A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema (ME) With Center Involvement Secondary to Diabetes Mellitus (RISE)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Genentech
ClinicalTrials.gov Identifier:
NCT00473330
First received: May 13, 2007
Last updated: July 31, 2013
Last verified: July 2013
Results First Received: December 10, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Treatment
Conditions: Diabetes Mellitus
Macular Edema
Interventions: Drug: Ranibizumab
Drug: Sham injection

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Patients were recruited from study sites in the United States and Argentina. There were 10 patients from Argentina.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Ranibizumab 0.3 mg Patients received ranibizumab 0.3 mg monthly administered intravitreally for 36 months.
Ranibizumab 0.5 mg Patients received ranibizumab 0.5 mg monthly administered intravitreally for 36 months.
Sham Injection/Ranibizumab 0.5 mg Patients received a sham intravitreal injection monthly for 24 months. Patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months.

Participant Flow:   Overall Study
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection/Ranibizumab 0.5 mg  
STARTED     125     125     127  
COMPLETED     98     100     86  
NOT COMPLETED     27     25     41  
Adverse Event                 4                 4                 1  
Death                 6                 4                 4  
Lost to Follow-up                 5                 5                 10  
Physician Decision                 2                 1                 3  
Subject non-compliance                 1                 2                 1  
Subject needed other treatment                 0                 1                 3  
Subject's decision                 9                 8                 19  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Ranibizumab 0.3 mg Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 24 months.
Ranibizumab 0.5 mg Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 24 months.
Sham Injection Patients randomized to this group received a sham intravitreal injection monthly for 24 months.
Total Total of all reporting groups

Baseline Measures
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection     Total  
Number of Participants  
[units: participants]
  125     125     127     377  
Age  
[units: years]
Mean ± Standard Deviation
  61.7  ± 8.9     62.8  ± 10.0     61.8  ± 9.8     62.1  ± 9.6  
Gender  
[units: participants]
       
Female     52     60     53     165  
Male     73     65     74     212  



  Outcome Measures
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1.  Primary:   Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Month 24   [ Time Frame: Baseline to Month 24 ]

2.  Secondary:   Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24 and 36   [ Time Frame: Baseline to Months 24 and 36 ]

3.  Secondary:   Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24 and 36   [ Time Frame: Months 24 and 36 ]

4.  Secondary:   Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24 and 36   [ Time Frame: Baseline to Months 24 and 36 ]

5.  Secondary:   Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24 and 36 in Patients With Focal Edema at Baseline   [ Time Frame: Baseline to Months 24 and 36 ]

6.  Secondary:   Mean Change From Baseline in Central Foveal Thickness at Months 24 and 36   [ Time Frame: Baseline to Months 24 and 36 ]

7.  Secondary:   Percentage of Patients With a ≥ 3-step Worsening From Baseline in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale Score for Eyes at Months 24 and 36   [ Time Frame: Baseline to Months 24 and 36 ]

8.  Secondary:   Percentage of Patients With Resolution of Leakage at Month 24   [ Time Frame: Baseline to Month 24 ]

9.  Secondary:   Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36   [ Time Frame: Baseline to Months 24 and 36 ]

10.  Secondary:   Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Month 36   [ Time Frame: Baseline to Month 36 ]


  Serious Adverse Events


  Other Adverse Events
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Time Frame Adverse events were recorded from the first day of treatment through Month 36.
Additional Description The sham Months 0-36 group includes patients randomized to sham; the majority crossed-over to ranibizumab 0.5 mg in Year 3. The sham Months 0-24 group includes patients who received sham during the first 24 months of the study. Serious adverse events that occurred after early crossover to ranibizumab (defined as prior to Month 25) are not included.

Frequency Threshold
Threshold above which other adverse events are reported   5%  

Reporting Groups
  Description
Ranibizumab 0.3 mg Patients received ranibizumab 0.3 mg monthly administered intravitreally for 36 months.
Ranibizumab 0.5 mg Patients received ranibizumab 0.5 mg monthly administered intravitreally for 36 months.
Sham Injection/Ranibizumab 0.5 mg - Months 0-36 Patients received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Data in this column represent the safety data in the sham group during the entire 36 months of the trial; most patients crossed over to receive ranibizumab 0.5 mg monthly in the third year.
Sham Injection - Months 0-24 Patients received a sham intravitreal injection monthly for 24 months. Data in this column represent the safety data in the sham group during the first 24 months of the trial when patients were receiving only sham injections. Safety data shown here are also included in the Sham/Ranibizumab 0.5 mg - Months 0-36 column.

