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

History of Changes

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

	Infants ATV 300 mg / RTV 100 mg	Infants ATV 400 mg / RTV 100 mg
STARTED	20 ^[1]	20 ^[2]
COMPLETED	20	20
NOT COMPLETED	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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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

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1. Primary:

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

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2. Primary:

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

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3. Primary:

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

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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 ]

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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 ]

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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 ]

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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 ]

Show Outcome Measure 7

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. ]

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Measure Type	Primary
Measure Title	Mean ATV Trough Plasma Concentration (Cmin) 24 Hours Following the Daily Dose
Measure Description	Cmin = plasma concentration 24 hours post dose of atazanavir at specified time points.
Time Frame	Pregnancy Weeks 12 to 28, 28 to 36, and 4-6 Weeks Postpartum at 24 hours following the daily dose.
Safety Issue	No

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.
Treated participants in the PK concentration data set.

Reporting Groups

	Description
Mothers ATV 300 mg / RTV 100 mg Second Trimester	Mothers receiving ATV/RTV 300/100 mg once daily (QD) + ZDV/3TC 300/150 mg twice daily (BID) during weeks 12 to 28 of pregnancy. 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.
Mothers ATV 300 mg / RTV 100 mg Third Trimester	Mothers receiving ATV/RTV 300/100 mg QD + ZDV/3TC 300/150 mg BID during weeks 28 to 36 of pregnancy. 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.
Mothers ATV 400 mg / RTV 100 mg Third Trimester	Mothers receiving ATV/RTV 400/100 mg QD + ZDV/3TC 300/150 mg BID during weeks 28 to 36 of pregnancy. 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.

Measured Values

	Mothers ATV 300 mg / RTV 100 mg Second Trimester	Mothers ATV 300 mg / RTV 100 mg Third Trimester	Mothers ATV 400 mg / RTV 100 mg Third Trimester
Number of Participants Analyzed [units: participants]	9	20	20
Mean ATV Trough Plasma Concentration (Cmin) 24 Hours Following the Daily Dose [units: ng•h / mL] Geometric Mean ( 95% Confidence Interval )	663.78 ( 492.65 to 894.35 )	668.48 ( 529.06 to 844.64 )	916.63 ( 665.77 to 1,262.02 )

No statistical analysis provided for Mean ATV Trough Plasma Concentration (Cmin) 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. ]

Show Outcome Measure 9

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 ]

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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 ]

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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 ]

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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 ]

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14. Secondary:

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

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15. Secondary:

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

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16. Secondary:

Mean HIV RNA Level at Baseline [ Time Frame: Baseline ]

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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 ]

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18. Secondary:

Mean CD4 Cell Count at Baseline [ Time Frame: Baseline ]

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19. Secondary:

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

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20. Secondary:

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

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21. Secondary:

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

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22. Secondary:

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

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23. Secondary:

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

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24. Secondary:

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

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25. Secondary:

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

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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 ]

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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 ]

Show Outcome Measure 27

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.

Limitations and Caveats

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
No text entered.

Results Point of Contact:

Name/Title: BMS Study Director
Organization: Bristol-Myers Squibb
e-mail: clinical.trials@bms.com

No publications provided by Bristol-Myers Squibb

Publications automatically indexed to this study:

Conradie F, Zorrilla C, Josipovic D, Botes M, Osiyemi O, Vandeloise E, Eley T, Child M, Bertz R, Hu W, Wirtz V, McGrath D. Safety and exposure of once-daily ritonavir-boosted atazanavir in HIV-infected pregnant women. HIV Med. 2011 Oct;12(9):570-9. Epub 2011 May 16.

Responsible Party:	Bristol-Myers Squibb
ClinicalTrials.gov Identifier:	NCT00326716 History of Changes
Other Study ID Numbers:	AI424-182
Study First Received:	May 15, 2006
Results First Received:	January 5, 2011
Last Updated:	November 4, 2011
Health Authority:	United States: Food and Drug Administration Republic of South Africa: National Ministry of Health

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