Efficacy and safety of the CRTh2 antagonist AZD1981 as add-on therapy to inhaled corticosteroids and long-acting β₂-agonists in patients with atopic asthma

Figures & data

Figure 1 Study design.

Note: Symbicort^® (budesonide/formoterol): AstraZeneca, Gothenburg, Sweden.
Abbreviations: R, randomization; pMDI, pressurized metered-dose inhaler.

Figure 2 Pattern of AZD1981 tablet formulation dispensed for the different treatment arms.

Abbreviations: BID, twice daily; QD, once daily.

Table 1 Patient demographics and baseline characteristics*

	AZD1981						Placebo (n=161)
	10 mg BID (n=163)	40 mg BID (n=162)	100 mg BID (n=166)	400 mg BID (n=164)	80 mg QD (n=164)	200 mg QD (n=161)
Mean age (years)	44.5	46.3	46.4	46.6	45.4	46.7	45.7
Female, n (%)	80 (49.1)	82 (50.6)	87 (52.4)	76 (46.3)	78 (47.6)	82 (50.9)	76 (47.2)
Race, n (%)
White	113 (69.3)	121 (74.7)	120 (72.3)	117 (71.3)	119 (72.6)	115 (71.4)	119 (73.9)
Black	3 (1.8)	1 (0.6)	5 (3)	5 (3)	2 (1.2)	6 (3.7)	4 (2.5)
Asian	32 (19.6)	25 (15.4)	29 (17.5)	27 (16.5)	32 (19.5)	26 (16.1)	24 (14.9)
Mean BMI, kg/m^2	27.8	28	27.8	27.4	26.4	27.4	26.8
Mean time since asthma diagnosis, years	17.3	18	18.6	18.6	18.3	18.5	17.5
Smoking status, n (%)
Never	144 (88.3)	136 (84)	152 (91.6)	139 (84.8)	143 (87.2)	137 (85.1)	146 (90.7)
Previous	19 (11.7)	26 (16)	14 (8.4)	25 (15.2)	21 (12.8)	24 (14.9)	15 (9.3)
IgE level, kU/L#
Median (range)	255 (3–5,193)	269 (8–13,886)	215 (3–17,058)	209 (11–11,208)	210 (3–19,450)	253 (5–8,002)	306 (3–9,215)
Mean	504	599	625	578	655	529	612
Mean eosinophil count, 10^9 cells/L (range)#	0.2996 (0–1.26)	0.3108 (0–1.54)	0.2791 (0.01–1.34)	0.2993 (0.01–2.03)	0.2673 (0–1.93)	0.2925 (0.02–4.47)	0.3207 (0.01–2.14)
Patients with Th2-high phenotype,‡ %	52	55	54	49	49	50	57

Notes:

* Based on the randomized-analysis set, which included the four subjects who did not receive treatment, but excluded GCP violations;

# based on the safety-analysis set, which excluded the four patients who did not receive treatment, but included GCP violations;

‡ Th2-high phenotype: blood eosinophil count ≥0.14×10⁹ cells/L and serum total IgE >100 kU/L.²⁹

Abbreviations: BID, twice daily; QD, once daily; BMI, body-mass index; Th, T helper; GCP, Good Clinical Practice.

Figure 3 Patient study flow.

Note: *Full-analysis set.
Abbreviations: BID, twice daily; QD, once daily; GCP, Good Clinical Practice.

Figure 4 Mean change from baseline.

Notes: (A) Morning predose, prebronchodilator forced expiratory volume in 1 second (FEV₁; primary efficacy end point) and (B) post-bronchodilator FEV₁. Data are mean changes from baseline to treatment average for the main analysis. Based on the full-analysis set, which excluded patients who did not receive treatment and patients with GCP violations.
Abbreviations: BID, twice daily; QD, once daily; GCP, Good Clinical Practice.

Figure 5 Mean change from baseline in the Asthma Control Questionnaire (ACQ)-5 score.

Notes: Data are mean changes from baseline to treatment average for the main analysis. Based on the full-analysis set, which excluded patients who did not receive treatment and patients with GCP violations.
Abbreviations: BID, twice daily; QD, once daily; GCP, Good Clinical Practice.

