Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

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

This study has been completed.
Sponsor:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT00084136
First received: June 7, 2004
Last updated: June 1, 2015
Last verified: June 2015
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
  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
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 
Overall Participants Analyzed 
[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) 
[1] Screening value used for study eligibility as no other pre-randomization CD4 cell counts available
CD4 count, Categorical [1] 
[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 
[1] Screening CD4 count used for study eligibility as no other pre-randomization counts available.
Plasma HIV-1 RNA, Continuous 
[Units: Log10 copies/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 


  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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