Other Adverse Events
    Ranibizumab 0.3 mg     Ranibizumab 0.5 mg     Sham Injection/Ranibizumab 0.5 mg - Months 0-36     Sham Injection - Months 0-24  
Total, other (not including serious) adverse events          
# participants affected / at risk     123/125     121/125     122/124     121/123  
Blood and lymphatic system disorders          
Anaemia † 1        
# participants affected / at risk     19/125 (15.20%)     17/125 (13.60%)     14/124 (11.29%)     11/123 (8.94%)  
Cardiac disorders          
Cardiac failure congestive † 1        
# participants affected / at risk     2/125 (1.60%)     13/125 (10.40%)     6/124 (4.84%)     2/123 (1.63%)  
Endocrine disorders          
Hypothyroidism † 1        
# participants affected / at risk     9/125 (7.20%)     6/125 (4.80%)     2/124 (1.61%)     1/123 (0.81%)  
Eye disorders          
Blepharitis (F) † 1 [3]        
# participants affected / at risk     7/125 (5.60%)     9/125 (7.20%)     2/124 (1.61%)     1/123 (0.81%)  
Blepharitis (S) † 1 [4]        
# participants affected / at risk     8/125 (6.40%)     7/125 (5.60%)     2/124 (1.61%)     1/123 (0.81%)  
Cataract (F) † 1 [3]        
# participants affected / at risk     30/125 (24.00%)     23/125 (18.40%)     28/124 (22.58%)     21/123 (17.07%)  
Cataract (S) † 1 [4]        
# participants affected / at risk     28/125 (22.40%)     21/125 (16.80%)     21/124 (16.94%)     18/123 (14.63%)  
Cataract cortical (F) † 1 [3]        
# participants affected / at risk     7/125 (5.60%)     7/125 (5.60%)     9/124 (7.26%)     12/123 (9.76%)  
Cataract cortical (S) † 1 [4]        
# participants affected / at risk     9/125 (7.20%)     8/125 (6.40%)     10/124 (8.06%)     13/123 (10.57%)  
Cataract nuclear (F) † 1 [3]        
# participants affected / at risk     6/125 (4.80%)     4/125 (3.20%)     8/124 (6.45%)     7/123 (5.69%)  
Cataract nuclear (S) † 1 [5]        
# participants affected / at risk     6/125 (4.80%)     6/125 (4.80%)     8/124 (6.45%)     8/123 (6.50%)  
Cataract subcapsular (F) † 1 [3]        
# participants affected / at risk     5/125 (4.00%)     5/125 (4.00%)     5/124 (4.03%)     7/123 (5.69%)  
Cataract subcapsular (S) † 1 [4]        
# participants affected / at risk     9/125 (7.20%)     9/125 (7.20%)     4/124 (3.23%)     7/123 (5.69%)  
Conjunctival haemorrhage (F) † 1 [3]        
# participants affected / at risk     19/125 (15.20%)     19/125 (15.20%)     12/124 (9.68%)     5/123 (4.07%)  
Conjunctival haemorrhage (S) † 1 [4]        
# participants affected / at risk     70/125 (56.00%)     66/125 (52.80%)     45/124 (36.29%)     39/123 (31.71%)  
Cystoid macular oedema (F) † 1 [3]        
# participants affected / at risk     11/125 (8.80%)     12/125 (9.60%)     10/124 (8.06%)     8/123 (6.50%)  
Cystoid macular oedema (S) † 1 [4]        
# participants affected / at risk     8/125 (6.40%)     4/125 (3.20%)     6/124 (4.84%)     5/123 (4.07%)  
Diabetic retinal oedema (F) † 1 [3]        
# participants affected / at risk     22/125 (17.60%)     23/125 (18.40%)     22/124 (17.74%)     18/123 (14.63%)  
Diabetic retinal oedema (S) † 1 [4]        
# participants affected / at risk     7/125 (5.60%)     10/125 (8.00%)     7/124 (5.65%)     7/123 (5.69%)  
Diabetic retinopathy (F) † 1 [3]        
# participants affected / at risk     12/125 (9.60%)     9/125 (7.20%)     16/124 (12.90%)     15/123 (12.20%)  
Diabetic retinopathy (S) † 1 [4]        
# participants affected / at risk     2/125 (1.60%)     4/125 (3.20%)     8/124 (6.45%)     8/123 (6.50%)  
Dry eye (F) † 1 [3]        
# participants affected / at risk     12/125 (9.60%)     10/125 (8.00%)     7/124 (5.65%)     5/123 (4.07%)  
Dry eye (S) † 1 [4]        
