Clinical Study of CN128 in Thalassemia Patients
Clinical Study of CN128 in Thalassemia Patients
1. Primary objectives:

 -  To determine the maximum tolerated dose (MTD) of CN128 for single oral
 administration in thalassemia patients aged 16 and above

 -  To study the pharmacokinetics of CN128 in thalassemia patients aged 16 and above

 2. Design:

 The study is designed as a randomized, double-blind, single ascending dose, phase Ia
 (first in human) trial.

 The study is consisted of: single dose ascending; dose escalation pharmacokinetics;
 metabolite structure identification in plasma, urine and feces.

 3. Subject inclusion criteria:

 -  Thalassemia patients with serum ferritin ≥500 μg/L

 -  Patients aged 16 and above

 -  Without blood transfusion within 1 week before admission, with hemoglobin ≥ 80 g/L

 -  Voluntarily participate in the experiment, and the process of obtaining informed
 consent form meeting the requirements of GCP

 4. Subject exclusion criteria:

 -  Hepatitis B surface antigen positive, hepatitis B core antibody positive and
 HBV-DNA positive, hepatitis C anti-HCV positive, HIV positive, Treponema pallidum
 positive

 -  Patients with history of active digestive tract diseases (including gastric ulcer,
 duodenal ulcer, gastroesophageal varices, ulcerative colitis, Crohn's disease,
 digestive tract tumors, familial genetic multiple intestinal polyps), history of
 digestive tract perforation, history of digestive tract surgery and influence on
 drug absorption, and other patients whom investigators believe to have potential
 intestinal complications

 -  Liver dysfunction (ALT or AST > 2.5×ULN); or renal dysfunction (serum creatinine >
 1.5×ULN)

 -  Uncontrolled active infections

 -  Patients currently taking CYP3A strong inducer or inhibitor drugs or drugs that may
 prolong the QT interval without temporary suspension of use or temporary
 substitution of the said drugs

 -  ect.

 5. Usage:

 After fasting for at least 10 hours, the whole tablet was swallowed with 240 mL warm
 water on an empty stomach. Water was forbidden within 1 hour before and after the
 administration. Water was allowed 1 hour after administration.

 6. Pharmacokinetic assessment of CN128 administration:

 PK parameters of CN128 include AUC 0-t, AUC 0-∞, Cmax, Tmax, t1/2, CL/F, Vd/F, MRT ,λz
 etc.

 7. Safety and tolerability assessments:

 Evaluation was based on the incidence of adverse events (AE) after administration,
 termination information, laboratory test results, 12-lead electrocardiogram and vital
 signs.

 8. Statistics
1. Primary objectives:

 · To determine the maximum tolerated dose (MTD) of CN128 for single oral administration
 in thalassemia patients aged 16 and above

 · To study the pharmacokinetics of CN128 in thalassemia patients aged 16 and above

 2. Design:

 The study is designed as a randomized, double-blind, single ascending dose, phase Ia
 (first in human) trial.

 The study is consisted of:

 · Single dose ascending: The trial will start with the lowest dose of CN128 given to 3
 subjects, and the lowest dose of placebo given to 1 subjects (2.5 mg/kg body weight
 [bw], single dose).The dose of second group is 5 mg/kg bw.The dose of third group is 10
 mg/kg bw.The dose of fourth group is 15 mg/kg bw.The dose of fifth group is 20 mg/kg
 bw.The dose of sixth group is 30 mg/kg bw.The dose of seventh group is 45 mg/kg bw.The
 dose of final group is 60 mg/kg bw.

 -  Dose escalation pharmacokinetics:

 AUC 0-t, AUC 0-∞, Cmax, Tmax, t1/2, CL/F, Vd/F, MRT ,λz etc.

 · Metabolite structure identification in plasma, urine and feces: Collecting plasma,
 urine and feces samples for identifying CN128 metabolites in them.