Table 2 Mean change from baseline in morning and evening and PEF and FEV₁ measured by the patient at home over 12 weeks of treatment*

	AZD1981; LS mean (95% CI)						Placebo
	10 mg BID	40 mg BID	100 mg BID	400 mg BID	80 mg QD	200 mg QD
Morning	n=162	n=161	n=164	n=163	n=164	n=159	n=160
PEF, L/min	0.36 (−6.44 to 7.16)	9.36 (2.54 to 16.18)	4.7 (−2.06 to 11.46)	5.80 (−0.99 to 12.59)	0.06 (−6.7 to 6.82)	0.6 (−6.26 to 7.47)	−1.65 (−8.49 to 5.18)
FEV1, L	−0.01 (−0.05 to 0.04)	0.05 (0–0.09)	0.03 (−0.01 to 0.08)	0.05 (0–0.09)	−0.02 (−0.07 to 0.02)	0 (−0.05 to 0.04)	0 (−0.04 to 0.05)
Evening	n=162	n=160	n=164	n=163	n=164	n=158	n=161
PEF, L/min	−2.93 (−9.88 to 4.02)	7.20 (0.21–14.19)	−0.2 (−7.11 to 6.71)	0.78 (−6.15 to 7.72)	−5.34 (−12.25 to 1.57)	−1.51 (−8.54 to 5.52)	0.27 (−6.69 to 7.24)
FEV1, L	−0.02 (−0.07 to 0.03)	0.03 (−0.02 to 0.08)	0.01 (−0.04 to 0.06)	0 (−0.05 to 0.05)	−0.05 (−0.09 to 0)	−0.02 (−0.07 to 0.03)	0.02 (−0.03 to 0.06)

Note:

* Based on the full-analysis set, which excluded patients who did not receive treatment and patients with GCP violations.

Abbreviations: BID, twice daily; QD, once daily; PEF, peak expiratory flow; FEV₁, forced expiratory volume in 1 second; GCP, Good Clinical Practice; LS, least squares.

Table 3 Cox regression analysis of time to treatment failure*

Comparison	n	Difference between groups
		HR	95% CI	P-value
AZD1981 10 mg BID vs placebo	163 vs 161	0.99	0.44–2.2	0.979
AZD1981 40 mg BID vs placebo	162 vs 161	0.82	0.35–1.89	0.634
AZD1981 100 mg BID vs placebo	164 vs 161	0.23	0.07–0.82	0.024
AZD1981 400 mg BID vs placebo	164 vs 161	0.31	0.1–0.98	0.045
AZD1981 80 mg QD vs placebo	164 vs 161	0.63	0.26–1.55	0.32
AZD1981 200 mg QD vs placebo	159 vs 161	0.73	0.31–1.74	0.48

Notes:

* Based on the full-analysis set, which excluded patients who did not receive treatment and patients with Good Clinical Practice violations. n = number of patients, first those in the AZD1981 treatment group then followed by those in the placebo group.

Abbreviations: BID, twice daily; QD, once daily; HR, hazard ratio.

Table 4 Summary of adverse events (AEs)*

AEs	AZD1981, n (%)						Placebo (n=163)
	10 mg BID (n=163)	40 mg BID (n=163)	100 mg BID (n=164)	400 mg BID (n=164)	80 mg QD (n=164)	200 mg QD (n=159)
Any AE#	56 (34.4)	49 (30.1)	46 (28)	46 (28)	40 (24.4)	46 (28.9)	49 (30.1)
Serious AE	0	0	3 (1.8)	0	1 (0.6)	1 (0.6)	1 (0.6)
Drug AE§	2 (1.2)	4 (2.5)	5 (3)	3 (1.8)	4 (2.4)	2 (1.3)	4 (2.5)
Ten most common AEs
Nasopharyngitis	10 (6.1)	5 (3.1)	7 (4.3)	4 (2.4)	9 (5.5)	10 (6.3)	6 (3.7)
Headache	2 (1.2)	3 (1.8)	7 (4.3)	2 (1.2)	4 (2.4)	7 (4.4)	2 (1.2)
Bronchitis	5 (3.1)	5 (3.1)	2 (1.2)	1 (0.6)	1 (0.6)	4 (2.5)	5 (3.1)
Pharyngitis	3 (1.8)	3 (1.8)	4 (2.4)	2 (1.2)	4 (2.4)	2 (1.3)	1 (0.6)
Asthma	4 (2.5)	2 (1.2)	4 (2.4)	2 (1.2)	3 (1.8)	0	3 (1.8)
Influenza	5 (3.1)	3 (1.8)	0	1 (0.6)	2 (1.2)	0	4 (2.5)
Sinusitis	3 (1.8)	0	2 (1.2)	1 (0.6)	2 (1.2)	2 (1.3)	1 (0.6)
Nausea	1 (0.6)	2 (1.2)	0	3 (1.8)	1 (0.6)	2 (1.3)	0
Respiratory tract infection	5 (3.1)	1 (0.6)	1 (0.6)	1 (0.6)	0	1 (0.6)	2 (1.2)
Upper respiratory tract infection	1 (0.6)	2 (1.2)	0	2 (1.2)	2 (1.2)	2 (1.3)	2 (1.2)

Notes:

* Based on safety-analysis set, which excluded the four patients who did not receive treatment, but included Good Clinical Practice violations;

# patients who had at least one AE.

§ Leading to study-drug discontinuation.

