UMIN-CTR Clinical Trial

Public title

Effect of tofogliflozin and pioglitazone on hepatic steatosis in non-alcoholic fatty liver disease (NAFLD) patients with type 2 diabetes. Randomized, open label pilot study.

Acronym

Effect of tofogliflozin and pioglitazone on hepatic steatosis in NAFLD patients with type 2 diabetes.

Scientific Title

Effect of tofogliflozin and pioglitazone on hepatic steatosis in non-alcoholic fatty liver disease (NAFLD) patients with type 2 diabetes. Randomized, open label pilot study.

Scientific Title:Acronym

Effect of tofogliflozin and pioglitazone on hepatic steatosis in NAFLD patients with type 2 diabetes.

Region

Japan

Condition

Non-alcoholic fatty liver disease (NAFLD) with type 2 diabetes

Classification by specialty

Hepato-biliary-pancreatic medicine

Endocrinology and Metabolism

Classification by malignancy

Others

Genomic information

YES

Narrative objectives1

The purpose of this study is to evaluate the effect of tofogliflozin and pioglitazone on liver fat content as measured by using magnetic resonance imaging (MRI) in non-alcoholic fatty liver disease (NAFLD) patients with type 2 diabetes.

Basic objectives2

Efficacy

Basic objectives -Others

Trial characteristics_1

Exploratory

Trial characteristics_2

Developmental phase

Not applicable

Primary outcomes

Change in liver fat content as measured by MRI-based proton density fat fraction (PDFF). <Time Frame: 24 weeks>

Key secondary outcomes

<Important secondary outcome>Change in serum ALT level. <Time Frame: 24 weeks>

<other secondary outcomes>
<1>
Secondary outcomes during randomization phase (mono-therapy), <Time Frame: 0 to 24 weeks >;
% change in liver fat by MRI-PDFF., >=10%, >=20% and >=30% reduction of MRI-PDFF., change in liver stiffness by MR elastography., >=5%, >=10% and >=15% reduction of liver stiffness., change in HbA1c, glucose, insulin, and HOMA-R., change in body weight and BMI., change in ALT, AST, gamma-GTP, ALP, total bilirubin and ALT/AST ratio., the proportion of normalization of ALT and AST level., platelet count, total protein albumin and choline esterase and ferritin., type IV collagen 7S, hsCRP, cytokeratin 18 fragment, adiponectin, ketone body fraction, M2BPG1, and urinary 8-OHdG., number(%) of adverse event.
<2>
Secondary outcomes during combination therapy phase <Time Frame: 24 to 48weeks>; liver fat content, liver stiffness, HbA1c, glucose, insulin, HOMA-R., body weight, BMI, ALT, AST, gamma-GTP, ALP, total bilirubin, ALT/AST ratio., the proportion of normalization of ALT and AST level, platelet count, total protein albumin and choline esterase, ferritin, type IV collagen 7S, hsCRP, cytokeratin 18 fragment, adiponectin, ketone body fraction, M2BPG1, urinary 8-OHdG., number(%) of adverse event.

Study type

Interventional

Basic design

Parallel

Randomization

Randomized

Randomization unit

Individual

Blinding

Open -but assessor(s) are blinded

Control

Active

Stratification

NO

Dynamic allocation

YES

Institution consideration

Blocking

Concealment

No. of arms

2

Purpose of intervention

Treatment

Type of intervention

Medicine

Interventions/Control_1

Tofogliflozin 20mg <Time Frame: 0 to 24 weeks> , Tofogliflozin 20mg + Pioglitazone 15-30mg <Time Frame: 24 to 48 weeks>

Interventions/Control_2

Pioglitazone 15-30mg <Time Frame: 0 to 24 weeks>, Tofoglifozin 20mg + Pioglitazone 15-30mg <Time Frame: 24 to 48 weeks>

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>Inclusion criteria for study entry;
1. men and women, aged 20-74 years.
2. Type 2 diabetic patients who have been treated with diet/exercise therapy.
3. HbA1c higher than 6.5% (measured within 90 days before study registration).
4. Clinically diagnosed NAFLD
5. ALT higher than the upper limited normal (measured within 90 days before study registration).
6. Patients who provide written consent to participate in the trial of their own free will.
<2>Inclusion criteria for randomization;
Patients with screening MRI-PDFF >= 10% steatosis.

