UMIN-CTR Clinical Trial

Public title

Phase I / IIa clinical trial for patients with hepatitis C or B virus derived liver cirrhosis by CBP / beta catenin inhibitor PRI-724

Acronym

Phase I / IIa clinical trial for patients with hepatitis C or B virus derived liver cirrhosis by PRI-724

Scientific Title

Phase I / IIa clinical trial for patients with hepatitis C or B virus derived liver cirrhosis by CBP / beta catenin inhibitor PRI-724

Scientific Title:Acronym

Phase I / IIa clinical trial for patients with hepatitis C or B virus derived liver cirrhosis by PRI-724

Region

Japan

Condition

HCV or HBV liver cirrhosis

Classification by specialty

Hepato-biliary-pancreatic medicine

Classification by malignancy

Others

Genomic information

NO

Narrative objectives1

To investigate the safety and efficacy of PRI - 724 against HCV or HBV liver cirrhosis.

Basic objectives2

Safety,Efficacy

Basic objectives -Others

Trial characteristics_1

Exploratory

Trial characteristics_2

Developmental phase

Phase I,II

Primary outcomes

Phase I:
Serious side effect expression rate
Phase IIa:
Amount of change from the baseline in liver tissue fibrosis area ratio by liver biopsy at 12 weeks after administration

Key secondary outcomes

Phase I:
(1) Adverse Event Expression Ratio
(2) Percentage of occurrence of side effects
(3) Pharmacokinetics
Phase IIa:
(1) Amount of change from measurement of liver stiffness by baseline from Fibro Scan at 12 weeks after administration
(2) Amount of change from baseline of Child-Pugh Score at 12 weeks after administration
(3) Amount of change from baseline for MELD score at 12 weeks after administration
(4) Change amount from baseline of modified Histological Activity Index (HAI) by liver biopsy at 12 weeks after administration

Study type

Interventional

Basic design

Single arm

Randomization

Non-randomized

Randomization unit

Blinding

Open -no one is blinded

Control

Uncontrolled

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

1

Purpose of intervention

Treatment

Type of intervention

Medicine

Interventions/Control_1

twice a week for 4 hours continuous intravenous administration of PRI-724

Interventions/Control_2

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

20

years-old

<=

Age-upper limit

75

years-old

>

Gender

Male and Female

Key inclusion criteria

(1) Patients with liver cirrhosis caused by HCV or HBV that satisfies the following 1) or 2) and satisfies 3)
1) Patients with serum HCV-RNA positive or HCV antibody positive
2) Patients with serum HBV-DNA positive or HBs antigen positive
3) confirmed liver cirrhosis by liver biopsy performed in the screening period patients who received diagnosis
(2) Patients with Child-Pugh classification in A or B status
(3) Patients who satisfy HCV cirrhosis from 1) to 3), HBV cirrhosis 4)
In the case of HCV cirrhosis;
1) Patients who have not reached SVR * with DAA therapy
2) Patients who are difficult to implement DAA therapy
3) Patients who have been over 24 weeks after achieving SVR * with DAA or IFN therapy
In case of HBV cirrhosis;
4) Patients who have been at least 24 weeks since the start of administration of Nucleotide analogue
* SVR is SVR 12.
(4) Patients with Performance Status 0 to 2
(5) Patients aged 20 years or over and under 75 when acquiring informed consent
(6) Regarding participation in this trial (including liver biopsy), patients who obtained informed consent by their own voluntary intention

Key exclusion criteria

(1) Patients with HCV and HBV co-infection, patients who came to cirrhosis due to causes other than HCV or HBV, or patients whose cause of cirrhosis is unknown
(2) Patients with esophageal gastric varices determined to be treated by endoscopic examination at screening
(3) Patients with complication or previous history of primary liver cancer
(4) Merger of malignant tumor or past patients (within 3 years before screening).
(5) Patients who can not be denied HIV, HTLV-1 or syphilis
(6) Serum creatinine value > ULN x 1.5
(7) Patients with poor control of diabetes, hypertension or heart failure
(8) Patients with psychiatric diseases judged to have the potential to influence the implementation of clinical trials
(9) Patients who have severe allergy to or contrast media
(10) Patients with HCV who have not passed the regulated period after treatment for HCV cirrhosis at registration.
(11) Patients whose dosage regimen was changed within 12 weeks prior to enrollment
(12) Patients who have history of drug or alcohol intoxication within 5 years before acquiring informed consent or who have history of drug or alcohol abuse within the past year
(13) Patients who participated in other clinical trials and clinical trials within 30 days prior to acquisition of consent, patients who used investigational drugs or investigational equipment
(14) Patients who received liver transplantation or other organ transplantation (including bone marrow transplantation) and patients who are difficult to intravenously administer
(15) Patients whose liver biopsy is expected to be difficult to perform
(16) Patients who are pregnant or nursing, or who are likely to become pregnant
(17) Male patients who do not obtain consent to contraception from the time of acquiring informed consent until the end of 12 weeks after the administration of investigational drug
(18) In addition, patients investigated by investigators or clinical trial doctors as judged unsuitable for this trial

Target sample size

34

Name of lead principal investigator

1st name	Kiminori
Middle name
Last name	Kimura

Organization

Tokyo Metropolitan Komagome Hospital

Division name

Division of Hepatology

Zip code

113-8677

Address

3-18-22 Honkomagome, Bunkyo-ku, Tokyo, Japan

TEL

03-3823-2101

Email

kiminori_kimura@tmhp.jp

Name of contact person

1st name	Kiminori
Middle name
Last name	Kimura

Organization

Tokyo Metropolitan Komagome Hospital

Division name

Division of Hepatology

Zip code

113-8677

Address

3-18-22 Honkomagome, Bunkyo-ku, Tokyo, Japan

TEL

03-3823-2101

Homepage URL

Email

kiminori_kimura@tmhp.jp

Institute

Tokyo Metropolitan Komagome Hospital

Institute

Department

Personal name

Organization

Japan Agency for Medical Research and Development

OHARA Pharmaceutical Co., Ltd.

