Prospective Evaluation of Anti-retroviral Combinations for Treatment Naive, HIV Infected Persons in Resource-limited Settings (PEARLS)

This study has been completed.
Sponsor:
Collaborator:
Information provided by:
AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT00084136
First received: June 7, 2004
Last updated: August 10, 2011
Last verified: August 2011
Results First Received: July 13, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: HIV Infections
Interventions: Drug: Atazanavir
Drug: Didanosine (enteric-coated)
Drug: Efavirenz
Drug: Emtricitabine
Drug: Emtricitabine/Tenofovir disoproxil fumarate
Drug: Lamivudine/Zidovudine

  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
Study participants were recruited at 43 sites from 9 countries: 28 in the US, 4 in India, 2 each in Brazil, Malawi, Peru and South Africa, and 1 each in Haiti, Thailand and Zimbabwe, between May 2005 to August 2007.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
HIV-infected, treatment-naive men and women, at least 18 years of age with CD4+ count <300 cells/mm^3.

Reporting Groups
  Description
ZDV/3TC+EFV ZDV/3TC+EFV participants will receive lamivudine/zidovudine and efavirenz
ddI+FTC+ATV

ddI+FTC+ATV participants will receive emtricitabine, atazanavir, and enteric-coated didanosine >

> On May 23, 2008, Arm B was closed following a planned interim review by the study's independent Data and Safety Monitoring Board (DSMB). The DSMB recommendation was based upon compelling evidence that Arm B had significantly more virologic failure (and therefore was inferior when) compared to Arm A. Participants still receiving Arm B medications were offered alternatives, and all participants continued to be followed.

TDF/FTC+EFV TDF/FTC+EFV participants will receive emtricitabine/tenofovir disoproxil fumarate and efavirenz

Participant Flow for 2 periods

Period 1:   PI Comparison
    ZDV/3TC+EFV     ddI+FTC+ATV     TDF/FTC+EFV  
STARTED     519     526     0  
COMPLETED     464 [1]   479 [1]   0  
NOT COMPLETED     55     47     0  
Death                 10                 9                 0  
Lost to Follow-up                 11                 8                 0  
Withdrawal by Subject                 33                 30                 0  
Clinic site closed                 1                 0                 0  
[1] Follow-up was until ddI+FTC+ATV arm was closed per DSMB recommendation on May 23, 2008.

Period 2:   NRTI Comparison
    ZDV/3TC+EFV     ddI+FTC+ATV     TDF/FTC+EFV  
STARTED     519     0     526  
COMPLETED     418 [1]   0     444 [1]
NOT COMPLETED     101     0     82  
Death                 20                 0                 18  
Lost to Follow-up                 14                 0                 12  
Withdrawal by Subject                 54                 0                 38  
Clinic site closed                 12                 0                 14  
Not reason above                 1                 0                 0  
[1] Follow-up though study closeout period (final visit between April 1 and May 31, 2010).



  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
ZDV/3TC+EFV ZDV/3TC+EFV participants will receive lamivudine/zidovudine and efavirenz
ddI+FTC+ATV

ddI+FTC+ATV participants will receive emtricitabine, atazanavir, and enteric-coated didanosine >

> On May 23, 2008, Arm B was closed following a planned interim review by the study's independent Data and Safety Monitoring Board (DSMB). The DSMB recommendation was based upon compelling evidence that Arm B had significantly more virologic failure (and therefore was inferior when) compared to Arm A. Participants still receiving Arm B medications were offered alternatives, and all participants continued to be followed.

