The development of AZD7624 for prevention of exacerbations in COPD: a randomized controlled trial

Figures & data

Figure 1 (A) isPLA of phosphorylated p38α in alveolar macrophages of lung tissue from COPD patients and controls. Data are representative of two experiments. (B) AZD7624 inhibition of LPS-stimulated pro-inflammatory cytokine TNF-α in human alveolar macrophages. Data are presented as mean ± SEM of n=4. AZD7624 attenuation of (C) sputum neutrophil % differential and (D) TNF-α changes from baseline compared with placebo in the human LPS challenge study. Data are presented as mean ± SEM of 24–27 subjects per treatment group. ^ap<0.001 vs placebo.

Abbreviations: isPLA, in situ proximity ligation assay; LPS, lipopolysaccharide; SEM, standard error of the mean; TNF-α, tumor necrosis factor-α.

Table 1 Adverse events, Proof of Mechanism studya

Variableb	AZD7624	Placebo	Total
	(n=27)	(n=24)	(N=30)
Participants with any AE	6 (22.2)	9 (37.5)	13 (43.3)
Gastrointestinal disorders	1 (3.7)	0	1 (3.3)
Dry mouth	1 (3.7)	0	1 (3.3)
General disorders and administration site conditions	0	3 (12.5)	3 (10.0)
Influenza-like illness	0	1 (4.2)	1 (3.3)
Pyrexia	0	2 (8.3)	2 (6.7)
Infections and infestations	2 (7.4)	2 (8.3)	4 (13.3)
Folliculitis	0	1 (4.2)	1 (3.3)
Upper respiratory tract infection	2 (7.4)	1 (4.2)	3 (10.0)
Injury, poisoning, and procedural complications	0	1 (4.2)	1 (3.3)
Arthropod bite	0	1 (4.2)	1 (3.3)
Nervous system disorders	1 (3.7)	2 (8.3)	3 (10.0)
Dizziness	0	1 (4.2)	1 (3.3)
Headache	0	1 (4.2)	1 (3.3)
Presyncope	1 (3.7)	0	1 (3.3)

Notes: Data are shown as number (%) of participants.

a The safety analysis included patients who received a drug during the treatment period.

b Events were coded according to preferred terms in MedDRA, a standardized dictionary for clinical trials.³⁸

Abbreviation: AE, adverse event.

Table 2 Baseline demographics, COPD Proof of Principle study

Characteristic	AZD7624 1.0 mg	Placebo
	(n=107)d	(n=105)
Age (years)	65.4±8.7	64.2±8.7
Female gender	40 (37.4)	36 (34.3)
BMI (kg/m^2)	27.9±5.9	27.5±5.4
Ethnicity
White	85 (79.4)	88 (83.8)
Black	7 (6.5)	2 (1.9)
Native American	3 (2.8)	4 (3.8)
Other	12 (11.2)	11 (10.5)
Peripheral oxygen saturation (%)	95.6±2.2	95.9±2.0
Former smoker	66 (61.7)	73 (69.5)
Pre-bronchodilator FEV1 (L)	1.14±0.48	1.15±0.46
Post-bronchodilator FEV1 (L)	1.22±0.49	1.29±0.50
Predicted post-bronchodilator FEV1 (%)	44.5±15.6	44.5±14.9
COPD severity (GOLD)a
GOLD 2	22 (20.6)	20 (19.0)
GOLD 3	49 (45.8)	46 (43.8)
GOLD 4	35 (32.7)	39 (37.1)
Exacerbations in the past 12 months
2	79 (73.8)	81 (77.0)
3	21 (19.6)	11 (10.5)
>3	6 (5.6)	11 (10.5)
SGRQ-Cb	56.5±0.1	60.4±18.4
BDIc	5.3±2.2	5.6±2.0
Concomitant LAMA	41 (38.3)	40 (38.1)

Notes: Data are shown as mean ± SD or n (%).

a The severity of COPD was determined on the basis of the 2015 GOLD grading of airflow limitation in patients with FEV₁/FVC <0.70 using post-bronchodilator spirometry, based on which GOLD 2: moderate with 50% <FEV₁ <80% of predicted, GOLD 3: severe with FEV₁ <50% predicted, and GOLD 4: very severe with FEV₁ <30% predicted.

b Scores on the SGRQ-C range from 0 to 100, with higher scores indicating worse health status.

c The BDI assesses breathlessness in patients with COPD. Scores range from 0 to 12. The lower the score, the worse the severity of dyspnea.

d One patient was excluded from the analysis following a review of protocol deviations owing to a lack of source data and Good Clinical Practice compliance.

Abbreviations: BDI, Baseline Dyspnea Index; BMI, body mass index; GOLD, Global Initiative for Chronic Obstructive Lung Disease; LAMA, long-acting muscarinic antagonist; SGRQ-C, St George’s Respiratory Questionnaire for COPD Patients.

Figure 2 Patient disposition. ^aInformed consent received. ^bOne patient was excluded from the analysis following review of protocol deviations owing to a lack of source data and Good Clinical Practice compliance. ^cPatient withdrawal recorded as “other” by study site investigators; one patient was unable to complete the study visits owing to terminal illness of family member; another patient was withdrawn by the study site investigator after a reassessment of patient eligibility (on day 4 after randomization). ^dCompletion status of two patients was not recorded.

