RELIANCE: Head to Head Study of Anti-VEGF Treatment.

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02577107
• Collaborator: (none)
• Enrollment: 12
• Location: 1
• Arms: 2
• Actual Duration (Months): 5.8
• Patients Per Site Per Month: 2.1

Study Details

Study Description

Brief Summary

An exploratory single site, open label, randomized, controlled study evaluated plasma vascular endothelial growth factor levels after intravitreal injection of ranibizumab (Lucentis) and conbercept (Langmu) for neovascular age-related macular degeneration

Condition or Disease	Intervention/Treatment	Phase
Age-related Macular Degeneration	Drug: ranibizumab; Drug: Conbercept	Phase 4

Detailed Description

This prospective, randomized, open label study enrolled patients with neovascular AMD who were naïve to anti-VEGF therapy or have not received intravitreal anti-VEGF therapy for the previous 3 months. Patients were randomized in two treatment arms for 3 months:

• Study arm 1: Three monthly injections of 0.5mg Ranibizumab

• Study arm 2: Three monthly injections of 0.5mg Conbercept Blood sample (plasma/serum) was collected at baseline (pre-dose), 3h post-injections and days 1, 3, 7 and 28, following doses 1 and 3 for PK and systemic VEGF analysis. The lab staff was blinded for treatment allocation.

Plasma VEGF concentration was measured by a blinded laboratory using Quantikine® ELISA kits. Serum ranibizumab and conbercept concentration will be determined using validated ELISA assay.

The study was divided into 2 stages: the 1st initial feasibility stage with 6 patients per arm (12 patients in total) to verify SD for sample size justification and 2nd stage to confirm the findings with justified sample size.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: An Exploratory Single Site, Open Label, Randomized, Controlled Study to Evaluate Plasma Vascular Endothelial Growth Factor Levels After Intravitreal Injection of Ranibizumab (Lucentis) and Conbercept (Langmu) for nAMD
• Actual Study Start Date: Jan 13, 2016
• Actual Primary Completion Date: Jul 9, 2016
• Actual Study Completion Date: Jul 9, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ranibizumab 0.5 mg Three monthly injections of 0.5mg Ranibizumab	Drug: ranibizumab; Other Names: Lucentis
Active Comparator: Conbercept 0.5 mg Three monthly injections of 0.5mg Conbercept	Drug: Conbercept; Other Names: Langmu

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Plasma Vascular Endothelial Growth Factor (VEGF) Concentration After First Injection at Visit 5 (Day 8 +/- 1 Day) [Baseline, Visit 5 (Day 8 +/- 1 day)]

   Change from baseline in plasma Vascular endothelial growth factor (VEGF) concentration after first injection at Visit 5 (Day 8 +/- 1 day).Blood sample was collected for systemic VEGF. VEGF was measured by a blinded laboratory using ELISA kits.

Secondary Outcome Measures

1. Change From Baseline in Plasma Vascular Endothelial Growth Factor (VEGF) Concentration After Third Injection at Visit 10 (Day 67 +/- 1 Day) [Baseline, Visit 10 (Day 67 +/- 1 day)]

   Change from baseline in plasma Vascular endothelial growth factor (VEGF) concentration after third injection at Visit 10 (Day 67 +/- 1 day). Blood sample was collected for systemic VEGF. VEGF will be measured by a blinded laboratory using ELISA kits.

2. Plasma VEGF Concentration at Baseline, Visit 2, 3, 4, 5, 6 After 1st Injection [Baseline, Visit 2, 3, 4, 5, 6]

   Blood sample will be collected for systemic VEGF. VEGF will be measured by a blinded laboratory using ELISA kits. Baseline, Visit Visit 2, 3, 4, 5, 6 after 1st injection

3. Plasma VEGF Concentration at Baseline, Visit 7, 8, 9, 10, 11 After 3rd Injection [Baseline, Visit 7, 8, 9, 10, 11]

   Blood sample will be collected for systemic VEGF. VEGF will be measured by a blinded laboratory using ELISA kits. Baseline, Visit 7, 8, 9, 10, 11 after 3rd injection

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Written informed consent must be obtained before any assessment is performed.

