Clinical trial NCT00220961: Actos Now for Prevention of Diabetes (ACT NOW)
Official title: Actos Now for Prevention of Diabetes (ACT NOW)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Impaired Glucose Tolerance
Type 2 Diabetes
Keywords: Impaired Glucose Tolerance
Type 2 Diabetes
Prevention
Pioglitazone
Lead sponsor: The University of Texas Health Science Center at San Antonio
Sponsor class: OTHER
Collaborators: name: University of Texas
name: Takeda Pharmaceuticals North America, Inc.
First posted: 2005-09-22
Enrollment: 602
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to examine whether pioglitazone versus placebo can reduce the conversion rate of impaired glucose tolerance (IGT) to type 2 diabetes mellitus

Detailed description: IGT is a prediabetic state. If IGT can be prevented from progressing to overt diabetes, the hyperglycemia-related complications of this devastating disease can be prevented. Subjects with IGT will be identified with an oral glucose tolerance test (OGTT). Eligible subjects also will have a measurement of first phase insulin secretion and insulin sensitivity using the frequently sampled intravenous glucose tolerance test (FSIVGTT) and carotid intimal media thickness using carotid ultrasound. Following these measurements subjects will be randomized to receive pioglitazone or placebo and they will return every 3 months for determination of fasting plasma glucose (FPG) concentration and interim medical history. Recruitment will take place over 15 months. From the time that the recruitment period ends, subjects will be followed for a total of 24 months on pioglitazone or placebo. The OGTT will be repeated at 15,27, and 39 months, or if the FPG is ≥ 126 mg/dl on the 3-month follow up visits. If the diagnosis of diabetes is established before month 39 or at month 39, the FSIVGTT and carotid ultrasound will be repeated. At 39 months, subjects will be washed out of pioglitazone or placebo and the OGTT, FSIVGTT, and carotid ultrasound will be repeated at month 45.

Eligibility criteria: Inclusion Criteria:

* Men and women
* All ethnic groups
* 18 years of age and older
* Impaired glucose tolerance by glucose tolerance test (fasting glucose 95-125 mg/dl and 2 hr glucose of 140-199 mg/dl)
* At least one of the following:

  * One or more components of the insulin resistance syndrome (HDL \< 40 mg/dl in females and \<35 mg/dl in males, fasting triglycerides \> 150 mg/dl, blood pressure \> 135/85 mmHg, BMI \> 24 kg/m2, waist circumference \> 102 cm in men and \> 88 cm in women)
  * One or more first degree relatives with type 2 diabetes
  * History of gestational diabetes
  * Polycystic ovarian disease
  * Minority ethnic background (Mexican American, African American, Asian and Pacific Islanders, Native American)

Exclusion Criteria:

* Type 2 diabetes
* Previously treated with thiazolidinediones (ever) or metformin (within one year)
* Previously treated with a sulfonylurea, a meglitinide, an alpha glucosidase inhibitor for more than a week within last year or within the 3 months prior to randomization
* Previously treated with insulin (other than during pregnancy) for more than one week within the last year or within the 3 months prior to randomization
* Cardiovascular disease
* Hospitalization for treatment of heart disease or stroke in past 6 months
* New York Heart Association Functional Class \> 2
* Left bundle branch block or third degree AV block
* Aortic stenosis
* SBP \> 180 mmHg or DBP \> 105 mmHg
* Renal disease
* Anemia
* Hepatitis
* GI diseases (pancreatitis, inflammatory bowel disease)
* Recent or significant abdominal surgery
* Advanced pulmonary disease
* Chronic infections
* Weight loss \> 10% in past 6 months
* Pregnancy and childbearing
* Major psychiatric disorders
* Excessive alcohol intake
* Thiazide use \> 25 mg per day
* Non-selective beta blockers
* Niacin
* Systemic glucocorticoids
* Weight loss or weight gain medication
* Thyroid disease-suboptimally treated
* Active endocrine diseases (Cushing's, acromegaly)
* Plasma triglycerides over 400 mg/dl (despite treatment)
* History bladder cancer
* Hematuria

