Diabetic Retinopathy
Conditions
Brief summary
LENS is a streamlined multicentre randomised placebo-controlled parallel-group trial investigating the effect of fenofibrate treatment on the progression of diabetic retinopathy/maculopathy.
Detailed description
LENS is a phase 4 randomised placebo-controlled clinical trial of fenofibrate in participants with diabetes and observable retinopathy or maculopathy. The trial aims to recruit approximately 1,060 participants and to treat them for a median duration of at least 4 years. The main aim of LENS is to investigate the effect of fenofibrate therapy on progression to referable diabetic retinopathy/maculopathy. The trial will be conducted using a pragmatic streamlined trial design with the only planned face-to-face visits being an initial screening visit, followed by a randomisation visit eight weeks later. Contact with participants thereafter will be by means of regular telephone or computer questionnaire, and outcome and safety data will also be sought by means of linkage to NHS Scotland registries. Prior to randomisation, eligible participants will enter an active run-in phase of 6 to 10 weeks.
Interventions
One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
DRUGPlacebo Oral Tablet
One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Sponsors
National Institute for Health Research, United Kingdom
University of Glasgow
University of Aberdeen
University of Dundee
University of Edinburgh
NHS Scotland Diabetic Retinopathy Screening Collaborative
University of Oxford
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 No maximum
Healthy volunteers
No
Inclusion criteria
1. Capable of giving informed consent 2. Diabetes Mellitus (any type except gestational diabetes) 3. Observable diabetic retinopathy/maculopathy (defined based on NHS Scotland grading criteria as: R1 in both eyes or R2 in one/both eyes at the most recent retinal screening assessment; or M1 in one/both eyes at any retinal screening assessment in the 3 years) 4. Willing to either complete electronic questionnaires or conduct telephone interviews for collection of data once every 6 months
Exclusion criteria
1. Clinically significant DR (defined as R3 or R4 or M2 in one or both eyes) 2. History of gallbladder disease (cholecystitis, symptomatic gallstones, cholecystectomy) 3. History of acute or chronic pancreatitis 4. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>2X the upper limit of normal (ULN) according to local NHS laboratory reference range at screening visit 5. ALT or AST \>2.5X ULN according to local NHS laboratory reference range at randomisation visit 6. Creatine kinase (CK) \>3X ULN according to local NHS laboratory reference range at screening visit 7. CK \>3X ULN according to local NHS laboratory reference range at randomisation visit 8. Estimated glomerular filtration rate (eGFR) \<40mL/min/1.73m2 at screening visit 9. eGFR \<30mL/min/1.73m2 at randomisation visit 10. Cirrhosis of any aetiology or any other serious hepatic disease (investigator opinion) 11. Female who is pregnant, breastfeeding, currently trying to become pregnant, or of child-bearing potential and not practising birth control 12. Ongoing vitamin K antagonist (warfarin, phenindione, acenocoumarol), cyclosporine, colchicine, ketoprofen, daptomycin, fibrate therapy, or treatment with rosuvastatin 40mg daily 13. Previous myositis, myopathy or rhabdomyolysis of any cause, or diagnosed hereditary muscle disorder 14. Ongoing renal replacement therapy 15. Any previous organ transplant 16. Previous reported intolerance to any fibrate 17. Medical history that might limit the individual's ability to take trial treatments for the duration of the study (e.g. severe respiratory disease, history of cancer within last 5 years other than non-melanoma skin cancer; or recent history of alcohol or substance misuse) 18. Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participant at risk because of participation in the trial, or may influence the result of the trial, or the participant's ability to participate in the trial 19. LENS participants can participate in other research studies, including clinical trials. The only exclusions related to co-enrolment will be: if any other study or trial excludes co-enrolment or if the intervention being investigated in another trial has the potential to interact with fenofibrate therapy. 20. Not adherent to active run-in treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 4.0 years (interquartile range, 3.6 to 4.3) years | Primary outcome was a composite of the development of referable diabetic retinopathy or referable maculopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). Referable diabetic retinopathy was defined by the NHS Scotland's grading criteria as any development of R3, R4 or M2 disease. R3 (referable background diabetic retinopathy): any of four or more blot hemorrhages in both inferior and superior hemi-fields, or venous beading, or intraretinal microvascular abnormalities (IRMA); R4 (proliferative diabetic retinopathy): any active new vessels, or vitreous hemorrhage; M2 (referable maculopathy): any blot hemorrhages, or hard exudates within a radius of ≤1 optic disc diameter of the centre of the fovea. Adverse event reports of eye procedures, vitreous haemorrhages and macular oedema were adjudicated by experienced doctors at the Central Co-ordinating Office (CCO), masked to treatment allocation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants in Subgroup Sex - Male With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 4.0 years (interquartile range, 3.6 to 4.3) years | Composite primary outcome in prespecified subgroup according to the baseline characteristic: Sex - male. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment. |
