Type 2 Diabetes
Conditions
Keywords
Diabetes mellitus type 2
Brief summary
The primary objective is to determine whether candesartan, compared to placebo reduces the progression of diabetic retinopathy in normoalbuminuric type 2 diabetic patients with retinopathy. The secondary objective is to determine whether candesartan, compared to placebo, reduces the incidence of clinically significant macular oedema (CSME) and/or proliferative diabetic retinopathy (PDR) and beneficially influences the rate change in urinary albumin excretion rate (UAER). This study is part of the DIRECT Programme also including a primary prevention study of diabetic retinopathy in type 1 diabetes and a secondary prevention study in type 1 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
32 mg oral tablet
Sponsors
AstraZeneca
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
37 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Male or female aged 37 - 75 years with type 2 diabetes diagnosed at age of 36 years or thereafter. * Duration of diabetes for \> 1 year and \< 20 years with stable diabetic therapy within last 6 months. * Patients with untreated resting mean sitting SBP \< 130 mmHg and mean sitting DBP \< 85 or treated resting mean SBP \< 160 mmHg and mean sitting DBP \< 90 mmHg with retinal photograph grading level \>20/10 up to \< 47/47 (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 or presence of proliferative 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 3-step or Greater Increase in Early Treatment of Diabetic Retinopathy Study (EDTRS) 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. | 3 steps were defined as either a 1-step change in one eye and a 2-step change in the other eye or as a 3-step change in one eye only. EDRTS is a scale with 11 steps (1-11). A generlized log-rank test was used to test difference between treatments. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With at Least a 3 Step Improvement or a Persistent 2-step Improvement in the ETDRS Severity Scale. | From baseline to end of study, i.e. 5 years. | 3 steps were defined as either a 1-step change in one eye and a 2-step change in the other eye or as a 3-step change in one eye only. EDRTS is a scale with 11 steps (1-11). |
| Number of Participants With Incident Clinically Significant Macular Edema (CSME) and/or Proliferative Diabetic Retinopathy (PDR). | From baseline to end of study, i.e. 5 years. | Clinically Significant Macular Edema (CSME) and Proliferative Diabetic Retinopathy (PDR) are diagnosed via retinal photographs. |
| 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 (post-randomisation, yearly assessments) for each patient. |
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. A total of 4717 patients enrolled into the programme of whom 1905 patients proceeded to randomization into Study 47.
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 | 951 |
| Placebo Placebo Comparator | 954 |
| Total | 1,905 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 36 | 34 |
| Overall Study | Mostly Lost to Follow Up | 8 | 13 |
| Overall Study | Patient Moving | 17 | 16 |
| Overall Study | Withdrawal by Subject | 83 | 91 |
Baseline characteristics
| Characteristic | Candesartan | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 142 Participants | 146 Participants | 288 Participants |
| Age, Categorical Between 18 and 65 years | 809 Participants | 808 Participants | 1617 Participants |
| Age, Continuous | 56.9 years STANDARD_DEVIATION 7.6 | 56.8 years STANDARD_DEVIATION 7.9 | 56.8 years STANDARD_DEVIATION 7.8 |
| Region of Enrollment Europe | 419 participants | 438 participants | 857 participants |
| Region of Enrollment Israel | 188 participants | 173 participants | 361 participants |
| Region of Enrollment Russian Federation | 162 participants | 165 participants | 327 participants |
| Region of Enrollment South Africa | 182 participants | 178 participants | 360 participants |
| Sex: Female, Male Female | 485 Participants | 472 Participants | 957 Participants |
| Sex: Female, Male Male | 466 Participants | 482 Participants | 948 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 50 / 949 | 18 / 953 |
| serious Total, serious adverse events | 301 / 949 | 267 / 953 |
Outcome results
Primary
Number of Participants With a 3-step or Greater Increase in Early Treatment of Diabetic Retinopathy Study (EDTRS) Severity Scale
3 steps were defined as either a 1-step change in one eye and a 2-step change in the other eye or as a 3-step change in one eye only. EDRTS is a scale with 11 steps (1-11). A generlized 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 3-step or Greater Increase in Early Treatment of Diabetic Retinopathy Study (EDTRS) Severity Scale | 161 Participants | 0.045 |
| Placebo | Number of Participants With a 3-step or Greater Increase in Early Treatment of Diabetic Retinopathy Study (EDTRS) Severity Scale | 182 Participants | 0.052 |
p-value: 0.199495% CI: [0.704, 1.076]Log Rank
Secondary
Number of Participants With at Least a 3 Step Improvement or a Persistent 2-step Improvement in the ETDRS Severity Scale.
3 steps were defined as either a 1-step change in one eye and a 2-step change in the other eye or as a 3-step change in one eye only. EDRTS is a scale with 11 steps (1-11).
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 (NUMBER) | Dispersion |
|---|---|---|---|
| Candesartan | Number of Participants With at Least a 3 Step Improvement or a Persistent 2-step Improvement in the ETDRS Severity Scale. | 180 Participants | 0.054 |
| Placebo | Number of Participants With at Least a 3 Step Improvement or a Persistent 2-step Improvement in the ETDRS Severity Scale. | 136 Participants | 0.04 |
Secondary
Number of Participants With Incident Clinically Significant Macular Edema (CSME) and/or Proliferative Diabetic Retinopathy (PDR).
Clinically Significant Macular Edema (CSME) and Proliferative Diabetic Retinopathy (PDR) are diagnosed via retinal photographs.
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 (NUMBER) | Dispersion |
|---|---|---|---|
| Candesartan | Number of Participants With Incident Clinically Significant Macular Edema (CSME) and/or Proliferative Diabetic Retinopathy (PDR). | 192 Participants | 0.06 |
| Placebo | Number of Participants With Incident Clinically Significant Macular Edema (CSME) and/or Proliferative Diabetic Retinopathy (PDR). | 193 Participants | 0.06 |
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 (post-randomisation, yearly assessments) 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). | 656 log (µg/min)/1000 year |
| Placebo | Rate of Change in Urinary Albumin Excretion Rate (UAER). | 718 log (µg/min)/1000 year |