14 CLINICAL STUDIES

The asthma development program for CINQAIR 3 mg/kg (administered once every 4 weeks) included 4 randomized, double-blind, placebo-controlled studies (Studies I-IV) 16 to 52 weeks in duration involving 981 patients 12 years of age and older. While patients aged 12 to 17 years were included in these trials, CINQAIR is not approved for use in this age group [see Use in Specific Populations (8.4)]. All subjects continued their background asthma therapy throughout the duration of the studies.

Studies I and II

Studies I and II were 52-week studies in 953 patients with asthma who were required to have a blood eosinophil count of at least 400/mcL (within 3 to 4 weeks of dosing), and at least 1 asthma exacerbation requiring systemic corticosteroid use over the past 12 months. The majority of patients (82%) were on medium-high dose inhaled corticosteroids plus a long-acting beta agonist (ICS/LABA) at baseline. Maintenance oral corticosteroids (OCS) (up to 10 mg of prednisone per day or equivalent) were allowed; 106 (11%) patients were on OCS at baseline. CINQAIR 3 mg/kg administered once every 4 weeks for a total of 13 doses was evaluated compared with placebo.

Study III

Study III was a 16-week study in 315 patients who were required to have a blood eosinophil count of at least 400/mcL at screening (within 3 to 4 weeks of dosing). Maintenance OCS were not allowed. CINQAIR 3 mg/kg or 0.3 mg/kg administered once every 4 weeks for a total of 4 doses was evaluated compared with placebo. While 2 doses of CINQAIR were studied, CINQAIR 3 mg/kg is the only recommended dose [see Dosage and Administration (2.1)].

Study IV

Study IV was a 16-week study in 496 patients unselected for baseline blood eosinophil levels (approximately 80% of patients had a screening [within 3 to 4 weeks of dosing] blood eosinophil count of less than 400/mcL). Maintenance OCS were not allowed. CINQAIR 3 mg/kg administered once every 4 weeks for a total of 4 doses was evaluated compared with placebo.

The demographics and baseline characteristics of these 4 studies is provided in Table 1.

Table 1: Demographics and Baseline Characteristics of Patients in Asthma Studies

	Study I (N=489)	Study II (N=464)	Study III (N=315)	Study IV (N=496)
* Baseline for lung function and eosinophil count is the day of randomization.
Mean age (yr)	47	47	44	45
Female (%)	63	63	58	64
White (%)	73	73	81	67
Duration of asthma, mean (yr)	19	18	20	26
Baseline Pre-bronchodilator FEV1, mean % predicted*	64	69	70	67
Baseline Reversibility, mean % ΔFEV1 post-SABA*	26	28	25	26
Baseline mean blood eosinophil count/mcL*	660	649	614	280
Mean number of exacerbations in previous year	1.99	1.94	2.03	1.86

FEV1=forced expiratory volume in 1 second; SABA=short-acting beta agonist.

All patients had to be on inhaled corticosteroid (ICS) background therapy and could have been receiving any combination of background therapies (ICS with or without another controller [non-ICS and/or OCS]).

Exacerbations

The primary endpoint for Studies I and II was the frequency of asthma exacerbations for each patient during the 52-week treatment period. An asthma exacerbation was defined as a worsening of asthma that required at least 1 of the following medical interventions:

1) Either the use of a systemic corticosteroid, or ≥ 2-fold an increase in the use of ICS for 3 or more days, and/or

2) Asthma-related emergency treatment including at least 1 of the following: an unscheduled visit to their healthcare professional for nebulizer treatment or other urgent treatment to prevent worsening of asthma symptoms; a visit to the emergency room for asthma-related treatment; or an asthma-related hospitalization.

The medical intervention had to be corroborated with at least 1 of the following: 1) a decrease in forced expiratory volume in 1 second (FEV1) by 20% or more from baseline, 2) a decrease in peak expiratory flow rate (PEFR) by 30% or more from baseline on 2 consecutive days, or 3) worsening of symptoms or other clinical signs per physician evaluation of the event.

In Studies I and II, patients receiving CINQAIR 3 mg/kg administered once every 4 weeks had significant reductions in the rate of all asthma exacerbations compared to placebo (Table 2). Exacerbations requiring the use of a systemic corticosteroid (e.g., OCS) as well as exacerbations resulting in hospitalization or an emergency room visit were each reduced with CINQAIR 3 mg/kg.