Table 3 Key secondary endpoints, COPD Proof of Principle study

Secondary endpoint	AZD7624 1.0 mg (n=107a)	Placebo (n=105)	AZD7624 vs placebo
	Change from baseline	Change from baseline	p-valueb
Number of ExDo events	40	29	0.25
Number of moderate or severe exacerbations	38	24	0.13
Number of moderate or severe exacerbations according to Anthonisen criteria fulfilled	17	15	0.75
Number of symptom-defined exacerbations as defined by EXACT daily dairy	42	50	0.44
Post-bronchodilator FEV1 (L)	−0.003 (0.26)	−0.03 (0.23)	0.51
Post-bronchodilator FVC (L)	−0.045 (0.40)	−0.018 (0.39)	0.05
FEV1/FVC	0.04 (0.06)	−0.007 (0.05)	0.15
SGRQ-C	−4.0 (19.6)	−5.1 (17.8)	0.52
TDI	1.6 (3.2)	1.7 (3.2)	0.49
EXACT E-RS	−0.2 (6.4)	−0.2 (6.3)	0.55
Use of reliever medication (average puffs per day)	−0.13 (2.27)	−0.29 (2.12)	0.22
Night-time awakenings (% of days during a 2-week period)	−8.98 (32.53)	−11.65 (33.90)	0.66
Secondary endpoint	AZD7624 (n=107a) vs placebo (n=105)
	HR	95% CI	p-valueb
Time to first moderate or severe exacerbations according to Anthonisen criteria fulfilled	0.93	0.43, 2.01	0.85
Time to symptom-defined exacerbations as defined by EXACT daily dairy	0.86	0.54, 1.38	0.54

Notes:

a One patient was excluded from the analysis following a review of protocol deviations owing to a lack of source data and Good Clinical Practice compliance.

b Mixed-effects repeated measures analysis, fitting treatment, country, LAMA maintenance treatment, visit, gender, smoking history, and treatment by visit interaction as fixed effects; patient as a random effect; and baseline assessment, age, BMI, and height as continuous covariates.

Abbreviations: BMI, body mass index; E-RS, Evaluating Respiratory Symptoms; ExDo, time to first event of moderate or severe COPD exacerbations or early dropout related to worsening of COPD symptoms; EXACT, EXAcerbations of Chronic pulmonary disease Tool; LAMA, long-acting muscarinic antagonist; SGRQ-C, St George’s Respiratory Questionnaire for COPD Patients; TDI, Transition Dyspnea Index.

Figure 3 (A) Time to first event of ExDo (HR =1.39, 95% CI 0.81, 2.40; p=0.24). (B) Time to first moderate or severe COPD exacerbation (HR =1.53, 95% CI 0.85, 2.76; p=0.15). (C) Time to first event of ExDo ≤2% eosinophils (HR =0.93, 95% CI 0.42, 2.05; p=0.85). (D) Time to first event of ExDo >2% eosinophils (HR =2.20, 95% CI 0.95, 5.09; p=0.07).

Abbreviation: ExDo, time to first event of moderate or severe COPD exacerbations or early dropout related to worsening of COPD symptoms.

Table 4 AEs and serious AEs, COPD Proof of Principle studya

Variableb	AZD7624 1.0 mg	Placebo	Total
	(n=108)	(n=105)	(N=213)
Participants with ≥1% AEs	71 (65.7)	48 (45.7)	119 (55.9)
AE that occurred in ≥2% of either treatment group
COPD	31 (28.7)	23 (21.9)	54 (25.4)
Cough	8 (7.4)	2 (1.9)	10 (4.7)
Dyspnea	8 (7.4)	4 (3.8)	12 (5.6)
Dysgeusia	5 (4.6)	1 (1.0)	6 (2.8)
Influenza	5 (4.6)	3 (2.9)	8 (3.8)
Back pain	4 (3.7)	1 (1.0)	5 (2.3)
Bronchitis	4 (3.7)	2 (1.9)	6 (2.8)
Nasopharyngitis	4 (3.7)	4 (3.8)	8 (3.8)
Fatigue	3 (2.8)	0	3 (1.4)
Hypertension	3 (2.8)	2 (1.9)	5 (2.3)
Productive cough	3 (2.8)	0	3 (1.4)
Asthenia	2 (1.9)	4 (3.8)	6 (2.8)
Sinusitis	1 (0.9)	3 (2.9)	4 (1.9)
Peripheral edema	0	3 (2.9)	3 (1.4)
Pain in extremity	0	3 (2.9)	3 (1.4)
Serious AE	11 (10.2)	11 (10.5)	22 (10.3)
Death	1 (0.9)	0	1 (0.5)
Participants who discontinued because of an AE	9 (8.3)	4 (3.8)	13 (6.1)

Notes: Data are shown as number (%) of participants.

a The safety analysis included patients who received a drug during the treatment period.

b Events were coded according to preferred terms in MedDRA, a standardized dictionary for clinical trials.³⁸

Abbreviation: AE, adverse event.

MedDRA [webpage on the Internet]Medical Dictionary for Regulartory Activities; 2014: version 17.0 Available from: https://www.meddra.org/how-to-use/support-documentation/englishAccessed February 1, 2018

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