Simvastatin is part of the pharmacotherapeutic group of HMG-CoA reductase inhibitors (ATC-Code: C10A A01). Simvastatin is licensed within the EU for hypercholesterolemia and cardiovascular prevention but for this trial its use will be outside its licensed indication. Oral Simvastatin will be taken 40mg daily (one tablet in the evening) for 4 weeks and then at week 4 up titrated to 80mg daily (two tablets in the evening.

Matched Placebo (one tablet in the evening) for 4 weeks and then at week 4 up titrated to two tablets daily in the evening.

Secondary Progressive Multiple Sclerosis

Simvastatin 40mg for first 4 weeks and 80mg (if tolerated) thereafter up to 17 weeks

Simvastatin

Department of Neuroinflammation, UCL Institute of Neurology

Simvastatin in Secondary Progressive Multiple Sclerosis

A Double-blind, Randomised, Placebo-controlled Single-site Study of High Dose Simvastatin Treatment for Secondary Progressive Multiple Sclerosis: Impact on Vascular Perfusion and Oxidative Damage

compared between patients on simvastatin or placebo using multiple linear regressions. ASL is an MRI method that allows non-invasive measurement of CBF using inversion of arterial water spins as a tracer.The aim is to explore whether subtlechangesinCBFoccur over time between placebo and simvastatin treated patients, including potential waning of the effects of the drug over time.

To explore whether statin treatment reduces glutamate levels. These will be measured applying an advanced MRI technique called spectroscopy which detects biochemical changes in the brain.

To establish if Adaptive Optics Scanning Laser Ophthalmoscope (AOSLO) measurements of blood flow are useful correlates for cerebral blood flow measurement on and off treatment.

To establish whether Arterial Spin Labelling (ASL) measurements of blood flow are useful correlates for cerebral blood flow measurement on and off treatment. The cerebral arterial hemodynamic measure bolus arrival time will be measured, as the time from labeling of blood in feeding arteries to its first arrival in the capillary network of the voxel of interest. This will be supported by a questionnaire investigating factors that influence brain perfusion (related to lifestyle and health, mental state, personality and cognition and use of caffeine and recreational drugs) to improve the accuracy and to facilitate the interpretation of perfusion-derived parameters.

To explore whether statin reduce the rate of brain atrophy, including grey matter volumes, on MRI (excluding the effect of pseudo-atrophy, which is a temporary response to the drug rather than an actual loss of tissue). The MRI images will be analysed using softwares developed at UCL to quantify the amount of brain tissue loss over time.

Clinician observed expanded disability status score (EDSS) is a method of quantifying disability in MS and records changes in disability over time. The EDSS scale ranges from 0 (no disability) to 10 (death due to MS) in 0.5 unit increments that represent higher levels of disability. Scoring is based on an examination by a neurologist and encompasses pyramidal, cerebellar, brainstem, sensory, bowel/bladder function in addition to visual, cerebral and other functions. Changes in score (including no changes) will be recorded to determine progression of disability.

Multiple Sclerosis Function Composite (MSFC) includes the 25 foot timed foot walk (25TFW), which involves marking a 25-foot distance in an unobstructed hallway; an assistive device (if needed) may be used by the participant and recorded. Their speed is then timed up to a time limit of 3 mins in both directions. Changes in scores will be recorded over the time-points described.

Multiple Sclerosis Function Composite (MSFC) includes the 9 hole peg test (9HPT). The 9-HPT is a quantitative measure of upper extremity (arm and hand) function. Both the dominant and non-dominant hands are tested twice (two consecutive trials of the dominant hand, followed immediately by two consecutive trials of the non-dominant hand). It is important that the 9-HPT be administered on a solid table (not a rolling hospital bedside table) and that the 9-HPT apparatus be anchored (e.g., with Dycem). The pegs are selected one at a time, using one hand only, and put into the holes as quickly as possible in any order until all the holes are filled. Then, without pausing, the pegs are removed one at a time and returned to the container. This is timed and recorded at the time-points described.

Patient reported multiple sclerosis impact scale version 2 (MSIS-29v2) is a self-administered questionnaire covering 29 items that asks to what degree MS has impacted the person physically and mentally over the past two weeks.

