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Laser-Ranibizumab-Triamcinolone for Diabetic Macular Edema (LRT for DME)

This study has been completed.
Sponsor:
Collaborators:
National Eye Institute (NEI)
Allergan
Genentech, Inc.
Information provided by (Responsible Party):
Jaeb Center for Health Research
ClinicalTrials.gov Identifier:
NCT00444600
First received: March 6, 2007
Last updated: August 25, 2016
Last verified: August 2016
Results First Received: January 14, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Outcomes Assessor);   Primary Purpose: Treatment
Conditions: Diabetic Retinopathy
Diabetic Macular Edema
Interventions: Drug: Triamcinolone Acetonide + laser
Drug: Ranibizumab + laser
Drug: Sham injection + laser
Drug: Ranibizumab + deferred laser

  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
Fifty two academic and community based sites across the United States recruited 691 study participants from March 2007 to December 2008.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants with two study eyes enrolled each eye in a different treatment group. Therefore, each treatment group/arm includes no more than one study eye for a given participant, and thus the numbers of eyes is equal to the number of participants in each arm.

Reporting Groups
  Description
Sham+Prompt Laser Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.
0.5 mg Ranibizumab+Prompt Laser 0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.
0.5 mg Ranibizumab+Deferred Laser 0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.
4 mg Triamcinolone+Prompt Laser 4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.

Participant Flow:   Overall Study
    Sham+Prompt Laser   0.5 mg Ranibizumab+Prompt Laser   0.5 mg Ranibizumab+Deferred Laser   4 mg Triamcinolone+Prompt Laser
STARTED   293 [1]   187 [1]   188 [1]   186 [1] 
COMPLETED   274 [1]   171 [1]   178 [1]   176 [1] 
NOT COMPLETED   19   16   10   10 
Death                7                5                3                2 
Dropped                11                11                7                7 
Missed visit                1                0                0                1 
[1] Number of eyes



  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
Sham+Prompt Laser Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.
0.5 mg Ranibizumab+Prompt Laser 0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.
0.5 mg Ranibizumab+Deferred Laser 0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.
4 mg Triamcinolone+Prompt Laser 4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.
Total Total of all reporting groups

Baseline Measures
   Sham+Prompt Laser   0.5 mg Ranibizumab+Prompt Laser   0.5 mg Ranibizumab+Deferred Laser   4 mg Triamcinolone+Prompt Laser   Total 
Overall Participants Analyzed 
[Units: Participants]
 293   187   188   186   854 
Age 
[Units: Years]
Median (Inter-Quartile Range)
 63 
 (57 to 69) 
 62 
 (56 to 70) 
 64 
 (58 to 70) 
 62 
 (55 to 70) 
 63 
 (56 to 70) 
Gender 
[Units: Participants]
         
Female   123   85   78   86   372 
Male   170   102   110   100   482 
Race/Ethnicity, Customized 
[Units: Participants]
         
White   202   131   134   134   601 
African American   51   30   25   32   138 
Hispanic or Latino   34   21   25   15   95 
Asian   4   1   2   4   11 
Native Hawaiian/Other Pacific Islander   0   1   0   0   1 
More than one race   1   1   1   0   3 
Unknown/not reported   1   2   1   1   5 
Visual Acuity Letter Score (approximate Snellen equivalent) by randomization strata 
[Units: Eyes]
         
≥66 (better than 20/50)   146   95   95   93   429 
≤65 (20/50 or worse)   147   92   93   93   425 
Classification of diabetic macular edema [1] 
[Units: Eyes]
         
Predominantly focal   78   60   68   53   259 
Neither predominantly focal or diffuse   71   46   41   48   206 
Predominantly diffuse   144   81   79   85   389 
[1] Based on clinical exam.
Number of study eyes 
[Units: Participants]
         
1 study eye   130   131   132   135   528 
2 study eyes   163   56   56   51   326 
Diabetes Type 
[Units: Participants]
         
Type 1   25   11   15   14   65 
Type 2   260   172   170   166   768 
Uncertain   8   4   3   6   21 
Duration of diabetes 
[Units: Years]
Median (Inter-Quartile Range)
 16 
 (9 to 22) 
 18 
 (12 to 24) 
 17 
 (11 to 22) 
 17 
 (11 to 24) 
 16 
 (10 to 23) 
HbA1c [1] 
[Units: Percentage]
Median (Inter-Quartile Range)
 7.3 
 (6.6 to 8.3) 
 7.3 
 (6.6 to 8.4) 
 7.5 
 (6.7 to 8.4) 
 7.4 
 (6.5 to 8.6) 
 7.3 
 (6.6 to 8.4) 
[1] Missing HbA1c data for 17, 3, 7 and 8 study participants in the sham+prompt laser, ranibizumab+prompt laser, ranibizumab+deferred laser and triamcinolone+prompt laser groups, respectively.
Prior cardiovascular event [1] 
[Units: Participants]
         
