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Clinical Trial Results:
A Prospective Single Arm, Open-label, International, Multicenter Study to Evaluate the Safety, Efficacy and Pharmacokinetics of Atazanavir (ATV) Powder Boosted With Ritonavir (RTV) With an Optimized NRTI Background Therapy, in Human Immunodeficiency Virus (HIV) Infected, Antiretroviral, Naive and Experienced Pediatric Subjects From 3 Months to Less Than 11 Years.(Pediatric Atazanavir International Clinical Evaluation: the PRINCE II Study)

Summary
EudraCT number	2010-024537-23
Trial protocol	GB PL ES Outside EU/EEA
Global end of trial date	22 Jan 2018

Results information
Results version number	v1(current)
This version publication date	05 Aug 2018
First version publication date	05 Aug 2018
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

AI424-451

ISRCTN number

US NCT number

NCT01335698

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussée de la Hulpe 185, Brussels, Belgium, 1170

Public contact

EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, clinical.trials@bms.com

Scientific contact

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-000804-PIP01-09

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

22 Jan 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

22 Jan 2018

Was the trial ended prematurely?

Main objective of the trial

To describe the safety of ATV powder formulation boosted with RTV based highly active antiretroviral therapy regimens in pediatric subjects dosed through a minimum of 24 weeks, as measured by the frequency of deaths, serious adverse events (SAEs), and discontinuation due to adverse events (AEs).

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

27 May 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 5

Country: Number of subjects enrolled

Brazil: 5

Country: Number of subjects enrolled

Chile: 5

Country: Number of subjects enrolled

Mexico: 21

Country: Number of subjects enrolled

Poland: 1

Country: Number of subjects enrolled

Romania: 2

Country: Number of subjects enrolled

Russian Federation: 5

Country: Number of subjects enrolled

South Africa: 109

Country: Number of subjects enrolled

Spain: 3

Country: Number of subjects enrolled

United States: 4

Worldwide total number of subjects

160

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

100

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Of 160 subjects enrolled, 99 received treatment.

Period 1 title

Treatment Stage 1

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Atazanavir, 150 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)

Arm description

Stage 1: HIV-infected pediatric subjects weighing 5 to <10 kg at baseline received atazanir powder formulation, 150 mg, with ritonavir oral solution, 80 mg, for 24 to 48 weeks. Subjects entering Stage 2 continued Stage 1 treatment but those aged 12 years or older or weighing at least 35 kg transitioned to capsules. Treatment continued until the subject reached 18 years of age or pediatric indication is locally approved and subject meets requirements to receive appropriate formulation.

Arm type

Experimental

Investigational medicinal product name

Atazanavir

Investigational medicinal product code

Other name

Reyataz BMS-232632

Pharmaceutical forms

Powder and solvent for oral solution

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)

Arm description

Arm type

Experimental

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Atazanavir

Investigational medicinal product code

Other name

Reyataz BMS-232632

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 10 to <15 kg)

Arm description

Stage 1: HIV-infected pediatric subjects weighing 10 to <15 kg at baseline received atazanir powder formulation, 200 mg, with ritozinavir oral solution, 80 mg, for 24 to 48 weeks. Subjects entering Stage 2 continued Stage 1 treatment but those aged 12 years or older or weighing at least 35 kg transitioned to capsules. Treatment continued until the subject reached 18 years of age or pediatric indication is locally approved and subject meets requirements to receive appropriate formulation.

Arm type

Experimental

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Atazanavir

Investigational medicinal product code

Other name

Reyataz BMS-232632

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Atazanavir, 250 mg + Ritonavir, 80 mg (Weight: 15 to <25 kg)

Arm description

Stage 1: HIV-infected pediatric subjects weighing 15 to <25 kg at baseline received atazanir powder formulation, 250 mg, with ritozinavir oral solution, 80 mg, for 24 to 48 weeks. Subjects entering Stage 2 continued Stage 1 treatment but those aged 12 years or older or weighing at least 35 kg transitioned to capsules. Treatment continued until the subject reached 18 years of age or pediatric indication is locally approved and subject meets requirements to receive appropriate formulation.

Arm type

Experimental

Investigational medicinal product name

Atazanavir

Investigational medicinal product code

Other name

Reyataz BMS-232632

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Atazanavir, 300 mg + Ritonavir, 100 mg (Weight: 25 to <35 kg)

Arm description

Stage 1: HIV-infected pediatric subjects weighing 10 to <15 kg at baseline received atazanir powder formulation, 300 mg, with ritozinavir capsule/tablets, 100 mg, for 24 to 48 weeks. Subjects entering Stage 2 continued Stage 1 treatment but those aged 12 years or older or weighing at least 35 kg transitioned to capsules. Treatment continued until the subject reached 18 years of age or pediatric indication is locally approved and subject meets requirements to receive appropriate formulation.

Arm type

Experimental

Investigational medicinal product name

Atazanavir

Investigational medicinal product code

Other name

Reyataz BMS-232632

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1 ^[1]	Atazanavir, 150 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 10 to <15 kg)	Atazanavir, 250 mg + Ritonavir, 80 mg (Weight: 15 to <25 kg)	Atazanavir, 300 mg + Ritonavir, 100 mg (Weight: 25 to <35 kg)
Started	23	12	21	35	8
Completed	15	4	16	26	6
Not completed	8	8	5	9	2
Consent withdrawn by subject	1	2	-	1	-
Adverse event, non-fatal	1	2	2	1	1
Poor compliance/noncompliance	-	1	-	2	-
Not specified	1	-	-	1	-
No longer meets study criteria	1	1	-	1	-
Lost to follow-up	1	1	-	-	-
Lack of efficacy	3	1	3	3	1

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial as out of 160 subjects who were enrolled only 99 were randomised. 1 subject no longer met study criteria, 5 subjects withdrew consent, 2 Other switched to another formulation, 1 was lost to follow up, 6 did not complete due to poor compliance/noncompliance, 5 experienced an adverse event, and 7 did not complete due to lack of efficacy.