TDF/FTC+EFV TDF/FTC+EFV participants will receive emtricitabine/tenofovir disoproxil fumarate and efavirenz
Total Total of all reporting groups

Baseline Measures
    ZDV/3TC+EFV     ddI+FTC+ATV     TDF/FTC+EFV     Total  
Number of Participants  
[units: participants]
  519     526     526     1571  
Age  
[units: years]
Mean ± Standard Deviation
  35  ± 9     35  ± 8     35  ± 9     35  ± 9  
Age, Customized  
[units: participants]
       
Between 18 and 29 years     141     146     146     433  
Between 30 and 39 years     244     221     225     690  
Between 40 and 49 years     100     129     116     345  
At least 50 years     34     30     39     103  
Gender  
[units: participants]
       
Female     241     256     242     739  
Male     278     270     284     832  
Region of Enrollment  
[units: participants]
       
Brazil     79     76     76     231  
Haiti     35     32     33     100  
India     81     86     88     255  
Malawi     74     74     73     221  
Peru     42     48     44     134  
South Africa     70     70     70     210  
Thailand     32     33     35     100  
United States     70     70     70     210  
Zimbabwe     36     37     37     110  
CD4 count, Continuous [1]
[units: cells/mm^3]
Mean ± Standard Deviation
  163  ± 85     167  ± 83     155  ± 81     162  ± 83  
CD4 count, Categorical [2]
[units: participants]
       
< 50 cells/mm^3     68     63     69     200  
Between 50 and 99 cells/mm^3     70     77     82     229  
Between 100 and 199 cells/mm^3     174     161     193     528  
Between 200 and 249 cells/mm^3     104     128     107     339  
Between 250 and 299 cells/mm^3     103     97     75     275  
Plasma HIV-1 RNA, Continuous  
[units: log10┬ácopies/mL]
Median ( Inter-Quartile Range )
  5.0  
  ( 4.6 to 5.4 )  
  5.1  
  ( 4.5 to 5.5 )  
  5.0  
  ( 4.5 to 5.5 )  
  5.0  
  ( 4.6 to 5.5 )  
Plasma HIV-1 RNA, Categorical  
[units: participants]
       
<= 400 copies/mL     3     6     3     12  
Between 400 and 4000 copies/mL     22     19     14     55  
Between 4001 and 40,000 copies/mL     103     119     124     346  
Between 40,001 and 400,000 copies/mL     311     283     284     878  
Between 400,001 and 749,999 copies/mL     45     58     55     158  
>= 750,000 copies/mL     35     40     46     121  
Missing     0     1     0     1  
[1] Screening value used for study eligibility as no other pre-randomization CD4 cell counts available
[2] Screening CD4 count used for study eligibility as no other pre-randomization counts available.



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Time to Treatment Failure (PI Comparison)   [ Time Frame: Virologic failure starting 14 weeks following randomization; disease progression starting 12 weeks following randomization; and death occurring at any time following randomization. Follow-up until ddI+FTC+ATV arm closed (May 22, 2008). ]

2.  Primary:   Time to Treatment Failure (NRTI Comparison)   [ Time Frame: Virologic failure starting 14 weeks following randomization; disease progression starting 12 weeks following randomization; and death occurring at any time following randomization. Follow-up through study closure (May 31, 2010). ]

3.  Secondary:   Time to Discontinuation of Initial Antiretroviral (ARV) Therapy (PI Comparison)   [ Time Frame: Throughout follow-up until ddI+FTC+ATV arm closed (May 22,2008) ]

4.  Secondary:   Time to Immunologic Failure (PI Comparison)   [ Time Frame: At or after Week 48 (including only follow-up until ddI+FTV+ATV arm closed - May 22,2008) ]

5.  Secondary:   Change in CD4 Count From Screening to Weeks 24, 48, 96 (PI Comparison)   [ Time Frame: weeks 24, 48 and 96 (including follow-up until ddI+FTC+ARV arm closed - May 22, 2008) ]

6.  Secondary:   Time to First Dose Modification or Grade 3 or 4 Adverse Event (PI Comparison)   [ Time Frame: Throughout study follow-up until ddI+FTC+ATV arm closed (May 22, 2008) ]

7.  Secondary:   Plasma HIV-1 Viral Load Fewer Than 400 Copies/ml (PI Comparison)   [ Time Frame: At Weeks 24 and 48 (including only follow-up until ddI+FTC+ARV arm closed - May 22, 2008) ]