2. Male or female patient ≥ 50 years of age.

3. Subfoveal CNV secondary to nAMD.

4. BCVA score must be between 73 and 24 letters as measured by ETDRS chart

Exclusion Criteria:

For both eyes

1. Any active periocular or ocular infection or inflammation

2. Uncontrolled glaucoma

3. Neovascularization of the iris or neovascular glaucoma. For study eye

4. Choroidal neovascularization of any other cause than wet AMD

5. Ocular disorders present that may confound interpretation of study results,

6. Previous treatment with verteporfin PDT (Visudyne®), external-beam radiation therapy, focal laser photocoagulation, vitrectomy, submacular surgery, or transpupillary thermotherapy.

7. Structural damage within 0.5 disc diameter of the center of the macula

8. Atrophy or fibrosis involving the center of the fovea.

9. Inability of obtaining required lab report. Ocular medical history

10. History of intravitreal injection with any anti-VEGF drugs within 3 months. Exclusion criteria for systemic medical conditions and treatment

11. Any type of systemic disease or its treatment

12. Any patients diagnosed with tumor.

13. Stroke or myocardial infarction less than 3 months.

14. Known hypersensitivity to indocyanine green, fluorescein, or any component of the investigational drug formulation.

15. Use of any systemic anti-VEGF drugs within 6 months. Exclusion criteria for patient

16. Patients who have participated in other investigational drug study within 60 days.

17. Pregnant or nursing (lactating) women.

18. Inability to comply with study or follow-up procedures.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Chengdu	Sichuan	China	610041

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: NCT02577107
• Other Study ID Numbers: CRFB002ACN07
• First Posted: Oct 16, 2015
• Last Update Posted: Nov 30, 2017
• Last Verified: Jul 1, 2017

• 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: Age-related macular degeneration,; ranibizumab,; conbercept,; plasma VEGF; PK
• Additional relevant MeSH terms: Macular Degeneration; Ranibizumab

Study Results

Participant Flow

Arm/Group Title	Ranibizumab 0.5 mg	Conbercept 0.5 mg
Arm/Group Description	Three monthly injections of 0.5mg Ranibizumab	Three monthly injections of 0.5mg Conbercept
Period Title: Overall Study
STARTED	6	6
COMPLETED	6	5
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Ranibizumab 0.5 mg	Conbercept 0.5 mg	Total
Arm/Group Description	Three monthly injections of 0.5mg Ranibizumab	Three monthly injections of 0.5mg Conbercept	Total of all reporting groups
Overall Participants	6	6	12
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.3 (5.50)	69.3 (8.41)	67.3 (7.09)
Sex: Female, Male (Count of Participants)
Female	0 0%	1 16.7%	1 8.3%
Male	6 100%	5 83.3%	11 91.7%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Plasma Vascular Endothelial Growth Factor (VEGF) Concentration After First Injection at Visit 5 (Day 8 +/- 1 Day)
Description	Change from baseline in plasma Vascular endothelial growth factor (VEGF) concentration after first injection at Visit 5 (Day 8 +/- 1 day).Blood sample was collected for systemic VEGF. VEGF was measured by a blinded laboratory using ELISA kits.
Time Frame	Baseline, Visit 5 (Day 8 +/- 1 day)

Outcome Measure Data

Analysis Population Description

Per-protocol Set refers to all subjects who completed the study without any major deviation from the study protocol.

Arm/Group Title	Ranibizumab 0.5 mg	Conbercept 0.5 mg
Arm/Group Description	Three monthly injections of 0.5mg Ranibizumab	Three monthly injections of 0.5mg Conbercept
Measure Participants	6	5
Mean (Standard Deviation) [pg/mL]	5.720 (9.5547)	-25.833 (22.8145)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Conbercept 0.5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	20.314
	Confidence Interval	(2-Sided) 95%; 9.618 to 31.011
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.1613
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Plasma Vascular Endothelial Growth Factor (VEGF) Concentration After Third Injection at Visit 10 (Day 67 +/- 1 Day)
Description	Change from baseline in plasma Vascular endothelial growth factor (VEGF) concentration after third injection at Visit 10 (Day 67 +/- 1 day). Blood sample was collected for systemic VEGF. VEGF will be measured by a blinded laboratory using ELISA kits.
Time Frame	Baseline, Visit 10 (Day 67 +/- 1 day)

Outcome Measure Data

Analysis Population Description

Per-protocol Set refers to all subjects who completed the study without any major deviation from the study protocol.