Period 2 title

Treatment Stage 2

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Atazanavir, 150 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)

Arm description

Arm type

Experimental

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Atazanavir

Investigational medicinal product code

Other name

Reyataz BMS-232632

Pharmaceutical forms

Powder and solvent for oral solution

Routes of administration

Oral use

Dosage and administration details

Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)

Arm description

Arm type

Experimental

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Atazanavir

Investigational medicinal product code

Other name

Reyataz BMS-232632

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 10 to <15 kg)

Arm description

Arm type

Experimental

Investigational medicinal product name

Atazanavir

Investigational medicinal product code

Other name

Reyataz BMS-232632

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Atazanavir, 250 mg + Ritonavir, 80 mg (Weight: 15 to <25 kg)

Arm description

Arm type

Experimental

Investigational medicinal product name

Ritonavir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Stage 1: HIV-infected pediatric patients weighing 15 to <25 kg at baseline received atazanir powder formulation, 250 mg, with ritozinavir oral solution, 80 mg, for 24 to 48 weeks. Patients entering Stage 2 continued Stage 1 treatment but those aged 12 years or older or weighing at least 35 kg transitioned to capsules. Treatment continued until the patient reached 18 years of age or pediatric indication is locally approved and patient meets requirements to receive appropriate formulation

Investigational medicinal product name

Atazanavir

Investigational medicinal product code

Other name

Reyataz BMS-232632

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Atazanavir, 300 mg + Ritonavir, 100 mg (Weight: 25 to <35 kg)

Arm description

Arm type

Experimental

Investigational medicinal product name

Atazanavir

Investigational medicinal product code

Other name

Reyataz BMS-232632

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Stage 1: HIV-infected pediatric patients weighing 10 to <15 kg at baseline received atazanir powder formulation, 300 mg, with ritozinavir capsule/tablets, 100 mg, for 24 to 48 weeks. Patients entering Stage 2 continued Stage 1 treatment but those aged 12 years or older or weighing at least 35 kg transitioned to capsules. Treatment continued until the patient reached 18 years of age or pediatric indication is locally approved and patient meets requirements to receive appropriate formulation

Number of subjects in period 2	Atazanavir, 150 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 10 to <15 kg)	Atazanavir, 250 mg + Ritonavir, 80 mg (Weight: 15 to <25 kg)	Atazanavir, 300 mg + Ritonavir, 100 mg (Weight: 25 to <35 kg)
Started	15	4	16	26	6
Completed	4	1	11	18	5
Not completed	11	3	5	8	1
Consent withdrawn by subject	3	1	1	-	-
Adverse event, non-fatal	2	-	-	3	-
Poor compliance/noncompliance	1	-	1	3	1
Capsules received at state hospital	1	-	-	-	-
Lost to follow-up	1	-	-	-	-
Subject no longer meets study criteria	-	-	-	1	-
Lack of efficacy	2	1	3	1	-
Switched to another formulation	1	1	-	-	-

Baseline characteristics

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Reporting group title

Atazanavir, 150 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)

Reporting group description

Reporting group title

Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)

Reporting group description

Reporting group title

Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 10 to <15 kg)

Reporting group description

Reporting group title

Atazanavir, 250 mg + Ritonavir, 80 mg (Weight: 15 to <25 kg)

Reporting group description

Reporting group title

Atazanavir, 300 mg + Ritonavir, 100 mg (Weight: 25 to <35 kg)

Reporting group description

Reporting group values	Atazanavir, 150 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 10 to <15 kg)	Atazanavir, 250 mg + Ritonavir, 80 mg (Weight: 15 to <25 kg)	Atazanavir, 300 mg + Ritonavir, 100 mg (Weight: 25 to <35 kg)	Total
Number of subjects	23	12	21	35	8	99
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	22	11	3	0	0	36
Children (2-11 years)	1	1	18	35	8	63
Adolescents (12-17 years)	0	0	0	0	0	0
Adults (18-64 years)	0	0	0	0	0	0
From 65-84 years	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0
Age Continuous
Units: months
arithmetic mean (standard deviation)	8.4 ± 6.42	10.5 ± 9.21	37.4 ± 12.44	67.2 ± 16.70	93.4 ± 15.53	-
Sex: Female, Male
Units: Subjects
Female	12	6	12	18	3	51
Male	11	6	9	17	5	48
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	1	2	1	0	4
Not Hispanic or Latino	1	1	1	1	0	4
Unknown or Not Reported	22	10	18	33	8	91
Race/Ethnicity, Customized
Units: Subjects
White	2	2	12	13	3	32
Black/African American	19	6	7	20	5	57
Other	2	4	2	2	0	10
Region of Enrollment
Units: Subjects
North America\|	2	1	9	4	2	18
South America\|	1	1	1	4	1	8
Africa\|	20	10	8	21	5	64
Europe\|	0	0	3	6	0	9
Country
Units: Subjects
Argentina	0	1	1	2	0	4
Brazil	0	0	0	1	0	1
Chile	1	0	0	1	1	3
Mexico	1	1	7	4	2	15
Poland	0	0	1	0	0	1
Romania	0	0	0	1	0	1
Russia	0	0	1	3	0	4
South Africa	20	10	8	21	5	64
Spain	0	0	1	2	0	3
United States	1	0	2	0	0	3

End points

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Reporting group title

Atazanavir, 150 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)

Reporting group description

Reporting group title

Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)

Reporting group description

Reporting group title

Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 10 to <15 kg)

Reporting group description

Reporting group title

Atazanavir, 250 mg + Ritonavir, 80 mg (Weight: 15 to <25 kg)

Reporting group description

Reporting group title

Atazanavir, 300 mg + Ritonavir, 100 mg (Weight: 25 to <35 kg)

Reporting group description

Reporting group title

Atazanavir, 150 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)

Reporting group description

Reporting group title

Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)

Reporting group description

Reporting group title

Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 10 to <15 kg)

Reporting group description

Reporting group title

Atazanavir, 250 mg + Ritonavir, 80 mg (Weight: 15 to <25 kg)

Reporting group description

Reporting group title

Atazanavir, 300 mg + Ritonavir, 100 mg (Weight: 25 to <35 kg)

Reporting group description

Primary: Number of Participants Who Died and With Adverse Events (AEs) Leading to Discontinuation, Hyperbilirubinemia, Jaundice, First-degree Arterioventricular Block, Tachycardia, and Rash on ATV Powder

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End point title

Number of Participants Who Died and With Adverse Events (AEs) Leading to Discontinuation, Hyperbilirubinemia, Jaundice, First-degree Arterioventricular Block, Tachycardia, and Rash on ATV Powder ^[1]

End point description

AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment.