Patient reported Multiple Sclerosis Walking Score version 2 (MSWSv2) is a 12 item self-administered questionnaire that measures walking performance over the previous two weeks. Each items is summed to generate a total score which is then transformed to a scale ranging from 0 to 100. Higher scores indicate greater impact on walking. Changes in scores will be recorded over the time-points described.

The EuroQol Health Related Quality of Life (EQ5d5L) is a five-item questionnaire that assesses mobility, self-care, pain/discomfort, anxiety/depression and a person's usual activities. It incorporates an additional visual analogue scale (VAS) which enables a calculation of quality of life years (QALY) so health economic analyses can be performed. Each item of the EQ5D5L is responded to on a scale as follows: no problems, slight problems, moderate problems, severe problems and extreme problems. Changes in scores will be recorded over the time-points described.

Blood samples from these patients will be taken at baseline and at weeks 4, 16 and 20 to investigate the effect of statins on vascular leakage and free radical damage. Biomarkers will be determined as follows: (i) For RNA/DNA oxidative damage serum levels of 8-hydroxyguanosine (8-OHG)/8-hydroxydeoxyguanosine (8-OHdG); (ii) Protein oxidative damage will be determined by assaying plasma proteins for nitrotyrosine and carbonyl content; and (iii) Detection of lipid oxidative damage by assaying for the advanced lipid peroxidation end products 4-hydroxynonenal (4-HNE or HNE), malondialdehyde (MDA), 8-iso-prostaglandin F2α and thiobarbituric acid reactive substances (TBARS) (Miller et al., 2012).

Frontal Assessment Battery (FAB). The FAB is a brief tool that can be used at the bedside or in a clinic setting to assist in discriminating between dementias with a frontal dysexecutive phenotype and Dementia of Alzheimer‟s Type (DAT).
The FAB has validity in distinguishing Fronto-temporal type dementia from DAT in mildly demented patients (MMSE > 24). Total score is from a maximum of 18, higher scores indicating better performance. Changes in scores will be recorded over the time-points described.

Symbol Digit Modalities Test (SDMT) is measure of cognitive impairment. The subject is asked to match single digits to symbols using a key as a guide that pairs the numbers to the symbols. They are presented with a page headed by a key that pairs the single digits 1-9 with nine symbols and they then write or orally report their responses in a scoring form. It can be administered in oral and written form and is timed and guided by a trained examiner ie. suitably qualified member of the research team. Changes in scores will be recorded over the time-points described.

Oxygen saturation of retinal vessels will be measured using the Oxymap T1. The device measures oxygen saturation quickly and non-invasively by taking two simultaneous images of the retina using two different wavelengths to determine the amount of oxygen bound haemoglobin in the blood.

Density of retinal vessels will be measured using optical coherence tomography angiography (OCTA). OCTA is a method of retinal imaging which is non-invasive and involves the patient holding their head still and staring at a dim light while imaging takes place.

Inner retinal thickness will be measured using optical coherence tomography (OCT). OCT is a method of retinal imaging which is non-invasive and involves the patient holding their head still and staring at a dim light while imaging takes place.

To assess changes in axonal parameters, such as fiber orientation dispersion and axonal densities occurring over time using NODDI, an advanced MRI technique that reflects the microstructural complexity of dendrites and axons in vivo.

To assess whether patients develop new lesions or pre-existing lesions enlarge over time as surrogate markers for the inflammatory process.

No identifiable patient information will be supplied to other researchers external to the organisation.

University College, London

MS Society

Patients were administered 0.5-mg IVR injections monthly for 6 months.

Totally, 25 eyes of 25 patients (13 males, 12 females, mean age 63.80±11.45 years; range: 41–80 years) were included in the study

Baseline Characteristics

Sex: Female, Male

Race (NIH/OMB)

Duration of Diabetes Mellitus(DM) (year)

HbA1c(%)

ETDRS charts present a series of five letters of equal difficulty on each row for a total of 14 lines (70 letters). An ETDRS letter score can be calculated as follows: when 20 or more letters are read correctly at 4.0 m, the visual acuity letter score is equal to the total number of letters read correctly at 4.0 m plus 30. If fewer than 20 letters are read correctly at 4.0 m, the visual acuity letter score is equal to the total number of letters read correctly at 4.0 m plus the total number of letters read correctly at 1.0 m in the first six lines.

