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APOLLO: The Study of an Investigational Drug, Patisiran (ALN-TTR02), for the Treatment of Transthyretin (TTR)-Mediated Amyloidosis

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ClinicalTrials.gov Identifier: NCT01960348
Recruitment Status : Completed
First Posted : October 10, 2013
Results First Posted : September 6, 2018
Last Update Posted : December 11, 2018
Sponsor:
Information provided by (Responsible Party):
Alnylam Pharmaceuticals

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Conditions TTR-mediated Amyloidosis
Amyloidosis, Hereditary
Amyloid Neuropathies, Familial
Familial Amyloid Polyneuropathies
Amyloid Neuropathies
Amyloidosis, Hereditary, Transthyretin-Related
Interventions Drug: patisiran (ALN-TTR02)
Drug: Sterile Normal Saline (0.9% NaCl)
Enrollment 225
Recruitment Details A total of 225 patients with hereditary transthyretin (hATTR) amyloidosis were enrolled and randomized in the study.
Pre-assignment Details  
Arm/Group Title Patisiran (ALN-TTR02) Placebo
Hide Arm/Group Description All patients who received at least 1 dose of patisiran (ALN-TTR02) All patients who received at least 1 dose of placebo
Period Title: Overall Study
Started 148 77
Completed [1] 138 55
Not Completed 10 22
Reason Not Completed
Adverse event, not serious             2             2
Adverse event, serious fatal             6             5
Adverse event, serious non-fatal             0             3
Withdrawal by Subject             1             11
Physician Decision             0             1
Protocol Violation             1             0
[1]
Participants who completed this study could enter the extension study NCT02510261 (ALN-TTR02-006)
Arm/Group Title Patisiran (ALN-TTR02) Placebo Total
Hide Arm/Group Description All patients who received at least 1 dose of patisiran (ALN-TTR02) All patients who received at least 1 dose of placebo Total of all reporting groups
Overall Number of Baseline Participants 148 77 225
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 148 participants 77 participants 225 participants
59.6  (11.96) 62.2  (10.76) 60.5  (11.61)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 148 participants 77 participants 225 participants
<65 years
86
  58.1%
44
  57.1%
130
  57.8%
65-74 years
53
  35.8%
24
  31.2%
77
  34.2%
≥75 years
9
   6.1%
9
  11.7%
18
   8.0%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 148 participants 77 participants 225 participants
Female
39
  26.4%
19
  24.7%
58
  25.8%
Male
109
  73.6%
58
  75.3%
167
  74.2%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 148 participants 77 participants 225 participants
Hispanic or Latino
17
  11.5%
11
  14.3%
28
  12.4%
Not Hispanic or Latino
130
  87.8%
65
  84.4%
195
  86.7%
Unknown or Not Reported
1
   0.7%
1
   1.3%
2
   0.9%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 148 participants 77 participants 225 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
27
  18.2%
25
  32.5%
52
  23.1%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
4
   2.7%
1
   1.3%
5
   2.2%
White
113
  76.4%
50
  64.9%
163
  72.4%
More than one race
2
   1.4%
0
   0.0%
2
   0.9%
Unknown or Not Reported
2
   1.4%
1
   1.3%
3
   1.3%
Baseline NIS   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 148 participants 77 participants 225 participants
NIS <50
62
  41.9%
35
  45.5%
97
  43.1%
NIS ≥50
86
  58.1%
42
  54.5%
128
  56.9%
[1]
Measure Description:

The Neuropathy Impairment Score is an assessment of motor weakness (NIS-W), sensation (NIS-S) and reflexes (NIS-R) scored based on physical exam findings.

NIS-W is a measure of motor strength, comprised of cranial nerve and both upper and lower limb motor assessments. The minimum and maximum values are 0 and 192, respectively. A higher score indicates a worse outcome.

