DREAM: Regorafenib Eye Drops: Investigation of Efficacy and Safety in Neovascular Age Related Macular Degeneration

• Sponsor: Bayer (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02222207
• Collaborator: (none)
• Enrollment: 52
• Locations: 149
• Arms: 8
• Duration (Months): 8
• Patients Per Site: 0.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

Part A (Phase IIa):

Primary objectives:

The study part A is designed to investigate whether the use of regorafenib eye drops can help patients with neovascular (wet) Age-Related Macular Degeneration (wAMD) to see better after 4 weeks and 12 weeks after inclusion into this study.

Secondary objectives:

The study will also evaluate the safety and tolerability of the regorafenib eye drops.

Part B (Phase IIb):

Primary objectives:

The study part B is designed to investigate:

• how often the regorafenib eye drops need to be given per day

• whether the use of regorafenib eye drops can help patients with neovascular (wet) Age-Related Macular Degeneration (wAMD) to see better after 4 weeks and 12 weeks after inclusion into this study.

Secondary objectives:

The study will also evaluate how the different dosings of regorafenib eye drops affect patients vision, the safety and the tolerability.

Condition or Disease	Intervention/Treatment	Phase
Macular Degeneration	Drug: Regorafenib, ophthalmic oily suspension (BAY73-4506); Procedure: Sham IVT; Drug: Ranibizumab; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Combined Phase IIa / IIb Study of the Efficacy, Safety, and Tolerability of Repeated Topical Doses of Regorafenib Eye Drops, in Treatment-naïve Subjects With Neovascular Age Related Macular Degeneration
• Study Start Date: Oct 1, 2014
• Actual Primary Completion Date: May 1, 2015
• Actual Study Completion Date: Jun 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Regorafenib [A] Part A: Patients will receive Regorafenib eye drops	Drug: Regorafenib, ophthalmic oily suspension (BAY73-4506); Subjects receive Regorafenib as eye drops
Experimental: Regorafenib [B1] Part B: Regorafenib eye drops dose 1; plus sham IVT (Intravitreal therapy) once every 4 weeks	Drug: Regorafenib, ophthalmic oily suspension (BAY73-4506); Subjects receive Regorafenib as eye drops; Procedure: Sham IVT; Sham injections
Experimental: Regorafenib [B2] Part B: Regorafenib eye drops dose 2; plus sham IVT (Intravitreal therapy) once every 4 weeks	Drug: Regorafenib, ophthalmic oily suspension (BAY73-4506); Subjects receive Regorafenib as eye drops; Procedure: Sham IVT; Sham injections
Experimental: Regorafenib [B3] Part B: Regorafenib eye drops dose 3; plus sham IVT (Intravitreal therapy) once every 4 weeks	Drug: Regorafenib, ophthalmic oily suspension (BAY73-4506); Subjects receive Regorafenib as eye drops; Procedure: Sham IVT; Sham injections
Experimental: Regorafenib [B4] Part B: Regorafenib eye drops dose 4; plus sham IVT (Intravitreal therapy) once every 4 weeks	Drug: Regorafenib, ophthalmic oily suspension (BAY73-4506); Subjects receive Regorafenib as eye drops; Procedure: Sham IVT; Sham injections
Experimental: Regorafenib [B5] Part B: Regorafenib eye drops dose 5; plus sham IVT (Intravitreal therapy) once every 4 weeks	Drug: Regorafenib, ophthalmic oily suspension (BAY73-4506); Subjects receive Regorafenib as eye drops; Procedure: Sham IVT; Sham injections
Experimental: Regorafenib [B6] Part B: Regorafenib eye drops dose 6; plus sham IVT (Intravitreal therapy) once every 4 weeks	Drug: Regorafenib, ophthalmic oily suspension (BAY73-4506); Subjects receive Regorafenib as eye drops; Procedure: Sham IVT; Sham injections
Active Comparator: Ranibizumab Ranibizumab IVT once every 4 weeks; plus placebo eye drops to match the regorafenib eye drop regimens	Drug: Ranibizumab; Subjects receive Ranibizumab as intravitreal injection; Drug: Placebo; Placebo eye drops

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Study Week 4 for Study Part A [Baseline, Week 4]

   Participants will be assessed at each clinic visit for best corrected visual acuity using the early treatment diabetic retinopathy study chart. Visual function of the study eye and the fellow eye was assessed using the ETDRS. The participant's ETDRS testing score was recorded in the appropriate eCRF page at each study visit. For participants that dropped out or received rescue treatment the last observation before drop-out or administration of rescue treatment was carried forward. A higher score represents better functioning.

