DIRECT: Diabetic Retinopathy Candesartan Trials

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00252733
• Collaborator: Takeda (Industry)
• Enrollment: 5,238
• Locations: 3
• Arms: 2
• Duration (Months): 82
• Patients Per Site: 1746
• Patients Per Site Per Month: 21.3

Study Details

Study Description

Brief 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.

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.

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes	Drug: candesartan cilexetil	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 5238 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effects of Candesartan Cilexetil (Candesartan) on Diabetic Retinopathy in Type 1 Diabetic Patients Without Retinopathy.
• Study Start Date: Jun 1, 2001
• Actual Primary Completion Date: Apr 1, 2008
• Actual Study Completion Date: Apr 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: 1 Placebo
Experimental: 2 candesartan cilexetil	Drug: candesartan cilexetil; 32 mg once daily oral tablet given over 60 months; Other Names: ATACAND

Outcome Measures

Primary Outcome Measures

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

   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.

Secondary Outcome Measures

1. 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 for each patient.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 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).

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 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

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Herston		Australia
2	Research Site	Perth		Australia
3	Research Site	Odense		Denmark

Sponsors and Collaborators

• AstraZeneca
• Takeda

Investigators

• Study Director: AstraZeneca Atacand Medical Science Director, MD, AstraZeneca

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info
• CSR-D2453C00045.pdf

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT00252733
• Other Study ID Numbers: D2453C00045; DIRECT; SH-AHM-0045
• First Posted: Nov 15, 2005
• Last Update Posted: May 14, 2014
• Last Verified: Apr 1, 2014

• Keywords provided by AstraZeneca: Diabetes Mellitus, Insulin-Dependent
• Additional relevant MeSH terms: Diabetic Retinopathy; Candesartan; Candesartan cilexetil

Study Results

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. 4514 patients type 1 diabetes were enrolled of whom 1421 proceeded to randomization, 711 to the candesartan arm and 710 to the placebo arm.
Pre-assignment Detail	The most common reason for not being randomized was that all eligibility criteria were not fulfilled, followed by withdrawn informed consent.

Arm/Group Title	Candesartan	Placebo
Arm/Group Description	Candesartan cilexetil 32 mg once daily	Placebo Comparator
Period Title: Overall Study
STARTED	711	710
COMPLETED	605	618
NOT COMPLETED	106	92

Baseline Characteristics

Arm/Group Title	Candesartan	Placebo	Total
Arm/Group Description	Candesartan cilexetil 32 mg once daily	Placebo Comparator	Total of all reporting groups
Overall Participants	711	710	1421
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29.60 (8.0)	29.90 (8.1)	29.75 (8.05)
Sex: Female, Male (Count of Participants)
Female	298 41.9%	318 44.8%	616 43.3%
Male	413 58.1%	392 55.2%	805 56.7%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Candesartan	Placebo
Arm/Group Description	Candesartan cilexetil 32 mg once daily	Placebo Comparator
Measure Participants	711	710
Number [Participants]	178 (0.071) 25%	217 (0.086) 30.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Candesartan, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0508
	Comments
	Method	Log Rank
	Comments	Generalized
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.821
	Confidence Interval	(2-Sided) 95%; 0.673 to 1.001
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Rate of Change in Urinary Albumin Excretion Rate (UAER).
Description	An estimate of the slope from fitting a linear regression of log(UAER) over time for each patient.
Time Frame	From baseline to end of study, i.e. 5 years.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Candesartan	Placebo
Arm/Group Description	Candesartan cilexetil 32 mg once daily	Placebo Comparator
Measure Participants	711	710
Least Squares Mean (95% Confidence Interval) [log (µg/min)/year]	0.510	0.543

