# Presentation: 501757

## Vitrase (Hyaluronidase for Injection)

- Advisory Committee Meeting
- March 17, 2003
- Jennifer D. Harris, MD
- Medical Officer
- Division of Anti-inflammatory, Analgesic, and Ophthalmic
- Drug Products
- Food and Drug Administration

## Overview

- Choice of Endpoints
- Issues surrounding their validity
- p-value Correction for Multiple    Endpoints
- Efficacy Results
- Safety Considerations
- Conclusions

## Choice of Endpoints

- Proposed Composite
- Clearance of Vitreous Hemorrhage
- Best Corrected Visual Acuity (BCVA)

## Proposed Composite

- Patients were classified as a ‘success’ if the hemorrhage cleared sufficiently to facilitate the diagnosis of the underlying retinal pathology and to provide treatment, if necessary, of the underlying condition

## Proposed Composite

- Laser treatment completed
***or***
- Visualization of the retina revealed that surgery was required and was performed to correct the underlying pathology (e.g., vitrectomy for macular traction detachment, cryo-retinopexy for retinal tear, scleral buckle for peripheral detachment, etc.),
***or***
- Visualization of the macula and a minimum of 180 degrees of the vitreous base allowed for a diagnosis that the underlying cause of the hemorrhage had been resolved without the need for further therapy and with documentation by a fundus photograph.

## Laser Treatment Completed

- Ill-defined
- Variable between ophthalmologists
- Many causes of VH not amenable to laser treatment

## Visualization of Retina

- Potentially clinically meaningful:
- if it allows for earlier diagnosis of pathology
- if the earlier diagnosis translates into better patient outcomes
- Patient is now exposed to additional invasive procedure

## Visualization of Macula

- Potentially clinically meaningful
- macula clear - patient’s vision should be improved
- What about the other 180° ?

## Proposed Composite

- Potentially useful as a surrogate endpoint if it can be   validated as clinically meaningful
- Interpretation may be difficult based on variability (Style of Practice)
- Underlying pathology may be missed
- Patients may be exposed to two invasive procedures

## Surrogate Endpoints and Validation

- Surrogate Endpoints -
- do not directly measure how a patient feels, functions, 	or survives
- substitute for a clinically meaningful endpoint
- Must Validate -
- adequate and well controlled trials to show that the intervention on the surrogate endpoint translates into the desired clinical outcome

## Proposed Composite

- Potential surrogate
- Not validated
- Validation plan not completed
- Therefore, endpoint not accepted by the Agency

## Vitreous Hemorrhage Density

**Grading Scale**
- Grade 0 - view of the retina/easily treatable
- Grade 1 - retinal detail visible, some hemorrhage present but laser   photocoagulation would still be possible
- Grade 2 - large retinal vessels visible, central retinal detail is not visible enough to adequately place panretinal photocoagulation posterior to the equator
- Grade 3 - red reflex is visible but no central retinal detail is seen posterior to the equator
- Grade 4 - no red reflex

## Vitreous Hemorrhage Density

**Success Criteria**
- Proliferative diabetic retinopathy (PDR) - at   least 6 clock hours with density grades of 0 or 1
- Branch retinal vein occlusion (BRVO) - at least 3 clock hours with density grades of 0 or 1

## Vitreous Hemorrhage Density

- Clinical meaning not validated
- Impact on trial design
- Only addresses vitreous hemorrhage associated with PDR or BRVO
- Does not address retinal tears, detachments, trauma, etc.

## Improvement in BCVA

- Doubling of the Visual Angle
- 3 step change on ETDRS (Early Treatment Diabetic Retinopathy Study)
- Vision Chart (e.g. 20/80  20/40, etc)

## Improvement in BCVA

-  Universally Accepted
-  Clinically Meaningful
- “Gold Standard” for Clinical   	Trials

## Multiple Endpoints	

- 3 Doses      *with*   3 Possible Endpoints     *at*  3 Different Timepoints
- 7.5 IU Vitrase		Proposed Composite		Month 1
- 55 IU Vitrase		Clearance of VH		Month 2
- 75 IU Vitrase		BCVA				Month 3

## p-value ?

- 		   Dose 1	   Dose 2	     Dose 3
- timepoint 1
- timepoint 2
- timepoint 3

- ?