Key exclusion criteria

1. Alcohol consumption greater than 30g/day ethanol for males or 20g/day ethanol for females.
2. Patients diagnosed viral hepatitis.
3. Other causes of liver disease including autoimmune and drug -induced hepatic injury.
4. Patients diagnosed hepatic cirrhosis or serious hepatic dysfunction (Child-Pugh B and C).
5. Platelet count < 150,000/mm3 (measured within 90 days before study registration).
6. BMI < 22 kg/m2 (measured within 90 days before study registration).
7. ALT >= 5 times higher than the upper limited normal (measured within 90 days before study registration)
8. Serious renal dysfunction or eGFR < 60 mL /min/1.73 m2 (measured within 90 days before study registration).
9. Type 1 diabetes or HbA1c >= 9.0% (measured within 90 days before study registration)
10. Patients using SGLT2 inhibitors, pioglitazone, insulin or GLP-1 agonists.
11. Patients taking vitamin E.
12. Contraindications to the MRI (for example, patients using heart pacemaker).
13. Patients who can not undergo MRI (for example, patients who can not hold breath long enough or patients with iron overload).
14. Heart failure (NYHA III or more)
15. Patients with cancer or history of cancer in previous 5 years.
16. Severe ketosis, diabetic coma or precoma.
17. Sever infection, within one week before or after the surgery, sever injury.
18. History of hypersensitivity to any of the ingredients of the study drug.
19. Pregnant women, women suspected of being pregnant.
20. Lactating women or patients who can not prevent conception during study period.
21. Patients who are ineligible in the opinion of the investigator.

Target sample size

40

Name of lead principal investigator

1st name	Masato
Middle name
Last name	Yoneda

Organization

Yokohama City University Graduate School of Medicine

Division name

Department of Gastroenterology and Hepatology

Zip code

2360004

Address

3-9 Fukuura, Kanazawa-ku, Yokohama city, Kanagawa, Japan

TEL

045-787-2640

Email

yoneda-ycu@umin.ac.jp

Name of contact person

1st name	Masato
Middle name
Last name	Yoneda

Organization

Yokohama City University Graduate School of Medicine

Division name

Department of Gastroenterology and Hepatology

Zip code

236004

Address

3-9 Fukuura, Kanazawa-ku, Yokohama city, Kanagawa, Japan

TEL

045-787-2640

Homepage URL

Email

yoneda-ycu@umin.ac.jp

Institute

Yokohama City University

Institute

Department

Personal name

Organization

Kowa company ltd.

Organization

Division

Category of Funding Organization

Profit organization

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

Yokohama City Hospital IRB

Address

3-9 Fukuura, Kanazawa-Ku, Yokohama, Japan

Tel

0453707627

Email

rinri@yokohama-cu.ac.jp

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

Date of disclosure of the study information

2017

Year

12

Month

15

Day

URL releasing protocol

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956674/

Publication of results

Published

URL related to results and publications

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888333/

Number of participants that the trial has enrolled

40

Results

Both tofogliflozin and pioglitazone improved the primary endpoint (absolute change in MRI-PDFF), the primary secondary endpoint (absolute change in ALT), and glucose metabolism after 24 weeks of monotherapy. It was also suggested that the combination of both drugs may further improve HbA1c and hepatic lipids, and that tofogliflozin may reduce the weight gain side effect of pioglitazone by combination therapy.

Results date posted

2021

Year

12

Month

14

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

Patients in the pioglitazone-treated group (19 patients) had a mean age of 58.8 +/- 8.1 years, a male ratio of 42.1%, a mean BMI of 30.8 +/- 1.1 kg/m2 , and a mean HbA1c of 7.06 +/- 0.64%, while patients in the tofogliflozin-treated group (21 patients) had a mean age of 58.4 +/- 12.2 years, a male ratio of 61.9%, a mean BMI of 29.4 +/- 1.0 kg/m2, and mean HbA1c 7.22 +/- 0.88%, showing no significant difference between the two groups.

Participant flow

Thirty-eight of 40 patients completed the protocol-specified 24 weeks of monotherapy. Discontinuations were due to incidental detection of thyroid cancer (1 patient) and severe edema side effects (1 patient). Thirty-two patients were converted to combination therapy in the protocol-specified ancillary studies, and all 32 patients completed the combination therapy without any adverse events.

