Trial Outcomes & Findings for Study of Aclidinium Bromide/Formoterol Fumarate Compared With Salmeterol/Fluticasone Propionate in Patients With Chronic Obstructive Pulmonary Disease (COPD) (NCT NCT01908140)
NCT ID: NCT01908140
Last Updated: 2016-03-07
Results Overview
Peak FEV1 define at the highest value observed in the 3h after the morning IMP administration
Recruitment status
COMPLETED
Study phase
PHASE3
Target enrollment
933 participants
Primary outcome timeframe
At Week 24
Results posted on
2016-03-07
Participant Flow
This study was conducted at 140 activated sites. A total of 121 sites randomised patients. The first patient was screened in Oct 2013 and the last patient visit was in Aug 2014.
Patients fulfilling inclusion/exclusion criteria at the time of the screening visit were entered into a run-in period of 14-21 days to assess disease stability.
Participant milestones
| Measure |
Aclidinium Bromide / Formoterol Fumarate
Experimental: Aclidinium Bromide / Formoterol Fumarate Aclidinium Bromide 400 μg / Formoterol Fumarate 12 μg BID for 24 Weeks
|
Salmeterol / Fluticasone
Active Comparator: Salmeterol / Fluticasone propionate Salmeterol 50 μg / Fluticasone propionate 500 μg BID for 24 Weeks
|
|---|---|---|
|
Overall Study
STARTED
|
468
|
465
|
|
Overall Study
COMPLETED
|
402
|
386
|
|
Overall Study
NOT COMPLETED
|
66
|
79
|
Reasons for withdrawal
| Measure |
Aclidinium Bromide / Formoterol Fumarate
Experimental: Aclidinium Bromide / Formoterol Fumarate Aclidinium Bromide 400 μg / Formoterol Fumarate 12 μg BID for 24 Weeks
|
Salmeterol / Fluticasone
Active Comparator: Salmeterol / Fluticasone propionate Salmeterol 50 μg / Fluticasone propionate 500 μg BID for 24 Weeks
|
|---|---|---|
|
Overall Study
Other or Progressive Disease
|
5
|
12
|
|
Overall Study
Lack of Efficacy
|
7
|
5
|
|
Overall Study
Withdrawal by Subject
|
23
|
24
|
|
Overall Study
Lost to Follow-up
|
1
|
6
|
|
Overall Study
Protocol Violation
|
8
|
9
|
|
Overall Study
Adverse Event
|
22
|
23
|
Baseline Characteristics
Study of Aclidinium Bromide/Formoterol Fumarate Compared With Salmeterol/Fluticasone Propionate in Patients With Chronic Obstructive Pulmonary Disease (COPD)
Baseline characteristics by cohort
| Measure |
Aclidinium Bromide / Formoterol Fumarate
n=467 Participants
Experimental: Aclidinium Bromide / Formoterol Fumarate Aclidinium Bromide 400 μg / Formoterol Fumarate 12 μg BID for 24 Weeks
|
Salmeterol / Fluticasone
n=466 Participants
Active Comparator: Salmeterol / Fluticasone propionate Salmeterol 50 μg / Fluticasone propionate 500 μg BID for 24 Weeks
|
Total
n=933 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Customized
Age (years), mean (SD)
|
63.5 years
STANDARD_DEVIATION 8.1 • n=5 Participants
|
63.3 years
STANDARD_DEVIATION 7.5 • n=7 Participants
|
63.4 years
STANDARD_DEVIATION 7.8 • n=5 Participants
|
|
Sex: Female, Male
Female
|
160 Participants
n=5 Participants
|
166 Participants
n=7 Participants
|
326 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
307 Participants
n=5 Participants
|
300 Participants
n=7 Participants
|
607 Participants
n=5 Participants
|
|
Region of Enrollment
Austria
|
23 participants
n=5 Participants
|
24 participants
n=7 Participants
|
47 participants
n=5 Participants
|
|
Region of Enrollment
Bulgaria
|
30 participants
n=5 Participants
|
32 participants
n=7 Participants
|
62 participants
n=5 Participants
|
|
Region of Enrollment
Canada
|
12 participants
n=5 Participants
|
6 participants
n=7 Participants
|
18 participants
n=5 Participants
|
|
Region of Enrollment
Czech Republic
|
11 participants
n=5 Participants
|
14 participants
n=7 Participants
|
25 participants
n=5 Participants
|
|
Region of Enrollment
France
|
10 participants
n=5 Participants
|
4 participants
n=7 Participants
|
14 participants
n=5 Participants
|
|
Region of Enrollment
Germany
|
118 participants
n=5 Participants
|
136 participants
n=7 Participants
|
254 participants
n=5 Participants
|
|
Region of Enrollment
Hungary
|
50 participants
n=5 Participants
|
48 participants
n=7 Participants
|
98 participants
n=5 Participants
|
|
Region of Enrollment
Italy
|
6 participants
n=5 Participants
|
5 participants
n=7 Participants
|
11 participants
n=5 Participants
|
|
Region of Enrollment
Lithuania
|
17 participants
n=5 Participants
|
10 participants
n=7 Participants
|
27 participants
n=5 Participants
|
|
Region of Enrollment
Netherlands
|
11 participants
n=5 Participants
|
11 participants
n=7 Participants
|
22 participants
n=5 Participants
|
|
Region of Enrollment
Poland
|
67 participants
n=5 Participants
|
55 participants
n=7 Participants
|
122 participants
n=5 Participants
|
|
Region of Enrollment
South Africa
|
68 participants
n=5 Participants
|
66 participants
n=7 Participants
|
134 participants
n=5 Participants
|
|
Region of Enrollment
Spain
|
28 participants
n=5 Participants
|
34 participants
n=7 Participants
|
62 participants
n=5 Participants
|
|
Region of Enrollment
United Kingdom
|
16 participants
n=5 Participants
|
21 participants
n=7 Participants
|
37 participants
n=5 Participants
|
PRIMARY outcome
Timeframe: At Week 24Population: ITT population: randomized patients who took at least one dose of IMP and have a baseline FEV1 assessment. PP population: subset of ITT constituted by patients who met all inclusion/exclusion criteria liable to affect the efficacy ssessment, attained sufficient compliance to treatment and did not present serious deviations of the protocol.
