UMIN-CTR Clinical Trial

Basic information
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
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

Objectives
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

Assessment
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.

Base
Study type	Interventional

Study design
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

Intervention
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

Eligibility
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

Research contact person
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

Public contact
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

Sponsor
Institute	Yokohama City University
Institute
Department

Funding Source
Organization	Kowa company ltd.
Organization
Division
Category of Funding Organization	Profit organization
Nationality of Funding Organization

Other related organizations
Co-sponsor
Name of secondary funder(s)

IRB Contact (For public release)
Organization	Yokohama City Hospital IRB
Address	3-9 Fukuura, Kanazawa-Ku, Yokohama, Japan
Tel	0453707627
Email	rinri@yokohama-cu.ac.jp

Secondary IDs
Secondary IDs	NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2
IND to MHLW

Institutions
Institutions

Other administrative information
Date of disclosure of the study information	2017 Year 12 Month 15 Day

Related information
URL releasing protocol	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956674/
Publication of results	Published

Result
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

Progress
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
Other related information

Management information
Registered date	2017 Year 12 Month 11 Day
Last modified on	2021 Year 12 Month 14 Day

Link to view the page
URL(English)	https://upload.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000034645