Trial Outcomes & Findings for Study of Peretinoin for Suppressing Recurrence of HCV-positive HCC (NCT NCT01640808)

Last Updated: 2020-12-02

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

616 participants

Primary outcome timeframe

Date of randomization to the date of recurrence of HCC (followed every 12 weeks) or death (whichever occurs first)

Results posted on

2020-12-02

Participant Flow

Screened:778 Enrolled:616 Received treatment:610

Participant milestones

Participant milestones
Measure	NIK-333(Peretinoin) NIK-333(peretinoin): 600mg (8 x 75mg capsules) orally, twice a day	Placebo Placebo: Placebo (8 x Placebo capsules) orally, twice a day
Overall Study STARTED	309	307
Overall Study Subjects Received Treatment	305	305
Overall Study COMPLETED	251	291
Overall Study NOT COMPLETED	58	16

Reasons for withdrawal

Reasons for withdrawal
Measure	NIK-333(Peretinoin) NIK-333(peretinoin): 600mg (8 x 75mg capsules) orally, twice a day	Placebo Placebo: Placebo (8 x Placebo capsules) orally, twice a day
Overall Study Unable to continue dynamic CT	14	4
Overall Study Withdrawal by Subject	12	4
Overall Study Lost to Follow-up	4	0
Overall Study Start an antiviral therapy using IFN	3	0
Overall Study Administration of anticancer drugs	2	1
Overall Study Physician Decision	19	5
Overall Study Randomized but not treated	4	2

Baseline Characteristics

Study of Peretinoin for Suppressing Recurrence of HCV-positive HCC

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	NIK-333(Peretinoin) n=301 Participants NIK-333(peretinoin): 600mg (8 x 75mg capsules) orally, twice a day	Placebo n=304 Participants Placebo: Placebo (8 x Placebo capsules) orally, twice a day	Total n=605 Participants Total of all reporting groups
Age, Customized <65 years	51 Participants n=5 Participants	44 Participants n=7 Participants	95 Participants n=5 Participants
Age, Customized Between 65 and 75 years	100 Participants n=5 Participants	124 Participants n=7 Participants	224 Participants n=5 Participants
Age, Customized >=75 years	150 Participants n=5 Participants	136 Participants n=7 Participants	286 Participants n=5 Participants
Sex: Female, Male Female	118 Participants n=5 Participants	123 Participants n=7 Participants	241 Participants n=5 Participants
Sex: Female, Male Male	183 Participants n=5 Participants	181 Participants n=7 Participants	364 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	NIK-333(Peretinoin) n=301 Participants NIK-333(peretinoin): 600mg (8 x 75mg capsules) orally, twice a day	Placebo n=304 Participants Placebo: Placebo (8 x Placebo capsules) orally, twice a day
Recurrence-free Survival	809.0 Days Interval 650.0 to 1026.0	751.0 Days Interval 600.0 to 928.0

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	NIK-333(Peretinoin) n=301 Participants NIK-333(peretinoin): 600mg (8 x 75mg capsules) orally, twice a day	Placebo n=304 Participants Placebo: Placebo (8 x Placebo capsules) orally, twice a day
Disease-free Survival	686.0 Days Interval 532.0 to 860.0	642.0 Days Interval 528.0 to 771.0

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	NIK-333(Peretinoin) n=301 Participants NIK-333(peretinoin): 600mg (8 x 75mg capsules) orally, twice a day	Placebo n=304 Participants Placebo: Placebo (8 x Placebo capsules) orally, twice a day
Time to Recurrence	842.0 Days Interval 673.0 to 1094.0	764.0 Days Interval 608.0 to 936.0

Adverse Events

NIK-333(Peretinoin)

Serious events: 222 serious events

Other events: 253 other events

Deaths: 0 deaths

Placebo

Serious events: 223 serious events

Other events: 193 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Administrator of clinical trial information

Pharmaceutical Division, Clinical Administration Dept.

