DIRECT Design and Rationale
Why was the DIRECT Programme needed?
What are the treatment interventions?
What were the inclusion criteria?
What were the outcome measurements?
What was the schedule of interventions and assessments?
Why was the DIRECT Programme needed?
The potential benefits of inhibition of the renin-angiotensin system (RAS) on diabetic retinopathy do not appear to be fully accounted for by effects on blood pressure (1). Such findings from EUCLID and other studies need to be confirmed as these studies were not sufficiently powered and retinopathy was not the primary endpoint.
What is the DIRECT Programme?
The DIRECT Programme consists of three randomised, double-blind, placebo-controlled multicentre studies that were designed to assess if blockade of the RAS with candesartan cilexetil halts the progression of, and possibly prevents, diabetic retinopathy. Candesartan cilexetil is an angiotensin receptor blocker (ARB) that inhibits the binding of angiotensin II to the AT1 receptor. The DIRECT Programme is the largest trial on primary and secondary prevention of retinopathy in Type 1 and Type 2 diabetes.
Who has been enrolled?
Over 5,200 normoalbuminuric patients with Type 1 or Type 2 diabetes were randomised to one of three studies:
Study Descriptions
| Study | Patient Type | Clinical Outcome | N |
| DIRECT-Prevent 1 | Type 1 diabetes without retinopathy | Incidence of retinopathy (primary prevention) | 1,421 |
| DIRECT-Protect 1 | Type 1 diabetes with non-proliferative retinopathy | Progression of retinopathy (secondary prevention) | 1,905 |
| DIRECT-Protect 2 | Type 2 diabetes with non-proliferative retinopathy | Progression of retinopathy |
1,905 |
The studies were conducted in 309 clinical centres from 30 countries. Follow-up was at least 4 years.
What are the treatment interventions?
Patients are randomised to either active treatment with candesartan cilexetil (16 mg titrated to 32 mg, if tolerated) or matching placebo.
- DIRECT-Prevent 1: Patients with Type 1 diabetes and no retinopathy who were normoalbuminuric and
- DIRECT-Protect 2: Patients with Type 1 diabetes and evidence of retinopathy who were normoalbuminuric and normotensive
- DIRECT-Protect 2: Patients with Type 2 diabetes and evidence of retinopathy who were normoalbuminuric and normotensive or treated with an anti-hypertensive other than a RAS inhibitor
Study |
Retinopathy (ETDRS scale) |
Microalbuminuria |
Blood Pressure (mmHg) |
DIRECT-Prevent 1 |
10/10 |
No |
SBP/DBP ≤130/85 |
DIRECT-Protect 1 |
≥20/10 up to ≤47/47 |
No |
SBP/DBP ≤130/85 |
DIRECT-Protect 2 |
≥20/10 up to ≤47/47 |
No |
Untreated: SBP/DBP ≤130/85 |
ETDRS=Early Treatment of Diabetic Retinopathy Study (2)
SBP=systolic blood pressure
DBP=diastolic blood pressure
What were the outcome measurements?
Primary endpoint:
- DIRECT-Prevent 1: Incidence of retinopathy in Type 1 diabetes: A 2-step progression from 10/10 on the ETDRS scale
- DIRECT-Protect 1 and 2: Progression of retinopathy in Type 1 and Type 2 diabetes: A 3-step increase on the ETDRS scale.
- Pooled analysis of all 3 studies: development of microalbuminuria
Main secondary endpoint:
- Secondary objectives included regression of diabetic retinopathy (only in DIRECT-Protect 1 and 2): at least a 3-step improvement or a persistent 2-step improvement confirmed in 2 consecutive photography sets, in the ETDRS severity scale, from baseline to any retinal photograph taken after randomisation
- Rate of change in urinary albumin excretion rate
- Incidence of clinically significant macular oedema (CSME) and/or proliferative retinopathy (PDR) (secondary prevention studies)
Other investigations:
- Change in HbA1c from baseline to the end of study
- Change in serum lipids from baseline to the end of study
- Change in blood pressure from baseline to the end of study
- Visual acuity.
What was the schedule of interventions and assessments?
References
1. Chaturvedi N, Sjolie AK, Stephenson JM et al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet 1998; 351(9095): 28–31.
2. ETDRS Research Group. Early Treatment Diabetic Retinopathy Study Research Group: Grading diabetic retinopathy from stereoscopic color fundus photographs: An extension of the modified Airlie House classification. ETDRS Report Number 10. Ophthalmology 1991; 98: 786–806.
Further details of the study designs of the three studies in the DIRECT Programme are given in the rationale and study design publication (The DIRECT Programme Study Group. The DIabetic REtinopathy Candesartan Trials (DIRECT) Programme: rationale and study design. JRAAS 2002;3:255–261).
To download a copy of the publication please click here.