Adverse Events

Time Frame	During treatment, up to 5 years.
Adverse Event Reporting Description	The population used was the safety population which includes all patients who received at least 1 dose of randomized study drug and for whom any post-randomization data were available.
Arm/Group Title	Candesartan		Placebo
Arm/Group Description	Candesartan cilexetil 32 mg once daily		Placebo Comparator
All Cause Mortality
	Candesartan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Candesartan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	102/710 (14.4%)		112/710 (15.8%)
Blood and lymphatic system disorders
Anaemia	1/710 (0.1%)		0/710 (0%)
Bicytopenia	0/710 (0%)		1/710 (0.1%)
Iron Deficiency Anaemia	1/710 (0.1%)		0/710 (0%)
Lymphoid Tissue Hyperplasia	1/710 (0.1%)		0/710 (0%)
Cardiac disorders
Myocardial Infarction	0/710 (0%)		4/710 (0.6%)
Acute Coronary Syndrome	0/710 (0%)		1/710 (0.1%)
Angina Pectoris	1/710 (0.1%)		0/710 (0%)
Atrial Flutter	0/710 (0%)		1/710 (0.1%)
Cardiac Failure Acute	0/710 (0%)		1/710 (0.1%)
Coronary Artery Disease	0/710 (0%)		1/710 (0.1%)
Palpitations	0/710 (0%)		1/710 (0.1%)
Pericardial Disease	0/710 (0%)		1/710 (0.1%)
Pericardial Effusion	0/710 (0%)		1/710 (0.1%)
Pericarditis	0/710 (0%)		1/710 (0.1%)
Congenital, familial and genetic disorders
Phimosis	0/710 (0%)		1/710 (0.1%)
Endocrine disorders
Basedow's Disease	0/710 (0%)		1/710 (0.1%)
Hyperthyroidism	1/710 (0.1%)		0/710 (0%)
Eye disorders
Diplopia	1/710 (0.1%)		0/710 (0%)
Gastrointestinal disorders
Dyspepsia	0/710 (0%)		2/710 (0.3%)
Gastritis	1/710 (0.1%)		2/710 (0.3%)
Inguinal Hernia	0/710 (0%)		2/710 (0.3%)
Abdominal Pain	0/710 (0%)		1/710 (0.1%)
Appendicitis Perforated	1/710 (0.1%)		0/710 (0%)
Coeliac Disease	1/710 (0.1%)		0/710 (0%)
Colitis Ulcerative	0/710 (0%)		1/710 (0.1%)
Enteritis	1/710 (0.1%)		0/710 (0%)
Gastric Ulcer	1/710 (0.1%)		0/710 (0%)
Gastrointestinal Haemorrhage	1/710 (0.1%)		0/710 (0%)
Haemorrhoidal Haemorrhage	1/710 (0.1%)		1/710 (0.1%)
Hiatus Hernia	0/710 (0%)		1/710 (0.1%)
Ileus	1/710 (0.1%)		1/710 (0.1%)
Intestinal Obstruction	1/710 (0.1%)		0/710 (0%)
Mallory-Weiss Syndrome	0/710 (0%)		1/710 (0.1%)
Pancreatitis Chronic	0/710 (0%)		1/710 (0.1%)
Tooth Disorder	0/710 (0%)		1/710 (0.1%)
General disorders
Chest Pain	0/710 (0%)		1/710 (0.1%)
Generalised Oedema	0/710 (0%)		1/710 (0.1%)
Hepatobiliary disorders
Cholecystitis Acute	0/710 (0%)		1/710 (0.1%)
Hepatitis	1/710 (0.1%)		0/710 (0%)
Immune system disorders
Hypersensitivity	0/710 (0%)		2/710 (0.3%)
Sarcoidosis	0/710 (0%)		1/710 (0.1%)
Infections and infestations
Gastroenteritis	9/710 (1.3%)		1/710 (0.1%)
Appendicitis	4/710 (0.6%)		3/710 (0.4%)
Pneumonia	3/710 (0.4%)		2/710 (0.3%)
