Development of Novel Clinical Endpoints in Intermediate AMD (MACUSTAR)

• ClinicalTrials.gov Identifier: NCT03349801
• Recruitment Status: Active, not recruiting
• First Posted: November 22, 2017
• Last Update Posted: May 24, 2022
• Sponsor: Frank G. Holz
• Collaborators: Bayer; Moorfields Eye Hospital NHS Foundation Trust; Novartis Pharmaceuticals; Association for Innovation and Biomedical Research on Light and Image; City, University of London; European Clinical Research Infrastructure Network; La Fondation Voir et Entendre; Hoffmann-La Roche; Radboud University Medical Center; University of Sheffield; University College, London; Carl Zeiss Meditec AG; Innovative Medicines Initiative
• Information provided by (Responsible Party): Frank G. Holz, University Hospital, Bonn

Tracking Information

• First Submitted Date: November 10, 2017
• First Posted Date: November 22, 2017
• Last Update Posted Date: May 24, 2022
• Actual Study Start Date: March 26, 2018
• Estimated Primary Completion Date: November 30, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 19, 2017)

• Mean change from baseline in best corrected visual acuity (BCVA) using an early treatment diabetic retinopathy study (ETDRS) chart [ Time Frame: 3 years from baseline ]
  standard parameter, tested for comparison (reference variable)
• Mean change from baseline in scotopic and mesopic microperimetry sensitivity [ Time Frame: 3 years from baseline ]
• Mean change from baseline in low luminance visual acuity (LLVA) [ Time Frame: 3 years from baseline ]
• Mean change from baseline in vanishing optotypes visual acuity (VA) [ Time Frame: 3 years from baseline ]
• Mean change from baseline in low luminance deficit (LLD) [ Time Frame: 3 years from baseline ]
  LLD = BCVA-LLVA
• Mean change from baseline in absolute rod threshold of the dark adaptation test [ Time Frame: 3 years from baseline ]
• Mean change from baseline in rod intercept time of the dark adaptation test [ Time Frame: 3 years from baseline ]
• Proportion of subjects with progression in dark adaptation deficit beyond coefficient of repeatability structural [ Time Frame: 3 years from baseline ]
• Mean change from baseline in the cube root of drusen volume by spectral-domain optical coherence tomography (SD-OCT) [ Time Frame: 3 years from baseline ]
• Mean change from baseline in retinal thickness by spectral-domain optical coherence tomography (SD-OCT) [ Time Frame: 3 years from baseline ]
• Focal pigmentary changes captured by colour fundus photography (CFP) [ Time Frame: 3 years from baseline ]
• Presence of refractile deposits [ Time Frame: 3 years from baseline ]
• Presence of intraretinal cystoid spaces [ Time Frame: 3 years from baseline ]
• Presence of localized retinal pigment epithelium (RPE) hypertransmission [ Time Frame: 3 years from baseline ]
• Presence of localized disruption of ellipsoid zone [ Time Frame: 3 years from baseline ]
• Presence of localized subsidence of the outer plexiform layer and the inner nuclear layer [ Time Frame: 3 years from baseline ]
• Presence of hyporeflective wedge-shaped bands [ Time Frame: 3 years from baseline ]
• Presence of reticular drusen/subretinal drusenoid deposits and associated local changes as determined by multimodal imaging [ Time Frame: 3 years from baseline ]
• Changes in localized fundus autofluorescence signal alterations [ Time Frame: 3 years from baseline ]
• Proportion of subjects with reduction in drusen volume [ Time Frame: 3 years from baseline ]
• Proportion of subjects with study eye that progressed to geogrphic atrophy (GA) and/or neovascular age-related macular degeneration (nAMD) [ Time Frame: 3 years from baseline ]
• Proportion of subjects with conversions to late AMD detected with fluorescein angiography (FA) that could be detected with OCT-A (at equipped sites) [ Time Frame: 3 years from baseline ]
• Presence of quiescent choroidal neovascularisation (CNV) as assessed by optical coherence tomography angiography (OCT-A) (at equipped sites) [ Time Frame: 3 years from baseline ]
• OCT-A findings (at equipped sites) [ Time Frame: 3 years from baseline ]
• Mean change from baseline in patient-reported low luminance visual functioning, as measured by the vision impairment in low luminance (VILL) questionnaire, including the domains of reading & accessing information [ Time Frame: 3 years from baseline ]
• Mean change from baseline in patient-reported low luminance visual functioning, as measured by the VILL questionnaire, including the domains of Orientation & mobility (incl. driving) [ Time Frame: 3 years from baseline ]
• Mean change from baseline in patient-reported low luminance visual functioning, as measured by the VILL questionnaire, including the domains of safety [ Time Frame: 3 years from baseline ]
• Mean change from baseline in patient-reported low luminance visual functioning, as measured by the VILL questionnaire, including the domains of socio-emotional well-being [ Time Frame: 3 years from baseline ]
• Change in utility index from baseline as measure by the patient-reported outcome measure (PROM) utility index [ Time Frame: 3 years from baseline ]
• Mean change from baseline in patient-reported health status and utility using the EQ-5D-5L questionnaire (EuroQol Group) [ Time Frame: 3 years from baseline ]