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	NIK-333(Peretinoin) n=305 participants at risk NIK-333(peretinoin): 600mg (8 x 75mg capsules) orally, twice a day	Placebo n=305 participants at risk Placebo: Placebo (8 x Placebo capsules) orally, twice a day
Blood and lymphatic system disorders Anaemia	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Blood and lymphatic system disorders Pancytopenia	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Blood and lymphatic system disorders Thrombocytopenia	1.3% 4/305 • Number of events 4 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Cardiac disorders Acute myocardial infarction	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Cardiac disorders Angina pectoris	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Cardiac disorders Aortic valve stenosis	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Cardiac disorders Bradycardia	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Cardiac disorders Cardiac failure	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Cardiac disorders Cardiac failure congestive	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Cardiac disorders Coronary artery stenosis	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Ear and labyrinth disorders Meniere's disease	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Ear and labyrinth disorders Sudden hearing loss	0.66% 2/305 • Number of events 3 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Eye disorders Blepharochalasis	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Eye disorders Cataract	0.66% 2/305 • Number of events 2 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	2.3% 7/305 • Number of events 7 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Eye disorders Macular fibrosis	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Abdominal discomfort	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Abdominal distension	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Abdominal pain	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Ascites	5.2% 16/305 • Number of events 16 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	1.3% 4/305 • Number of events 4 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Colitis ischaemic	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Colitis ulcerative	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Constipation	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Dental caries	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Diarrhoea	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Enterocolitis	1.3% 4/305 • Number of events 4 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Injury, poisoning and procedural complications Patella fracture	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Gastric polyps	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Gastric ulcer	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Haemorrhoids	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Inguinal hernia	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.66% 2/305 • Number of events 2 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Oesophageal varices haemorrhage	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Pancreatitis acute	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.98% 3/305 • Number of events 3 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Periodontal disease	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Gastric varices	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Gastric antral vascular ectasia	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Large intestine polyp	1.3% 4/305 • Number of events 4 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	1.3% 4/305 • Number of events 4 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Large intestinal haemorrhage	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Varices oesophageal	2.6% 8/305 • Number of events 8 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	2.3% 7/305 • Number of events 10 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Gastric varices haemorrhage	0.33% 1/305 • Number of events 1 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.00% 0/305 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.

Other adverse events
Measure	NIK-333(Peretinoin) n=305 participants at risk NIK-333(peretinoin): 600mg (8 x 75mg capsules) orally, twice a day	Placebo n=305 participants at risk Placebo: Placebo (8 x Placebo capsules) orally, twice a day
Gastrointestinal disorders Ascites	13.4% 41/305 • Number of events 42 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	3.9% 12/305 • Number of events 14 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Constipation	11.5% 35/305 • Number of events 39 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	7.9% 24/305 • Number of events 24 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Diarrhoea	11.1% 34/305 • Number of events 41 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	9.2% 28/305 • Number of events 32 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Gastrointestinal disorders Gastrooesophageal reflux disease	7.2% 22/305 • Number of events 22 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	2.0% 6/305 • Number of events 6 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
General disorders Oedema peripheral	13.1% 40/305 • Number of events 42 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	7.2% 22/305 • Number of events 26 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
General disorders Pyrexia	6.9% 21/305 • Number of events 25 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	5.2% 16/305 • Number of events 17 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Hepatobiliary disorders Hepatic function abnormal	5.2% 16/305 • Number of events 16 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	4.6% 14/305 • Number of events 16 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Infections and infestations Cystitis	10.5% 32/305 • Number of events 45 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	4.6% 14/305 • Number of events 20 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Infections and infestations Nasopharyngitis	35.7% 109/305 • Number of events 167 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	32.5% 99/305 • Number of events 187 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Injury, poisoning and procedural complications Contusion	8.2% 25/305 • Number of events 27 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	4.3% 13/305 • Number of events 13 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Investigations Albumin urine present	6.9% 21/305 • Number of events 22 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	1.6% 5/305 • Number of events 6 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Metabolism and nutrition disorders Hypokalaemia	5.9% 18/305 • Number of events 19 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	1.6% 5/305 • Number of events 6 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Musculoskeletal and connective tissue disorders Arthralgia	5.9% 18/305 • Number of events 20 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	4.6% 14/305 • Number of events 15 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Musculoskeletal and connective tissue disorders Back pain	12.5% 38/305 • Number of events 40 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	5.6% 17/305 • Number of events 17 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Musculoskeletal and connective tissue disorders Muscle spasms	4.3% 13/305 • Number of events 13 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	5.2% 16/305 • Number of events 18 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Nervous system disorders Headache	5.9% 18/305 • Number of events 19 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	5.9% 18/305 • Number of events 23 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Psychiatric disorders Insomnia	7.9% 24/305 • Number of events 24 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	3.3% 10/305 • Number of events 10 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Respiratory, thoracic and mediastinal disorders Cough	3.9% 12/305 • Number of events 14 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	5.6% 17/305 • Number of events 27 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Skin and subcutaneous tissue disorders Nail disorder	6.6% 20/305 • Number of events 20 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	0.66% 2/305 • Number of events 2 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Skin and subcutaneous tissue disorders Pruritus	8.9% 27/305 • Number of events 29 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	10.8% 33/305 • Number of events 38 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Skin and subcutaneous tissue disorders Rash	5.6% 17/305 • Number of events 18 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	4.3% 13/305 • Number of events 16 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.
Vascular disorders Hypertension	31.1% 95/305 • Number of events 100 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.	9.8% 30/305 • Number of events 31 • From the starting day of study drug administration to 35 days after the discontinuation of the study drug administration, up to approximately 4.3 years. Safety analysis set consisted of 610 subjects who received treatment. Since the number of SAE of HCC recurrence is larger than other SAEs and is greater in the Placebo group than in NIK-333 group, we consider that there is a concern of underestimating the safety issue from the following points. * It becomes difficult to understand what extent SAE that pose a safety concern have occurred. * The incidence of SAE in placebo group and NIK-333 group appears to be similar.