TMC125 Safety and Tolerability: 24-week Results of the Pooled DUET-1
and -2 Trials
R Haubrich, M Schechter, S Walmsley, M Peeters, M Janssens, G De Smedt
on behalf of the DUET-1 and DUET-2 study groups
TTCA0062-07262-1
Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.
Inclusion criteria plasma viral load >5,000 HIV-1 RNA copies/mL and stable therapy for
≥8 weeks ≥1 NNRTI mutations,‡ current or documented historical ≥3 primary PI mutations sites: Thailand, Australia, Europe and the Americas
DUET: Study Design
24-week primary analysis
Randomized
*All patients received a background regimen of DRV/r plus NRTIs and optional enfuvirtide
TMC125 + BR*
Placebo + BR*
‡From extended list of NNRTI mutations; BR = background regimen; DRV/r = darunavir with low-dose ritonavir; RAM = resistance-associated mutation
TTCA0062-07262-2
Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.
Baseline Characteristics and Treatment Duration
Parameter, % or median (range)
TMC125 group (n=599)
Placebo group(n=604)
Treatment duration at time of analysis (weeks) 30 (1–60) 29 (3–55)
Patient demographics
Male (%) 90 89Caucasian (%) 70 70Age 45 (18–77) 45 (18–72)
Disease characteristics
Viral load (log10 copies/mL) 4.8 (2.7–6.8) 4.8 (2.2–6.5)
Viral load >100,000 copies/mL 38 36
CD4 cells (cells/mm3) 99 (1.0–789) 109 (0.0–912)
CD4 cells <50 cells/mm3 36 35
CDC category C (%) 58 59
Hepatitis B/C coinfection 13 12
Patient history Psychiatric symptoms (any type) 46 42
NNRTI-associated rash 8 14
Prior ARV use 10 ARVs (%) 80 83
TTCA0062-07262-3
Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.
Overview of Adverse Events
Parameter, %TMC125 group
(n=599)Placebo group
(n=604)
Any AE (any cause) 92 93Grade 3 AE 22 25Grade 4 AE 7 9Serious AE (SAE) 13 19Death (any cause) 1 2Discontinuation due to AE 6 4
Most common AEs (>10% in either group, regardless of severity and causality)*Rash (any type) 17 9Diarrhea 15 20Nausea 14 11Headache 9 12
AEs leading to death were not reported in more than one patient except for pneumonia and sepsis (n=2 each) in the placebo group
None of the deaths in the TMC125 group were considered related to TMC125
*excluding injection site reactions; §p=0.0001 vs placebo; AE = adverse event
TTCA0062-07262-4
Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.
Grade 3 and 4 Adverse Events
AE regardless of causality, n (%)TMC125 group
(n=599)Placebo group
(n=604)
Any grade 3/4 AE 25 27
Most common grade 3/4 clinical AEs (>0.5% in pooled TMC125 group)*
Rash (any type) 1.3 0
Peripheral neuropathy 1.0 0
Pancreatitis 0.7 0
Pneumocystis jiroveci pneumonia 0.7 0.7
Renal failure 0.7 0.3
*excluding injection site reactions and grade 3/4 laboratory abnormalities reported as AEs
TTCA0062-07262-5
Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.
Rash
In the TMC125 group: Early onset: median 12 days Limited duration: median 11 days Low severity: most mild to moderate; 1.3% grade 3, none grade 4
mostly maculopapular; no mucosal involvement Infrequently led to discontinuation: 2.2% of patients (0% with placebo)
most resolved with continued treatment
Clinical associations with rash No association with baseline CD4 cell count No increased risk with prior NNRTI-related rash
Investigator assessment of cause of rash, %
TMC125 group (n=599)
Placebo group(n=604) Significance
Any cause 17 9.4 p<0.001
Possibly related to study medication 12 4.8
TTCA0062-07262-6
Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.
Incidence of Rash by Gender
Patients experiencing rash (any type), %
TMC125 group
Male (n=539) Female (n=60)
Overall incidence 16 28Grade 3 1.1 3.3
Leading to permanent discontinuation 1.9 5.0
Higher incidence in women: 28% vs 16% in men No clear difference in severity or discontinuations between genders
TTCA0062-07262-7
Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.
Incidence and Prevalence of Rash (Any Type) by Treatment Group
Incidence Prevalence
Placebo group (n=604)TMC125 group (n=599)
Inci
den
ce
(%)
10
8
6
4
2
0
Pre
vale
nce
(%
)
0 4 8 12 16 20 24
Week0 4 8 12 16 20 24
Week
10
8
6
4
2
0
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Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.
