Trial Outcomes & Findings for Lowering Events in Non-proliferative Retinopathy in Scotland (NCT NCT03439345)

Last Updated: 2025-05-14

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

1151 participants

Primary outcome timeframe

4.0 years (interquartile range, 3.6 to 4.3) years

Results posted on

2025-05-14

Participant Flow

Participant milestones

Participant milestones
Measure	Fenofibrate 145 mg Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Overall Study STARTED	576	575
Overall Study COMPLETED	576	573
Overall Study NOT COMPLETED	0	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Fenofibrate 145 mg Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Overall Study Lost to Follow-up	0	1
Overall Study Consent withdrawn	0	1

Baseline Characteristics

Blood pressure data missing for 70 participants

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Fenofibrate 145 mg n=576 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=575 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Total n=1151 Participants Total of all reporting groups
Diastolic blood pressure	75.4 mm Hg STANDARD_DEVIATION 9.4 • n=542 Participants • Blood pressure data missing for 70 participants	75.5 mm Hg STANDARD_DEVIATION 9.3 • n=539 Participants • Blood pressure data missing for 70 participants	75.5 mm Hg STANDARD_DEVIATION 9.4 • n=1081 Participants • Blood pressure data missing for 70 participants
Age, Continuous	60.8 years STANDARD_DEVIATION 12.4 • n=576 Participants	60.6 years STANDARD_DEVIATION 12.3 • n=575 Participants	60.7 years STANDARD_DEVIATION 12.3 • n=1151 Participants
Sex: Female, Male Female	156 Participants n=576 Participants	156 Participants n=575 Participants	312 Participants n=1151 Participants
Sex: Female, Male Male	420 Participants n=576 Participants	419 Participants n=575 Participants	839 Participants n=1151 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=576 Participants	0 Participants n=575 Participants	0 Participants n=1151 Participants
Race/Ethnicity, Customized Asian	4 Participants n=576 Participants	6 Participants n=575 Participants	10 Participants n=1151 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=576 Participants	0 Participants n=575 Participants	0 Participants n=1151 Participants
Race/Ethnicity, Customized Black or African American	1 Participants n=576 Participants	2 Participants n=575 Participants	3 Participants n=1151 Participants
Race/Ethnicity, Customized White	567 Participants n=576 Participants	558 Participants n=575 Participants	1125 Participants n=1151 Participants
Race/Ethnicity, Customized Other	4 Participants n=576 Participants	9 Participants n=575 Participants	13 Participants n=1151 Participants
Race/Ethnicity, Customized Unknown or Not Reported	0 Participants n=576 Participants	0 Participants n=575 Participants	0 Participants n=1151 Participants
Region of Enrollment United Kingdom	576 participants n=576 Participants	575 participants n=575 Participants	1151 participants n=1151 Participants
Type of diabetes mellitus Type 1	154 Participants n=576 Participants	151 Participants n=575 Participants	305 Participants n=1151 Participants
Type of diabetes mellitus Type 2	421 Participants n=576 Participants	423 Participants n=575 Participants	844 Participants n=1151 Participants
Type of diabetes mellitus Other	1 Participants n=576 Participants	1 Participants n=575 Participants	2 Participants n=1151 Participants
Duration of diabetes	18.3 years STANDARD_DEVIATION 10.5 • n=576 Participants	17.7 years STANDARD_DEVIATION 10.0 • n=575 Participants	18 years STANDARD_DEVIATION 10.25 • n=1151 Participants
Retinopathy grading (worse grade) No retinopathy (R0)	5 Participants n=576 Participants	4 Participants n=575 Participants	9 Participants n=1151 Participants
Body mass index	30.9 kg/m^2 STANDARD_DEVIATION 6.4 • n=559 Participants • Body mass index data missing for 35 participants.	30.7 kg/m^2 STANDARD_DEVIATION 6.0 • n=557 Participants • Body mass index data missing for 35 participants.	30.8 kg/m^2 STANDARD_DEVIATION 6.2 • n=1116 Participants • Body mass index data missing for 35 participants.
Retinopathy grading (worse grade) Mild background retinopathy (R1)	562 Participants n=576 Participants	564 Participants n=575 Participants	1126 Participants n=1151 Participants
