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Drug Trials Snapshot: Tavalisse

HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to the TAVALISSE Package Insert for complete information.

TAVALISSE (fostamatinib disodium hexahydrate)
ta vah leese
Rigel Pharmaceuticals, Inc.
Approval date: April 17, 2018


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

TAVALISSE is a drug used to treat adults with low platelet count due to chronic immune thrombocytopenia (ITP) when a prior treatment for ITP has not worked well enough. Chronic immune thrombocytopenia is an autoimmune bleeding disorder. In patients with ITP, the blood doesn't clot as it should because of a low platelet count.

How is this drug used?

TAVALISSE is a tablet that is taken twice daily. After 4 weeks, the dosage can be increased as necessary, to reduce the risk of bleeding.

What are the benefits of this drug?

More patients treated with TAVALISSE achieved pre-determined platelet counts, in comparison to patients who received placebo.

What are the benefits of this drug (results of trials used to assess efficacy)?

The table below summarizes the primary endpoint results for the individual trials based on intend-to-treat (ITT) population.

Table 2. Trial Outcomes from Placebo-Controlled Clinical Trials -ITT population

Trial Outcome

Trial 1

Trial 2

TAVALISSE
(N=51)

Placebo
(N=25)

TAVALISSE
(N=50)

Placebo
(N=24)

n (%)

n (%)

n (%)

n (%)

Stable platelet response1,2

9 (18)

0 (0)

8 (16)

1 (4)

p3 = 0.03

NS

1 Includes all patients with platelet counts and excludes patients whose platelet counts were measured following rescue therapy after Week 10

2 Stable platelet response was prospectively defined as a platelet count of at least 50 x 109/L on at least 4 of the 6 visits between Weeks 14 and 24

3 p-value from Fisher Exact test
Adapted from TAVALISSE Prescribing Information

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

  • Sex: TAVALISSE worked similarly in men and women.
  • Race: Most of the patients were White. Differences in how well the drug worked among races could not be determined because of the small number of patients in other races.
  • Age: TAVALISSE worked similarly in patients younger and older than 65 years of age.

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

The tables below summarize efficacy results by sex, race and age. Racial subgroup differences were investigated between White race and all other races combined since the majority of patients were White.

Due to the small sample size, these exploratory analyses should be interpreted with caution.

Table 3. Subgroup Analyses of the Primary Efficacy Endpoint with Last Observation Carried Forward (LOCF) for Trial 1 (ITT Population)

Sub-group

Arm

Yes

# Pts

%Yes

Diff%
(TAVALISSE-placebo)

95% CI*

95% CI**

      
     Sex

Women

TAVALISSE

5

30

16.7

16.7

3.3, 30.0

-13.0, 44.5

Placebo

0

17

0.0

Men

TAVALISSE

4

21

19.0

19.0

2.3, 35.8

-22.0, 56.8

Placebo

0

8

0.0

    Race

Non- White

TAVALISSE

2

7

28.6

28.6

-4.9, 62.0

-35.3, 80.6

Placebo

0

4

0.0

White

TAVALISSE

7

44

15.9

15.9

5.1, 26.7

-10.6, 41.0

Placebo

0

21

0.0

 

 Age

<65>

TAVALISSE

6

32

18.8

18.8

5.2, 32.3

-10.3, 46.0

Placebo

0

18

0.0

≥65 years

TAVALISSE

3

19

15.8

15.8

-0.6, 32.2

-27.0, 57.8

Placebo

0

7

0.0

diff=Difference (TAVALISSE – Placebo)

* Interval based on Normal approximation, ** Exact interval

FDA Review

Table 4. Subgroup Analyses of the Primary Efficacy Endpoint with Last Observation Carried
Forward LOCF for Trial 2 (ITT Population)

Sub-group

Arm

Yes

# Pts

%Yes

Diff%
TAVALISSE-placebo)

95% CI*

95% CI**

Sex

Women

TAVALISSE

5

31

16.1

16.1
 

3.2, 29.1

-16.6, 46.8

Placebo

0

13

0.0

Men

TAVALISSE

4

19

21.1

12.0
 

-13.0, 37.0

-25.0, 46.5

Placebo

1

11

9.1

Race

White

TAVALISSE

9

50

18.0

13.8

0.5, 27.1

-10.9, 37.5

Placebo

1

24

4.2

Age

<65>

TAVALISSE

8

41

19.5

19.5
 

7.4, 31.6

-6.9, 44.4

Placebo

0

20

0.0

≥65 years

TAVALISSE

1

9

11.1

-13.9
 

-61.0, 33.3

-68.7, 43.4

Placebo

1

4

25.0

 diff=Difference (TAVALISSE – Placebo)

* Interval based on Normal approximation, ** Exact interval

FDA Review

What are the possible side effects?