2. Change From Baseline in BCVA as Measured by ETDRS Letter Score at Study Week 12 for Study Part A [Baseline, Week 12]

   Participants were assessed at each clinic visit for best corrected visual acuity using the early treatment diabetic retinopathy study chart. Visual function of the study eye and the fellow eye was assessed using the ETDRS protocol. ETDRS testing score was recorded in the appropriate eCRF page at each study visit. For participants that dropped out or received rescue treatment the last observation before drop-out or administration of rescue treatment was carried forward. A higher score represents better functioning.

Secondary Outcome Measures

1. Percentage of Participants With Individual Changes in BCVA of Greater Than Equal to (>=) 0 Letters of Vision From Study Week 4 to Week 12 for Study Part A [Week 4, Week 12]

   Participants were assessed at each clinic visit for BCVA using the early treatment diabetic retinopathy study chart. For participants that dropped out or received rescue treatment the last observation before drop-out or administration of rescue treatment was carried forward.

2. Percentage of Participants With a Loss in BCVA of >= 10 Letters From Baseline to Study Week 12 for Study Part A [Baseline, Week 12]

   Participants were assessed at each clinic visit for BCVA using the early treatment diabetic retinopathy study chart. For participants that dropped out or received rescue treatment the last observation before drop-out or administration of rescue treatment was carried forward.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Able to read (or, if unable to read due to visual impairment, be read to verbatim by the person administering the informed consent or a family member) and able to understand the informed consent form (ICF)

• Men and women ≥ 50 years of age

• Active primary subfoveal CNV (Choroidal neovascularization) lesions secondary to AMD (Age-related macular degeneration), including juxtafoveal lesions that affect the fovea as evidenced by FA (Fluorescein angiography) in the study eye and reviewed by the central reading center

• The area of CNV must occupy at least 50% of total lesion in the study eye, as determined by FA review at the central reading center

• Evidence of intraretinal and/or subretinal fluid on OCT (Optical coherence tomography)

• Early Treatment Diabetic Retinopathy Study BCVA of 73 to 25 letters (20/40 to 20/320 Snellen equivalent) in the study eye

• Willing, committed, and able to return for all clinic visits and complete all study related procedures

• Women of childbearing potential and men must agree to use adequate contraception when sexually active. This applies since signing of the ICF until one month after the EOS (end of study) visit. The definition of adequate contraception will be based on the judgment of the investigator.

Exclusion Criteria:

• Concurrent disease in the study eye, other than AMD (e.g., corneal diseases and dystrophies, conjunctival diseases, eye lid abnormalities, or any other diseases of the cornea and macula, or optic nerve abnormality) that could compromise visual acuity, likely require medical or surgical intervention during the study period, would limit the potential to gain or lose vision during study treatment, or could otherwise confound interpretation of the results

• Total lesion size (including neovascularization, scar, blood) > 12 disc areas (30.5 mm2) as assessed by FA

• Only one functional eye, even if that eye is otherwise eligible for the study

• Prior ocular or systemic treatment or surgery for neovascular AMD in the study eye except dietary supplements or vitamins

• Prior treatment with any systemic anti-VEGF (Vascular endothelial growth factor) agent

• Use of systemic or ocular treatment with an investigational drug within 12 weeks prior to start of study treatment

• Any other condition that would require frequent chronic co-administration of other topical eye medications that would interfere with study drug administration (e.g. contact lens)

• Symptoms or conditions consistent with contraindications listed in the current local label for ranibizumab

• Participation in an investigational study within 30 days prior to start of study treatment that involved treatment with any drug (excluding vitamins and minerals) or device

