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A Study to Compare Tenofovir Disoproxil Fumarate Versus Adefovir Dipivoxil for the Treatment of HBeAg-Negative Chronic Hepatitis B

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT00117676
First received: June 30, 2005
Last updated: February 4, 2016
Last verified: February 2016
Results First Received: February 11, 2010  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Chronic Hepatitis B
Interventions: Drug: TDF
Drug: ADV
Drug: TDF placebo
Drug: ADV placebo
Drug: FTC/TDF

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
There were 79 enrolling sites in 15 countries. The first participant was screened on 07 June 2005, and the last participant was randomized on 15 May 2006. The last participant observation for the primary endpoint analysis (Week 48) was 13 April 2007. The last participant observation for the Week 384 analysis was 20 September 2013.

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
TDF-TDF Tenofovir disoproxil fumarate (TDF) 300 mg plus placebo to match adefovir dipivoxil (ADV) (double-blind period), followed by TDF 300 mg (open-label period). Participants may have added emtricitabine (FTC; as part of FTC 200 mg/TDF 300 mg fixed-dose combination (FDC) tablet) to their treatment regimen in the open-label period.
ADV-TDF ADV 10 mg plus placebo to match TDF (double-blind period), followed by TDF 300 mg (open-label period). Participants may have added FTC (as part of FTC 200 mg/TDF 300 mg FDC tablet) to their treatment regimen in the open-label period.

Participant Flow for 8 periods

Period 1:   Double-blind Period Through Week 48
    TDF-TDF   ADV-TDF
STARTED   250   125 
COMPLETED   244   121 
NOT COMPLETED   6   4 
Lost to Follow-up                1                0 
Protocol Violation                0                1 
Safety, Tolerability, or Efficacy Reason                5                2 
Withdrew Consent                0                1 

Period 2:   Open-label Period: Weeks 49 - 96
    TDF-TDF   ADV-TDF
STARTED   235 [1]   112 [1] 
COMPLETED   225   110 
NOT COMPLETED   10   2 
Lost to Follow-up                2                0 
Safety, Tolerability, or Efficacy Reason                3                1 
Withdrew Consent                5                1 
[1] 9 participants completed 48 weeks but did not continue on study.

Period 3:   Open-label Period: Weeks 97 - 144
    TDF-TDF   ADV-TDF
STARTED   225   110 
COMPLETED   219   109 
NOT COMPLETED   6   1 
Lost to Follow-up                4                1 
Safety, Tolerability, or Efficacy Reason                1                0 
Withdrew Consent                1                0 

Period 4:   Open-label Period: Weeks 145 - 192
    TDF-TDF   ADV-TDF
STARTED   219   109 
COMPLETED   209   106 
NOT COMPLETED   10   3 
Investigator's Discretion                2                0 
Lost to Follow-up                3                1 
Withdrew Consent                5                2 

Period 5:   Open-label Period: Weeks 193 - 240
    TDF-TDF   ADV-TDF
STARTED   209   106 
COMPLETED   202   103 
NOT COMPLETED   7   3 
Investigator's Discretion                1                1 
Lost to Follow-up                0                1 
Safety, Tolerability, or Efficacy Reason                2                0 
Withdrew Consent                4                1 

Period 6:   Open-label Period: Weeks 241 - 288
    TDF-TDF   ADV-TDF
STARTED   202   103 
COMPLETED   192   100 
NOT COMPLETED   10   3 
Investigator's Discretion                0                1 
Lost to Follow-up                2                1 
Protocol Violation                2                0 
Safety, Tolerability, or Efficacy Reason                1                0 
Withdrew Consent                5                1 

Period 7:   Open-label Period: Weeks 289 - 336
    TDF-TDF   ADV-TDF
STARTED   192   100 
COMPLETED   183   93 
NOT COMPLETED   9   7 
Investigator's Discretion                7                4 
Lost to Follow-up                2                2 
Withdrew Consent                0                1 