Genotype Class   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 148 participants 77 participants 225 participants
Early onset V30M (<50 years of age at onset)
13
   8.8%
10
  13.0%
23
  10.2%
All other mutations (including late onset V30M)
135
  91.2%
67
  87.0%
202
  89.8%
[1]
Measure Description: Transthyretin (TTR) genotype class, collected at baseline
Previous Tetramer Stabilizer Use   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 148 participants 77 participants 225 participants
Yes
78
  52.7%
41
  53.2%
119
  52.9%
No
70
  47.3%
36
  46.8%
106
  47.1%
[1]
Measure Description: Prior use of tafamidis meglumine or diflunisal
Baseline mNIS+7   [1] 
Mean (Standard Deviation)
Unit of measure:  Points
Number Analyzed 148 participants 77 participants 225 participants
80.93  (41.507) 74.61  (37.041) 78.77  (40.064)
[1]
Measure Description: The mNIS+7 is a composite score that quantitates motor, sensory, and autonomic neurologic impairment due to injury of large and small nerves. The minimum and maximum values are 0 and 304, respectively. A higher score indicates a worse outcome.
1.Primary Outcome
Title Modified Neuropathy Impairment Score +7 (mNIS+7)
Hide Description The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in mNIS+7 at 18 months. The mNIS+7 is a composite score that quantitates motor, sensory, and autonomic neurologic impairment due to injury of large and small nerves. The minimum and maximum values are 0 and 304, respectively. A higher score indicates a worse outcome.
Time Frame 18mo
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol (PP) population: All randomized participants who received at least 1 dose of patisiran-LNP or placebo, completed baseline and the 18-month mNIS+7 assessments, and did not experience any major protocol deviations that may have impacted the efficacy results.
Arm/Group Title Patisiran (ALN-TTR02) Placebo
Hide Arm/Group Description:
All patients who received at least 1 dose of patisiran (ALN-TTR02)
All patients who received at least 1 dose of placebo
Overall Number of Participants Analyzed 137 51
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
-6.03  (1.739) 27.96  (2.602)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Patisiran (ALN-TTR02), Placebo
Comments In the mixed-effect model repeated measures (MMRM) model, the outcome variable is change from baseline in mNIS+7. The model includes baseline mNIS+7 score as covariate and fixed effect terms including treatment group, visit, treatment-by-visit interaction, genotype, age at hATTR symptom onset, previous tetramer stabilizer use and region.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0000001
Comments P=9.262E-24
Method Mixed-effect Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Squares Mean Difference
Estimated Value -33.99
Confidence Interval (2-Sided) 95%
-39.86 to -28.13
Parameter Dispersion
Type: Standard Error of the Mean
Value: 2.974
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Questionnaire
Hide Description The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in Norfolk QoL-DN at 18 months. The Norfolk QoL-DN questionnaire is a standardized 35-item patient-reported outcomes measure that is sensitive to the different features of diabetic neuropathy - small fiber, large fiber, and autonomic nerve function. The minimum and maximum values are -4 and 136, respectively. A higher score indicates a worse outcome.
Time Frame 18mo
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol (PP) population: All randomized participants who received at least 1 dose of patisiran-LNP or placebo, completed baseline and the 18-month Norfolk QoL-DN assessments, and did not experience any major protocol deviations that may have impacted the efficacy results.
Arm/Group Title Patisiran (ALN-TTR02) Placebo
Hide Arm/Group Description:
All patients who received at least 1 dose of patisiran (ALN-TTR02)
All patients who received at least 1 dose of placebo
Overall Number of Participants Analyzed 136 48
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
-6.7  (1.77) 14.4  (2.73)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Patisiran (ALN-TTR02), Placebo
Comments In the mixed-effect model repeated measures (MMRM) model, the outcome variable is change from baseline in Norfolk QOL-DN total score. The model includes baseline Norfolk QOL-DN score as covariate and fixed effect terms including treatment group, visit, treatment-by-visit interaction, baseline NIS, genotype, age at hATTR symptom onset, previous tetramer stabilizer use and region.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0000001
Comments P=1.103E-10
Method Mixed-effect Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Squares Mean Difference
Estimated Value -21.1
Confidence Interval (2-Sided) 95%
-27.2 to -15.0
Parameter Dispersion
Type: Standard Error of the Mean
Value: 3.10
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Neurological Impairment Score-Weakness (NIS-W) Score
Hide Description The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in NIS-W at 18 months. NIS-W is a measure of motor strength, comprised of cranial nerve and both upper and lower limb motor assessments. The minimum and maximum values are 0 and 192, respectively. A higher score indicates a worse outcome.