Anogenital Warts	0/710 (0%)		2/710 (0.3%)
Bronchitis	2/710 (0.3%)		0/710 (0%)
Gastroenteritis Viral	1/710 (0.1%)		2/710 (0.3%)
Pharyngitis	2/710 (0.3%)		0/710 (0%)
Pilonidal Cyst	2/710 (0.3%)		1/710 (0.1%)
Pulmonary Tuberculosis	2/710 (0.3%)		2/710 (0.3%)
Pyelonephritis	2/710 (0.3%)		0/710 (0%)
Acute Sinusitis	1/710 (0.1%)		0/710 (0%)
Cat Scratch Disease	0/710 (0%)		1/710 (0.1%)
Cellulitis	1/710 (0.1%)		0/710 (0%)
Cystitis	1/710 (0.1%)		0/710 (0%)
Gangrene	1/710 (0.1%)		0/710 (0%)
Hepatitis B	1/710 (0.1%)		1/710 (0.1%)
Hepatitis Viral	1/710 (0.1%)		0/710 (0%)
Pyelonephritis Chronic	0/710 (0%)		1/710 (0.1%)
Sinusitis	1/710 (0.1%)		0/710 (0%)
Tooth Abscess	0/710 (0%)		1/710 (0.1%)
Toxoplasmosis	0/710 (0%)		1/710 (0.1%)
Urinary Tract Infection	1/710 (0.1%)		0/710 (0%)
Viral Labyrinthitis	0/710 (0%)		1/710 (0.1%)
Viral Upper Respiratory Tract Infection	0/710 (0%)		1/710 (0.1%)
Injury, poisoning and procedural complications
Ankle Fracture	2/710 (0.3%)		3/710 (0.4%)
Facial Bones Fracture	3/710 (0.4%)		0/710 (0%)
Hand Fracture	0/710 (0%)		2/710 (0.3%)
Head Injury	2/710 (0.3%)		1/710 (0.1%)
Multiple Injuries	2/710 (0.3%)		0/710 (0%)
Contusion	1/710 (0.1%)		0/710 (0%)
Femoral Neck Fracture	0/710 (0%)		1/710 (0.1%)
Foot Fracture	0/710 (0%)		1/710 (0.1%)
Foreign Body In Eye	0/710 (0%)		1/710 (0.1%)
Humerus Fracture	0/710 (0%)		1/710 (0.1%)
Joint Dislocation	1/710 (0.1%)		0/710 (0%)
Joint Injury	0/710 (0%)		1/710 (0.1%)
Limb Crushing Injury	1/710 (0.1%)		0/710 (0%)
Limb Injury	1/710 (0.1%)		0/710 (0%)
Lumbar Vertebral Fracture	1/710 (0.1%)		1/710 (0.1%)
Overdose	0/710 (0%)		1/710 (0.1%)
Road Traffic Accident	1/710 (0.1%)		1/710 (0.1%)
Spinal Fracture	1/710 (0.1%)		0/710 (0%)
Tendon Rupture	1/710 (0.1%)		0/710 (0%)
Traumatic Amputation	0/710 (0%)		1/710 (0.1%)
Investigations
Blood Creatine Phosphokinase Increased	0/710 (0%)		1/710 (0.1%)
HIV Test Positive	1/710 (0.1%)		0/710 (0%)
International Normalised Ratio Increased	0/710 (0%)		1/710 (0.1%)
Metabolism and nutrition disorders
Diabetic Ketoacidosis	12/710 (1.7%)		17/710 (2.4%)
Hypoglycaemia	17/710 (2.4%)		16/710 (2.3%)
Diabetes Mellitus Inadequate Control	1/710 (0.1%)		6/710 (0.8%)
Ketoacidosis	3/710 (0.4%)		5/710 (0.7%)
Hyperglycaemia	3/710 (0.4%)		4/710 (0.6%)
Dehydration	0/710 (0%)		2/710 (0.3%)
Hypoglycaemic Seizure	2/710 (0.3%)		0/710 (0%)
Shock Hypoglycaemic	1/710 (0.1%)		0/710 (0%)
Musculoskeletal and connective tissue disorders
Intervertebral Disc Protrusion	2/710 (0.3%)		2/710 (0.3%)
Bursitis	0/710 (0%)		1/710 (0.1%)
Compartment Syndrome	0/710 (0%)		1/710 (0.1%)
Musculoskeletal Chest Pain	0/710 (0%)		1/710 (0.1%)
Musculoskeletal Pain	0/710 (0%)		1/710 (0.1%)
