Pharmacokinetics of Atazanavir/Ritonavir in HIV-1 Infected Pregnant Women

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00326716
First received: May 15, 2006
Last updated: November 4, 2011
Last verified: November 2011
Results First Received: January 5, 2011  
Study Type: Interventional
Study Design: Allocation: Non-Randomized;   Endpoint Classification: Pharmacokinetics Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: HIV Infection
Intervention: Drug: Atazanavir + Ritonavir + Combivir

  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
Pregnant participants were enrolled at 6 sites: United States (2), South Africa (3), and Puerto Rico (1).

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Of the 69 enrolled participants, 28 mothers were not treated. Failure to continue to meet enrollment criteria resulting in discontinuation in 24/28 participants and 4 were not treated: 1 poor/no compliance, 1 met exclusion criteria, 1 was ARV naive subject with HIV RNA < 400 c/mL, and 1 was unable to comply with study procedures.

Reporting Groups
  Description
Mother ATV 300 mg / RTV 100 mg Mothers receiving atazanavir (ATV) / ritonavir (RTV) 300/100 mg once daily (QD) + lamivudine (ZDV) / zidovudine (3TC) 300/150 mg twice daily (BID) during the third trimester. Each dose of ATV/RTV (taken with a light meal or snack) was taken approximately 24 hours apart. Each dose of ZDV/3TC (taken with or without food) was taken approximately 12 hours apart.
Mother ATV 400 mg / RTV 100 mg Mothers receiving ATV/RTV 400/100 mg QD + ZDV/3TC 300/150 mg BID during the third trimester. Each dose of ATV/RTV (taken with a light meal or snack) was taken approximately 24 hours apart. Each dose of ZDV/3TC (taken with or without food) was taken approximately 12 hours apart.
Infants ATV 300 mg / RTV 100 mg Infants born to mothers receiving treatment with ATV 300 mg / RTV 100 mg during the third trimester of pregnancy.
Infants ATV 400 mg / RTV 100 mg Infants born to mothers receiving treatment with ATV 400 mg / RTV 100 mg during the third trimester of pregnancy.

Participant Flow for 2 periods

Period 1:   Pre-Natal Mothers
    Mother ATV 300 mg / RTV 100 mg     Mother ATV 400 mg / RTV 100 mg     Infants ATV 300 mg / RTV 100 mg     Infants ATV 400 mg / RTV 100 mg  
STARTED     20     21     0     0  
COMPLETED     19 [1]   19 [1]   0 [2]   0 [2]
NOT COMPLETED     1     2     0     0  
Discontinued ATV Before Delivery                 1                 2                 0                 0  
[1] Completion was defined as completing the study.
[2] Completion was defined as completing all follow up visits through 6 months.

Period 2:   Infants
    Mother ATV 300 mg / RTV 100 mg     Mother ATV 400 mg / RTV 100 mg     Infants ATV 300 mg / RTV 100 mg     Infants ATV 400 mg / RTV 100 mg  
STARTED     0     0     20 [1]   20 [2]
COMPLETED     0     0     20     20  
NOT COMPLETED     0     0     0     0  
[1] All infants were followed.
[2] All infants were followed. One mother withdrew consent pre-delivery and her infant was not followed.



  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
Mother ATV 300 mg / RTV 100 mg Mothers receiving ATV/RTV 300/100 mg QD + ZDV/3TC 300/150 mg BID during the third trimester. Each dose of ATV/RTV (taken with a light meal or snack) was taken approximately 24 hours apart. Each dose of ZDV/3TC (taken with or without food) was taken approximately 12 hours apart.
Mother ATV 400 mg / RTV 100 mg Mothers receiving ATV/RTV 400/100 mg QD + ZDV/3TC 300/150 mg BID during the third trimester. Each dose of ATV/RTV (taken with a light meal or snack) was taken approximately 24 hours apart. Each dose of ZDV/3TC (taken with or without food) was taken approximately 12 hours apart.
Total Total of all reporting groups

Baseline Measures
    Mother ATV 300 mg / RTV 100 mg     Mother ATV 400 mg / RTV 100 mg     Total  
Number of Participants  
[units: participants]
  20     21     41  
Age  
[units: participants]
     
<=18 years     0     0     0  
Between 18 and 65 years     20     21     41  
>=65 years     0     0     0  
Age  
[units: Years]
Median ( Full Range )
  29  
  ( 21 to 38 )  
  28  
  ( 19 to 37 )  
  28  
  ( 19 to 38 )  
Gender  
[units: participants]
     