- p = 0.05 0.0459
- 3 endpoints + 3 doses + 3 timepoints  p = 0.0051 	(0.0459/9)
- 1 endpoint + 1 dose + 3 timepoints  p = 0.0153 (0.0459/3)

## Cumulative Percentages of Patients Achieving a 3-Line Improvement in BCVAStudy VIT-02

- <date/time>

- Cumulative Percentages of Patients Achieving a 3-Line Improvement in BCVAStudy VIT-02

- 		Saline Control 	7.5 IU Vitrase	55 IU Vitrase	75 IU Vitrase
- 	n=193		n=181		n=179		n=197
- Month 1		34 (17.6)	**54 (29.8%)**	50 (27.9%)	**62 (31.5%)**				**p=0.008**		p=0.024		**p=0.002**
- Month 2		51 (26.4%)	61 (33.7%)**	****70 (39.1%)****	****79 (40.1%)**
**	****	****	****	**p=0.155		**p=0.012****	****	****p=0.006**
- Month 3		70 (36.3%)	67 (37.0%)	78 (43.6%)	89 (45.2%)				p=0.966		p=0.183		p=0.092

## Cumulative Percentages of Patients Achieving a 3-Line Improvement in BCVAStudy VIT-03

- 		Saline Control	55 IU Vitrase	75 IU Vitrase
- 		n=190		n=186		n=180
- Month 1		43 (22.6%)	62 (33.3%)	43 (23.9%)
- 				p=0.028		p=0.870
- Month 2		54 (28.4%)	**80 (43.0%)**	65 (36.1%)
- 				**p=0.004****	**	p=0.141
- Month 3		62 (32.6%)	**86 (46.2%)**	75 (41.7%)
- 				**p=0.009****	**	p=0.091

## 55IU Vitrase vs. Saline at 2 monthsVIT-02

## 55 IU Vitrase vs. Saline at 2 monthsVIT-03

## Cumulative Percentages with Reduction in Vitreous Hemorrhage DensityVIT-02

- 		Saline Control	7.5 IU Vitrase	55 IU Vitrase	75 IU Vitrase
- 		n=193		n=181		n=179		n=197
- month 1		22 (11.4%)	**45 (24.9%)**	37 (20.7%)	**48 (24.4%)**
- 				**p=0.001**		p=0.021		**p=0.001**
- month 2		45 (23.3%)	60 (33.1%)	**63 (35.2%)**	**71 (36.0%)**
- 				p=0.046		**p=0.016****	**	**p=0.008**
- month 3		61 (31.6%)	65 (35.9%)	73 (40.8%)	84 (42.6%)
- 				p=0.441		p=0.083		p=0.032

## Cumulative Percentages with Reduction in Vitreous Hemorrhage DensityVIT-03

- 		Saline Control	55 IU Vitrase	75 IU Vitrase
- 		n=190		n=186		n=180
- Month 1		20 (10.5%)	**37 (19.9%)**	24 (13.3%)
- 				**p=0.017**		p=0.501
- Month 2		37 (19.5%)	**57 (30.6%)**	43 (23.9%)
- 				**p=0.017****	**	p=0.366
- Month 3		48 (25.3%)	68 (36.6%)	60 (33.3%)
- 				p=0.024		p=0.111

## Cumulative Incidence of Patients Achieving Proposed Composite VIT-02 

- 		Saline Control	7.5 IU Vitrase	55 IU Vitrase	75 IU Vitrase
- 		n=193		n=181		n=179		n=197
- month 1		12 (6.2%)	23 (12.7%)	**27 (15.1%)**	**28 (14.2%)**
- 				p=0.048		**p=0.009**		**p=0.015**
- month 2		33 (17.1%)	46 (25.4%)	**56 (31.3%)**	**55 (27.9%)**
- 				p=0.065		**p=0.002**		**p=0.015**
- month 3		57 (29.5%)	57 (31.5%)	68 (38.0%)	70 (35.5%)
- 				p=0.765		p=0.106		p=0.248

## Cumulative Incidence of Patients Achieving Proposed Composite VIT-03

- 		Saline Control	55 IU Vitrase	75 IU Vitrase
- 		n=190		n=186		n=180
- Month 1		9 (4.7%)		21 (11.3%)	12 (6.7%)
- 				p=0.031		p=0.564
- Month 2		29 (15.3%)	37 (19.9%)	25 (13.9%)
- 				p=0.296		p=0.820
- Month 3		41 (21.6%)	52 (28.0%)	45 (25.0%)
- 				p=0.189		p=0.512