8.  Secondary:   Time to Loss of Virologic Response by Week 48 (Defined by FDA TLOVR Algorithm - Excluding Study Allowed ARV Substitutions)(PI Comparison)   [ Time Frame: Week 48 (using follow-up only until closing of ddI+FTV+ATV arm on May 22,2008) ]

9.  Secondary:   Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(PI Comparison)   [ Time Frame: Week 48 (using follow-up only until closing of ddI+FTV+ATV arm on May 22,2008) ]

10.  Secondary:   Time to Discontinuation of Initial Antiretroviral (ARV) Therapy (NRTI Comparison)   [ Time Frame: Throughout follow-up until study closed (May 31,2010) ]

11.  Secondary:   Time to Immunologic Failure (NRTI Comparison)   [ Time Frame: At or after Week 48 (including all follow-up through study closure - May 31,2010) ]

12.  Secondary:   Change in CD4 Count From Screening to Weeks 24, 48, 96 (NRTI Comparison)   [ Time Frame: weeks 24, 48 and 96 (including all follow-up through to study closure on May 31, 2010) ]

13.  Secondary:   Plasma HIV-1 Viral Load Fewer Than 400 Copies/ml (NRTI Comparison)   [ Time Frame: At Weeks 24 and 48 (including follow-up through to study closure on May 31, 2010) ]

14.  Secondary:   Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Excluding Study Allowed ARV Substitutions)(NRTI Comparison)   [ Time Frame: Week 48 (using follow-up through study closure on May 31,2010) ]

15.  Secondary:   Time to Loss of Virologic Response at Week 96 (Defined by FDA TLOVR Algorithm - Excluding Study Allowed ARV Substitutions)(NRTI Comparison)   [ Time Frame: Week 96 (using follow-up through to study closure on May 31,2010) ]

16.  Secondary:   Time to Loss of Virologic Response at Week 48 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(NRTI Comparison)   [ Time Frame: Week 48 using follow-up through study closure on May 31,2010 ]

17.  Secondary:   Time to Loss of Virologic Response at Week 96 (Defined by FDA TLOVR Algorithm - Including All ARV Substitutions)(NRTI Comparison)   [ Time Frame: Week 96 using follow-up through study closure on May 31,2010 ]

18.  Secondary:   Time to First Dose Modification or Grade 3 or 4 Adverse Event (NRTI Comparison)   [ Time Frame: Throughout study follow-up until study closure (May 31, 2010) ]


  Serious Adverse Events
  Hide Serious Adverse Events

Time Frame Throughout study follow-up (until May 31, 2010 or earlier only if participant prematurely left the study).
Additional Description Standard Level reporting by DAIDS EAE Manual,May 6, 2004(http://rcc.tech-res.com/safetyandpharmacovigilance/). ATV-related, asymptomatic hyperbilirubinemia or jaundice without LFT elevation does not require (EAE) reporting. IRIS events do not fulfill the DAIDS EAE reporting criteria, even if the event is severe in intensity.

Reporting Groups
  Description
ZDV/3TC+EFV No text entered.
ddI+FTC+ATV No text entered.
TDF/FTC+EFV No text entered.

