The Efficacy of Oral Everolimus in Patients With Neovascular Age-related Macular Degeneration

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00857259
• Collaborator: (none)
• Enrollment: 16
• Locations: 12
• Arms: 3
• Patients Per Site: 1.3

Study Details

Study Description

Brief Summary

The study will assess the safety and efficacy of Everolimus (RAD001) alone or in combination with Lucentis in patients with neo-vascular age related macular degeneration (AMD)

Condition or Disease	Intervention/Treatment	Phase
Choroidal Neo-Vascular Age-onset Macular Degeneration; Age-related Macular Degeneration	Drug: Everolimus; Drug: Ranibizumab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-masked, Parallel Group Study to Assess the Efficacy of Oral Everolimus, Either Alone or Added to Lucentis, in Patients With Neovascular Age-related Macular Degeneration
• Study Start Date: Feb 1, 2009
• Actual Primary Completion Date: Jul 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Everolimus 5 mg 5 mg orally once daily plus sham ocular injection on Day 1 (Baseline) until Day 28	Drug: Everolimus; 5 mg oral tablet
Active Comparator: Ranibizumab 0.5 mg Ranibizumab intra-vitreal therapy (IVT) 0.5 mg on Day 1 (baseline)	Drug: Ranibizumab; 0.5 mg administered by intravitreal injection
Active Comparator: Oral Everolimus (5mg) and Ranibizumab (0.5mg) Everolimus orally 5 mg once daily plus Ranibizumab Intra-vitreal therapy (IVT) 0.5 mg on day 1 (baseline)	Drug: Everolimus; 5 mg oral tablet; Drug: Ranibizumab; 0.5 mg administered by intravitreal injection

Outcome Measures

Primary Outcome Measures

1. Change in Central Retinal Thickness From Baseline to Week 4, as Measured by Optical Coherence Tomography (OCT) [Baseline and 4 weeks]

   Central retinal thickness was assessed by Optical coherence tomography (OCT). The primary thickness endpoint was the mean thickness of the foveal field of the macula map produced by the analysis of the sequence of six radial scans. Foveal field thickness was the average thickness of a circular field with a diameter of 1 mm. OCT images were analyzed by a central reading center.

Secondary Outcome Measures

1. Change in Visual Acuity From Baseline to Week 4 in Patients Treated With Everolimus [Baseline and week 4]

   Best corrected visual acuity (BCVA) was assessed on both eyes. BCVA measurements were taken in sitting position using Early Treatment Diabetic Retinopathy Study (ETDRs)-like visual acuity testing charts at an initial testing distance specific to test charts. BCVA is measured from the number of letters the patient can read on the eye chart.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with neovascular Age-Related Macular Degeneration (AMD)

• Best corrected visual acuity ( BCVA) of 20/40 or worse in study eye

• Patients with predominantly classic, minimally classic, or occult choroidal neovascularization in the macula of one eye (the study eye) who have had an inadequate response to VEGF inhibitors in the study eye. Inadequate response is defined as a gain of less than one line of visual acuity and persistent macular edema (central sub-fiel thickness ≥ 300 μm as measured by Optical Coherence Tomography (OCT) despite a minimum of 3 treatments with Lucentis or Avastin

Exclusion Criteria:

• Any concurrent ocular condition in the study eye that may result in substantial change in vision during the study

• Uncontrolled medical conditions such as cancer, angina, diabetes, viral or fungal infections, impaired lung function, history of stroke

• Patients who have macular edema in the study eye that, in the judgment of the investigator, is unlikely to respond to treatment. Examples of features that may guide the investigator's judgment about unresponsiveness are large regions of geographic atrophy, retinal angiomatous proliferation, or large regions of sub-retinal fibrosis. The presence of one of these features excludes a patient only if the investigator judges the study eye to have irreversible macular edema.

• active bacterial, fungal or viral infections at the time of enrollment, e.g. hepatitis B or C infection. Patients with risk factors for hepatitis B should be tested for hepatitis B viral load and serological markers at screening (a positive HBV-DNA, HBsAg). Patients with risk factors for hepatitis C should be tested using HCVRNA-PCR at screening. A clinical history of hepatitis B or hepatitis C will exclude the patient from the study.