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Development of Novel Clinical Endpoints in Intermediate AMD
• Official Title: Development of Novel Clinical Endpoints for Interventional Clinical Trials With a Regulatory and Patient Access Intention in Patients With Intermediate Age-related Macular Degeneration (AMD)
• Brief Summary: Development of novel clinical endpoints for interventional clinical trials with a regulatory and patient access intention in patients with intermediate age-related macular degeneration (AMD) - MACUSTAR

Detailed Description

The purpose of the MACUSTAR clinical study is to develop novel clinical endpoints for clinical trials with a regulatory and patient access intention in patients with intermediate age-related macular degeneration (iAMD). Additional objectives are to characterize the visual impairment in iAMD and its progression, as well as identify risk factors for progression to late stage AMD.

Moreover, MACUSTAR aims to optimize and standardize most relevant existing and/or rapidly available clinical endpoints in:

• visual functional outcomes measures
• structural outcomes measures
• patient reported outcomes measures (PROMs)

The study will be composed by two parts:

• a cross-sectional part to technically evaluate the functional and structural outcome measures to support a biomarker qualification by regulatory authorities and payers; and
• a longitudinal part to assess the prognostic power of changes in retinal sensitivity (as measured by microperimetry) for progression from iAMD to late AMD (nAMD and GA).

• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided

Biospecimen

Retention:   Samples With DNA

Description:

Blood samples are collected in the study for two purposes: biobanking and genetic analysis. Detailed instructions on processing and storage of blood samples are provided in a specific manual that will be provided to the clinical sites. Blood samples are stored in a pseudonimysed form.

• Sampling Method: Non-Probability Sample

Study Population

The study will include subjects with no AMD or normal aging changes and subjects with AMD classified in accordance with the international Beckman Classification.

A total of 750 subjects will be recruited:

• 300 subjects will participate in the Cross-sectional part:

  • 50 with normal aging changes, no AMD
  • 50 with early AMD,
  • 50 with late AMD
  • 150 with iAMD

• 650 subjects will participate in the longitudinal part:

  • 600 iAMD
  • 50 early AMD

• Condition: Age Related Macular Degeneration (AMD)

Intervention

Other: No intervention

According to clinical practice.

Study Groups/Cohorts

• no AMD
  No interventions
  Intervention: Other: No intervention
• early AMD
  No interventions.
  Intervention: Other: No intervention
• intermediate AMD
  No interventions.
  Intervention: Other: No intervention
• late AMD
  No interventions.
  Intervention: Other: No intervention

Publications *

• Terheyden JH, Pondorfer SG, Behning C, Berger M, Carlton J, Rowen D, Bouchet C, Poor S, Luhmann UFO, Leal S, Holz FG, Butt T, Brazier JE, Finger RP; MACUSTAR consortium. Disease-specific assessment of Vision Impairment in Low Luminance in age-related macular degeneration - a MACUSTAR study report. Br J Ophthalmol. 2022 Mar 30:bjophthalmol-2021-320848. doi: 10.1136/bjophthalmol-2021-320848. Online ahead of print.
• Terheyden JH, Behning C, Luning A, Wintergerst L, Basile PG, Tavares D, Melicio BA, Leal S, Weissgerber G, Luhmann UFO, Crabb DP, Tufail A, Hoyng C, Berger M, Schmid M, Silva R, Martinho CV, Cunha-Vaz J, Holz FG, Finger RP; MACUSTAR consortium. Challenges, facilitators and barriers to screening study participants in early disease stages-experience from the MACUSTAR study. BMC Med Res Methodol. 2021 Mar 17;21(1):54. doi: 10.1186/s12874-021-01243-8.
• Terheyden JH, Holz FG, Schmitz-Valckenberg S, Luning A, Schmid M, Rubin GS, Dunbar H, Tufail A, Crabb DP, Binns A, Sanchez CI, Hoyng C, Margaron P, Zakaria N, Durbin M, Luhmann U, Zamiri P, Cunha-Vaz J, Martinho C, Leal S, Finger RP; MACUSTAR consortium. Clinical study protocol for a low-interventional study in intermediate age-related macular degeneration developing novel clinical endpoints for interventional clinical trials with a regulatory and patient access intention-MACUSTAR. Trials. 2020 Jul 18;21(1):659. doi: 10.1186/s13063-020-04595-6.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: November 5, 2020): 718
• Original Estimated Enrollment (submitted: November 19, 2017): 750
• Estimated Study Completion Date: November 30, 2022
• Estimated Primary Completion Date: November 30, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

General Inclusion criteria (applicable to all groups)

1. Male and female subjects.
2. Aged 55 - 85 years at baseline.
3. Able and willing to provide written informed consent and to comply with the study protocol visits and assessments.

