IMPAACT P1066: Raltegravir (RAL) safety and efficacy in HIV infected (+) youth 2 to 18

years of age through week 48S. Nachman1, E. Acosta2, N. Zheng3, H. Teppler4, B. Homony4, X. Xu4,

C. Alvero3, E. Handelsman5, C. Worrell6, B. Graham7, M. Toye8, E. Petzold9, A. Wiznia10, and the P1066 Group

XIX International AIDS Conference 2012Washington DC, USA, 22-27 July, 2012

B40: Clinical trials and antiretroviral therapy in children and adolescents

1SUNY Stony Brook, Pediatrics, Stony Brook, United States; 2University of Alabama at Birmingham, Birmingham, United States;

3Harvard School of Public Health, Boston, United States; 4Merck, North Wales, United States;

5Division of AIDS, NIAID, NIH, Bethesda, United States; 6Natl Inst of Child Hlth and Human Devt, Bethesda, United States;

7Frontier Science Inc, Buffalo, United States; 8Baystate Medical Center, Springfield, United States;

9Social and Scientific Systems, Durham, United States; 10Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, United States

Background

New antiretrovirals are needed for HIV+ children.

IMPAACT P1066 is an international Phase I/II open label multicenter trial to evaluate pharmacokinetics (PK), safety, tolerability, and efficacy of multiple RAL formulations in treatment experienced HIV+ youth

Study Design (1) Open label, multi-center study conducted in US, South

Africa, Botswana, Brazil, Argentina Population: HIV+ youth who failed ≥ one ART regimen

with HIV RNA >1000 < 2yrs may have failed only PMTCT

2-stage study: Stage 1 performed intensive PK for dose

finding/safety Stage 2 enrolled additional patients at selected (final)

dose Dose selection based on intensive PK and safety data:

RAL film-coated (adult) tabs: 400 mg BID for 6-18 yrs and ≥ 25kg

RAL chewable: weight-based dosing at ~6mg/kg (75-300mg) BID for 2 -<12 yrs

RAL oral granules for suspension (< 2yrs) ongoing RAL was given with an optimized background regimen Subjects were enrolled sequentially in 5 age cohorts

Study Design (2)Formulation Summary

Cohort Age FormulationI 12-18 yrs Adult

IIA 6-11 yrs AdultIIB 6-11 yrs ChewableIII 2-5 yrs ChewableIV 6mos – 2 yrs Granules for SuspV 4wks – 6mos Granules for Susp

Chewables available in 25 mg and 100 mg (scored), orange banana flavorGranules in sachets of 100 mg, reconstitute in 5mL water, banana flavor

Study Design (3)Endpoints: Safety: Grade 3+ or serious adverse events (AE) Efficacy:

Primary: vRNA < 400c/mL or ≥1 log reduction Secondary: vRNA < 50c/mL, change in CD4 count (%) Used Observed Failure missing data approach

Time points: Primary: 24 wk Secondary: 48 wk

Analysis Populations: Primary : subjects who received only the final selected dose ITT population: all treated subjects

Here we present demographics and 48 week safety and efficacy data in 96 subjects 2-18yr (Cohorts I-III) who received RAL only at the final selected dose

Total(2-18 yrs)

Cohort III(2-<6 yrs)

Cohort IIB (6-<12 yrs)

Cohort IIA (6-<12 yrs)

Cohort I (12-18 yrs)

N=96N=20N=13N=4N=59

Film coated tablet Chewable tablet

Median Age (yrs) 15 10.5 9 3 13

Male Gender 51% 75% 54% 35% 49%

Black Race 59% 75% 54% 60% 59%vRNA (log 10 c/mL), mean [range]

4.3 [3.1-6] 4.4 [3.5-4.9] 4.3 [3.5-5.2] 4.3 [2.7-5.3] 4.3 [2.7-6]

CD4 cells/mm3, median 397 807 529 1087 481

CDC HIV category B or C 76% 25% 23% 40% 59%

Prior NNRTI 86% 75% 85% 50% 78%

Prior PI 97% 75% 62% 60% 83%

Subject Baseline Characteristics (Final Dose)

