Thiazolidinedione Intervention With Vitamin D Evaluation

Phase 4

Terminated

Conditions: Diabetes Mellitus, Type 2

Interventions: Dietary Supplement: Placebo
Dietary Supplement: Vitamin D
Drug: pioglitazone
Drug: rosiglitazone

Registration Number: NCT00879970

Lead Sponsor: GlaxoSmithKline

Brief Summary: This study will answer two separate questions.

The first question is to test the cardiovascular effects of long-term treatment with rosiglitazone or pioglitazone when used as part of standard of care compared to similar standard of care without rosiglitazone or pioglitazone in patients with type 2 diabetes who have a history of or are at risk for cardiovascular disease.

The second question will compare the effects of long-term supplementation of vitamin D on death and cancer

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 1332

Inclusion Criteria

Men or women with: a) newly detected type 2 diabetes based on a fasting plasma glucose greater than or equal to 7.0 mmol/l (126 mg/dL) or a 2 hour plasma glucose (FPG) greater than or equal to 11.1 mmol/l (200 mg/dL) on an oral glucose tolerance test, or b) a history of type 2 diabetes
Hemoglobin A1c (A1C) 6.5-9.5% inclusive (for assays with upper limit of normal of 6%) within one month of screening
Age ≥ 50 years and evidence of vascular disease defined as ≥1of:
- prior myocardial infarction
- prior stroke
- coronary, carotid or peripheral artery revascularization ≥ 4 years earlier
- previous documented myocardial ischemia on either an exercise stress test or on any cardiac imaging, or previous unstable angina with ECG changes or cardiac enzyme elevation OR
Age ≥ 55 years and evidence of subclinical vascular disease defined as ≥1 of:
- microalbuminuria or proteinuria
- history of treated or untreated hypertension with left ventricular hypertrophy by electrocardiogram (ECG) or echocardiogram
  - 50% stenosis on any imaging of coronary, carotid or lower extremity arteries
- ankle/brachial index <0.9 OR
Age ≥ 60 years and at least 2 of the following cardiovascular disease risk factors:
- current tobacco use
- LDL-c ≥3.4 mmol/L (130 mg/dL) or on a lipid lowering medication
- HDL-c < 1.0 mmol/L (40 mg/dL) for men and < 1.3 mmol/L (50 mg/dL) for women or triglycerides ≥ 2.3 mmol/L (200 mg/dL)
- BP lowering medication use or untreated SBP ≥ 140 mmHg or DBP ≥ 95 mmHg
- Waist to hip ratio > 1.0 for men and > 0.8 for women
On no insulin and on less than or equal to 2 anti-diabetes drugs where at least one drug is at or below the half-maximal dose (as indicated in the MOP) with stable dosing for 10 weeks prior to screening

Exclusion Criteria

Type 1 diabetes
Current need for insulin treatment
Symptomatic hyperglycemia requiring immediate therapy in the judgment of the physician
An acute cardiovascular event within 30 days prior to randomization
Symptomatic heart failure (i.e. New York Heart Association class II or higher) or any episode of previous pulmonary edema or known ejection fraction < 0.4 or current use of loop diuretics
Any fracture within the past 1 year
Currently planned coronary, carotid or peripheral artery revascularization or cardiac valve surgery
Coronary, carotid or peripheral artery revascularization within the 4 years prior to screening in the absence of angina, MI, or stroke in the intervening period
End stage renal disease requiring renal replacement therapy
Receiving drug therapy to treat liver disease
A diagnosis of cancer (other than superficial squamous, basal cell skin cancer, or adequately treated cervical carcinoma in situ) in the past 3 years or current treatment for the active cancer (other than prophylactic)
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level > 2.5 times the upper limit of normal
A prior heart transplant or awaiting a heart transplant
Previous or current hypercalcemia, hyperparathyroidism, osteomalacia or other contraindication for vitamin D therapy
Regular use of or indication for greater than 400IU of vitamin D daily
Clinically or medically unstable with expected survival < 1 year
Unwillingness to permit sites to contact their primary physicians to communicate information about the study and the participant's data
Any other factor likely to limit protocol compliance or reporting of adverse events
Inability to discontinue a TZD (if taking one) in the judgement of the physician/investigator
Contraindications to or history of hypersensitivity to the investigational products
History of renal stones within the past 2 years
Participation in another clinical trial of an investigational agent