Organization

Division

Category of Funding Organization

Japanese Governmental office

Nationality of Funding Organization

Japan

Co-sponsor

PRISM Pharma Co., Ltd.
OHARA Pharmaceutical Co.,Ltd.

Name of secondary funder(s)

Organization

Komagome Hospital Institutional Review Board

Address

3-18-22 Honkomagome, Bunkyo-ku, Tokyo, Japan

Tel

03-3823-2101

Email

km_koma_chiken@tmhp.jp

Secondary IDs

YES

Study ID_1

NCT03620474

Org. issuing International ID_1

ClinicalTrials.gov

Study ID_2

Org. issuing International ID_2

IND to MHLW

30-1053

Institutions

東京都立駒込病院（東京都）
国立国際医療研究センター国府台病院（千葉県）
九州大学病院（福岡県）

Date of disclosure of the study information

2018

Year

07

Month

18

Day

URL releasing protocol

https://clinicaltrials.gov/ct2/show/NCT03620474?term=PRI-724&draw=2&rank=1

Publication of results

Published

URL related to results and publications

https://doi.org/10.1016/j.ebiom.2022.104069

Number of participants that the trial has enrolled

27

Results

Three patients from phase 1 who received the recommended dose were evaluated to obtain efficacy and safety data in phase 2a. The most common adverse events (AEs) were diarrhoea and nausea. PRI-724 did not decrease hepatic fibrosis with any statistical significance, either by ordinal scoring or measurement of collagen proportionate area at 12 weeks; however, we observed statistically significant improvements in liver stiffness, Model for End-stage Liver Disease (MELD) score, and serum albumin level.

Results date posted

2022

Year

07

Month

28

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

2022

Year

05

Month

20

Day

Baseline Characteristics

There were 10 patients with HCV cirrhosis and five with HBV cirrhosis (CP class A: 8 patients; and CP class B: 7 patients) in the phase 1 trial. Of the 15 patients, nine had HCV cirrhosis and six had HBV cirrhosis in the phase 2a trial.

Participant flow

We screened 34 patients and enrolled 15 in the phase 1 trial. In this study, 3 patients were enrolled in Level 1, 6 patients in Level 2 (3 of whom were additional patients after administration of 6 patients in Level 3), and 6 patients in Level 3. The safety and PK at Level 1 (140 mg/m2/4 h) were confirmed in the first 3 patients enrolled, and the transition to Level 2 (280 mg/m2/4 h) was decided. Once the safety and PK were confirmed in the three patients enrolled in Level 2, they were transitioned to Level 3 (380 mg/m2/4 h). Three patients were enrolled in Level 3 to confirm their safety and PK, and it was decided to add 3 to Level 3. In the phase 2a trial, we administered 280 mg/m2/4 h PRI-724 to 15 patients at three hospitals. Because three of the 15 patients were administered the recommended dose of 280 mg/m2/4 h in phase 1, and a post-treatment liver biopsy was performed with their consent, these three patients were included in the evaluation of the phase 2a results.

Adverse events

We observed four SAEs among three (one from phase 1 and two from phase 2a) of the 27 patients. We concluded that three of the SAEs were unrelated to PRI-724: prolonged hospitalisation due to viral infection (phase 1), anaemia due to liver cirrhosis before PRI-724 treatment, and spontaneous bacterial peritonitis after the end of treatment (phase 2a). One of the four SAEs was possibly related to the PRI-724 (observed in the 380 mg/m2/4 h cohort). During treatment of all patients, we observed various AEs, including liver dysfunction (15%, 4/27) and gastrointestinal symptoms [diarrhoea (26%, 7/27), nausea (22%, 6/27), vomiting (15%, 4/27), and loss of appetite (22%, 6/27)].

Outcome measures

The primary endpoints of phase 1 were safety, tolerability, and dose-limiting toxicities of multiple escalating doses of PRI-724 when administered via intravenous infusion. Safety was measured by analysing the frequency and severity of AEs. The secondary endpoint was the determination of PRI-724 pharmacokinetics (PK) in vivo. Plasma PRI-724 and C-82 concentration-time data were analysed by non-compartmental methods. These included the maximum drug concentration (Cmax), the time to Cmax (Tmax), the terminal half-life (t1/2), and the area under the plasma concentration-time curve (AUC).
The primary endpoint of phase 2a was the efficacy of liver cirrhosis treatment, which was assessed by examining changes relative to baseline in the area of liver tissue fibrosis according to liver biopsy at 12 weeks post-treatment. The secondary endpoint was the change relative to baseline in liver stiffness measure (LSM) according to FibroScan (Echosens, Waltham, MA, USA), CP score, Model for End-stage Liver Disease (MELD) score, and modified HAI score at 12 weeks.

Plan to share IPD

IPD sharing Plan description

Recruitment status

Main results already published

Date of protocol fixation

2018

Year

04

Month

24

Day

Date of IRB

2018

Year

05

Month

25

Day

Anticipated trial start date

2018

Year

07

Month

24

Day

Last follow-up date

2021

Year

07

Month

12

Day

Date of closure to data entry

Date trial data considered complete

2021

Year

10

Month

09

Day

Date analysis concluded

2021

Year

12

Month

22

Day

Other related information

Registered date

2018

Year

07

Month

12

Day

Last modified on

2022

Year

08

Month

04

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000038025