TAVALISSE may cause serious side effects such as high blood pressure (hypertension), increased liver enzymes, decreased white blood cell count (neutropenia), and fetal harm.

The most commonly reported side effects are diarrhea, high blood pressure, nausea, respiratory infection, dizziness, increased liver enzymes, rash, abdominal pain, fatigue, chest pain and decreased white blood cell count.

What are the possible side effects (results of trials used to assess safety)?

The table below summarizes adverse reactions in the clinical trials.

Table 5. Incidence of Common (≥ 5%) Adverse Reactions from Clinical Trials 1 and 2 (Safety Population*)

Adverse Reaction

TAVALISSE
(N=102)

Placebo
(N=48)

Mild
%

Moderate
%

Severe
%

TOTAL
%

Mild
%

Moderate
%

Severe
%

TOTAL
%

Diarrhea1

21

10

1

31

13

2

0

15

Hypertension2

17

9

2

28

10

0

2

13

Nausea

16

3

0

19

8

0

0

8

Dizziness

8

2

1

11

6

2

0

8

ALT increased

5

6

0

11

0

0

0

0

AST increased

5

4

0

9

0

0

0

0

Respiratory infection3

7

4

0

11

6

0

0

6

Rash4

8

1

0

9

2

0

0

2

Abdominal pain5

5

1

0

6

2

0

0

2

Fatigue

4

2

0

6

0

2

0

2

Chest pain

2

3

1

6

2

0

0

2

Neutropenia6

3

2

1

6

0

0

0

0

ALT = Alanine aminotransferase AST = Aspartate aminotransferase

Note: Common adverse reactions defined as all adverse reactions occurring at a rate of ≥ 5% of patients in the TAVALISSE group and greater than placebo rate.

*The Safety Population differed from the ITT Population: One patient randomized to the placebo arm was assigned to the wrong treatment by mistake, and was treated with fostamatinib for 2 weeks. This patient’s efficacy data were analyzed with the placebo arm, but the safety data were analyzed with the fostamatinib arm.

1 Includes diarrhea and frequent bowel movement.

2 Includes hypertension, blood pressure (BP) increased, BP diastolic abnormal, and BP diastolic increased.

3 Includes upper respiratory tract infection, respiratory tract infection, lower respiratory tract infection, and viral upper respiratory tract infection.

4 Includes rash, rash erythematous and rash macular.

5 Includes abdominal pain, and abdominal pain upper.

6 Includes neutropenia and neutrophil count decreased.

TAVALISSE Prescribing Information

Were there any differences in side effects among sex, race and age?

  • Sex: The occurrence of side effects was similar in men and women.
  • Race: Most of the patients in the trials were White. Differences in the occurrence of side effects among races could not be determined, because of the small number of patients in other races.
  • Age: The occurrence of serious adverse events1 was higher in patients 65 years and older.

1Serious adverse event was defined as any event that resulted in one of the following: death, life-threatening event, required hospitalization or extended a current hospital stay, persistent or significant disability/incapacity, or congenital anomaly or birth defect

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

The tables below summarize adverse events (AE) by sex and age subgroups. Racial subgroup differences were not investigated because the majority of patients were White. 

Table 6. Pooled Analysis of Adverse Events by Sex (Safety Population)

 

TAVALISSE (n=102)

Placebo (n=48)

Women
(n=61)

Men
(n=41)

Women
(n=30)

Men
(n=18)

All AEs

52 (85.2%)

33 (75.0%)

24 (80.0%)

13 (72.2%)

 Serious AEs

8 (13.1%)

5 (12.2%)

8 (26.7%)

3 (16.7%)

  AEs leading to withdrawal

7 (11.5%)

3 (7.3%)

4 (13.3%)

0

  AEs leading to death

1 (<>

0

1 (3.3%)

0

Table 7. Pooled Analysis of Adverse Events by Age (Safety Population)

 

TAVALISSE (n=102)

Placebo (n=48)

<65>
(n=74)

≥65 years
(n=28)

<65>
(n=37)

≥65 years
(n=11)

All AEs

59 (79.7%)

26 (92.9%)

31 (83.8%)

6 (54.5%)

 Serious AEs

7 (9.5%)

6 (21.4%)

10 (27.0%)

1 (9.1%)

 AEs leading to withdrawal

5 (6.8%)

5 (17.9%)

2 (5.4%)

2 (18.2%)

 AEs leading to death

0

1 (3.6%)

0

1 (9.1%)

FDA Review

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved TAVALISSE based on evidence from two clinical trials, Trial 1 (NCT02076399) and Trial 2 (NCT02076412) of 150 patients with chronic ITP.