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Retina-Vitreous Associates Medical Group	Beverley Hills	California	United States	90211
2	Retinal Consultants Medical Group, Inc.	Sacramento	California	United States
3	Porter Adventist Hospital, Diagnostic Eye Laboratory	Denver	Colorado	United States	80210
4	Discover Vision Center	Independence	Missouri	United States	64055
5	Novartis Investigative Site	Bristol		United Kingdom
6	Novartis Investigative Site	Frimley		United Kingdom
7	Novartis Investigative Site	Liverpool		United Kingdom
8	Novartis Investigative Site	London		United Kingdom
9	Novartis Investigative Site	Oxford		United Kingdom
10	Novartis Investigative site	Portsmouth		United Kingdom
11	Novartis Investigative Site	Southampton		United Kingdom
12	Novartis Investigator Site	Wolverhampton		United Kingdom

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00857259
• Other Study ID Numbers: CRAD001A2203; EudraCT number: 2008-003550-15
• First Posted: Mar 6, 2009
• Last Update Posted: Aug 19, 2011
• Last Verified: Jul 1, 2011

• Keywords provided by , ,: AMD; macular degeneration; Everolimus; Lucentis; Ranibizumab; Choroidal Neo-Vascular (CNV) age-onset macular degeneration; Age-related Macular Degeneration (AMD)
• Additional relevant MeSH terms: Macular Degeneration; Everolimus; Ranibizumab

Study Results

Participant Flow

Arm/Group Title	Everolimus 5 mg	Ranibizumab 0.5 mg	Everolimus and Ranibizumab
Arm/Group Description	5 mg orally once daily plus sham ocular injection on Day 1 (Baseline)	Ranibizumab intra-vitreal therapy (IVT) 0.5 mg on Day 1 (baseline)	Everolimus oral 5 mg once daily plus ranibizumab Intra-vitreal therapy (IVT) 0.5 mg on day 1 (baseline)
Period Title: Overall Study
STARTED	8	1	7
COMPLETED	7	1	6
NOT COMPLETED	1	0	1

Baseline Characteristics

Arm/Group Title	Everolimus 5 mg	Ranibizumab 0.5 mg	Everolimus and Ranibizumab	Total
Arm/Group Description	5 mg orally once daily plus sham ocular injection on Day 1 (Baseline)	Ranibizumab intra-vitreal therapy (IVT) 0.5 mg on Day 1 (baseline)	Everolimus oral 5 mg once daily plus ranibizumab Intra-vitreal therapy (IVT) 0.5 mg on day 1 (baseline)	Total of all reporting groups
Overall Participants	8	1	7	16
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	75.9 (3.44)	71.00	78.1 (14.23)	76.6 (9.49)
Sex: Female, Male (Count of Participants)
Female	3 37.5%	0 0%	6 85.7%	9 56.3%
Male	5 62.5%	1 100%	1 14.3%	7 43.8%

Outcome Measures

1. Primary Outcome

Title	Change in Central Retinal Thickness From Baseline to Week 4, as Measured by Optical Coherence Tomography (OCT)
Description	Central retinal thickness was assessed by Optical coherence tomography (OCT). The primary thickness endpoint was the mean thickness of the foveal field of the macula map produced by the analysis of the sequence of six radial scans. Foveal field thickness was the average thickness of a circular field with a diameter of 1 mm. OCT images were analyzed by a central reading center.
Time Frame	Baseline and 4 weeks

Outcome Measure Data

Analysis Population Description

The Per Protocol Analysis Set (PPAS)consisted of all patients in the Full Analysis Set (FAS)who received study drug, completed the treatment phase of the trial without clinically significant protocol deviations and had non-missing central retinal thickness values for the study eye at both baseline and Day 28.

Arm/Group Title	Oral Everolimus 5 mg	Ranibizumab 0.5 mg	Everolimus 5 mg and Ranibizumab 0.5 mg
Arm/Group Description	5 mg once daily plus sham ocular injection on Day 1 (Baseline)	Ranibizumab intra-vitreal therapy 0.5 mg on Day 1 (baseline)	Everolimus orally 5 mg once daily plus Ranibizumab intra-vitreal therapy (IVT) 0.5 mg on day 1 (baseline)
Measure Participants	6	1	6
Baseline	454.8 (59.56)	306.0	244.3 (80.37)
Week 4	492.2 (122.16)	308.0	217.6 (33.87)
Change from Baseline	37.3 (67.31)	2.0	-41.0 (56.18)

2. Secondary Outcome

Title	Change in Visual Acuity From Baseline to Week 4 in Patients Treated With Everolimus
Description	Best corrected visual acuity (BCVA) was assessed on both eyes. BCVA measurements were taken in sitting position using Early Treatment Diabetic Retinopathy Study (ETDRs)-like visual acuity testing charts at an initial testing distance specific to test charts. BCVA is measured from the number of letters the patient can read on the eye chart.
Time Frame	Baseline and week 4

Outcome Measure Data

Analysis Population Description

The Per Protocol Analysis Set (PPAS)consisted of all patients in the Full Analysis Set (FAS)who received study drug, completed the treatment phase of the trial without clinically significant protocol deviations and had non-missing central retinal thickness values for the study eye at both baseline and Day 28.