# participants affected / at risk     13/125 (10.40%)     11/125 (8.80%)     8/124 (6.45%)     6/123 (4.88%)  
Eye irritation (S) † 1 [4]        
# participants affected / at risk     13/125 (10.40%)     12/125 (9.60%)     9/124 (7.26%)     8/123 (6.50%)  
Eye pain (F) † 1 [3]        
# participants affected / at risk     10/125 (8.00%)     13/125 (10.40%)     7/124 (5.65%)     3/123 (2.44%)  
Eye pain (S) † 1 [4]        
# participants affected / at risk     35/125 (28.00%)     30/125 (24.00%)     28/124 (22.58%)     23/123 (18.70%)  
Eye pruritus (S) † 1 [4]        
# participants affected / at risk     7/125 (5.60%)     5/125 (4.00%)     8/124 (6.45%)     7/123 (5.69%)  
Foreign body sensation in eyes (S) † 1 [4]        
# participants affected / at risk     17/125 (13.60%)     8/125 (6.40%)     6/124 (4.84%)     5/123 (4.07%)  
Lacrimation increased (S) † 1 [4]        
# participants affected / at risk     8/125 (6.40%)     15/125 (12.00%)     8/124 (6.45%)     7/123 (5.69%)  
Macular fibrosis (F) † 1 [3]        
# participants affected / at risk     15/125 (12.00%)     15/125 (12.00%)     14/124 (11.29%)     0/123 (0.00%)  
Macular fibrosis (S) † 1 [4]        
# participants affected / at risk     8/125 (6.40%)     16/125 (12.80%)     10/124 (8.06%)     0/123 (0.00%)  
Macular oedema (F) † 1 [3]        
# participants affected / at risk     45/125 (36.00%)     46/125 (36.80%)     47/124 (37.90%)     41/123 (33.33%)  
Macular oedema (S) † 1 [4]        
# participants affected / at risk     25/125 (20.00%)     29/125 (23.20%)     26/124 (20.97%)     24/123 (19.51%)  
Maculopathy (F) † 1 [3]        
# participants affected / at risk     0/125 (0.00%)     2/125 (1.60%)     0/124 (0.00%)     15/123 (12.20%)  
Maculopathy (S) † 1 [4]        
# participants affected / at risk     0/125 (0.00%)     0/125 (0.00%)     1/124 (0.81%)     8/123 (6.50%)  
Ocular hyperaemia (S) † 1 [4]        
# participants affected / at risk     20/125 (16.00%)     14/125 (11.20%)     14/124 (11.29%)     13/123 (10.57%)  
Photophobia (S) † 1 [4]        
# participants affected / at risk     7/125 (5.60%)     5/125 (4.00%)     1/124 (0.81%)     0/123 (0.00%)  
Posterior capsule opacification (F) † 1 [3]        
# participants affected / at risk     10/125 (8.00%)     4/125 (3.20%)     4/124 (3.23%)     3/123 (2.44%)  
Retinal aneurysm (F) † 1 [3]        
# participants affected / at risk     10/125 (8.00%)     6/125 (4.80%)     6/124 (4.84%)     5/123 (4.07%)  
Retinal aneurysm (S) † 1 [4]        
# participants affected / at risk     10/125 (8.00%)     6/125 (4.80%)     4/124 (3.23%)     3/123 (2.44%)  
Retinal exudates (F) † 1 [6]        
# participants affected / at risk     22/125 (17.60%)     15/125 (12.00%)     27/124 (21.77%)     24/123 (19.51%)  
Retinal exudates (S) † 1 [4]        
# participants affected / at risk     28/125 (22.40%)     24/125 (19.20%)     28/124 (22.58%)     25/123 (20.33%)  
Retinal haemorrhage (F) † 1 [3]        
# participants affected / at risk     24/125 (19.20%)     37/125 (29.60%)     25/124 (20.16%)     23/123 (18.70%)  
Retinal haemorrhage (S) † 1 [4]        
# participants affected / at risk     18/125 (14.40%)     20/125 (16.00%)     26/124 (20.97%)     25/123 (20.33%)  
Retinal neovascularisation (F) † 1 [3]        
# participants affected / at risk     12/125 (9.60%)     18/125 (14.40%)     19/124 (15.32%)     16/123 (13.01%)  
Retinal neovascularisation (S) † 1 [4]        
# participants affected / at risk     0/125 (0.00%)     6/125 (4.80%)     18/124 (14.52%)     17/123 (13.82%)  
Vision blurred (F) † 1 [3]        
# participants affected / at risk     7/125 (5.60%)     6/125 (4.80%)     6/124 (4.84%)     5/123 (4.07%)  
Vision blurred (S) † 1 [4]        