| Number of Participants in Subgroup - HbA1c Unknown With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 4.0 years (interquartile range, 3.6 to 4.3) years | Composite primary outcome in prespecified subgroup according to the baseline characteristic - HbA1c at Screening - Unknown. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment. |
| Number of Participants in Subgroup With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment, Within 1 Year of Randomization | Up to 1 year from randomisation. | Composite primary outcome in prespecified subgroup according to the baseline characteristic: Timing of primary outcome - Within first year. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment. |
| Number of Participants in Subgroup With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment, After 1 Year From Randomization | 4.0 years (interquartile range, 3.6 to 4.3) years, excluding any primary outcome events within the first year of randomisation. | Composite primary outcome in prespecified subgroup according to the baseline characteristic: Timing - After first year. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment. |
| Number of Participants With the Individual Component of the Composite Primary Outcome: Development of Referable Diabetic Retinopathy or Maculopathy | 4.0 years (interquartile range, 3.6 to 4.3) years | Progression of Diabetic Retinopathy/Maculopathy to a referable grade (R3 or R4 or M2) based on the NHS Scotland grading scheme in at least one eye. |
| Number of Participants With the Individual Component of Composite Primary Outcome: Treatment for Diabetic Retinopathy or Maculopathy | 4.0 years (interquartile range, 3.6 to 4.3) years | Treatment for diabetic retinopathy or maculopathy (including intravitreal injection of medication, retinal laser therapy, or vitrectomy) in either eye. |
| Number of Participants With Any Progression of Diabetic Retinopathy or Maculopathy Across the NHS Scotland Retinopathy Grading Scale | 4.0 years (interquartile range, 3.6 to 4.3) years | Any progression of diabetic retinopathy or maculopathy across the NHS Scotland retinopathy grading scale. R4 = Proliferative DR, R3 = Referable background DR, R2 = Observable background DR. R1 = Mild background DR, R0 = No DR anywhere (where R4 is the highest severity grade and R0 is the lowest grade); M2 = Referable maculopathy, M1 = Observable maculopathy, M0 = No Maculopathy (where M2 is the highest severity grade and M0 is the lowest grade). |
| Number of Participants With Referable Maculopathy (Exudates or Blot Haemorrhages Within One Disc Diameter of the Fovea) | 4.0 years (interquartile range, 3.6 to 4.3) years | The presence of hard exudates or blot haemorrhages within 1 disc diameter of the macula/fovea |
| Number of Participants With The Development of Macular Oedema | 4.0 years (interquartile range, 3.6 to 4.3) years | The accumulation of macular fluid as determined by optical coherence tomography (OCT) imaging or on adverse event report |
| Visual Acuity | 4.0 years (interquartile range, 3.6 to 4.3) years | Based on measurement of visual acuity at retinal screening visits. Baseline visual acuity was taken from routine measurement within NHS Scotland's Diabetic Eye Screening programme (using the latest value within 18 months of randomisation). Visual acuity after randomisation was obtained by averaging available results for a participant. Conversion from Snellen to LogMAR was applied where necessary. This analysis is based on the better eye: if only 1 eye with results, analyse that eye; if 2 eyes, use eye with better acuity; if identical acuity in both eyes, use the right eye. LogMAR typically ranges from -0.3 (20/10 vision on the Snellen chart) to 1 (20/200 vision). Lower scores indicate better vision. |
| Visual Function, Based on the National Eye Institute Visual Functioning Questionnaire 25 (VFQ-25). | 4.0 years (interquartile range, 3.6 to 4.3) years | Visual function is based on the Visual Function Questionnaire-25. Visual function was defined by the composite score derived from the VFQ-25. VFQ-25 data were collected at the screening visit, after two years and at the end of the study. Results from two years and end-of-study were averaged to provide a trial-averaged result for a participant. The VFQ-25 composite score ranges from 0 to 100, where higher scores indicate better visual function. It is calculated by averaging results from up to 11 vision-related sub-scales. |
| Quality of Life, Based on the EQ-5D Index Score | 4.0 years (interquartile range, 3.6 to 4.3) years | Quality of life was measured using the EQ-5D instrument, and valued by mapping to the EQ-5D-3L UK value set using the mapping function developed by Hernandez Alava et al. Pharmaco Economics (2022). EQ-5D data were collected at the screening visit, after two years and at the end of the study. Results from two years and end-of-study were averaged to provide a trial-averaged result for a participant. Possible scores range from -0.59 to 1.00, where 1 is the best possible health state and 0 represents a quality of life considered equivalent to death. |
| Quality of Life, Based on the EQ-5D Visual Analogue Scale. | 4.0 years (interquartile range, 3.6 to 4.3) years | EQ-5D Visual Analogue Scale data were collected at the screening visit, after two years and at the end of the study. Results from two years and end-of-study were averaged to provide a trial-averaged result for a participant. EQ VAS scores range from 0 to 100, where 100 is the best possible health state. |
| Cost to the Health Service | 2 years | Health economic analysis: cost to the health service over 2 years. This included (i) hospital inpatient and outpatient activity (costed with nationally representative NHS costs); (ii) costs of fenofibrate (based on 200mg NHS cost); (iii) laboratory tests (NHS cost (including nurse/doctor time)); (iv) community prescribed medicines (NHS costs); (v) NHS Scotland retinal screening (published NHS unit costs); (vi) treatment for advanced retinopathy: for relevant participants, application of assumptions regarding usual number of injections from UK cohort study. |