 3. Subject inclusion criteria:

 · Thalassemia patients with serum ferritin ≥500 μg/L

 -  Patients aged 16 and above

 -  Without blood transfusion within 1 week before admission, with hemoglobin ≥ 80 g/L

 -  Voluntarily participate in the experiment, and the process of obtaining informed
 consent form meeting the requirements of GCP

 4. Subject exclusion criteria:

 · Hepatitis B surface antigen positive, hepatitis B core antibody positive and HBV-DNA
 positive, hepatitis C anti-HCV positive, HIV positive, Treponema pallidum positive

 · Patients with history of active digestive tract diseases (including gastric ulcer,
 duodenal ulcer, gastroesophageal varices, ulcerative colitis, Crohn's disease, digestive
 tract tumors, familial genetic multiple intestinal polyps), history of digestive tract
 perforation, history of digestive tract surgery and influence on drug absorption, and
 other patients whom investigators believe to have potential intestinal complications

 · Liver dysfunction (ALT or AST > 2.5×ULN); or renal dysfunction (serum creatinine >
 1.5×ULN)

 · Uncontrolled active infections

 · Patients currently taking CYP3A strong inducer or inhibitor drugs or drugs that may
 prolong the QT interval without temporary suspension of use or temporary substitution of
 the said drugs

 · Allergic constitution: allergic to or with contraindication of main ingredients or
 excipients of CN128 tablets (microcrystalline cellulose, cross-linked sodium
 carboxymethyl cellulose, silica, sodium stearate fumarate, Opadry)

 · Patients who have abnormal ECG with clinical significance: congenital long QT syndrome
 or known family history of long QT syndrome; QTc > 450ms (male) or QTc > 470ms (female);
 patients who have ventricular or atrial tachyarrhythmia with clinical significance, etc.

 · Family planning participants (including male subjects) during or within three months
 after the trial

 · Patients with a history of blood donation within 3 months before the trial

 · Patients with a history of smoking (more than 5 cigarettes or products with equivalent
 nicotine per day), alcoholism (more than 14 units of alcohol per week: 1 alcohol unit
 equals 10 mL or 8 g pure alcohol; 25 mL 40% liquor, 330 mL 5% beer, 175 mL 12% red wine
 equals 1.0, 1.5, 2.0 alcohol units respectively), drug abuse and addiction history

 · Patients who smoke, drink or eat any food containing alcohol, xanthine or grapefruit
 (including chocolate, tea, coffee or cola drinks) within 48 h before the using of test
 drug

 · The subject of any other clinical trials within 3 months before using of the test drug
 except for non interventional studies

 -  Patients with positive results of nicotine and urine drug screening

 -  Patients with difficult venous blood collection

 -  Any patient with conditions which the investigators resume inappropriate to
 participate in this study, such as: poor health status, poor compliance,
 unwillingness or inability to comply with treatment regimens, including delayed
 visits

 5. Usage:

 After fasting for at least 10 hours, the whole tablet was swallowed with 240 mL warm
 water on an empty stomach. Water was forbidden within 1 hour before and after the
 administration. Water was allowed 1 hour after administration.

 6. Pharmacokinetic assessment of CN128 administration:

 PK parameters of CN128 include AUC 0-t, AUC 0-∞, Cmax, Tmax, t1/2, CL/F, Vd/F, MRT ,λz
 etc.

 7. Safety and tolerability assessments:

 Evaluation was based on the incidence of adverse events (AE) after administration,
 termination information, laboratory test results, 12-lead electrocardiogram and vital
 signs.

 8. Statistics:

 -  Pharmacokinetic analysis:

 Phoenix WinNonlin software (Pharsight Corporation, version 7.0) was used to estimate and
 analyze the parameters of PK in non-atrioventricular model according to dosage. The
 pharmacokinetic parameters were calculated in actual time to fully reflect the
 characteristics of drug absorption, distribution, metabolism and excretion in human body. The
 PK parameters of each participant were calculated according to the following methods. PK
 parameters include:

 AUC0-t, AUC0-∞, Cmax, Tmax, t1/2, CL/F, Vd/F, MRT, λz; Descriptive statistics of
 untransformed data of drug concentration in plasma at each time point, AUC0 t, AUC0-∞, Cmax,
 Tmax, t1/2, CL/F, Vd/F, MRT and λz were summarized. Descriptive statistics was used in the
 analysis of Number (N), arithmetic mean, geometric mean, standard deviation (SD), CV,
 minimum, median and maximum.

