Clinical trial NCT03244085: A Study to Investigate the Safety, Efficacy and Pharmacokinetic Profile of Multiple Doses of QL-007 in Chronic Hepatitis B Patients
Official title: An Open-Label Phase 1b Study to Evaluate the Dose-Related Safety, Efficacy, and Pharmacokinetic Profile of Different Doses of QL-007 in Chronic Hepatitis B Patients
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Chronic Hepatitis b
Lead sponsor: Qilu Pharmaceutical Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2017-08-09
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This is a nonrandomized, open-label, no-control, dose-escalation Phase 1b trial in 18 patients with chronic HBV infection to determine the safety, preliminary efficacy, and pharmacokinetics (PK) of QL-007 after administration over 28 days of multiple oral doses in a fasted state at the following planned dose levels: 200 mg/day (100 mg two times a day (BID)), 400 mg/day (200 mg BID), then 600 mg once daily (QD), with 6 patients for each cohort.

Detailed description: Administration of the next dose level will occur only if the preceding dose was determined to be safe and well tolerated. The decision to proceed to the next higher dose level will be made by a Safety Review Committee (SRC) based upon review of efficacy and safety data including AEs, safety laboratory results, vital signs and ECGs. PK data for up to 12 hours post-dose will also be reviewed. The review will be conducted after the last subject in a cohort completes the Day 28 visit. The planned dose levels can be modified based on the data reviewed.

Eligibility criteria: Inclusion Criteria:

1. Adult (age 18-65 years inclusive) males or females with chronic HBV (positive for serum hepatitis B surface antigen (HBsAg) or HBV DNA for ≥ 6 months) prior to baseline.
2. Anti-HBV treatment-naive adults; adults who have taken oral anti-HBV nucleoside therapy with the last dose ≥ 4 weeks prior to screening are also eligible.
3. Positive or negative for hepatitis B e antigen (HBeAg).
4. HBV DNA ≥ 20,000 IU/mL.
5. ALT levels could be normal or elevated to \< 10 times upper limit of normal.
6. Creatinine clearance ≥ 70 mL/min.
7. The following laboratory criteria have been met:

   * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
   * Hemoglobin (Hgb) ≥ 8 g/dL
   * Platelets ≥ 75 x 109/L
8. Negative serum pregnancy test for females of childbearing potential
9. For men and women who are not postmenopausal (ie, ≥ 12 months of non-therapy-induced amenorrhea, confirmed by follicle stimulating hormone (FSH), if not on hormone replacement) or surgically sterile (vasectomy in males or absence of ovaries and/or uterus or tubal ligation in females) agreement to remain abstinent or use a highly effective method of contraception during the treatment period and at least through week 12 after last dose.
10. Participants must have signed an ICF indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study and comply with the study procedures and restrictions.

Exclusion Criteria

Patients will be excluded from the study if one or more of the following criteria are applicable:

1. Known co-infection with HIV, hepatitis C virus (HCV) or hepatitis D virus (HDV)
2. Presence of autoimmune disorders
3. History of liver disease other than Hepatitis B
4. History of Gilbert's Disease
5. Any sign of decompensated liver disease
6. Known or suspected cirrhosis
7. Evidence of hepatocellular carcinoma
8. Patient has clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 months), such as:

   * unstable angina within 6 months prior to screening;
   * myocardial infarction within 6 months prior to screening;
   * history of documented congestive heart failure (New York Heart Association functional classification III-IV);
   * uncontrolled hypertension defined by a systolic blood pressure (SBP) ≥ 160 mm Hg and/or diastolic blood pressure (DBP) ≥ 100 mm Hg, with or without antihypertensive medication;
   * initiation or adjustment of antihypertensive medication(s) is allowed prior to screening;
   * ventricular arrhythmias; supraventricular and nodal arrhythmias not controlled with medication;
   * other cardiac arrhythmia not controlled with medication;
   * corrected QTc \> 450 msec using Fridericia correction on the screening ECG.
9. Electrolyte abnormalities.
10. Impaired GI function or GI disease that may alter absorption of QL-007.
11. Ongoing GI AEs \> grade 2 (eg, nausea, vomiting, or diarrhea) at screening.
12. Receiving medications that meet one of the following criteria and that cannot be discontinued ≥ 1 week prior to the start of treatment QL 007:

    * Medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes (see Appendix 3; please refer to https://crediblemeds.org/pdftemp/pdf/CombinedList.pdf
    * Moderate or strong inhibitors or strong inducers of CYP3A (please refer to http://medicine.iupui.edu/flockhart/table.htm or http://www.druginteractioninfo.org)
    * Unstable or increasing doses of corticosteroids
    * Enzyme-inducing anticonvulsive agents
    * Herbal supplements.
13. Alcohol or substance abuse
14. History of bleeding diathesis
15. Patients with a history of seizures, central nervous system disorders or psychiatric disability thought to be clinically significant in the opinion of the investigator.
16. History of clinically significant gastrointestinal, cardiovascular, endocrine, renal, ocular, pulmonary, psychiatric or neurological disease.

Primary outcomes:
measure: Incidence of Adverse Events of QL-007
timeFrame: From randomization up to Day 36
Secondary outcomes:
measure: Peak Plasma Concentration (Cmax) of QL-007 following multiple doses
timeFrame: On Day 1, Day 3, Day 8, Day 15, Day 22 and Day 28, samples will be collected pre-dose; on Day 1 and 28, samples will also be collected at 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h and 12h post dose.
measure: The time to Cmax (tmax) of QL-007 following multiple doses
timeFrame: On Day 1, Day 3, Day 8, Day 15, Day 22 and Day 28, samples will be collected pre-dose; on Day 1 and 28, samples will also be collected at 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h and 12h post dose.
measure: AUC0-t (area under the plasma concentration versus time curve) of QL-007 following multiple doses
timeFrame: On Days 1, 3, 8, 15, 22 and 28, samples will be collected pre-dose; on Day 1 and 28, samples will also be collected at 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h and 12h post dose.
measure: AUC0-∞ of QL-007 following multiple doses
timeFrame: On Day 1, Day 3, Day 8, Day 15, Day 22 and Day 28, samples will be collected pre-dose; on Day 1 and 28, samples will also be collected at 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h and 12h post dose.
measure: t1/2 (terminal elimination half-life) of QL-007 following multiple doses
timeFrame: On Day 1, Day 3, Day 8, Day 15, Day 22 and Day 28, samples will be collected pre-dose; on Day 1 and 28, samples will also be collected at 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h and 12h post dose.
measure: Vz/F(apparent volume of distribution for the terminal disposition phase) of QL-007 following multiple doses
timeFrame: On Day 1, Day 3, Day 8, Day 15, Day 22 and Day 28, samples will be collected pre-dose; on Day 1 and 28, samples will also be collected at 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h and 12h post dose.
measure: CL/F (apparent clearance) of QL-007 following multiple doses
timeFrame: On Day 1, Day 3, Day 8, Day 15, Day 22 and Day 28, samples will be collected pre-dose; on Day 1 and 28, samples will also be collected at 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h and 12h post dose.
measure: Change in serum HBsAg from baseline at Day 1, Day 3, Day 8, Day 15, Day 22 and Day 28
timeFrame: Day 1, Day 3, Day 8, Day 15, Day 22 and Day 28
measure: Change in serum HBV DNA from baseline at Day3, 8, 15, 22 and 28
timeFrame: Day 1, Day 3, Day 8, Day 15, Day 22 and Day 28
Other outcomes:
Locations:
city: Wellington
country: New Zealand
facility: P3 Research
Study officials:
References: