Atazanavir
BMS-232632
AI424044
Interim Clinical Study Report: Long-term Lipid/Safety Data
Name of Sponsor/Company:
Bristol-Myers Squibb
Individual Study Table Referring
to the Dossier
(For National Authority Use
Only)
Name of Finished Product:
Not Available
Name of Active Ingredient:
Atazanavir (BMS-232632)
SYNOPSIS
Interim Clinical Study Report: Long-term Lipid/Safety Data AI424044
TITLE OF STUDY: A Study to Assess Long-term Antiviral Activity, Safety, Including Serum Lipids,
and Tolerability of Atazanavir in Combination with Stavudine (d4T) and Lamivudine (3TC) in Subjects
Previously Treated with Nelfinavir (NFV) or BMS-232632
INVESTIGATORS: Total of 45 investigators
STUDY CENTERS: Total of 45 study centers: 19 in Europe, 15 in North America, 6 in South America,
3 in Africa, 2 in Asia
PUBLICATIONS: XIV International AIDS Conference, July, 2002; 4th International Lipodystrophy
Workshop, September, 2002
STUDY PERIOD:
Date first subject enrolled: 27-Jun-2001
Date last subject completed: Study Ongoing (LPLV for this report: 24-Jul-2002)
CLINICAL PHASE: IIIB
OBJECTIVES:
Research Hypothesis:
A switch from nelfinavir (NFV) to atazanavir (ATV, BMS-232632) 400 mg will be associated with an
improvement in serum lipids, as assessed by a decrease in total cholesterol after 12 weeks of ATV therapy
in combination with d4T and 3TC.
Primary Objective:
To assess long-term safety and tolerability of atazanavir (including metabolic complications) in subjects
who have completed participation in BMS Protocol AI424008.
Secondary Objectives:
1) To assess the improvement in total cholesterol for subjects who switched from NFV/d4T/3TC (from
study AI424008) to ATV 400 mg/d4T/3TC.
2) To assess the long-term antiviral duration of effect of atazanavir on subjects who have completed
AI424008 as measured by changes in HIV RNA and CD4 cell count, and development of HIV-related
clinical events.
3) To assess on-study PR and QTc intervals.
4) To assess pharmacokinetic measurements of atazanavir during and after dose reduction.
Approved v1.0 930002764 1.0
Atazanavir
BMS-232632
AI424044
Interim Clinical Study Report: Long-term Lipid/Safety Data
METHODOLOGY: This was an open-label (initially blinded to ATV dose), roll-over/switch study
designed to assess the impact on lipid concentration in subjects who switched from NFV to ATV and to
assess longer term safety and antiviral activity in HIV-infected subjects who had completed participation in
BMS Protocol AI424008. Subjects originally assigned to ATV received the same drug regimen that they
received in study AI424008 (i.e., ATV 400 mg/d4T/3TC or ATV 600 mg/d4T/3TC), including any
previous ATV dose reduction due to hyperbilirubinemia or previous changes in nucleosides. Subjects
originally assigned to NFV received ATV 400 mg in combination with d4T/3TC or previously changed
nucleosides.
NUMBER OF SUBJECTS: 346 subjects were enrolled
DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION: HIV-infected men and women who had
completed BMS Protocol AI424008 (i.e., off treatment reason was “completed treatment as per protocol”),

with a plasma HIV RNA viral load < 10,000 c/mL (Roche AMPLICOR ), who in the Investigator’s
opinion, had demonstrated compliance with the study medication and treatment visits.
TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS:
Atazanavir was supplied as gray or blue capsules and taken orally once a day at a dose of 400 mg or
600 mg.
ATV 200 mg capsules (gray):
batch numbers: 8MBM117, C99331
ATV 200 mg capsules (blue):
batch numbers: 8MHM292, B5467
ATV Placebo capsules (gray):
batch numbers: N98173, N99045
DURATION OF TREATMENT: Subjects were to continue on study for at least 48 weeks after
enrollment of the last subject, until approval of ATV for commercial use by the appropriate health
authorities, whichever was later, or until BMS made a decision not to continue development of ATV.
