Study to Evaluate Efficacy and Safety of Benralizumab in Reducing Oral Corticosteroid Use in Adult Patients With Severe Asthma (PONENTE)

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ClinicalTrials.gov Identifier: NCT03557307

Recruitment Status : Completed

First Posted : June 15, 2018

Results First Posted : June 28, 2022

Last Update Posted : June 28, 2022

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

AstraZeneca

Study Type	Interventional
Study Design	Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition	Asthma
Intervention	Biological: Benralizumab
Enrollment	598

Participant Flow

Recruitment Details	705 participants provided informed consent and were assigned a unique enrollment number prior to screening. Of the 705 patients screened, 598 (84.8%) were eligible to receive Benralizumab 30 mg and entered the study. All 598 (100%) patients received the study drug.
Pre-assignment Details	In PONENTE, at the first visit, ie, the enrollment visit 1, patients were assigned an enrollment number and then evaluated regarding the protocol mandated inclusion and exclusion criteria. After screening and evaluation, only those eligible to receive Benralizumab 30 mg were assigned treatment and entered a 4 week induction phase on a stable dose of oral corticosteroids (OCS).


Arm/Group Title	Benra 30 mg
Arm/Group Description	Benralizumab 30 mg administered sub...
Arm/Group Description	Benralizumab 30 mg administered subcutaneously every 4 weeks
Period Title: To End of OCS Reduction Phase
Started ^[1]	598
Completed ^[2]	563
Not Completed	35
Reason Not Completed
Withdrawal by Subject	10
Adverse Event	7
Protocol Violation	6
Lost to Follow-up	5
other	3
Death	2
Failure to meet inclusion/exclusion criteria	2
[1] Received study drug [2] Could not reduce OCS dose further according to protocol.
Period Title: Maintenance Phase
Started ^[1]	563
Completed ^[2]	536
Not Completed	27
Reason Not Completed
Adverse Event	4
Death	3
Lost to Follow-up	2
Pregnancy	2
Protocol Violation	11
Withdrawal by Subject	2
other	3
[1] Completed OCS reduction phase. [2] Marked 'Completed' to subject's status on the Disposition CRF

Baseline Characteristics

Arm/Group Title		Benra 30 mg
Arm/Group Description		Benralizumab 30 mg administered sub...
Arm/Group Description		Benralizumab 30 mg administered subcutaneously every 4 weeks
Overall Number of Baseline Participants		598
Baseline Analysis Population Description		...
Baseline Analysis Population Description		Full analysis set
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	598 participants
		53.3 (13.59)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	598 participants
	Female	383 64.0%
	Male	215 36.0%
Race/Ethnicity, Customized ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	589 participants
	White	475 80.6%
	Black or African American	26 4.4%
	Asian	29 4.9%
	Native Hawaiian or other Pacific Islander	1 0.2%
	American Indian or Alaska Native	46 7.8%
	Other	12 2.0%
		[1] Measure Analysis Population Description: Race of 9 patients in Full Analysis Set is not recorded.

Outcome Measures

1.Primary Outcome


Title	Patients Who Achieve 100% Reduction in Daily OCS Dose
Description	Patients who achieve 100% reduction in daily OCS dose that are sustain...
Description	Patients who achieve 100% reduction in daily OCS dose that are sustained over at least 4 weeks without worsening of asthma
Time Frame	Baseline to end of OCS reduction phase, an average of approximately 200 days (The duration of the OCS reduction phase may vary based on asthma exacerbations, asthma worsening, HPA integrity , or other safety issues altering the OCS titration schedule.)

Outcome Measure Data

Analysis Population Description

Full analysis set - All enrolled patients who received at least one dose of benralizumab are included in the FAS, irrespective of their protocol adherence and continued participation in the study.