| Cost-effectiveness (Incremental Cost Per QALY Gained) | Projected over 10 year horizon | Health economic analysis: Cost-effectiveness (incremental cost per QALY gained). The result is the value of GBP (British Pound) expenditure required to gain 1 quality adjusted life year for fenofibrate therapy vs. standard care. Years gained are presented by arm with 95% credible intervals taken as 2.5th and 97.5th percentile of simulated probabilistic output. |
| Number of Participants in Subgroup Sex - Female With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 4.0 years (interquartile range, 3.6 to 4.3) years | Composite primary outcome in prespecified subgroup according to the baseline characteristic: Sex - female. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment. |
| Number of Participants in Subgroup Age <60y With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 4.0 years (interquartile range, 3.6 to 4.3) years | Composite primary outcome in prespecified subgroup according to the baseline characteristic: Age \<60 years. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment. |
| Number of Participants in Subgroup Age ≥60y With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment. | 4.0 years (interquartile range, 3.6 to 4.3) years | Composite primary outcome in prespecified subgroup according to the baseline characteristic: Age ≥60 years. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment. |
| Number of Participants in Subgroup - Type 1 Diabetes With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 4.0 years (interquartile range, 3.6 to 4.3) years | Composite primary outcome in prespecified subgroup according to the baseline characteristic: Type of Diabetes - type 1 diabetes. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment. |
| Number of Participants in Subgroup - Type 2 or Other Type of Diabetes With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 4.0 years (interquartile range, 3.6 to 4.3) years | Composite primary outcome in prespecified subgroup according to the baseline characteristic: Type 2 and other diabetes. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment. |
| Number of Participants in Subgroup - eGFR <60 mL/Min/1.73m^2 With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 4.0 years (interquartile range, 3.6 to 4.3) years | Primary outcome in prespecified subgroup according to the baseline characteristic: Renal function at Randomisation - eGFR \<60mL/min/1.73m\^2). The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment. |
| Number of Participants in Subgroup - eGFR ≥60 mL/Min/1.73m^2 With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 4.0 years (interquartile range, 3.6 to 4.3) years | Composite primary outcome in prespecified subgroup according to the baseline characteristic: Renal function at Randomisation - eGFR ≥60mL/min/1.73m\^2. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment. |
| Number of Participants in Subgroup - HbA1c <70 mmol/Mol With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 4.0 years (interquartile range, 3.6 to 4.3) years | Primary outcome in prespecified subgroup according to the baseline characteristic: HbA1c at Screening \<70mmol/mol. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment. |
| Number of Participants in Subgroup - HbA1c ≥70 mmol/Mol With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 4.0 years (interquartile range, 3.6 to 4.3) years | Primary outcome in prespecified subgroup according to the baseline characteristic-HbA1c at Screening - ≥70mmol/mol. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Occurrence of Non-traumatic Lower Limb Amputations | 4.0 years (interquartile range, 3.6 to 4.3) years | Composite of any non-traumatic lower limb amputation (defined as minor amputation \[distal to the ankle\] or major amputation \[through or proximal to the ankle\]). |
| Number of Participants With Occurrence of Major Cardiovascular Events (Myocardial Infarction, Stroke, Coronary or Peripheral Revascularisation) | 4.0 years (interquartile range, 3.6 to 4.3) years | This outcome is a composite of myocardial infarction, stroke, coronary artery revascularisation and peripheral artery revascularisation. |
| Percentage Change in Urine Albumin:Creatinine Ratio | 4.0 years (interquartile range, 3.6 to 4.3) years | Based on collection of biochemical data. Urine albumin: creatinine ratio (UACR) results. Urine was collected for measurement of UACR at LENS screening visits wherever possible (baseline results). Post randomization UACR results came from measurements conducted part of routine care. Post randomisation results for a participant were averaged for each participant. Separate values for participants assigned fenofibrate and placebo are reported as geometric mean (95% confidence intervals) and the difference between arms is reported as a percentage difference (95% confidence intervals) |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Fenofibrate 145 mg Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease) | 576 |
| Placebo Oral Tablet Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease) | 575 |
| Total | 1,151 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Consent withdrawn | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | Fenofibrate 145 mg | Placebo Oral Tablet | Total |
|---|---|---|---|
| Age, Continuous | 60.8 years STANDARD_DEVIATION 12.4 | 60.6 years STANDARD_DEVIATION 12.3 | 60.7 years STANDARD_DEVIATION 12.3 |
| Baseline medications Insulin | 256 participants | 249 participants | 505 participants |
| Baseline medications Non-insulin glucose-lowering therapy | 396 participants | 389 participants | 785 participants |
| Baseline medications Renin-angiotensin system inhibitor | 345 participants | 341 participants | 686 participants |
| Baseline medications Statin | 425 participants | 429 participants | 854 participants |
| Body mass index | 30.9 kg/m^2 STANDARD_DEVIATION 6.4 | 30.7 kg/m^2 STANDARD_DEVIATION 6 | 30.8 kg/m^2 STANDARD_DEVIATION 6.2 |
| Cardiovascular disease | 103 Participants | 96 Participants | 199 Participants |
| Creatinine at Randomisation | 1.01 mg/dl STANDARD_DEVIATION 0.26 | 1.00 mg/dl STANDARD_DEVIATION 0.25 | 1.01 mg/dl STANDARD_DEVIATION 0.25 |
| Creatinine at Screening | 0.88 mg/dl STANDARD_DEVIATION 0.21 | 0.88 mg/dl STANDARD_DEVIATION 0.21 | 0.88 mg/dl STANDARD_DEVIATION 0.21 |
| Diastolic blood pressure | 75.4 mm Hg STANDARD_DEVIATION 9.4 | 75.5 mm Hg STANDARD_DEVIATION 9.3 | 75.5 mm Hg STANDARD_DEVIATION 9.4 |
| Duration of diabetes | 18.3 years STANDARD_DEVIATION 10.5 | 17.7 years STANDARD_DEVIATION 10 | 18 years STANDARD_DEVIATION 10.25 |
| Estimated Glomerular Filtration Rate (eGFR) at Randomisation <60 ml/min/1.73 m^2 | 130 Participants | 131 Participants | 261 Participants |
| Estimated Glomerular Filtration Rate (eGFR) at Randomisation ≥60 ml/min/1.73 m^2 | 446 Participants | 444 Participants | 890 Participants |
| Estimated Glomerular Filtration Rate (eGFR) at Screening <60ml/min/1.73 m^2 | 58 Participants | 40 Participants | 98 Participants |
| Estimated Glomerular Filtration Rate (eGFR) at Screening ≥60ml/min/1.73 m^2 | 518 Participants | 535 Participants | 1053 Participants |
| Haemoglobin A1C (HbA1c): | 66.4 mmol/mol STANDARD_DEVIATION 16.1 | 66.3 mmol/mol STANDARD_DEVIATION 15.9 | 66.4 mmol/mol STANDARD_DEVIATION 16 |
| HDL cholesterol (mg/dl) | 51 mg/dl STANDARD_DEVIATION 16 | 50 mg/dl STANDARD_DEVIATION 15 | 50.5 mg/dl STANDARD_DEVIATION 15.5 |
| Maculopathy grading (worse eye) No maculopathy (M0) | 517 Participants | 515 Participants | 1032 Participants |
| Maculopathy grading (worse eye) Observable diabetic maculopathy (M1) | 59 Participants | 60 Participants | 119 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 6 Participants | 10 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 9 Participants | 13 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 567 Participants | 558 Participants | 1125 Participants |
| Region of Enrollment United Kingdom | 576 participants | 575 participants | 1151 participants |
| Retinal laser treatment or intravitreal injections or vitrectomy | 53 Participants | 59 Participants | 112 Participants |
| Retinopathy grading (worse grade) Mild background retinopathy (R1) | 562 Participants | 564 Participants | 1126 Participants |
| Retinopathy grading (worse grade) No retinopathy (R0) | 5 Participants | 4 Participants | 9 Participants |
| Retinopathy grading (worse grade) Observable background retinopathy (R2) | 9 Participants | 7 Participants | 16 Participants |
| Sex: Female, Male Female | 156 Participants | 156 Participants | 312 Participants |
| Sex: Female, Male Male | 420 Participants | 419 Participants | 839 Participants |
| Systolic blood pressure | 136.7 mm Hg STANDARD_DEVIATION 17.2 | 136.4 mm Hg STANDARD_DEVIATION 17.9 | 136.6 mm Hg STANDARD_DEVIATION 17.5 |
| Total cholesterol (mg/dl) | 156 mg/dl STANDARD_DEVIATION 37 | 157 mg/dl STANDARD_DEVIATION 38 | 156.5 mg/dl STANDARD_DEVIATION 37.5 |
| Triglycerides (IQR) (mg/dl) | 137 mg/dl | 138 mg/dl | 137 mg/dl |
| Type of diabetes mellitus Other | 1 Participants | 1 Participants | 2 Participants |
| Type of diabetes mellitus Type 1 | 154 Participants | 151 Participants | 305 Participants |
| Type of diabetes mellitus Type 2 | 421 Participants | 423 Participants | 844 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 35 / 576 | 38 / 575 |
| other Total, other adverse events | 17 / 576 | 21 / 575 |
| serious Total, serious adverse events | 208 / 576 | 204 / 575 |
Outcome results
Primary
Number of Participants With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment
Primary outcome was a composite of the development of referable diabetic retinopathy or referable maculopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). Referable diabetic retinopathy was defined by the NHS Scotland's grading criteria as any development of R3, R4 or M2 disease. R3 (referable background diabetic retinopathy): any of four or more blot hemorrhages in both inferior and superior hemi-fields, or venous beading, or intraretinal microvascular abnormalities (IRMA); R4 (proliferative diabetic retinopathy): any active new vessels, or vitreous hemorrhage; M2 (referable maculopathy): any blot hemorrhages, or hard exudates within a radius of ≤1 optic disc diameter of the centre of the fovea. Adverse event reports of eye procedures, vitreous haemorrhages and macular oedema were adjudicated by experienced doctors at the Central Co-ordinating Office (CCO), masked to treatment allocation.
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on time to the first occurrence.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fenofibrate 145 mg | Number of Participants With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 131 Participants |
| Placebo Oral Tablet | Number of Participants With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 168 Participants |
p-value: 0.00695% CI: [0.58, 0.91]Regression, Cox
Secondary
Cost-effectiveness (Incremental Cost Per QALY Gained)
Health economic analysis: Cost-effectiveness (incremental cost per QALY gained). The result is the value of GBP (British Pound) expenditure required to gain 1 quality adjusted life year for fenofibrate therapy vs. standard care. Years gained are presented by arm with 95% credible intervals taken as 2.5th and 97.5th percentile of simulated probabilistic output.
