TWEYES: Safety and Tolerability of Ranibizumab in Mono/Bilateral Wet Age Related Macular Degeneration (w-AMD) Patients in Eyes With BCVA<2/10 and/or 2nd Affected Eye

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01986907
• Collaborator: (none)
• Enrollment: 1,049
• Locations: 101
• Arm: 1
• Actual Duration (Months): 27.4
• Patients Per Site: 10.4
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety and efficacy of ranibizumab in patients affected by wet age related macular degeneration (wAMD).

Condition or Disease	Intervention/Treatment	Phase
Wet Age Related Macular Degeneration	Drug: ranibizumab	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 1049 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 12 Months, Prospective, Multicenter, Open-label, Single Arm Interventional Study Assessing the Safety and Tolerability of 0.5 mg Ranibizumab in Mono/Bilateral Wet AMD Patients in Eyes With (Best-Corrected Distance Visual Acuity) BCVA Below 2/10 and/or Second Affected Eye
• Actual Study Start Date: Mar 4, 2014
• Actual Primary Completion Date: Jun 15, 2016
• Actual Study Completion Date: Jun 15, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Ranibizumab Administered as an Intravitreal injection

Drug: ranibizumab; All patients will receive ranibizumab 0.5 mg/0.05 ml according to approved label: treatment is given monthly until maximum VA is achieved (i.e. stable VA for three consecutive monthly assessments performed while on ranibizumab treatment). Thereafter according to approved label, patients should be monitored monthly for visual acuity and treatment is to be resumed when monitoring indicates loss of visual acuity due to disease activity. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections).

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Systemic Drug-related Adverse Events [Baseline to Month 12]

   Monitoring and recording all adverse events, including serious adverse events.

2. Number of Eyes With Ocular Drug-related Adverse Events [Baseline to Month 12]

   Monitoring and recording all adverse events, including serious adverse events.

Secondary Outcome Measures

1. Overall Number of Ranibizumab Injections [Baseline to month 12]

2. Time Interval Between Injections in Bilateral Disease [Baseline to month 12]

   Mean number of days between two consecutive injections per eye

3. Mean Number of Injections Per Patient [Baseline to month 12]

   Number of injections per patient

Eligibility Criteria

Criteria

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

Inclusion Criteria

Male or female patients aged 50 years or above Willing and capable to provide informed written consent Eye(s) eligible for ranibizumab treatment, with a BCVA below 2/10 due to wet AMD and/or Second eye eligible for ranibizumab treatment, with first eye treated (currently or previously) with ranibizumab, whichever BCVA. In bilateral wAMD patients, the second eye can be included only if the first eye has been treated at least 14 days before with ranibizumab

Exclusion Criteria:

Active intraocular inflammation (grade trace or above) in either eye Any ocular or periocular active infection (current or suspected), e.g. conjunctivitis, keratitis, scleritis, uveitis, endophtalmitis, in either eye Risk factors for retinal pigment epithelial tear (including pigment epithelial retinal detachment) Ocular disorders that may confound interpretation of results compromise visual acuity or require medical or surgical intervention during the study period including cataract, retinal vascular occlusion, retinal detachment or macular hole Uncontrolled glaucoma in either eye (IOP ≥ 30 mmHg on medication or according to investigator's judgment) History of vitrectomy in the study eye History of stroke or transient ischemic attack Systemic treatment with any VEGF inhibitor in the 90 days prior to study enrollment Ocular treatment of the study eye with any anti-angiogenic drugs within 1 month prior to study enrollment Any intraocular surgery in the study eye within 28 days prior to enrollment Women of childbearing potential UNLESS using effective contraception during treatment Pregnant or lactating women Simultaneous participation in a study that includes administration of any investigational drug Known hypersensitivity to ranibizumab or any component of the ranibizumab formulation Inability to comply with study procedures.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Alessandria	AL	Italy	15100
2	Novartis Investigative Site	Casale Monferrato	AL	Italy	15033
3	Novartis Investigative Site	Ancona	AN	Italy	60126
4	Novartis Investigative Site	Acquaviva delle Fonti	BA	Italy	70021
5	Novartis Investigative Site	Putignano	BA	Italy	70017
6	Novartis Investigative Site	Terlizzi	BA	Italy	70038
7	Novartis Investigative Site	Bergamo	BG	Italy	24127
8	Novartis Investigative Site	Belluno	BL	Italy	32100
9	Novartis Investigative Site	Bologna	BO	Italy	40138
10	Novartis Investigative Site	Brescia	BS	Italy	25123
11	Novartis Investigative Site	Desenzano del Garda	BS	Italy	25015
12	Novartis Investigative Site	Bolzano	BZ	Italy	39100
13	Novartis Investigative Site	Cagliari	CA	Italy	09124
14	Novartis Investigative Site	Larino	CB	Italy
15	Novartis Investigative Site	Caserta	CE	Italy	81100
16	Novartis Investigative Site	Chieti	CH	Italy	66100
17	Novartis Investigative Site	Ceva	CN	Italy	12073
18	Novartis Investigative Site	Cuneo	CN	Italy	12100
19	Novartis Investigative Site	Como	CO	Italy	22100
20	Novartis Investigative Site	San Feramo Della Battaglia	CO	Italy	22020
21	Novartis Investigative Site	Acireale	CT	Italy	95024
22	Novartis Investigative Site	Catania	CT	Italy	95123
23	Novartis Investigative Site	Catania	CT	Italy	95124
24	Novartis Investigative Site	Catanzaro	CZ	Italy	88100
25	Novartis Investigative Site	Forlì	FC	Italy	47100
26	Novartis Investigative Site	Cona	FE	Italy	44100
27	Novartis Investigative Site	Foggia	FG	Italy	71100
28	Novartis Investigative Site	San Giovanni Rotondo	FG	Italy	71013
29	Novartis Investigative Site	Genova	GE	Italy	16132
30	Novartis Investigative Site	Genova	GE	Italy	16153
31	Novartis Investigative Site	Rapallo	GE	Italy	16035
32	Novartis Investigative Site	Crotone	KR	Italy	88074
33	Novartis Investigative Site	Tricase	LE	Italy	73039
34	Novartis Investigative Site	Terracina	LT	Italy	04019
35	Novartis Investigative Site	Messina	ME	Italy	98125
36	Novartis Investigative Site	Milazzo	ME	Italy	98057
37	Novartis Investigative Site	Cinisello Balsamo	MI	Italy	20092