Yes   93   66   61   61   281 
No   200   121   127   125   573 
[1] Based on medical history of condition.
Hypertension 
[Units: Participants]
         
Yes   240   154   156   148   698 
No   53   33   32   38   156 
Prior Panretinal Photocoagulation 
[Units: Eyes]
         
Yes   48   36   31   37   152 
No   245   151   157   149   702 
Prior treatment for diabetic macular edema 
[Units: Eyes]
         
No   105   74   74   61   314 
Yes   188   113   114   125   540 
Prior laser for diabetic macular edema 
[Units: Eyes]
         
Yes   173   101   101   114   489 
No   120   86   87   72   365 
Prior IVT for diabetic macular edema [1] 
[Units: Eyes]
         
Yes   39   22   36   31   128 
No   254   165   152   155   726 
[1] IVT = intravitreal triamcinolone
Prior vitrectomy for diabetic macular edema 
[Units: Eyes]
         
Yes   15   7   5   12   39 
No   278   180   183   174   815 
Prior peribulbar triamcinolone for diabetic macular edema 
[Units: Eyes]
         
Yes   12   9   5   5   31 
No   281   178   183   181   823 
Prior anti-VEGF for diabetic macular edema [1] 
[Units: Eyes]
         
Yes   24   24   21   20   89 
No   269   163   167   166   765 
[1] VEGF = vascular endothelial growth factor
Intraocular pressure 
[Units: mmHg]
Median (Inter-Quartile Range)
 16 
 (14 to 18) 
 16 
 (14 to 18) 
 16 
 (14 to 18) 
 16 
 (14 to 18) 
 16 
 (14 to 18) 
Currently on intraocular pressure lowering medicine for glaucoma or ocular hypertension 
[Units: Eyes]
         
Yes   5   6   4   2   17 
No   288   181   184   184   837 
Lens status [1] 
[Units: Eyes]
         
Phakic   192   131   134   124   581 
Anterior Chamber Intraocular Lense   3   1   1   0   5 
Posterior Chamber Intraocular Lense   98   55   53   62   268 
[1] Based on clinical exam.
E-ETDRS Visual Acuity Letter Score [1] 
[Units: Letter Score]
Median (Inter-Quartile Range)
 65 
 (56 to 73) 
 66 
 (55 to 72) 
 66 
 (58 to 72) 
 66 
 (57 to 72) 
 66 
 (56 to 72) 
[1] Best corrected visual acuity letter score as measured by a certified tester using an electronic visual acuity testing machine based on the Early Treatment Diabetic Retinopathy Study (ETDRS) method. Best value on the scale 97, worst 0.
Central subfield thickness on optical coherence tomography 
[Units: Microns]
Median (Inter-Quartile Range)
 407 
 (309 to 505) 
 371 
 (302 to 464) 
 382 
 (298 to 488) 
 374 
 (298 to 463) 
 381 
 (306 to 485) 
Retinal volume on optical coherence tomography 
[Units: Microns]
Median (Inter-Quartile Range)
 8.7 
 (7.8 to 10.0) 
 8.4 
 (7.5 to 9.6) 
 8.4 
 (7.4 to 9.8) 
 8.5 
 (7.8 to 9.7) 
 8.5 
 (7.7 to 9.7) 
Optical coherence tomography cystoid abnormality 
[Units: Eyes]
         
No evidence   19   13   12   8   52 
Questionable or definite   274   171   174   177   796 
Cannot grade or missing   0   3   2   1   6 
Optical coherence tomography subretinal fluid present 
[Units: Eyes]
         
No evidence   222   149   140   146   657 
Questionable or definite   70   36   45   38   189 
Cannot grade   1   2   3   2   8 
ETDRS retinopathy severity level (ETDRS description) [1] 
[Units: Eyes]
         
Diabetic retinopathy absent   5   4   3   1   13 
Minimal non-proliferative DR   2   2   3   3   10 
Mild to moderately severe non-proliferative DR   171   103   107   95   476 
Severe non-proliferative DR   22   16   11   15   64 
Scars of full or partial PRP present;PDR absent   38   30   30   29   127 
Mild to moderate proliferative DR   33   24   22   34   113 
High risk proliferative DR   7   4   1   3   15 
Cannot grade   10   1   2   4   17 
Missing   5   3   9   2   19 
[1]

ETDRS = Early Treatment Diabetic Retinopathy Study; DR = diabetic retinopathy; PDR = proliferative diabetic retinopathy.

