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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT00116805
First received: June 30, 2005
Last updated: January 26, 2017
Last verified: January 2017
Results First Received: February 11, 2010  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, 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
Participants were enrolled at study sites in North America, Europe, and Australia/New Zealand. The first participant was screened on 09 June 2005. The last study visit occurred on 28 January 2016.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
603 participants were screened.

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) to their treatment regimen (as part of FTC 200 mg/TDF 300 mg fixed-dose combination (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.

Participant Flow for 10 periods

Period 1:   Double-blind Period Through Week 48
    TDF-TDF   ADV-TDF
STARTED   176   90 
COMPLETED   165   85 
NOT COMPLETED   11   5 
Lost to Follow-up                6                2 
Protocol Violation                1                1 
Withdrew Consent                4                2 

Period 2:   Open-label Period Weeks 49 - 96
    TDF-TDF   ADV-TDF
STARTED   154 [1]   84 [2] 
COMPLETED   144   83 
NOT COMPLETED   10   1 
Investigator's Discretion                1                0 
Lost to Follow-up                2                0 
Protocol Violation                2                0 
Safety, Tolerability, or Efficacy Reason                1                0 
Seroconversion                2                0 
Withdrew Consent                2                1 
[1] 11 participants completed 48 weeks but did not continue on study.
[2] 1 participant completed 48 weeks but did not continue on study.

Period 3:   Open-label Period Weeks 97 - 144
    TDF-TDF   ADV-TDF
STARTED   144   83 
COMPLETED   133   74 
NOT COMPLETED   11   9 
Completed Study                1                0 
Investigator's Discretion                2                0 
Lost to Follow-up                5                2 
Protocol Violation                0                1 
Seroconversion                2                3 
Withdrew Consent                1                3 

Period 4:   Open-label Period Weeks 145 - 192
    TDF-TDF   ADV-TDF
STARTED   133   74 
COMPLETED   123   68 
NOT COMPLETED   10   6 
Completed Study                1                1 
Investigator's Discretion                2                0 
Lost to Follow-up                3                1 
Protocol Violation                1                0 
Safety, Tolerability, or Efficacy Reason                0                1 
Seroconversion                0                1 
Withdrew Consent                3                2 

Period 5:   Open-label Period Weeks 193 - 240
    TDF-TDF   ADV-TDF
STARTED   123   68 
COMPLETED   110   64 
NOT COMPLETED   13   4 
Completed Study                0                1 
Investigator's Discretion                1                0 
Lost to Follow-up                3                0 
Safety, Tolerability, or Efficacy Reason                2                2 
Withdrew Consent                7                1 

Period 6:   Open-label Period Weeks 241 - 288
    TDF-TDF   ADV-TDF
STARTED   110   64 
COMPLETED   104   64 
NOT COMPLETED   6   0 
Safety, Tolerability, or Efficacy Reason                2                0 
Withdrew Consent                4                0 

Period 7:   Open-label Period Weeks 289 - 336
    TDF-TDF   ADV-TDF
STARTED   104   64 
COMPLETED   98   57 
NOT COMPLETED   6   7 
Completed Study                0                1 
Investigator's Discretion                3                2 
Lost to Follow-up                1                1 
Protocol Violation                0                1 
Safety, Tolerability, or Efficacy Reason                0                1 
Study Site Discontinued                0                1 
Withdrew Consent                2                0 

Period 8:   Open-label Period Weeks 337 - 384
    TDF-TDF   ADV-TDF
STARTED   98   57 
COMPLETED   90   56 
NOT COMPLETED   8   1 
Completed Study                1                0 
Investigator's Discretion                1                0 
Lost to Follow-up                2                0 
Protocol Violation                1                0 
Withdrew Consent                3                1 

Period 9:   Open-label Period Weeks 385 - 432
    TDF-TDF   ADV-TDF
STARTED   59 [1]   30 [2] 
COMPLETED   57   30 
NOT COMPLETED   2   0 
Investigator’s Discretion                1                0 
Withdrew Consent                1                0 
[1] 31 participants completed 384 weeks but did not continue on study.
[2] 26 participants completed 384 weeks but did not continue on study.