Time frame: Projected over 10 year horizon
Population: QALY calculated based on quality of life data from EQ-5D questionnaires collected at baseline, at approximately 2 years and at the end of the trial.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Fenofibrate 145 mg | Cost-effectiveness (Incremental Cost Per QALY Gained) | 5.434 Years gained |
| Placebo Oral Tablet | Cost-effectiveness (Incremental Cost Per QALY Gained) | 5.419 Years gained |
Secondary
Cost to the Health Service
Health economic analysis: cost to the health service over 2 years. This included (i) hospital inpatient and outpatient activity (costed with nationally representative NHS costs); (ii) costs of fenofibrate (based on 200mg NHS cost); (iii) laboratory tests (NHS cost (including nurse/doctor time)); (iv) community prescribed medicines (NHS costs); (v) NHS Scotland retinal screening (published NHS unit costs); (vi) treatment for advanced retinopathy: for relevant participants, application of assumptions regarding usual number of injections from UK cohort study.
Time frame: 2 years
Population: Comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo over 2 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Fenofibrate 145 mg | Cost to the Health Service | 3566 GBP (British Pounds) |
| Placebo Oral Tablet | Cost to the Health Service | 3820 GBP (British Pounds) |
95% CI: [-1062, 624]
Secondary
Number of Participants in Subgroup Age <60y With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment
Composite primary outcome in prespecified subgroup according to the baseline characteristic: Age \<60 years. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment.
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on time to the first occurrence
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fenofibrate 145 mg | Number of Participants in Subgroup Age <60y With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 68 Participants |
| Placebo Oral Tablet | Number of Participants in Subgroup Age <60y With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 93 Participants |
Comparison: Cox proportional hazards regression analyses were used to estimate the hazard ratio and 95% confidence intervals, comparing all participants allocated active fenofibrate with all those allocated placebo.95% CI: [0.52, 0.97]
Secondary
Number of Participants in Subgroup Age ≥60y With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment.
Composite primary outcome in prespecified subgroup according to the baseline characteristic: Age ≥60 years. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment.
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on time to the first occurrence
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fenofibrate 145 mg | Number of Participants in Subgroup Age ≥60y With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment. | 63 Participants |
| Placebo Oral Tablet | Number of Participants in Subgroup Age ≥60y With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment. | 75 Participants |
Comparison: Cox proportional hazards regression analyses were used to estimate the hazard ratio and 95% confidence intervals, comparing all participants allocated active fenofibrate with all those allocated placebo.95% CI: [0.55, 1.07]
Secondary
Number of Participants in Subgroup - eGFR <60 mL/Min/1.73m^2 With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment
Primary outcome in prespecified subgroup according to the baseline characteristic: Renal function at Randomisation - eGFR \<60mL/min/1.73m\^2). The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment.
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on time to the first occurrence.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fenofibrate 145 mg | Number of Participants in Subgroup - eGFR <60 mL/Min/1.73m^2 With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 17 Participants |
| Placebo Oral Tablet | Number of Participants in Subgroup - eGFR <60 mL/Min/1.73m^2 With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 32 Participants |
Comparison: Cox proportional hazards regression analyses were used to estimate the hazard ratio and 95% confidence intervals, comparing all participants allocated active fenofibrate with all those allocated placebo.95% CI: [0.28, 0.93]
Secondary
Number of Participants in Subgroup - eGFR ≥60 mL/Min/1.73m^2 With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment
Composite primary outcome in prespecified subgroup according to the baseline characteristic: Renal function at Randomisation - eGFR ≥60mL/min/1.73m\^2. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment.
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on time to the first occurrence
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fenofibrate 145 mg | Number of Participants in Subgroup - eGFR ≥60 mL/Min/1.73m^2 With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 114 Participants |
| Placebo Oral Tablet | Number of Participants in Subgroup - eGFR ≥60 mL/Min/1.73m^2 With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 136 Participants |
Comparison: Cox proportional hazards regression analyses were used to estimate the hazard ratio and 95% confidence intervals, comparing all participants allocated active fenofibrate with all those allocated placebo.95% CI: [0.6, 0.99]
Secondary
Number of Participants in Subgroup - HbA1c <70 mmol/Mol With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment
Primary outcome in prespecified subgroup according to the baseline characteristic: HbA1c at Screening \<70mmol/mol. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment.
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on time to the first occurrence.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fenofibrate 145 mg | Number of Participants in Subgroup - HbA1c <70 mmol/Mol With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 63 Participants |
| Placebo Oral Tablet | Number of Participants in Subgroup - HbA1c <70 mmol/Mol With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 81 Participants |
Comparison: Cox proportional hazards regression analyses were used to estimate the hazard ratio and 95% confidence intervals, comparing all participants allocated active fenofibrate with all those allocated placebo.95% CI: [0.49, 0.95]
Secondary
Number of Participants in Subgroup - HbA1c ≥70 mmol/Mol With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment
Primary outcome in prespecified subgroup according to the baseline characteristic-HbA1c at Screening - ≥70mmol/mol. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment.
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on time to the first occurrence.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fenofibrate 145 mg | Number of Participants in Subgroup - HbA1c ≥70 mmol/Mol With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 57 Participants |
| Placebo Oral Tablet | Number of Participants in Subgroup - HbA1c ≥70 mmol/Mol With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 79 Participants |
Comparison: Cox proportional hazards regression analyses were used to estimate the hazard ratio and 95% confidence intervals, comparing all participants allocated active fenofibrate with all those allocated placebo.95% CI: [0.53, 1.06]
Secondary
Number of Participants in Subgroup - HbA1c Unknown With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment
Composite primary outcome in prespecified subgroup according to the baseline characteristic - HbA1c at Screening - Unknown. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment.
