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

 -  To study the tolerance and safety of multiple oral administration of CN128 in
 patients with thalassemia aged 16 years and above.

 -  To study the pharmacokinetics of CN128 in thalassemia patients aged 16 and above by
 multiple oral administrations of CN128

 2. Design:

 The study is designed as a safety, tolerability and pharmacokinetic parameters study,
 phase Ib trial.

 The study is consisted of: multiple dose tolerance and safety study; multiple
 administration pharmacokinetics.

 3. Subject inclusion criteria:

 -  Thalassemia patients with serum ferritin ≥ 500 µg/L

 -  Patients aged 16 and above

 -  HB≥80 g/L before administration

 -  Voluntarily participate in the experiment, and the process of obtaining informed
 consent met 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

 -  History of active digestive tract diseases (including gastric ulcer, duodenal
 ulcer, gastroesophageal varices, ulcerative colitis, Crohn's disease, digestive
 tract tumors, familial genetic polyps), history of digestive tract perforation,
 history of digestive tract surgery and influence on drug absorption, and other
 investigators believe that patients with 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:

 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:

 PK parameters of CN128 include AUC 0-t, AUC 0-∞, Cmax, Tmax, t1/2, CL/F, Vd/ F, MRT, λz,
 Css-av, Css-min, Css-max, Accumulation rate, Fluctuation index, etc.

 7. Safety and tolerability assessments:

 Evaluation was based on the incidence rate of adverse events (AE) after the
 administration, study termination information, vital signs, physical examination,
 laboratory tests and ECG.

 8. Statistics
1. Primary objectives:

 -  To study the tolerance and safety of multiple oral administration of CN128 in
 patients with thalassemia aged 16 years and above.

 -  To study the pharmacokinetics of CN128 in thalassemia patients aged 16 and above by
 multiple oral administrations of CN128

 2. Design:

 The study is designed as a safety, tolerability and pharmacokinetic parameters study,
 phase Ib trial.

 The study is consisted of:

 • Multiple dose tolerance and safety study: 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).

 • Multiple administration pharmacokinetics: AUC 0-t, AUC 0-∞, Cmax, Tmax, t1/2, CL/F,
 Vd/ F, MRT, λz, Css-av, Css-min, Css-max, Accumulation rate, Fluctuation index, etc.

 3. Subject inclusion criteria:

 -  Thalassemia patients with serum ferritin ≥ 500 µg/L

 -  Patients aged 16 and above

 -  HB≥80 g/L before administration

 -  Voluntarily participate in the experiment, and the process of obtaining informed
 consent met 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

 -  History of active digestive tract diseases (including gastric ulcer, duodenal
 ulcer, gastroesophageal varices, ulcerative colitis, Crohn's disease, digestive
 tract tumors, familial genetic polyps), history of digestive tract perforation,
 history of digestive tract surgery and influence on drug absorption, and other
 investigators believe that patients with 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
 using of test drug

 -  The subjects should not join in other clinical drug or instrument study or some
 other clinical studies within 3 months before taking the study drug, except for non
 interventional studies;

 -  Patients with positive results of nicotine and urine drug screening

 -  Patients with difficulty in venous blood collection

 -  Patients with positive blood pregnancy test results

 -  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:

 Subjects started fasting for solid from 21:00 on the day before the study and for liquid
 within 1 h before and after the administration. Subjects in each dose group received a
 single administration on the first day of the study on an empty stomach. Blood samples
 were collected at different time points before and within 48 hours after the
 administration (before the administration on day 3). No administration was conducted on
 day 2. continuous administration was conducted from day 3 to day 8, twice a day, once in
 the morning on an empty stomach, once in 12 hours (±15min). The valley concentration
 blood samples were collected in the morning on day 6, 7 and 8. In the morning of day 9,
 a single administration was conducted on an empty stomach. Blood samples were taken at
 the different time points before and within 48 hours after the administration on day 9.
 Each dose was taken with 240 mL warm water.Except for the water taken together with the
 tablets, it should be ensured that the water was banned for 1 hour before and after the
 valley concentration blood sample collection from day 6 to day 8 and 1 hour before and
 after the administration in the morning on day 1 and day 9.

 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,
 Css-av, Css-min, Css-max, Accumulation rate, Fluctuation index, etc.

 7. Safety and tolerability assessments:

 Evaluation was based on the incidence rate of adverse events (AE) after the
 administration, study termination information, vital signs (including body temperature,
 pulse, breathing, sitting blood pressure) and physical examination (including height,
 weight, general condition, skin, neck (including thyroid), eyes, ears, nose, throat,
 chest, abdomen, back, lymph nodes, limbs and nervous system examinations, and laboratory
 tests (blood routine, urine routine, blood biochemistry, coagulation function, serum
 iron, thyroid gland and parathyroid gland function), ECG to evaluate the status.

 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 real 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, Css_av, Css_min, Css_max, Accumulation
 rate and Fluctuation index.

 Descriptive statistics were summarized on untransformed datas of drug concentration in plasma
 at each time point: AUC0 t, AUC0-∞, Cmax, Tmax, t1/2, CL/F, Vd/F, MRTλz, Css_av, Css_min,
 Css_max, R and DF. Descriptive statistics was used in the analysis of Number (N), arithmetic
 mean, geometric mean, standard deviation (SD), CV, minimum, median and maximum. Average and
 individual time-concentration curves were drawn according to the study group.

 • 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. 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 changes from 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 multiple dose in human (DLT); Determine the maximum
 tolerable dose of multiple dose in human (MTD).
Subject inclusion criteria:

 -  Thalassemia patients with serum ferritin ≥ 500 µg/L

 -  Patients aged 16 and above

 -  HB≥80 g/L before administration

 -  Voluntarily participate in the experiment, and the process of obtaining informed
 consent met 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

 -  History of active digestive tract diseases (including gastric ulcer, duodenal ulcer,
 gastroesophageal varices, ulcerative colitis, Crohn's disease, digestive tract tumors,
 familial genetic polyps), history of digestive tract perforation, history of digestive
 tract surgery and influence on drug absorption, and other investigators believe that
 patients with 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 using of test
 drug

 -  The subjects should not join in other clinical drug or instrument study or some other
 clinical studies within 3 months before taking the study drug, except for non
 interventional studies;

 -  Patients with positive results of nicotine and urine drug screening

 -  Patients with difficulty in venous blood collection

 -  Patients with positive blood pregnancy test results

 -  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