However, subjects with a confirmed HIV RNA of > 1,000 copies/mL at Week 12 or later were to be
discontinued from the study.
REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION, BATCH NUMBERS:
Not applicable
CRITERIA FOR EVALUATION:
Antiviral Efficacy: Efficacy was assessed by the proportion of responders, using different response
definitions. One analysis assessed Virologic Response - Observed Cases (VR-OC), presented for the Limit
of Quantification (LOQ) of 400 c/mL, the lower limit of detectability for the standard assay, and
LOQ = 50 c/mL, the lower limit of the ultra-sensitive assay. Other analyses summarized the changes from
entry in log10 HIV RNA level, time to virologic rebound, and CD4 cell count.
Safety: Safety was assessed by the magnitude of change from entry in lipid (total cholesterol, HDL
cholesterol, fasting LDL cholesterol, fasting triglycerides) concentrations at scheduled visit weeks for
subjects who switched from NFV/d4T/3TC (in study AI424008) to ATV 400 mg/d4T/3TC. Additional
endpoints assessed by the proportion of subjects in each cohort experiencing discontinuations, serious
adverse events, new or worsening adverse events, and laboratory abnormalities.
STATISTICAL METHODS: This report presents safety and efficacy analyses through 24 weeks of ATV
therapy. The principal safety analysis compared the Week 12 percent change from entry in total cholesterol
concentrations for subjects who switched from NFV/d4T/3TC (in study AI424008) to ATV
400 mg/d4T/3TC. This analysis used the evaluable safety data set which included treated subjects. Lipid
values used in the analysis were those measured as early as four days before the first dose of ATV in
AI424044 through 30 days after the last dose of ATV in AI424044. To assess whether the Week 12 mean
Approved v1.0 930002764 1.0
Atazanavir
BMS-232632
AI424044
Interim Clinical Study Report: Long-term Lipid/Safety Data
percent changes in lipids from entry were significantly less than zero, the comparison used a 95% CI and
p-value based on the t-distribution. Durability of the effect on all lipid parameters for all treatment cohorts
was summarized similarly.
The frequency of adverse events, serious adverse events, deaths, laboratory abnormalities, and therapy
discontinuations due to adverse events were tabulated by treatment cohort.
All efficacy analyses were exploratory and used the evaluable efficacy data set which included treated
subjects. Plasma HIV RNA levels and CD4 cell counts as early as four days before the first dose of ATV
therapy in AI424044 through four days after the last dose of ATV in AI424044 were included in the
analyses.
The efficacy analyses assessed the proportion of responders using the VR-OC definition, presented for the
LOQ of 400 c/mL and 50 c/mL. Other analyses summarized the changes from entry in log10 HIV RNA
level, time to virologic rebound, and CD4 cell count.
Interim Analyses: A planned interim analysis (the principal analysis for lipid assessment) was performed
after the last subject completed 12 weeks of treatment. The primary objective of that interim analysis was
to assess the improvement in total cholesterol for subjects who switched from NFV in AI424008 to ATV
400 mg.
RESULTS:
•
Discontinuations were infrequent and comparable among treatment cohorts.
•
No subjects switching from NFV to ATV discontinued for treatment failure/lack of efficacy.
•
Median time on protease inhibitor (PI) therapy was comparable among treatment cohorts:
approximately 36 weeks in study AI424044 and approximately 109 weeks from the start of study
AI424008.