Arm/Group Title	Benra 30 mg
Arm/Group Description:	Benralizumab 30 mg administered sub...
Arm/Group Description:	Benralizumab 30 mg administered subcutaneously every 4 weeks
Overall Number of Participants Analyzed	598
Measure Type: Count of Participants Unit of Measure: Participants
	376 62.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Clopper-Pearson Exact CI
	Comments	One sample Confidence Interval

Method of Estimation	Estimation Parameter	percentage
	Estimated Value	62.9
	Confidence Interval	(2-Sided) 95% 58.86 to 66.76
	Estimation Comments	Percentage of patients who achieved 100% reduction in daily OCS dose that are sustained over at least 4 weeks without worsening of asthma

2.Primary Outcome


Title	Patients Who Achieve 100% Reduction or a Daily OCS Dose of <=5mg
Description	Patients who achieve 100% reduction or a daily OCS dose of <=5mg, i...
Description	Patients who achieve 100% reduction or a daily OCS dose of <=5mg, if reason for no further OCS reduction is Adrenal Insufficiency, that are sustained over at least 4 weeks without worsening of asthma
Time Frame	Baseline to end of OCS reduction phase, an average of approximately 200 days (The duration of the OCS reduction phase may vary based on asthma exacerbations, asthma worsening, HPA integrity , or other safety issues altering the OCS titration schedule.)

Outcome Measure Data

Analysis Population Description

All enrolled patients who received at least one dose of benralizumab are included in the FAS, irrespective of their protocol adherence and continued participation in the study.


Arm/Group Title	Benra 30 mg
Arm/Group Description:	Benralizumab 30 mg administered sub...
Arm/Group Description:	Benralizumab 30 mg administered subcutaneously every 4 weeks
Overall Number of Participants Analyzed	598
Measure Type: Count of Participants Unit of Measure: Participants
	490 81.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Clopper-Pearson Exact CI
	Comments	One sample Confidence Interval

Method of Estimation	Estimation Parameter	percentage
	Estimated Value	81.9
	Confidence Interval	(2-Sided) 95% 78.62 to 84.94
	Estimation Comments	Percentage of patients who achieve 100% reduction or a daily OCS dose of <=5mg, if reason for no further OCS reduction is Adrenal Insufficiency, that are sustained over at least 4 weeks without worsening of asthma

3.Secondary Outcome


Title	Patients Who Achieve a Daily OCS of ≤5mg
Description	Patients who achieve a daily OCS dose of ≤5 mg (regardless of re...
Description	Patients who achieve a daily OCS dose of ≤5 mg (regardless of reason for no further OCS reduction), that are sustained over at least 4 weeks without worsening of asthma
Time Frame	Baseline to end of OCS reduction phase, an average of approximately 200 days (The duration of the OCS reduction phase may vary based on asthma exacerbations, asthma worsening, HPA integrity , or other safety issues altering the OCS titration schedule.)

Outcome Measure Data

Analysis Population Description

Full analysis set - All enrolled patients who received at least one dose of benralizumab are included in the FAS, irrespective of their protocol adherence and continued participation in the study.


Arm/Group Title	Benra 30 mg
Arm/Group Description:	Benralizumab 30 mg administered sub...
Arm/Group Description:	Benralizumab 30 mg administered subcutaneously every 4 weeks
Overall Number of Participants Analyzed	598
Measure Type: Count of Participants Unit of Measure: Participants
	547 91.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Clopper-Pearson Exact CI
	Comments	One sample Confidence Interval

Method of Estimation	Estimation Parameter	percentage
	Estimated Value	91.5
	Confidence Interval	(2-Sided) 95% 88.94 to 93.58
	Estimation Comments	Percentage of patients who achieve a daily OCS dose of ≤5 mg (regardless of reason for no further OCS reduction), that are sustained over at least 4 weeks without worsening of asthma

4.Secondary Outcome


Title	Patients Who Achieve a ≥90%, ≥75%, and ≥50% Reduction in Daily OCS Dose
Description	Patients who achieve a ≥90%, ≥75%, and ≥50% reductio...
Description	Patients who achieve a ≥90%, ≥75%, and ≥50% reduction in daily OCS dose that are sustained over at least 4 weeks without worsening of asthma
Time Frame	Baseline to end of OCS reduction phase, an average of approximately 200 days (The duration of the OCS reduction phase may vary based on asthma exacerbations, asthma worsening, HPA integrity , or other safety issues altering the OCS titration schedule.)