Primary outcomes:
measure: Prevention of Type 2 Diabetes
timeFrame: 2.4 years
Secondary outcomes:
measure: Change From Baseline in Fasting Plasma Glucose of 2.4 Years
timeFrame: Baseline versus 2.4 years
measure: Change From Baseline in Plasma Insulin Concentration During Oral Glucose Tolerance Test
timeFrame: Baseline versus 2.4 years
measure: Change From Baseline in Matsuda Index of Insulin Sensitivity (There Are no Minimum/Maximum Values)
timeFrame: Baseline versus 2.4 years
measure: Change in Atherosclerosis
timeFrame: Baseline versus 2.4 years
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Carl T. Hayden VA Medical Center
state: Arizona
city: Los Angeles
country: United States
facility: USC-Keck School of Medicine
state: California
city: San Diego
country: United States
facility: University of California San Diego-San Diego VA Medical Center
state: California
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Baton Rouge
country: United States
facility: Pennington Biomedical Research Center
state: Louisiana
city: Brooklyn
country: United States
facility: SUNY Health Science Center
state: New York
city: Memphis
country: United States
facility: University of Tennessee
state: Tennessee
city: San Antonio
country: United States
facility: Texas Diabetes Institute
state: Texas
Study officials:
affiliation: Texas Diabetes Institute
name: Ralph A. DeFronzo, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ipsen EO, Madsen KS, Chi Y, Pedersen-Bjergaard U, Richter B, Metzendorf MI, Hemmingsen B. Pioglitazone for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus. Cochrane Database Syst Rev. 2020 Nov 19;11(11):CD013516. doi: 10.1002/14651858.CD013516.pub2.
citation: Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, Henry RR, Kitabchi AE, Mudaliar S, Ratner RE, Stentz FB, Musi N, Reaven PD, DeFronzo RA. Diabetes Incidence and Glucose Tolerance after Termination of Pioglitazone Therapy: Results from ACT NOW. J Clin Endocrinol Metab. 2016 May;101(5):2056-62. doi: 10.1210/jc.2015-4202. Epub 2016 Mar 16.
citation: Tripathy D, Cobb JE, Gall W, Adam KP, George T, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, Henry RR, Kitabchi AE, Mudaliar S, Ratner RE, Stentz FB, Reaven PD, Musi N, Ferrannini E, DeFronzo RA. A novel insulin resistance index to monitor changes in insulin sensitivity and glucose tolerance: the ACT NOW study. J Clin Endocrinol Metab. 2015 May;100(5):1855-62. doi: 10.1210/jc.2014-3824. Epub 2015 Jan 20.
citation: Tripathy D, Clement SC, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Gastaldelli A, Henry RR, Kitabchi AE, Mudaliar S, Ratner RE, Stentz FB, Musi N, Reaven PD, DeFronzo RA. Baseline adiponectin levels do not influence the response to pioglitazone in ACT NOW. Diabetes Care. 2014 Jun;37(6):1706-11. doi: 10.2337/dc13-1745. Epub 2014 Apr 4.
citation: Saremi A, Schwenke DC, Buchanan TA, Hodis HN, Mack WJ, Banerji M, Bray GA, Clement SC, Henry RR, Kitabchi AE, Mudaliar S, Ratner RE, Stentz FB, Musi N, Tripathy D, DeFronzo RA, Reaven PD. Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors. Arterioscler Thromb Vasc Biol. 2013 Feb;33(2):393-9. doi: 10.1161/ATVBAHA.112.300346. Epub 2012 Nov 21.
citation: DeFronzo RA, Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, Henry RR, Hodis HN, Kitabchi AE, Mack WJ, Mudaliar S, Ratner RE, Williams K, Stentz FB, Musi N, Reaven PD; ACT NOW Study. Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med. 2011 Mar 24;364(12):1104-15. doi: 10.1056/NEJMoa1010949.
citation: Defronzo RA, Banerji M, Bray GA, Buchanan TA, Clement S, Henry RR, Kitabchi AE, Mudaliar S, Musi N, Ratner R, Reaven PD, Schwenke D, Stentz FB, Tripathy D. Actos Now for the prevention of diabetes (ACT NOW) study. BMC Endocr Disord. 2009 Jul 29;9:17. doi: 10.1186/1472-6823-9-17.