Subject Disposition And Demography
Treatment Regimen (ATV/d4T/3TC) and Cohort:
Enrolled and Treated on AI424044 - N
Discontinued Prior to 27-Aug-2002 - N (%)
Continuing on Treatment - N (%)
Age:
Median (Min, Max)
ATV 400
N = 139
ATV 600
N = 144
139
144
NFVÞ
ÞATV
N = 63
63
12
(9)
9
(6)
6
(10)
127
(91)
135
(94)
57
(90)
36 (19, 65)
37 (21, 59)
35 (20, 70)
Gender (%):
Male
62
65
59
Race (%):
White
54
54
51
Black
22
25
24
Asian/Pacific Islanders
16
15
19
Hispanic/Latino
4
2
5
Other
4
4
2
Approved v1.0 930002764 1.0
Atazanavir
BMS-232632
AI424044
Interim Clinical Study Report: Long-term Lipid/Safety Data
Subject Disposition And Demography
Treatment Regimen (ATV/d4T/3TC) and Cohort:
ATV 400
N = 139
ATV 600
N = 144
NFVÞ
ÞATV
N = 63
Entry HIV RNA (log10 c/mL)
Median (Min, Max)
1.76 (1.69, 4.81)
1.69 (1.69, 4.69)
1.78 (1.69, 4.05)
Entry CD4 (cells/mm )
Median (Min, Max)
472 (122, 1427)
524 (44, 1518)
543 (184, 1782)
a
a
a
3
Entry is prior to ATV therapy in AI424044
SAFETY RESULTS:
Lipids:
•
Twelve weeks after a switch from NFV to ATV, the following were observed:
−
a significant reduction (p < 0.0001) in total cholesterol (TC), fasting LDL cholesterol (LDL-C),
and fasting triglycerides (TG)
−
an increase in HDL cholesterol
−
decreases in the proportions of subjects with undesirable total cholesterol (≥ 240 mg/dL) and LDL
cholesterol (≥ 130 mg/dL) per National Cholesterol Education Program (NCEP) guidelines
−
median Week 12 levels of total cholesterol, fasting LDL cholesterol, and fasting triglycerides
comparable to median baseline levels in study AI424008
In each case, changes in serum lipid concentrations were maintained through Week 24.
•
Treatment in the ATV 400 mg and 600 mg cohorts did not result in clinically relevant increases in
these lipid parameters after 12 weeks of continued ATV therapy. This was maintained through
Week 24.
•
Ten subjects took serum lipid reducing agents in study AI424008 prior to entry in study AI424044
(ATV 400, 2 subjects; ATV 600, 2 subjects; NFVÞATV, 6 subjects). Concomitant serum lipid
reducing agent use during treatment in study AI424044 was higher among subjects in the NFVÞATV
cohort (7 subjects, 11%) than among subjects in the ATV 400 (6 subjects, 4%) and ATV
600 (4 subjects, 3%) cohorts.
Approved v1.0 930002764 1.0
Atazanavir
BMS-232632
AI424044
Interim Clinical Study Report: Long-term Lipid/Safety Data
Week 12 Lipids - Mean Percent Change from Entry
Treatment Regimen (ATV/d4T/3TC) and Cohort:
ATV 400
(N = 139)
ATV 600
(N = 144)
NFVÞ
ÞATV
(N = 63)
Total cholesterol
+1%
+2%
-16%
Fasting LDL cholesterol
-3%
-6%
-21%
Fasting triglycerides
+8%
+11%
-28%
HDL cholesterol
0%
0%
+5%
Lipid
a
b
a
a
a
b
p < 0.0001
p < 0.05
Median Lipid (Total and Fasting LDL Cholesterol, Triglycerides)
Concentrations in AI424008 and AI424044 - Subjects who Switched
from NFV to ATV (NFVÞ
ÞATV)
225
200
175
n
n
n
150
l
o
125
100
l
o
o
l
75
008 B/L
044 Entry
Weeks
Lipid
Group: Number at risk
TC
63
LDL-C
54
TG
54
TC
nnn N=63
LDL-C
lll N=63
044 Week 12
TG
ooo N=63
57
33
48
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41
55
Atazanavir
BMS-232632
AI424044
Interim Clinical Study Report: Long-term Lipid/Safety Data
Deaths, Adverse Events and Laboratory Abnormalities:
•
One death was reported in the NFVÞATV cohort (congestive heart failure).
•
SAEs were infrequent, and the incidence was comparable among the treatment cohorts.
•
Seven subjects discontinued due to AEs (ATV 400, 1%; ATV 600, 2%; NFVÞATV, 3%).
•
The incidence of adverse events leading to discontinuation of study therapy was low and comparable
among treatment cohorts.
•
The overall incidence of treatment-emergent adverse events was comparable among treatment cohorts.
New or worsening jaundice and scleral icterus were observed in ≤ 6% of subjects among treatment
cohorts.