Outcome Measure Data

Analysis Population Description

Full analysis set - All enrolled patients who received at least one dose of benralizumab are included in the FAS, irrespective of their protocol adherence and continued participation in the study.


Arm/Group Title	Benra 30 mg
Arm/Group Description:	Benralizumab 30 mg administered sub...
Arm/Group Description:	Benralizumab 30 mg administered subcutaneously every 4 weeks
Overall Number of Participants Analyzed	598
Measure Type: Count of Participants Unit of Measure: Participants
≥90% reduction	383 64.0%
≥75% reduction	412 68.9%
≥50% reduction	489 81.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Clopper-Pearson Exact CI
	Comments	One sample Confidence Interval (≥90% reduction)

Method of Estimation	Estimation Parameter	percentage
	Estimated Value	64.0
	Confidence Interval	(2-Sided) 95% 60.06 to 67.90
	Estimation Comments	Percentage of patients who achieve >=90% reduction in daily OCS dose that are sustained over at least 4 weeks without worsening of asthma

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Clopper-Pearson Exact CI
	Comments	One sample Confidence Interval (>=75% reduction)

Method of Estimation	Estimation Parameter	percentage
	Estimated Value	68.9
	Confidence Interval	(2-Sided) 95% 65.02 to 72.59
	Estimation Comments	Percentage of patients who achieve >=75% reduction in daily OCS dose that are sustained over at least 4 weeks without worsening of asthma

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Clopper-Pearson Exact CI
	Comments	One sample Confidence Interval (>=50% reduction)

Method of Estimation	Estimation Parameter	percentage
	Estimated Value	81.8
	Confidence Interval	(2-Sided) 95% 78.44 to 84.79
	Estimation Comments	Percentage of patients who achieve >=50% reduction in daily OCS dose that are sustained over at least 4 weeks without worsening of asthma

5.Secondary Outcome


Title	Change From Baseline in Average Daily OCS Dose (mg)
Description	Change from baseline in average daily OCS dose (mg) from start of OCS ...
Description	Change from baseline in average daily OCS dose (mg) from start of OCS reduction to end of the OCS reduction phase
Time Frame	Baseline to end of OCS reduction phase, an average of approximately 200 days (The duration of the OCS reduction phase may vary based on asthma exacerbations, asthma worsening, HPA integrity , or other safety issues altering the OCS titration schedule.)

Outcome Measure Data

Analysis Population Description

Full analysis set - All enrolled patients who received at least one dose of benralizumab are included in the FAS, irrespective of their protocol adherence and continued participation in the study.


Arm/Group Title	Benra 30 mg
Arm/Group Description:	Benralizumab 30 mg administered sub...
Arm/Group Description:	Benralizumab 30 mg administered subcutaneously every 4 weeks
Overall Number of Participants Analyzed	593
Mean (95% Confidence Interval) Unit of Measure: mg
	-8.50 (-9.10 to -7.90)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Benra 30 mg
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Clopper-Pearson Exact CI
	Comments	One sample Confidence Interval

Method of Estimation	Estimation Parameter	percentage change from baseline
	Estimated Value	-76.92
	Confidence Interval	(2-Sided) 95% -79.90 to -73.94
	Estimation Comments	Percentage change from baseline in daily OCS dose at the end of OCS reduction phase

