1 tolvaptan for the treatment of hyponatremia aliza thompson, md medical officer cardiovascular and...
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Tolvaptan for the Treatment of Hyponatremia
Aliza Thompson, MDAliza Thompson, MD
Medical OfficerMedical Officer
Cardiovascular and Renal Drugs Advisory Cardiovascular and Renal Drugs Advisory Committee MeetingCommittee Meeting
June 25, 2008June 25, 2008
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Tolvaptan’s Phase 3 Hyponatremia Trials
Time (Days)
Se
rum
So
diu
m (
mE
q/L
)
0 10 20 30 40Time (day)
128
130
132
134
136
Ser
um S
odiu
m L
evel
(m
)
OPC-15/60MGPLACEBO
0 10 20 30 40Time (day)
128
130
132
134
136
Ser
um
So
diu
m L
evel
(m
)
OPC-15/60MGPLACEBO
Tolvaptan
Placebo
Study 156-03-238 Study 156-02-235
Washout Washout
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Outline
• Who was studied in tolvaptan’s development program?
• Is serum sodium a valid surrogate for benefit in this population?
• Did the development program establish tolvaptan’s safety in this population?
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Who was targeted?
Inclusion criteria• Hyponatremia (sodium < 135 mEq/L) in euvolemic or hypervolemic
states
Exclusion criteria • Acute and transient hyponatremia associated with head trauma
or postoperative state
• Sodium < 120 mEq/L with associated neurologic impairment (symptoms such as apathy, confusion, seizures, etc)
• Likely to require IV saline for correction of symptomatic or
asymptomatic severe hyponatremia during the course of the study.
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Who was enrolled?
0
30
60
90
120
Number of Subjects
Tolvaptan Placebo
130-134 125-129 <125
Sodium (mEq/L)
Mean Sodium (mEq/L): 129.1 mEq/L 128.9 mEq/L
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Published literature: key considerations
Are the findings generalizable to the population treated with tolvaptan?
level of serum sodium acute vs. chronic hyponatremia underlying etiology
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The clinical significance of “mild” hyponatremia
Hyponatremia and…
• falls in the elderly
• morbidity and mortality in heart failure patients
• morbidity and health related quality of life in cirrhotics
Is this association or is this causation?
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Phase 3 Hyponatremia Studies: Secondary Endpoints
1. Average daily area under the curve of change in sodium up to Day 4, sodium < 130 mEq/L subgroup
2. Average daily area under the curve of change in sodium up to Day 30, sodium <130 mEq/L subgroup
3. Percentage of subjects with normalized sodium at Day 4
4. Percentage of subjects with normalized sodium at Day 30
5. Time to first normalization in sodium 6. Change from baseline in sodium at Day 4
7. Change from baseline in sodium at Day 30
8. Percentage of subjects requiring fluid restriction 9. Urine output at Day 1 10. Change from baseline in body weight at Day 1 for hypervolemic subjects.11. Fluid balance at Day 1 for hypervolemic patients
12. Change from baseline in the SF-12 Physical Component Summary and Mental Component Summary Scales
13. Categorical change in sodium at Day 4 and Day 30, subgroup with sodium < 130 mEq/L
14. Categorical change in sodium at Day 4 and Day 30, subgroup with sodium ≥ 130 mEq/L
15. Percentage of subjects designated as treatment failures due to need for saline infusion
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Phase 3 hyponatremia studies: Mental Component of the SF-12 (Day 30)
Analysis
Mean Baseline(SD)
Mean Change(number of subjects) Treatment
EffectP-value
Tolvaptan Placebo Tolvaptan Placebo
Last Observation Carried Forward
42.3(11.7)
45.4(11.8)
6.4(N=83)
1.1(N=71) 3.9 .02
Observed Cases
42.2(11.7)
46.7(12.1)
8.0(N=71)
0.9(N=58) 5.3 .004
Analysis
Mean Baseline(SD)
Mean Change(number of subjects) Treatment
EffectP-value
Tolvaptan Placebo Tolvaptan Placebo
Last Observation Carried Forward
44.7(12.0)
45.1(11.9)
4.5(N=101)
2.0(N=103) 2.2 0.15
Observed Cases
45.2(12.3)
45.4(12.1)
4.9(N=86)
2.4(N=85) 2.4 0.12
Trial 156-02-235
Trial 156-03-238
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Phase 3 hyponatremia studies: Hyponatremia Disease Specific Survey
• Developed internally by sponsor
• Conducted in trial 156-03-238 at 3 time points during the course of the study
• Following submission to NDA, exploratory analyses combined 4 questions to calculate a “mental component”
• Difference in mental component score at Day 30 (estimated treatment effect -1.9 and -2.7 for subjects with a serum sodium < 135 and < 130 mEq/L respectively)
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Phase 3 hyponatremia studies: Neurologic Examination
• Included physician assessment of level of consciousness, ataxia, stance, gait, coordination*, muscle strength and tone, reflexes, dysarthria, tremor…
• Depending on trial, measurements appear to be made 6 to 7 times during the course of the study
• Differences between tolvaptan and placebo-treatment arms:
– reflexes R and L achilles Week 1 in trial 156-02-235
– stance with eyes closed at Week 2 in trial 156-03-238
– ataxia at Day 37 in trial 156-03-238 (when subjects had been off drug for 7 days)
*Limited data collected on stance, gait and coordination in trial 156-02-235
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Tolvaptan’s development programs
Hyponatremia indicationTolvaptan-treated subjects in phase 3
hyponatremia trials (N=223)
Subjects with hyponatremia due to SIADH/Other, Heart Failure or Cirrhosis
Worsening heart failure indicationTolvaptan-treated subjects in phase 3 heart
failure trials (N=2063)
Subset of heart failure subjects who also happened to have hyponatremia
N=242
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Hyponatremic subjects in Phase 3 Heart Failure Trials
• No difference in Kansas City Cardiomyopathy Questionnaire
• Changes in body weight at day 1 and inpatient day 7 or discharge (< 1 kg difference between treatment arms)
• Changes in patient-assessed dyspnea at Day 1
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The data tell us about tolvaptan as a treatment for worsening heart failure.
