Type 1 DiabetesPhase 3DIRECTNCT00252733

Diabetic Retinopathy Candesartan Trials

A Phase 3 study testing candesartan cilexetil in people with Type 1 Diabetes, run by AstraZeneca at 3 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 18 to 50 years
Conditions the study is for: Type 1 Diabetes
What is being tested?: candesartan cilexetil
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 5,238 participants
Where: 3 sitesin 2 countries
Study dates: Jun 2001to Apr 2008
Phase: Phase 3
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 50 years
All sexes
No healthy volunteers
Adult

Who may be able to join

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).

Who cannot join

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

Show all 14Show fewer

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

Trial locations and contacts

3 sites in 2 countries.

Country

City, postcode or hospital

3 sites in 2 countries

Australia2 sites

Research Site
Herston
Research Site
Perth

Other trials in Australia

Denmark1 site

Research Site
Odense

Other trials in Denmark

About this study

Official title: Effects of Candesartan Cilexetil (Candesartan) on Diabetic Retinopathy in 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.

Conditions: Type 1 Diabetes
Being tested: candesartan cilexetil
Keywords: Diabetes Mellitus, Insulin-Dependent
Medical subject headings: Diabetes Mellitus, Type 1

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

candesartan cilexetilDrug
Also called ATACAND
32 mg once daily oral tablet given over 60 months

Study groups in NCT00252733
Study group	Role	What they receive
1	No intervention	Placebo
2	Experimental	candesartan cilexetil Receives: Drug: candesartan cilexetil

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: From baseline to end of study, i.e. 5 years, with visits after a half year, one year and thereafter one visit per year.

Secondary outcomes (1)

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.
Measured: From baseline to end of study, i.e. 5 years.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Jun 2001Apr 2008

First posted15 Nov 2005 (estimated)
Study startJun 2001
Primary completionApr 2008
Study completionApr 2008

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (5)Papers the sponsor has linked to this study.
Other trials for Type 1 DiabetesStudies of the same condition, open and under way.
More trials run by AstraZenecaThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 5,238 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00252733
Sponsor's protocol ID: D2453C00045
Other IDs: DIRECT, SH-AHM-0045
Acronym: DIRECT
Status last verified: Apr 2014
First submitted: 10 Nov 2005
Last updated: 14 May 2014
Results posted: Yes, on ClinicalTrials.gov

Publications

Natale P, Palmer SC, Navaneethan SD, Craig JC, Strippoli GF. Angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers for preventing the progression of diabetic kidney disease. Cochrane Database Syst Rev. 2024 Apr 29;4(4):CD006257. doi: 10.1002/14651858.CD006257.pub2.
PubMed 38682786
Sjolie AK, Klein R, Porta M, Orchard T, Fuller J, Parving HH, Bilous R, Aldington S, Chaturvedi N. Retinal microaneurysm count predicts progression and regression of diabetic retinopathy. Post-hoc results from the DIRECT Programme. Diabet Med. 2011 Mar;28(3):345-51. doi: 10.1111/j.1464-5491.2010.03210.x.
PubMed 21309844
Porta M, Hainer JW, Jansson SO, Malm A, Bilous R, Chaturvedi N, Fuller JH, Klein R, Orchard T, Parving HH, Sjolie AK; DIRECT Study Group. Exposure to candesartan during the first trimester of pregnancy in type 1 diabetes: experience from the placebo-controlled DIabetic REtinopathy Candesartan Trials. Diabetologia. 2011 Jun;54(6):1298-303. doi: 10.1007/s00125-010-2040-1. Epub 2011 Jan 12.
PubMed 21225239
Bilous R, Chaturvedi N, Sjolie AK, Fuller J, Klein R, Orchard T, Porta M, Parving HH. Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials. Ann Intern Med. 2009 Jul 7;151(1):11-20, W3-4. doi: 10.7326/0003-4819-151-1-200907070-00120. Epub 2009 May 18.
PubMed 19451554
Chaturvedi N, Porta M, Klein R, Orchard T, Fuller J, Parving HH, Bilous R, Sjolie AK; DIRECT Programme Study Group. Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials. Lancet. 2008 Oct 18;372(9647):1394-402. doi: 10.1016/S0140-6736(08)61412-9. Epub 2008 Sep 25.
PubMed 18823656

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 14 May 2014. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Effects of Candesartan Cilexetil (Candesartan) on Diabetic Retinopathy in Type 1 Diabetic Patients Without Retinopathy.
ClinicalTrials.gov ID: NCT00252733
Acronym / sponsor ID: DIRECT / D2453C00045
Conditions: Type 1 Diabetes
Keywords: Diabetes Mellitus, Insulin-Dependent
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 5,238 participants (actual)
Lead sponsor: AstraZenecaIndustry (pharma, biotech, devices)
Collaborators: Takeda
Study start: Jun 2001
Primary completion: Apr 2008 (actual)
Study completion: Apr 2008 (actual)
First posted: 15 Nov 2005 (estimated)
Results: Posted 13 Apr 2012

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

The secondary objective is to determine whether candesartan, compared to placebo, beneficially influences the rate of change in urinary albumin excretion rate (UAER).