•
A switch from NFV to ATV was associated with a low incidence of new or worsening diarrhea (2%).
•
Grade 3 - 4 hepatic transaminase elevations were infrequent (≤ 2%) among all treatment cohorts.
•
A switch from NFV to ATV was associated with elevations in total bilirubin; the incidence of
Grade 3 - 4 elevations were higher for subjects who continued on ATV (ATV 400, 26%; ATV 600,
44%) than for those subjects who switched (13%). Grade 4 elevations in total bilirubin were transient
and occurred in five subjects (ATV 400, 1 subject; ATV 600, 4 subjects); three of these subjects, all in
the ATV 600 cohort, had Grade 4 elevations and dose-reduced in accordance with the protocol. There
were no Grade 4 elevations in total bilirubin in subjects in the NFVÞATV cohort.
Other Safety Results of Particular Clinical Interest
Treatment Regimen (ATV/d4T/3TC) and Cohort:
ATV 400
N = 139
ATV 600
N = 144
Deaths - n (%)
0
0
Discontinuation due to any AEs - n (%)
Asthenia
Fatigue
Pericarditis
Disorder gastrointestinal
Icterus eye
Lipodystrophy
Weight decreased
Disorder urinary tract
2
(1)
0
0
0
0
0
1 (< 1)
0
1 (<1)
3
0
1
1
1
1
0
1
0
Serious AEs - n (%)
3
5
a
Treatment-Emergent Adverse Events
Any adverse event - n (%)
Infection
Lipodystrophy
Abdominal pain
Rash
Peripheral neurologic symptom
Jaundice
Scleral icterus
Nausea
Gr 1 - 4
94 (68)
41 (29)
13 (9)
4 (3)
6 (4)
3 (2)
4 (3)
1 (< 1)
1 (< 1))
(2)
(2)
(< 1)
(< 1)
(< 1)
(< 1)
(< 1)
(3)
Gr 3 - 4 Gr 1 - 4 Gr 3 - 4
6 (4)
107 (74)
9 (6)
0
46 (32)
0
1 (< 1) 14 (10)
0
0
10 (7)
1 (< 1)
0
8 (6)
0
0
9 (6)
0
0
8 (6)
0
0
6 (4)
0
1 (< 1)
8 (6)
0
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NFVÞ
ÞATV
N = 63
1
(2)
2
1
0
0
0
0
1
0
0
(3)
(2)
3
(5)
Gr 1 - 4
50 (79)
22 (35)
6 (10)
5 (8)
5 (8)
4 (6)
4 (6)
3 (5)
3 (5)
(2)
Gr 3 - 4
3 (5)
0
0
0
0
1 (2)
1 (2)
0
0
Atazanavir
BMS-232632
AI424044
Interim Clinical Study Report: Long-term Lipid/Safety Data
Other Safety Results of Particular Clinical Interest
Treatment Regimen (ATV/d4T/3TC) and Cohort:
ATV 400
N = 139
Headache
Fatigue
Fever
Diarrhea
13 (9)
2 (1)
2 (1)
5 (4)
1 (< 1)
1 (< 1)
0
0
ATV 600
N = 144
9 (6)
3 (2)
4 (3)
5 (3)
0
0
0
0
NFVÞ
ÞATV
N = 63
12 (19)
0
4 (6)
0
3 (5)
0
1 (2)
0
b
Grade 3 - 4 Lab Abnormalities - n (%)
ALT/SGPT elevation
AST/SGOT elevation
Total bilirubin elevation
Neutropenia
a
b
2/137 (1)
0/137 (0)
35/137 (26)
2/137 (1)
3/144 (2)
0/144 (0)
64/144 (44)
3/142 (2)
0/63 (0)
0/63 (0)
8/63 (13)
1/63 (2)
New or worsening from the start of therapy in AI424044
Worst on-study abnormality from the start of therapy in AI424044
EFFICACY RESULTS:
•
The proportion of subjects with virologic response (VR-OC) through Week 24 with HIV RNA levels
< 400 c/mL and < 50 c/mL was comparable among treatment cohorts.
