Atazanavir
BMS-232632
AI424007
Clinical Study Report - Stage I/Stage II
CLINICAL REPORT SYNOPSIS
TITLE OF STUDY: Evaluation of the Safety and Antiviral Efficacy of a Novel HIV-1 Protease
Inhibitor, BMS-232632, Alone and in Combination with d4T and ddI as Compared to a Reference
Combination Regimen
INVESTIGATORS: 39
STUDY CENTERS: 39: 17 US; 2 Canada; 2 Argentina, 3 Germany; 3 Italy; 2 Netherlands; 2 Poland;
2 Portugal; 2 South Africa; 4 Spain
PUBLICATIONS: 7th Conference on Retroviruses and Opportunistic Infections, January, 2000; 40th
Interscience Conference on Antimicrobial Agents and Chemotherapy, September, 2000; 5th International
Congress on Drug Therapy in HIV Infection, October, 2000; International Symposium on Drugs Affecting
Lipid Metabolism, September, 2001; European HIV Conference, October, 2001.
STUDY PERIOD:
Date first subject enrolled: 22-Mar-1999
Date last subject completed: 48 Weeks; 31-Mar-2001 - Study Ongoing
CLINICAL PHASE: II
OBJECTIVES: The overall objective of this study was to compare the antiviral activity and safety of
atazanavir through 48 weeks of dosing.
Primary Objective:
Stage I: To compare the safety and antiviral activity of three dose levels of atazanavir (ATV) with
nelfinavir (NFV) both as monotherapy (over a two week period) and in combination with ddI and d4T
(over 46 additional weeks) in antiretroviral naïve HIV-infected subjects with RNA levels ≥ 5,000 and
≤ 750,000 copies/mL.
Stage II: To compare the antiviral activity of three dose levels of atazanavir (ATV) with nelfinavir (NFV)
both as monotherapy (over a two week period) and in combination with ddI and d4T (over 46 additional
weeks) in antiretroviral naïve HIV-infected subjects with plasma HIV RNA levels ≥ 2,000 copies/mL.
METHODOLOGY: This study randomized 420 antiretroviral naïve HIV-infected subjects (98 in Stage I,
322 in Stage II) and was a two-stage, randomized, active-controlled, four arm study designed to evaluate
and compare the safety, tolerability, and antiviral activity of 1) atazanavir at 3 different doses with NFV
over 2 weeks of monotherapy; and 2) atazanavir at 3 different doses in combination with d4T and ddI with
NFV in combination with d4T and ddI over 46 additional weeks, in antiretroviral naïve subjects who had a
3
3
CD4 cell count of ≥ 100 cells/mm (≥ 75 cells/mm in subjects with no prior AIDS-defining diagnoses)
and a plasma HIV RNA viral load > 2,000 copies/mL (Roche Amplicor). The dose level of atazanavir was
blinded. Randomization was stratified for HIV RNA level (< 30,000 c/mL; ≥ 30,000 c/mL).
In addition, this study contained three substudies (PK/PD, viral dynamics, and immunology). Enrollment
into these substudies was voluntary and available to a small subset of study sites. Enrollment into viral
dynamics and immunology substudies was specified prior to randomization and subjects in both Stage I and
Stage II who were randomized to either atazanavir or NFV were eligible for participation. Enrollment into
the PK/PD substudy was available only to subjects randomized to atazanavir. All substudies are discussed
in separate reports.
Approved v4.0 930000930 4.0
Atazanavir
BMS-232632
AI424007
Clinical Study Report - Stage I/Stage II
NUMBER OF SUBJECTS/PATIENTS:
Stage I: 98 subjects were randomized
Stage II: 322 subjects were randomized
DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION:
3
Stage I: Plasma HIV RNA viral load of ≥ 5,000 and ≤ 750,000 copies/mL and CD4 count ≥ 100 cells/mm
3
(≥ 75 cells/mm in subjects with no prior AIDS-defining diagnoses).
3
Stage II: Plasma HIV RNA viral load of ≥ 2,000 copies/mL and CD4 count ≥ 100 cells/mm
3
(≥ 75 cells/mm in subjects with no prior AIDS-defining diagnoses).
TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS:
Atazanavir was supplied as grey capsules and taken orally once a day at dose levels of 200 mg, 400 mg and
500 mg.
Atazanavir 100 mg capsules:
N98177, C99193, N99028, N00097, N98178
Atazanavir 200 mg capsules:
N98178, C99274, C99331, N00104, C99179
Atazanavir placebo capsules:
N98173, N99026, N99045
In addition, all subjects received oral doses of ddI (400 mg QD if ≥ 60 kg or 250 mg QD if < 60 kg) and
d4T (40 mg BID if ≥ 60 kg or 30 mg BID if < 60 kg).
