Thiazolidinedione Intervention With Vitamin D Evaluation

AVANDIA CV Outcomes Study: Thiazolidinedione Intervention With Vitamin D Evaluation (TIDE) A Multicenter Randomized Double-Blind Placebo-Controlled Trial of a Thiazolidinedione or Placebo and of Vitamin D or Placebo In People With Type 2 Diabetes at Risk For Cardiovascular Disease

Status

Terminated

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00879970

Acronym

TIDE

Enrollment

1332

Registered

2009-04-13

Start date

2009-05-31

Completion date

2010-11-30

Last updated

2017-04-18

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Diabetes Mellitus, Type 2

Keywords

Cardiovascular Outcomes

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

Interventions

DRUGpioglitazone

Pioglitazone30 mg and 45 mg tablets are over-encapsulated with Swedish orange size DB-AA capsule shell.

DRUGrosiglitazone

Rosiglitazone 4 mg and 8 mg tablets are over-encapsulated with Swedish orange size DB-AA capsule shell.

DRUGplacebo

Placebo to match is Swedish orange size DB-AA capsule filled with white to off-white non-active powder blend.

DIETARY_SUPPLEMENTVitamin D

Vitamin D factor intervention

DIETARY_SUPPLEMENTPlacebo

Vitamin D factor intervention

Study design

Allocation

RANDOMIZED

Intervention model

FACTORIAL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

50 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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 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 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.
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 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.

Countries

Argentina, Canada, Chile, Colombia, Czechia, Denmark, Finland, Germany, India, Italy, Latvia, Mexico, Netherlands, Norway, Pakistan, Peru, Philippines, Romania, Russia, Slovakia, South Africa, Sweden, Thailand, United Kingdom, United States

Participant flow

Recruitment details

1332 participants were included in the TZD randomization, and 1221 of 1332 participants were included in the Vitamin D randomization.

Pre-assignment details

Randomization occurred subsequent to a 3-week rosiglitazone (RSG) and vitamin D Single-blind Run-in Phase to assess compliance and tolerability. Participants received an RSG tablet (4 milligrams \[mg\]) and a vitamin D tablet (1000 international units \[IU\]) once a day.

Participants by arm

Arm	Count
Placebo Matching placebo tablet was administered once a day (OD) for a mean duration of 162 days.	541
Pioglitazone (PIO) PIO tablet was administered in the dose of 30-45 milligrams (mg) OD for a mean duration of 162 days.	392
Rosiglitazone (RSG) RSG tablet was administered in the dose of 4-8 mg OD for a mean duration of 162 days.	399
Total	1,332

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004
Period 1 TZD Randomization	Death	2	1	0	0	0
Period 1 TZD Randomization	Final or Study Hold Visits Not Completed	2	0	1	0	0
Period 1 TZD Randomization	Lost to Follow-up	1	0	1	0	0
Period 1 TZD Randomization	Refused to Attend Final Visit	3	3	4	0	0
Period 2 Vitamin D Randomization	Death	0	0	0	2	0
Period 2 Vitamin D Randomization	Lost to Follow-up	0	0	0	0	1
Period 2 Vitamin D Randomization	Refused to Attend Final Visit	0	0	0	2	6

Baseline characteristics

Characteristic	Placebo	Pioglitazone (PIO)	Rosiglitazone (RSG)	Total
Age, Continuous	66.4 Years STANDARD_DEVIATION 6.8	66.3 Years STANDARD_DEVIATION 6.6	66.5 Years STANDARD_DEVIATION 6.4	66.4 Years STANDARD_DEVIATION 6.6
Race/Ethnicity, Customized Arab/ Persian	1 participants	1 participants	0 participants	2 participants
Race/Ethnicity, Customized Black African	45 participants	35 participants	26 participants	106 participants
Race/Ethnicity, Customized European/ Caucasian/ White	330 participants	241 participants	255 participants	826 participants
Race/Ethnicity, Customized Japanese	1 participants	0 participants	1 participants	2 participants
Race/Ethnicity, Customized Malays	1 participants	0 participants	0 participants	1 participants
Race/Ethnicity, Customized Missing	1 participants	0 participants	0 participants	1 participants
Race/Ethnicity, Customized Native Hawaiian/ Australian or Other Asian Pacific	1 participants	1 participants	0 participants	2 participants
Race/Ethnicity, Customized Native North American	1 participants	2 participants	4 participants	7 participants
Race/Ethnicity, Customized Native South American	33 participants	26 participants	24 participants	83 participants
Race/Ethnicity, Customized Other Asian	10 participants	6 participants	6 participants	22 participants
Race/Ethnicity, Customized South Asian	63 participants	46 participants	48 participants	157 participants
Race/Ethnicity, Customized Sub-Saharan African	1 participants	0 participants	0 participants	1 participants
Race/Ethnicity, Customized Unknown	53 participants	34 participants	35 participants	122 participants
Sex: Female, Male Female	220 Participants	167 Participants	161 Participants	548 Participants
Sex: Female, Male Male	321 Participants	225 Participants	238 Participants	784 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	36 / 541	35 / 392	21 / 399	0 / 0	0 / 0
serious Total, serious adverse events	7 / 541	5 / 392	2 / 399	2 / 614	9 / 607

Outcome results

Primary

Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD)

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).

Time frame: From Randomization at Visit 3 up to the Final Visit (average of 162 days)

Population: Intent-to-Treat (ITT) Population: all randomized participants

Arm	Measure	Group	Value (NUMBER)
Placebo	Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD)	CV Death/Non-Fatal MI/Non-Fatal Stroke	5 participants
Placebo	Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD)	CV Death	1 participants
Placebo	Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD)	Non-Fatal MI	2 participants
Placebo	Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD)	Non-Fatal Stroke	2 participants
Pioglitazone (PIO)	Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD)	CV Death/Non-Fatal MI/Non-Fatal Stroke	2 participants
Pioglitazone (PIO)	Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD)	Non-Fatal Stroke	2 participants
Pioglitazone (PIO)	Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD)	CV Death	0 participants
Pioglitazone (PIO)	Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD)	Non-Fatal MI	0 participants
Rosiglitazone (RSG)	Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD)	Non-Fatal Stroke	0 participants
Rosiglitazone (RSG)	Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD)	CV Death	0 participants
Rosiglitazone (RSG)	Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD)	Non-Fatal MI	1 participants
Rosiglitazone (RSG)	Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD)	CV Death/Non-Fatal MI/Non-Fatal Stroke	1 participants
Vitamin D Placebo	Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD)	CV Death/Non-Fatal MI/Non-Fatal Stroke	3 participants
Vitamin D Placebo	Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD)	CV Death	1 participants
Vitamin D Placebo	Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD)	Non-Fatal Stroke	1 participants
Vitamin D Placebo	Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD)	Non-Fatal MI	1 participants
Vitamin D	Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD)	Non-Fatal Stroke	1 participants
Vitamin D	Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD)	Non-Fatal MI	1 participants
Vitamin D	Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD)	CV Death	0 participants
Vitamin D	Number of Participants With the Indicated Components of the Composite Cardiovascular Outcome for Thiazolidinedione (TZD)	CV Death/Non-Fatal MI/Non-Fatal Stroke	2 participants

Primary

Number of Participants With the Indicated Components of the Composite Outcome for Vitamin D

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.