 · Linear correlation analysis for dosage: The dose dependence of Cmax, AUC0-t and AUC0-∞ was
 evaluated. Linear correlation analysis of main pharmacokinetic parameters and dosage was done
 for each subject by power model.

 · Safety analysis: All AE, treatment emergent adverse events (TEAE), drug-related TEAE, grade
 3 or above TEAE, serious adverse events (SAE), drug-related SAE, TEAE leading to death, TEAE
 leading to termination of trial, drug-relation TEAE leading to termination of trial and
 drug-related TEAE leading to discontinuation of use of test drug were summarized for case
 number, subject number and incidence rate. Summary of cases and incidence. P value for the
 incidence of these AEs with different classifications was calculated by Fisher's exact test.

 TEAE, SAE, drug-related TEAE, drug-related SAE, TEAE leading to the termination of the trial,
 and TEAE leading to the discontinuation of drug use were summarized and described according
 to the system organ classification (SOC), preferred terminology (PT) and study group. The
 severity of TEAE and drug-related TEAE was also summarized according to SOC, PT and study
 groups.

 The measured value of parameters and change of baseline of vital signs, 12-lead ECG, physical
 examination, clinical laboratory examination, etc. were summarized according to the planned
 time point and the study group.

 Determine dose-limited toxicity of a single dose in human (DLT); Determine the maximum
 tolerated dose of a single dose in human (MTD).
Subject inclusion criteria:

 -  Thalassemia patients with serum ferritin ≥500 μg/L

 -  Patients aged 16 and above

 -  Without blood transfusion within 1 week before admission, with hemoglobin ≥ 80 g/L

 -  Voluntarily participate in the experiment, and the process of obtaining informed
 consent form meeting the requirements of GCP

 Subject exclusion criteria:

 -  Hepatitis B surface antigen positive, hepatitis B core antibody positive and HBV-DNA
 positive, hepatitis C anti-HCV positive, HIV positive, Treponema pallidum positive

 -  Patients with history of active digestive tract diseases (including gastric ulcer,
 duodenal ulcer, gastroesophageal varices, ulcerative colitis, Crohn's disease,
 digestive tract tumors, familial genetic multiple intestinal polyps), history of
 digestive tract perforation, history of digestive tract surgery and influence on drug
 absorption, and other patients whom investigators believe to have potential intestinal
 complications

 -  Liver dysfunction (ALT or AST > 2.5×ULN); or renal dysfunction (serum creatinine >
 1.5×ULN)

 -  Uncontrolled active infections

 -  Patients currently taking CYP3A strong inducer or inhibitor drugs or drugs that may
 prolong the QT interval without temporary suspension of use or temporary substitution
 of the said drugs

 -  Allergic constitution: allergic to or with contraindication of main ingredients or
 excipients of CN128 tablets (microcrystalline cellulose, cross-linked sodium
 carboxymethyl cellulose, silica, sodium stearate fumarate, Opadry)

 -  Patients who have abnormal ECG with clinical significance: congenital long QT syndrome
 or known family history of long QT syndrome; QTc > 450ms (male) or QTc > 470ms
 (female); patients who have ventricular or atrial tachyarrhythmia with clinical
 significance, etc.

 -  Family planning participants (including male subjects) during or within three months
 after the trial

 -  Patients with a history of blood donation within 3 months before the trial

 -  Patients with a history of smoking (more than 5 cigarettes or products with equivalent
 nicotine per day), alcoholism (more than 14 units of alcohol per week: 1 alcohol unit
 equals 10 mL or 8 g pure alcohol; 25 mL 40% liquor, 330 mL 5% beer, 175 mL 12% red
 wine equals 1.0, 1.5, 2.0 alcohol units respectively), drug abuse and addiction
 history

 -  Patients who smoke, drink or eat any food containing alcohol, xanthine or grapefruit
 (including chocolate, tea, coffee or cola drinks) within 48 h before the using of test
 drug

 -  The subject of any other clinical trials within 3 months before using of the test drug
 except for non interventional studies

 -  Patients with positive results of nicotine and urine drug screening

 -  Patients with difficult venous blood collection

 -  Any patient with conditions which the investigators resume inappropriate to
 participate in this study, such as: poor health status, poor compliance, unwillingness
 or inability to comply with treatment regimens, including delayed visits