DIabetic Retinopathy Candesartan Trials. (DIRECT)

This study has been completed.
Information provided by (Responsible Party):
ClinicalTrials.gov Identifier:
First received: November 10, 2005
Last updated: May 9, 2014
Last verified: April 2014

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.

Condition Intervention Phase
Type 1 Diabetes
Drug: candesartan
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: DIRECT: DIabetic Retinopathy Candesartan Trials. Effects of Candesartan Cilexetil (Candesartan) on Diabetic Retinopathy in Type 1 Diabetic Patients With Retinopathy.

Resource links provided by NLM:

Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • Number of Participants With a 3-step or Greater Increase in Early Treatment of Diabetic Retinopathy Study (EDTRS) Severity Scale [ 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. ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • Number of Participants With a Regression of Diabetic Retinopathy. [ Time Frame: From baseline to the end of the study, i.e., 5 years ] [ Designated as safety issue: No ]
    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). [ Time Frame: From baseline to end of study, i.e. 5 years. ] [ Designated as safety issue: No ]
    Clinically Significant Macular Edema (CSME) and Proliferative Diabetic Retinopathy (PDR) are diagnosed via retinal photographs.

  • Rate of Change in Urinary Albumin Excretion Rate (UAER). [ Time Frame: From baseline to end of study, i.e. 5 years. ] [ Designated as safety issue: No ]
    An estimate of the slope from fitting a linear regression of log (UAER) over time (post-randimisation, yearly assessments) for each patient

Enrollment: 1850
Study Start Date: August 2001
Study Completion Date: April 2008
Primary Completion Date: February 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: candesartan
candesartan cilexetil 32 mg once daily
Drug: candesartan
32 mg oral tablet
Other Name: ATACAND
No Intervention: placebo


Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts 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
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00252720

Sponsors and Collaborators
Study Director: AstraZeneca Atacand Medical Science Director, MD AstraZeneca
  More Information

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT00252720     History of Changes
Other Study ID Numbers: D2453C00046  DIRECT  SH-AHM-0046 
Study First Received: November 10, 2005
Results First Received: March 19, 2012
Last Updated: May 9, 2014
Health Authority: Denmark: Danish Medicines Agency

Keywords provided by AstraZeneca:
Diabetes mellitus type 1

Additional relevant MeSH terms:
Diabetic Retinopathy
Retinal Diseases
Cardiovascular Diseases
Diabetes Complications
Diabetes Mellitus
Diabetic Angiopathies
Endocrine System Diseases
Eye Diseases
Vascular Diseases
Candesartan cilexetil
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Antihypertensive Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on May 26, 2016