnormal renal function (serum creatinine> 1.5 × ULN);
  -  Active infection uncontrolled;
  -  The patients who are currently taking CYP3A strong inducer or strong inhibitor drugs or the drug may extend the QT interval , but can not temporarily interrupt the use of such drugs, and can not use other drugs to replace;
  -  Allergic constitution: Allergy or contraindications to the main ingredients or excipients of CN128 tablets (microcrystalline cellulose, croscarmellose sodium, silica, sodium stearyl fumarate, Opadry);
  -  ECG abnormalities have clinical significance: congenital long QT syndrome or known family history of long QT syndrome; QTc> 450ms (male) or QTc> 470 ms (female); clinically significant ventricular or atrial Fast arrhythmia;
  -  Birth planner (including male subjects) within or within 3 months after the end of the trial;
  -  Blood donation in the last 3 month;
  -  Have a history of addictions (more than 5 cigarettes / day or use a considerable amount of nicotine products), alcoholism history (more than 14 alcohol consumption per week: 1 alcohol unit equal to 10mL or 8g pure alcohol, 25mL 40% white wine, 330mL 5 % Beer, 175mL 12% of the wine, respectively, about 1.0,1.5,2.0 alcohol units), drug abuse history, history of drug abuse;
  -  Smoking within 48 hours before applying the drug or using any food or drink (including chocolate, tea, coffee or cola drinks, etc.) containing alcohol, xanthine or grapefruit;
  -  Participated in other clinical trials in the three months before taking the test preparation, except for non-interventional studies;
  -  Nicotine, urine screening results were positive;
  -  Blood collection difficulties;
  -  Blood test for pregnancy was positive;
  -  Unsuitable to participate in the trial considered by the researchers (such as Poor health, poor compliance, unwillingness or inability to comply with treatment plan, including failure to visit on time).

Relevance to patient case: not relevant