Period 8:   Open-label Period: Weeks 337 - 384
    TDF-TDF   ADV-TDF
STARTED   183   93 
COMPLETED   176   90 
NOT COMPLETED   7   3 
Investigator's Discretion                1                1 
Lost to Follow-up                3                1 
Study Site Discontinued                1                0 
Withdrew Consent                2                1 



  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.
Randomized and Treated Analysis Set: all participants who were randomized and received at least one dose of study medication

Reporting Groups
  Description
TDF-TDF TDF 300 mg plus placebo to match ADV (double-blind period), followed by TDF 300 mg (open-label period). Participants may have added emtricitabine (FTC) to their treatment regimen (as part of FTC 200 mg/TDF 300 mg FDC tablet) in the open-label period.
ADV-TDF ADV 10 mg plus placebo to match TDF (double-blind period), followed by TDF 300 mg (open-label period). Participants may have added FTC to their treatment regimen (as part of FTC 200 mg/TDF 300 mg FDC tablet) in the open-label period.
Total Total of all reporting groups

Baseline Measures
   TDF-TDF   ADV-TDF   Total 
Overall Participants Analyzed 
[Units: Participants]
 250   125   375 
Age 
[Units: Participants]
     
<=18 years   0   1   1 
Between 18 and 65 years   247   123   370 
>=65 years   3   1   4 
Age 
[Units: Years]
Mean (Standard Deviation)
 44  (10.6)   43  (10.0)   44  (10.4) 
Gender 
[Units: Participants]
     
Female   57   28   85 
Male   193   97   290 
Race/Ethnicity, Customized 
[Units: Participants]
     
American Indian or Alaska Native   0   0   0 
Asian   63   30   93 
Native Hawaiian or Other Pacific Islander   7   2   9 
Black or African American   8   4   12 
White   161   81   242 
More than one race   0   0   0 
Unknown or Not Reported   11   8   19 
Region of Enrollment 
[Units: Participants]
     
United States   25   11   36 
Greece   19   9   28 
Spain   15   6   21 
Turkey   11   3   14 
Italy   6   0   6 
United Kingdom   5   2   7 
France   13   5   18 
Czech Republic   7   5   12 
Canada   29   18   47 
Poland   13   11   24 
Australia   14   8   22 
Bulgaria   49   23   72 
Germany   19   11   30 
Netherlands   1   1   2 
New Zealand   24   12   36 
Baseline Alanine Aminotransferase (ALT) Above the Upper Limit of the Normal (ULN) Range [1] 
[Units: Participants]
     
Yes   236   118   354 
No   14   7   21 
[1] The ULN was 43 U/L for males and 34 U/L for females aged 18 to < 69, and 35 U/L for males and 32 U/L for females aged ≥ 69.
Prior Lamivudine or FTC Treatment 
[Units: Participants]
     
Yes   43   23   66 
No   207   102   309 
Baseline Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) 
[Units: Log10 copies/mL]
Mean (Standard Deviation)
 6.86  (1.308)   6.98  (1.266)   6.90  (1.294) 
Baseline Knodell Necroinflammatory Score [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 7.8  (2.45)   7.8  (2.20)   7.8  (2.37) 
[1] Based on Knodell numerical scoring of liver biopsy specimens. The Knodell necroinflammatory score is the combined necrosis and inflammation domain scores and ranges 0 (best) to 14 (worst).


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Percentage of Participants With HBV DNA < 400 Copies/mL and Histological Improvement (2-point Reduction in Knodell Necroinflammatory Score Without Worsening in Knodell Fibrosis Score) at Week 48   [ Time Frame: Baseline; Week 48 ]

2.  Secondary:   Percentage of Participants With HBV DNA < 400 Copies/mL at Week 48   [ Time Frame: Week 48 ]

3.  Secondary:   Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 96   [ Time Frame: Week 96 ]

4.  Secondary:   Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 144, 192, 240, 288, 336, and 384   [ Time Frame: Weeks 144, 192, 240, 288, 336, and 384 ]