•
The proportion of subjects in response (VR-OC) with HIV RNA levels < 400 c/mL increased from
study entry to Week 24 in all treatment cohorts (ATV 400, 78% to 83%; ATV 600, 78% to 85%;
NFVÞATV, 73% to 87%).
•
Few subjects had increases in HIV RNA greater than 1.0 log10 c/mL (ATV 400, 7%; ATV 600, 2%;
NFVÞATV, 2%) at Week 24.
•
Mean increases from study entry in CD4 cell counts through Week 24 were comparable among the
treatment cohorts.
Approved v1.0 930002764 1.0
Atazanavir
BMS-232632
AI424044
Interim Clinical Study Report: Long-term Lipid/Safety Data
Week 24 Efficacy Results
Treatment Regimen (ATV/d4T/3TC) and Cohort:
ATV 400
a
HIV RNA Change from Entry
c
NFVÞ
ÞATV
b
Proportion HIV RNA < LOQ
LOQ = 400 c/mL
LOQ = 50 c/mL
ATV 600
Responders/Evaluable (%)
111/133 (83)
80/133 (60)
118/139 (85)
78/139 (56)
54/62 (87)
37/62 (60)
d
Responders/Evaluable (%)
≤ 0.5 log10 c/mL
104/122 (85)
112/127 (88)
55/59 (93)
> 0.5 log10 c/mL
18/122 (15)
15/127 (12)
4/59 (7)
≤ 1.0 log10 c/mL
114/122 (93)
124/127 (98)
58/59 (98)
> 1.0 log10 c/mL
8/122 (7)
3/127 (2)
CD4 cell count (cells/mm )
b
c
d
1/59 (2)
Mean Change from Entry (SE)
(N = 139)
(N = 144)
(N = 63)
44 (14.0)
43 (12.9)
29 (18.2)
3
a
c
Virologic Response - Observed Cases (VR-OC)
Subjects with Week 24 HIV RNA measurements
Entry is prior to ATV therapy in AI424044
Subjects with entry and Week 24 HIV RNA measurements
CONCLUSIONS:
•
A switch from NFV to ATV 400 mg as part of a three-drug treatment regimen with d4T and 3TC
resulted in improved serum lipid parameters (total cholesterol, HDL cholesterol, fasting LDL
cholesterol and fasting triglycerides) through 12 and 24 weeks after the switch in PI therapy.
•
ATV was associated with minimal changes in total cholesterol, LDL cholesterol, and triglyceride
concentrations through 24 weeks of continued treatment.
•
In all cohorts, ATV was safe and well tolerated; the frequency of adverse events was comparable for
all three treatment cohorts.
•
No new safety signals were identified in the cumulative experience of studies AI424008/AI424044
combined after a median of approximately 36 weeks of additional ATV therapy in the ATV 400 and
ATV 600 cohorts, reflective of a median time on ATV therapy of approximately 109 weeks.
•
Grade 3 - 4 elevations in total bilirubin were observed less frequently among subjects switching from
NFV to ATV than those continuing on ATV or those who initiated ATV in study AI424008.
•
The majority of subjects in all treatment cohorts maintained continued virologic suppression through
an additional 24 weeks of treatment, and the proportion of subjects with virologic response (VR-OC)
through Week 24 with HIV RNA levels < 400 c/mL and < 50 c/mL was comparable among treatment
cohorts, including subjects in the ATV 400 and ATV 600 cohorts with a median time on ATV therapy
of approximately 109 weeks.
•
The proportion of subjects in response (VR-OC) with HIV RNA levels < 400 c/mL increased from
study entry to Week 24 in all treatment cohorts (ATV 400, 78% to 83%; ATV 600, 78% to 85%;
NFVÞATV, 73% to 87%).
Approved v1.0 930002764 1.0
Atazanavir
BMS-232632
•
AI424044
Interim Clinical Study Report: Long-term Lipid/Safety Data
The choice of the 400 mg dose of ATV previously selected for Phase III studies is supported by the
long-term efficacy rates observed in the present study. ATV 600 mg was not observed to provide better
response rates than ATV 400 mg, and ATV 600 mg was associated with a greater frequency of
elevated bilirubin.
DATE OF REPORT: 16-Oct-2002
Approved v1.0 930002764 1.0