• Lactating women and women of child-bearing potential with either a positive pregnancy test result or no pregnancy test at screening are excluded. Postmenopausal women must be amenorrheic for at least 12 months in order not to be considered of child bearing potential.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Tucson	Arizona	United States	85704
2		Arcadia	California	United States	91007
3		Beverly Hills	California	United States	90211
4		Campbell	California	United States	95008
5		Costa Mesa	California	United States	92626
6		Laguna Hills	California	United States	92653
7		Mountain View	California	United States	94040
8		Santa Ana	California	United States	92705
9		Golden	Colorado	United States	80401
10		Boynton Beach	Florida	United States	33426
11		Fort Myers	Florida	United States	33912
12		Miami	Florida	United States	33143
13		Plantation	Florida	United States	33324
14		Sarasota	Florida	United States	34239
15		Stuart	Florida	United States	34994
16		Winter Haven	Florida	United States	33880
17		Decatur	Georgia	United States	30030
18		New Albany	Indiana	United States	47150
19		Leawood	Kansas	United States	66211
20		Wichita	Kansas	United States	67226
21		Louisville	Kentucky	United States	40207
22		Eunice	Louisiana	United States	70535
23		Boston	Massachusetts	United States	02114
24		Grand Rapids	Michigan	United States	49525
25		Florissant	Missouri	United States	63031
26		Teaneck	New Jersey	United States	07666
27		Asheville	North Carolina	United States	28803
28		West Mifflin	Pennsylvania	United States	15122
29		Greenville	South Carolina	United States	29605
30		Rapid City	South Dakota	United States	57701
31		Austin	Texas	United States	78705
32		Houston	Texas	United States	77030
33		McAllen	Texas	United States	78503
34		San Antonio	Texas	United States	78240
35		Temple	Texas	United States	76508
36		The Woodlands	Texas	United States	77384
37		Charlottesville	Virginia	United States	22908
38		Strathfield	New South Wales	Australia	2135
39		Sydney	New South Wales	Australia	2000
40		Westmead	New South Wales	Australia	2145
41		Nedlands	Western Australia	Australia	6009
42		Parramatta		Australia	2150
43		Wien		Austria	1090
44		Wien		Austria	1130
45		Calgary	Alberta	Canada	T2H 0C8
46		Edmonton	Alberta	Canada	T5H 0X5
47		Vancouver	British Columbia	Canada	V5Z 3N9
48		Halifax	Nova Scotia	Canada	B3H 2Y9
49		London	Ontario	Canada	N6A 4V2
50		Mississauga	Ontario	Canada	L4W 1W9
51		Montreal	Quebec	Canada	H1T 2M4
52		Montreal	Quebec	Canada	H4P 2S4
53		Sherbrooke	Quebec	Canada	J1J 2B8
54		Osorno	Los Lagos	Chile	5311138
55		Metropolitana	Santiago	Chile	7510168
56		Vitacura	Santiago	Chile	7650710
57		Santiago		Chile	8380456
58		Bogota	Distrito Capital de Bogotá	Colombia	0
59		Hradec Kralove		Czech Republic	500 05
60		Praha 2		Czech Republic	128 08
61		Praha 4		Czech Republic	140 00
62		Praha 7		Czech Republic	170 00
63		Paris	Cedex 12	France	75557
64		Boredaux		France	33076
65		Lyon		France	69003
66		Tübingen	Baden-Württemberg	Germany	72076
67		München	Bayern	Germany	81377
68		München	Bayern	Germany	81675
69		Bonn	Nordrhein-Westfalen	Germany	53105
70		Köln	Nordrhein-Westfalen	Germany	50937
71		Münster	Nordrhein-Westfalen	Germany	48145
72		Mainz	Rheinland-Pfalz	Germany	55131
73		Dresden	Sachsen	Germany	01067
74		Dresden	Sachsen	Germany	01307
75		Leipzig	Sachsen	Germany	04103
76		Berlin		Germany	12203
77		Hamburg		Germany	20251
78		Hong Kong		Hong Kong
79		Kowloon		Hong Kong
80		Budapest		Hungary	1082
81		Budapest		Hungary	1106
82		Budapest		Hungary	1133
83		Debrecen		Hungary	4032
84		Pecs		Hungary	7621
85		Afula		Israel	1834111
86		Beer Sheva		Israel	8410101
87		Haifa		Israel	3109601
88		Haifa		Israel	3436212
89		Jerusalem		Israel	9112001
90		Kfar Saba		Israel	4428164
91		Petah Tikva		Israel	4941492
92		Ramat Gan		Israel	5262000
93		Rehovot		Israel	7610001
94		Tel Aviv		Israel	6423906
95		Zerifin		Israel	6093000
96		Udine	Friuli-Venezia Giulia	Italy	33100
97		Roma	Lazio	Italy	00133
98		Roma	Lazio	Italy	00198
99		Milano	Lombardia	Italy	20122
100		Milano	Lombardia	Italy	20157
101		Firenze	Toscana	Italy	50134
102		Padova	Veneto	Italy	35128
103		Ancona		Italy	60126
104		Bologna		Italy	40138
105		Milano		Italy	20132
106		Sassari		Italy	07100
107		Inba-gun	Chiba	Japan	285-0922
108		Miyako-gun	Fukuoka	Japan	800-0344
109		Sapporo	Hokkaido	Japan	004-0041
110		Sapporo	Hokkaido	Japan	060-8604
111		Himeji	Hyogo	Japan	671-1227
112		Yamato	Kanagawa	Japan	242-0001
113		Yokohama	Kanagawa	Japan	222-0011
114		Iga	Mie	Japan	518-0842
115		Chofu	Tokyo	Japan	182-0024
116		Itabashi-ku	Tokyo	Japan	173-0015
117		Ota-ku	Tokyo	Japan	143-0013
118		Taito-ku	Tokyo	Japan	111-0051
119		Fukuoka		Japan	812-0011
120		Kumamoto		Japan	860-0027
121		Nagasaki		Japan	852-8511
122		Nara		Japan	630-8305
123		Osaka		Japan	530-0001
124		Osaka		Japan	533-0024
125		Seongnam-si	Gyeonggido	Korea, Republic of	463-707
126		Busan		Korea, Republic of	49241
127		Incheon		Korea, Republic of	405-760
128		Seoul		Korea, Republic of	03080
129		Seoul		Korea, Republic of	05505
130		Seoul		Korea, Republic of	135-710
131		Seoul		Korea, Republic of	137-701
132		Bratislava		Slovakia	85107
133		Ruzomberok		Slovakia	03426
134		Trencin		Slovakia	91171
135		Zilina		Slovakia	01008
136		Zilina		Slovakia	01207
137		L'Hospitalet de Llobregat	Barcelona	Spain	08907
138		San Cugat del Vallès	Barcelona	Spain	08190
139		Barakaldo	Vizcaya	Spain	48903
140		Albacete		Spain	02006
141		Barcelona		Spain	08035
142		Sevilla		Spain	41013
143		Sevilla		Spain	41071
144		Valencia		Spain	46014
145		Valencia		Spain	46015
146		Valladolid		Spain	47012
147		Bern		Switzerland	3010
148		Lausanne		Switzerland	1004
149		Zürich		Switzerland	8063