Female     20     21     41  
Male     0     0     0  
Race (NIH/OMB)  
[units: Participants]
     
American Indian or Alaska Native     0     0     0  
Asian     0     0     0  
Native Hawaiian or Other Pacific Islander     0     0     0  
Black or African American     17     19     36  
White     3     1     4  
More than one race     0     1     1  
Unknown or Not Reported     0     0     0  
Region of Enrollment  
[units: participants]
     
North America     6     6     12  
Africa     14     15     29  
HIV RNA Distribution at Baseline  
[units: c/mL]
     
<50     3     1     4  
50 to < 30,000     13     13     26  
30,000 to < 100,000     3     6     9  
>= 100,000     1     1     2  
Infant Gestational Age at Delivery  
[units: Weeks]
Median ( Full Range )
  38  
  ( 35 to 40 )  
  38  
  ( 35 to 41 )  
  38  
  ( 35 to 41 )  



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Infant Gestational Age at Delivery   [ Time Frame: At the time of delivery ]

2.  Primary:   Infant Gender   [ Time Frame: At the time of delivery ]

3.  Primary:   Infant Race   [ Time Frame: At the time of delivery ]

4.  Primary:   Mean ATV Maximum Plasma Concentration (Cmax) in One Dosing Interval   [ Time Frame: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum ]

5.  Primary:   Mean RTV Maximum Plasma Concentration (Cmax) in One Dosing Interval   [ Time Frame: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum ]

6.  Primary:   Mean ATV Area Under the Concentration Curve (AUC TAU)   [ Time Frame: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum ]

7.  Primary:   Mean RTV Area Under the Concentration Curve (AUC TAU)   [ Time Frame: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum ]

8.  Primary:   Mean ATV Trough Plasma Concentration (Cmin) 24 Hours Following the Daily Dose   [ Time Frame: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum at 24 hours following the daily dose. ]

9.  Primary:   Mean RTV Trough Plasma Concentration (Cmin) 24 Hours Following the Daily Dose   [ Time Frame: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum at 24 hours following the daily dose. ]

10.  Primary:   Mean ATV Terminal Elimination Half Life (T 1/2)   [ Time Frame: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum ]

11.  Primary:   Mean RTV Terminal Elimination Half Life (T 1/2)   [ Time Frame: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum ]

12.  Primary:   Mean ATV Time of Maximum Observed Plasma Concentration (Tmax)   [ Time Frame: Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum ]

13.  Primary:   Mean RTV Time of Maximum Observed Plasma Concentration (Tmax)   [ Time Frame: Pregnancy Weeks 12 to 28, Weeks 28 to 36, and 4-6 Weeks Postpartum ]

14.  Secondary:   Maternal HIV Ribonucleic Acid (RNA) Level on Day of Delivery   [ Time Frame: Day of Delivery ± 2 Days ]

15.  Secondary:   Median Change From Baseline to Day of Delivery in Maternal HIV RNA Level   [ Time Frame: Baseline, Day of Delivery ± 2 Days ]

16.  Secondary:   Mean HIV RNA Level at Baseline   [ Time Frame: Baseline ]

17.  Secondary:   Median Change From Baseline to Day of Delivery in Maternal Cluster of Differentiation 4 (CD4) Cell Count   [ Time Frame: Baseline, Day of Delivery ± 2 Days ]

18.  Secondary:   Mean CD4 Cell Count at Baseline   [ Time Frame: Baseline ]

19.  Secondary:   Infant HIV Status   [ Time Frame: Birth Through 6 Months on Study ]

20.  Secondary:   Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)   [ Time Frame: During study period and 30 days post-study. ]

21.  Secondary:   Number of Participants With Grade 2 to Grade 4 AEs and SAEs   [ Time Frame: During Study Period and 30 Days Post-Study. ]

22.  Secondary:   SAEs in Enrolled Mothers   [ Time Frame: During Study Period and 30 Days Post-Study. ]

23.  Secondary:   SAEs in Enrolled Infants   [ Time Frame: Birth Through Week 16 of Life ]

24.  Secondary:   Mean Atazanavir Maternal Plasma Concentration and Neonatal Cord Blood Concentration   [ Time Frame: At Time of Delivery ]