Safety At Week 48

Grade 3 + AEs 15 subjects had Grade 3+ clinical AEs

1 subject with drug related [DR] psychomotor hyperactivity, abnormal behavior and insomnia

16 subjects with Grade 3+ laboratory AEs (1 with DR AST and ALT)

Serious AEs 14 subjects with serious clinical AEs (1 with DR rash) 2 subjects with serious laboratory AEs (1 with DR

transaminase increased) No discontinuations due to AEs and no deaths

Efficacy: Percent of Patients (95% CI) with vRNA<400 c/mL or 1 Log10 Decline from Baseline

(Final Dose)

0 4 8 12 24 36 48

Weeks

0

20

40

60

80

100

Percent of P

atients with H

IV R

NA

1 Log10

Drop

or<400 Copies/m

L

Number of Contributing Patients

Cohort ICohort IIACohort IIBCohort IIITotal

Week 24 Week 48 72.4% 75.0% 50.0% 75.0% 76.9% 90.9% 70.0% 84.2% 71.6% 78.9%

96 91 90 95 95 94 90Total

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Efficacy: Percent of Patients (95% CI) with vRNA<400 c/mL or 1 Log10 Decline from Baseline (All Treated)

0 4 8 12 24 36 48

Weeks

0

20

40

60

80

100

Percent of P

atients with H

IV R

NA

1 Log10

Drop

or<400 Copies/m

L

Number of Contributing Patients

Cohort ICohort IIACohort IIBCohort IIITotal

Week 24 Week 48 73.5% 76.1% 62.5% 75.0% 77.8% 93.8% 71.4% 85.0% 72.4% 79.8%

126 121 119 125 123 123 119Total

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Efficacy: Percent of Patients (95% CI) with vRNA<50 c/mL (Final Dose)

0 4 8 12 24 36 48

Weeks

0

20

40

60

80

100

Percent of P

atients with H

IV R

NA

<50 Copies/m

L

Number of Contributing Patients

Week 24 Week 48 55.2% 57.1% 50.0% 50.0% 53.8% 54.5% 50.0% 57.9% 53.7% 56.7%

Cohort ICohort IIACohort IIBCohort IIITotal

96 91 90 95 95 94 90Total

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Efficacy: Change From Baseline in CD4 cells/mm3 (Final Dose)

0 4 8 12 24 36 48

Weeks

-600

-400

-200

0

200

400

600

Change From

Baseline in C

D4 C

ell Count

Number of Contributing Patients

Cohort ICohort IIACohort IIBCohort IIITotal

Week 24 Week 48 114.4 168.2 -35.8 189.5 143.4 76.8 147.2 158.1 119.0 155.7

95 95 88 94 94 92 90Total

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Conclusions Two RAL formulations were studied in HIV

infected youth ages 2 to 18 years; PK targets were met for both formulations

At the selected final doses RAL was well-tolerated and showed favorable virologic and immunologic responses through 48 weeks of treatment

Data from All Treated subjects (who received other than Final Dose, N=126) were consistent

Conclusions (2) Data from this study has been used in

obtaining US FDA approval for use of raltegravir in HIV+ youth ages 2-18 yrs

RAL film-coated tablet: 400 mg BID Ages 12 to 18 yrs Ages 6 to <12 yrs, weight ≥ 25kg

RAL chewable tablet Ages 2 to <12 yrs, weight ≥10kg: weight

based dosing (75-300mg) BID

Recommended Dose for Raltegravir (ISENTRESS) Chewable Tablets in Pediatric Patients 2 to Less Than 12 Years of Age –

From US Product CircularBody weight (kg) Dose Number of Chewable

tablets

10 to <14 kg 75 mg twice daily 3 x 25 mg twice daily14 to <20 kg 100 mg twice daily 1 x 100 mg twice daily20 to <28 kg 150 mg twice daily 1.5 x 100* mg twice

daily28 to < 40 kg 200 mg twice daily 2 x 100 mg twice dailyAt least 40 kg 300 mg twice daily 3 x 100 twice daily• The weight based dosing recommendation for the chewable

tables is based on approximately 6 mg/kg/dose twice daily

• *The 100 mg chewable tablet is scored and can be divided into equal halves

The study team would like to thank the sponsors, sites and families who

participated in this study NIAID: Ed Handelsman NICHD: Carol Worrell Merck: Hedy Teppler Merck: Brenda Homony Merck: Xia Xu Merck: Matthew Rizk Merck: Larissa Wenning Merck: Elizabeth Rhee SDAC: Terrence Fenton SDAC: Nan Zheng SDAC: Carmelita Alvero SSS: Kim Hudgens and