Time Frame 18mo
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol (PP) population: All randomized participants who received at least 1 dose of patisiran-LNP or placebo, completed baseline and the 18-month NIS-W assessments, and did not experience any major protocol deviations that may have impacted the efficacy results.
Arm/Group Title Patisiran (ALN-TTR02) Placebo
Hide Arm/Group Description:
All patients who received at least 1 dose of patisiran (ALN-TTR02)
All patients who received at least 1 dose of placebo
Overall Number of Participants Analyzed 137 51
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
0.05  (1.306) 17.93  (1.959)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Patisiran (ALN-TTR02), Placebo
Comments In the mixed-effect model repeated measures (MMRM) model, the outcome variable is change from baseline in NIS-W. The model includes baseline NIS-W score as covariate and fixed effect terms including treatment group, visit, treatment-by-visit interaction, genotype, age at hATTR symptom onset, previous tetramer stabilizer use and region.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0000001
Comments P=1.404E-13
Method Mixed-effect Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Squares Mean Difference
Estimated Value -17.87
Confidence Interval (2-Sided) 95%
-22.32 to -13.43
Parameter Dispersion
Type: Standard Error of the Mean
Value: 2.254
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Rasch-built Overall Disability Scale (R-ODS) Score
Hide Description The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in R-ODS score at 18 months. The R-ODS is comprised of a 24-item linearly weighted scale that specifically captures activity and social participation limitations in patients. The minimum and maximum values are 0 and 48, respectively. A higher score indicates a better outcome.
Time Frame 18mo
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol (PP) population: All randomized participants who received at least 1 dose of patisiran-LNP or placebo, completed baseline and either the 18-month R-ODS assessments, and did not experience any major protocol deviations that may have impacted the efficacy results.
Arm/Group Title Patisiran (ALN-TTR02) Placebo
Hide Arm/Group Description:
All patients who received at least 1 dose of patisiran (ALN-TTR02)
All patients who received at least 1 dose of placebo
Overall Number of Participants Analyzed 138 54
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
0.0  (0.59) -8.9  (0.88)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Patisiran (ALN-TTR02), Placebo
Comments In the mixed-effect model repeated measures (MMRM) model, the outcome variable is change from baseline in R-ODS value. The model includes baseline R-ODS score as covariate and fixed effect terms including treatment group, visit, treatment-by-visit interaction, baseline NIS, genotype, age at hATTR symptom onset, previous tetramer stabilizer use and region.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0000001
Comments P=4.066E-16
Method Mixed-effect Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Squares Mean Difference
Estimated Value 9.0
Confidence Interval (2-Sided) 95%
7.0 to 10.9
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.01
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Timed 10-meter Walk Test (10-MWT, Gait Speed)
Hide Description The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in 10-MWT at 18 months. Ability to ambulate (gait speed) was assessed through the 10-meter walk test (10-MWT). The walk had to be completed without assistance from another person; ambulatory aids such as canes and walkers were permitted.
Time Frame 18mo
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol (PP) population: All randomized participants who received at least 1 dose of patisiran-LNP or placebo, completed baseline and the 18-month 10-MWT assessments, and did not experience any major protocol deviations that may have impacted the efficacy results.
Arm/Group Title Patisiran (ALN-TTR02) Placebo
Hide Arm/Group Description:
All patients who received at least 1 dose of patisiran (ALN-TTR02)
All patients who received at least 1 dose of placebo
Overall Number of Participants Analyzed 138 55
Least Squares Mean (Standard Error)
Unit of Measure: m/sec
0.077  (0.0242) -0.235  (0.0358)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Patisiran (ALN-TTR02), Placebo
Comments In the mixed-effect model repeated measures (MMRM) model, the outcome variable is change from baseline in 10-meter walk test result. The model includes baseline 10-meter walk test result as covariate and fixed effect terms including treatment group, visit, treatment-by-visit interaction, baseline NIS, genotype, age at hATTR symptom onset, previous tetramer stabilizer use and region.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0000001
Comments P=1.875E-12
Method Mixed-effect Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Squares Mean Difference
Estimated Value 0.311
Confidence Interval (2-Sided) 95%
0.230 to 0.393
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.0415
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Modified Body Mass Index (mBMI)
Hide Description The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in mBMI at 18 months. The nutritional status of patients was evaluated using the mBMI; calculated as the product of BMI (weight in kilograms divided by the square of height in meters) and serum albumin (g/L).