Peak FEV1 define at the highest value observed in the 3h after the morning IMP administration
Outcome measures
| Measure |
Aclidinium Bromide / Formoterol Fumarate
n=389 Participants
Experimental: Aclidinium Bromide / Formoterol Fumarate Aclidinium Bromide 400 μg / Formoterol Fumarate 12 μg BID for 24 Weeks
|
Salmeterol / Fluticasone
n=376 Participants
Active Comparator: Salmeterol / Fluticasone propionate Salmeterol 50 μg / Fluticasone propionate 500 μg BID for 24 Weeks
|
|---|---|---|
|
Peak Forced Expiratory Volume in One Second (FEV1) at Week 24
|
1.655 Liters
Standard Error 0.011
|
1.562 Liters
Standard Error 0.011
|
SECONDARY outcome
Timeframe: At Week 24Population: PP population defined as a subset of ITT constituted by patients who met all inclusion/exclusion criteria liable to affect the efficacy ssessment, attained sufficient compliance to treatment and did not present serious deviations of the protocol.
The TDI includes the same 3 categories as BDI and 7 ratings indicating the magnitude of the change from baseline in each category: from -3 ("major deterioration") to zero ("no change") to +3 ("major improvement"). Category scores are added to compute the Focal Score (from -9 to 9)
Outcome measures
| Measure |
Aclidinium Bromide / Formoterol Fumarate
n=353 Participants
Experimental: Aclidinium Bromide / Formoterol Fumarate Aclidinium Bromide 400 μg / Formoterol Fumarate 12 μg BID for 24 Weeks
|
Salmeterol / Fluticasone
n=341 Participants
Active Comparator: Salmeterol / Fluticasone propionate Salmeterol 50 μg / Fluticasone propionate 500 μg BID for 24 Weeks
|
|---|---|---|
|
Transition Dyspnoea Index (TDI) Focal Score at Week 24
|
1.9 TDI Focal Score
Standard Error 0.17
|
1.9 TDI Focal Score
Standard Error 0.17
|
Adverse Events
Aclidinium Bromide / Formoterol Fumarate
Serious events: 35 serious events
Other events: 124 other events
Deaths: 0 deaths
Salmeterol / Fluticasone
Serious events: 33 serious events
Other events: 135 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Aclidinium Bromide / Formoterol Fumarate
n=467 participants at risk
Experimental: Aclidinium Bromide / Formoterol Fumarate Aclidinium Bromide 400 μg / Formoterol Fumarate 12 μg BID for 24 Weeks
|
Salmeterol / Fluticasone
n=466 participants at risk
Active Comparator: Salmeterol / Fluticasone propionate Salmeterol 50 μg / Fluticasone propionate 500 μg BID for 24 Weeks
|
|---|---|---|
|
Blood and lymphatic system disorders
Anaemia
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Cardiac disorders
Coronary Artery Disease
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Cardiac disorders
Cardiac Failure
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Cardiac disorders
Myocardial Infarction
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.00%
0/466 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Cardiac disorders
Cor Pulmonale
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.00%
0/466 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Cardiac disorders
Artrial fibrillation
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Cardiac disorders
Artrial flutter
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.00%
0/466 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Congenital, familial and genetic disorders
Arrhythmogenic right ventricular dysp
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.00%
0/466 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Eye disorders
Cataract
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Gastrointestinal disorders
Hiatus hernia
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Gastrointestinal disorders
Peptic ulcer haemorrhage
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.00%
0/466 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
General disorders
Sudden death
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.00%
0/466 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
General disorders
Chest Pain
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Hepatobiliary disorders
Gallbladder disorder
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Infections and infestations
Endometritis
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.00%
0/466 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Infections and infestations
Varicella
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.00%
0/466 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Infections and infestations
Pneumonia
|
0.43%
2/467 • Number of events 2 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.86%
4/466 • Number of events 4 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Infections and infestations
Bronchitis
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.00%
0/466 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Infections and infestations
Lower respiratory tract and infection
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Infections and infestations
Lung abscess
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Infections and infestations
Urosepsis
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Injury, poisoning and procedural complications
Ankle fracture
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.00%
0/466 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Injury, poisoning and procedural complications
Grastroenteritis radiation
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Injury, poisoning and procedural complications
Forearm fracture