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on time to the first occurrence.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fenofibrate 145 mg | Number of Participants in Subgroup - HbA1c Unknown With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 11 Participants |
| Placebo Oral Tablet | Number of Participants in Subgroup - HbA1c Unknown With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 8 Participants |
Comparison: Cox proportional hazards regression analyses were used to estimate the hazard ratio and 95% confidence intervals, comparing all participants allocated active fenofibrate with all those allocated placebo.95% CI: [0.55, 3.57]
Secondary
Number of Participants in Subgroup Sex - Female With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment
Composite primary outcome in prespecified subgroup according to the baseline characteristic: Sex - female. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment.
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on time to the first occurrence
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fenofibrate 145 mg | Number of Participants in Subgroup Sex - Female With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 32 Participants |
| Placebo Oral Tablet | Number of Participants in Subgroup Sex - Female With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 47 Participants |
Comparison: Cox proportional hazards regression analyses were used to estimate the hazard ratio and 95% confidence intervals, comparing all participants allocated active fenofibrate with all those allocated placebo.95% CI: [0.4, 1]
Secondary
Number of Participants in Subgroup Sex - Male With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment
Composite primary outcome in prespecified subgroup according to the baseline characteristic: Sex - male. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment.
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on time to the first occurrence
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fenofibrate 145 mg | Number of Participants in Subgroup Sex - Male With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 99 Participants |
| Placebo Oral Tablet | Number of Participants in Subgroup Sex - Male With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 121 Participants |
Comparison: Cox proportional hazards regression analyses were used to estimate the hazard ratio and 95% confidence intervals, comparing all participants allocated active fenofibrate with all those allocated placebo.95% CI: [0.58, 0.99]
Secondary
Number of Participants in Subgroup - Type 1 Diabetes With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment
Composite primary outcome in prespecified subgroup according to the baseline characteristic: Type of Diabetes - type 1 diabetes. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment.
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on time to the first occurrence
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fenofibrate 145 mg | Number of Participants in Subgroup - Type 1 Diabetes With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 38 Participants |
| Placebo Oral Tablet | Number of Participants in Subgroup - Type 1 Diabetes With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 45 Participants |
Comparison: Cox proportional hazards regression analyses were used to estimate the hazard ratio and 95% confidence intervals, comparing all participants allocated active fenofibrate with all those allocated placebo.95% CI: [0.51, 1.21]
Secondary
Number of Participants in Subgroup - Type 2 or Other Type of Diabetes With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment
Composite primary outcome in prespecified subgroup according to the baseline characteristic: Type 2 and other diabetes. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment.
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on time to the first occurrence
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fenofibrate 145 mg | Number of Participants in Subgroup - Type 2 or Other Type of Diabetes With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 93 Participants |
| Placebo Oral Tablet | Number of Participants in Subgroup - Type 2 or Other Type of Diabetes With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment | 123 Participants |
Comparison: Cox proportional hazards regression analyses were used to estimate the hazard ratio and 95% confidence intervals, comparing all participants allocated active fenofibrate with all those allocated placebo.95% CI: [0.54, 0.93]
Secondary
Number of Participants in Subgroup With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment, After 1 Year From Randomization
Composite primary outcome in prespecified subgroup according to the baseline characteristic: Timing - After first year. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment.
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years, excluding any primary outcome events within the first year of randomisation.
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on time to the first occurrence
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fenofibrate 145 mg | Number of Participants in Subgroup With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment, After 1 Year From Randomization | 86 Participants |
| Placebo Oral Tablet | Number of Participants in Subgroup With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment, After 1 Year From Randomization | 105 Participants |
Comparison: Cox proportional hazards regression analyses were used to estimate the hazard ratio and 95% confidence intervals, comparing all participants allocated active fenofibrate with all those allocated placebo.95% CI: [0.56, 0.99]
Secondary
Number of Participants in Subgroup With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment, Within 1 Year of Randomization
Composite primary outcome in prespecified subgroup according to the baseline characteristic: Timing of primary outcome - Within first year. The primary outcome was a composite of the development of referable diabetic retinopathy, or treatment for diabetic retinopathy or maculopathy (including retinal laser therapy, vitrectomy or intravitreal injection of medication). The definition for referable diabetic retinopathy is provided above in '1. Primary Outcome: Number of Participants with Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment.
Time frame: Up to 1 year from randomisation.
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on time to the first occurrence.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fenofibrate 145 mg | Number of Participants in Subgroup With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment, Within 1 Year of Randomization | 45 Participants |
| Placebo Oral Tablet | Number of Participants in Subgroup With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment, Within 1 Year of Randomization | 63 Participants |
Comparison: Cox proportional hazards regression analyses were used to estimate the hazard ratio and 95% confidence intervals, comparing all participants allocated active fenofibrate with all those allocated placebo.95% CI: [0.48, 1.03]
Secondary
Number of Participants With Any Progression of Diabetic Retinopathy or Maculopathy Across the NHS Scotland Retinopathy Grading Scale
Any progression of diabetic retinopathy or maculopathy across the NHS Scotland retinopathy grading scale. R4 = Proliferative DR, R3 = Referable background DR, R2 = Observable background DR. R1 = Mild background DR, R0 = No DR anywhere (where R4 is the highest severity grade and R0 is the lowest grade); M2 = Referable maculopathy, M1 = Observable maculopathy, M0 = No Maculopathy (where M2 is the highest severity grade and M0 is the lowest grade).