Subjects demonstrating intolerance to d4T on study were permitted to substitute ZDV for d4T, while
subjects demonstrating intolerance to ddI on study were permitted to substitute 3TC or ddI EC (for
gastrointestinal intolerance to ddI RMT formulation) for ddI.
Subjects < 60 kg at entry whose weight increased to ≥ 70 kg on study were switched to the full dose of ddI
and d4T. Subjects whose weight decreased to < 70 kg during the study had the option to switch to lower
doses of d4T and ddI at the discretion of their physician.
DURATION OF TREATMENT:
Two weeks of atazanavir or nelfinavir as monotherapy; followed by a minimum of an additional 46 weeks
at assigned triple therapy regimens (atazanavir/ddI/d4T at 3 doses of atazanavir vs NFV/ddI/d4T) after
randomization of last subject. Subjects waiting to enroll into the rollover protocol (AI424-041) could have
received continuation of open-label therapy.
REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS:
NFV was supplied as a 250 mg light blue tablet and three tablets were taken three times a day for a total
dose level of 2250 mg daily.
NFV 250 mg tablets:
TT20371A, ST11071A, 826601, TBB004, TT22271A, YT21061A, YT21351A,
TBR015, TT21631A, TT21581A
CRITERIA FOR EVALUATION:
Efficacy: The primary criteria for response was the comparison of the change from baseline of viral
suppression of plasma HIV RNA expressed in log10 through 48 weeks of therapy. Secondary criteria
included the proportion of subjects with HIV RNA < 400 c/mL (and < 50 c/mL) at 48 weeks and changes
in CD4 cell count over 48 weeks.
Approved v4.0 930000930 4.0
Atazanavir
BMS-232632
AI424007
Clinical Study Report - Stage I/Stage II
Safety: Safety was assessed by the proportion of subjects in each treatment regimen experiencing adverse
events, serious adverse events, discontinuations for adverse events and laboratory abnormalities.
Interim Analyses: Safety and preliminary antiviral activity for Stage I subjects was reviewed after 4, 12,
and 24 weeks of dosing by an unblinded BMS committee. Additional unplanned analyses were performed
at Week 4, including approximately two-thirds of the subjects, and at Week 8. The Week 4 reviews also
assessed the two-week monotherapy phase. For Stage II, two unplanned interim analyses for regulatory
submission were done at Week 12 on one-half of the subjects and just prior to all subjects reaching
Week 24 including 277 subjects randomized through March 16, 2000.
Pharmacokinetic/Pharmacodynamic, Viral Dynamics and Immunology Analysis: Detailed in separate
reports.
STATISTICAL METHODS:
The targeted sample size in Stage I was not based on statistical considerations. Stage II was powered
(> 95%) to demonstrate similarity of antiviral activity of three atazanavir doses of 200 mg, 400 mg, and
500 mg compared to nelfinavir when administered as a triple combination therapy. The primary endpoint
was the magnitude of reduction in HIV RNA levels from baseline over 48 weeks of treatment compared
using the Time-Averaged Difference (TAD). The TAD between each atazanavir regimen and nelfinavir
regimen in change from baseline in log10 HIV RNA level over 48 weeks of therapy were computed along
with a 98.3% confidence interval. Analyses were stratified by qualifying HIV RNA level obtained prior to
randomization (< 30,000 mL and ≥ 30,000 c/mL). Week 2 changes from baseline in HIV RNA were also
compared. The percent of subjects classified as responders at levels of HIV RNA < 400 c/mL and
< 50 c/mL were analyzed using Virologic Response (randomized subjects: VR-R and completers: VR-C)
and Treatment Response Without Prior Failure (randomized subjects: TRWPF) analyses. Safety was
assessed by tabulation of adverse events, serious adverse events, changes in laboratory values, and
incidence of study deaths.
EFFICACY RESULTS:
Analyses of the primary efficacy measure of the change from baseline of suppression of plasma HIV RNA
(expressed in log10) through 2 weeks of monotherapy and 46 weeks of triple therapy in Stage II
demonstrated the similarity of atazanavir at dose levels of 200 mg, 400 mg, and 500 mg QD compared with
nelfinavir 750 mg TID.
All atazanavir dose levels produced reductions in HIV RNA levels during the 2 week monotherapy period
comparable to those observed in nelfinavir treated subjects. Based on mean difference estimates and
95% CIs, all treatment groups were similar in Stage II subjects. A slightly better response was observed in
the nelfinavir subjects compared to atazanavir treated subjects except for those treated with atazanavir
500 mg. Comparable results were seen in Stage I subjects.