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 2

Arm	Type	Receives
1	No intervention	–Placebo
2	Experimental	Drug: candesartan cilexetilcandesartan cilexetil

Who may qualify

Ages: 18 to 50 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult

Key inclusion criteria (3 listed)

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).

Key exclusion criteria (14 listed)

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)

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
candesartan cilexetilAlso: ATACAND32 mg once daily oral tablet given over 60 months	Drug	2

Primary outcome

Number of Participants With a 2-step or Greater Increase in Early Treatment Diabetic Retinopathy Study (ETDRS) 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.
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.

1 secondary outcome

Rate of Change in Urinary Albumin Excretion Rate (UAER).
Time frame: From baseline to end of study, i.e. 5 years.

Results and safety

Results posted to the registry on 13 Apr 2012, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Candesartan	711	605
Placebo	710	618

Primary outcome: Number of Participants With a 2-step or Greater Increase in Early Treatment Diabetic Retinopathy Study (ETDRS) 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.. Number. Unit: Participants

Measure	Candesartan n = 711	Placebo n = 710
Value	178 (0.071)	217 (0.086)

Candesartan vs Placebo: Hazard Ratio (HR): 0.821 (95% CI 0.673 to 1.001), p = 0.0508, Log Rank

Population analysed: The population was the Intention To Treat population which includes all randomized patients with any post-randomization data.

1 secondary outcome is reported in the full results.

Adverse events

Time frame: During treatment, up to 5 years.. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Candesartan	102 of 710 (14.4%)	85 of 710 (12%)	Not reported
Placebo	112 of 710 (15.8%)	43 of 710 (6.1%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 14 May 2014.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 38682786Natale P, Palmer SC, Navaneethan SD, Craig JC, Strippoli GF. Angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers for preventing the progression of diabetic kidney disease. Cochrane Database Syst Rev. 2024 Apr 29;4(4):CD006257. doi: 10.1002/14651858.CD006257.pub2.
Derived from this study: PubMed 21309844Sjolie AK, Klein R, Porta M, Orchard T, Fuller J, Parving HH, Bilous R, Aldington S, Chaturvedi N. Retinal microaneurysm count predicts progression and regression of diabetic retinopathy. Post-hoc results from the DIRECT Programme. Diabet Med. 2011 Mar;28(3):345-51. doi: 10.1111/j.1464-5491.2010.03210.x.
Derived from this study: PubMed 21225239Porta M, Hainer JW, Jansson SO, Malm A, Bilous R, Chaturvedi N, Fuller JH, Klein R, Orchard T, Parving HH, Sjolie AK; DIRECT Study Group. Exposure to candesartan during the first trimester of pregnancy in type 1 diabetes: experience from the placebo-controlled DIabetic REtinopathy Candesartan Trials. Diabetologia. 2011 Jun;54(6):1298-303. doi: 10.1007/s00125-010-2040-1. Epub 2011 Jan 12.
Derived from this study: PubMed 19451554Bilous R, Chaturvedi N, Sjolie AK, Fuller J, Klein R, Orchard T, Porta M, Parving HH. Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials. Ann Intern Med. 2009 Jul 7;151(1):11-20, W3-4. doi: 10.7326/0003-4819-151-1-200907070-00120. Epub 2009 May 18.
Derived from this study: PubMed 18823656Chaturvedi N, Porta M, Klein R, Orchard T, Fuller J, Parving HH, Bilous R, Sjolie AK; DIRECT Programme Study Group. Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials. Lancet. 2008 Oct 18;372(9647):1394-402. doi: 10.1016/S0140-6736(08)61412-9. Epub 2008 Sep 25.
Related InfoLink provided by the sponsor.
CSR-D2453C00045.pdfLink provided by the sponsor.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

AstraZeneca Atacand Medical Science Director, MD study director

AstraZeneca

3 sites in 2 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing candesartan cilexetil in people with Type 1 Diabetes, run by AstraZeneca at 3 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 14 May 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Australia, Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 13 Apr 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With a 2-step or Greater Increase in Early Treatment Diabetic Retinopathy Study (ETDRS) 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.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00252733, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 May 2014.