Adverse Events

Time Frame	From first dose of study drug until end of study, with an average of 405 days.
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	Benra 30 mg
Arm/Group Description	Benralizumab 30 mg administered sub...
Arm/Group Description	Benralizumab 30 mg administered subcutaneously every 4 weeks
All-Cause Mortality
	Benra 30 mg
	Affected / at Risk (%)
Total	5/598 (0.84%)
Serious Adverse Events Serious Adverse Events
	Benra 30 mg
	Affected / at Risk (%)	# Events
Total	89/598 (14.88%)
Cardiac disorders
Acute myocardial infarction ^† 1	4/598 (0.67%)	4
Angina unstable ^† 1	2/598 (0.33%)	2
Cardiac arrest ^† 1	2/598 (0.33%)	2
Cardiac failure congestive ^† 1	1/598 (0.17%)	1
Coronary artery disease ^† 1	1/598 (0.17%)	1
Myocardial ischaemia ^† 1	1/598 (0.17%)	1
Ventricular extrasystoles ^† 1	1/598 (0.17%)	1
Ear and labyrinth disorders
Meniere's disease ^† 1	1/598 (0.17%)	1
Gastrointestinal disorders
Abdominal pain ^† 1	1/598 (0.17%)	1
Anal fistula ^† 1	1/598 (0.17%)	1
Ileus ^† 1	2/598 (0.33%)	2
Pancreatitis ^† 1	1/598 (0.17%)	1
Pancreatitis acute ^† 1	1/598 (0.17%)	2
General disorders
Sudden cardiac death ^† 1	1/598 (0.17%)	1
Hepatobiliary disorders
Cholelithiasis ^† 1	1/598 (0.17%)	1
Infections and infestations
COVID-19 ^† 1	1/598 (0.17%)	1
Chronic sinusitis ^† 1	2/598 (0.33%)	2
Diverticulitis ^† 1	2/598 (0.33%)	2
Gastroenteritis ^† 1	1/598 (0.17%)	1
H1N1 influenza ^† 1	1/598 (0.17%)	1
Haemophilus infection ^† 1	1/598 (0.17%)	1
Infected bite ^† 1	1/598 (0.17%)	1
Influenza ^† 1	5/598 (0.84%)	5
Lower respiratory tract infection bacterial ^† 1	1/598 (0.17%)	1
Pelvic abscess ^† 1	1/598 (0.17%)	1
Peritonitis ^† 1	1/598 (0.17%)	1
Pneumonia ^† 1	11/598 (1.84%)	11
Pneumonia bacterial ^† 1	2/598 (0.33%)	2
Pneumonia haemophilus ^† 1	2/598 (0.33%)	2
Pneumonia influenzal ^† 1	1/598 (0.17%)	2
Pneumonia pseudomonal ^† 1	1/598 (0.17%)	1
Respiratory tract infection ^† 1	1/598 (0.17%)	1
Respiratory tract infection bacterial ^† 1	1/598 (0.17%)	1
Sepsis ^† 1	3/598 (0.50%)	3
Urosepsis ^† 1	1/598 (0.17%)	1
Injury, poisoning and procedural complications
Alcohol poisoning ^† 1	1/598 (0.17%)	1
Craniocerebral injury ^† 1	1/598 (0.17%)	1
Humerus fracture ^† 1	1/598 (0.17%)	1
Multiple fractures ^† 1	1/598 (0.17%)	1
Post procedural haemorrhage ^† 1	1/598 (0.17%)	1
Rib fracture ^† 1	1/598 (0.17%)	1
Spinal fracture ^† 1	1/598 (0.17%)	1
Tendon rupture ^† 1	1/598 (0.17%)	1
Investigations
Oxygen saturation decreased ^† 1	1/598 (0.17%)	1
Metabolism and nutrition disorders
Diabetes mellitus inadequate control ^† 1	1/598 (0.17%)	1
Type 2 diabetes mellitus ^† 1	1/598 (0.17%)	1
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion ^† 1	1/598 (0.17%)	1
Osteonecrosis ^† 1	1/598 (0.17%)	1
Polymyalgia rheumatica ^† 1	1/598 (0.17%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon ^† 1	1/598 (0.17%)	1
Basal cell carcinoma ^† 1	1/598 (0.17%)	1
Malignant glioma ^† 1	1/598 (0.17%)	1
Neurofibroma ^† 1	1/598 (0.17%)	1
Uterine leiomyoma ^† 1	1/598 (0.17%)	1
Nervous system disorders
Apallic syndrome ^† 1	1/598 (0.17%)	1
Carotid artery aneurysm ^† 1	1/598 (0.17%)	1
Dizziness postural ^† 1	1/598 (0.17%)	1
Generalised tonic-clonic seizure ^† 1	1/598 (0.17%)	1
Sciatica ^† 1	1/598 (0.17%)	1
Renal and urinary disorders
Acute kidney injury ^† 1	1/598 (0.17%)	1
Reproductive system and breast disorders
Breast calcifications ^† 1	1/598 (0.17%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure ^† 1	1/598 (0.17%)	1
Aspirin-exacerbated respiratory disease ^† 1	1/598 (0.17%)	1
Asthma ^† 1	23/598 (3.85%)	33
Atelectasis ^† 1	1/598 (0.17%)	1
Chronic rhinosinusitis with nasal polyps ^† 1	1/598 (0.17%)	1
Dyspnoea ^† 1	1/598 (0.17%)	1
Haemoptysis ^† 1	1/598 (0.17%)	1
Pharyngeal swelling ^† 1	1/598 (0.17%)	1
Respiratory failure ^† 1	1/598 (0.17%)	1
Vascular disorders
Embolism arterial ^† 1	1/598 (0.17%)	1
Hypertensive emergency ^† 1	1/598 (0.17%)	1
1 Term from vocabulary, MedDRA 23.0 † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	3%
	Benra 30 mg
	Affected / at Risk (%)	# Events
Total	181/598 (30.27%)
General disorders
Influenza like illness ^† 1	33/598 (5.52%)	34
Infections and infestations
Nasopharyngitis ^† 1	64/598 (10.70%)	92
Sinusitis ^† 1	19/598 (3.18%)	22
Upper respiratory tract infection ^† 1	25/598 (4.18%)	28
Viral upper respiratory tract infection ^† 1	28/598 (4.68%)	31
Nervous system disorders
Headache ^† 1	29/598 (4.85%)	38
Vascular disorders
Hypertension ^† 1	21/598 (3.51%)	21
1 Term from vocabulary, MedDRA 23.0 † Indicates events were collected by systematic assessment