Criteria are based on the ETDRS fundus photographic risk factors for the progression of diabetic retinopathy. ETDRS report no. 12. Ophthalmology 1991; 98:823-833



  Outcome Measures
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1.  Primary:   Mean Change in Visual Acuity (Letters) From Baseline to 1 Year Adjusted for Baseline Visual Acuity   [ Time Frame: from baseline to 1 Year ]

2.  Primary:   Distribution of Change in Visual Acuity (Letters) From Baseline to 1 Year   [ Time Frame: from baseline to 1 Year ]

3.  Primary:   Change in Visual Acuity From Baseline to 1 Year Among Eyes That Were Pseudophakic at Baseline   [ Time Frame: from baseline to 1 Year ]

4.  Primary:   Change in Visual Acuity From Baseline to 1 Year Among Eyes That Had Prior Treatment for Diabetic Macular Edema   [ Time Frame: from baseline to 1 Year ]

5.  Primary:   Change in Visual Acuity From Baseline to 1 Year Grouped by Baseline Visual Acuity Letter Score   [ Time Frame: from baseline to 1 Year ]

6.  Primary:   Change in Visual Acuity From Baseline to 1 Year Grouped by Optical Coherence Tomography Central Subfield Thickness   [ Time Frame: from baseline to 1 Year ]

7.  Primary:   Change in Visual Acuity From Baseline to 1 Year Grouped by Diabetic Retinopathy Severity   [ Time Frame: from baseline to 1 Year ]

8.  Primary:   Change in Visual Acuity From Baseline to 1 Year Grouped by Diffuse vs. Focal Edema as Characterized by the Investigator   [ Time Frame: from baseline to 1 Year ]

9.  Secondary:   Change in Retinal Thickening of Central Subfield on Optical Coherence Tomography From Baseline to 1 Year   [ Time Frame: from baseline to 1 year ]

10.  Secondary:   Number of Injections in First Year   [ Time Frame: from baseline to 1 year ]

11.  Secondary:   Number of Laser Treatments Received Prior to the 1 Year Visit   [ Time Frame: 1 Year ]

12.  Secondary:   Percentage of Eyes Receiving Laser at the 48 Week Visit (%)   [ Time Frame: 1 Year ]

13.  Secondary:   Mean Optical Coherence Tomography Retinal Volume at 1 Year   [ Time Frame: 1 Year ]

14.  Secondary:   Mean Change in Optical Coherence Tomography Retinal Volume From Baseline to 1 Year   [ Time Frame: from baseline to 1 Year ]

15.  Other Pre-specified:   Central Subfield Thickness < 250 With at Least a 25 Micron Decrease From Baseline to 1 Year   [ Time Frame: 1 Year ]

16.  Other Pre-specified:   Distribution of Logarithmic Transformation of Optical Coherence Tomography (LogOCT) Improvement and Worsening   [ Time Frame: 1 Year ]

17.  Other Pre-specified:   Eyes With Alternative Treatments Prior to the 1-year Visit   [ Time Frame: 1 Year ]

18.  Other Pre-specified:   Change From Moderately Severe Non-proliferative Diabetic Retinopathy or Better From Baseline to 1-year   [ Time Frame: from baseline to 1 Year ]

19.  Other Pre-specified:   Change From Severe Non-proliferative Diabetic Retinopathy or Worse From Baseline to 1-year   [ Time Frame: from baseline to 1 Year ]

20.  Other Pre-specified:   Cardiovascular Events According to Antiplatelet Trialists' Collaboration Through 1 Year   [ Time Frame: 1 Year ]

21.  Other Pre-specified:   Major Ocular Adverse Events During First Year of Follow-Up   [ Time Frame: 1 Year ]


  Serious Adverse Events
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Time Frame 1 Year
Additional Description All ocular adverse events are listed under treatment group drug. Participants with a systemic adverse event with two study eyes are listed under the sham/ranibizumab or triamcinolone combination.