End point type

Primary

End point timeframe

Day one to week 300 (approximately 22-Jan-2018)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were planned for this endpoint

End point values	Atazanavir, 150 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 10 to <15 kg)	Atazanavir, 250 mg + Ritonavir, 80 mg (Weight: 15 to <25 kg)	Atazanavir, 300 mg + Ritonavir, 100 mg (Weight: 25 to <35 kg)
Number of subjects analysed	23	12	21	35	8
Units: Subjects
Deaths\|	0	0	0	0	0
AEs leading to discontinuation\|	3	2	2	2	1
Hyperbilirubinemia-related adverse events	2	0	9	7	0
Jaundice\|	0	0	3	3	0
Atrioventricular block, first degree\|	0	0	0	1	0
Tachycardia\|	0	0	1	0	0
Rash\|	3	0	4	5	1

No statistical analyses for this end point

Primary: Number of Participants who experienced a SAE on ATV Powder

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End point title

Number of Participants who experienced a SAE on ATV Powder ^[2]

End point description

SAE= any of the the following: is life-threatening (defined as an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe), requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is an important medical event (defined as a medical event(s) that may not be immediately life threatening or result in death or hospitalization but, based upon appropriate medical and scientific judgment, may jeopardize the subject or may require intervention [eg, medical, surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples of such events include, but are not limited to, intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization

End point type

Primary

End point timeframe

Day one to week 300 (approximately 22-Jan-2018)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: only summary statistics were provided

End point values	Atazanavir, 150 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 10 to <15 kg)	Atazanavir, 250 mg + Ritonavir, 80 mg (Weight: 15 to <25 kg)	Atazanavir, 300 mg + Ritonavir, 100 mg (Weight: 25 to <35 kg)
Number of subjects analysed	23	12	21	35	8
Units: Subjects	6	3	8	8	0

No statistical analyses for this end point

Primary: Number of Participants With A Center of Disease Control and Prevention (CDC) Class C AIDS Event on ATV Powder

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End point title

Number of Participants With A Center of Disease Control and Prevention (CDC) Class C AIDS Event on ATV Powder ^[3]

End point description

The CDC disease staging system assesses the severity of HIV disease by CD4 cell counts and by the presence of specific HIV-related conditions. CD4 counts are classified as 1: ≥500 cells/µL, 2: 200-499 cells/µL, and 3: <200 cells/µL. Children with HIV infection are also classified in each of several categories. Category N: Not symptomatic. Category A: Mildly symptomatic. Category B: Moderately symptomatic. Category C: Severely symptomatic.

End point type

Primary

End point timeframe

Day one to week 300 (approximately 22-Jan-2018)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were planned for this endpoint

End point values	Atazanavir, 150 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 10 to <15 kg)	Atazanavir, 250 mg + Ritonavir, 80 mg (Weight: 15 to <25 kg)	Atazanavir, 300 mg + Ritonavir, 100 mg (Weight: 25 to <35 kg)
Number of subjects analysed	23	12	21	35	8
Units: Subjects
Pulmonary tuberculosis\|	2	0	1	0	0
Lymph node tuberculosis\|	0	0	0	1	0
Tuberculosis\|	0	0	0	1	0
Oropharyngeal Candidiasis	1	0	0	0	0

No statistical analyses for this end point

Primary: Number of Participants With Laboratory Test Results Meeting the Criteria for Grade 3-4 Abnormality on ATV powder

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End point title

Number of Participants With Laboratory Test Results Meeting the Criteria for Grade 3-4 Abnormality on ATV powder ^[4]

End point description

Criteria of the Division of AIDS for grading the severity of adult and pediatric adverse events as follows: Grade (Gr) 1=mild; Gr 2=moderate; Gr 3=severe; Gr 4=potentially life-threatening. Neutrophils (absolute) (adult and infants >7 days): Gr 1=1.000-1300/mm^3; Gr 2=750-999 mm^3; Gr 3=500-749 mm^3; Gr 4= <500 mm^3. Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase: Gr 1=1.25-2.5*upper limit of normal (ULN); Gr 2=2.6-5.0*ULN; Gr 3=5.1-10.0*ULN; Gr 4= >10.0*ULN. Bilirubin, total (adults and infants >14 days): Gr 1=1.1-1.5*ULN; Gr 2=1.6-2.5*ULN; Gr 3=2.6-5.0*ULN; Gr 4= >5.0*ULN. Lipase: Gr 1=1.1-1.5*ULN; Gr 2=1.6-3.0*ULN; Gr 3=3.1-5.0*ULN; Gr 4= >5.0*ULN. Bicarbonate, serum low: Gr 1=16.0 mEq/L-<lower limit of normal; Gr 2=11.0-15.9 mEq/L; Gr 3=8.0-10.9 mEq/L; Gr 4= <8 mEq/L. By criteria of the World Health Organization: Amylase: Gr 1=1.0-1.39*ULN; Gr 2=1.40-2.09*ULN; Gr 3.=2.10-5.0*ULN; Gr 4= >5.0*ULN.