Retinopathy grading (worse grade) Observable background retinopathy (R2)	9 Participants n=576 Participants	7 Participants n=575 Participants	16 Participants n=1151 Participants
Maculopathy grading (worse eye) No maculopathy (M0)	517 Participants n=576 Participants	515 Participants n=575 Participants	1032 Participants n=1151 Participants
Maculopathy grading (worse eye) Observable diabetic maculopathy (M1)	59 Participants n=576 Participants	60 Participants n=575 Participants	119 Participants n=1151 Participants
Retinal laser treatment or intravitreal injections or vitrectomy	53 Participants n=576 Participants	59 Participants n=575 Participants	112 Participants n=1151 Participants
Cardiovascular disease	103 Participants n=576 Participants	96 Participants n=575 Participants	199 Participants n=1151 Participants
Systolic blood pressure	136.7 mm Hg STANDARD_DEVIATION 17.2 • n=542 Participants • Blood pressure data missing for 70 participants	136.4 mm Hg STANDARD_DEVIATION 17.9 • n=539 Participants • Blood pressure data missing for 70 participants	136.6 mm Hg STANDARD_DEVIATION 17.5 • n=1081 Participants • Blood pressure data missing for 70 participants
Haemoglobin A1C (HbA1c):	66.4 mmol/mol STANDARD_DEVIATION 16.1 • n=538 Participants • HbA1c data missing for 74 participants.	66.3 mmol/mol STANDARD_DEVIATION 15.9 • n=539 Participants • HbA1c data missing for 74 participants.	66.4 mmol/mol STANDARD_DEVIATION 16.0 • n=1077 Participants • HbA1c data missing for 74 participants.
Creatinine at Screening	0.88 mg/dl STANDARD_DEVIATION 0.21 • n=576 Participants	0.88 mg/dl STANDARD_DEVIATION 0.21 • n=575 Participants	0.88 mg/dl STANDARD_DEVIATION 0.21 • n=1151 Participants
Creatinine at Randomisation	1.01 mg/dl STANDARD_DEVIATION 0.26 • n=576 Participants	1.00 mg/dl STANDARD_DEVIATION 0.25 • n=575 Participants	1.01 mg/dl STANDARD_DEVIATION 0.25 • n=1151 Participants
Estimated Glomerular Filtration Rate (eGFR) at Screening <60ml/min/1.73 m^2	58 Participants n=576 Participants	40 Participants n=575 Participants	98 Participants n=1151 Participants
Estimated Glomerular Filtration Rate (eGFR) at Screening ≥60ml/min/1.73 m^2	518 Participants n=576 Participants	535 Participants n=575 Participants	1053 Participants n=1151 Participants
Estimated Glomerular Filtration Rate (eGFR) at Randomisation <60 ml/min/1.73 m^2	130 Participants n=576 Participants	131 Participants n=575 Participants	261 Participants n=1151 Participants
Estimated Glomerular Filtration Rate (eGFR) at Randomisation ≥60 ml/min/1.73 m^2	446 Participants n=576 Participants	444 Participants n=575 Participants	890 Participants n=1151 Participants
Total cholesterol (mg/dl)	156 mg/dl STANDARD_DEVIATION 37 • n=572 Participants • Total cholesterol data missing for 12 participants.	157 mg/dl STANDARD_DEVIATION 38 • n=567 Participants • Total cholesterol data missing for 12 participants.	156.5 mg/dl STANDARD_DEVIATION 37.5 • n=1139 Participants • Total cholesterol data missing for 12 participants.
HDL cholesterol (mg/dl)	51 mg/dl STANDARD_DEVIATION 16 • n=568 Participants • HDL cholesterol data missing for 23 participants.	50 mg/dl STANDARD_DEVIATION 15 • n=560 Participants • HDL cholesterol data missing for 23 participants.	50.5 mg/dl STANDARD_DEVIATION 15.5 • n=1128 Participants • HDL cholesterol data missing for 23 participants.
Triglycerides (IQR) (mg/dl)	137 mg/dl n=571 Participants • Triglyceride data missing for 17 participants.	138 mg/dl n=563 Participants • Triglyceride data missing for 17 participants.	137 mg/dl n=1134 Participants • Triglyceride data missing for 17 participants.
Baseline medications Non-insulin glucose-lowering therapy	396 participants n=576 Participants	389 participants n=575 Participants	785 participants n=1151 Participants
Baseline medications Insulin	256 participants n=576 Participants	249 participants n=575 Participants	505 participants n=1151 Participants
Baseline medications Statin	425 participants n=576 Participants	429 participants n=575 Participants	854 participants n=1151 Participants
Baseline medications Renin-angiotensin system inhibitor	345 participants n=576 Participants	341 participants n=575 Participants	686 participants n=1151 Participants