25.  Secondary:   Median Infant Total Bilirubin Level   [ Time Frame: Birth (Day 1), Day 3, Day 5, and Day 7 of Life ]

26.  Secondary:   Mean Atazanavir Plasma Protein Binding   [ Time Frame: Pregnancy Weeks 28 to Delivery at 3 Hours Postdose and 24 Hours Postdose, and Time of Delivery ]

27.  Secondary:   Multicenter AIDS Cohort Study (MACS) Participant Adherence to Regimen and Drug Components for ATV 300 mg / RTV 100 mg Test Dose   [ Time Frame: Study Week 2, Pregnancy Weeks 20 to Weeks 28, Pregnancy Weeks 28 to Delivery, Week 2 Postpartum, Week 4 Postpartum ]


  Serious Adverse Events


  Other Adverse Events
  Hide Other Adverse Events

Time Frame No text entered.
Additional Description No text entered.

Frequency Threshold
Threshold above which other adverse events are reported   5%  

Reporting Groups
  Description
Infant ATV 300 mg / RTV 100 mg Infants of mothers taking ATV 300 mg / RTV 100 mg at birth.
Infant ATV 400 mg / RTV 100 mg Infants of mothers taking ATV 400 mg / RTV 100 mg at birth.
Mother ATV 300 mg / RTV 100 mg Mothers receiving ATV/RTV 300/100 mg QD + ZDV/3TC 300/150 mg BID during the third trimester. Each dose of ATV/RTV (taken with a light meal or snack) was taken approximately 24 hours apart. Each dose of ZDV/3TC (taken with or without food) was taken approximately 12 hours apart.
Mother ATV 400 mg / RTV 100 mg Mothers receiving ATV/RTV 400/100 mg QD + ZDV/3TC 300/150 mg BID during the third trimester. Each dose of ATV/RTV (taken with a light meal or snack) was taken approximately 24 hours apart. Each dose of ZDV/3TC (taken with or without food) was taken approximately 12 hours apart.