End point type

Primary

End point timeframe

Day one to week 300 (approximately 22-Jan-2018)

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics were planned for this endpoint

End point values	Atazanavir, 150 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 10 to <15 kg)	Atazanavir, 250 mg + Ritonavir, 80 mg (Weight: 15 to <25 kg)	Atazanavir, 300 mg + Ritonavir, 100 mg (Weight: 25 to <35 kg)
Number of subjects analysed	23	12	21	35	8
Units: Subjects
Neutrophils (absolute)(n=23, 11, 21, 34, 8)\|	0	0	4	6	0
Alanine aminotransferase (n=23, 12, 21, 34, 8)\|	4	1	1	2	0
Aspartate aminotransferase (n=23, 12, 21, 34, 8)\|	2	0	1	0	0
Alkaline phosphatase (n=23, 12, 21, 34, 8)\|	1	2	1	0	0
Total bilirubin (n=23, 12, 21, 34, 8)\|	4	1	10	5	2
Amylase (n=23, 12, 21, 34, 8)\|	15	7	6	6	1
Lipase (n=23, 12, 21, 34, 8)\|	3	2	0	2	1
Bicarbonate (n=23, 12, 21, 34, 8)	2	0	0	0	0
Albumin (n=23, 12, 21, 34, 8)	1	1	0	1	0
Calcium, High (n=23, 12, 21, 34, 8)	0	0	0	1	0
Chloride, Low (n=23, 12, 21, 34, 8)	0	0	0	1	0
Total Cholesterol, Fasting (n=23, 12, 21, 34, 8)	0	0	1	0	0
LDL Cholesterol, Fasting (n=23, 12, 21, 34, 8)	0	0	1	0	0
Glucose, Fasting, Low (n=23, 12, 21, 34, 8)	0	0	1	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With HIV RNA <50 copies/mL and <400 copies/mL in the Week 24 Atazanavir Powder Cohort and the Eligible Week 48 Atazanavir Powder Cohort

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End point title

Number of Subjects With HIV RNA <50 copies/mL and <400 copies/mL in the Week 24 Atazanavir Powder Cohort and the Eligible Week 48 Atazanavir Powder Cohort

End point description

Virologic success includes patients with HIV RNA <50 copies/mL. Two cohorts were assessed: The Atazanavir Powder Cohort=patients who received treatment and did not switch to capsule before analysis Week 24 or before their HIV RNA Week 24 assessment, and the Eligible Week 48 Atazanavir Powder Cohort=patients who initiated study treatment at least 48 weeks before last person last visit and did not switch to capsule before analysis Week 48 or before their HIV RNA Week 48 assessment.

End point type

Secondary

End point timeframe

Day 1 of treatment to weeks 24 and 48

End point values	Atazanavir, 150 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 10 to <15 kg)	Atazanavir, 250 mg + Ritonavir, 80 mg (Weight: 15 to <25 kg)	Atazanavir, 300 mg + Ritonavir, 100 mg (Weight: 25 to <35 kg)
Number of subjects analysed	23	12	21	35	8
Units: Subjects
Week 24: HIV RNA<50 copies/mL	10	2	10	19	5
Week 24: HIV RNA<400 copies/mL	15	5	15	24	6
Week 48: HIV RNA<50 copies/mL (n=23, 1, 20, 34, 2)	11	0	6	18	1
Week 48:HIV RNA<400 copies/mL (n=23, 1, 20, 34, 2)	14	1	14	22	1

No statistical analyses for this end point

Secondary: Mean change from baseline in HIV RNA on ATV powder

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End point title

Mean change from baseline in HIV RNA on ATV powder

End point description

Human immunodeficiency virus ribonucleic acid (HIV RNA) change from baseline using observed values

End point type

Secondary

End point timeframe

Baseline to Weeks 24 and 48

End point values	Atazanavir, 150 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 10 to <15 kg)	Atazanavir, 250 mg + Ritonavir, 80 mg (Weight: 15 to <25 kg)	Atazanavir, 300 mg + Ritonavir, 100 mg (Weight: 25 to <35 kg)
Number of subjects analysed	23	12	21	35	8
Units: Log copies per millileter
arithmetic mean (standard error)
Week 24 (n=21, 7, 19, 29, 7)\|	-2.10 ± 0.2863	-3.07 ± 0.4780	-2.69 ± 0.2257	-2.66 ± 0.1550	-2.24 ± 0.3821
Week 48 (n=16, 2, 15, 25, 1)\|	-2.31 ± 0.3174	-4.06 ± 0.1649	-2.91 ± 0.1883	-2.70 ± 0.1269	-3.97 ± 99999

No statistical analyses for this end point

Secondary: Mean change from baseline in CD4 percent on ATV powder

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End point title

Mean change from baseline in CD4 percent on ATV powder

End point description

Change in CD4 percent using observed values

End point type

Secondary

End point timeframe

Baseline to Weeks 24 and 48

End point values	Atazanavir, 150 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 10 to <15 kg)	Atazanavir, 250 mg + Ritonavir, 80 mg (Weight: 15 to <25 kg)	Atazanavir, 300 mg + Ritonavir, 100 mg (Weight: 25 to <35 kg)
Number of subjects analysed	21	11	15	30	8
Units: Percent
arithmetic mean (standard error)
Week 24 (n=17, 4, 12, 23, 6)\|	5.1 ± 1.521	4.0 ± 1.581	5.4 ± 2.448	6.3 ± 1.280	-0.3 ± 4.349
Week 48 (n=12, 0, 9, 19, 1)\|	2.8 ± 3.167	99999 ± 99999	8.9 ± 2.182	7.5 ± 1.825	1.0 ± 99999

No statistical analyses for this end point

Secondary: CD4 Cell Count Changes From Baseline on ATV powder

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End point title

CD4 Cell Count Changes From Baseline on ATV powder

End point description

CD4 cell count change from baseline using observed values

End point type

Secondary

End point timeframe

Baseline to Weeks 24 and 48

End point values	Atazanavir, 150 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 10 to <15 kg)	Atazanavir, 250 mg + Ritonavir, 80 mg (Weight: 15 to <25 kg)	Atazanavir, 300 mg + Ritonavir, 100 mg (Weight: 25 to <35 kg)
Number of subjects analysed	20	11	13	27	8
Units: Cells/mm^3
arithmetic mean (standard error)
Week 24 (n=15, 4, 9, 19, 6)\|	218.7 ± 259.102	67.8 ± 425.659	247.1 ± 110.739	246.1 ± 72.044	145.8 ± 78.443
Week 48 (n=10, 0, 8, 16. 1)\|	-409.8 ± 437.686	99999 ± 99999	400.0 ± 156.021	335.4 ± 108.925	213.0 ± 99999