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.43%
2/466 • Number of events 2 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Injury, poisoning and procedural complications
Radius fracture
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Metabolism and nutrition disorders
Malnutrition
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Musculoskeletal and connective tissue disorders
Polymyalgia rheumatica
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Musculoskeletal and connective tissue disorders
Osteoporotic fracture
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Musculoskeletal and connective tissue disorders
Spinal column stenosis
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.00%
0/466 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of head
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm malignant
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.00%
0/466 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Small cell lung cancer
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.00%
0/466 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Nervous system disorders
Ischaemic stroke
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.00%
0/466 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Nervous system disorders
Cerebrovascular accident
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Nervous system disorders
Dementia
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Nervous system disorders
Transient ischaemic attack
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Psychiatric disorders
Depression
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.00%
0/466 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Psychiatric disorders
Schizoaffective disorder depressive
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Psychiatric disorders
Suicidal ideation
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.00%
0/466 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Renal and urinary disorders
Renal failure
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.00%
0/466 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Renal and urinary disorders
Renal failure acute
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.00%
0/466 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Reproductive system and breast disorders
Uterine prolapse
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Reproductive system and breast disorders
Adnexa uteri mass
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.00%
0/466 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Respiratory, thoracic and mediastinal disorders
COPD (exacerbation)
|
2.8%
13/467 • Number of events 15 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
1.7%
8/466 • Number of events 9 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Respiratory, thoracic and mediastinal disorders
Respiratory failure
|
0.43%
2/467 • Number of events 2 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.00%
0/466 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Vascular disorders
Hypertensive crisis
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.00%
0/466 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Vascular disorders
Thrombosis
|
0.21%
1/467 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.00%
0/466 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Vascular disorders
Peripheral arterial occlusive disease
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Vascular disorders
Subclavian artery stenosis
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.21%
1/466 • Number of events 1 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Vascular disorders
Hypertension
|
0.00%
0/467 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
0.43%
2/466 • Number of events 2 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
Other adverse events
| Measure |
Aclidinium Bromide / Formoterol Fumarate
n=467 participants at risk
Experimental: Aclidinium Bromide / Formoterol Fumarate Aclidinium Bromide 400 μg / Formoterol Fumarate 12 μg BID for 24 Weeks
|
Salmeterol / Fluticasone
n=466 participants at risk
Active Comparator: Salmeterol / Fluticasone propionate Salmeterol 50 μg / Fluticasone propionate 500 μg BID for 24 Weeks
|
|---|---|---|
|
Infections and infestations
Nasopharyngitis
|
5.6%
26/467 • Number of events 30 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
6.0%
28/466 • Number of events 33 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Nervous system disorders
Headache
|
6.0%
28/467 • Number of events 42 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
6.9%
32/466 • Number of events 46 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
|
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
|
15.0%
70/467 • Number of events 82 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
16.1%
75/466 • Number of events 81 • 24 Weeks treatment + 2 weeks follow-up (±3 days)
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee All the information related to this clinical trial is considered strictly confidential and is the property of AstraZeneca. This information will not be given to a third party without the written consent of AstraZeneca. Publication and/or presentation, whether complete or partial, of any part of the data or results of this trial will be subject to revision and written agreement between the investigator and AstraZeneca.
- Publication restrictions are in place
Restriction type: OTHER