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Drug Trials Snapshots ADAKVEO

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 ADAKVEO Package Insert for complete information.

ADAKVEO (crizanlizumab-tmca)
ah dak vee oh
Novartis Pharmaceuticals Corporation
Approval date: November 15, 2019


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

ADAKVEO is used to reduce the frequency of certain crises episodes (called vaso-oclusive crises) in patients 16 years of age and older who have sickle cell disease.

Sickle cell is an inherited blood disorder in which the red blood cells are abnormally shaped (in a crescent or "sickle" shape). Vaso-oclusive crisis (VOC) is a common and painful complication of sickle cell disease that occurs when blood circulation is obstructed by sickled red blood cells leading to severe pain and organ damage.

How is this drug used?

ADAKVEO is given by a healthcare provider directly into the vein (intravenous infusion) over 30 minutes. First two infusions are given 2 weeks apart followed by an infusion every 4 weeks thereafter.

What are the benefits of this drug?

Patients treated with ADAKVEO experienced fewer health care visits for VOC per year (about 1.63 visits), compared to patients who received a placebo (about 2.98 visits).

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

Efficacy of ADAKVEO was evaluated by the annual rate of VOCs leading to a healthcare visit. A healthcare visit is defined as an acute episode of pain with no cause other than a VOC event that required a patient be taken to a medical facility and was treated with oral or parenteral opioids, or parenteral NSAIDs.

Table 1. Efficacy Results from Trial 1 in Sickle Cell Diseasea

Event

ADAKVEOb

(n = 67)

Placebob
    (n = 65)

Treatment Difference Estimatec

Annual rate of VOCa

1.63

2.98

HL = -1.01, (-2.00, 0.00)

Annual rate of days hospitalized

4

6.87

 

 

HL, hodges-lehmann; VOC, vasoocclusive crisis
aVOCs were as assessed by an independent review committee
bStandard median
cHL median difference [95% confidence interval (CI)]

ADAKVEO Prescribing Information

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

  • Sex: ADAKVEO worked similarly in males and females.
  • Race: The majority of patients were Black or African Americans. The number of patients in other races were limited; therefore, differences in how ADAKVEO worked among races could not be determined.
  • Age: The majority of patients were adults between 18-63 years of age. There were not enough patients older than 65 years to determine whether there was any difference in how ADAKVEO worked between older and younger patients.

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

Subgroup efficacy analysis was performed only on sex groups because most patients were Black or African Americans between 18-63 years of age.

Table 2. Primary Endpoint Analysis by Sex (Intent-to-Treat population-ITT)

ITT Population

ADAKVEO (N=67)

Placebo (N=65)

Male, n (%)

32 (47.8)

27 (41.5)

Standard median

2.50

2.00

1Median difference, (95% CI)

-0.02, (-1.98, 1.02)

---

Female, n (%)

35 (52.2)

38 (58.5)

Standard median

1.18

3.00

1Median difference, (95% CI)

-1.93, (-3.00, -0.75)

---

Adapted from FDA Review

What are the possible side effects?

ADAKVEO may cause serious infusion-related reactions and platelet clumping.

Most common side effects of ADAKVEO include nausea, joint pain, back pain and fever.

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

The table below summarizes adverse reaction in the Trial 1.

Table 3. Adverse Reactions (≥ 10%) in Patients Receiving ADAKVEO With a Difference Between Arms of > 3% Compared to Placebo in Trial 1

 

 

Adverse Reactions

ADAKVEO
N = 66
n (%)

Placebo
N = 62
n (%)

All Grades

Grade ≥ 3

All Grades

Grade ≥ 3

 Gastrointestinal Disorders

  Nausea

12 (18)

0

7 (11)

1 (2)

 Musculoskeletal and Connective Tissue

  Arthralgia

12 (18)

1 (2)

5 (8)

1 (2)

  Back pain

10 (15)

0

7 (11)

0

 General Disorders and Administration Site

  Pyrexia

7 (11)

1 (2)

4 (7)

0

ADAKVEO Prescribing Information

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

  • Sex: The occurrence of side effects was similar between males and females.
  • Race: The majority of patients were Black or African Americans. The number of patients in other races were limited; therefore, differences in how ADAKVEO worked among races could not be determined.
  • Age: The majority of patients were adults between 18-63 years of age. There were not enough patients older than 65 years to determine whether there was any difference in side effects between older and younger patients.

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

Subgroup differences in adverse events between males and females is presented below. Race and age subgroups were not analyzed because most of the patients were Black or African Americans and between 18-63 years of age.