Sponsors and Collaborators

• Bayer

Investigators

• Study Director: Bayer Study Director, Bayer

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT02222207
• Other Study ID Numbers: 15984; 2012-003763-22
• First Posted: Aug 21, 2014
• Last Update Posted: Sep 8, 2016
• Last Verified: Jul 1, 2016

• Keywords provided by Bayer: neovascular Age-related Macular Degeneration
• Additional relevant MeSH terms: Macular Degeneration; Wet Macular Degeneration; Ranibizumab

Study Results

Participant Flow

Recruitment Details	The study was conducted at 27 centers, between 10 October 2014 (first subject first visit) and 17 June 2015 (last subject last visit).
Pre-assignment Detail	Study was planned to be conducted in 2 parts, Part A and B, in Part A 89 subjects were enrolled, of them 37 were screen failure and 52 were assigned to treatment, 1 subject was excluded from all analysis sets due to protocol deviations and 51 subjects were analyzed. Part B was not initiated and the study terminated following completion of Part A.

Arm/Group Title	Part A Regorafenib
Arm/Group Description	Participants self-administered 30 milligram per milliliter (mg/mL), 25 microliter (mcL),1 drop of Regorafenib eye drops, topically thrice daily (TID) to the study eye for 12 weeks.
Period Title: Overall Study
STARTED	52
Treated and Valid for Full Analysis Set	51
COMPLETED	48
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Part A Regorafenib
Arm/Group Description	Participants self-administered 30 milligram per milliliter (mg/mL), 25 microliter (mcL),1 drop of Regorafenib eye drops, topically thrice daily (TID) to the study eye for 12 weeks.
Overall Participants	51
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	75 (8.4)
Sex: Female, Male (Count of Participants)
Female	29 56.9%
Male	22 43.1%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score at Study Week 4 for Study Part A
Description	Participants will be assessed at each clinic visit for best corrected visual acuity using the early treatment diabetic retinopathy study chart. Visual function of the study eye and the fellow eye was assessed using the ETDRS. The participant's ETDRS testing score was recorded in the appropriate eCRF page at each study visit. For participants that dropped out or received rescue treatment the last observation before drop-out or administration of rescue treatment was carried forward. A higher score represents better functioning.
Time Frame	Baseline, Week 4

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): included participants who received at least one dose of study medication.