Approved v4.0 930000930 4.0
Atazanavir
BMS-232632
AI424007
Clinical Study Report - Stage I/Stage II
Change in log10 HIV RNA from Baseline - Week 2 Monotherapy
Treatment Regimen: ddI/d4T/PI
ATV (QD)
Subset
Stage II: N
Mean (SE)
NFV (TID)
200 mg
400 mg
500 mg
750 mg
68
70
64
70
-1.18
(0.09)
-1.27
(0.08)
-1.58
(0.07)
-1.36
0.17
(-0.06, 0.39)
0.09
(-0.13, 0.30)
-0.23
(-0.43, -0.02)
(0.08)
ATV - NFV:
Mean
difference
estimate
(95% CI)
a
N = 19
Stage I: N
Mean (SE)
N = 20
N = 29
-1.41
(0.19)
-1.41
(0.08)
-1.39
(0.11)
0.10
(-0.36, 0.55)
0.10
(-0.18, 0.38)
0.12
(-0.21, 0.44)
N = 19
-1.51
(0.12)
ATV - NFV:
Mean
difference
estimate
(95% CI)
a
a
Stratified by qualifying HIV RNA, Cochran Mantel-Haenszel weighting.
Based on longitudinal analyses of median HIV RNA levels for Stage II subjects, HIV RNA levels were
reduced below 400 copies/mL within 8 to 12 weeks after treatment initiation in all regimens. TAD
estimates and the 98.3% CIs for changes in HIV RNA levels through Week 48 for Stage II subjects met
pre-specified criteria for similarity of all atazanavir regimens to the nelfinavir regimen. Consistent results
were observed for the Stage I subjects.
TAD Estimate (98.3% CI)- Week 48 Stage II Subjects
Analysis
a
a
ATV 200 − NFV
ATV 400 − NFV
ATV 500 − NFV
Overall
0.02
(-0.21, 0.26)
0.08
(-0.16, 0.32)
-0.18
(-0.43, 0.07)
Last observation carried forward
0.04
(-0.20, 0.28)
0.01
(-0.23, 0.25)
0.00
(-0.25, 0.25)
Stratified by qualifying HIV RNA.
Approved v4.0 930000930 4.0
Atazanavir
BMS-232632
AI424007
Clinical Study Report - Stage I/Stage II
The comparability of the atazanavir regimens to the nelfinavir regimen was further confirmed by the
number of subjects meeting the key secondary endpoints of proportion LOQ < 400 and LOQ < 50 for
Stage II subjects. For LOQ < 400: VR-R ranged from 59% to 64% for atazanavir regimens versus 56% for
NFV; VR-C ranged from 73% to 76% for atazanavir versus 70% for NFV (all 95% confidence limits were
greater than - 12% for both VR-R and VR-C); TRWPF ranged from 59% to 61% for atazanavir versus 60%
for NFV. For LOQ < 50: VR-R ranged from 28% to 42% for atazanavir versus 39% for NFV; VR-C
ranged from 33% to 52% for atazanavir versus 48% for NFV; TRWPF ranged from 30% to 35% for
atazanavir versus 28% for NFV (all 95% lower confidence limits were greater than -12% for TRWPF).
3
CD4 cell counts increased approximately 200 cells/mm through 48 weeks of treatment in both the
atazanavir and nelfinavir subjects with slightly greater increases in atazanavir subjects. The TAD estimates
3
and 95% CIs were contained between ± 50 cells/mm indicating similarity.
SAFETY RESULTS:
Recognizing that this study was only blinded to dose of atazanavir, the number and type of on-study
adverse events was similar across treatment regimens with the exception of diarrhea (reported more
frequently in the nelfinavir subjects and a well-recognized side effect of nelfinavir) and jaundice and scleral
icterus (reported only by atazanavir subjects and recognized as related to atazanavir). The rates of
Grade 3 - 4 adverse events in the atazanavir subjects were comparable to those in nelfinavir subjects. Ten
subjects developed lactic acidosis syndrome, eight on atazanavir and two on NFV for incidence rates of
22.6 and 17.5 per 1000 patient years, respectively. All but two of the subjects with lactic acidosis syndrome
were women and two were pregnant. Three of these subjects with lactic acidosis syndrome (two on
atazanavir, one on NFV) died.
A total of four subjects, one each in the atazanavir 200 mg and nelfinavir regimens and two in the
atazanavir 500 mg regimen, died during the study. An additional atazanavir 200 mg subject died of a
gunshot wound 102 days after the last dose of study medication. A sixth subject who was receiving
atazanavir 500 mg was reported to have died after database lock. There were 72 subjects who reported
serious adverse events during the study, but there was no apparent treatment-related pattern of type or
frequency. Twenty-eight subjects (7%) discontinued study treatment due to one or more adverse events.