Period 10:   Open-label Period Weeks 433 - 480
    TDF-TDF   ADV-TDF
STARTED   57   29 [1] 
COMPLETED   53   29 
NOT COMPLETED   4   0 
Investigator’s Discretion                1                0 
Withdrew Consent                3                0 
[1] 1 participant completed 432 weeks but did not continue on study.



  Baseline Characteristics
  Hide Baseline Characteristics

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]
 176   90   266 
Age 
[Units: Participants]
Count of Participants
     
<=18 years      3   1.7%      1   1.1%      4   1.5% 
Between 18 and 65 years      173  98.3%      89  98.9%      262  98.5% 
>=65 years      0   0.0%      0   0.0%      0   0.0% 
Age 
[Units: Years]
Mean (Standard Deviation)
 34  (11.3)   34  (12.2)   34  (11.6) 
Sex: Female, Male 
[Units: Participants]
Count of Participants
     
Female      57  32.4%      26  28.9%      83  31.2% 
Male      119  67.6%      64  71.1%      183  68.8% 
Region of Enrollment 
[Units: Participants]
     
United States   30   14   44 
Greece   1   2   3 
Spain   7   2   9 
Turkey   10   4   14 
Italy   0   1   1 
United Kingdom   6   1   7 
France   11   3   14 
Czech Republic   3   5   8 
Canada   17   10   27 
Poland   16   8   24 
Australia   22   6   28 
Bulgaria   17   11   28 
Germany   20   8   28 
Netherlands   6   4   10 
New Zealand   10   11   21 
Baseline Alanine Aminotransferase (ALT) above the Upper Limit of the Normal (ULN) Range [1] 
[Units: Participants]
     
Yes   169   90   259 
No   7   0   7 
[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   8   1   9 
No   168   89   257 
Baseline Hepatitis B Deoxyribonucleic Acid (HBV DNA) 
[Units: Log10 copies/mL]
Mean (Standard Deviation)
 8.64  (1.076)   8.88  (0.930)   8.72  (1.033) 
Baseline Knodell Necroinflammatory Score [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 8.3  (2.11)   8.5  (2.07)   8.4  (2.09) 
[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 Week 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:   Percentage of Participants With HBV DNA < 400 Copies/mL at Weeks 432 and 480   [ Time Frame: Weeks 432 and 480 ]

6.  Secondary:   Change From Baseline in HBV DNA at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480   [ Time Frame: Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480 ]

7.  Secondary:   Change From Week 48 in HBV DNA at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480   [ Time Frame: Week 48; Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480 ]

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

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

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

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

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

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

14.  Secondary:   Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48   [ Time Frame: Baseline; Week 48 ]

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

16.  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 ]

17.  Secondary:   Percentage of Participants With ALT Normalization at Weeks 432 and 480   [ Time Frame: Baseline; Weeks 432 and 480 ]

18.  Secondary:   Change From Baseline in ALT at Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480   [ Time Frame: Baseline; Weeks 48, 96, 144, 192, 240, 288, 336, 384, 432, and 480 ]

19.  Secondary:   Change From Week 48 in ALT at Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480   [ Time Frame: Week 48; Weeks 96, 144, 192, 240, 288, 336, 384, 432, and 480 ]

20.  Secondary:   Percentage of Participants With Hepatitis B e Antigen (HBeAg) Loss/Seroconversion at Week 48   [ Time Frame: Baseline; Week 48 ]

21.  Secondary:   Percentage of Participants With HBeAg Loss or Seroconversion to Anti-HBe at Week 96   [ Time Frame: Baseline; Week 96 ]

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

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

24.  Secondary:   Percentage of Participants With HBsAg Loss or Seroconversion to Anti-HBs at Weeks 144, 192, 240, 288, 336, 384, 432, and 480   [ Time Frame: Baseline; Weeks 144, 192, 240, 288, 336, 384, 432, and 480 ]

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

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

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

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

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

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

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

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

33.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 432 (Resistance Surveillance)   [ Time Frame: Baseline; Weeks 385 to 432 ]

34.  Secondary:   Number of Participants With HBV Genotypic Changes From Baseline at Week 480 (Resistance Surveillance)   [ Time Frame: Baseline; Weeks 433 to 480 ]


  Serious Adverse Events
  Hide Serious Adverse Events

Time Frame Baseline to Week 480
Additional Description Randomized and Treated Analysis Set: all participants who were randomized and received at least one dose of study drug.

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).

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).