Time Frame 18mo
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol (PP) population: All randomized participants who received at least 1 dose of patisiran-LNP or placebo, completed baseline and the 18-month mBMI assessments and did not experience any major protocol deviations that may have impacted the results..
Arm/Group Title Patisiran (ALN-TTR02) Placebo
Hide Arm/Group Description:
All patients who received at least 1 dose of patisiran (ALN-TTR02)
All patients who received at least 1 dose of placebo
Overall Number of Participants Analyzed 133 52
Least Squares Mean (Standard Error)
Unit of Measure: kg/m^2 × albumin g/L
-3.7  (9.57) -119.4  (14.51)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Patisiran (ALN-TTR02), Placebo
Comments In the mixed-effect model repeated measures (MMRM) model, the outcome variable is change from baseline in mBMI. The model includes baseline mBMI as covariate and fixed effect terms including treatment group, visit, treatment-by-visit interaction, baseline NIS, genotype, age at hATTR symptom onset, previous tetramer stabilizer use and region.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0000001
Comments P=8.832E-11
Method Mixed-effect Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Squares Mean Difference
Estimated Value 115.7
Confidence Interval (2-Sided) 95%
82.4 to 149.0
Parameter Dispersion
Type: Standard Error of the Mean
Value: 16.91
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Autonomic Symptoms Questionnaire (Composite Autonomic Symptom Score [COMPASS 31])
Hide Description The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in COMPASS 31 at 18 months. The COMPASS 31 is a measure of autonomic neuropathy symptoms. The questions evaluated 6 autonomic domains (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor). The minimum and maximum values are 0 and 100, respectively. A higher score indicates a worse outcome.
Time Frame 18mo
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol (PP) population: All randomized participants who received at least 1 dose of patisiran-LNP or placebo, completed baseline and the 18-month COMPASS 31 assessments, and did not experience any major protocol deviations that may have impacted the efficacy results.
Arm/Group Title Patisiran (ALN-TTR02) Placebo
Hide Arm/Group Description:
All patients who received at least 1 dose of patisiran (ALN-TTR02)
All patients who received at least 1 dose of placebo
Overall Number of Participants Analyzed 136 53
Least Squares Mean (Standard Error)
Unit of Measure: score on a scale
-5.29  (1.300) 2.24  (1.940)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Patisiran (ALN-TTR02), Placebo
Comments In the mixed-effect model repeated measures (MMRM) model, the outcome variable is change from baseline in COMPASS-31 total score. The model includes baseline COMPASS-31 score as covariate and fixed effect terms including treatment group, visit, treatment-by-visit interaction, baseline NIS, genotype, age at hATTR symptom onset, previous tetramer stabilizer use and region.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0008
Comments [Not Specified]
Method Mixed-effect Model Repeated Measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Squares Mean Difference
Estimated Value -7.53
Confidence Interval (2-Sided) 95%
-11.89 to -3.16
Parameter Dispersion
Type: Standard Error of the Mean
Value: 2.213
Estimation Comments [Not Specified]
Time Frame All Adverse Events (AEs) that occurred from start of study drug administration through End of Study (Day 567), or Follow-up (Day 602) if patient did not enter open-label extension study. AEs for patients with Rapid Disease Progression at Month 9 who stopped dosing were collected through Day 294 (42 days after last dose).
Adverse Event Reporting Description The same event may appear as both an AE and a Serious Adverse Event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study. Safety population: All participants who received at least 1 dose of patisiran-LNP or placebo. Participants were analyzed according to the treatment received.
