JCHR

Full Protocol

 

Study Objective

 

 Primary Objective:

1.  To assess whether treatment with pemafibrate (0.2 mg orally BID) compared with placebo reduces rates of diabetic retinopathy worsening in adults with type 2 diabetes and diabetic retinopathy without neovascularization who are participating in the parent PROMINENT trial. 

 

Secondary Objectives:

1   To assess whether treatment with pemafibrate (0.2 mg orally BID) compared with placebo reduces rates of diabetic macular edema development or visual acuity worsening.

2.  To assess whether treatment with pemafibrate compared with placebo affects safety or tolerability in the cohort of participants with diabetic retinopathy in at least one eye.

 

Study Design and Synopsis of Protocol

A.    Study Design

·         Longitudinal ancillary study to the PROMINENT trial.

 

B.     Major Eligibility Criteria 

·         Already randomized at US or Canadian sites in the PROMINENT study   

a.       Enrollment visit into the ancillary study must be conducted within 3 months of randomization into the PROMINENT trial.

·         Ability to cooperate with dilated ophthalmic examination and imaging procedures

·         At least one eye meets the following study eye inclusion criteria:

a.       ETDRS Diabetic Retinopathy Severity level between 20 and 53 (minimal to severe NPDR), inclusive, according to the investigator and confirmed by central Reading Center grading.

·         Major study eye exclusion criteria are:

a.       Neovascularization on clinical exam or fundus photographs 

b.      Current central-involved DME based on optical coherence tomography  (OCT) central subfield thickness (CST)

                                                              i.      Zeiss Cirrus: CST = 290µm in women or = 305µm in men

                                                            ii.      Heidelberg Spectralis: CST = 305µm in women or = 320µm in men

c.       Major non-diabetic intraocular pathology that in the opinion of the investigator would substantially and adversely affect visual acuity or lead to ocular neovascularization during the course of the study

d.      Anticipated need for intravitreous anti-VEGF, intravitreous corticosteroid, or PRP in the next 6 months following randomization

e.       History of intravitreous anti-VEGF or corticosteroid treatment within the prior year for any indication.

f.        Any history of PRP or vitrectomy

 

Participants may have 1 or 2 study eyes based on how many eyes meet eligibility criteria.

 

C.    Estimated Sample Size

At least 600 individuals are expected to be eligible and to enroll in the study at US and Canadian DRCR.net clinical sites that have geographic proximity to the parent PROMINENT clinical site.  Recruitment will continue until the PROMINENT trial has completed enrollment, with up to  a maximum of 900 enrolling in PROMINENT-Eye

.

 D.    Protocol Summary

 

Participants in the parent PROMINENT study will be referred to partnering DRCR.net sites for comprehensive ophthalmologic examination including visual acuity, fundus photography and spectral domain optical coherence tomography (OCT) to be performed within 3 months of the PROMINENT randomization visit.  Participants who meet eligibility criteria at this visit will be eligible for two or three additional study ophthalmic visits through 4 years (see Table in Section E below). Participants who do not meet ocular eligibility will be discontinued from the ancillary PROMINENT-Eye Study, but not from the parent study.  If intravitreous anti-VEGF or corticosteroid treatment, PRP, or vitrectomy will be administered to a study eye for any indication for the first time since entering the study, when possible, all study procedures should be performed prior to implementing treatment to establish retinopathy severity before therapy is initiated.  Participants who receive treatment will continue follow-up through 4 years.

 

E.     Schedule of Study Visit and Examination Procedures

 

	Screening/ Baselinea	2 yearb ± 2 months	4 yearb ± 2 monthsc	Prior to DME/PDR Treatment Initiationd
Visit and Visit Window
Best corrected visual acuity	X	X	X	X
Eye Exame	X	X	X	X
DRCR.net Fundus Photographye,f	X	X	X	X
Spectral Domain OCTe,g	X	X	X	X
Collection of Adverse Events occurring during the visit	X	X	X	X

1. a. lyses will be performed on the comparison between 7 modified fields and the UWFTo be performed within 3 months of the PROMINENT randomization visit
2. DddfjlsTime from randomization into the PROMINENT trial.
3. If the PROMINENT trial ends before a participant reaches the 4 year visit, one final visit within 3 months of the PROMINENT trial ending will be completed.
4. All study procedures should be performed prior to the initiation of treatment for DME or DR in a study eye. 
5. After pupil dilation
6. The widest camera type available will be used for color fundus photography.
7. Participants may opt out of eye exam particularly if they have recently had an eye exam

 

F.     Outcomes

Primary outcome:    The primary outcome is diabetic retinopathy worsening or DME development (composite outcome) defined as any of the following:

 ·         For participants with 2 study eyes:  3-step worsening on the ETDRS Retinopathy Severity Scale for Persons (Table 1) at a protocol visit

·         For participants with one study eye:  2-step worsening on the ETDRS Retinopathy Severity Scale for Individual Eyes (Table 2) in the study eye at a protocol visit

·         Procedure undertaken for the treatment of PDR at any time (even in the absence of photographic documentation) including PRP, intravitreous anti-VEGF, or vitrectomy in either study eye

·         Treatment initiated for the treatment of DME at any time (even in the absence of OCT documentation) including anti-VEGF, corticosteroids, focal/grid laser, or vitrectomy

·         Development of central-involved DME on OCT with vision loss at the 2 or 4-year visit defined as OCT central subfield thickness above the machine and gender specific thresholds (see Section 2.2.2 for details) with at least a 10% increase in thickness from baseline and visual acuity 20/32 or worse (letter score = 78)

 

Secondary outcomes include a treatment comparison of the following:

 

Participant-Level Outcomes*:

·         Percentage of participants with 3-step diabetic retinopathy worsening on color photos or receiving treatment for PDR in either eye at any time               (irrespective of DME status or treatment)

·         Percentage of participants with 3-step diabetic retinopathy worsening on color photos 

·         Percentage of participants receiving treatment for PDR in either eye at any time

·         Percentage of participants that develop central-involved DME on OCT with vision loss or receive treatment for DME in either eye at any time                  (irrespective of DR status or treatment)

·         Percentage of eyes that develop central-involved DME on OCT with vision loss

·         Percentage of participants receiving treatment for DME in either eye at any time

·         Percentage of participants with at least 1, 2 or 3-line losses in visual acuity in either eye

 

*Relates to either eye for bilateral participants and to the study eye for unilateral participants

 

Eye-Level Outcomes (evaluated only for eyes with baseline ETDRS Severity Levels 20 to 53):

·         Percentage of eyes with diabetic retinopathy worsening, defined as a 2-step worsening on color photos on the eye-level scale,                                         development of central-involved DME on OCT with vision loss, or treatment for DME or PDR

·         Percentage of eyes with diabetic retinopathy worsening on color photos or receiving treatment for PDR at any time (irrespective of DME                          status or treatment)

·         Percentage of eyes with 2-step diabetic retinopathy worsening on color photos

·         Percentage of eyes receiving treatment for PDR at any time

·         Percentage of eyes that develop central-involved DME on OCT with vision loss or receive treatment for DME at any time (irrespective of DR                  status or treatment)

·         Percentage of eyes that develop central-involved DME on OCT with vision loss

·         Percentage of eyes receiving treatment for DME at any time

·         Mean change in OCT central subfield thickness

·         Mean change in visual acuity

·         Percentage of eyes with at least 1, 2 or 3-line losses in visual acuity

 

Safety outcomes:

·         Adverse events and changes from randomization in ALT, AST, CK, or creatinine as a function of the treatment arm (pemafibrate vs. placebo) in participants with diabetic retinopathy in at least one eye

 

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