BCVA (ETDRS letters)

Central retinal thickness (CRT) was measured using optical coherence tomography

CRT (um)

Total microaneurysms (number)

MA turnover was calculated by adding the MA formation rate (number of new MAs detected/month) to the MA disappearance rate (number of MAs that resolved/month)

Microaneurysm-turnover

Perifoveal non-perfused area (mm^2)

BCVA was performed using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at baseline and 6 months. The BCVA compare the degree of improvement or worsening of vision at baseline and 6 months. (value at 6 months minus value at baseline)

Before the treatment regimen, assessment of BCVA using the ETDRS charts.

BCVA Baseline

After completion of the treatment regimen during 6 months, assessment of BCVA using the ETDRS charts.

BCVA Resulte

The Best Corrected Visual Acuity (BCVA)

CRT was performed using OCT at each visit. The OCT measured at each visit was analyzed statistically. the CMT compare the degree of improvement or worsening of vision at baseline and 6 months. (value at 6 months minus value at baseline)

Before the treatment regimen, assessment of CRT using the OCT.

CRT Baseline

After the treatment regimen during 6 months, assessment of CRT using the OCT.

CRT Resulte

Central Macular Thickness(CMT)

The number of MAs in individual retinas were evaluated during 6 months using fundus photography and FA imaging. The Retmarker software was used for automatic measurement and analysis of changes in number and extent of MAs on fundus photographs and to calculate the total number and turnover of MAs. Changes in MAs were analyzed statistically. the total number of MAs compare the degree of improvement or worsening of vision at baseline and 6 months. (value at 6 months minus value at baseline)

The number of MAs in individual retinas were evaluated at first visit using fundus photography and FA imaging. The Retmarker software was used for automatic measurement and analysis of changes in number and extent of MAs on fundus photographs and to calculate the total number and turnover of MAs.

Total MA Baseline

The number of MAs in individual retinas were evaluated during 6 months using fundus photography and FA imaging. The Retmarker software was used for automatic measurement and analysis of changes in number and extent of MAs on fundus photographs and to calculate the total number and turnover of MAs.

Total MA Resulte

The Total Number of Microaneurysm

number of new MAs detected/month The MAs in individual retinas were evaluated at 6 months using fundus photography. The Retmarker (version 1.0.2 by Retmarker Ltd, Coimbra, Portugal) software was used for automatic measurement and analysis of changes in number and extent of MAs on fundus photographs and to calculate the total number and turnover of MAs. MA turnover was calculated by adding the MA formation rate (number of new MAs detected/month) to the MA disappearance rate (number of MAs that resolved/month). The microaneurysm formation rate compare the degree of improvement or worsening of vision at baseline and 6 months. (value at 6 months minus value at baseline)

The Retmarker software was used for automatic measurement and analysis of MA formation at first visit.

The MA Formation Rate Baseline

The Retmarker software was used for automatic measurement and analysis of MA formation during monthly 6 months

The MA Formation Rate Resulte

The Microaneurysm Formation Rate

Number of MAs that resolved/month The MAs in individual retinas were evaluated at 6 months using fundus photography. The Retmarker (version 1.0.2 by Retmarker Ltd, Coimbra, Portugal) software was used for automatic measurement and analysis of changes in number and extent of MAs on fundus photographs and to calculate the total number and turnover of MAs. MA turnover was calculated by adding the MA formation rate (number of new MAs detected/month) to the MA disappearance rate (number of MAs that resolved/month). The microaneurysm disappearance rate compare the degree of improvement or worsening of vision at baseline and 6 months. (value at 6 months minus value at baseline)

The Retmarker software was used for automatic measurement and analysis of MA disappearance at first visit.

The MA Disappearance Rate Baseline

The Retmarker software was used for automatic measurement and analysis of MA disappearance during monthly 6 months.

The MA Disappearance Rate Resulte

The Microaneurysm Disappearance Rate

The microaneurysm formation rate + The microaneurysm disappearance rate The MAs in individual retinas were evaluated at 6 months using fundus photography. The Retmarker (version 1.0.2 by Retmarker Ltd, Coimbra, Portugal) software was used for automatic measurement and analysis of changes in number and extent of MAs on fundus photographs and to calculate the total number and turnover of MAs. MA turnover was calculated by adding the MA formation rate (number of new MAs detected/month) to the MA disappearance rate (number of MAs that resolved/month). The microaneurysm turnover compare the degree of improvement or worsening of vision at baseline and 6 months. (value at 6 months minus value at baseline)

The Retmarker software was used for automatic measurement and analysis of MA turnover at first visit.