 
Arm/Group Title Patisiran (ALN-TTR02) Placebo
Hide Arm/Group Description All patients who received at least 1 dose of patisiran (ALN-TTR02) All patients who received at least 1 dose of placebo
All-Cause Mortality
Patisiran (ALN-TTR02) Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   7/148 (4.73%)      6/77 (7.79%)    
Show Serious Adverse Events Hide Serious Adverse Events
Patisiran (ALN-TTR02) Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   54/148 (36.49%)      31/77 (40.26%)    
Blood and lymphatic system disorders     
Anaemia  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Anaemia of chronic disease  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Cardiac disorders     
Arteriosclerosis coronary artery  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Atrial fibrillation  1  2/148 (1.35%)  2 1/77 (1.30%)  1
Atrioventricular block  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Atrioventricular block complete  1  3/148 (2.03%)  3 0/77 (0.00%)  0
Cardiac amyloidosis  1  2/148 (1.35%)  2 1/77 (1.30%)  1
Cardiac arrest  1  2/148 (1.35%)  2 1/77 (1.30%)  1
Cardiac failure  1  3/148 (2.03%)  3 2/77 (2.60%)  2
Cardiac failure acute  1  0/148 (0.00%)  0 1/77 (1.30%)  2
Cardiac failure chronic  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Cardiac failure congestive  1  3/148 (2.03%)  3 2/77 (2.60%)  3
Cardio-respiratory arrest  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Cardiogenic shock  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Cardiomyopathy  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Conduction disorder  1  1/148 (0.68%)  1 1/77 (1.30%)  1
Pulseless electrical activity  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Restrictive cardiomyopathy  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Ventricular dyssynchrony  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Ventricular fibrillation  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Ventricular tachycardia  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Congenital, familial and genetic disorders     
Hereditary neuropathic amyloidosis  1  0/148 (0.00%)  0 2/77 (2.60%)  2
Hypertrophic cardiomyopathy  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Phimosis  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Syringomyelia  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Ear and labyrinth disorders     
Deafness unilateral  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Vertigo  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Eye disorders     
Maculopathy  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Vitreous haemorrhage  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Vitreous opacities  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Gastrointestinal disorders     
Ascites  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Constipation  1  0/148 (0.00%)  0 2/77 (2.60%)  2
Diarrhoea  1  8/148 (5.41%)  9 1/77 (1.30%)  1
Gastritis  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Gastrointestinal haemorrhage  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Gastrointestinal motility disorder  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Hiatus hernia  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Impaired gastric emptying  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Large intestine polyp  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Oesophagitis  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Vomiting  1  1/148 (0.68%)  1 3/77 (3.90%)  3
General disorders     
Asthenia  1  0/148 (0.00%)  0 1/77 (1.30%)  4
Chest discomfort  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Device battery issue  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Device dislocation  1  1/148 (0.68%)  2 0/77 (0.00%)  0
Gait disturbance  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Influenza like illness  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Non-cardiac chest pain  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Oedema peripheral  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Sudden cardiac death  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Systemic inflammatory response syndrome  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Hepatobiliary disorders     
Cholangitis  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Cholecystitis  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Immune system disorders     
Amyloidosis  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Infections and infestations     
Bacteraemia  1  0/148 (0.00%)  0 1/77 (1.30%)  2
Bronchitis  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Cellulitis  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Endocarditis staphylococcal  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Erysipelas  1  1/148 (0.68%)  1 1/77 (1.30%)  1