Limitations and Caveats

During COVID-19 pandemic, for ongoing patients, patient dosing, and scheduled visits are inevitable impacted. But the primary endpoint is not impacted.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Maria Jison, MD Global Clinical Head, FASENRA, Late-stage R&I
Organization:	AstraZeneca
Phone:	+13013980340
EMail:	Maria.Jison@astrazeneca.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Menzies-Gow A, Gurnell M, Heaney LG, Corren J, Bel EH, Maspero J, Harrison T, Jackson DJ, Price D, Lugogo N, Kreindler J, Burden A, de Giorgio-Miller A, Padilla K, Martin UJ, Garcia Gil E. Oral corticosteroid elimination via a personalised reduction algorithm in adults with severe, eosinophilic asthma treated with benralizumab (PONENTE): a multicentre, open-label, single-arm study. Lancet Respir Med. 2022 Jan;10(1):47-58. doi: 10.1016/S2213-2600(21)00352-0. Epub 2021 Oct 4. Erratum In: Lancet Respir Med. 2021 Dec;9(12):e114.

Menzies-Gow A, Corren J, Bel EH, Maspero J, Heaney LG, Gurnell M, Wessman P, Martin UJ, Siddiqui S, Garcia Gil E. Corticosteroid tapering with benralizumab treatment for eosinophilic asthma: PONENTE Trial. ERJ Open Res. 2019 Sep 25;5(3):00009-2019. doi: 10.1183/23120541.00009-2019. eCollection 2019 Jul.

Layout table for additonal information

Responsible Party:	AstraZeneca
ClinicalTrials.gov Identifier:	NCT03557307
Other Study ID Numbers:	D3250C00065
First Submitted:	May 14, 2018
First Posted:	June 15, 2018
Results First Submitted:	February 7, 2022
Results First Posted:	June 28, 2022
Last Update Posted:	June 28, 2022

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