Liz Petzold

FSTRF: Bobbie Graham Pharmacist: Lynette Purdue Pharmacologist: Edward Acosta Virologist: Lisa Frenkel Immunologist: Steve Douglas Lab Technologist: Nancy Tustin Lab Manager: Carrie Fry Investigators: Steve Spector

IMPAACT domestic and international site staff and investigators

Backups

Background: New antiretrovirals are needed for HIV+ children. IMPAACT P1066 is a Phase I/II open label multicenter trial to evaluate pharmacokinetics (PK), safety, tolerability, and efficacy of multiple RAL formulations in treatment experienced HIV+ youth. RAL was given with an optimized background regimen. Dose selection was based upon intensive PK and safety data: 400 mg BID of RAL film-coated tablet (6-18 years) and weight-based dosing (~6mg/kg BID) of RAL chewable tablet (2 to < 12 years). Here we present safety and efficacy results at 24 and 48 weeks in the 96 subjects who received the selected RAL dose.

Methods: Subjects were stratified sequentially in 3 age cohorts (I, 12-18 years; II, 6-< 12 years; III, 2-< 6 years); Cohort I enrolled first. Safety data through Week 48 was assessed. Grade 3+ or serious adverse events (AE) were summarized. Primary virologic endpoint was vRNA < 400c/mL or ≥1 log reduction. Secondary endpoints were vRNA < 50c/mL, and change in CD4 count (%). Efficacy analyses used Observed Failure missing data approach.

Results: Baseline characteristics, virologic and immunologic responses at weeks 24 and 48 for 96 subjects are in tables. Overall, virologic response was observed in 78.9%, RNA < 50c/mL in 56.7%, with mean CD4 increase 155.7 cells/uL. Through Week 48, there were 15 subjects with Grade 3+ clinical AEs (1 subject with drug related [DR] psychomotor hyperactivity, abnormal behavior and insomnia); 16 subjects with Grade 3+ laboratory AEs (1 with DR AST and ALT); 15 subjects with serious clinical AEs (1 with DR rash); 2 subjects with serious laboratory AEs (1 with DR transaminase increased); no discontinuations due to AEs and no deaths.

Conclusions: Two RAL formulations were studied in HIV infected youth ages 2 to 18 years. At the selected doses, both formulations were well-tolerated and showed favorable virologic and immunologic responses.

Cohort I (12-18yrs)

Cohort IIA (6-<12yrs)

Cohort IIB (6-<12yrs)

Cohort III (2-<6yrs)

Total (2-18 yr)

N=59 N=4 N=13 N=20 N=96

WEEK 24 RESPONSE

Achieved ≥1 log10 HIV RNA decline or <400 c/mL 72.4% 50% 76.9% 70% 71.6%

Achieved HIV RNA <50 c/mL 55.2% 50% 53.8% 50% 53.7%

Mean CD4 change from baseline cells/mm3 (%)

114.4 (4.1%)

-35.8 (2.2%)

143.4 (0.8%)

147.2 (5.3%)

119.0 (3.8%)

WEEK 48 RESPONSE

Achieved ≥1 log10 HIV RNA decline or <400 c/mL 75% 75% 90.9% 84.2% 78.9%

Achieved HIV RNA <50 c/mL 57.1% 50% 54.5% 57.9% 56.7%

Mean CD4 change from baseline cells/mm3 (%)

168.2 (5.2%)

189.5 (6.0%)

76.8 (1.6%)

158.1 (4.3%)

155.7 (4.6%)

Efficacy Outcomes at Week 24 and 48(Final Dose, Observed Failure Approach)

P1066: Raltegravir Steady State PK Parameters Following Administration of Recommended Dose

(from US Product Circular)