Arm/Group Title	Part A Regorafenib
Arm/Group Description	Participants self-administered 30 milligram per milliliter (mg/mL), 25 microliter (mcL),1 drop of Regorafenib eye drops, topically thrice daily (TID) to the study eye for 12 weeks.
Measure Participants	50
Mean (Standard Deviation) [Score on scale]	1.18 (7.55)

2. Primary Outcome

Title	Change From Baseline in BCVA as Measured by ETDRS Letter Score at Study Week 12 for Study Part A
Description	Participants were assessed at each clinic visit for best corrected visual acuity using the early treatment diabetic retinopathy study chart. Visual function of the study eye and the fellow eye was assessed using the ETDRS protocol. ETDRS testing score was recorded in the appropriate eCRF page at each study visit. For participants that dropped out or received rescue treatment the last observation before drop-out or administration of rescue treatment was carried forward. A higher score represents better functioning.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): included subjects who received at least one dose of study medication.

Arm/Group Title	Part A Regorafenib
Arm/Group Description	Participants self-administered 30 milligram per milliliter (mg/mL), 25 microliter (mcL),1 drop of Regorafenib eye drops, topically thrice daily (TID) to the study eye for 12 weeks.
Measure Participants	50
Mean (Standard Deviation) [Score on scale]	-2.36 (7.68)

3. Secondary Outcome

Title	Percentage of Participants With Individual Changes in BCVA of Greater Than Equal to (>=) 0 Letters of Vision From Study Week 4 to Week 12 for Study Part A
Description	Participants were assessed at each clinic visit for BCVA using the early treatment diabetic retinopathy study chart. For participants that dropped out or received rescue treatment the last observation before drop-out or administration of rescue treatment was carried forward.
Time Frame	Week 4, Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): included subjects who received at least one dose of study medication.

Arm/Group Title	Part A Regorafenib
Arm/Group Description	Participants self-administered 30 milligram per milliliter (mg/mL), 25 microliter (mcL),1 drop of Regorafenib eye drops, topically thrice daily (TID) to the study eye for 12 weeks.
Measure Participants	50
Number [percentage of participants]	42 82.4%

4. Secondary Outcome

Title	Percentage of Participants With a Loss in BCVA of >= 10 Letters From Baseline to Study Week 12 for Study Part A
Description	Participants were assessed at each clinic visit for BCVA using the early treatment diabetic retinopathy study chart. For participants that dropped out or received rescue treatment the last observation before drop-out or administration of rescue treatment was carried forward.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): included subjects who received at least one dose of study medication.

Arm/Group Title	Part A Regorafenib
Arm/Group Description	Participants self-administered 30 milligram per milliliter (mg/mL), 25 microliter (mcL),1 drop of Regorafenib eye drops, topically thrice daily (TID) to the study eye for 12 weeks.
Measure Participants	50
Number [percentage of participants]	16 31.4%

Adverse Events

Time Frame	From the start of study treatment until 30 days after last dose of study drug treatment (up to Week 16).
Arm/Group Title	Part A Regorafenib
Arm/Group Description	Participants self-administered 30 mg/mL, 25 mcL, 1 drop of regorafenib eye drops, topically thrice daily (TID) to the study eye for 12 weeks.
All Cause Mortality
	Part A Regorafenib
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Part A Regorafenib
	Affected / at Risk (%)	# Events
Total	3/51 (5.9%)
Cardiac disorders
Acute myocardial infarction	1/51 (2%)
Injury, poisoning and procedural complications
Ankle fracture	1/51 (2%)
Investigations
Visual acuity tests abnormal	1/51 (2%)
Other (Not Including Serious) Adverse Events
	Part A Regorafenib
	Affected / at Risk (%)	# Events
Total	11/51 (21.6%)
Eye disorders
Visual acuity reduced	6/51 (11.8%)
Investigations
Visual acuity tests abnormal	5/51 (9.8%)

Limitations/Caveats

As the study was prematurely terminated since pre-defined proof of concept (PoC) criteria were not met in Part A, hence part B was not initiated. Part B related end points and data were not reported since it is not conducted.

More Information

Certain Agreements

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

In mulit centre studies result of study are to be published only through coordination by Bayer in order to combine the results of all centres. Center free to publish its results provided the overall results have not been published within 18 months from study completion (data base lock), subject to the compliance to remaining terms set forth in the PI contract.