Intermediate AMD

1. Study eye must have iAMD and,
2. The fellow eye must have iAMD and/or, in addition, extrafoveal GA (no atrophy within the central ETDRS subfield), maximum total GA size is 1.25 mm2.
3. ETDRS letter chart BCVA in the study eye not worse than 72 letters (approximately 20/40 Snellen VA equivalent).
4. All general inclusion criteria.

Late AMD

1. Subjects with bilateral GA, bilateral nAMD or nAMD in one eye and GA in the other.
2. BCVA between 20/80 and 20/200 in study eye.
3. All general inclusion criteria.

Early AMD

1. Subjects with medium drusen > 63μm and ≤ 125μm and no AMD pigmentary abnormalities in both eyes and not signs of intermediate or late AMD.
2. All general inclusion criteria.

No AMD

1. No signs of early, intermediate or late AMD in both eyes.
2. All general inclusion criteria only.

Exclusion Criteria:

General Exclusion criteria (applicable to all groups)

1. Media opacity or eye movement disorder (nystagmus) that interferes with retinal imaging data quality in the opinion of the investigator.
2. Severe ptosis, extraocular motility restriction or head tremor preventing adequate fundus visualization in the opinion of the investigator.
3. Any signs of nAMD or GA (does not apply to the late AMD group).
4. Any concurrent intraocular condition in the study eye (e. g. glaucoma or cataract) that, in the opinion of the investigator would either require surgical intervention during the study to prevent or treat visual loss that might result from that condition or affect interpretation of study results.
5. Severe non-proliferative diabetic retinopathy, or proliferative diabetic retinopathy.
6. Any diabetic macular edema or macular disease
7. Ocular disorders in the study eye (i. e., pre-retinal membrane) at the time of enrolment that may confound interpretation of study results and compromise visual acuity.
8. Diagnosis of uncontrolled glaucoma with intraocular pressure of >30 mmHg (despite current pharmacological or non-pharmacological treatment).
9. Known systemic illness which in the opinion of the investigator will prevent from actively participating in the study.
10. Concomitant treatment for AMD in either eye (concomitant use of vitamins/supplements is not excluded; does not apply to the late AMD group).
11. Any periocular or intravitreal injections (IVT) in either eye (does not apply to the late AMD group).
12. Participation in any other interventional trial.
13. Obvious retinal changes due to causes other than AMD (e.g. evidenced by an existing diagnosis of monogenetic macular dystrophies, Stargardt disease, cone rod dystrophy, or toxic maculopathies).
14. Any history of allergies to fluorescein.

Intermediate AMD

1. Any GA in the study eye
2. Any extrafoveal GA larger than 1.25 mm2 in the fellow eye.
3. All general exclusion criteria.

Late AMD

1. All general exclusion criteria only.

Early AMD

1. Intermediate or late AMD (following Beckman classification) in any eye.
2. All general exclusion criteria.

No AMD

1. Early to late AMD (following Beckman classification) in any eye.
2. All general exclusion criteria.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 55 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Denmark, France, Germany, Italy, Netherlands, Portugal, United Kingdom

Administrative Information

• NCT Number: NCT03349801
• Other Study ID Numbers: ECR-AMD-2017-13; MACUSTAR ( Other Grant/Funding Number: Innovative Medicines Innitiative )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Frank G. Holz, University Hospital, Bonn
• Original Responsible Party: Same as current
• Current Study Sponsor: Frank G. Holz
• Original Study Sponsor: Same as current

Collaborators

• Bayer
• Moorfields Eye Hospital NHS Foundation Trust
• Novartis Pharmaceuticals
• Association for Innovation and Biomedical Research on Light and Image
• City, University of London
• European Clinical Research Infrastructure Network
• La Fondation Voir et Entendre
• Hoffmann-La Roche
• Radboud University Medical Center
• University of Sheffield
• University College, London
• Carl Zeiss Meditec AG
• Innovative Medicines Initiative

Investigators

• Principal Investigator: Frank Holz, Prof. Dr. med.; University Hospital, Bonn

• PRS Account: University Hospital, Bonn
• Verification Date: May 2022