5.  Secondary:   Change From Baseline in HBV DNA at Weeks 48, 96, 144, 192, 240, 288, 336, and 384   [ Time Frame: Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, and 384 ]

6.  Secondary:   Change From Week 48 in HBV DNA at Weeks 96, 144, 192, 240, 288, 336, and 384   [ Time Frame: Week 48; Weeks 96, 144, 192, 240, 288, 336, and 384 ]

7.  Secondary:   Percentage of Participants With Histological Response at Week 48   [ Time Frame: Baseline; Week 48 ]

8.  Secondary:   Percentage of Participants With Histological Response at Week 240   [ Time Frame: Baseline; Week 240 ]

9.  Secondary:   Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 48   [ Time Frame: Baseline; Week 48 ]

10.  Secondary:   Change From Baseline in Knodell and Ishak Necroinflammatory Scores at Week 240   [ Time Frame: Baseline; Week 240 ]

11.  Secondary:   Ranked Assessment of Necroinflammation and Fibrosis at Week 48   [ Time Frame: Baseline; Week 48 ]

12.  Secondary:   Ranked Assessment of Necroinflammation and Fibrosis at Week 240   [ Time Frame: Baseline; Week 240 ]

13.  Secondary:   Percentage of Participants With ALT Normalization at Week 48   [ Time Frame: Baseline; Week 48 ]

14.  Secondary:   Percentage of Participants With ALT Normalization at Weeks 96   [ Time Frame: Baseline; Week 96 ]

15.  Secondary:   Percentage of Participants With ALT Normalization at Weeks 144, 192, 240, 288, 336, and 384   [ Time Frame: Baseline; Weeks 144, 192, 240, 288, 336, and 384 ]

16.  Secondary:   Change From Baseline in ALT at Weeks 48, 96, 144, 192, 240, 288, 336, and 384   [ Time Frame: Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, and 384 ]

17.  Secondary:   Change From Week 48 in ALT at Weeks 96, 144, 192, 240, 288, 336, and 384   [ Time Frame: Week 48; Weeks 96, 144, 192, 240, 288, 336, and 384 ]

18.  Secondary:   Percentage of Participants With Hepatitis B S-Antigen (HBsAg) Loss or Seroconversion Antibody to HBs (Anti-HBs) at Week 48   [ Time Frame: Baseline; Week 48 ]

19.  Secondary:   Percentage of Participants With HBsAg Loss and/or Seroconversion to Anti-HBs at Week 96   [ Time Frame: Baseline; Week 96 ]

20.  Secondary:   Percentage of Participants With HBsAg Loss and/or Seroconversion to Anti-HBs at Weeks 144, 192, 240, 288, 336, and 384   [ Time Frame: Baseline; Weeks 144, 192, 240, 288, 336, and 384 ]

21.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 48 (Resistance Surveillance)   [ Time Frame: Baseline; Week 48 ]

22.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 96 (Resistance Surveillance)   [ Time Frame: Baseline; Weeks 49 to 95 ]

23.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 144 (Resistance Surveillance)   [ Time Frame: Baseline; Weeks 97 to 144 ]

24.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 192 (Resistance Surveillance)   [ Time Frame: Baseline; Weeks 145 to 192 ]

25.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 240 (Resistance Surveillance)   [ Time Frame: Baseline; Weeks 193 to 240 ]

26.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 288 (Resistance Surveillance)   [ Time Frame: Baseline; Weeks 241 to 288 ]

27.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 336 (Resistance Surveillance)   [ Time Frame: Baseline; Weeks 289 to 336 ]

28.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 384 (Resistance Surveillance)   [ Time Frame: Baseline; Weeks 337 to 384 ]


  Serious Adverse Events
  Hide Serious Adverse Events

Time Frame Baseline to Week 384
Additional Description Randomized and Treated Analysis Set: all participants who were randomized and received at least one dose of study medication.