Reporting Groups
  Description
Sham + Prompt Laser Laser was given within 3 to 10 days after sham injections, Laser = Focal/grid photocoagulation
Ranibizumab + Prompt Laser 0.5 mg intravitreal ranibizumab plus prompt (within 3–10 days after injection) focal/grid photocoagulation
Ranibizumab + Deferred Laser 0.5 mg intravitreal ranibizumab with deferred (24 weeks) focal/grid photocoagulation
Triamcinolone + Prompt Laser 4 mg intravitreal triamcinolone plus prompt (within 3–10 days after injection) focal/grid photocoagulation
Sham + Ranibizumab + Laser Participants in this group had 2 study eyes, the right eye was assigned randomly with equal probability to one of the four groups (Sham + prompt laser, ranibizumab + prompt laser, ranibizumab + deferred laser, triamcinolone + prompt laser). If the right eye was assigned to a treatment group other than the sham + prompt laser group, then the left eye was assigned to the sham + prompt laser group. If the right eye was assigned to the sham prompt + prompt laser group, then the left eye was assigned randomly to one of the other three groups.
Sham + Ranibizumab + Deferred Laser Participants in this group had 2 study eyes, the right eye was assigned randomly with equal probability to one of the four groups (Sham + prompt laser, ranibizumab + prompt laser, ranibizumab + deferred laser, triamcinolone + prompt laser). If the right eye was assigned to a treatment group other than the sham + prompt laser group, then the left eye was assigned to the sham + prompt laser group. If the right eye was assigned to the sham prompt + prompt laser group, then the left eye was assigned randomly to one of the other three groups.
Sham + Triamcinolone + Laser Participants in this group had 2 study eyes, the right eye was assigned randomly with equal probability to one of the four groups (Sham + prompt laser, ranibizumab + prompt laser, ranibizumab + deferred laser, triamcinolone + prompt laser). If the right eye was assigned to a treatment group other than the sham + prompt laser group, then the left eye was assigned to the sham + prompt laser group. If the right eye was assigned to the sham prompt + prompt laser group, then the left eye was assigned randomly to one of the other three groups.