No statistical analyses for this end point

Secondary: Number of Participants With Emergent Genotypic Substitutions on ATV Powder Through Week 48

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End point title

Number of Participants With Emergent Genotypic Substitutions on ATV Powder Through Week 48

End point description

Newly emergent substitutions are on-treatment substitutions that were not detected at baseline.Viral rebound in the resistance analysis was defined as: Less than a 1 log10 drop from baseline in plasma HIV RNA level by Week 16, confirmed by a second plasma HIV RNA level redrawn within 2 and 4 weeks from original sample. Or, a plasma HIV RNA level >200 c/mL after Week 24, confirmed by a second plasma HIV RNA level redrawn within 2 and 4 weeks from original sample. Or, repeated plasma HIV RNA level ≥50 c/mL after Week 48. Viral rebound was defined as a plasma HIV RNA level ≥400 c/mL at any time in a patient who had previously achieved a plasma HIV RNA level <50 c/mL. Or, a plasma HIV RNA level ≥50 c/mL and <1,000 c/mL followed by a return to virologic suppression was considered a viral blip and not a viral rebound. NRTI=nucleoside reverse transcriptase inhibitor

End point type

Secondary

End point timeframe

Baseline through Week 48

End point values	Atazanavir, 150 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 10 to <15 kg)	Atazanavir, 250 mg + Ritonavir, 80 mg (Weight: 15 to <25 kg)	Atazanavir, 300 mg + Ritonavir, 100 mg (Weight: 25 to <35 kg)
Number of subjects analysed	10	2	10	13	1
Units: Subjects
Any PI substitutions\|	4	0	4	3	0
Any IAS-USA PI substitutions\|	1	0	2	0	0
Any select RT substitutions\|	2	1	2	1	0
NRTI\|	1	1	2	1	0

No statistical analyses for this end point

Secondary: PK profile of ATV powder formulation with RTV

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End point title

PK profile of ATV powder formulation with RTV ^[5]

End point description

To describe the PK profile of ATV powder formulation with RTV in pediatric subjects weighing 25 - < 35 kg and/or 6 to < 11 years of age and for the new 5 - < 10 kg cohort (200 mg ATV and 80 mg RTV) in terms of ATV maximum observed plasma concentration (Cmax), minimum plasma concentration (Cmin), and area under the concentration-time curve (AUC)

End point type

Secondary

End point timeframe

Baseline to Week 2Baseline to

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only summary statistics were planned for this endpoint

End point values	Atazanavir, 200 mg + Ritonavir, 80 mg (Weight: 5 to <10 kg)	Atazanavir, 250 mg + Ritonavir, 80 mg (Weight: 15 to <25 kg)	Atazanavir, 300 mg + Ritonavir, 100 mg (Weight: 25 to <35 kg)
Number of subjects analysed	12	35	8
Units: subjects
arithmetic mean (standard deviation)
Cmax\|	5776.70 ± 3417.208	5644.12 ± 3093.516	4893.75 ± 2523.959
Cmin\|	718.90 ± 432.747	857.06 ± 599.221	1030.64 ± 1070.932
AUC(TAU)\|	49387.12 ± 26890.782	59671.80 ± 31706.655	56356.00 ± 35233.024

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to 305 weeks approximately

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

Atazanavir 150 mg (Baseline weight: 5 to < 10 kg)

Reporting group description

Human immunodeficiency virus (HIV)-infected pediatric subjects having baseline weight between 5 to less than (<) 10 kilogram (kg) received 150 milligram (mg) atazanavir powder formulation, with 80 mg per milliliter (mg/ml) ritonavir oral solution once daily (QD) for 24 to 48 weeks in Stage 1. Subjects entering Stage 2 continued Stage 1 treatment but those aged 12 years or older or weighing at least 35 kg transitioned to atazanavir capsules. Treatment continued until the subject reached 18 years of age or pediatric indication is locally approved and subject meets requirements to receive appropriate formulation.

Reporting group title

Atazanavir 200 mg (Baseline weight: 5 to < 10 kg)

Reporting group description

HIV-infected pediatric subjects having baseline weight between 5 to < 10 kg received 200 mg atazanavir powder formulation, with 80 mg/ml ritonavir oral solution QD for 24 to 48 weeks in Stage 1. Subjects entering Stage 2 continued Stage 1 treatment but those aged 12 years or older or weighing at least 35 kg transitioned to atazanavir capsules. Treatment continued until the patient reached 18 years of age or pediatric indication is locally approved and subject meets requirements to receive appropriate formulation.

Reporting group title

Atazanavir 200 mg (Baseline weight: 10 to < 15 kg)

Reporting group description

HIV-infected pediatric subjects having baseline weight between 10 to < 15 kg received 200 mg atazanavir powder formulation, with 80 mg/ml ritonavir oral solution QD for 24 to 48 weeks in Stage 1. Subjects entering Stage 2 continued Stage 1 treatment but those aged 12 years or older or weighing at least 35 kg transitioned to atazanavir capsules. Treatment continued until the subject reached 18 years of age or pediatric indication is locally approved and subject meets requirements to receive appropriate formulation.

Reporting group title

Atazanavir 250 mg (Baseline weight: 15 to < 25 kg)

Reporting group description

HIV-infected pediatric subjects having baseline weight between 15 to < 25 kg received 250 mg atazanavir powder formulation, with 80 mg/ml ritonavir oral solution QD for 24 to 48 weeks in Stage 1. Subjects entering Stage 2 continued Stage 1 treatment but those aged 12 years or older or weighing at least 35 kg transitioned to atazanavir capsules. Treatment continued until the subject reached 18 years of age or pediatric indication is locally approved and subject meets requirements to receive appropriate formulation.

Reporting group title

Atazanavir 300 mg (Baseline weight: 25 to < 35 kg)

Reporting group description

HIV-infected pediatric subjects having baseline weight between 25 to < 35 kg received 300 mg atazanavir powder formulation, with ritonavir 100 mg/mL oral solution or 100 mg capsule or tablets QD for 24 to 48 weeks in Stage 1. Subjects entering Stage 2 continued Stage 1 treatment but those aged 12 years or older or weighing at least 35 kg transitioned to atazanavir capsules. Treatment continued until the subject reached 18 years of age or pediatric indication is locally approved and subject meets requirements to receive appropriate formulation.