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 480), 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 to their treatment regimen (as part of FTC 200 mg/TDF 300 mg FDC tablet) 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   15/176 (8.52%)   7/90 (7.78%)   41/238 (17.23%) 
Blood and lymphatic system disorders       
Thrombocytopenia † 1       
# participants affected / at risk   1/176 (0.57%)   0/90 (0.00%)   0/238 (0.00%) 
Cardiac disorders       
Acute myocardial infarction † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Angina pectoris † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Ischaemic cardiomyopathy † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Myocarditis † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Congenital, familial and genetic disorders       
Congenital anomaly in offspring † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Gastrointestinal disorders       
Inguinal hernia † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
General disorders       
Chest pain † 1       
# participants affected / at risk   0/176 (0.00%)   1/90 (1.11%)   1/238 (0.42%) 
Hepatobiliary disorders       
Cholecystitis chronic † 1       
# participants affected / at risk   0/176 (0.00%)   1/90 (1.11%)   0/238 (0.00%) 
Cholelithiasis † 1       
# participants affected / at risk   1/176 (0.57%)   0/90 (0.00%)   0/238 (0.00%) 
Hepatitis † 1       
# participants affected / at risk   1/176 (0.57%)   0/90 (0.00%)   1/238 (0.42%) 
Infections and infestations       
Abscess soft tissue † 1       
# participants affected / at risk   1/176 (0.57%)   0/90 (0.00%)   0/238 (0.00%) 
Diverticulitis † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Epididymitis † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Gastroenteritis † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Groin abscess † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Hepatitis B † 1       
# participants affected / at risk   1/176 (0.57%)   0/90 (0.00%)   0/238 (0.00%) 
Orchitis † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Respiratory tract infection † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Sepsis † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Skin infection † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Urinary tract infection † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Injury, poisoning and procedural complications       
Arthropod bite † 1       
# participants affected / at risk   0/176 (0.00%)   1/90 (1.11%)   0/238 (0.00%) 
Lower limb fracture † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Procedural dizziness † 1       
# participants affected / at risk   1/176 (0.57%)   0/90 (0.00%)   0/238 (0.00%) 
Skull fracture † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Subdural haematoma † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Ulna fracture † 1       
# participants affected / at risk   1/176 (0.57%)   0/90 (0.00%)   0/238 (0.00%) 
Investigations       
Alanine aminotransferase increased † 1       
# participants affected / at risk   6/176 (3.41%)   4/90 (4.44%)   6/238 (2.52%) 
Aspartate aminotransferase increased † 1       
# participants affected / at risk   2/176 (1.14%)   1/90 (1.11%)   2/238 (0.84%) 
Blood creatine phosphokinase increased † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Glucose urine present † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   2/238 (0.84%) 
Metabolism and nutrition disorders       
Diabetes mellitus inadequate control † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Musculoskeletal and connective tissue disorders       
Musculoskeletal chest pain † 1       
# participants affected / at risk   0/176 (0.00%)   1/90 (1.11%)   0/238 (0.00%) 
Osteoarthritis † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Osteoporosis † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Synovial cyst † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Breast cancer † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Colon adenoma † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Hepatic cancer † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Hepatic cancer metastatic † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Hepatic neoplasm † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Hepatocellular carcinoma † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   2/238 (0.84%) 
Hodgkin's disease † 1       
# participants affected / at risk   1/176 (0.57%)   0/90 (0.00%)   0/238 (0.00%) 
Lung cancer metastatic † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Lymphoma † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Prostate cancer † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   2/238 (0.84%) 
Tonsillar neoplasm † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Nervous system disorders       
Diabetic neuropathy † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Facial spasm † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Seizure † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Subarachnoid haemorrhage † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Transient ischaemic attack † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   2/238 (0.84%) 
Psychiatric disorders       
Drug dependence † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Renal and urinary disorders       
Calculus ureteric † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   3/238 (1.26%) 
Tubulointerstitial nephritis † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Reproductive system and breast disorders       
Ovarian cyst ruptured † 1       
# participants affected / at risk   1/176 (0.57%)   0/90 (0.00%)   0/238 (0.00%) 
Surgical and medical procedures       
Abortion induced † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Vascular disorders       
Thrombosis † 1       
# participants affected / at risk   0/176 (0.00%)   0/90 (0.00%)   1/238 (0.42%) 
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 18.1




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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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