38	Novartis Investigative Site	Legnano	MI	Italy	20025
39	Novartis Investigative Site	Milano	MI	Italy	20100
40	Novartis Investigative Site	Milano	MI	Italy	20122
41	Novartis Investigative Site	Milano	MI	Italy	20123
42	Novartis Investigative Site	Milano	MI	Italy	20132
43	Novartis Investigative Site	Milano	MI	Italy	20142
44	Novartis Investigative Site	Rozzano	MI	Italy	20089
45	Novartis Investigative Site	Vizzolo Predabissi	MI	Italy	20070
46	Novartis Investigative Site	Nuoro	NU	Italy	08100
47	Novartis Investigative Site	Palermo	PA	Italy	90127
48	Novartis Investigative Site	Palermo	PA	Italy	90146
49	Novartis Investigative Site	Piacenza	PC	Italy	29100
50	Novartis Investigative Site	Camposampiero	PD	Italy	35012
51	Novartis Investigative Site	Monselice	PD	Italy	35043
52	Novartis Investigative Site	Padova	PD	Italy	35100
53	Novartis Investigative Site	Padova	PD	Italy	35128
54	Novartis Investigative Site	Pescara	PE	Italy	65124
55	Novartis Investigative Site	Citta' di Castello	PG	Italy	06012
56	Novartis Investigative Site	Foligno	PG	Italy	06034
57	Novartis Investigative Site	Perugia	PG	Italy	06100
58	Novartis Investigative Site	Pordenone	PN	Italy	33170
59	Novartis Investigative Site	Parma	PR	Italy	43100
60	Novartis Investigative Site	Pavia	PV	Italy	27100
61	Novartis Investigative Site	Reggio Calabria	RC	Italy	89124
62	Novartis Investigative Site	Correggio	RE	Italy	42015
63	Novartis Investigative Site	Reggio Emilia	RE	Italy	42123
64	Novartis Investigative Site	Civitavecchia	RM	Italy	00053
65	Novartis Investigative Site	Roma	RM	Italy	00133
66	Novartis Investigative Site	Roma	RM	Italy	00161
67	Novartis Investigative Site	Roma	RM	Italy	00168
68	Novartis Investigative Site	Roma	RM	Italy	00184
69	Novartis Investigative Site	Roma	RM	Italy	00186
70	Novartis Investigative Site	Roma	RM	Italy	00189
71	Novartis Investigative Site	Riccione	RN	Italy	47838
72	Novartis Investigative Site	Eboli	SA	Italy	84025
73	Novartis Investigative Site	Salerno	SA	Italy	84131
74	Novartis Investigative Site	Sondrio	SO	Italy	23100
75	Novartis Investigative Site	Sarzana	SP	Italy	19038
76	Novartis Investigative Site	Sassari	SS	Italy	07100
77	Novartis Investigative Site	Savona	SV	Italy	17100
78	Novartis Investigative Site	Taranto	TA	Italy	74100
79	Novartis Investigative Site	Teramo	TE	Italy	64100
80	Novartis Investigative Site	Torino	TO	Italy	10122
81	Novartis Investigative Site	Torino	TO	Italy	10152
82	Novartis Investigative Site	Torino	TO	Italy	10153
83	Novartis Investigative Site	Terni	TR	Italy	05100
84	Novartis Investigative Site	Trieste	TS	Italy	34129
85	Novartis Investigative Site	Conegliano	TV	Italy	31015
86	Novartis Investigative Site	Treviso	TV	Italy	31100
87	Novartis Investigative Site	Udine	UD	Italy	33100
88	Novartis Investigative Site	Busto Arsizio	VA	Italy	21052
89	Novartis Investigative Site	Somma Lombardo	VA	Italy	21019
90	Novartis Investigative Site	Varese	VA	Italy	21100
91	Novartis Investigative Site	Santorso	VI	Italy	36014
92	Novartis Investigative Site	Vicenza	VI	Italy	36100
93	Novartis Investigative Site	Legnago	VR	Italy	37045
94	Novartis Investigative Site	Negrar	VR	Italy	37024
95	Novartis Investigative Site	Verona	VR	Italy	37126
96	Novartis Investigative Site	Borgomanero		Italy	28021
97	Novartis Investigative Site	Galliate		Italy	28066
98	Novartis Investigative Site	Napoli		Italy	80131
99	Novartis Investigative Site	Napoli		Italy	80132
100	Novartis Investigative Site	Napoli		Italy	80138
101	Novartis Investigative Site	Pozzuoli		Italy	80078