Table 4. Adverse Events by Sex

 

 Adverse Event

Safety Population
N=128

 

                       Male

                     Female

 

ADAKVEO
N=32

Placebo
N=26

ADAKVEO
N=34

Placebo (n=36)

 Any TEAE, n (%)

26 (81.3)

23 (88.5)

31 (91.2)

32 (88.9)

 ≥ Grade 3, n (%)

7 (21.9)

5 (19.2)

5 (14.7)

7 (19.4)

 SAE, n (%)

8 (25)

5 (19.2)

9 (26.5)

12 (33.3)

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved ADAKVEO based on evidence from one clinical trial (Trial 1/NCT01895361) of 132 patients with SS diseases who had a history of VOC. The trial was conducted at 60 sites in the United States, Brazil and Jamaica.

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

Figure 1. Baseline Demographics by Sex

Pie chart summarizing how many men and women were in the clinical trial. In total, 73 women (55%) and 59 men (45%) participated in the clinical trial.

FDA Review

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

Figure 2. Baseline Demographics by Race

Pie chart summarizing the percentage of patients by race enrolled in the clinical trial. In total, 7 White (4%), Black or African American 120 (91%) and Other 5 (4%)

FDA Review

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

Figure 3. Baseline Demographics by Age

Pie charts summarizing how many individuals of certain age groups were enrolled in the clinical trial. In total,  88 (67%) were 16-25 years, and 44 (33%) of patients were 25-63 years and older.)

FDA Review

Who participated in the trials?

Demographics of trial participants are presented below.

Table 5. Baseline Demographics (Efficacy Population-ITT)

 

Demographic Parameters

ADAKVEO
(N= 67)
n (%)

Placebo (N=65)
n (%)

TOTAL
(N=132)
n (%)

Sex

 

 

 

Male

32 (47.8)

27 (41.5)

59 (44.7)

Female

35 (52.2)

38 (58.5)

73 (55.3)

Race

 

 

 

Black or African American

60 (89.5)

60 (92.3)

120 (91)

White

4 (6)

3 (4.6)

7 (5.3)

Other1

3 (4.5)

2 (3.1)

5 (3.7)

Age

 

 

 

Mean years (SD)

30.9 (10.89)

29. 3 (10.36)

30.1 (10.6)

Median (years)

29

26

28

Min, max (years)

16, 63

16, 56

16,63

Age Group

 

 

 

16-25 years

47 (70.1)

41 (63.1)

88 (66.7)

25-63 years

20 (29.9)

24 (36.9)

44 (33.3)

Ethnicity

 

 

 

Hispanic or Latino

20 (29.9)

11 (16.9)

31(23.5)

Not Hispanic or Latino

45 (67.2)

53 (81.5)

98 (74.2)

Unknown

2 (3)

1 (1.5)

3 (2.3)

Region

 

 

 

US

46 (68.7)

53 (81.5)

99 (75)

Brazil/Jamaica

21 (31.3)

12 (18.5)

33 (25)

1Includes Mixed and Multiracial

Adapted from FDA Review

How were the trials designed?

There was one trial that evaluated the benefit and side effects of ADAKVEO in patients with SS disease. Patients had to have a history of 2-10 VOCs in the previous 12 months. Patients received at random either ADAKVEO or placebo infusions. The first two infusions were given 2 weeks apart followed by an infusion every 4 weeks. Trials lasted 52 weeks. Nether the patients not the healthcare providers knew which treatment had been given until the end of the trial.

The benefit of ADAKVEO was assessed by counting the number of VOCs healthcare visits that required pain treatments over a 1-year period.

How were the trials designed?

The efficacy and safety of ADAKVEO were evaluated in patients with sickle cell disease in a 52-week, randomized, multicenter, placebo-controlled, double-blind trial. Patients had various SS genotypes (HbSS, HbSC, HbS/beta0-thalassemia, HbS/beta+-thalassemia, and others), and a history of 2-10 VOCs in the previous 12 months. Patients received ADAKVEO or placebo administered over a period of 30 minutes by intravenous infusion on Week 0, Week 2, and every 4 weeks thereafter for a treatment duration of 52 weeks.

Efficacy was evaluated by the annual rate of VOCs leading to a healthcare visit defined as an acute episode of pain with no cause other than a vaso-occlusive event that required a medical facility visit and treatment with oral or parenteral opioids, or parenteral NSAIDs.

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.

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