Reporting Groups
  Description
Double-Blind TDF

Adverse events this reporting group include those occurring in the TDF-TDF group during the double-blind period only (baseline to Week 48).

TDF 300 mg plus placebo to match ADV (double-blind period), followed by TDF 300 mg (open-label period). Participants may have added FTC (as part of FTC 200 mg/TDF 300 mg FDC tablet) to their treatment regimen in the open-label period.

Double-Blind ADV

Adverse events this reporting group include those occurring in the ADV-TDF group during the double-blind period only (baseline to Week 48).

ADV 10 mg plus placebo to match TDF (double-blind period), followed by TDF 300 mg (open-label period). Participants may have added FTC (as part of FTC 200 mg/TDF 300 mg FDC tablet) to their treatment regimen in the open-label period.

Open-Label TDF

Adverse events for this reporting group include those occurring during the open-label TDF 300 mg period (Week 49 up to Week 384), regardless of which group they were randomized to in the double-blind period.

TDF 300/mg+ADV placebo or ADV 10 mg+TDF placebo (double-blind period), followed by TDF 300 mg (open-label period). Participants may have added FTC (as part of FTC 200 mg/TDF 300 mg FDC tablet) to their treatment regimen in the open-label period.


Serious Adverse Events
    Double-Blind TDF   Double-Blind ADV   Open-Label TDF
Total, serious adverse events       
# participants affected / at risk   12/250 (4.80%)   7/125 (5.60%)   81/347 (23.34%) 
Blood and lymphatic system disorders       
Anaemia † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Iron deficiency anaemia † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Cardiac disorders       
Angina pectoris † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   3/347 (0.86%) 
Angina unstable † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   2/347 (0.58%) 
Atrial fibrillation † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Coronary artery disease † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Myocardial infarction † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Sick sinus syndrome † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Endocrine disorders       
Hyperparathyroidism † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Eye disorders       
Cataract † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Gastrointestinal disorders       
Abdominal pain † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   2/347 (0.58%) 
Haemorrhoids † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   2/347 (0.58%) 
Inguinal hernia † 1       
# participants affected / at risk   1/250 (0.40%)   0/125 (0.00%)   1/347 (0.29%) 
Abdominal hernia † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Abdominal pain upper † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Colitis † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Diarrhoea † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Gastrooesophageal reflux disease † 1       
# participants affected / at risk   1/250 (0.40%)   0/125 (0.00%)   0/347 (0.00%) 
Haemorrhoidal haemorrhage † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Intestinal obstruction † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Pancreatitis † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Pancreatitis acute † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Small intestinal obstruction † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
General disorders       
Chest pain † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   4/347 (1.15%) 
Granuloma † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Malaise † 1       
# participants affected / at risk   1/250 (0.40%)   0/125 (0.00%)   0/347 (0.00%) 
Condition aggravated † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Hepatobiliary disorders       
Hepatitis † 1       
# participants affected / at risk   0/250 (0.00%)   1/125 (0.80%)   1/347 (0.29%) 
Cholecystitis acute † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Cholelithiasis † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Hepatocellular carcinoma † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Liver disorder † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Infections and infestations       
Pneumonia † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   4/347 (1.15%) 
Appendicitis † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   2/347 (0.58%) 
Abscess limb † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Cellulitis † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Diverticulitis † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Erysipelas † 1       
# participants affected / at risk   1/250 (0.40%)   0/125 (0.00%)   0/347 (0.00%) 
Liver abscess † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Lower respiratory tract infection † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Lung infection † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Pneumonia pneumococcal † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Sepsis † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Septic shock † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Wound infection † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Injury, poisoning and procedural complications       
Lower limb fracture † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   2/347 (0.58%) 
Arterial injury † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Concussion † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Fall † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Foot fracture † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Hand fracture † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Head injury † 1       
# participants affected / at risk   1/250 (0.40%)   0/125 (0.00%)   0/347 (0.00%) 
Injury † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Limb injury † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Meniscus injury † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Overdose † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Post procedural haemorrhage † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Procedural hypotension † 1       