## Cumulative Incidence of Vitrectomy at Each Post-treatment Visit VIT-02

- 		Saline Control	7.5 IU Vitrase	55 IU Vitrase	75 IU Vitrase
- 		n=193		n=181		n=179		n=197
- on or prior to	3 (1.6%)		7 (3.9%)		1 (0.6%)		2 (1.0%)
- month 1
- on or prior to	9 (4.7%)		12 (6.6%)	11 (6.1%)	7 (3.6%)
- month 2
- on or prior to	48 (24.9%)	50 (27.6%)	36 (20.1%)	46 (23.4%)
- month 3
- on or prior to	83 (43%)	90 (49.7%)	77 (43.0%)	89 (45.2%)
- month 12

## Cumulative Incidence of Vitrectomy at Each Post-treatment Visit VIT-03

- 			Saline Control	55 IU Vitrase	75 IU Vitrase
- 			n=190		n=186		n=180
- on or prior to		4 (2.1%)		3 (1.6%)		1 (0.6%)
- month 1
- on or prior to		8 (4.2%)		5 (2.7%)		4 (2.2%)
- month 2
- on or prior to		29 (15.3%)	21 (11.3%)	25 (13.9%)
- month 3
- on or prior to		62 (32.6%)	51 (27.4%)	58 (32.2%)
- month 12

## Discontinued PatientsVIT-02

- 		Saline Control	7.5 IU Vitrase	55 IU Vitrase	75 IU Vitrase
- 		n=193		n=181		n=179		n=197
- month 1		9 (4.7%)		8 (4.4%)		10 (5.6%)	14 (7.1%)
- month 2		4 (2.1%)		6 (3.3%)		4 (2.2%)		6 (3.0%)
- month 3		6 (3.1%)		6 (3.3%)		4 (2.2%)		6 (3.0%)
- cumulative	19 (9.9%)	20 (11.0%)	18 (10%)	26 (13.2%)

## Discontinued PatientsVIT-03

- 		Saline Control	55 IU Vitrase	75 IU Vitrase
- 		n=190		n=186		n=180
- Month 1		7 (3.7%)		5 (2.7%)		2 (1.1%)
- Month 2		0 		3 (1.6%)		3 (1.7%)
- Month 3		7 (3.7%)		1 (0.54%)	3 (1.7%)
- cumulative	14 (7.4%)	9 (4.8%)		8 (4.4%)

## Death Rate

**Study****	****	****	****% (# deaths)**
- VIT-02		5.4% (40/740)
- VIT-03		5.1% (28/551)

- Majority of Causes: Cardiovascular (MI, Embolus, Stroke, etc)
- Other Causes: Renal Failure, Sepsis, Malignancy

## Safety

- Similar events seen in all treatment groups
- Most are likely to be related to intraocular injection versus Vitrase

## Safety (continued)

- Increased risk of dose dependent sterile hypopyon
- Increased risk of dose dependent iritis
- All sterile hypopyon appeared to clear with topical steroids and cycloplegics

## Conclusions

- Replicative efficacy demonstrated in BCVA at 2 months for 55 IU Vitrase dose
- Approximately 50% of patients have non-functional vision  (i.e. Count fingers, hand motion or light perception)
- Replicative efficacy demonstrated in clearance of vitreous hemorrhage at 2 months for 55 IU Vitrase dose
- Efficacy no longer present at month 3

## Questions

- Has sufficient evidence been submitted to support the efficacy of Vitrase for the treatment of vitreous hemorrhage?
- If not, then what additional studies are needed to establish the efficacy of this product?
- Are additional analyses of the current data needed to understand the efficacy or safety of Vitrase for the treatment of vitreous hemorrhage?

## Questions (continued)

- Should the potential interaction (positive and/or negative) of Vitrase with current treatments for vitreous hemorrhage be evaluated?
- Are there adverse experiences that are of particular concern for this product?
- Is there a concern about the death rate observed in these studies?
- Do the benefits of using Vitrase outweigh the risks in the treatment of vitreous hemorrhage?