Gastroenteritis  1  0/148 (0.00%)  0 1/77 (1.30%)  2
Infected skin ulcer  1  1/148 (0.68%)  2 0/77 (0.00%)  0
Pneumonia  1  3/148 (2.03%)  3 3/77 (3.90%)  3
Pneumonia bacterial  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Post procedural cellulitis  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Respiratory tract infection  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Sepsis  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Staphylococcal sepsis  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Urinary tract infection  1  0/148 (0.00%)  0 4/77 (5.19%)  5
Urosepsis  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Injury, poisoning and procedural complications     
Cervical vertebral fracture  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Fall  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Joint dislocation  1  1/148 (0.68%)  2 0/77 (0.00%)  0
Lower limb fracture  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Road traffic accident  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Spinal compression fracture  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Traumatic haematoma  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Investigations     
Drug level increased  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Investigation  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Liver function test abnormal  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Metabolism and nutrition disorders     
Cachexia  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Dehydration  1  1/148 (0.68%)  1 3/77 (3.90%)  5
Hypoalbuminaemia  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Hypocalcaemia  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Hypoglycaemia  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Hypokalaemia  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Hyponatraemia  1  0/148 (0.00%)  0 2/77 (2.60%)  2
Musculoskeletal and connective tissue disorders     
Back pain  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Lumbar spinal stenosis  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Neuropathic arthropathy  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Atypical fibroxanthoma  1  1/148 (0.68%)  2 0/77 (0.00%)  0
Bladder cancer  1  1/148 (0.68%)  2 0/77 (0.00%)  0
Colon cancer metastatic  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Colorectal cancer metastatic  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Renal oncocytoma  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Nervous system disorders     
Ataxia  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Cerebral infarction  1  1/148 (0.68%)  2 0/77 (0.00%)  0
Epilepsy  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Hypoxic-ischaemic encephalopathy  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Ischaemic stroke  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Posterior reversible encephalopathy syndrome  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Subarachnoid haemorrhage  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Syncope  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Transient ischaemic attack  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Psychiatric disorders     
Depression  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Hallucinations, mixed  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Renal and urinary disorders     
Acute kidney injury  1  1/148 (0.68%)  1 4/77 (5.19%)  5
Urinary retention  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Reproductive system and breast disorders     
Benign prostatic hyperplasia  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Breast mass  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Prostatitis  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Respiratory, thoracic and mediastinal disorders     
Acute pulmonary oedema  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Dyspnoea  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Hypoxia  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Pleural effusion  1  1/148 (0.68%)  1 1/77 (1.30%)  1
Pneumonia aspiration  1  0/148 (0.00%)  0 2/77 (2.60%)  2
Pulmonary embolism  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Pulmonary oedema  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Respiratory failure  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Skin and subcutaneous tissue disorders     
Dermatitis  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Skin ulcer  1  1/148 (0.68%)  1 1/77 (1.30%)  1
Surgical and medical procedures     
Liver transplant  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Vascular disorders     
Deep vein thrombosis  1  2/148 (1.35%)  2 0/77 (0.00%)  0