PRIMARY outcome

Timeframe: 4.0 years (interquartile range, 3.6 to 4.3) years

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=576 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=575 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Number of Participants With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment	131 Participants	168 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=576 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=575 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Number of Participants With the Individual Component of the Composite Primary Outcome: Development of Referable Diabetic Retinopathy or Maculopathy	130 Participants	168 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=576 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=575 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Number of Participants With the Individual Component of Composite Primary Outcome: Treatment for Diabetic Retinopathy or Maculopathy	17 Participants	28 Participants

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=576 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=575 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Number of Participants With Any Progression of Diabetic Retinopathy or Maculopathy Across the NHS Scotland Retinopathy Grading Scale	185 Participants	231 Participants

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=576 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=575 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Number of Participants With Referable Maculopathy (Exudates or Blot Haemorrhages Within One Disc Diameter of the Fovea)	107 Participants	149 Participants

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=576 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=575 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Number of Participants With The Development of Macular Oedema	22 Participants	43 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=555 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=557 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Visual Acuity	0.06 LogMAR Interval 0.05 to 0.07	0.05 LogMAR Interval 0.05 to 0.06

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=491 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=498 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Visual Function, Based on the National Eye Institute Visual Functioning Questionnaire 25 (VFQ-25).	90 score on a scale Interval 89.0 to 91.0	89 score on a scale Interval 89.0 to 90.0

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=490 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=495 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Quality of Life, Based on the EQ-5D Index Score	0.75 score on a scale Interval 0.73 to 0.76	0.75 score on a scale Interval 0.74 to 0.76

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=491 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=495 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Quality of Life, Based on the EQ-5D Visual Analogue Scale.	75 score on a scale Interval 74.0 to 76.0	76 score on a scale Interval 75.0 to 77.0

SECONDARY outcome

Timeframe: 2 years

Population: Comparisons among all randomised participants of the effects of allocation to fenofibrate versus placebo over 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.

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=576 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=575 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Cost to the Health Service	3566 GBP (British Pounds) Interval 3088.0 to 4364.0	3820 GBP (British Pounds) Interval 3052.0 to 4749.0

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=576 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=575 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Cost-effectiveness (Incremental Cost Per QALY Gained)	5.434 Years gained Interval 5.332 to 5.54	5.419 Years gained Interval 5.319 to 5.525

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=420 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=419 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Number of Participants in Subgroup Sex - Male With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment	99 Participants	121 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=156 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=156 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Number of Participants in Subgroup Sex - Female With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment	32 Participants	47 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=249 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=264 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Number of Participants in Subgroup Age <60y With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment	68 Participants	93 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=327 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=311 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Number of Participants in Subgroup Age ≥60y With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment.	63 Participants	75 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=154 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=151 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Number of Participants in Subgroup - Type 1 Diabetes With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment	38 Participants	45 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=422 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=424 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Number of Participants in Subgroup - Type 2 or Other Type of Diabetes With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment	93 Participants	123 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=130 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=131 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Number of Participants in Subgroup - eGFR <60 mL/Min/1.73m^2 With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment	17 Participants	32 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=446 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=444 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Number of Participants in Subgroup - eGFR ≥60 mL/Min/1.73m^2 With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment	114 Participants	136 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=361 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=346 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Number of Participants in Subgroup - HbA1c <70 mmol/Mol With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment	63 Participants	81 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=177 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=193 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Number of Participants in Subgroup - HbA1c ≥70 mmol/Mol With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment	57 Participants	79 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=38 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=36 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Number of Participants in Subgroup - HbA1c Unknown With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment	11 Participants	8 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=576 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=575 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Number of Participants in Subgroup With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment, Within 1 Year of Randomization	45 Participants	63 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=525 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=509 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Number of Participants in Subgroup With Progression to Referable Diabetic Retinopathy or Maculopathy, or Treatment, After 1 Year From Randomization	86 Participants	105 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