Other Adverse Events
    Infant ATV 300 mg / RTV 100 mg     Infant ATV 400 mg / RTV 100 mg     Mother ATV 300 mg / RTV 100 mg     Mother ATV 400 mg / RTV 100 mg  
Total, other (not including serious) adverse events          
# participants affected / at risk     20/20     20/20     20/20     20/21  
Blood and lymphatic system disorders          
ANAEMIA † 1        
# participants affected / at risk     1/20 (5.00%)     1/20 (5.00%)     2/20 (10.00%)     4/21 (19.05%)  
LYMPHADENOPATHY † 1        
# participants affected / at risk     1/20 (5.00%)     1/20 (5.00%)     0/20 (0.00%)     0/21 (0.00%)  
Congenital, familial and genetic disorders          
HYDROCELE † 1        
# participants affected / at risk     0/20 (0.00%)     1/20 (5.00%)     0/20 (0.00%)     0/21 (0.00%)  
CONGENITAL NAEVUS † 1        
# participants affected / at risk     1/20 (5.00%)     0/20 (0.00%)     0/20 (0.00%)     0/21 (0.00%)  
ATRIAL SEPTAL DEFECT † 1        
# participants affected / at risk     0/20 (0.00%)     1/20 (5.00%)     0/20 (0.00%)     0/21 (0.00%)  
Eye disorders          
CONJUNCTIVITIS † 1        
# participants affected / at risk     3/20 (15.00%)     1/20 (5.00%)     0/20 (0.00%)     0/21 (0.00%)  
OCULAR ICTERUS † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     2/20 (10.00%)     1/21 (4.76%)  
CONJUNCTIVAL HAEMORRHAGE † 1        
# participants affected / at risk     0/20 (0.00%)     1/20 (5.00%)     0/20 (0.00%)     0/21 (0.00%)  
Gastrointestinal disorders          
NAUSEA † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     4/20 (20.00%)     2/21 (9.52%)  
VOMITING † 1        
# participants affected / at risk     1/20 (5.00%)     3/20 (15.00%)     5/20 (25.00%)     2/21 (9.52%)  
DIARRHOEA † 1        
# participants affected / at risk     1/20 (5.00%)     3/20 (15.00%)     3/20 (15.00%)     1/21 (4.76%)  
DYSPEPSIA † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     3/20 (15.00%)     2/21 (9.52%)  
TOOTHACHE † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     3/20 (15.00%)     1/21 (4.76%)  
CONSTIPATION † 1        
# participants affected / at risk     1/20 (5.00%)     3/20 (15.00%)     2/20 (10.00%)     1/21 (4.76%)  
ABDOMINAL PAIN † 1        
# participants affected / at risk     1/20 (5.00%)     2/20 (10.00%)     2/20 (10.00%)     1/21 (4.76%)  
ABDOMINAL HERNIA † 1        
# participants affected / at risk     0/20 (0.00%)     1/20 (5.00%)     0/20 (0.00%)     1/21 (4.76%)  
MOUTH ULCERATION † 1        
# participants affected / at risk     1/20 (5.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
UMBILICAL HERNIA † 1        
# participants affected / at risk     2/20 (10.00%)     3/20 (15.00%)     0/20 (0.00%)     0/21 (0.00%)  
TONGUE GEOGRAPHIC † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
RECTAL HAEMORRHAGE † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
ABDOMINAL DISTENSION † 1        
# participants affected / at risk     0/20 (0.00%)     1/20 (5.00%)     0/20 (0.00%)     0/21 (0.00%)  
ABDOMINAL PAIN LOWER † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     2/20 (10.00%)     0/21 (0.00%)  
PAROTID GLAND ENLARGEMENT † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
GASTROOESOPHAGEAL REFLUX DISEASE † 1        
# participants affected / at risk     1/20 (5.00%)     4/20 (20.00%)     1/20 (5.00%)     0/21 (0.00%)  
General disorders          
MASS † 1        
# participants affected / at risk     0/20 (0.00%)     1/20 (5.00%)     0/20 (0.00%)     0/21 (0.00%)  
PAIN † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     1/21 (4.76%)  
FATIGUE † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     4/20 (20.00%)     0/21 (0.00%)  
PYREXIA † 1        
# participants affected / at risk     1/20 (5.00%)     1/20 (5.00%)     0/20 (0.00%)     0/21 (0.00%)  
OEDEMA PERIPHERAL † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     2/21 (9.52%)  
Hepatobiliary disorders          
JAUNDICE † 1        
# participants affected / at risk     9/20 (45.00%)     10/20 (50.00%)     4/20 (20.00%)     6/21 (28.57%)  
HEPATOMEGALY † 1        
# participants affected / at risk     0/20 (0.00%)     2/20 (10.00%)     0/20 (0.00%)     0/21 (0.00%)  
Infections and infestations          
IMPETIGO † 1        
# participants affected / at risk     1/20 (5.00%)     0/20 (0.00%)     0/20 (0.00%)     0/21 (0.00%)  
MASTITIS † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
RHINITIS † 1        
# participants affected / at risk     0/20 (0.00%)     3/20 (15.00%)     0/20 (0.00%)     2/21 (9.52%)  
INFLUENZA † 1        
# participants affected / at risk     0/20 (0.00%)     1/20 (5.00%)     1/20 (5.00%)     2/21 (9.52%)  
SINUSITIS † 1        
# participants affected / at risk     1/20 (5.00%)     0/20 (0.00%)     0/20 (0.00%)     0/21 (0.00%)  
BODY TINEA † 1        
# participants affected / at risk     0/20 (0.00%)     1/20 (5.00%)     0/20 (0.00%)     0/21 (0.00%)  
BRONCHITIS † 1        
# participants affected / at risk     2/20 (10.00%)     0/20 (0.00%)     0/20 (0.00%)     3/21 (14.29%)  
TRACHEITIS † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