The Microaneurysm Turnover Baseline

The Retmarker software was used for automatic measurement and analysis of MA turnover during monthly 6 months.

The Microaneurysm Turnover Results

The Microaneurysm Turnover

Using ImageJ software (version 1.52a) by FAG image. The Perifoveal non-perfusion area in FAG compare the degree of improvement or worsening of vision at baseline and 6 months. (value at 6 months minus value at baseline)

The perifoveal non-perfused areas in individual retinas were evaluated at first visit using fundus photography and FA imaging. The Retmarker software was used for automatic measurement and analysis of changes in number and extent of MAs on fundus photographs and to calculate the total number and turnover of MAs

Perifoveal Non-perfusion Area Baseline

The perifoveal non-perfused areas in individual retinas were evaluated during monthly 6 months using fundus photography and FA imaging. The Retmarker software was used for automatic measurement and analysis of changes in number and extent of MAs on fundus photographs and to calculate the total number and turnover of MAs

Perifoveal Non-perfusion Area Results

Perifoveal Non-perfusion Area in FAG (mm²)

Systemic adverse events (MI, CVA, etc), Ocular adverse events (retinal detachment, RPE tear, endophthalmitis, uveitis, vitreous hemorrhage, subretinal hemorrhage, cataract , IOP elevation, etc) at baseline and each visit.

Complications and adverse events on patients were evaluated.

Safety Parameters Results

Safety Parameters

25 eyes of 25 type 2 diabetes mellitus patients with macular edema were included between August 2016 and February 2019. For 6 months, patients were administered 0.5-mg intra-vitreal Lucentis(Ranibizumab) injections monthly.

Lucentis(Ranivizumab)

Overall Study

Dr. Seung Joon Lee

Systemic adverse events (MI, CVA, etc), Ocular adverse events (retinal detachment, RPE tear, endophthalmitis, uveitis, vitreous hemorrhage, subretinal hemorrhage, cataract , IOP elevation, etc) on patients were evaluated.

Adverse Event

Nonproliferative Diabetic Retinopathy

Local anesthesia with T-caine with Saline irrigation. Routine eye drap was done by potadine-cotton ball. Lucentis injected to vitreous cavity, finally dressing.

Lucentis

Effects of Intravitreal Ranibizumab for Macular Edema With Nonproliferative Diabetic Retinopathy

Prospective, Single-center, Six-month Study of Intravitreal Ranibizumab for Macular Edema With Nonproliferative Diabetic Retinopathy: Effects on Microaneurysm Turnover and Non-perfused Retinal Area

Yun-Sik Yang

MD, PhD

Wonkwang University Hospital

Novartis Korea Ltd.

Focal laser photocoagulation (modified Early Treatment Diabetic Retinopathy Study (ETDRS) technique)

Posterior peribulbar injection of 40 mg triamcinolone (Kenalog)

Anterior peribulbar injection of 20 mg triamcinolone

Posterior peribulbar injection of 40 mg triamcinolone followed after one month by laser

Anterior peribulbar injection of 20 mg triamcinolone followed after one month by laser

Modified Early Treatment diabetic retinopathy Study technique (m-ETDRS, Laser burns-50 microns, gray intensity Multiple settings (all completed in single setting).

Focal Laser Photocoagulation

Posterior Peribulbar Injection of 40 mg Triamcinolone

Anterior Peribulbar Injection of 20 mg Triamcinolone

Posterior peribulbar injection of 40 mg triamcinolone followed by focal photocoagulation after one month

Posterior Peribulbar Injection of 40 mg Triamcinolone + Laser

Anterior peribulbar injection of 20 mg triamcinolone followed by focal photocoagulation after one month

Anterior Peribulbar Injection of 20 mg Triamcinolone + Laser

Total

Race/Ethnicity, Customized

Cystoid Abnormality on Ocular Coherence Tomography (OCT)

Diabetes Type

Best corrected visual acuity letter score as measured by a certified tester using an electronic early treatment diabetic retinopathy study (e-ETDRS) method and approximate Snellen equivalent. Best value on the scale is 97, worst value 0.

Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity

Received Prior Focal Photocoagulation

Received Prior Scatter (Panretinal) Photocoagulation

Ocular Coherence Tomography (OCT) images were obtained at each visit following pupil dilation by a certified operator using the OCT3 machine (Carl Zeiss Meditec Inc., Dublin, CA). Scans were 6 mm length and included the 6 radial line pattern for quantitative measures and the cross hair pattern (6-12 to 9-3 o'clock) for qualitative assessment of retinal morphology.

Subretinal Fluid on Ocular Coherence Tomography (OCT)

Measured by Ocular Coherence Tomography (OCT). OCT images were obtained at each visit following pupil dilation by a certified operator using the OCT3 machine (Carl Zeiss Meditec Inc., Dublin, CA). Scans were 6 mm length and included the 6 radial line pattern for quantitative measures and the cross hair pattern (6-12 to 9-3 o'clock) for qualitative assessment of retinal morphology.

Central Subfield Thickness

Duration of Diabetes

Hemoglobin A1c

Intraocular Pressure (mm Hg)

Baseline Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) Visual Acuity Letter Score: best value = 97; letter score worst value = 0

Mean visual acuity letter score

Total Retinal Volume (mm^3)

Change in Central Subfield Thickening from Baseline measured on Optical Coherence Tomography (OCT). OCT images were obtained at each visit following pupil dilation by a certified operator using the OCT3 machine (Carl Zeiss Meditec Inc., Dublin, CA). Scans were 6 mm length and included the 6 radial line pattern for quantitative measures and the cross hair pattern (6-12 to 9-3 o'clock) for qualitative assessment of retinal morphology. Negative changes represent a decrease in retinal thickening.

Change in Central Subfield Thickening From Baseline Through 34 Weeks

Number of eyes that were retreated at 17 weeks. According to the protocol, primary criterion for retreatment was central subfield thickness >=250 microns or macular edema was still present according to the investigator's judgment.

Persistence/Recurrence of Diabetic Macular Edema (DME) Either Retreated or Meeting Criteria for Retreatment at 17 Weeks

Change in visual acuity letter score as measured by a certified tester using an electronic visual acuity testing machine based on the electronic Early Treatment for Diabetic Retinopathy Study(E-ETDRS) technique. Letter score best value = 97 and worst value = 0; an increase in a letter score by 10 is considered clinically significant. Negative changes represent a worsening in visual acuity.

Change in Visual Acuity Letter Score From Baseline Through 34 Weeks

Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) mean visual acuity letter score: best value = 97; letter score worst value = 0

Mean Visual Acuity Letter Score at Each Follow-up Visit

Number of eyes that had a reduction in central subfield retinal thickness by ≥ 50% at each follow-up. Change in Central Subfield Thickening from Baseline measured on Optical Coherence Tomography (OCT). OCT images were obtained at each visit following pupil dilation by a certified operator using the OCT3 machine (Carl Zeiss Meditec Inc., Dublin, CA). Scans were 6 mm length and included the 6 radial line pattern for quantitative measures and the cross hair pattern (6-12 to 9-3 o'clock) for qualitative assessment of retinal morphology.

Reduction of ≥ 50% in Retinal Thickening in the Central Subfield From Baseline Through 34 Weeks

Primary criterion for retreatment is central subfield thickness >=250 microns. Central subfield thickness of <250 microns indicates no need for retreatment. Change in Central Subfield Thickening from Baseline measured on Optical Coherence Tomography (OCT). OCT images were obtained at each visit following pupil dilation by a certified operator using the OCT3 machine (Carl Zeiss Meditec Inc., Dublin, CA). Scans were 6 mm length and included the 6 radial line pattern for quantitative measures and the cross hair pattern (6-12 to 9-3 o'clock) for qualitative assessment of retinal morphology.

Central Subfield Thickness <250 Microns From Baseline Through 34 Weeks

4-Week Visit

8-Week Visit

17-Week Visit

34-Week Visit

Adam R. Glassman, M.S., Director

Diabetic Macular Edema

Focal laser photocoagulation (modified Early Treatment Diabetic Retinopathy Study technique)

uveitis/hypoxia

Simvastatin in Secondary Progressive Multiple Sclerosis

Effects of Intravitreal Ranibizumab for Macular Edema With Nonproliferative Diabetic Retinopathy

A Pilot Study of Peribulbar Triamcinolone Acetonide for Diabetic Macular Edema

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