UMIN-CTR Clinical Trial

Public title

Crossover trial comparing sera obtained from diabetic patients before and after pioglitazone administration on cholesterol efflux from macrophages

Acronym

Pioglitazone and cholesterol efflux

Scientific Title

Crossover trial comparing sera obtained from diabetic patients before and after pioglitazone administration on cholesterol efflux from macrophages

Scientific Title:Acronym

Pioglitazone and cholesterol efflux

Region

Japan

Condition

Diabetes

Classification by specialty

Endocrinology and Metabolism

Classification by malignancy

Others

Genomic information

NO

Narrative objectives1

To investigate whether pioglitazone enhance cholesterol efflux and ABCA1/G1 expressions in macrophages, we plan to obtain blood from diabetic patients before and after orally administtation of pioglitazone, and compare them.

Basic objectives2

Efficacy

Basic objectives -Others

Trial characteristics_1

Trial characteristics_2

Developmental phase

Primary outcomes

Macrophage ABCA1/G1 expressions and cholesterol efflux cultured under sera obtained from diabetic patients

Key secondary outcomes

Study type

Interventional

Basic design

Cross-over

Randomization

Randomized

Randomization unit

Blinding

Open -but assessor(s) are blinded

Control

Placebo

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

2

Purpose of intervention

Treatment

Type of intervention

Medicine

Interventions/Control_1

Oral administration of pioglitazone

Interventions/Control_2

Oral administration of placebo

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

Type 2 diabetic patients who are treated with piogliitazone at least for 6 months and have good tolerance without relevant side effects

Key exclusion criteria

Poor-controlled diabetes (HbA1c>8.0 %)

Target sample size

15

Name of lead principal investigator

1st name
Middle name
Last name	Katsunori Ikewaki

Organization

National Defense Medical College

Division name

Department of Internal Medicine I

Zip code

Address

3-2 Namiki, Tokorozawa, JAPAN 359-8513

TEL

04-2995-1597

Email

katsunorike@ndmc.ac.jp

Name of contact person

1st name
Middle name
Last name	Makoto Ayaori

Organization

National Defense Medical College I

Division name

Department of Internal Medicine

Zip code

Address

3-2 Namiki, Tokorozawa, JAPAN 359-8513

TEL

04-2995-1597

Homepage URL

Email

ayaori@ndmc.ac.jp

Institute

National Defense Medical College

Institute

Department

Personal name

Organization

Foundation for Promotion of Defense Medicine

Organization

Division

Category of Funding Organization

Non profit foundation

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

Address

Tel

Email

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

2010

Year

09

Month

15

Day

URL releasing protocol

Publication of results

Published

URL related to results and publications

http://www.sciencedirect.com/science/article/pii/S0021915011007349

Number of participants that the trial has enrolled

Results

Objective
Pioglitazone, a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist, reportedly reduces cardiovascular events in diabetic patients. ATP cassette binding transporters (ABC) A1 and G1 are pivotal molecules for cholesterol efflux (ChE) from macrophages and high density lipoprotein biogenesis, and the A1 transporter is regulated by a PPARgamma-liver receptor X (LXR) pathway. Also, pioglitazone induces ABCG1 expression, though the exact mechanism remains unclear. We therefore investigated the effects of pioglitazone on ABCA1/G1 expression in vitro and ex vivo.
Methods
The effects of pioglitazone on ChE and ABCA1/G1 expressions inmacrophages were assessed. Then, mRNA was quantified in macrophages when PPARgamma/LXR inhibition by siRNA or overexpression of oxysterol sulfotransferase was performed. ABCA1/G1 promoter activity with mutated LXR-responsive elements was also measured. As an ex vivo study, 15 type 2 diabetic patients were administered pioglitazone or placebo, and ChE assays and protein expressions were determined using macrophages cultured with the corresponding sera.
Results
Pioglitazone increased LXRalpha/ABCA1/G1 expressions, which enhanced ChE from macrophages. Inhibition of PPARgamma/LXR pathways revealed that LXR was primarily involved in pioglitazone's transactivation of ABCA1 but only partially involved for ABCG1. Promoter assays showed that ABCG1 was regulated more by the promoter in intron 4 than that upstream of exon 1 but both promoters were responsive to LXR activation. Sera obtained after pioglitazone treatment promoted ChE and ABCA1/G1 expressions in macrophages.
Conclusion
Pioglitazone enhanced ChE from macrophages by increasing ABCA1/G1 in LXR-dependent and -independent manners. Our comparable in vitro and ex vivo results shed new light on pioglitazone's ovel anti-atherogenic property.

Results date posted

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

Participant flow

Adverse events

Outcome measures

Plan to share IPD

IPD sharing Plan description

Recruitment status

Terminated

Date of protocol fixation

2010

Year

08

Month

10

Day

Date of IRB

Anticipated trial start date

2010

Year

09

Month

01

Day

Last follow-up date

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

Registered date

2010

Year

09

Month

10

Day

Last modified on

2013

Year

09

Month

12

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000005033