Adjuvant Anti-Mineralocorticoid-Receptor Treatment in Anti-VEGF Refractory Neovascular Age-Related Macular Degeneration

Prospective, non-comparative, mono-center pilot study. Patients with neovascular age-related macular degeneration (nAMD), responding insufficiently to the maximal standard care with monthly intravitreal anti-VEGF injections are given adjuvant oral mineralocorticoid receptor antagonists for 4 months and observed for any changes in vision or retinal structure during the 4 months of adjuvant treatment, plus 2 additional months without adjuvant treatment.

Study Overview

• Status: Completed
• Conditions: Neovascular Age-related Macular Degeneration
• Intervention / Treatment: Drug: Spironolactone 50 MG

Detailed Description

Hypothesis Systemic anti-Mineralocorticoid-Receptor treatment may be a valuable adjuvant treatment in anti-VEGF refractory nAMD, potentially allowing for better absorption of the exudative fluid.

Aim To estimate the effect of systemic anti-Mineralocorticoid-Receptor treatment on eyes with nAMD which have remained exudative despite monthly anti-VEGF treatment for at least 6 months prior to enrolment.

Objectives Primary objective

• To calculate the changes induced in retinal thickness following adjunct systemic anti-Mineralocorticoid-Receptor treatment Secondary objective

• To calculate the changes induced following adjunct systemic anti-Mineralocorticoid-Receptor treatment in the following ocular parameters

  • Thickness of the neuro-retina (foveal)
  • Amount of subretinal fluid (foveal and highest elevation)
  • Height of retinal pigment epithelium detachment (foveal and highest elevation)
  • Central (Subfoveal) choroidal thickness, and at 500um nasal and temporal to the fovea
  • Presence / absence of exudative signs on OCT, according to the type of fluid (intraretinal cysts, subretinal fluid)
  • Best corrected visual acuity (number of letters)

Medications:

Standard medical treatment (monthly intravitreal injections with anti-VEGF) will be continued during this trial, no current medications will be altered. The medication spironolactone, an MR antagonist will be added to the currently prescribed medications (phase IV). The standard dose of 50mg once daily per os will be prescribed for 3 months (first week 25mg only for treatment introduction and safety), tapered during month 4 (25mg once daily).

In the case of a patient current taking a medication with contra-indications for this drug, then the conflicting medication will be exchanged for an equivalent treatment option, where this is not possible then these patients will be excluded from the study. The patient will be withdrawn from the study in case of any serious side effects attributable to spironolactone (increased K+ above 5.5mmol/l).

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of neovascular age-related macular degeneration, as confirmed on angiography by a retinal specialist (IM or AA)
• Aged more than 50 years (inherent to AMD)
• Unresponsive to maximal (monthly) anti-VEFG treatment (Ranibizumab or Aflibercept) for at least 6 months: persistant intra- or subretinal fluid on spectral domain optical coherence tomography at each visit 1 month after last injection.
• Treatment with anti-VEGF for nAMD for at least 12 months
• No contra-indications for adjunctive Spironolactone treatment

Exclusion Criteria:

• Confounding retinal pathology eg. myopic chorioretinopathy, diabetic retinopathy, vascular occlusion, retinal dystrophy and other retinal pathology
• Polypoidal choroidal vasculopathy
• Vitreomacular traction
• Poor quality OCT (image quality does not allow the grading / measures on OCT)
• High arterial pressure (>160/100)
• K+>5.0 mmol/l at baseline
• Na+ <135 mmol/l at baseline
• Creatinine clearance under 30mL/min (calculation : coefficient*(140-age)*weight/creatinine in the serum; coefficient = 1.23 for males and 1.04 for females)
• Acute renal failure
• Renal dialysis
• Non-specified renal problem
• Arrhythmia
• Cardiovascular comorbidity with thromboembolic risk
• Known hypersensitivity to Spironolactone
• Ongoing medication with eplerenone (Inspra®)
• Decompensated hepatic cirrhosis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Single treatment arm	Drug: Spironolactone 50 MG; oral administration of Spironolactone, 25mg daily for 1 week, then 50mg daily until visit Month 3, followed by 25mg daily from visit Month 3 to visit Month 4

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Retinal thickness change	retinal thickness in micrometers measured from the internal limiting membrane (ILM) to Bruch's membrane on optical coherence tomography	Month 3, Month 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best-corrected visual acuity	on ETDRS chart	Month 3, Month 6
central retinal thickness	automatic values from SD-OCT after segmentation correction, in micrometers	Month 3, Month 6
central retinal volume	automatic values from SD-OCT after segmentation correction	Month 3, Month 6
foveal retinal thickness	manual measurement in micrometers from ILM to Bruch membrane at the fovea	Month 3, Month 6
maximum neuroretinal thickness with cystic changes	manual measure in micrometers from ILM to outer segments of photoreceptors	Month 3, Month 6
subretinal fluid thickness	manual measure in micrometers between outer segment layer and pigment epithelium	Month 3, Month 6
pigment epithelium detachment height	manual measure in micrometers from the RPE layer to Bruch's membrane	Month 3, Month 6
subfoveal choroidal thickness	manual measure in micrometers on enhanced depth OCT imaging	Month 3, Month 6

Collaborators and Investigators

• Sponsor: Dr Irmela MANTEL

Study record dates

Study Major Dates

• Study Start (Actual): September 19, 2014
• Primary Completion (Actual): September 22, 2015
• Study Completion (Actual): September 22, 2015

Study Registration Dates

• First Submitted: November 13, 2018
• First Submitted That Met QC Criteria: November 15, 2018
• First Posted (Actual): November 16, 2018

Study Record Updates

• Last Update Posted (Actual): November 16, 2018
• Last Update Submitted That Met QC Criteria: November 15, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Eye Diseases; Retinal Degeneration; Retinal Diseases; Macular Degeneration; Wet Macular Degeneration; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Spironolactone
• Other Study ID Numbers: 184/14

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No