What do they tell us about the clinical benefits of treating a patient with tolvaptan
to raise serum sodium?
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The Safety Database (N=3294)
60718%
14223%
22337%
24240%
268782%
Subjects with hyponatremia
Phase 3 hyponatremia trials
Phase 3 heart failure trials
Other trials
Subjects with heart failure or hyponatremia
Subjects with hyponatremia
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Subjects with hyponatremia (N=607)
529%
13723%
41868%
130-134
125-129
<125
10016%
41068%
9716%
Heart FailureCirrhosisSIADH/other
By Serum Sodium Level (mEq/L)
By Underlying Etiology
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Tolvaptan’s development programs
Worsening heart failure indicationTolvaptan-treated subjects in phase 3 heart
failure trials (N=2063)
Subset of heart failure subjects who also happened to have hyponatremia
Hyponatremia indicationTolvaptan-treated subjects in phase 3
hyponatremia trials (N=223)
Hyponatremia due to SIADH/Other, Heart Failure or Cirrhosis
N=242
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Mortality in the phase 3 heart failure studies
47.5
24.1
42.7
24.4
0 20 40 60
Subgroupwith
hyponatremia
All treatedsubjects
Percent of subjects with fatalities
Tolvaptan Placebo
(CI: 41.2, 53.8); Total N= 242
Deaths on treatment or within 7 days of stopping
(CI: 36.3, 49.1); Total N=232
(CI: 22.3, 25.9); Total N= 2063
(CI: 22.5, 26.3); Total N= 2055
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The Safety Database (N=3294)
Subjects with hyponatremia
Phase 3 hyponatremia trials
Phase 2 trials
Subjects with heart failure or hyponatremia
Subjects with hyponatremia
60718%
14223%
22337%
Phase 3 heart failure trials
24240%
268782%
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Mortality in heart failure subjects with hyponatremia
Other trials enrolling heart failure subjects with
hyponatremia
Subjects with hyponatremia enrolled in phase 2 heart failure
trialsTolvaptan: 13.2% (12/91) Placebo: 10.0% (4/40)
Subjects with heart failure enrolled in placebo-controlled
hyponatremia trialsTolvaptan: 11.5% (10/87)
Placebo: 7.6% (6/79)
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0 10 20 30
GI bleed orecchymosis*
Ecchymosis*
GI bleed
Percentage of subjects (%)
Placebo(N=57)
Tolvaptan(N=63)
*Includes hematomas
Adverse events in subjects with cirrhosis
17.5 % (CI: 8.1, 26.9)
1.8% (CI: 0, 5.3)
9.5% (CI: 2.3, 16.7)
9.5% (CI: 2.3, 16.7)
1.8% (CI: 0, 5.3)
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Can the findings in tolvaptan’s development program be extrapolated to a population with more severe hyponatremia?
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Baseline Serum Sodium (mM)Ste
ad
y S
tate
Se
rum
So
diu
m C
ha
ng
e f
rom
Ba
selin
e (
mM
)
110 115 120 125 130 135 140
01
02
03
0
Efficacy in tolvaptan’s phase 3 hyponatremia trials
Change in
Sodium (mEq/L)
Study 156-02-235 Study 156-03-238
Baseline Sodium (mEq/L)
110 115 120 125 130 135 140
010
2030
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Safety
Subjects with hyponatremia: N=607
Serum Sodium Level (mEq/L)
529%
13723%
41868%
130-134
125-129
<125
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Closing Comments
• Who was studied in tolvaptan’s development program?– patients with mild and seemingly asymptomatic
hyponatremia
• Is serum sodium a valid surrogate for benefit in this population?– The clinical significance of raising serum sodium in
this population remains unclear
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Closing Comments
• Did the development program establish tolvaptan’s safety in this population?
– The database is limited, in particular with respect to subjects with SIADH, cirrhosis, and greater degrees of hyponatremia
– In the setting of subtle or uncertain benefits, the tolerance for risk should be low
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Closing Comments
• Can we generalize these findings to a population with more severe hyponatremia?