Adverse events

During 24 weeks of monotherapy, one patient in the pioglitazone-treated group had severe edema and one patient in the pioglitazone-treated group had an incidental finding of thyroid cancer (12 and 8 weeks after pioglitazone initiation, respectively). Compared to baseline, body weight decreased to 2.83 +/- 2.86 kg (-3.6% from baseline) in the tofogliflozin group and increased to 1.39 +/- 2.62 kg (1.7%) in the pioglitazone group after 24 weeks of treatment. Edema or weight gain of 3% or more occurred in 31.6% (6/19) of patients in the pioglitazone group, and no patient in the tofogliflozin group had weight gain of 3% or more. One case (4.8%) of urinary tract infection was observed in the tofogliflozin group. In the pioglitazone group, one patient discontinued treatment due to severe edema. No life-threatening events or treatment-related deaths occurred during the study period in either group. No adverse events occurred during the combination therapy.

Outcome measures

(Monotherapy) Changes in hepatic steatosis after 24 weeks of treatment with pioglitazone and tofogliflozin were evaluated using MRI-PDFF, and there was a 7.54% reduction in the pioglitazone group and a 4.12% reduction in the tofogliflozin group. 24-week ALT levels were -33.8 IU/mL (P<0.0001) in the pioglitazone group and -23.3 IU/mL (P=0.0115) in the tofogliflozin group compared to baseline.
Changes in liver fibrosis: After 24 weeks of treatment with pioglitazone and tofogliflozin, changes in liver stiffness were evaluated using MR elastography liver stiffness measurement (MRE-LSM). 0.34 kPa was observed in the pioglitazone group and 0.14 kPa in the tofogliflozin group.
HbA1c improved significantly in both groups (P=0.0003 and P=0.0013 in the pioglitazone and tofogliflozin groups, respectively), and the difference between groups was not significant (P=0.1052).
Urinary 8-OHdG levels were significantly decreased in the tofogliflozin group (P=0.0005) but not in the pioglitazone group (P=0.1138). Adiponectin was significantly increased in the pioglitazone group (P=0.0003) but not in the tofogliflozin group (P=0.1100), and the changes were significantly different (P<0.0001). CK-18 fragment M30 antigen was significantly decreased in both groups (P=0.0007 and P=0.0048 in the tofogliflozin and pioglitazone groups, respectively). Ketone bodies, acetoacetate and 3-hydroxybutyrate, were significantly increased in the tofogliflozin group, while no change was observed in the pioglitazone group.
Analysis of PNPLA3 and TM6SF2: Analysis of PNPLA3 genotype showed no significant difference in PNPLA3 genotype expression in pioglitazone group (CC: n=2, CG: n=8, GG: n=7) and tofogliflozin group (CC: n=5, CG: n=8, GG: n=8). There was no significant difference in the genotype of TM6SF2 between pioglitazone group (CC: n=14, CT: n=3, TT: n=0) and tofogliflozin group (CC: n=17, CG: n=3, GG: n=1). Furthermore, stratification based on PNPLA3 and TM6SF2 genotypes showed no significant difference in treatment efficacy between the two groups.
(Combination therapy) In an analysis of 32 patients who received the combination therapy (12 patients in the initial pioglitazone group and 20 patients in the initial tofogliflozin group), PDFF improved by -5.56% and -3.36%, respectively, with pioglitazone and tofogliflozin monotherapy (24 weeks), and the addition of 24 weeks of combination therapy improved PDFF by additionally -0.87% and -1.33%, respectively. Similarly, AST and ALT changes were also significantly improved by the combination therapy of tofogliflozin monotherapy followed by pioglitazone compared to monotherapy.
In the first 24-week monotherapy study, improvement in MRE was observed only with pioglitazone. but the combination of pioglitazone followed by tofogliflozin showed significant additional improvement compared to monotherapy.
Pioglitazone monotherapy resulted in 3.3% increase in body weight, but the combination therapy of pioglitazone and tofogliflozin offset this body weight gain.

Plan to share IPD

IPD sharing Plan description

Recruitment status

Completed

Date of protocol fixation

2017

Year

11

Month

15

Day

Date of IRB

2017

Year

10

Month

19

Day

Anticipated trial start date

2018

Year

01

Month

01

Day

Last follow-up date

2020

Year

11

Month

27

Day

Date of closure to data entry

Date trial data considered complete

2020

Year

12

Month

31

Day

Date analysis concluded

2021

Year

09

Month

16

Day

Other related information

Registered date

2017

Year

12

Month

11

Day

Last modified on

2021

Year

12

Month

14

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034645