Arm/Group Title	Ranibizumab 0.5 mg	Conbercept 0.5 mg
Arm/Group Description	Three monthly injections of 0.5mg Ranibizumab	Three monthly injections of 0.5mg Conbercept
Measure Participants	6	5
Mean (Standard Deviation) [pg/mL]	-0.100 (17.4799)	-22.220 (12.9239)

3. Secondary Outcome

Title	Plasma VEGF Concentration at Baseline, Visit 2, 3, 4, 5, 6 After 1st Injection
Description	Blood sample will be collected for systemic VEGF. VEGF will be measured by a blinded laboratory using ELISA kits. Baseline, Visit Visit 2, 3, 4, 5, 6 after 1st injection
Time Frame	Baseline, Visit 2, 3, 4, 5, 6

Outcome Measure Data

Analysis Population Description

Per-protocol Set refers to all subjects who completed the study without any major deviation from the study protocol.

Arm/Group Title	Ranibizumab 0.5 mg	Conbercept 0.5 mg
Arm/Group Description	Three monthly injections of 0.5mg Ranibizumab	Three monthly injections of 0.5mg Conbercept
Measure Participants	6	5
Baseline	31.400 (6.3816)	42.200 (23.4269)
Visit 2 (Day 1)	30.958 (19.9813)	14.920 (12.4920)
Visit 3 (Day 2 +/- 1)	36.517 (19.2783)	24.590 (39.2435)
Visit 4 (Day 4 +/- 1)	29.150 (5.5587)	7.213 (4.9250)
Visit 5 (Day 8 +/- 1)	37.000 (4.7979)	19.075 (4.5051)
Visit 6 (Day 30 +/- 4)	27.092 (13.2356)	25.270 (15.0967)

4. Secondary Outcome

Title	Plasma VEGF Concentration at Baseline, Visit 7, 8, 9, 10, 11 After 3rd Injection
Description	Blood sample will be collected for systemic VEGF. VEGF will be measured by a blinded laboratory using ELISA kits. Baseline, Visit 7, 8, 9, 10, 11 after 3rd injection
Time Frame	Baseline, Visit 7, 8, 9, 10, 11

Outcome Measure Data

Analysis Population Description

Per-protocol Set refers to all subjects who completed the study without any major deviation from the study protocol.

Arm/Group Title	Ranibizumab 0.5 mg	Conbercept 0.5 mg
Arm/Group Description	Three monthly injections of 0.5mg Ranibizumab	Three monthly injections of 0.5mg Conbercept
Measure Participants	6	5
Baseline	36.250 (11.8610)	36.520 (19.2278)
Visit 7 (Day 60 +/- 4)	34.383 (12.7727)	5.720 (2.1690)
Visit 8 (Day 61 +/- 1)	46.533 (48.1293)	6.820 (4.6287)
Visit 9 (Day 63 +/- 1)	54.067 (40.2585)	8.070 (4.6452)
Visit 10 (Day 67 +/- 1)	36.150 (25.4399)	14.300 (9.6690)
Visit 11 (Day 90 +/- 4)	45.067 (18.0828)	56.020 (27.0819)

Adverse Events

Time Frame	Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
Arm/Group Title	Ranibizumab 0.5 mg		Conbercept 0.5 mg
Arm/Group Description	Three monthly injections of 0.5mg Ranibizumab		Three monthly injections of 0.5mg Conbercept
All Cause Mortality
	Ranibizumab 0.5 mg		Conbercept 0.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ranibizumab 0.5 mg		Conbercept 0.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		2/6 (33.3%)
Infections and infestations
Infectious pneumonia	0/6 (0%)		1/6 (16.7%)
Injury, poisoning and procedural complications
Craniocerebral injury	0/6 (0%)		1/6 (16.7%)
Fracture of jaw	0/6 (0%)		1/6 (16.7%)
Fracture of rib	0/6 (0%)		1/6 (16.7%)
Pulmonary contusion	0/6 (0%)		1/6 (16.7%)
Thoracic injury	0/6 (0%)		1/6 (16.7%)
Respiratory, thoracic and mediastinal disorders
COPD	0/6 (0%)		1/6 (16.7%)
Other (Not Including Serious) Adverse Events
	Ranibizumab 0.5 mg		Conbercept 0.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/6 (16.7%)		3/6 (50%)
Ear and labyrinth disorders
Dizziness	0/6 (0%)		1/6 (16.7%)
Eye disorders
Conjunctival congestion	0/6 (0%)		1/6 (16.7%)
Infections and infestations
Upper respiratory infection	1/6 (16.7%)		1/6 (16.7%)
Nervous system disorders
Headache	0/6 (0%)		1/6 (16.7%)
Migraine	1/6 (16.7%)		0/6 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/6 (0%)		1/6 (16.7%)

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.