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on time to the first occurrence
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fenofibrate 145 mg | Number of Participants With Any Progression of Diabetic Retinopathy or Maculopathy Across the NHS Scotland Retinopathy Grading Scale | 185 Participants |
| Placebo Oral Tablet | Number of Participants With Any Progression of Diabetic Retinopathy or Maculopathy Across the NHS Scotland Retinopathy Grading Scale | 231 Participants |
Comparison: Cox proportional hazards regression analyses were used to estimate the hazard ratio and 95% confidence intervals, comparing all participants allocated active fenofibrate with all those allocated placebo.p-value: 0.00395% CI: [0.61, 0.9]Regression, Cox
Secondary
Number of Participants With Referable Maculopathy (Exudates or Blot Haemorrhages Within One Disc Diameter of the Fovea)
The presence of hard exudates or blot haemorrhages within 1 disc diameter of the macula/fovea
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on time to the first occurrence
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fenofibrate 145 mg | Number of Participants With Referable Maculopathy (Exudates or Blot Haemorrhages Within One Disc Diameter of the Fovea) | 107 Participants |
| Placebo Oral Tablet | Number of Participants With Referable Maculopathy (Exudates or Blot Haemorrhages Within One Disc Diameter of the Fovea) | 149 Participants |
Comparison: Cox proportional hazards regression analyses were used to estimate the hazard ratio and 95% confidence intervals, comparing all participants allocated active fenofibrate with all those allocated placebo.p-value: 0.00195% CI: [0.52, 0.85]Regression, Cox
Secondary
Number of Participants With The Development of Macular Oedema
The accumulation of macular fluid as determined by optical coherence tomography (OCT) imaging or on adverse event report
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on time to the first occurrence
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fenofibrate 145 mg | Number of Participants With The Development of Macular Oedema | 22 Participants |
| Placebo Oral Tablet | Number of Participants With The Development of Macular Oedema | 43 Participants |
Comparison: Cox proportional hazards regression analyses were used to estimate the hazard ratio and 95% confidence intervals, comparing all participants allocated active fenofibrate with all those allocated placebo.p-value: 0.00895% CI: [0.3, 0.84]Regression, Cox
Secondary
Number of Participants With the Individual Component of Composite Primary Outcome: Treatment for Diabetic Retinopathy or Maculopathy
Treatment for diabetic retinopathy or maculopathy (including intravitreal injection of medication, retinal laser therapy, or vitrectomy) in either eye.
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on time to first occurrence.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fenofibrate 145 mg | Number of Participants With the Individual Component of Composite Primary Outcome: Treatment for Diabetic Retinopathy or Maculopathy | 17 Participants |
| Placebo Oral Tablet | Number of Participants With the Individual Component of Composite Primary Outcome: Treatment for Diabetic Retinopathy or Maculopathy | 28 Participants |
Comparison: Cox proportional hazards regression analyses were used to estimate the hazard ratio and 95% confidence intervals, comparing all participants allocated active fenofibrate with all those allocated placebo.p-value: 0.0895% CI: [0.31, 1.06]Regression, Cox
Secondary
Number of Participants With the Individual Component of the Composite Primary Outcome: Development of Referable Diabetic Retinopathy or Maculopathy
Progression of Diabetic Retinopathy/Maculopathy to a referable grade (R3 or R4 or M2) based on the NHS Scotland grading scheme in at least one eye.
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on time to the first occurrence.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fenofibrate 145 mg | Number of Participants With the Individual Component of the Composite Primary Outcome: Development of Referable Diabetic Retinopathy or Maculopathy | 130 Participants |
| Placebo Oral Tablet | Number of Participants With the Individual Component of the Composite Primary Outcome: Development of Referable Diabetic Retinopathy or Maculopathy | 168 Participants |
Comparison: Cox proportional hazards regression analyses were used to estimate the hazard ratio and 95% confidence intervals, comparing all participants allocated active fenofibrate with all those allocated placebo.p-value: 0.00595% CI: [0.57, 0.91]Regression, Cox
Secondary
Quality of Life, Based on the EQ-5D Index Score
Quality of life was measured using the EQ-5D instrument, and valued by mapping to the EQ-5D-3L UK value set using the mapping function developed by Hernandez Alava et al. Pharmaco Economics (2022). EQ-5D data were collected at the screening visit, after two years and at the end of the study. Results from two years and end-of-study were averaged to provide a trial-averaged result for a participant. Possible scores range from -0.59 to 1.00, where 1 is the best possible health state and 0 represents a quality of life considered equivalent to death.
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on trial-averaged EQ-5D Index Score. Collected at baseline, at approximately 2 years and at the end of the trial.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Fenofibrate 145 mg | Quality of Life, Based on the EQ-5D Index Score | 0.75 score on a scale |
| Placebo Oral Tablet | Quality of Life, Based on the EQ-5D Index Score | 0.75 score on a scale |
Comparison: The estimates were derived from linear mixed model repeated measures.p-value: 0.9395% CI: [-0.02, 0.02]Regression, Cox
Secondary
Quality of Life, Based on the EQ-5D Visual Analogue Scale.
EQ-5D Visual Analogue Scale data were collected at the screening visit, after two years and at the end of the study. Results from two years and end-of-study were averaged to provide a trial-averaged result for a participant. EQ VAS scores range from 0 to 100, where 100 is the best possible health state.
