Hepatic Neoplasm Malignant Recurrent
Conditions
Brief summary
The purpose of this study is to verify the superiority of NIK-333 (Peretinoin) to placebo in inhibiting the recurrence of HCV-positive HCC in patients showing complete cure of the disease, with the recurrence-free survival as the primary endpoint, in a multi-center, randomized, double-blind, placebo-controlled, parallel-group comparison study.
Interventions
DRUGNIK-333(peretinoin)
600mg (8 x 75mg capsules) orally, twice a day
DRUGPlacebo
Placebo (8 x Placebo capsules) orally, twice a day
Sponsors
Kowa Company, Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with HCV-positive HCC who meet the following conditions before radical treatment * Patients diagnosed as having typical HCC on dynamic CT,CTA/CTAP, or dynamic MRI (nodule visualized as a high signal intensity area in the arterial phase and as a relatively low signal intensity area in the portal and equilibrium phases) performed within 8 weeks (56 days) before treatment start prior to radical therapy * Patients with the first primary HCC or the first recurrence of primary HCC 2. Patients who received the radical therapies. The treatment duration (from the start to the end of the treatment) should be within 4 weeks (28 days) for each of the radical therapies. 3. Patients showing a complete cure, as confirmed by the dynamic CT images taken from 8 weeks (56 days) to 12 weeks (84 days) after the end of the treatment show a non-stained low-concentration area overlapping the tumor image observed before complete cure. 4. Patients who are able to begin treatment with the study drug within 8 weeks (56 days) after dynamic CT to confirm complete cure 5. Patients confirmed of satisfying the following conditions based on the screening performed at subject registration * Positive for serum hepatitis C virus nucleic acid (HCV-RNA) * Grade A on Child-Pugh classification * Platelet count of 50 000/µL or higher 6. Patients with ECOG Performance Status score of 0 to 1 7. Patients of the age of 20 years or older at the time of informed consent
Exclusion criteria
1. Patients positive for HBs antigen 2. Patients showing vascular invasion of HCC on imaging diagnosis 3. Patients who have also undergone transcatheter arterial embolization therapy (TAE/TACE), transarterial infusion therapy (TAI), and chemolipiodolization in combination with the radical therapy 4. 4 Patients who want to receive antiviral therapy such as concomitant therapy with intaferon during the study period 5. Patients who have received other study drugs, anticancer drugs, or interferons after radical therapy 6. Patients who have hypertension as a complication, and whose blood pressure cannot be controlled by drug therapy (systolic blood pressure of 160 mmHg or higher or diastolic blood pressure of 100 mmHg or higher, as determined at subject registration) 7. Patients who have a history of allergy to CT contrast media, and whose participation in this study is judged to be inappropriate by the investigator or the subinvestigator 8. Patients with a history of total gastrectomy 9. Patients with a history of cardiac arrest 10. Patients with any of the following laboratory values or complications * Creatinine\>= 1.5mg/dL * Albumin urine \>= 1000mg/g Creatinine * Cardiac disorder corresponding to CTC-AE grade 3 in severity * HbA1c \>= 7.4 under treatment with insulin * Autoimmune disease or asthma being treated with oral steroid 11. Patients confirmed of having another malignant neoplasm or who had undergone a radical therapy of HCC within the past 5 years to treat another malignant neoplasm (however, this does not apply to endoscopic resection and resection of intraepithelial carcinoma) 12. Patients who are pregnant, who have a possibility of being pregnant or who have a desire to become pregnant during the study period 13. Lactating women 14. Patients who have a history of allergy to retinoid-related substances (vitamin A, etc.) in the past 15. Patients who participated in another clinical study within past 6 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence-free Survival | Date of randomization to the date of recurrence of HCC (followed every 12 weeks) or death (whichever occurs first) | HCC recurrence was defined as the appearance of new intrahepatic lesions which was confirmed based on findings of hypervascularity (nodules enhanced in the arterial phase and washout in the late phase) by dynamic CT images, or a new extrahepatic metastasis. Recurrence of intrahepatic HCC was evaluated by an independent image reading committee. RFS was defined as the time from randomization to HCC recurrence or death from any cause, whichever occurred first. For subjects who terminated the study without HCC recurrence or death, RFS was censored at the day of the latest dynamic CT examination. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival | Date of randomization to the date of recurrence of HCC (followed every 12 weeks), death, or secondary cancer (malignant tumors other than HCC)(whichever occurs first) | DFS was defined as the time from randomization to HCC recurrence, death from any cause or occurrence of secondary cancer (malignant tumors other than HCC), whichever occurred first. For subjects who terminated the study without HCC recurrence, death, or occurrence of secondary cancer, DFS was censored at the day of the latest dynamic CT examination. |