Trial 1 was conducted at 35 sites in the following countries: Australia, Canada, Denmark, Hungary, Italy, Netherlands, United Kingdom, and United States.

Trial 2 was conducted at 23 sites. In the following countries: Austria, Bulgaria, Czech Republic, Germany, Norway, Poland, Romania, and Spain.

Figure 1 summarizes how many men and women were in the clinical trials.

 Figure 1. Baseline Demographics by Sex

Pie chart summarizing how many men and women were in the clinical trials. In total, 59 men (39%) and  91 women (61%) participated in the trial.

FDA Review

Figure 2 summarizes the percentage of patients by race in the clinical trials.

Figure 2. Baseline Demographics by Race

Pie chart summarizing the percentage of patients by race in clinical trials. In total, 139 White (93%), 5 Asian (3%), 4 Black or African American (3%) and 2 Other (1%) race patients, participated in the clinical trials

 

Table 1. Baseline Demographics by Race


Race

Number of Patients

Percentage

White

139

93%

Asian

5

3%

Black or African American

4

3%

Other

2

1%

FDA Review

Figure 3 summarizes the percentage of patients by age in the clinical trials.

Figure 3. Baseline Demographics by Age

 Pie charts summarizing how many individuals of certain age groups were in the clinical trials. In total, 111 patients  were younger than 65 years (74%), and  39 patients were  65 years and older (26 %)

FDA Review

Who participated in the trials?

The table below summarizes demographics of patients that participated in both trials.

Table 8. Patient Demographics in Trials 1 and 2 Combined (ITT Population)

 

TAVALISSE
N=101
n(%)

Placebo
N=49
n(%)

Total
N=150
n(%)

Sex

   Women

61 (60%)

30 (61%)

91 (61%)

   Men

40 (40%)

19 (39%)

59 (39%)

Race

  White

94 (93%)

45 (92%)

139 (93%)

  Asian

3 (3%)

2 (4%)

5 (3%)

  Black or African  American

2 (2%)

2 (4%)

4 (3%)

  Other

2 (2%)

0

2 (1%)

Age (years)

  Median

54

54

54

  Range

22-88

20-78

20-88

Age Group

  < 65="">

73 (72%)

38 (78%)

111 (74%)

  ≥ 65 years

28 (28%)

11(22%)

39 (26%)

Ethnicity

 

 

 

  Hispanic

3 (3%)

1 (2%)

4 (3%)

  Non-Hispanic

98 (97%)

48 (98%)

146 (97%)

Country

  US

12 (12%)

8 (16%)

20 (13%)

  Non-US

89 (88%)

41 (84%)

130 (87%)

FDA Review

How were the trials designed?

The trials enrolled adult patients with immune thrombocytopenic purpura (ITP), whose prior treatment for ITP has not worked well enough. Patients were, however, allowed to continue previous ITP treatment during the trial.

All patients were randomly assigned to receive either TAVALISSE or placebo tablets twice daily for 24 weeks. After 4 weeks, the dose could be increased if necessary to reduce the risk of bleeding.

The benefit of TAVALISSE was assessed based on the percentage of patients who achieved and maintained the pre-determined platelet count between treatment weeks 14 to 24 in TAVALISSE and placebo groups respectively.

How were the trials designed?

FDA approved TAVALISSE based on data from two identical, randomized, placebo-controlled, multi-center trials in patients with persistent or chronic ITP, who had an insufficient response to previous treatment. Randomization was stratified for prior splenectomy and severity of thrombocytopenia and stable concurrent ITP therapy (glucocorticoids [< 20="" mg="" prednisone="" equivalent="" per="" day],="" azathioprine,="" or="" danazol)="" was="" allowed.="" in="" both="" trials,="" patients="" were="" randomized="" to="" receive="" tavalisse="" or="" placebo="" twice="" daily="" for="" 24="" weeks.="" to="" decrease="" the="" risk="" of="" bleeding,="" patients="" that="" did="" not="" respond="" to="" treatment="" after="" 4="" weeks="" underwent="" dose="">

In both trials, the primary endpoint was the stable platelet response (at least 50 x109/L on at least 4 of the 6 visits between Weeks 14 to 24).

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

PRESCRIBING INFORMATION

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