Nervous System*
Similar incidence to placebo: 15% in TMC125 group versus 18% in placebo group (p=0.09)
Low severity: mostly grade 1 and 2
Did not lead to discontinuation: none in TMC125 group and 1.0% of placebo group
Patients experiencing nervous system-related AEs, %
TMC125 group (n=599)
Placebo group (n=604)
Grade 3 0.3 1.6
Grade 4 0 0
Most common (reported in ≥1.0% of patients in the TMC125 group)
Headache 9 12
Dizziness 3 4
Somnolence 2 2
*Includes only nervous system events associated with the use of approved NNRTIs
TTCA0062-07262-9
Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.
Psychiatric Disorders
Patients experiencing psychiatric-related AEs, %
TMC125 group
(n=599)
Placebo group
(n=604)
Grade 3 0.2 1.3Grade 4 0 0.2
Most common (reported in ≥1.0% of patients in the TMC125 group)Insomnia 6 7Depression 3 5Anxiety 3 3Sleep disorder 1 1
Similar incidence to placebo: 13% in TMC125 group versus 15% in placebo group (p=0.3)
Low severity: mostly grade 1 and 2
Infrequently lead to discontinuation: 1 patient (0.2%) in each group
No increased risk in patients with a history of psychiatric disorders
Abnormal dreams/nightmares in 5 patients (0.8%) in each group and no episodes of hallucinations, suicidal ideation or manic symptoms with TMC125
TTCA0062-07262-10
Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.
Hepatic AEs and Laboratory Abnormalities
20
0
–20
–400 8 16 24 32 40 48
ALT
Ch
ang
e f
rom
b
asel
ine
(U/L
)
Week
20
0
–20
–400 8 16 24 32 40 48
AST
Week
TMC125 group Placebo group
ALT = alanine aminotransferase; AST = aspartate aminotransferase
Hepatic AEs, %TMC125 group
(n=599)Placebo group
(n=604)
Any cause or severity 5.3 5.1Grade 3/4 3.8 3.1
Grade 3/4 in hepatitis coinfected patients 4.2 4.4
Leading to discontinuation 0.7 0.7
Laboratory abnormalities
ALT elevated (grade 3 or 4) 1.9 and 0.7 1.3 and 0.3
AST elevated (grade 3 or 4) 2.0 and 0.5 1.3 and 0.3
TTCA0062-07262-11
Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.
Treatment-emergent Laboratory Abnormalities
Parameter, %TMC125 group
(n=599)Placebo group
(n=604)
At least one laboratory abnormality 98 100
Grade 1/2 93 93
Grade 3/4 32 32
Most common (>2% in TMC125 group) grade 3/4 laboratory abnormalities
Amylase (>2x ULN) 7.5 7.9
Triglycerides (>750mg/dL) 7.0 4.3
Total cholesterol (>300mg/dL) 5.8 4.1
Increased LDL-cholesterol (190mg/dL)
5.2 5.4
Decreased neutrophils (<750mg/dL) 3.7 6.3
Increased glucose (>250mg/dL) 2.5 2.0
Increased ALT (>5x ULN) 2.5 1.7
Increased AST (>5x ULN) 2.5 1.7
Abstract 1210
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal
TTCA0062-07262-12
Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.
-200
-150
-100
-50
0
50
0 8 16 24 32 40 48
-5
0
5
10
15
20
0 8 16 24 32 40 48
0
20
40
60
80
100
0 8 16 24 32 40 48
HDLLDL calculated
Lipid Changes over Time
Total cholesterol/HDL Triglycerides
-100-80-60-40-20
02040
0 8 16 24 32 40 48
TMC125 group Placebo group
HDL = high density lipoprotein; LDL = low density lipoprotein
Ch
ang
e f
rom
b
asel
ine
(mg
/dL
)C
han
ge
fro
m
bas
elin
e (m
g/d
L)
Week Week
TTCA0062-07262-13
Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.
Hospitalizations
0
5
10
15
20
Pat
ien
ts h
osp
ital
ized
at
leas
t o
nce
b
y 24
wee
ks (
%)
16%
11%
Placebo groupTMC125 group
p=0.0031
0
500
1000
1500
2000
1700
1105
Cu
mu
lati
ve d
ays
ho
spit
aliz
ed
by
24 w
eeks
TTCA0062-07262-14
Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.
Safety Conclusions from DUET
Assessing safety/ tolerability of this new agent in a complex background was facilitated by the placebo-controlled design
Safety and tolerability of TMC125 was similar to placebo
Rash, the only AE to occur more frequently with TMC125 generally mild to moderate often resolved with continued treatment associated with low discontinuation (2% versus 0% with placebo)
Overall, most AEs were of low severity and infrequently led to discontinuation 6% vs 4% in the TMC125 vs placebo groups
TMC125 was not associated with any increase in laboratory abnormalities, including hepatic and lipid parameters
TMC125 provides a tolerable new option for treatment-experienced patients not associated with common NNRTI side effects
TTCA0062-07262-15
Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.
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