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01986907
• Other Study ID Numbers: CRFB002AIT02; 2013-003333-15
• First Posted: Nov 19, 2013
• Last Update Posted: Jul 19, 2019
• Last Verified: May 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: wet AMD; macular degeneration; ranibizumab; mono-bilateral; poor visual acuity; retinal disease; eye disease; Angiogenesis Inhibitors; Angiogenesis Modulating Agents
• Additional relevant MeSH terms: Macular Degeneration; Ranibizumab

Study Results

Participant Flow

Recruitment Details	Patients were recruited from investigative sites located in Italy.
Pre-assignment Detail	This reporting group includes all treated patients (one eye or both eyes)

Arm/Group Title	Ranibizumab
Arm/Group Description	patients treated with 0.5mg ranibizumab
Period Title: Overall Study
STARTED	936
COMPLETED	774
NOT COMPLETED	162

Baseline Characteristics

Arm/Group Title	Ranibizumab
Arm/Group Description	patients treated with 0.5mg ranibizumab
Overall Participants	936
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	78.68 (7.34)
Age, Customized (Count of Participants)
18 to less than 65 years	33 3.5%
65 to 74 years	212 22.6%
75 to 84 years	483 51.6%
85 years and older	208 22.2%
Sex: Female, Male (Count of Participants)
Female	582 62.2%
Male	354 37.8%
Treatment by Eye (Count of Participants)
Unilateral treatment	823 87.9%
Bilateral treatment	113 12.1%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Systemic Drug-related Adverse Events
Description	Monitoring and recording all adverse events, including serious adverse events.
Time Frame	Baseline to Month 12

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	Ranibizumab
Arm/Group Description	patients treated with 0.5mg ranibizumab
Measure Participants	936
Serious Adverse Event	3 0.3%
Non Serious Adverse Event	0 0%

2. Secondary Outcome

Title	Overall Number of Ranibizumab Injections
Time Frame	Baseline to month 12

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	Ranibizumab
Arm/Group Description	patients treated with 0.5mg ranibizumab
Measure Participants	936
Mean (Standard Deviation) [injections per patient]	5.97 (3.62)

3. Secondary Outcome

Title	Time Interval Between Injections in Bilateral Disease
Description	Mean number of days between two consecutive injections per eye
Time Frame	Baseline to month 12

Outcome Measure Data

Analysis Population Description

This analysis population includes all eyes naïve to ranibizumab, i.e., had not been treated with the study medication (or with the equivalent commercial formulation) before the first study drug injection, regardless of whether the contralateral eye had been treated.

Arm/Group Title	Ranibizumab
Arm/Group Description	patients treated with 0.5mg ranibizumab
Measure Participants	936
Measure eyes	771
Mean (Standard Deviation) [days]	51.94 (26.56)

4. Secondary Outcome

Title	Mean Number of Injections Per Patient
Description	Number of injections per patient
Time Frame	Baseline to month 12

Outcome Measure Data

Analysis Population Description

Safety set

Arm/Group Title	Ranibizumab Overall	Unilaterally Treted	Bilaterally Treated
Arm/Group Description	patients treated with 0.5mg ranibizumab
Measure Participants	936	823	113
Mean (Standard Deviation) [injections]	5.97 (3.62)	5.35 (2.88)	10.55 (4.98)

5. Primary Outcome

Title	Number of Eyes With Ocular Drug-related Adverse Events
Description	Monitoring and recording all adverse events, including serious adverse events.
Time Frame	Baseline to Month 12

Outcome Measure Data

Analysis Population Description

Safety Set

Arm/Group Title	Ranibizumab
Arm/Group Description	patients treated with 0.5mg ranibizumab
Measure Participants	936
Measure eyes	1049
Serious Adverse Event	1
Non Serious Adverse Event	8