Table 2: Frequency of Asthma Exacerbations during the 52-Week Treatment Period in Patients with Severe Asthma with an Eosinophilic Phenotype (Studies I and II)*
	Treatment Arm	Asthma Exacerbation Rate	Rate Ratio (95% CI)
* Randomized patients
All exacerbations
Study I	CINQAIR 3 mg/kg (n=245)	0.90	0.5 (0.37, 0.67)
Study I	Placebo (n=244)	1.80	0.5 (0.37, 0.67)
Study II	CINQAIR 3 mg/kg (n=232)	0.86	0.41 (0.28, 0.59)
Study II	Placebo (n=232)	2.11	0.41 (0.28, 0.59)
Exacerbations requiring systemic corticosteroid use
Study I	CINQAIR 3 mg/kg (n=245)	0.72	0.45 (0.33, 0.62)
Study I	Placebo (n=244)	1.60	0.45 (0.33, 0.62)
Study II	CINQAIR 3 mg/kg (n=232)	0.65	0.39 (0.27, 0.58)
Study II	Placebo(n=232)	1.66	0.39 (0.27, 0.58)
Exacerbations resulting in a hospitalization and/or emergency room visit
Study I	CINQAIR 3 mg/kg (n=245)	0.14	0.66 (0.32, 1.36)
Study I	Placebo(n=244)	0.21	0.66 (0.32, 1.36)
Study II	CINQAIR 3 mg/kg (n=232)	0.03	0.69 (0.29, 1.65)
Study II	Placebo (n=232)	0.05	0.69 (0.29, 1.65)

The proportion of patients who did not experience an asthma exacerbation during the 52-week treatment period was higher in the CINQAIR 3 mg/kg group (62% and 75%) compared with the placebo group (46% and 55%), in Studies I and II, respectively. The time to first asthma exacerbation was significantly longer for the groups receiving CINQAIR 3 mg/kg compared with placebo in both Studies I and II. A representative figure from Study I is shown below (Figure 1). Study II showed similar results.

Figure 1: Time to First Asthma Exacerbation by Treatment Group in Patients with Severe Asthma with an Eosinophilic Phenotype (Study I)

Lung Function

The effect of CINQAIR 3 mg/kg administered once every 4 weeks on FEV1 over time relative to placebo was assessed in all 4 studies (Table 3). FEV1 was the primary endpoint in the 16-week lung function studies: Study III (Figure 2) and Study IV.

Study III also studied a lower dose, CINQAIR 0.3 mg/kg, that produced significant but numerically smaller changes in FEV1 and blood eosinophil reduction compared with the 3 mg/kg dose. While 2 doses of CINQAIR were studied, CINQAIR 3 mg/kg is the only recommended dose [see Dosage and Administration (2.1)].

Study IV was the only study to test CINQAIR 3 mg/kg in asthma patients unselected for blood eosinophils (measured 3 to 4 weeks prior to dosing); association of treatment effect (i.e., difference between CINQAIR and placebo in the change in FEV1 at Week 16) and baseline blood eosinophils was not observed.

Table 3: Mean Change (95% CI) from Baseline in FEV1 in mL Over 16 Weeks (Difference from CINQAIR and Placebo) in Patients with Severe Asthma with an Eosinophilic Phenotype

* Study IV studied asthma patients unselected for blood eosinophils
Study	FEV1 Change in mL
Study I	137 (76, 198)
Study II	93 (30, 155)
Study III	160 (60, 259)
Study IV*	76 (-6,158)

Improvements in FEV1 were observed at 4 weeks following the first dose of CINQAIR for Studies I and II and maintained through Week 52.

Figure 2: Mean Change from Baseline in FEV1 in Patients with Severe Asthma with an Eosinophilic Phenotype (Study III)

The Asthma Control Questionnaire-7 (ACQ-7) and Asthma Quality of Life Questionnaire (AQLQ) were both assessed in Studies I, II, and III. The responder rate for both measures was defined as an improvement in score of 0.5 or more as threshold over 16 weeks.

For ACQ-7, the responder rate for those randomized to CINQAIR vs. placebo was 69% vs. 65% for Study I, 70% vs. 58% for Study II, and 64% vs. 58% for Study III.
For AQLQ, the responder rate for those randomized to CINQAIR vs. placebo was 66% vs. 58% for Study I, 67% vs. 55% for Study II, and 64% vs. 48% for Study III.