Long-term Clinical Study of CN128 in Thalassemia Patients
Long-term Clinical Study of CN128 in Thalassemia Patients
1. 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 48 weeks.

 -  Subjects' medication status, uncomfortable symptoms, concomitant medication or
 non-drug therapy were recorded daily.

 3. 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.

 4. 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;

 -  etc.

 5. 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.

 6. Safety assessments:

 Safety evaluations include adverse events, adverse reactions, severe adverse events, and
 severe adverse reactions; growth; total and free testosterone in men,
 follicle-generating hormone and luteinizing hormonin in women; vital signs and
 electrocardiogram; hearing, laboratory test, urine pregnancy test (women of childbearing
 age), etc.

 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.
Clinical Trial - IIa - Study Description - Detailed Description

 1. 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.

 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 48 weeks.

 -  Administration plan:

 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). After
 taking CN128 at 15 mg/kg, if unacceptable toxicity associated with CN128 is found, the
 dosage will be reduce to 10 mg/kg. If no symptoms appear, the dose can be increased to
 15 mg/kg. If the unacceptable toxicity related to CN128 still occurs, 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). The dose will be assessed once
 every two or four weeks.

 Subjects' medication status, uncomfortable symptoms, concomitant medication or non-drug
 therapy were recorded daily.

 3. 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.

 4. Subject exclusion criteria:

 -  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.

 5. 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.

 6. 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 hormonin in women; vital signs and
 electrocardiogram; hearing, laboratory test (blood routine, blood biochemistry,
 coagulation function, thyroid and para-gland function, urine routine, etc.), urine
 pregnancy test (women of childbearing age), etc.

 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.
 Summarize the incidence of adverse events, adverse reactions, adverse events
 leading to withdrawal from the trial, adverse events leading to death, severe
 adverse events, and severe adverse reactions. The incidence is calculated by
 subsystem, symptom/sign. Severity of adverse events and adverse reactions: if
 multiple adverse events occur in the same subject, the most serious one is included
 in the analysis; if different adverse events occurred in the same subject, the most
 severe adverse events were counted in the analysis. Drug exposure during the study:
 describe medication compliance during the study, actual dose, administration
 adjustments during the study, whether the study was discontinued, and reasons for
 the suspension.

 -  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.
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.

 Exclusion Criteria:

 -  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.