Study & Design

Study Type: INTERVENTIONAL

Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
TZD placebo	Placebo	Matching placebo tablet was administered once a day (OD) for the duration of 5.5 years
Vitamin D	Vitamin D	Active comparator
Vitamin D placebo	Placebo	Placebo Comparator
pioglitazone	pioglitazone	PIO tablet was administered in the dose of 30 milligrams (mg) OD initially and could be titrated to a maximum dose of 45 mg at or after the 6-month visit. After 1 year of treatment, the dose of PIO was increased to 45 mg OD for the duration of 5.5 years.
rosiglitazone	rosiglitazone	RSG tablet was administered in the dose of 4 mg OD initially and could be titrated to a maximum dose of 8 mg at or after the 6-month visit. After 1 year of treatment, the dose of RSG was increased to 8 mg OD for the duration of 5.5 years.

Primary Outcome Measures

Name	Time	Method
Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD)	From Randomization at Visit 3 up to the Final Visit (average of 162 days)	An event adjudication committee (EAC) adjudicated all occurrences of the components of the composite cardiovascular (CV; related to heart) outcome for TZD. Components are the first occurrence of cardiovascular death for which a non-heart-related cause has not been identified; non-fatal myocardial infarction (MI) (death of heart muscle from sudden blockage of a coronary artery by blood clot not leading to death); and non-fatal stroke (rapidly developing loss of brain function\[s\] due to disturbance in the blood supply to the brain not leading to death).
Number of Participants With the Indicated Components of the Composite Outcome for Vitamin D	From Randomization at Visit 3 to Final Visit (up to 162 days)	An EAC adjudicated all occurrences of the components of the composite outcome for vitamin D. Components are the first occurrence of death or cancer requiring hospitalization, treatment with medicines (chemotherapy), or surgery.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Any Revascularization	From Randomization at Visit 3 to Final Visit (up to 162 days)	Revascularization is defined as any surgical procedure for the provision of a new, additional, or augmented blood supply to heart muscle. Data regarding the need for any revascularization were adjudicated by the EAC and sent to the data monitoring committee (IDMC) on a regular basis for unblinded review.
Number of Participants With Need for Hospitalization for Any Reason	From Randomization at Visit 3 to Final Visit (up to 162 days)	Data regarding the need for hospitalization for any reason were collected and were then forwarded to the independent data monitoring committee (IDMC) on a regular basis for unblinded review.
Number of Participants With Need for Hospitalization for Congestive Heart Failure (CHF), Shortness of Breath, Pneumonia, or Angina	From Randomization at Visit 3 to Final Visit (up to 162 days)	CHF is a condition in which the heart is not able to pump adequate blood to meet the body's needs. Shortness of breath is defined as difficulty in breathing. Pneumonia is an infection of the lungs, caused by various microorganisms. Angina is defined as severe chest pain due to lack of adequate blood supply of the heart muscle because of obstruction/spasm of the heart's blood vessels. Data regarding the need for hospitalization due to any of these reasons were adjudicated by the EAC and sent to the IDMC on a regular basis for unblinded review.
Number of Participants With Composite Microvascular Outcome	From Randomization at Visit 3 to Final Visit (up to 162 days)	The components of the composite microvascular outcome are retinopathy, decline in eGFR, vitrectomy, and renal replacement surgery. Retinopathy is defined as damage to the inner lining of the eye (retina). Decline in eGFR is defined as a \>=30% reduction in kidney function. Vitrectomy is a surgery to remove some or all of the fluid (vitreous humor) from the eye. Renal replacement therapy includes all the life-supporting treatments for renal failure. Data regarding the number of participants with changes in micro blood vessels (composite microvascular outcome) were collected at each visit.
Number of Participants With Retinopathy Requiring Laser Therapy, a Decline in Estimated Glomerular Filtration Rate (eGFR), Vitrectomy, and Renal Replacement Therapy	From Randomization at Visit 3 to Final Visit (up to 162 days)	Retinopathy is defined as damage to the inner lining of the eye (retina). Decline in eGFR is defined as a \>=30% reduction in kidney function. Vitrectomy is a surgery to remove some or all of the fluid (vitreous humor) from the eye. Renal replacement therapy includes all the life-supporting treatments for renal failure. Data on the number of participants with all of these microvascular outcomes were collected at each visit. Data regarding the number of participants with these microvascular outcomes were adjudicated by the EAC and sent to the IDMC on a regular basis for unblinded review.