Serious Adverse Events
    ZDV/3TC+EFV     ddI+FTC+ATV     TDF/FTC+EFV  
Total, serious adverse events        
# participants affected / at risk     86/519 (16.57%)     84/526 (15.97%)     55/526 (10.46%)  
Blood and lymphatic system disorders        
Anaemia † 1      
# participants affected / at risk     12/519 (2.31%)     2/526 (0.38%)     2/526 (0.38%)  
Bone marrow failure † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Bone marrow toxicity † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Neutropenia † 1      
# participants affected / at risk     17/519 (3.28%)     8/526 (1.52%)     2/526 (0.38%)  
Pancytopenia † 1      
# participants affected / at risk     0/519 (0.00%)     2/526 (0.38%)     0/526 (0.00%)  
Thrombocytopenia † 1      
# participants affected / at risk     2/519 (0.39%)     2/526 (0.38%)     1/526 (0.19%)  
Cardiac disorders        
Acute coronary syndrome † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     1/526 (0.19%)  
Angina pectoris † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Arrhythmia † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Cardiac failure congestive † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Hypertrophic cardiomyopathy † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Myocardial infarction † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     1/526 (0.19%)  
Ear and labyrinth disorders        
Vertigo † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     1/526 (0.19%)  
Gastrointestinal disorders        
Abdominal pain † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Ascites † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Diarrhoea † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Intestinal obstruction † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     1/526 (0.19%)  
Oesophageal ulcer † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Pancreatitis † 1      
# participants affected / at risk     2/519 (0.39%)     5/526 (0.95%)     0/526 (0.00%)  
Pancreatitis acute † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Pancreatitis chronic † 1      
# participants affected / at risk     1/519 (0.19%)     1/526 (0.19%)     0/526 (0.00%)  
Peritonitis † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Vomiting † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     1/526 (0.19%)  
General disorders        
Death † 1      
# participants affected / at risk     4/519 (0.77%)     0/526 (0.00%)     1/526 (0.19%)  
Pyrexia † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Sudden death † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     1/526 (0.19%)  
Hepatobiliary disorders        
Hepatitis † 1      
# participants affected / at risk     4/519 (0.77%)     5/526 (0.95%)     1/526 (0.19%)  
Hepatorenal syndrome † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Hepatotoxicity † 1      
# participants affected / at risk     2/519 (0.39%)     0/526 (0.00%)     2/526 (0.38%)  
Hyperbilirubinaemia † 1      
# participants affected / at risk     1/519 (0.19%)     8/526 (1.52%)     0/526 (0.00%)  
Jaundice cholestatic † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Immune system disorders        
Drug hypersensitivity † 1      
# participants affected / at risk     1/519 (0.19%)     2/526 (0.38%)     0/526 (0.00%)  
Hypersensitivity † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     1/526 (0.19%)  
Infections and infestations        
AIDS related complex † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Abortion infected † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     1/526 (0.19%)  
Bronchopneumonia † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     1/526 (0.19%)  
Chikungunya virus infection † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Corynebacterium sepsis † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Cryptococcosis † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Disseminated tuberculosis † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     2/526 (0.38%)  
Encephalitis viral † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Gastroenteritis † 1      
# participants affected / at risk     2/519 (0.39%)     4/526 (0.76%)     1/526 (0.19%)  
HIV infection † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Herpes zoster † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Lower respiratory tract infection † 1      
# participants affected / at risk     2/519 (0.39%)     1/526 (0.19%)     0/526 (0.00%)  
Malaria † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     1/526 (0.19%)  
Meningitis † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Meningitis tuberculous † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     1/526 (0.19%)  
Pneumocystis jiroveci pneumonia † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     1/526 (0.19%)  
Pneumonia † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Pneumonia bacterial † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     1/526 (0.19%)  
Progressive multifocal leukoencephalopathy † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Psoas abscess † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     1/526 (0.19%)  
Pulmonary tuberculosis † 1      
# participants affected / at risk     1/519 (0.19%)     1/526 (0.19%)     0/526 (0.00%)  
Sepsis † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     2/526 (0.38%)  
Septic shock † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     1/526 (0.19%)  
Tuberculosis † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Injury, poisoning and procedural complications        
Gun shot wound † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Stab wound † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Investigations        
Alanine aminotransferase increased † 1      
# participants affected / at risk     0/519 (0.00%)     2/526 (0.38%)     1/526 (0.19%)  
Aspartate aminotransferase increased † 1      
# participants affected / at risk     1/519 (0.19%)     2/526 (0.38%)     1/526 (0.19%)  
Blood alkaline phosphatase increased † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Blood bilirubin increased † 1      