Serious adverse events	Atazanavir 150 mg (Baseline weight: 5 to < 10 kg)	Atazanavir 200 mg (Baseline weight: 5 to < 10 kg)	Atazanavir 200 mg (Baseline weight: 10 to < 15 kg)	Atazanavir 250 mg (Baseline weight: 15 to < 25 kg)	Atazanavir 300 mg (Baseline weight: 25 to < 35 kg)
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 23 (26.09%)	3 / 12 (25.00%)	8 / 21 (38.10%)	8 / 35 (22.86%)	0 / 8 (0.00%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 23 (0.00%)	0 / 12 (0.00%)	1 / 21 (4.76%)	2 / 35 (5.71%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 23 (0.00%)	0 / 12 (0.00%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	0 / 23 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	1 / 23 (4.35%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Overdose
subjects affected / exposed	0 / 23 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	2 / 35 (5.71%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Accidental exposure to product
subjects affected / exposed	1 / 23 (4.35%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis chemical
subjects affected / exposed	0 / 23 (0.00%)	1 / 12 (8.33%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Lymphadenopathy
subjects affected / exposed	0 / 23 (0.00%)	0 / 12 (0.00%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 23 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Immune reconstitution inflammatory syndrome
subjects affected / exposed	0 / 23 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Pancreatitis acute
subjects affected / exposed	1 / 23 (4.35%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 23 (0.00%)	0 / 12 (0.00%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Varicocele
subjects affected / exposed	0 / 23 (0.00%)	0 / 12 (0.00%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 23 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Gastroenteritis
subjects affected / exposed	1 / 23 (4.35%)	1 / 12 (8.33%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysentery
subjects affected / exposed	1 / 23 (4.35%)	0 / 12 (0.00%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis A
subjects affected / exposed	1 / 23 (4.35%)	0 / 12 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	1 / 23 (4.35%)	0 / 12 (0.00%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 23 (4.35%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infective corneal ulcer
subjects affected / exposed	0 / 23 (0.00%)	0 / 12 (0.00%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 23 (4.35%)	0 / 12 (0.00%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otitis media
subjects affected / exposed	0 / 23 (0.00%)	0 / 12 (0.00%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pertussis
subjects affected / exposed	0 / 23 (0.00%)	1 / 12 (8.33%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	0 / 23 (0.00%)	1 / 12 (8.33%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 23 (0.00%)	0 / 12 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Varicella
subjects affected / exposed	0 / 23 (0.00%)	0 / 12 (0.00%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Atazanavir 150 mg (Baseline weight: 5 to < 10 kg)	Atazanavir 200 mg (Baseline weight: 5 to < 10 kg)	Atazanavir 200 mg (Baseline weight: 10 to < 15 kg)	Atazanavir 250 mg (Baseline weight: 15 to < 25 kg)	Atazanavir 300 mg (Baseline weight: 25 to < 35 kg)
Total subjects affected by non serious adverse events
subjects affected / exposed	22 / 23 (95.65%)	10 / 12 (83.33%)	20 / 21 (95.24%)	32 / 35 (91.43%)	6 / 8 (75.00%)
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	4 / 23 (17.39%)	0 / 12 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)
occurrences all number	4	0	0	1	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	8 / 23 (34.78%)	2 / 12 (16.67%)	0 / 21 (0.00%)	2 / 35 (5.71%)	0 / 8 (0.00%)
occurrences all number	10	2	0	2	0
Lymphadenopathy
subjects affected / exposed	1 / 23 (4.35%)	1 / 12 (8.33%)	2 / 21 (9.52%)	4 / 35 (11.43%)	0 / 8 (0.00%)
occurrences all number	1	1	5	4	0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	3 / 23 (13.04%)	0 / 12 (0.00%)	7 / 21 (33.33%)	2 / 35 (5.71%)	2 / 8 (25.00%)
occurrences all number	3	0	7	2	2
Gastrointestinal disorders
Vomiting
subjects affected / exposed	7 / 23 (30.43%)	1 / 12 (8.33%)	5 / 21 (23.81%)	9 / 35 (25.71%)	2 / 8 (25.00%)
occurrences all number	10	9	6	15	2
Diarrhoea
subjects affected / exposed	6 / 23 (26.09%)	0 / 12 (0.00%)	3 / 21 (14.29%)	3 / 35 (8.57%)	1 / 8 (12.50%)
occurrences all number	9	0	5	3	1
Dental caries
subjects affected / exposed	4 / 23 (17.39%)	1 / 12 (8.33%)	3 / 21 (14.29%)	1 / 35 (2.86%)	0 / 8 (0.00%)
occurrences all number	4	1	3	1	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 23 (13.04%)	2 / 12 (16.67%)	0 / 21 (0.00%)	9 / 35 (25.71%)	1 / 8 (12.50%)