Two (2%) atazanavir 400 mg and 10 (9%) atazanavir 500 mg subjects required dose reduction during the
study, which was protocol mandated for increased total bilirubin.
Approved v4.0 930000930 4.0
Atazanavir
BMS-232632
AI424007
Clinical Study Report - Stage I/Stage II
Most Frequently Reported Adverse Events − Treated Subjects
a
Number of Subjects (%)
Treatment Regimen: ddI/d4T/PI
ATV (QD)
a
NFV (TID)
200 mg
N = 102
400 mg
N = 101
500 mg
N = 107
750 mg
N = 100
Infection
47
(46)
53
(52)
64
(60)
53
(53)
Nausea
25
(25)
35
(35)
32
(30)
18
(18)
Pain abdomen
25
(25)
31
(31)
24
(22)
23
(23)
Headache
22
(22)
26
(26)
22
(21)
19
(19)
Diarrhea
23
(23)
25
(25)
32
(30)
61
(61)
Peripheral neurologic symptoms
25
(25)
23
(23)
21
(20)
19
(19)
Rash
12
(12)
22
(22)
22
(21)
14
(14)
Vomiting
15
(15)
20
(20)
21
(20)
19
(19)
Events reported are those occurring in ≥ 20% of subjects in any ATV regimen.
Laboratory adverse events of any grade were reported for 116 subjects with the greatest number occurring
in the atazanavir 500 mg subjects. Hyperbilirubinemia was the most frequently observed laboratory adverse
event and was most common in the atazanavir 400 mg (20%) and 500 mg (29%) regimens. Five percent of
atazanavir 200 mg subjects and 1% of nelfinavir subjects experienced hyperbilirubinemia. Total
cholesterol, LDL cholesterol, and triglyceride levels remained essentially stable in the atazanavir subjects
regardless of dose. By contrast, nelfinavir subjects experienced pronounced increases of > 20% in these
lipid levels over the 48-week treatment period that were significantly greater than those in atazanavir
subjects (p < 0.001, all ATV 400 mg comparisons to NFV). HDL cholesterol levels remained relatively
unchanged for both the atazanavir and nelfinavir subjects.
Approved v4.0 930000930 4.0
Atazanavir
BMS-232632
AI424007
Clinical Study Report - Stage I/Stage II
Lipids Mean Percent Change From Baseline at Week 48
Treatment Comparison
Estimate (95% CI)
Lipid
ATV 200 - NFV
ATV 400 - NFV
ATV 500 - NFV
Total Cholesterol
-16.1% (-20.5%, -11.4%)a
HDL Cholesterol
0.9% % (-6.6%, 8.9%)
LDL Cholesterol
-20.9% (-29.1%, -11.8%)a
-29.2% (-38.6%, -18.2%a) -21.7% (-30.0%, -12.5%)a
Triglycerides
-30.4% (-43.7%, -14.1%)b
-28.6% (-41.3%, -13.3%)b -24.9% (-39.2%, -7.4%)c
a
b
c
-16.4% (-20.8%, -11.8%)a -15.4% (-20.3%, -10.3%)a
3.3%
(-4.9%, 12.3%)
0.4%
(-9.3%, 11.0%)
p < 0.0001.
p < 0.001.
p < 0.01.
CONCLUSIONS:
In a triple therapy regimen, atazanavir administered QD at doses of 200 mg, 400 mg and 500 mg provided
antiviral activity similar to nelfinavir 750 mg TID as measured by HIV RNA change from baseline
expressed as a Time-Averaged Difference through Week 48. All doses of atazanavir were comparable to
nelfinavir as measured by the proportion of subjects responding to treatment with HIV RNA < 400 c/mL
and < 50 c/mL by multiple measures of virologic response (all randomized and completers) and treatment
response without prior failure analyses, showing durability of effect over 48 weeks of treatment. Atazanavir
also provided similar efficacy as nelfinavir when both were administered as monotherapies over a
two-week period.
Atazanavir at all doses was safe and well tolerated and was associated with a clinically significant lower
incidence of diarrhea than observed with nelfinavir and with a somewhat higher incidence of lactic acidosis
syndrome. Atazanavir at all studied doses was not associated with an increase in cholesterol, LDL
cholesterol or triglyceride levels over the 48 weeks of treatment. By contrast, marked increases for these
lipids were observed in the nelfinavir treated subjects.
Over the 48-week treatment period, atazanavir 500 mg was associated with higher incidences of
hyperbilirubinemia, requiring dose reduction than the 200 mg and 400 mg atazanavir doses.
Based on the overall efficacy and safety profiles of the three atazanavir doses studied, 400 mg appeared to
be the optimal dose in treatment naive subjects.
DATE OF REPORT: 07-Aug-2002
Approved v4.0 930000930 4.0