Serious Adverse Events
    Sham + Prompt Laser   Ranibizumab + Prompt Laser   Ranibizumab + Deferred Laser   Triamcinolone + Prompt Laser   Sham + Ranibizumab + Laser   Sham + Ranibizumab + Deferred Laser   Sham + Triamcinolone + Laser
Total, serious adverse events               
# participants affected / at risk   53/130 (40.77%)   46/131 (35.11%)   41/132 (31.06%)   57/135 (42.22%)   21/56 (37.50%)   20/56 (35.71%)   12/51 (23.53%) 
Cardiac disorders               
Arrhythmia * 1               
# participants affected / at risk   1/130 (0.77%)   1/131 (0.76%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Cardiac failure * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   0/132 (0.00%)   1/135 (0.74%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Cardiac failure congestive * 1               
# participants affected / at risk   2/130 (1.54%)   8/131 (6.11%)   0/132 (0.00%)   4/135 (2.96%)   4/56 (7.14%)   3/56 (5.36%)   0/51 (0.00%) 
Cardio-respiratory arrest * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   1/56 (1.79%)   0/56 (0.00%)   0/51 (0.00%) 
Cardiomegaly * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   2/56 (3.57%)   0/51 (0.00%) 
Heart rate increased * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   1/132 (0.76%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Heart rate irregular * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Left ventricular hypertrophy * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   1/56 (1.79%)   0/51 (0.00%) 
Myocardial infacrtion * 1               
# participants affected / at risk   3/130 (2.31%)   0/131 (0.00%)   1/132 (0.76%)   2/135 (1.48%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Tachycardia * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   1/56 (1.79%)   0/51 (0.00%) 
Transient ischaemic attack * 1               
# participants affected / at risk   2/130 (1.54%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Bradycardia * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Supraventricular tachycardia * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   1/132 (0.76%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Arteriosclerosis coronary artery * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   1/132 (0.76%)   2/135 (1.48%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Endocrine disorders               
Diabetes mellitus * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   1/56 (1.79%)   0/56 (0.00%)   0/51 (0.00%) 
Diabetes mellitus inadequate control * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   1/135 (0.74%)   0/56 (0.00%)   0/56 (0.00%)   1/51 (1.96%) 
Diabetic ketoacidosis * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   1/135 (0.74%)   1/56 (1.79%)   1/56 (1.79%)   0/51 (0.00%) 
Eye disorders               
Cataract * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Endophthalmitis * 1               
# participants affected / at risk   2/130 (1.54%)   1/131 (0.76%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   1/56 (1.79%)   0/51 (0.00%) 
Intraocular pressure increased * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   1/135 (0.74%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Retinal vein occlusion * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   2/135 (1.48%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Glaucoma * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   1/135 (0.74%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Iris neovascularisation * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Gastrointestinal disorders               
Food poisoning * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   1/135 (0.74%)   1/56 (1.79%)   0/56 (0.00%)   0/51 (0.00%) 
Gastroenteritis * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   1/51 (1.96%) 
Gastroesophageal reflux disease * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Impaired gastric emptying * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   2/132 (1.52%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Diverticulitis * 1               
# participants affected / at risk   2/130 (1.54%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Gastric bypass * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   1/56 (1.79%)   0/56 (0.00%)   0/51 (0.00%) 
Gastrointestinal haemorrhage * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Vomiting * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   2/135 (1.48%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
General disorders               
Abdominal pain * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   1/135 (0.74%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Anemia * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   1/132 (0.76%)   1/135 (0.74%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Angina pectoris * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   0/132 (0.00%)   1/135 (0.74%)   0/56 (0.00%)   1/56 (1.79%)   0/51 (0.00%) 
Blood potassium increased * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   2/132 (1.52%)   2/135 (1.48%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Cellulitis * 1               
# participants affected / at risk   0/130 (0.00%)   2/131 (1.53%)   0/132 (0.00%)   2/135 (1.48%)   0/56 (0.00%)   1/56 (1.79%)   0/51 (0.00%) 
Chest pain * 1               
# participants affected / at risk   5/130 (3.85%)   0/131 (0.00%)   3/132 (2.27%)   2/135 (1.48%)   2/56 (3.57%)   0/56 (0.00%)   0/51 (0.00%) 
Convulsion * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   1/56 (1.79%)   0/56 (0.00%)   0/51 (0.00%) 
Death * 1               
# participants affected / at risk   2/130 (1.54%)   1/131 (0.76%)   2/132 (1.52%)   2/135 (1.48%)   1/56 (1.79%)   1/56 (1.79%)   0/51 (0.00%) 
Dehydration * 1               
# participants affected / at risk   2/130 (1.54%)   0/131 (0.00%)   1/132 (0.76%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Dysarthria * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   1/51 (1.96%) 
Dyspnoea * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Goitre * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   1/135 (0.74%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Haematochezia * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Hernia * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   1/51 (1.96%) 
Hyperglycaemia * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   2/132 (1.52%)   0/135 (0.00%)   0/56 (0.00%)   1/56 (1.79%)   0/51 (0.00%) 
Oedema peripheral * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   0/132 (0.00%)   2/135 (1.48%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Pain in extremity * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   1/135 (0.74%)   0/56 (0.00%)   0/56 (0.00%)   1/51 (1.96%) 
Post procedural complications * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   1/132 (0.76%)   1/135 (0.74%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Presyncope * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   1/56 (1.79%)   0/56 (0.00%)   0/51 (0.00%) 
Pulmonary oedema * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   1/132 (0.76%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Rhabdomyolysis * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   1/132 (0.76%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Syncope * 1               
# participants affected / at risk   0/130 (0.00%)   2/131 (1.53%)   0/132 (0.00%)   1/135 (0.74%)   0/56 (0.00%)   1/56 (1.79%)   0/51 (0.00%) 
Vertigo * 1               