occurrences all number	3	2	0	14	1
Nasal congestion
subjects affected / exposed	5 / 23 (21.74%)	4 / 12 (33.33%)	0 / 21 (0.00%)	3 / 35 (8.57%)	0 / 8 (0.00%)
occurrences all number	6	4	0	3	0
Rhinorrhoea
subjects affected / exposed	5 / 23 (21.74%)	0 / 12 (0.00%)	2 / 21 (9.52%)	3 / 35 (8.57%)	0 / 8 (0.00%)
occurrences all number	6	0	2	3	0
Asthma
subjects affected / exposed	0 / 23 (0.00%)	0 / 12 (0.00%)	4 / 21 (19.05%)	1 / 35 (2.86%)	0 / 8 (0.00%)
occurrences all number	0	0	4	1	0
Rhinitis allergic
subjects affected / exposed	0 / 23 (0.00%)	1 / 12 (8.33%)	3 / 21 (14.29%)	1 / 35 (2.86%)	0 / 8 (0.00%)
occurrences all number	0	2	7	1	0
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	2 / 23 (8.70%)	0 / 12 (0.00%)	5 / 21 (23.81%)	1 / 35 (2.86%)	0 / 8 (0.00%)
occurrences all number	4	0	7	3	0
Jaundice
subjects affected / exposed	0 / 23 (0.00%)	0 / 12 (0.00%)	3 / 21 (14.29%)	3 / 35 (8.57%)	0 / 8 (0.00%)
occurrences all number	0	0	6	6	0
Skin and subcutaneous tissue disorders
Eczema
subjects affected / exposed	5 / 23 (21.74%)	2 / 12 (16.67%)	2 / 21 (9.52%)	2 / 35 (5.71%)	0 / 8 (0.00%)
occurrences all number	6	3	3	2	0
Dermatitis diaper
subjects affected / exposed	5 / 23 (21.74%)	3 / 12 (25.00%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)
occurrences all number	6	3	0	0	0
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	16 / 23 (69.57%)	5 / 12 (41.67%)	5 / 21 (23.81%)	10 / 35 (28.57%)	1 / 8 (12.50%)
occurrences all number	50	7	9	16	1
Gastroenteritis
subjects affected / exposed	14 / 23 (60.87%)	3 / 12 (25.00%)	10 / 21 (47.62%)	7 / 35 (20.00%)	1 / 8 (12.50%)
occurrences all number	27	6	17	8	1
Nasopharyngitis
subjects affected / exposed	2 / 23 (8.70%)	0 / 12 (0.00%)	8 / 21 (38.10%)	5 / 35 (14.29%)	0 / 8 (0.00%)
occurrences all number	12	0	23	10	0
Tinea capitis
subjects affected / exposed	7 / 23 (30.43%)	1 / 12 (8.33%)	3 / 21 (14.29%)	4 / 35 (11.43%)	0 / 8 (0.00%)
occurrences all number	14	2	4	5	0
Lower respiratory tract infection
subjects affected / exposed	7 / 23 (30.43%)	5 / 12 (41.67%)	1 / 21 (4.76%)	1 / 35 (2.86%)	0 / 8 (0.00%)
occurrences all number	11	13	1	1	0
Oral candidiasis
subjects affected / exposed	9 / 23 (39.13%)	4 / 12 (33.33%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 8 (0.00%)
occurrences all number	11	7	1	0	0
Otitis media
subjects affected / exposed	6 / 23 (26.09%)	3 / 12 (25.00%)	0 / 21 (0.00%)	2 / 35 (5.71%)	1 / 8 (12.50%)
occurrences all number	10	6	1	2	1
Pharyngitis
subjects affected / exposed	2 / 23 (8.70%)	0 / 12 (0.00%)	5 / 21 (23.81%)	5 / 35 (14.29%)	0 / 8 (0.00%)
occurrences all number	4	0	11	6	0
Candida nappy rash
subjects affected / exposed	8 / 23 (34.78%)	2 / 12 (16.67%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 8 (0.00%)
occurrences all number	12	2	1	0	0
Impetigo
subjects affected / exposed	7 / 23 (30.43%)	0 / 12 (0.00%)	2 / 21 (9.52%)	2 / 35 (5.71%)	0 / 8 (0.00%)
occurrences all number	7	0	3	2	0
Acarodermatitis
subjects affected / exposed	6 / 23 (26.09%)	0 / 12 (0.00%)	1 / 21 (4.76%)	3 / 35 (8.57%)	0 / 8 (0.00%)
occurrences all number	9	0	1	4	0
Helminthic infection
subjects affected / exposed	7 / 23 (30.43%)	2 / 12 (16.67%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)
occurrences all number	15	3	0	1	0
Otitis media acute
subjects affected / exposed	7 / 23 (30.43%)	0 / 12 (0.00%)	0 / 21 (0.00%)	3 / 35 (8.57%)	0 / 8 (0.00%)
occurrences all number	15	0	0	5	0
Pneumonia
subjects affected / exposed	4 / 23 (17.39%)	1 / 12 (8.33%)	1 / 21 (4.76%)	2 / 35 (5.71%)	0 / 8 (0.00%)
occurrences all number	4	1	1	2	0
Bronchitis
subjects affected / exposed	2 / 23 (8.70%)	0 / 12 (0.00%)	2 / 21 (9.52%)	3 / 35 (8.57%)	0 / 8 (0.00%)
occurrences all number	2	0	2	3	0
Conjunctivitis
subjects affected / exposed	2 / 23 (8.70%)	0 / 12 (0.00%)	1 / 21 (4.76%)	4 / 35 (11.43%)	0 / 8 (0.00%)
occurrences all number	2	0	1	4	0
Tonsillitis
subjects affected / exposed	3 / 23 (13.04%)	1 / 12 (8.33%)	1 / 21 (4.76%)	2 / 35 (5.71%)	0 / 8 (0.00%)
occurrences all number	4	1	1	3	0
Viral upper respiratory tract infection
subjects affected / exposed	3 / 23 (13.04%)	1 / 12 (8.33%)	2 / 21 (9.52%)	1 / 35 (2.86%)	0 / 8 (0.00%)
occurrences all number	8	1	7	7	0
Influenza
subjects affected / exposed	1 / 23 (4.35%)	0 / 12 (0.00%)	2 / 21 (9.52%)	2 / 35 (5.71%)	1 / 8 (12.50%)
occurrences all number	1	0	2	5	1
Body tinea
subjects affected / exposed	0 / 23 (0.00%)	3 / 12 (25.00%)	0 / 21 (0.00%)	2 / 35 (5.71%)	0 / 8 (0.00%)
occurrences all number	0	3	0	2	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 23 (4.35%)	1 / 12 (8.33%)	1 / 21 (4.76%)	2 / 35 (5.71%)	0 / 8 (0.00%)
occurrences all number	1	1	2	3	0
Hypercholesterolaemia
subjects affected / exposed	0 / 23 (0.00%)	0 / 12 (0.00%)	5 / 21 (23.81%)	0 / 35 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	7	0	0