Arm/Group Title	Everolimus 5 mg	Ranibizumab 0.5 mg	Everolimus 5 mg and Ranibizumab 0.5 mg
Arm/Group Description	5 mg orally once daily plus sham ocular injection on Day 1 (Baseline)	Ranibizumab intra-vitreal therapy (IVT) 0.5 mg on Day 1 (Baseline)	Everolimus oral 5 mg once daily plus ranibizumab Intra-vitreal therapy (IVT) 0.5 mg on day 1 (baseline)
Measure Participants	6	1	5
Baseline	46 (16.91)	67.0	55.3 (10.54)
4 Weeks	43 (17.09)	69.0	63.2 (12.32)
Change in baseline	-3 (7.59)	2.0	4.4 (5.73)

Adverse Events

Adverse Event Reporting Description	Only two arms are represented in the Serious Adverse Events and Adverse Events > 5% Tables. The Ranibizumab 0.5 mg IVT arm is omitted because there were no SAEs or AEs reported in that treatment group.
Arm/Group Title	Oral Everolimus 5 mg		Everolimus 5 mg and Ranibizumab 0.5 mg
Arm/Group Description	5 mg once daily plus sham ocular injection on Day 1 (Baseline)		Everolimus orally 5 mg once daily plus Ranibizumab intra-vitreal therapy (IVT) 0.5 mg on day 1 (baseline)
All Cause Mortality
	Oral Everolimus 5 mg		Everolimus 5 mg and Ranibizumab 0.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Oral Everolimus 5 mg		Everolimus 5 mg and Ranibizumab 0.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Oral Everolimus 5 mg		Everolimus 5 mg and Ranibizumab 0.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/8 (75%)		5/7 (71.4%)
Eye disorders
Lacrimation increased	0/8 (0%)		1/7 (14.3%)
Macular degeneration	1/8 (12.5%)		0/7 (0%)
Optic disc haemorrhage	1/8 (12.5%)		0/7 (0%)
Vitreous floaters	1/8 (12.5%)		0/7 (0%)
Gastrointestinal disorders
Diarrhoea	1/8 (12.5%)		2/7 (28.6%)
Mouth ulceration	1/8 (12.5%)		1/7 (14.3%)
Nausea	0/8 (0%)		2/7 (28.6%)
Tongue ulceration	1/8 (12.5%)		0/7 (0%)
General disorders
Oedema peripheral	0/8 (0%)		1/7 (14.3%)
Infections and infestations
Furuncle	1/8 (12.5%)		0/7 (0%)
Nasopharyngitis	1/8 (12.5%)		0/7 (0%)
Pneumonia	0/8 (0%)		1/7 (14.3%)
Injury, poisoning and procedural complications
Periorbital haematoma	1/8 (12.5%)		0/7 (0%)
Investigations
Blood cholesterol increased	0/8 (0%)		1/7 (14.3%)
Blood creatine phosphokinase increased	0/8 (0%)		1/7 (14.3%)
Blood lactate dehydrogenase increased	1/8 (12.5%)		0/7 (0%)
Blood triglycerides increased	1/8 (12.5%)		0/7 (0%)
Musculoskeletal and connective tissue disorders
Neck pain	0/8 (0%)		1/7 (14.3%)
Osteopenia	1/8 (12.5%)		0/7 (0%)
Pain in extremity	0/8 (0%)		1/7 (14.3%)
Nervous system disorders
Headache	1/8 (12.5%)		1/7 (14.3%)
Migraine	0/8 (0%)		1/7 (14.3%)
Psychiatric disorders
Insomnia	0/8 (0%)		1/7 (14.3%)
Respiratory, thoracic and mediastinal disorders
Cough	0/8 (0%)		1/7 (14.3%)
Dyspnoea	1/8 (12.5%)		0/7 (0%)
Nasal discomfort	0/8 (0%)		1/7 (14.3%)
Oropharyngeal pain	1/8 (12.5%)		1/7 (14.3%)
Skin and subcutaneous tissue disorders
Pruritus	0/8 (0%)		1/7 (14.3%)
Vascular disorders
Aortic wall hypertrophy	0/8 (0%)		1/7 (14.3%)
Hypertension	1/8 (12.5%)		0/7 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial; or disclosure of the trial results in their entirety.