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)

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=462 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=474 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Percentage Change in Urine Albumin:Creatinine Ratio	13.6 mg/g Interval 12.1 to 15.3	15.5 mg/g Interval 13.8 to 17.5

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=576 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=575 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Number of Participants With Occurrence of Major Cardiovascular Events (Myocardial Infarction, Stroke, Coronary or Peripheral Revascularisation)	45 Participants	43 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 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 \[through or proximal to the ankle\]).

Outcome measures

Outcome measures
Measure	Fenofibrate 145 mg n=576 Participants Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=575 Participants Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Number of Participants With Occurrence of Non-traumatic Lower Limb Amputations	4 Participants	11 Participants

Adverse Events

Fenofibrate 145 mg

Serious events: 208 serious events

Other events: 17 other events

Deaths: 35 deaths

Placebo Oral Tablet

Serious events: 204 serious events

Other events: 21 other events

Deaths: 38 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Fenofibrate 145 mg n=576 participants at risk Fenofibrate 145 mg: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)	Placebo Oral Tablet n=575 participants at risk Placebo Oral Tablet: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)
Eye disorders Eye disorders	0.35% 2/576 • 4 years Data collected were: (i) all deaths, (ii) all serious adverse events (AEs), (iii) all reasons for stopping study treatment (serious and non-serious AEs). It was pre-specified that it was only mandatory to record non-serious AEs if they led to cessation of study treatment. These are listed under 'Other AEs' below. AEs are reported according to MedDRA System Organ Class.	0.35% 2/575 • 4 years Data collected were: (i) all deaths, (ii) all serious adverse events (AEs), (iii) all reasons for stopping study treatment (serious and non-serious AEs). It was pre-specified that it was only mandatory to record non-serious AEs if they led to cessation of study treatment. These are listed under 'Other AEs' below. AEs are reported according to MedDRA System Organ Class.
Gastrointestinal disorders Gastrointestinal disorders	1.0% 6/576 • 4 years Data collected were: (i) all deaths, (ii) all serious adverse events (AEs), (iii) all reasons for stopping study treatment (serious and non-serious AEs). It was pre-specified that it was only mandatory to record non-serious AEs if they led to cessation of study treatment. These are listed under 'Other AEs' below. AEs are reported according to MedDRA System Organ Class.	0.87% 5/575 • 4 years Data collected were: (i) all deaths, (ii) all serious adverse events (AEs), (iii) all reasons for stopping study treatment (serious and non-serious AEs). It was pre-specified that it was only mandatory to record non-serious AEs if they led to cessation of study treatment. These are listed under 'Other AEs' below. AEs are reported according to MedDRA System Organ Class.
Hepatobiliary disorders Hepatobiliary disorders	0.00% 0/576 • 4 years Data collected were: (i) all deaths, (ii) all serious adverse events (AEs), (iii) all reasons for stopping study treatment (serious and non-serious AEs). It was pre-specified that it was only mandatory to record non-serious AEs if they led to cessation of study treatment. These are listed under 'Other AEs' below. AEs are reported according to MedDRA System Organ Class.	0.17% 1/575 • 4 years Data collected were: (i) all deaths, (ii) all serious adverse events (AEs), (iii) all reasons for stopping study treatment (serious and non-serious AEs). It was pre-specified that it was only mandatory to record non-serious AEs if they led to cessation of study treatment. These are listed under 'Other AEs' below. AEs are reported according to MedDRA System Organ Class.
Investigations Investigations	0.17% 1/576 • 4 years Data collected were: (i) all deaths, (ii) all serious adverse events (AEs), (iii) all reasons for stopping study treatment (serious and non-serious AEs). It was pre-specified that it was only mandatory to record non-serious AEs if they led to cessation of study treatment. These are listed under 'Other AEs' below. AEs are reported according to MedDRA System Organ Class.	0.52% 3/575 • 4 years Data collected were: (i) all deaths, (ii) all serious adverse events (AEs), (iii) all reasons for stopping study treatment (serious and non-serious AEs). It was pre-specified that it was only mandatory to record non-serious AEs if they led to cessation of study treatment. These are listed under 'Other AEs' below. AEs are reported according to MedDRA System Organ Class.