# participants affected / at risk   0/250 (0.00%)   1/125 (0.80%)   0/347 (0.00%) 
Road traffic accident † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Wound † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Wrist fracture † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Investigations       
Alanine aminotransferase increased † 1       
# participants affected / at risk   3/250 (1.20%)   0/125 (0.00%)   1/347 (0.29%) 
Aspartate aminotransferase increased † 1       
# participants affected / at risk   1/250 (0.40%)   0/125 (0.00%)   0/347 (0.00%) 
Hepatitis B DNA increased † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Metabolism and nutrition disorders       
Diabetes mellitus † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Diabetes mellitus inadequate control † 1       
# participants affected / at risk   0/250 (0.00%)   1/125 (0.80%)   0/347 (0.00%) 
Diabetic ketoacidosis † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Musculoskeletal and connective tissue disorders       
Intervertebral disc protrusion † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   3/347 (0.86%) 
Back pain † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Bone cyst † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Bursitis † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Liposarcoma † 1       
# participants affected / at risk   0/250 (0.00%)   1/125 (0.80%)   0/347 (0.00%) 
Musculoskeletal pain † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Myopathy toxic † 1       
# participants affected / at risk   0/250 (0.00%)   1/125 (0.80%)   0/347 (0.00%) 
Osteitis † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Osteoarthritis † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Osteopenia † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Osteoporosis † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Spinal osteoarthritis † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Tenosynovitis stenosans † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Hepatocellular carcinoma † 1       
# participants affected / at risk   2/250 (0.80%)   0/125 (0.00%)   6/347 (1.73%) 
Cervix carcinoma † 1       
# participants affected / at risk   1/250 (0.40%)   1/125 (0.80%)   0/347 (0.00%) 
Nasopharyngeal cancer † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   2/347 (0.58%) 
Adenocarcinoma † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Bladder neoplasm † 1       
# participants affected / at risk   1/250 (0.40%)   0/125 (0.00%)   0/347 (0.00%) 
Cholangiocarcinoma † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Colon cancer † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Colon neoplasm † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Craniopharyngioma † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Gastric cancer † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Lung adenocarcinoma † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Lung neoplasm malignant † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Metastases to peritoneum † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Mixed hepatocellular cholangiocarcinoma † 1       
# participants affected / at risk   1/250 (0.40%)   0/125 (0.00%)   0/347 (0.00%) 
Prostate cancer † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Salivary gland adenoma † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Uterine leiomyoma † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Metastatic gastric cancer † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Nervous system disorders       
Subarachnoid haemorrhage † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   2/347 (0.58%) 
Cerebral infarction † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Diabetic neuropathy † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Epilepsy † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Facial neuralgia † 1       
# participants affected / at risk   0/250 (0.00%)   1/125 (0.80%)   0/347 (0.00%) 
Loss of consciousness † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Sciatica † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Psychiatric disorders       
Depression † 1       
# participants affected / at risk   0/250 (0.00%)   1/125 (0.80%)   1/347 (0.29%) 
Psychotic disorder † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   2/347 (0.58%) 
Agitation † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Bipolar disorder † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Delusional disorder, unspecified type † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Dissociative disorder † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Schizophrenia † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Schizophrenia, paranoid type † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Renal and urinary disorders       
Renal failure † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Urogenital fistula † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Reproductive system and breast disorders       
Benign prostatic hyperplasia † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Endometrial adenocarcinoma † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Fibrocystic breast disease † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Ovarian cyst † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Ovarian cyst ruptured † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Respiratory, thoracic and mediastinal disorders       
Bronchiectasis † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Lung disorder † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Vascular disorders       
Haematoma † 1       
# participants affected / at risk   0/250 (0.00%)   1/125 (0.80%)   1/347 (0.29%) 
Arteritis † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Hypertension † 1       
# participants affected / at risk   0/250 (0.00%)   0/125 (0.00%)   1/347 (0.29%) 
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 16.1




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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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