Osteoarthritis	0/710 (0%)		1/710 (0.1%)
Osteonecrosis	1/710 (0.1%)		1/710 (0.1%)
Periarthritis	1/710 (0.1%)		0/710 (0%)
Rhabdomyolysis	1/710 (0.1%)		0/710 (0%)
Spinal Osteoarthritis	1/710 (0.1%)		0/710 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine Leiomyoma	2/710 (0.3%)		0/710 (0%)
Acrochordon	1/710 (0.1%)		0/710 (0%)
Benign Neoplasm Of Thyroid Gland	1/710 (0.1%)		0/710 (0%)
Breast Cancer	0/710 (0%)		1/710 (0.1%)
Cervix Carcinoma	0/710 (0%)		1/710 (0.1%)
Colon Cancer	0/710 (0%)		1/710 (0.1%)
Retroperitoneal Neoplasm	1/710 (0.1%)		0/710 (0%)
Skin Papilloma	1/710 (0.1%)		0/710 (0%)
Teratoma Benign	0/710 (0%)		1/710 (0.1%)
Thyroid Cancer	0/710 (0%)		1/710 (0.1%)
Nervous system disorders
Convulsion	1/710 (0.1%)		2/710 (0.3%)
Hypoglycaemic Coma	2/710 (0.3%)		2/710 (0.3%)
Carpal Tunnel Syndrome	0/710 (0%)		1/710 (0.1%)
Cerebral Infarction	1/710 (0.1%)		0/710 (0%)
Cerebrovascular Accident	1/710 (0.1%)		1/710 (0.1%)
Diabetic Autonomic Neuropathy	0/710 (0%)		1/710 (0.1%)
Epilepsy	1/710 (0.1%)		0/710 (0%)
Guillain-Barre Syndrome	1/710 (0.1%)		0/710 (0%)
Hydrocephalus	0/710 (0%)		1/710 (0.1%)
Leukoencephalomyelitis	0/710 (0%)		1/710 (0.1%)
Multiple Sclerosis	1/710 (0.1%)		1/710 (0.1%)
Radiculitis Brachial	1/710 (0.1%)		0/710 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion Spontaneous	0/710 (0%)		2/710 (0.3%)
Abortion	1/710 (0.1%)		0/710 (0%)
Intra-Uterine Death	1/710 (0.1%)		0/710 (0%)
Psychiatric disorders
Depression	3/710 (0.4%)		1/710 (0.1%)
Completed Suicide	0/710 (0%)		1/710 (0.1%)
Confusional State	1/710 (0.1%)		0/710 (0%)
Suicide Attempt	1/710 (0.1%)		0/710 (0%)
Renal and urinary disorders
Haematuria	1/710 (0.1%)		0/710 (0%)
Ureteric Obstruction	0/710 (0%)		1/710 (0.1%)
Reproductive system and breast disorders
Menorrhagia	0/710 (0%)		2/710 (0.3%)
Bartholin's Cyst	0/710 (0%)		1/710 (0.1%)
Endometriosis	1/710 (0.1%)		0/710 (0%)
Menstruation Irregular	1/710 (0.1%)		0/710 (0%)
Ovarian Cyst	0/710 (0%)		1/710 (0.1%)
Vaginal Haemorrhage	0/710 (0%)		1/710 (0.1%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/710 (0.1%)		0/710 (0%)
Nasal Polyps	1/710 (0.1%)		0/710 (0%)
Pneumothorax	0/710 (0%)		1/710 (0.1%)
Sleep Apnoea Syndrome	1/710 (0.1%)		0/710 (0%)
Skin and subcutaneous tissue disorders
Rash	1/710 (0.1%)		0/710 (0%)
Skin Ulcer	1/710 (0.1%)		0/710 (0%)
Vascular disorders
Arthralgia	0/710 (0%)		1/710 (0.1%)
Deep Vein Thrombosis	0/710 (0%)		1/710 (0.1%)
Other (Not Including Serious) Adverse Events
	Candesartan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	85/710 (12%)		43/710 (6.1%)
Vascular disorders
Hypotension	85/710 (12%)		43/710 (6.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.