Type 1 Diabetes
Conditions
Keywords
Diabetes Mellitus, Insulin-Dependent
Brief summary
The primary objective is to determine whether candesartan, compared to placebo reduces the incidence of diabetic retinopathy in normotensive, normoalbuminuric type 1 diabetic patients without retinopathy. The secondary objective is to determine whether candesartan, compared to placebo, beneficially influences the rate of change in urinary albumin excretion rate (UAER). This study is part of the DIRECT Programme also including secondary prevention studies of diabetic retinopathy in both type 1 and type 2 diabetes. The primary objective for all three pooled studies is to determine whether candesartan, compared to placebo, reduces the incidence of microalbuminuria in type 1 and type 2 diabetic patients.
Interventions
DRUGcandesartan cilexetil
32 mg once daily oral tablet given over 60 months
Sponsors
Takeda
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Type 1 diabetes diagnosed before age of 36 years and in need for continuous insulin treatment within 1 year of diagnosis of diabetes are included. * Duration of diabetes for \> 1 year and \< 15 years with stable diabetic therapy within last 6 months. * Patients with untreated resting mean sitting SBP \< 130 mmHg, mean sitting DBP \< 85 mmHg and with retinal photograph grading level 10/10 (on ETDRS severity scale).
Exclusion criteria
* Patients with the following conditions are excluded from participation in the study: * Cataract or media opacity of a degree which precludes taking gradable retinal photographs * Angle closure glaucoma, which precludes pharmacological dilatation of the pupil * History of retinopathy * History or presence of clinical significant macular oedema (CSME) * History or evidence of photocoagulation of the retina Other retinal conditions which may mask assessment, eg, retinal vein occlusion * Positive micral dipstick test * Presence of secondary diabetes * Pregnant or lactating women or women of child bearing potential not practicing an adequate method of contraception * Need of treatment with ACE-inhibitor * Haemodynamically significant aortic or mitral valve stenosis * Known renal artery stenosis or kidney transplantation * Hypersensitivity to study drug * Severe concomitant disease which may interfere with the assessment of the patient, eg, malignancy, as judged by the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a 2-step or Greater Increase in Early Treatment Diabetic Retinopathy Study (ETDRS) Severity Scale. | From baseline to end of study, i.e. 5 years, with visits after a half year, one year and thereafter one visit per year. | Two steps were defined as either a 1-step change in each eye or as a 2-step change in one eye only. ETDRS is a scale with 11 steps (1-11, where a score of 1 represents no retinopathy and a score of 11 represents proliferative retinopathy). A generalized log-rank test was used to test difference between treatments. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Change in Urinary Albumin Excretion Rate (UAER). | From baseline to end of study, i.e. 5 years. | An estimate of the slope from fitting a linear regression of log(UAER) over time for each patient. |
Countries
Australia, Denmark
Participant flow
Recruitment details
First subject enrolled in the DIRECT Programme 8 June 2001 and last subject completed the DIRECT Programme 16 April 2008 mainly in hospital based clinics. 4514 patients type 1 diabetes were enrolled of whom 1421 proceeded to randomization, 711 to the candesartan arm and 710 to the placebo arm.
Pre-assignment details
The most common reason for not being randomized was that all eligibility criteria were not fulfilled, followed by withdrawn informed consent.
Participants by arm
| Arm | Count |
|---|---|
| Candesartan Candesartan cilexetil 32 mg once daily | 711 |
| Placebo Placebo Comparator | 710 |
| Total | 1,421 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 7 | 5 |
| Overall Study | Lost to Follow-up | 12 | 6 |
| Overall Study | Multiple Reasons | 14 | 14 |
| Overall Study | Withdrawal by Subject | 73 | 67 |
Baseline characteristics
| Characteristic | Candesartan | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 29.60 years STANDARD_DEVIATION 8 | 29.90 years STANDARD_DEVIATION 8.1 | 29.75 years STANDARD_DEVIATION 8.05 |
| Sex: Female, Male Female | 298 Participants | 318 Participants | 616 Participants |
| Sex: Female, Male Male | 413 Participants | 392 Participants | 805 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 85 / 710 | 43 / 710 |
| serious Total, serious adverse events | 102 / 710 | 112 / 710 |
Outcome results
Primary
Number of Participants With a 2-step or Greater Increase in Early Treatment Diabetic Retinopathy Study (ETDRS) Severity Scale.
Two steps were defined as either a 1-step change in each eye or as a 2-step change in one eye only. ETDRS is a scale with 11 steps (1-11, where a score of 1 represents no retinopathy and a score of 11 represents proliferative retinopathy). A generalized log-rank test was used to test difference between treatments.
Time frame: From baseline to end of study, i.e. 5 years, with visits after a half year, one year and thereafter one visit per year.
Population: The population was the Intention To Treat population which includes all randomized patients with any post-randomization data.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Candesartan | Number of Participants With a 2-step or Greater Increase in Early Treatment Diabetic Retinopathy Study (ETDRS) Severity Scale. | 178 Participants | 0.071 |
| Placebo | Number of Participants With a 2-step or Greater Increase in Early Treatment Diabetic Retinopathy Study (ETDRS) Severity Scale. | 217 Participants | 0.086 |
p-value: 0.050895% CI: [0.673, 1.001]Log Rank
Secondary
Rate of Change in Urinary Albumin Excretion Rate (UAER).
An estimate of the slope from fitting a linear regression of log(UAER) over time for each patient.
Time frame: From baseline to end of study, i.e. 5 years.
Population: The population was the Intention To Treat population which includes all randomized patients with any post-randomization data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Candesartan | Rate of Change in Urinary Albumin Excretion Rate (UAER). | 0.510 log (µg/min)/year |
| Placebo | Rate of Change in Urinary Albumin Excretion Rate (UAER). | 0.543 log (µg/min)/year |