| Time to Recurrence | Date of randomization to the date of recurrence of HCC(followed every 12 weeks) | TTR was defined as the time from randomization to HCC recurrence. For subjects who terminated the study without HCC recurrence, TTR was censored at the day of the latest dynamic CT examination. |
Countries
Japan
Participant flow
Pre-assignment details
Screened:778 Enrolled:616 Received treatment:610
Participants by arm
| Arm | Count |
|---|---|
| NIK-333(Peretinoin) NIK-333(peretinoin): 600mg (8 x 75mg capsules) orally, twice a day | 301 |
| Placebo Placebo: Placebo (8 x Placebo capsules) orally, twice a day | 304 |
| Total | 605 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administration of anticancer drugs | 2 | 1 |
| Overall Study | Lost to Follow-up | 4 | 0 |
| Overall Study | Physician Decision | 19 | 5 |
| Overall Study | Randomized but not treated | 4 | 2 |
| Overall Study | Start an antiviral therapy using IFN | 3 | 0 |
| Overall Study | Unable to continue dynamic CT | 14 | 4 |
| Overall Study | Withdrawal by Subject | 12 | 4 |
Baseline characteristics
| Characteristic | NIK-333(Peretinoin) | Placebo | Total |
|---|---|---|---|
| Age, Customized <65 years | 51 Participants | 44 Participants | 95 Participants |
| Age, Customized >=75 years | 150 Participants | 136 Participants | 286 Participants |
| Age, Customized Between 65 and 75 years | 100 Participants | 124 Participants | 224 Participants |
| Sex: Female, Male Female | 118 Participants | 123 Participants | 241 Participants |
| Sex: Female, Male Male | 183 Participants | 181 Participants | 364 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 253 / 305 | 193 / 305 |
| serious Total, serious adverse events | 222 / 305 | 223 / 305 |
Outcome results
Primary
Recurrence-free Survival
HCC recurrence was defined as the appearance of new intrahepatic lesions which was confirmed based on findings of hypervascularity (nodules enhanced in the arterial phase and washout in the late phase) by dynamic CT images, or a new extrahepatic metastasis. Recurrence of intrahepatic HCC was evaluated by an independent image reading committee. RFS was defined as the time from randomization to HCC recurrence or death from any cause, whichever occurred first. For subjects who terminated the study without HCC recurrence or death, RFS was censored at the day of the latest dynamic CT examination.
Time frame: Date of randomization to the date of recurrence of HCC (followed every 12 weeks) or death (whichever occurs first)
Population: Full analysis set (FAS) consisted of 605 subjects among 616 randomized subjects. Reasons for 11 excluded subjects are as following;~* 6 Subjects (NIK-333 group: 4, Placebo group: 2) who did not take any study drugs~* 5 Subjects (NIK-333 group: 4, Placebo group: 1) who had no efficacy data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NIK-333(Peretinoin) | Recurrence-free Survival | 809.0 Days |
| Placebo | Recurrence-free Survival | 751.0 Days |
p-value: 0.35195% CI: [0.72, 1.124]Log Rank
Secondary
Disease-free Survival
DFS was defined as the time from randomization to HCC recurrence, death from any cause or occurrence of secondary cancer (malignant tumors other than HCC), whichever occurred first. For subjects who terminated the study without HCC recurrence, death, or occurrence of secondary cancer, DFS was censored at the day of the latest dynamic CT examination.
Time frame: Date of randomization to the date of recurrence of HCC (followed every 12 weeks), death, or secondary cancer (malignant tumors other than HCC)(whichever occurs first)
Population: Full analysis set (FAS) consisted of 605 subjects among 616 randomized subjects. Reasons for 11 excluded subjects are as following;~* 6 Subjects (NIK-333 group: 4, Placebo group: 2) who did not take any study drugs~* 5 Subjects (NIK-333 group: 4, Placebo group: 1) who had no efficacy data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NIK-333(Peretinoin) | Disease-free Survival | 686.0 Days |
| Placebo | Disease-free Survival | 642.0 Days |
p-value: 0.22295% CI: [0.706, 1.085]Log Rank
Secondary
Time to Recurrence
TTR was defined as the time from randomization to HCC recurrence. For subjects who terminated the study without HCC recurrence, TTR was censored at the day of the latest dynamic CT examination.
Time frame: Date of randomization to the date of recurrence of HCC(followed every 12 weeks)
Population: Full analysis set (FAS) consisted of 605 subjects among 616 randomized subjects. Reasons for 11 excluded subjects are as following;~* 6 Subjects (NIK-333 group: 4, Placebo group: 2) who did not take any study drugs~* 5 Subjects (NIK-333 group: 4, Placebo group: 1) who had no efficacy data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NIK-333(Peretinoin) | Time to Recurrence | 842.0 Days |
| Placebo | Time to Recurrence | 764.0 Days |
p-value: 0.27995% CI: [0.703, 1.108]Log Rank