Abbreviations: BID, twice daily; QD, once daily.

Table S1 Institutional review boards and ethics committees by country

Argentina	Comité Independiente de Etica
	Comité Independiente Etica Ensayos Farmacología Clínica
	Comité de Etica e Investigación
Brazil	Comitê de Ética em Pesquisa Pontifícia Universidade
	Católica do Rio Grande do Sul
	Comité de Etica em Pesquisa em Seres Humanos
	Comitê de Ética em Pesquisa em Seres Humanos da
	Faculdade de Medicina do ABC
	Comité Etica da Universidade Federal de Santa Catarina,
	Universidade Federal de Santa Catarina
	Comité de Etica do Hospital Emilio Ribas
	Comitê de Ética em Pesquisa da Santa Casa de Misericordia
	de Belo Horizonte
	Instituto Evandro Chagas em Pesquisa da Santa Casa de
	Misericórdia de Porto Ale
	CEP Hospital Universitário de Juiz de Fora
	Comité de Etica em Pesquisa da Centro Integrado de
	Atenção a Saúde Unimed Vitoria
	Instituto Evandro Chagas em Pesquisa do Hospital Clínicas
	da Faculdade Medicina da Universidade de Sao Paulo
Japan	Oji General Hospital
	Koizumi Clinic of Respiratory and Internal Medicine
	Tokyo Eki Center Building Clinic
	Yokohama City Minato Red Cross Hospital
	Ibaraki-higashi National Hospital Organization
	Kawai Chest Clinic
	Nakatani Hospital
	Hiroshima Allergy and Respiratory Clinic
	Sakaide City Hospital
	Oita Central Institutional Review Board
	Seiwa-kai Nagata Hospital
	National Hospital Organization Kochi National Hospital
	Nihonbashi Sakura Clinic
	National Hospital Organization Asahikawa Medical Center
	Kitahiroshima Chuo Clinic
	Kobori Clinic
	Matsue City Hospital
	Kyosokai Medical Cooperation Adventist Medical Centre
	Nishi-Umeda Clinic
	Nihonbashi Sakura Clinic
	Medical Corporation Shintoukai Yokohama Minoru Clinic
	Nihon University Hospital
	Kobori Clinic
	Kitahiroshima Central Clinic
	Takahashi Internal Medicine and Respiratory Clinic
	National Hospital Organization Fukuyama Medical Center
	Osaka Pharmacology Clinical Research Hospital
Mexico	Comité de Bioética y Biosegu en Investigación del Grupo
	Christus Muguerza
	Comité de Bioética del Instituto de Ciencias Biomédicas
	Angele
	Comité de Ética del Hospital Ángeles Tijuana
	Comité de Ética del Instituto Jaliscience de Investigación
	Clinica
	IEC Comité Indepen de Etica Investigación y
	Bioseguridad Bajio
Romania	Comisia Nationala de Etica Studiul Clinic al Medicamentului
Russian	Central Clinical Hospital
Federation	Moscow Medicine and Dentistry Clinical Hospital
	Municipal Clinical Emergency Hospital 2
	First Pavlov State Medical University of St Petersburg
	St George Hospital
	GP GNTs Institute of Immunology of Federal Biomedical
	Agency
	Moscow Hospital
	North Ossetian State Medical Academy
	Novosibirsk Regional Clinical Hospital
	Novosibirsk State Medical University
	St Petersburg Polyclinic
	Ural State Medical Academy
	Inter-VUZ Ethics Committee
Slovakia	Banskobystrickeho Samospravneho Kraja
	Bratislavskeho Samospravneho Kraja
	Kosickeho Samospravneho Kraja
	Nitrianskeho Samospravneho Kraja
	Presovskom Samospravnom Kraji
	Trencianskom samospravnom Kraji
	Trnavskeho Samospravneho Kraja
	Ustredna Vojenska Nemocnica (Central Military Hospital)
	Ruzomberok
	Zilinskeho Samospravneho Kraja
	Fakultna Nemocnica s Poliklinikou FD Roosevelta
South	Pharma Ethics
Africa	Groote Schuur Hospital
Ukraine	Central Ethics Committee of the Ministry of Health
USA	Western Institutional Review Board

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