CANDIDIASIS † 1        
# participants affected / at risk     1/20 (5.00%)     2/20 (10.00%)     0/20 (0.00%)     0/21 (0.00%)  
ORAL HERPES † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
PHARYNGITIS † 1        
# participants affected / at risk     1/20 (5.00%)     0/20 (0.00%)     0/20 (0.00%)     0/21 (0.00%)  
TONSILLITIS † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     0/20 (0.00%)     2/21 (9.52%)  
ENDOMETRITIS † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
OTITIS MEDIA † 1        
# participants affected / at risk     3/20 (15.00%)     1/20 (5.00%)     0/20 (0.00%)     1/21 (4.76%)  
SKIN CANDIDA † 1        
# participants affected / at risk     0/20 (0.00%)     1/20 (5.00%)     0/20 (0.00%)     0/21 (0.00%)  
WOUND SEPSIS † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
BRONCHIOLITIS † 1        
# participants affected / at risk     2/20 (10.00%)     0/20 (0.00%)     0/20 (0.00%)     0/21 (0.00%)  
HERPES ZOSTER † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
GASTROENTERITIS † 1        
# participants affected / at risk     1/20 (5.00%)     1/20 (5.00%)     0/20 (0.00%)     1/21 (4.76%)  
NASOPHARYNGITIS † 1        
# participants affected / at risk     0/20 (0.00%)     1/20 (5.00%)     2/20 (10.00%)     1/21 (4.76%)  
VIRAL INFECTION † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
WOUND INFECTION † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
ORAL CANDIDIASIS † 1        
# participants affected / at risk     3/20 (15.00%)     3/20 (15.00%)     2/20 (10.00%)     0/21 (0.00%)  
VAGINAL INFECTION † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     0/20 (0.00%)     2/21 (9.52%)  
VAGINITIS BACTERIAL † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     1/21 (4.76%)  
FUNGAL SKIN INFECTION † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
URINARY TRACT INFECTION † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     6/21 (28.57%)  
SKIN BACTERIAL INFECTION † 1        
# participants affected / at risk     1/20 (5.00%)     0/20 (0.00%)     0/20 (0.00%)     0/21 (0.00%)  
VULVOVAGINAL CANDIDIASIS † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     1/21 (4.76%)  
LOWER RESPIRATORY TRACT INFECTION † 1        
# participants affected / at risk     1/20 (5.00%)     0/20 (0.00%)     0/20 (0.00%)     0/21 (0.00%)  
UPPER RESPIRATORY TRACT INFECTION † 1        
# participants affected / at risk     4/20 (20.00%)     10/20 (50.00%)     8/20 (40.00%)     4/21 (19.05%)  
Injury, poisoning and procedural complications          
OVERDOSE † 1        
# participants affected / at risk     0/20 (0.00%)     1/20 (5.00%)     0/20 (0.00%)     0/21 (0.00%)  
ARTHROPOD BITE † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
PROCEDURAL PAIN † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
SKIN LACERATION † 1        
# participants affected / at risk     0/20 (0.00%)     1/20 (5.00%)     0/20 (0.00%)     0/21 (0.00%)  
VACCINATION COMPLICATION † 1        
# participants affected / at risk     1/20 (5.00%)     0/20 (0.00%)     0/20 (0.00%)     0/21 (0.00%)  
Investigations          
CARDIAC MURMUR † 1        
# participants affected / at risk     0/20 (0.00%)     2/20 (10.00%)     0/20 (0.00%)     0/21 (0.00%)  
WEIGHT DECREASED † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
HAEMOGLOBIN DECREASED † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
CULTURE URINE POSITIVE † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
WHITE BLOOD CELLS URINE POSITIVE † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     2/20 (10.00%)     0/21 (0.00%)  
ELECTROCARDIOGRAM T WAVE INVERSION † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
Metabolism and nutrition disorders          
ANOREXIA † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     1/21 (4.76%)  
HYPOGLYCAEMIA † 1        
# participants affected / at risk     1/20 (5.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
DECREASED APPETITE † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
GESTATIONAL DIABETES † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
Musculoskeletal and connective tissue disorders          
BURSITIS † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
BACK PAIN † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     1/21 (4.76%)  
ARTHRALGIA † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
JOINT STIFFNESS † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
JOINT HYPEREXTENSION † 1        
# participants affected / at risk     0/20 (0.00%)     1/20 (5.00%)     0/20 (0.00%)     0/21 (0.00%)  
Nervous system disorders          
SYNCOPE † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
HEADACHE † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     7/20 (35.00%)     2/21 (9.52%)  
SCIATICA † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
DIZZINESS † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     3/20 (15.00%)     1/21 (4.76%)  
POST HERPETIC NEURALGIA † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
