Type 1 Diabetes
Conditions
Keywords
Diabetes mellitus type 1
Brief summary
The primary objective is to determine whether candesartan, compared to placebo reduces the progression of diabetic retinopathy in normotensive, normoalbuminuric type 1 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 of 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 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
32 mg oral tablet
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 55 Years
Healthy volunteers
No
Inclusion criteria
* Male or female aged 18 - 55 years with 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 \< 20 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 \> 20/10 up to \< 47/47 (on ETDRS severity scale).
Exclusion criteria
* Patients with the following conditions are excluded from participation on 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 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. | Retinopathy progression was defined as the first occurrence of at least a 3-step increase 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). A generlized log-rank test was used to test difference between treatments. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Regression of Diabetic Retinopathy. | From baseline to the end of the study, i.e., 5 years | Regression of diabetic retinopathy was defined as at least a 3 step improvement or a persistent 2-step improvement (confirmed in 2 consecutive photography sets) in the Early Treatment of Diabetic Retinopathy Study (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). |
| 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-randimisation, 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. The study investigators enrolled 4514 patients with type 1 diabetes to either Study 45 or 46, of whom 1905 proceeded to randomization into Study 46 (1421 into Study 45).
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 | 7 | 8 |
| Overall Study | Mainly patients lost to follow-up | 7 | 18 |
| Overall Study | Moving | 23 | 42 |
| Overall Study | Withdrawal by Subject | 95 | 97 |
Baseline characteristics
| Characteristic | Candesartan | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 951 Participants | 954 Participants | 1905 Participants |
| Age, Continuous | 31.5 years STANDARD_DEVIATION 8.5 | 31.9 years STANDARD_DEVIATION 8.5 | 31.7 years STANDARD_DEVIATION 8.5 |
| Region of Enrollment Canada | 69 participants | 71 participants | 140 participants |
| Region of Enrollment Europe | 595 participants | 619 participants | 1214 participants |
| Region of Enrollment Russian Federation | 186 participants | 162 participants | 348 participants |
| Region of Enrollment South Africa | 101 participants | 102 participants | 203 participants |
| Sex: Female, Male Female | 413 Participants | 401 Participants | 814 Participants |
| Sex: Female, Male Male | 538 Participants | 553 Participants | 1091 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 92 / 951 | 32 / 951 |
| serious Total, serious adverse events | 173 / 951 | 161 / 951 |
Outcome results
Primary
Number of Participants With a 3-step or Greater Increase in Early Treatment of Diabetic Retinopathy Study (EDTRS) Severity Scale
Retinopathy progression was defined as the first occurrence of at least a 3-step increase 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). 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 | 127 Participants | 0.034 |
| Placebo | Number of Participants With a 3-step or Greater Increase in Early Treatment of Diabetic Retinopathy Study (EDTRS) Severity Scale | 124 Participants | 0.033 |
p-value: 0.848795% CI: [0.8, 1.312]Log Rank
Secondary
Number of Participants With a Regression of Diabetic Retinopathy.
Regression of diabetic retinopathy was defined as at least a 3 step improvement or a persistent 2-step improvement (confirmed in 2 consecutive photography sets) in the Early Treatment of Diabetic Retinopathy Study (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 the end of the 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 a Regression of Diabetic Retinopathy. | 140 Participants | 0.039 |
| Placebo | Number of Participants With a Regression of Diabetic Retinopathy. | 139 Participants | 0.039 |
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 whick 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). | 110 Participants | 0.03 |
| Placebo | Number of Participants With Incident Clinically Significant Macular Edema (CSME) and/or Proliferative Diabetic Retinopathy (PDR). | 107 Participants | 0.03 |
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-randimisation, 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 randimized patients with any post-randomization data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Candesartan | Rate of Change in Urinary Albumin Excretion Rate (UAER). | 0.569 log (µg/min)/year |
| Placebo | Rate of Change in Urinary Albumin Excretion Rate (UAER). | 0.642 log (µg/min)/year |