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on trial-averaged EQ-5D Visual Analogue Scale. Collected at baseline, at approximately 2 years and at the end of the trial.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Fenofibrate 145 mg | Quality of Life, Based on the EQ-5D Visual Analogue Scale. | 75 score on a scale |
| Placebo Oral Tablet | Quality of Life, Based on the EQ-5D Visual Analogue Scale. | 76 score on a scale |
Comparison: The estimates were derived from a linear mixed model repeated measuresp-value: 0.4395% CI: [-2, 1]Regression, Cox
Secondary
Visual Acuity
Based on measurement of visual acuity at retinal screening visits. Baseline visual acuity was taken from routine measurement within NHS Scotland's Diabetic Eye Screening programme (using the latest value within 18 months of randomisation). Visual acuity after randomisation was obtained by averaging available results for a participant. Conversion from Snellen to LogMAR was applied where necessary. This analysis is based on the better eye: if only 1 eye with results, analyse that eye; if 2 eyes, use eye with better acuity; if identical acuity in both eyes, use the right eye. LogMAR typically ranges from -0.3 (20/10 vision on the Snellen chart) to 1 (20/200 vision). Lower scores indicate better vision.
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on trial-averaged visual acuity.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Fenofibrate 145 mg | Visual Acuity | 0.06 LogMAR |
| Placebo Oral Tablet | Visual Acuity | 0.05 LogMAR |
Comparison: The estimates were derived from linear mixed model repeated measures.p-value: 0.3695% CI: [-0.01, 0.01]Regression, Cox
Secondary
Visual Function, Based on the National Eye Institute Visual Functioning Questionnaire 25 (VFQ-25).
Visual function is based on the Visual Function Questionnaire-25. Visual function was defined by the composite score derived from the VFQ-25. VFQ-25 data were collected at the screening visit, after two years and at the end of the study. Results from two years and end-of-study were averaged to provide a trial-averaged result for a participant. The VFQ-25 composite score ranges from 0 to 100, where higher scores indicate better visual function. It is calculated by averaging results from up to 11 vision-related sub-scales.
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on trial-averaged VFQ-25 Composite Score. Collected at baseline, at approximately 2 years and at the end of the trial.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Fenofibrate 145 mg | Visual Function, Based on the National Eye Institute Visual Functioning Questionnaire 25 (VFQ-25). | 90 score on a scale |
| Placebo Oral Tablet | Visual Function, Based on the National Eye Institute Visual Functioning Questionnaire 25 (VFQ-25). | 89 score on a scale |
Comparison: The estimates were derived from linear mixed model repeated measures.p-value: 0.5895% CI: [-1, 1]Regression, Cox
Other Pre-specified
Number of Participants With Occurrence of Major Cardiovascular Events (Myocardial Infarction, Stroke, Coronary or Peripheral Revascularisation)
This outcome is a composite of myocardial infarction, stroke, coronary artery revascularisation and peripheral artery revascularisation.
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on time to the first occurrence.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fenofibrate 145 mg | Number of Participants With Occurrence of Major Cardiovascular Events (Myocardial Infarction, Stroke, Coronary or Peripheral Revascularisation) | 45 Participants |
| Placebo Oral Tablet | Number of Participants With Occurrence of Major Cardiovascular Events (Myocardial Infarction, Stroke, Coronary or Peripheral Revascularisation) | 43 Participants |
Comparison: Cox proportional hazards regression analyses were used to estimate the hazard ratio and 95% confidence intervals, comparing all participants allocated active fenofibrate with all those allocated placebo.95% CI: [0.69, 1.6]
Other Pre-specified
Number of Participants With Occurrence of Non-traumatic Lower Limb Amputations
Composite of any non-traumatic lower limb amputation (defined as minor amputation \[distal to the ankle\] or major amputation \[through or proximal to the ankle\]).
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on time to the first occurrence
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fenofibrate 145 mg | Number of Participants With Occurrence of Non-traumatic Lower Limb Amputations | 4 Participants |
| Placebo Oral Tablet | Number of Participants With Occurrence of Non-traumatic Lower Limb Amputations | 11 Participants |
Comparison: Cox proportional hazards regression analyses were used to estimate the hazard ratio and 95% confidence intervals, comparing all participants allocated active fenofibrate with all those allocated placebo.95% CI: [0.11, 1.12]
Other Pre-specified
Percentage Change in Urine Albumin:Creatinine Ratio
Based on collection of biochemical data. Urine albumin: creatinine ratio (UACR) results. Urine was collected for measurement of UACR at LENS screening visits wherever possible (baseline results). Post randomization UACR results came from measurements conducted part of routine care. Post randomisation results for a participant were averaged for each participant. Separate values for participants assigned fenofibrate and placebo are reported as geometric mean (95% confidence intervals) and the difference between arms is reported as a percentage difference (95% confidence intervals)
Time frame: 4.0 years (interquartile range, 3.6 to 4.3) years
Population: Intention-to-treat comparisons among randomised participants of the effects of allocation to fenofibrate versus placebo during the scheduled treatment period on trial-averaged UACR.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Fenofibrate 145 mg | Percentage Change in Urine Albumin:Creatinine Ratio | 13.6 mg/g |
| Placebo Oral Tablet | Percentage Change in Urine Albumin:Creatinine Ratio | 15.5 mg/g |
Comparison: Linear mixed model repeated measures analyses were conducted to estimate the trial-averaged percentage difference in geometric mean UACR between the randomised treatment groups. UACR data at baseline was available for 312 participants allocated fenofibrate and 310 participants allocated placebo.95% CI: [-25.8, 3.5]