Pregnancy, puerperium and perinatal conditions          
PREMATURE LABOUR † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     3/20 (15.00%)     1/21 (4.76%)  
PROLONGED LABOUR † 1        
# participants affected / at risk     1/20 (5.00%)     0/20 (0.00%)     0/20 (0.00%)     0/21 (0.00%)  
CAPUT SUCCEDANEUM † 1        
# participants affected / at risk     1/20 (5.00%)     0/20 (0.00%)     0/20 (0.00%)     0/21 (0.00%)  
JAUNDICE NEONATAL † 1        
# participants affected / at risk     1/20 (5.00%)     0/20 (0.00%)     0/20 (0.00%)     0/21 (0.00%)  
NEONATAL DISORDER † 1        
# participants affected / at risk     1/20 (5.00%)     0/20 (0.00%)     0/20 (0.00%)     0/21 (0.00%)  
FOETAL DISTRESS SYNDROME † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
PREGNANCY INDUCED HYPERTENSION † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     1/21 (4.76%)  
PREMATURE RUPTURE OF MEMBRANES † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     4/20 (20.00%)     1/21 (4.76%)  
Psychiatric disorders          
DEPRESSION † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
Renal and urinary disorders          
DYSURIA † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
PROTEINURIA † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
Reproductive system and breast disorders          
PELVIC PAIN † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     1/21 (4.76%)  
VAGINAL DISCHARGE † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     2/20 (10.00%)     2/21 (9.52%)  
VAGINAL HAEMORRHAGE † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     0/20 (0.00%)     2/21 (9.52%)  
Respiratory, thoracic and mediastinal disorders          
COUGH † 1        
# participants affected / at risk     5/20 (25.00%)     0/20 (0.00%)     4/20 (20.00%)     3/21 (14.29%)  
DYSPNOEA † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
SNEEZING † 1        
# participants affected / at risk     1/20 (5.00%)     0/20 (0.00%)     0/20 (0.00%)     0/21 (0.00%)  
EPISTAXIS † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
TACHYPNOEA † 1        
# participants affected / at risk     0/20 (0.00%)     3/20 (15.00%)     0/20 (0.00%)     0/21 (0.00%)  
RHINORRHOEA † 1        
# participants affected / at risk     1/20 (5.00%)     1/20 (5.00%)     0/20 (0.00%)     0/21 (0.00%)  
NASAL CONGESTION † 1        
# participants affected / at risk     7/20 (35.00%)     1/20 (5.00%)     0/20 (0.00%)     1/21 (4.76%)  
SINUS CONGESTION † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
NOCTURNAL DYSPNOEA † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
OROPHARYNGEAL PAIN † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     1/21 (4.76%)  
RESPIRATORY DISTRESS † 1        
# participants affected / at risk     0/20 (0.00%)     1/20 (5.00%)     0/20 (0.00%)     0/21 (0.00%)  
Skin and subcutaneous tissue disorders          
RASH † 1        
# participants affected / at risk     3/20 (15.00%)     4/20 (20.00%)     1/20 (5.00%)     3/21 (14.29%)  
ECZEMA † 1        
# participants affected / at risk     2/20 (10.00%)     3/20 (15.00%)     1/20 (5.00%)     1/21 (4.76%)  
DRY SKIN † 1        
# participants affected / at risk     0/20 (0.00%)     1/20 (5.00%)     0/20 (0.00%)     0/21 (0.00%)  
PRURITUS † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     0/20 (0.00%)     3/21 (14.29%)  
HEAT RASH † 1        
# participants affected / at risk     1/20 (5.00%)     0/20 (0.00%)     0/20 (0.00%)     0/21 (0.00%)  
PETECHIAE † 1        
# participants affected / at risk     1/20 (5.00%)     0/20 (0.00%)     0/20 (0.00%)     0/21 (0.00%)  
DERMATITIS † 1        
# participants affected / at risk     2/20 (10.00%)     2/20 (10.00%)     0/20 (0.00%)     0/21 (0.00%)  
SEBORRHOEA † 1        
# participants affected / at risk     0/20 (0.00%)     1/20 (5.00%)     0/20 (0.00%)     0/21 (0.00%)  
RASH MACULAR † 1        
# participants affected / at risk     1/20 (5.00%)     0/20 (0.00%)     0/20 (0.00%)     0/21 (0.00%)  
RASH GENERALISED † 1        
# participants affected / at risk     1/20 (5.00%)     0/20 (0.00%)     0/20 (0.00%)     0/21 (0.00%)  
DERMATITIS DIAPER † 1        
# participants affected / at risk     0/20 (0.00%)     1/20 (5.00%)     0/20 (0.00%)     0/21 (0.00%)  
NAIL PIGMENTATION † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
DERMATITIS ALLERGIC † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
NAIL DISCOLOURATION † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     1/20 (5.00%)     0/21 (0.00%)  
SEBORRHOEIC DERMATITIS † 1        
# participants affected / at risk     1/20 (5.00%)     1/20 (5.00%)     0/20 (0.00%)     0/21 (0.00%)  
Vascular disorders          
HYPERTENSION † 1        
# participants affected / at risk     0/20 (0.00%)     0/20 (0.00%)     3/20 (15.00%)     3/21 (14.29%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 12.0



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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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