Actos Now for Prevention of Diabetes (ACT NOW)

• ClinicalTrials.gov Identifier: NCT00220961
• Recruitment Status: Completed
• First Posted: September 22, 2005
• Results First Posted: August 11, 2016
• Last Update Posted: August 11, 2016
• Sponsor: The University of Texas Health Science Center at San Antonio
• Collaborators: University of Texas; Takeda Pharmaceuticals North America, Inc.
• Information provided by (Responsible Party): Ralph DeFronzo, MD, The University of Texas Health Science Center at San Antonio

Study Description

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

Condition or disease	Intervention/treatment	Phase
Impaired Glucose Tolerance; Type 2 Diabetes	Drug: Pioglitazone; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 602 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Actos Now for Prevention of Diabetes (ACT NOW)
• Study Start Date: January 2004
• Actual Primary Completion Date: April 2010
• Actual Study Completion Date: April 2010

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; Placebo tablet similar to pioglitazone tablet	Drug: Placebo; Placebo tablets similar to pioglitazone tablets - 1 tablet/day
Active Comparator: Pioglitazone; Pioglitazone tablet similar to placebo tablet	Drug: Pioglitazone; Pioglitazone tablets - 45 mg/day; Other Name: Actos

Outcome Measures

Primary Outcome Measures :

1. Prevention of Type 2 Diabetes [ Time Frame: 2.4 years ]
   Percentage of Participants with Type 2 Diabetes at 2.4 years Post-randomization

Secondary Outcome Measures :

1. Change From Baseline in Fasting Plasma Glucose of 2.4 Years [ Time Frame: Baseline versus 2.4 years ]
   Fasting Plasma Glucose
2. Change From Baseline in Plasma Insulin Concentration During Oral Glucose Tolerance Test [ Time Frame: Baseline versus 2.4 years ]
   Insulin secretion
3. Change From Baseline in Matsuda Index of Insulin Sensitivity (There Are no Minimum/Maximum Values) [ Time Frame: Baseline versus 2.4 years ]
   Insulin sensitivity The Matsuda index was calculated as 10,000/square root of (pre-meal glucose x pre-meal insulin x mean 120 min post-meal glucose x mean 120 min post-meal insulin), with higher numbers indicating better the insulin sensitivity.
4. Change in Atherosclerosis [ Time Frame: Baseline versus 2.4 years ]
   carotid intima thickness

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Arizona

Carl T. Hayden VA Medical Center

Phoenix, Arizona, United States, 85012

United States, California

USC-Keck School of Medicine

Los Angeles, California, United States, 90033

University of California San Diego-San Diego VA Medical Center

San Diego, California, United States, 92161

United States, District of Columbia

Georgetown University

Washington, District of Columbia, United States, 20007

United States, Louisiana

Pennington Biomedical Research Center

Baton Rouge, Louisiana, United States, 70808

United States, New York

SUNY Health Science Center

Brooklyn, New York, United States, 11203

United States, Tennessee

University of Tennessee

Memphis, Tennessee, United States, 38163

United States, Texas

Texas Diabetes Institute

San Antonio, Texas, United States, 78207

Sponsors and Collaborators

The University of Texas Health Science Center at San Antonio

University of Texas

Takeda Pharmaceuticals North America, Inc.

Investigators

• Principal Investigator: Ralph A. DeFronzo, M.D.; Texas Diabetes Institute

More Information

Additional Information:

American Diabetes Association 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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.

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.

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. Erratum In: Arterioscler Thromb Vasc Biol. 2013 May;33(5):e114.

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. Erratum In: N Engl J Med. 2011 Jul 14;365(2):189. N Engl J Med. 2011 Sep 1;365(9):869.

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.

• Responsible Party: Ralph DeFronzo, MD, Professor of Medicine, Chief of Diabetes, The University of Texas Health Science Center at San Antonio
• ClinicalTrials.gov Identifier: NCT00220961
• Other Study ID Numbers: 02-062A
• First Posted: September 22, 2005
• Results First Posted: August 11, 2016
• Last Update Posted: August 11, 2016
• Last Verified: June 2016

Keywords provided by Ralph DeFronzo, MD, The University of Texas Health Science Center at San Antonio:

Impaired Glucose Tolerance; Type 2 Diabetes; Prevention; Pioglitazone

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Intolerance; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Hyperglycemia; Pioglitazone; Hypoglycemic Agents; Physiological Effects of Drugs