Adverse Events

Time Frame	Adverse events are reported from time of first treatment until study exit (approximately 12 months)
Adverse Event Reporting Description	This reporting group (Safety Population) includes all treated participants (one or both eyes).
Arm/Group Title	Ranibizumab 0.5 mg
Arm/Group Description	Ranibizumab 0.5 mg
All Cause Mortality
	Ranibizumab 0.5 mg
	Affected / at Risk (%)	# Events
Total	9/936 (1%)
Serious Adverse Events
	Ranibizumab 0.5 mg
	Affected / at Risk (%)	# Events
Total	63/936 (6.7%)
Blood and lymphatic system disorders
Anaemia	2/936 (0.2%)
Bone marrow disorder	1/936 (0.1%)
Cardiac disorders
Angina pectoris	1/936 (0.1%)
Atrial fibrillation	2/936 (0.2%)
Atrioventricular block	1/936 (0.1%)
Cardiac arrest	1/936 (0.1%)
Cardiac failure	3/936 (0.3%)
Myocardial infarction	1/936 (0.1%)
Myocardial ischaemia	1/936 (0.1%)
Endocrine disorders
Goitre	1/936 (0.1%)
Eye disorders
Ocular hypertension	1/936 (0.1%)
Retinal haemorrhage	1/936 (0.1%)
Vitreous haemorrhage	1/936 (0.1%)
Gastrointestinal disorders
Faecaloma	1/936 (0.1%)
Gastritis	1/936 (0.1%)
Intestinal haemorrhage	1/936 (0.1%)
Intestinal obstruction	2/936 (0.2%)
Large intestine polyp	1/936 (0.1%)
Lumbar hernia	1/936 (0.1%)
Vomiting	1/936 (0.1%)
General disorders
Asthenia	1/936 (0.1%)
General physical health deterioration	1/936 (0.1%)
Hepatobiliary disorders
Hepatic lesion	1/936 (0.1%)
Infections and infestations
Escherichia sepsis	1/936 (0.1%)
Herpes zoster	1/936 (0.1%)
Influenza	1/936 (0.1%)
Pneumonia	5/936 (0.5%)
Pyelonephritis	1/936 (0.1%)
Sepsis	1/936 (0.1%)
Urinary tract infection	1/936 (0.1%)
Injury, poisoning and procedural complications
Fall	1/936 (0.1%)
Femur fracture	7/936 (0.7%)
Humerus fracture	1/936 (0.1%)
Lower limb fracture	1/936 (0.1%)
Pancreatic injury	1/936 (0.1%)
Pelvic fracture	1/936 (0.1%)
Metabolism and nutrition disorders
Hyponatraemia	1/936 (0.1%)
Musculoskeletal and connective tissue disorders
Arthritis	1/936 (0.1%)
Intervertebral disc protrusion	1/936 (0.1%)
Osteoarthritis	2/936 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	1/936 (0.1%)
Lung neoplasm malignant	3/936 (0.3%)
Metastases to central nervous system	1/936 (0.1%)
Prostate cancer recurrent	1/936 (0.1%)
Nervous system disorders
Cerebral haemorrhage	1/936 (0.1%)
Cerebrovascular accident	1/936 (0.1%)
Cognitive disorder	2/936 (0.2%)
Dizziness	1/936 (0.1%)
Myasthenia gravis	1/936 (0.1%)
Syncope	1/936 (0.1%)
Transient ischaemic attack	3/936 (0.3%)
Renal and urinary disorders
Acute kidney injury	1/936 (0.1%)
Haematuria	1/936 (0.1%)
Renal cyst	1/936 (0.1%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	2/936 (0.2%)
Dyspnoea	1/936 (0.1%)
Lung disorder	1/936 (0.1%)
Pleural effusion	1/936 (0.1%)
Pneumonitis	1/936 (0.1%)
Pneumothorax	1/936 (0.1%)
Pulmonary embolism	2/936 (0.2%)
Pulmonary oedema	2/936 (0.2%)
Respiratory disorder	1/936 (0.1%)
Respiratory failure	1/936 (0.1%)
Surgical and medical procedures
Mastectomy	1/936 (0.1%)
Transurethral prostatectomy	1/936 (0.1%)
Vascular disorders
Peripheral artery stenosis	1/936 (0.1%)
Peripheral ischaemia	1/936 (0.1%)
Other (Not Including Serious) Adverse Events
	Ranibizumab 0.5 mg
	Affected / at Risk (%)	# Events
Total	76/936 (8.1%)
Eye disorders
Cataract	10/936 (1.1%)
Conjunctival haemorrhage	13/936 (1.4%)
Neovascular age-related macular degeneration	34/936 (3.6%)
General disorders
Pyrexia	10/936 (1.1%)
Infections and infestations
Influenza	15/936 (1.6%)

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 trial results in their entirety.