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Were there any global substantial amendments to the protocol? Yes

14 Apr 2011

To allow use of both brand and generic locally approved and available NRTIs by removing statements not intended to have been in protocol section 6.7.1

20 Jan 2012

1) To allow that also the Ritonavir Trough plasma concentration at each scheduled visit from week 4 though week 48 will be evaluated from the sample tube collected for the ATV trough plasma concentration assessment as ATV/RTV can be assessed simultaneously. 2) Primary Objective: Clarified objective and aligned with the primary objective measurement used in the AI424-397 study. The frequency of AEs and lab abnormalities will be summarized but is not part of the primary objective analysis. 3) Removed an exploratory objective because the subjects duration of study participation in stage 2 is dependent on age (i.e. 18 years old) or by the timing of local pediatric indication. It’s expected that a significant proportion of subjects will discontinue from the study before reaching age 18. 4) Added a dosage of reyataz capsules with ritonovir capsules in case the body weight is between 15 and 20 kg. 5) Removed exclusion criterion “children of mothers with known maternal history of HB or HCV infection” has been removed as the HBV and HCV testing will be performed for all subjects regardless of the mother infection status and clarified in exclusion criterion 3c that the HCV and/or HBV testing are to be performed locally. 6) Exclusion criterion: Removed “as defined per protocol” as a 1st degree AV block is exclusionary. 7) Updated the RTV oral solution and RTV tablets storage conditions to be consistent with package insert. 8) Clarified that in the event that the min number of subjects per weight band with required follow up is projected not to be met due to discontinuation, then enrollment will be re-opened. 9) To allow that the timeline to the baseline visit may be extended to 50 days in cases where the test or re-test results are not available after 30 days. 10) Updated Time and Event Schedules to be consistent with the protocol and clarified notes. 11) Updated to be aligned with the Statistical Analysis Plan 12) To address inconsistencies/admin changes in the protocol

03 May 2012

1) To change the whole regimen, including ATV, in patients with confirmed virologic failure or virologic rebound above 1000 copies/mL based on the resistance profile at failure in accordance with the recommendations from guidelines as per FDA comments on sister study AI424-397 amendment 05. 2) To modify the definition of virologic failure in accordance with the updated 2011 DHHS pediatric guidelines in section 4.5.2 and clarify the virologic failure criteria to discontinue a subject in the study in Sections 3.5 and 4.5.2. 3) Table 4.1. Product description: Updated the ATV capsules storage conditions (excursions permitted 15-30°C) to be aligned with the SPC.

16 Jan 2013

To increase the inclusion upper age limit to < 11 years of age and updated title, research hypothesis and objectives accordingly. Following the AI424-397 intensive PK analysis, add new 5 - < 10kg cohort with higher ATV dose (200 mg ATV and 80 mg RTV). To increase the sample size from 75 to 95 subjects in order to treat approximately 10-15 subjects in the new cohort and have a minimum of 56 subjects with 48 weeks of follow-up on ATV powder overall and minimum number of subjects required per weight band. To switch all subjects in stage 2, who are still on the current atazanavir oral powder formulation (10% aspartame), to the new 4.2% aspartame atazanavir oral powder formulation and to collect palatability/acceptability data at the time of switch and after the switch in Sections 3.1.1 and 4.1. To allow use of RTV capsules or Tablets for subjects enrolled in the 25 - < 35kg weight band or moving into this weight band. Added new assay (Abbott RealTime HIV-1 RNA) to be used when Roche Amplicor HIV RNA is discontinued.

15 Apr 2014

1) Changes to the protocol were triggered by the outcome of a second Pediatric Investigational Plan request for modification procedure during which the Pediatric Committee (PDCO) in Europe determined that almost all the information needed to adequately assess safety, PK and efficacy data is available. The corresponding changes to the protocol are: To remove the minimum number of 6 subjects required for the 25-<35kg weight band with 48 weeks of ATV powder. To modify primary endpoint study duration from 48 Weeks to a minimum of 24 weeks and key secondary objectives. 2) To increase the blood volume collection from 1 up to 2 mL for HIV RNA testing when switching to the new Abbott Rea lTime HIV-1 assay after the Roche Amplicor assay is discontinued.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants Who Died and With Adverse Events (AEs) Leading to Discontinuation, Hyperbilirubinemia, Jaundice, First-degree Arterioventricular Block, Tachycardia, and Rash on ATV Powder

Primary: Number of Participants Who Died and With Adverse Events (AEs) Leading to Discontinuation, Hyperbilirubinemia, Jaundice, First-degree Arterioventricular Block, Tachycardia, and Rash on ATV Powder

Primary: Number of Participants who experienced a SAE on ATV Powder

Primary: Number of Participants who experienced a SAE on ATV Powder

Primary: Number of Participants With A Center of Disease Control and Prevention (CDC) Class C AIDS Event on ATV Powder

Primary: Number of Participants With A Center of Disease Control and Prevention (CDC) Class C AIDS Event on ATV Powder

Primary: Number of Participants With Laboratory Test Results Meeting the Criteria for Grade 3-4 Abnormality on ATV powder

Primary: Number of Participants With Laboratory Test Results Meeting the Criteria for Grade 3-4 Abnormality on ATV powder

Secondary: Number of Subjects With HIV RNA <50 copies/mL and <400 copies/mL in the Week 24 Atazanavir Powder Cohort and the Eligible Week 48 Atazanavir Powder Cohort

Secondary: Number of Subjects With HIV RNA <50 copies/mL and <400 copies/mL in the Week 24 Atazanavir Powder Cohort and the Eligible Week 48 Atazanavir Powder Cohort

Secondary: Mean change from baseline in HIV RNA on ATV powder

Secondary: Mean change from baseline in HIV RNA on ATV powder

Secondary: Mean change from baseline in CD4 percent on ATV powder

Secondary: Mean change from baseline in CD4 percent on ATV powder

Secondary: CD4 Cell Count Changes From Baseline on ATV powder

Secondary: CD4 Cell Count Changes From Baseline on ATV powder

Secondary: Number of Participants With Emergent Genotypic Substitutions on ATV Powder Through Week 48

Secondary: Number of Participants With Emergent Genotypic Substitutions on ATV Powder Through Week 48

Secondary: PK profile of ATV powder formulation with RTV

Secondary: PK profile of ATV powder formulation with RTV

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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