# participants affected / at risk   2/130 (1.54%)   0/131 (0.00%)   0/132 (0.00%)   1/135 (0.74%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Arthralgia * 1               
# participants affected / at risk   1/130 (0.77%)   1/131 (0.76%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Atrial fibrillation * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   2/132 (1.52%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Anxiety * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Blood glucose decreased * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   1/135 (0.74%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Cholecystitis acute * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   1/132 (0.76%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Contusion * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   1/56 (1.79%)   0/56 (0.00%)   0/51 (0.00%) 
Gout * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   1/132 (0.76%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Hemiparesis * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Hypersensitivity * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   1/135 (0.74%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Lymphoedema * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Nausea * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   1/135 (0.74%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Migraine * 1               
# participants affected / at risk   0/130 (0.00%)   2/131 (1.53%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Salivary gland disorder * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
hypoglycaemia * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   1/132 (0.76%)   0/135 (0.00%)   1/56 (1.79%)   0/56 (0.00%)   2/51 (3.92%) 
Anaemia of Chronic disease * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   1/132 (0.76%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Joint Injury * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   0/132 (0.00%)   1/135 (0.74%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Skin Ulcer * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   1/132 (0.76%)   1/135 (0.74%)   0/56 (0.00%)   1/56 (1.79%)   0/51 (0.00%) 
Infections and infestations               
Infection * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   0/132 (0.00%)   1/135 (0.74%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Localised infection * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   2/132 (1.52%)   3/135 (2.22%)   2/56 (3.57%)   0/56 (0.00%)   0/51 (0.00%) 
Musculoskeletal and connective tissue disorders               
Facial bones fracture * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Fracture * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   0/132 (0.00%)   0/135 (0.00%)   1/56 (1.79%)   0/56 (0.00%)   1/51 (1.96%) 
Multiple fractures * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Osteomyelitis * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Hip fracture * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Intervertebral disc protrusion * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   1/135 (0.74%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)               
Abdominal neoplasm * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Prostate cancer * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   1/132 (0.76%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Throat cancer * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   1/56 (1.79%)   0/51 (0.00%) 
Boneneoplasm malignant * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Nervous system disorders               
Neuropathy * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   1/132 (0.76%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Renal and urinary disorders               
Renal failure * 1               
# participants affected / at risk   1/130 (0.77%)   3/131 (2.29%)   1/132 (0.76%)   1/135 (0.74%)   0/56 (0.00%)   2/56 (3.57%)   1/51 (1.96%) 
Renal failure chronic * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Renal failure acute * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Urinary tract infection * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Reproductive system and breast disorders               
Breast cancer * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   1/132 (0.76%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Respiratory, thoracic and mediastinal disorders               
Bronchitis * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   1/56 (1.79%)   0/56 (0.00%)   0/51 (0.00%) 
Influenza * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   1/132 (0.76%)   1/135 (0.74%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Pneumonia * 1               
# participants affected / at risk   2/130 (1.54%)   1/131 (0.76%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Lung cancer metastatic * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Skin and subcutaneous tissue disorders               
Skin Ulcer * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   0/132 (0.00%)   1/135 (0.74%)   0/56 (0.00%)   1/56 (1.79%)   0/51 (0.00%) 
Surgical and medical procedures               
Arterial bypass operation * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   0/132 (0.00%)   1/135 (0.74%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Coronary arterial stent insertion * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   1/132 (0.76%)   0/135 (0.00%)   0/56 (0.00%)   1/56 (1.79%)   0/51 (0.00%) 
Hysterectomy * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   1/135 (0.74%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Knee operation * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   1/51 (1.96%) 
Leg amputation * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Shoulder operation * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   1/132 (0.76%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Stent placement * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   0/132 (0.00%)   1/135 (0.74%)   0/56 (0.00%)   1/56 (1.79%)   1/51 (1.96%) 
Biopsy thyroid gland * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   1/135 (0.74%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Vascular disorders               
Arteriosclerosis coronary artery * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   1/132 (0.76%)   2/135 (1.48%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
cerebrovascular accident * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   2/132 (1.52%)   1/135 (0.74%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Coronary artery disease * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   0/132 (0.00%)   1/135 (0.74%)   1/56 (1.79%)   0/56 (0.00%)   0/51 (0.00%) 
Hypertension * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   2/132 (1.52%)   3/135 (2.22%)   0/56 (0.00%)   0/56 (0.00%)   1/51 (1.96%) 
Hypotension * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Ischaemic stroke * 1               
# participants affected / at risk   3/130 (2.31%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   1/56 (1.79%)   0/51 (0.00%) 
Peripheral vascular disorder * 1               
# participants affected / at risk   0/130 (0.00%)   1/131 (0.76%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Arterial occlusive disease * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   1/132 (0.76%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Embolism * 1               
# participants affected / at risk   1/130 (0.77%)   0/131 (0.00%)   0/132 (0.00%)   0/135 (0.00%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
Pulmonary embolism * 1               
# participants affected / at risk   0/130 (0.00%)   0/131 (0.00%)   0/132 (0.00%)   1/135 (0.74%)   0/56 (0.00%)   0/56 (0.00%)   0/51 (0.00%) 
* Events were collected by non-systematic assessment
1 Term from vocabulary, MedDRA (Unspecified)




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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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