Number of Participants With Severe Lower Than Normal Blood Glucose Level (Hypoglycemia)	From Randomization at Visit 3 to Final Visit (up to 162 days)	Severe hypoglycemia is defined as hypoglycemia requiring assistance from another person with either a documented plasma glucose \<=36 mg/deciliter (2.0 millimole per liter \[mmol/L\]) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration. Hypoglycemia data were obtained from outcomes reported by the site. Data regarding hypoglycemia were adjudicated by the EAC and sent to the IDMC on a regular basis for unblinded review.
Number of Participants With Clinical Proteinuria	From Randomization at Visit 3 to Final Visit (up to 162 days)	Clinical proteinuria is defined as a laboratory detection of urinary protein excretion \> 0.5 grams (g) per 24 hours; spot urine analysis for albumin:creatinine ratio \>=300 milligrams/g; timed urine collection for albumin excretion \>=200 µg/minute or \>=300 mg/24 hours. Clinical proteinuria data were obtained from outcomes reported by the site.
Number of Participants With a Fracture	From Randomization at Visit 3 to Final Visit (up to 162 days)	Fracture is defined as a medical condition in which there is a break in the continuity of the bone. Fractures are defined as those breaks that are self reported plus confirmed by an X-ray. Data regarding all occurrences of any fracture were adjudicated by the EAC and sent to the IDMC on a regular basis for unblinded review.
Number of Participants With Hepatic Enzyme Increased or Abnormal Liver Function Tests	From Randomization at Visit 3 to Final Visit (up to 162 days)	Liver function tests are groups of clinical biochemistry laboratory blood assays designed to give information about the health of the liver. "Liver function test abnormal" and "hepatic enzyme increased" were obtained from adverse event data as reported by investigators based on the reference range of the reporting local laboratory methodology. The vitamin D arm was not analyzed for this outcome measure.
Number of Participants With Cognitive (Mental Processes) Decline (CD) From Baseline to the Year 2 Visit and the Final Visit	From Randomization at Visit 3 to Final Visit (up to 162 days)	CD is equivalent to a difference of \>=1.5 units on the Digit Symbol Substitution Test (DSST) score. The DSST is a neuropsychological test sensitive to brain damage, a serious loss of cognitive ability, age, and depression. It consists of digit-symbol pairs, followed by a list of digits. Under each digit the participant was asked to write the corresponding symbol as quickly as possible. The number of correct symbols within the allowed time (90 or 120 seconds) was measured in units (one correct score equals one unit).
Number of Participants With Erectile Dysfunction	From Randomization at Visit 3 to Final Visit (up to 162 days)	Erectile dysfunction (ED) is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance. ED was assessed by using the International Index of Erectile Dysfunction (IIED) questionnaire. This standardized and validated 15-item self-evaluation scale provides pre- and post-treatment clinic evaluations of erectile and orgasmic function, sexual desire, satisfaction with sexual intercourse, and general satisfaction.
Mean Score on Euro-QoL (EQ)-5D	From Randomization at Visit 3 to Final Visit (up to 162 days)	Quality of life (QoL) was assessed by using the Euro-QoL (EQ)-5D, a short questionnaire used for measuring health-related QoL. The preference weights are elicited by asking participants to place hypothetical health states on a visual analogue scale from "0" to "1", whereby a score of "1" represents the best health state imaginable and "0" represents a health state equivalent to being dead. Negative states are those worse than being dead.
Mean Score on Montreal Cognitive Assessment (MoCA) Test, as an Assessment of Cognitive Function (CF)	From Randomization at Visit 3 to Final Visit (up to 162 days)	CF was assessed with the 30-point (pt) MoCA test, involving a short-term memory recall task (T) (5 pts), a clock-drawing T (3 pts), a 3-dimensional cube copy (1 pt), a trail-making B T (1 pt), a phonemic fluency T (1 pt), a 2-item verbal abstraction T (2 pts), an attention T (1 pt), a serial subtraction T (3 pts), digits forward/ backward (1 pt each), a 3-item confrontation naming T (3 pts), repetition of 2 syntactically complex sentences (2 pts), and orientation to time/ place (6 pts). A score of 26 or above is normal.