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders	0.52% 3/576 • 4 years Data collected were: (i) all deaths, (ii) all serious adverse events (AEs), (iii) all reasons for stopping study treatment (serious and non-serious AEs). It was pre-specified that it was only mandatory to record non-serious AEs if they led to cessation of study treatment. These are listed under 'Other AEs' below. AEs are reported according to MedDRA System Organ Class.	0.35% 2/575 • 4 years Data collected were: (i) all deaths, (ii) all serious adverse events (AEs), (iii) all reasons for stopping study treatment (serious and non-serious AEs). It was pre-specified that it was only mandatory to record non-serious AEs if they led to cessation of study treatment. These are listed under 'Other AEs' below. AEs are reported according to MedDRA System Organ Class.
Nervous system disorders Nervous system disorders	0.69% 4/576 • 4 years Data collected were: (i) all deaths, (ii) all serious adverse events (AEs), (iii) all reasons for stopping study treatment (serious and non-serious AEs). It was pre-specified that it was only mandatory to record non-serious AEs if they led to cessation of study treatment. These are listed under 'Other AEs' below. AEs are reported according to MedDRA System Organ Class.	0.52% 3/575 • 4 years Data collected were: (i) all deaths, (ii) all serious adverse events (AEs), (iii) all reasons for stopping study treatment (serious and non-serious AEs). It was pre-specified that it was only mandatory to record non-serious AEs if they led to cessation of study treatment. These are listed under 'Other AEs' below. AEs are reported according to MedDRA System Organ Class.
Pregnancy, puerperium and perinatal conditions Pregnancy, puerperium and perinatal conditions	0.00% 0/576 • 4 years Data collected were: (i) all deaths, (ii) all serious adverse events (AEs), (iii) all reasons for stopping study treatment (serious and non-serious AEs). It was pre-specified that it was only mandatory to record non-serious AEs if they led to cessation of study treatment. These are listed under 'Other AEs' below. AEs are reported according to MedDRA System Organ Class.	0.17% 1/575 • 4 years Data collected were: (i) all deaths, (ii) all serious adverse events (AEs), (iii) all reasons for stopping study treatment (serious and non-serious AEs). It was pre-specified that it was only mandatory to record non-serious AEs if they led to cessation of study treatment. These are listed under 'Other AEs' below. AEs are reported according to MedDRA System Organ Class.
Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders	0.17% 1/576 • 4 years Data collected were: (i) all deaths, (ii) all serious adverse events (AEs), (iii) all reasons for stopping study treatment (serious and non-serious AEs). It was pre-specified that it was only mandatory to record non-serious AEs if they led to cessation of study treatment. These are listed under 'Other AEs' below. AEs are reported according to MedDRA System Organ Class.	0.17% 1/575 • 4 years Data collected were: (i) all deaths, (ii) all serious adverse events (AEs), (iii) all reasons for stopping study treatment (serious and non-serious AEs). It was pre-specified that it was only mandatory to record non-serious AEs if they led to cessation of study treatment. These are listed under 'Other AEs' below. AEs are reported according to MedDRA System Organ Class.
Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders	0.00% 0/576 • 4 years Data collected were: (i) all deaths, (ii) all serious adverse events (AEs), (iii) all reasons for stopping study treatment (serious and non-serious AEs). It was pre-specified that it was only mandatory to record non-serious AEs if they led to cessation of study treatment. These are listed under 'Other AEs' below. AEs are reported according to MedDRA System Organ Class.	0.52% 3/575 • 4 years Data collected were: (i) all deaths, (ii) all serious adverse events (AEs), (iii) all reasons for stopping study treatment (serious and non-serious AEs). It was pre-specified that it was only mandatory to record non-serious AEs if they led to cessation of study treatment. These are listed under 'Other AEs' below. AEs are reported according to MedDRA System Organ Class.

Additional Information

Associate Professor David Preiss

Nuffield Department of Population Health, University of Oxford

Phone: 01865 743 743

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place