Hypotension  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Orthostatic hypotension  1  3/148 (2.03%)  3 1/77 (1.30%)  1
Peripheral arterial occlusive disease  1  1/148 (0.68%)  1 0/77 (0.00%)  0
Peripheral ischaemia  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Shock haemorrhagic  1  0/148 (0.00%)  0 1/77 (1.30%)  1
Thrombophlebitis superficial  1  1/148 (0.68%)  1 0/77 (0.00%)  0
1
Term from vocabulary, MedDRA (18.0)
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Patisiran (ALN-TTR02) Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   143/148 (96.62%)      75/77 (97.40%)    
Blood and lymphatic system disorders     
Anaemia  1  3/148 (2.03%)  3 8/77 (10.39%)  11
Cardiac disorders     
Atrial fibrillation  1  11/148 (7.43%)  12 5/77 (6.49%)  6
Supraventricular extrasystoles  1  2/148 (1.35%)  2 5/77 (6.49%)  6
Atrioventricular block first degree  1  0/148 (0.00%)  0 4/77 (5.19%)  4
Ear and labyrinth disorders     
Vertigo  1  8/148 (5.41%)  11 1/77 (1.30%)  1
Eye disorders     
Cataract  1  8/148 (5.41%)  10 5/77 (6.49%)  5
Gastrointestinal disorders     
Diarrhoea  1  50/148 (33.78%)  156 28/77 (36.36%)  94
Constipation  1  22/148 (14.86%)  29 12/77 (15.58%)  17
Nausea  1  22/148 (14.86%)  50 16/77 (20.78%)  22
Vomiting  1  14/148 (9.46%)  20 6/77 (7.79%)  27
Dyspepsia  1  12/148 (8.11%)  23 3/77 (3.90%)  5
Gastrooesophageal reflux disease  1  8/148 (5.41%)  8 5/77 (6.49%)  5
Abdominal pain upper  1  3/148 (2.03%)  3 6/77 (7.79%)  8
Haemorrhoids  1  1/148 (0.68%)  3 5/77 (6.49%)  7
General disorders     
Oedema peripheral  1  43/148 (29.05%)  68 17/77 (22.08%)  35
Fatigue  1  18/148 (12.16%)  27 8/77 (10.39%)  18
Asthenia  1  14/148 (9.46%)  25 8/77 (10.39%)  11
Pyrexia  1  11/148 (7.43%)  12 5/77 (6.49%)  6
Peripheral swelling  1  4/148 (2.70%)  6 4/77 (5.19%)  6
Immune system disorders     
Infusion related reaction  1  28/148 (18.92%)  145 7/77 (9.09%)  79
Infections and infestations     
Urinary tract infection  1  19/148 (12.84%)  40 12/77 (15.58%)  18
Nasopharyngitis  1  15/148 (10.14%)  26 6/77 (7.79%)  11
Upper respiratory tract infection  1  13/148 (8.78%)  16 5/77 (6.49%)  6
Influenza  1  11/148 (7.43%)  13 4/77 (5.19%)  4
Bronchitis  1  9/148 (6.08%)  11 2/77 (2.60%)  2
Gastroenteritis  1  4/148 (2.70%)  5 4/77 (5.19%)  4
Injury, poisoning and procedural complications     
Fall  1  25/148 (16.89%)  47 22/77 (28.57%)  42
Contusion  1  4/148 (2.70%)  5 5/77 (6.49%)  5
Thermal burn  1  4/148 (2.70%)  7 4/77 (5.19%)  4
Investigations     
Weight decreased  1  6/148 (4.05%)  6 7/77 (9.09%)  7
Metabolism and nutrition disorders     
Vitamin D deficiency  1  7/148 (4.73%)  7 4/77 (5.19%)  4
Decreased appetite  1  6/148 (4.05%)  6 5/77 (6.49%)  9
Dehydration  1  1/148 (0.68%)  1 5/77 (6.49%)  5
Musculoskeletal and connective tissue disorders     
Muscle spasms  1  12/148 (8.11%)  18 1/77 (1.30%)  1
Arthralgia  1  11/148 (7.43%)  13 0/77 (0.00%)  0
Back pain  1  10/148 (6.76%)  11 6/77 (7.79%)  9
Pain in extremity  1  10/148 (6.76%)  13 8/77 (10.39%)  12
Osteoporosis  1  7/148 (4.73%)  7 7/77 (9.09%)  7
Muscular weakness  1  5/148 (3.38%)  8 11/77 (14.29%)  17
Myalgia  1  2/148 (1.35%)  4 4/77 (5.19%)  4
Nervous system disorders     
Dizziness  1  19/148 (12.84%)  24 11/77 (14.29%)  37
Headache  1  16/148 (10.81%)  25 9/77 (11.69%)  10
Neuralgia  1  10/148 (6.76%)  29 5/77 (6.49%)  13
Balance disorder  1  8/148 (5.41%)  10 2/77 (2.60%)  2
Paraesthesia  1  8/148 (5.41%)  23 3/77 (3.90%)  5
Somnolence  1  5/148 (3.38%)  13 4/77 (5.19%)  5
Hypoaesthesia  1  4/148 (2.70%)  6 5/77 (6.49%)  5
Syncope  1  2/148 (1.35%)  2 8/77 (10.39%)  9
Psychiatric disorders     
Insomnia  1  15/148 (10.14%)  24 7/77 (9.09%)  12
Depression  1  5/148 (3.38%)  5 5/77 (6.49%)  7
Renal and urinary disorders     
Haematuria  1  6/148 (4.05%)  9 7/77 (9.09%)  12
Respiratory, thoracic and mediastinal disorders     
Cough  1  15/148 (10.14%)  18 9/77 (11.69%)  11
Dyspnoea  1  9/148 (6.08%)  13 0/77 (0.00%)  0
Skin and subcutaneous tissue disorders     
Erythema  1  10/148 (6.76%)  51 2/77 (2.60%)  2
Skin ulcer  1  5/148 (3.38%)  7 5/77 (6.49%)  6
Skin lesion  1  2/148 (1.35%)  2 4/77 (5.19%)  4
Vascular disorders     
Hypotension  1  8/148 (5.41%)  8 5/77 (6.49%)  9
Orthostatic hypotension  1  7/148 (4.73%)  7 6/77 (7.79%)  7
1
Term from vocabulary, MedDRA (18.0)
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Chief Medical Officer
Organization: Alnylam Pharmaceuticals, Inc.
Phone: 866.330.0326
EMail: medinfo@alnylam.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Alnylam Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01960348     History of Changes
Other Study ID Numbers: ALN-TTR02-004
2013-002987-17 ( EudraCT Number )
First Submitted: October 9, 2013
First Posted: October 10, 2013
Results First Submitted: August 7, 2018
Results First Posted: September 6, 2018
Last Update Posted: December 11, 2018