# participants affected / at risk     15/125 (12.00%)     11/125 (8.80%)     7/124 (5.65%)     6/123 (4.88%)  
Visual acuity reduced (S) † 1 [4]        
# participants affected / at risk     8/125 (6.40%)     7/125 (5.60%)     10/124 (8.06%)     9/123 (7.32%)  
Vitreous detachment (F) † 1 [3]        
# participants affected / at risk     20/125 (16.00%)     23/125 (18.40%)     18/124 (14.52%)     16/123 (13.01%)  
Vitreous detachment (S) † 1 [4]        
# participants affected / at risk     21/125 (16.80%)     20/125 (16.00%)     19/124 (15.32%)     19/123 (15.45%)  
Vitreous floaters (F) † 1 [3]        
# participants affected / at risk     15/125 (12.00%)     10/125 (8.00%)     8/124 (6.45%)     5/123 (4.07%)  
Vitreous floaters (S) † 1 [4]        
# participants affected / at risk     22/125 (17.60%)     20/125 (16.00%)     10/124 (8.06%)     7/123 (5.69%)  
Vitreous haemorrhage (F) † 1 [3]        
# participants affected / at risk     10/125 (8.00%)     10/125 (8.00%)     10/124 (8.06%)     7/123 (5.69%)  
Vitreous haemorrhage (S) † 1 [4]        
# participants affected / at risk     4/125 (3.20%)     6/125 (4.80%)     17/124 (13.71%)     16/123 (13.01%)  
Gastrointestinal disorders          
Constipation † 1        
# participants affected / at risk     13/125 (10.40%)     15/125 (12.00%)     5/124 (4.03%)     3/123 (2.44%)  
Diarrhoea † 1        
# participants affected / at risk     12/125 (9.60%)     15/125 (12.00%)     7/124 (5.65%)     5/123 (4.07%)  
Dyspepsia † 1        
# participants affected / at risk     7/125 (5.60%)     1/125 (0.80%)     4/124 (3.23%)     3/123 (2.44%)  
Gastrooesophageal reflux disease † 1        
# participants affected / at risk     12/125 (9.60%)     11/125 (8.80%)     11/124 (8.87%)     5/123 (4.07%)  
Nausea † 1        
# participants affected / at risk     16/125 (12.80%)     18/125 (14.40%)     13/124 (10.48%)     10/123 (8.13%)  
Vomiting † 1        
# participants affected / at risk     8/125 (6.40%)     11/125 (8.80%)     7/124 (5.65%)     6/123 (4.88%)  
General disorders          
Oedema peripheral † 1        
# participants affected / at risk     8/125 (6.40%)     13/125 (10.40%)     8/124 (6.45%)     6/123 (4.88%)  
Pain † 1        
# participants affected / at risk     5/125 (4.00%)     8/125 (6.40%)     4/124 (3.23%)     3/123 (2.44%)  
Immune system disorders          
Seasonal allergy † 1        
# participants affected / at risk     11/125 (8.80%)     6/125 (4.80%)     6/124 (4.84%)     4/123 (3.25%)  
Infections and infestations          
Bronchitis † 1        
# participants affected / at risk     8/125 (6.40%)     9/125 (7.20%)     9/124 (7.26%)     5/123 (4.07%)  
Influenza † 1        
# participants affected / at risk     10/125 (8.00%)     11/125 (8.80%)     3/124 (2.42%)     0/123 (0.00%)  
Nasopharyngitis † 1        
# participants affected / at risk     18/125 (14.40%)     25/125 (20.00%)     13/124 (10.48%)     9/123 (7.32%)  
Pneumonia † 1        
# participants affected / at risk     7/125 (5.60%)     5/125 (4.00%)     8/124 (6.45%)     7/123 (5.69%)  
Sinusitis † 1        
# participants affected / at risk     6/125 (4.80%)     7/125 (5.60%)     11/124 (8.87%)     8/123 (6.50%)  
Upper respiratory tract infection † 1        
# participants affected / at risk     11/125 (8.80%)     11/125 (8.80%)     8/124 (6.45%)     6/123 (4.88%)  
Urinary tract infection † 1        
# participants affected / at risk     5/125 (4.00%)     14/125 (11.20%)     11/124 (8.87%)     9/123 (7.32%)  
Injury, poisoning and procedural complications          
Corneal abrasion (S) † 1 [4]        
# participants affected / at risk     4/125 (3.20%)     4/125 (3.20%)     7/124 (5.65%)     6/123 (4.88%)  
Fall † 1        