# participants affected / at risk     0/519 (0.00%)     8/526 (1.52%)     2/526 (0.38%)  
Blood creatine increased † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     2/526 (0.38%)  
Blood creatine phosphokinase increased † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Blood creatinine increased † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     1/526 (0.19%)  
Blood glucose increased † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Blood lactic acid increased † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Blood phosphorus decreased † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Haemoglobin decreased † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     2/526 (0.38%)  
Hepatic enzyme increased † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Lipase increased † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Liver function test abnormal † 1      
# participants affected / at risk     2/519 (0.39%)     3/526 (0.57%)     2/526 (0.38%)  
Neutrophil count decreased † 1      
# participants affected / at risk     5/519 (0.96%)     4/526 (0.76%)     0/526 (0.00%)  
Weight decreased † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     1/526 (0.19%)  
Metabolism and nutrition disorders        
Abnormal loss of weight † 1      
# participants affected / at risk     1/519 (0.19%)     2/526 (0.38%)     0/526 (0.00%)  
Dehydration † 1      
# participants affected / at risk     1/519 (0.19%)     1/526 (0.19%)     0/526 (0.00%)  
Diabetes mellitus † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Diabetic ketoacidosis † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Hyperkalaemia † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     1/526 (0.19%)  
Hypernatraemia † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Hypertriglyceridaemia † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Hypophosphataemia † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     1/526 (0.19%)  
Lactic acidosis † 1      
# participants affected / at risk     2/519 (0.39%)     2/526 (0.38%)     0/526 (0.00%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)        
Cervix carcinoma † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Gastric cancer † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Lymphoma † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     1/526 (0.19%)  
Non-Hodgkin's lymphoma † 1      
# participants affected / at risk     1/519 (0.19%)     1/526 (0.19%)     0/526 (0.00%)  
Squamous cell carcinoma of the cervix † 1      
# participants affected / at risk     0/519 (0.00%)     2/526 (0.38%)     0/526 (0.00%)  
Nervous system disorders        
Cerebral haemorrhage † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     1/526 (0.19%)  
Cerebral infarction † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Cranial nerve paralysis † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Dizziness † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     1/526 (0.19%)  
Encephalitis † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Haemorrhage intracranial † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Hepatic encephalopathy † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     1/526 (0.19%)  
Hydrocephalus † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Ischaemic stroke † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Monoplegia † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     1/526 (0.19%)  
Subarachnoid haemorrhage † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     1/526 (0.19%)  
Pregnancy, puerperium and perinatal conditions        
Abortion missed † 1      
# participants affected / at risk     1/519 (0.19%)     1/526 (0.19%)     0/526 (0.00%)  
Abortion spontaneous † 1      
# participants affected / at risk     3/519 (0.58%)     5/526 (0.95%)     2/526 (0.38%)  
Abortion spontaneous complete † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Abortion spontaneous incomplete † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     1/526 (0.19%)  
Blighted ovum † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Intra-uterine death † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     1/526 (0.19%)  
Stillbirth † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Psychiatric disorders        
Completed suicide † 1      
# participants affected / at risk     2/519 (0.39%)     0/526 (0.00%)     1/526 (0.19%)  
Depression † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     2/526 (0.38%)  
Major depression † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Mental disorder † 1      
# participants affected / at risk     0/519 (0.00%)     0/526 (0.00%)     1/526 (0.19%)  
Psychotic disorder † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Suicidal ideation † 1      
# participants affected / at risk     2/519 (0.39%)     1/526 (0.19%)     3/526 (0.57%)  
Suicide attempt † 1      
# participants affected / at risk     1/519 (0.19%)     2/526 (0.38%)     5/526 (0.95%)  
Renal and urinary disorders        
Nephrolithiasis † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Renal colic † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Renal failure † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     1/526 (0.19%)  
Renal failure acute † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Skin and subcutaneous tissue disorders        
Dapsone syndrome † 1      
# participants affected / at risk     0/519 (0.00%)     1/526 (0.19%)     0/526 (0.00%)  
Rash † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Stevens-Johnson syndrome † 1      
# participants affected / at risk     1/519 (0.19%)     1/526 (0.19%)     1/526 (0.19%)  
Surgical and medical procedures        
Abortion induced † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Vascular disorders        
Deep vein thrombosis † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Thrombosis † 1      
# participants affected / at risk     1/519 (0.19%)     0/526 (0.00%)     0/526 (0.00%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 14.0




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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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