# participants affected / at risk     3/125 (2.40%)     7/125 (5.60%)     6/124 (4.84%)     4/123 (3.25%)  
Investigations          
Blood glucose increased † 1        
# participants affected / at risk     7/125 (5.60%)     12/125 (9.60%)     6/124 (4.84%)     8/123 (6.50%)  
Intraocular pressure increased (F) † 1 [3]        
# participants affected / at risk     13/125 (10.40%)     8/125 (6.40%)     6/124 (4.84%)     4/123 (3.25%)  
Intraocular pressure increased (S) † 1 [4]        
# participants affected / at risk     26/125 (20.80%)     20/125 (16.00%)     8/124 (6.45%)     3/123 (2.44%)  
Metabolism and nutrition disorders          
Diabetes mellitus † 1        
# participants affected / at risk     17/125 (13.60%)     13/125 (10.40%)     11/124 (8.87%)     7/123 (5.69%)  
Hypercholesterolaemia † 1        
# participants affected / at risk     11/125 (8.80%)     8/125 (6.40%)     7/124 (5.65%)     7/123 (5.69%)  
Hyperkalaemia † 1        
# participants affected / at risk     4/125 (3.20%)     2/125 (1.60%)     8/124 (6.45%)     6/123 (4.88%)  
Hyperlipidaemia † 1        
# participants affected / at risk     5/125 (4.00%)     6/125 (4.80%)     7/124 (5.65%)     7/123 (5.69%)  
Hypoglycaemia † 1        
# participants affected / at risk     8/125 (6.40%)     2/125 (1.60%)     6/124 (4.84%)     5/123 (4.07%)  
Musculoskeletal and connective tissue disorders          
Arthralgia † 1        
# participants affected / at risk     7/125 (5.60%)     12/125 (9.60%)     5/124 (4.03%)     3/123 (2.44%)  
Back pain † 1        
# participants affected / at risk     5/125 (4.00%)     8/125 (6.40%)     12/124 (9.68%)     8/123 (6.50%)  
Pain in extremity † 1        
# participants affected / at risk     4/125 (3.20%)     7/125 (5.60%)     4/124 (3.23%)     2/123 (1.63%)  
Nervous system disorders          
Dizziness † 1        
# participants affected / at risk     4/125 (3.20%)     6/125 (4.80%)     10/124 (8.06%)     7/123 (5.69%)  
Headache † 1        
# participants affected / at risk     11/125 (8.80%)     9/125 (7.20%)     19/124 (15.32%)     14/123 (11.38%)  
Neuropathy peripheral † 1        
# participants affected / at risk     8/125 (6.40%)     8/125 (6.40%)     4/124 (3.23%)     4/123 (3.25%)  
Psychiatric disorders          
Anxiety † 1        
# participants affected / at risk     5/125 (4.00%)     10/125 (8.00%)     6/124 (4.84%)     4/123 (3.25%)  
Depression † 1        
# participants affected / at risk     7/125 (5.60%)     10/125 (8.00%)     9/124 (7.26%)     7/123 (5.69%)  
Insomnia † 1        
# participants affected / at risk     7/125 (5.60%)     5/125 (4.00%)     10/124 (8.06%)     6/123 (4.88%)  
Renal and urinary disorders          
Renal failure † 1        
# participants affected / at risk     9/125 (7.20%)     6/125 (4.80%)     9/124 (7.26%)     7/123 (5.69%)  
Renal failure chronic † 1        
# participants affected / at risk     7/125 (5.60%)     10/125 (8.00%)     3/124 (2.42%)     3/123 (2.44%)  
Respiratory, thoracic and mediastinal disorders          
Cough † 1        
# participants affected / at risk     12/125 (9.60%)     8/125 (6.40%)     6/124 (4.84%)     3/123 (2.44%)  
Dyspnoea † 1        
# participants affected / at risk     4/125 (3.20%)     8/125 (6.40%)     5/124 (4.03%)     3/123 (2.44%)  
Vascular disorders          
Hypertension † 1        
# participants affected / at risk     23/125 (18.40%)     27/125 (21.60%)     26/124 (20.97%)     21/123 (17.07%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA (13.1)
[3] (F)=fellow eye
[4] (S)=study eye
[5] Study eye
[6] (F)=study eye



  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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