An Efficacy and Safety Study of Reslizumab Subcutaneous in Patients With Oral Corticosteroid Dependent Asthma and Elevated Blood Eosinophils

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02501629
• Collaborator: (none)
• Enrollment: 177
• Locations: 127
• Arms: 2
• Actual Duration (Months): 26.2
• Patients Per Site: 1.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary objective of the study is to determine the ability of reslizumab administered by subcutaneous injection to produce a corticosteroid-sparing effect in patients with oral corticosteroid (OCS)-dependent asthma and elevated blood eosinophils, without loss of asthma control.

Condition or Disease	Intervention/Treatment	Phase
Asthma; Elevated Blood Eosinophils; Oral Corticosteroid Dependence	Drug: Reslizumab; Drug: Placebo; Drug: Non-Oral Corticosteroid (non-OCS) Asthma Medication; Drug: Oral Corticosteroid (OCS)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 177 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, 24-Week Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy and Safety Study of Reslizumab Subcutaneous Dosing (110 mg Every 4 Weeks) in Patients With Oral Corticosteroid Dependent Asthma and Elevated Blood Eosinophils
• Actual Study Start Date: Sep 29, 2015
• Actual Primary Completion Date: Jun 19, 2017
• Actual Study Completion Date: Dec 4, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Reslizumab 110 mg Reslizumab was administered by subcutaneous injection (sc) in a dosage of 110 mg (1.0 mL) every 4 weeks for a total of six doses.	Drug: Reslizumab; Reslizumab 110 mg was administered by qualified study personnel as subcutaneous injections in the upper arm(s) once every 4 weeks for a total of 6 doses. Drug was supplied in pre-filled syringes.; Other Names: CEP38072 ; Drug: Non-Oral Corticosteroid (non-OCS) Asthma Medication; Participants continue using their non-OCS background asthma medications without change during the study's treatment period.; Drug: Oral Corticosteroid (OCS); After screening and prior to study start, the participant's OCS dose was adjusted to determine the minimal effective OCS requirement.
Placebo Comparator: Placebo Matching placebo was administered by subcutaneous injection (sc) 1.0 mL every 4 weeks for a total of six doses.	Drug: Placebo; Placebo was administered by qualified study personnel as subcutaneous injections in the upper arm(s) once every 4 weeks for a total of 6 doses. Drug was supplied in pre-filled syringes.; Drug: Non-Oral Corticosteroid (non-OCS) Asthma Medication; Participants continue using their non-OCS background asthma medications without change during the study's treatment period.; Drug: Oral Corticosteroid (OCS); After screening and prior to study start, the participant's OCS dose was adjusted to determine the minimal effective OCS requirement.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Reduction In Daily Oral Corticosteroid (OCS) Dose During Weeks 20-24 As Compared to the Optimized Dose At Baseline [Baseline (Day 1), Weeks 20-24]

   The primary endpoint was the 5-level categorized percent reduction in OCS dose during weeks 20 to 24 compared with the optimized dose at baseline. The primary analysis incorporated data from all randomized patients. Analysis of the primary and secondary variables related to categorical OCS dose reduction incorporated missing data as non-responders. No decrease indicates there was no decrease in OCS, loss of baseline asthma control during weeks 20 to 24, or discontinuation from study drug.

Secondary Outcome Measures

1. Percentage of Participants Achieving a >=50% Reduction in OCS Dose at Weeks 20-24 Compared to Baseline While Maintaining Asthma Control [Baseline (Day 1), Weeks 20-24]

   Percentage of patients whose OCS dose at weeks 20-24 was reduced >=50% compared to baseline while maintaining asthma control. Patients listed as "no" did not achieve the 50% reduction in baseline OCS dose goal, or did achieve that goal but lost asthma control during weeks 20 to 24, or discontinued from study drug.

2. Percentage of Participants Achieving an OCS Dose of <=5 mg at Weeks 20-24 While Maintaining Asthma Control [Weeks 20-24]

   Percentage of participants whose OCS dose at weeks 20-24 was <=5 mg and they maintained asthma control. Patients listed as "no" had a week 20-24 OCS dose > 5 mg, or whose OCS dose was <=5 mg at weeks 20-24 but did not maintain asthma control, or they discontinued from study drug.

3. Percent Change From Baseline in Daily Oral Corticosteroid (OCS) Dose During Weeks 20-24 Using a Mixed Model for Repeated Measures [Baseline (Day 1), Weeks 20-24]

   The baseline OCS dose is the prescribed optimized OCS dose following the OCS optimization period. Endpoint data are presented using an on-treatment approach. In this context, 'endpoint' was defined as the last observation obtained at a scheduled or qualified early termination visit during the treatment period. Weeks 20-24 data is included between the Week 20 dose and Week 24 for completed patients; last dose of study drug to 4 weeks after the last dose of study drug for patients who discontinued treatment early. Measurements collected outside of these defined timeframes are excluded from the analyses. The mixed model repeated measures (MMRM) included fixed effects for treatment, visit, treatment by visit interaction, age group, and OCS dose group, duration of OCS use and baseline value as covariates, and patient as a random effect. Unstructured covariance was assumed for the repeated measures.

4. Percentage of Participants Achieving a >=5 mg Reduction in OCS Dose at Weeks 20-24 Compared to Baseline While Maintaining Asthma Control [Baseline (Day 1), Weeks 20-24]

   Percentage of participants whose OCS dose at weeks 20-24 was reduced by at least 5mg from baseline and maintained asthma control. Patients listed as "no" had a week 20-24 OCS dose that did not meet the threshold of a 5mg reduction, or whose OCS dose met the threshold but did not maintain asthma control, or discontinued from study drug.

5. Annualized Rate of Clinical Asthma Exacerbations (CAEs) [Day 1 through Week 24]

   The annual exacerbation rate is based on clinical asthma exacerbations reported by the investigator in the eCRF.

6. Percentage of Participants Achieving an OCS Dose of 0 mg at Weeks 20-24 While Maintaining Asthma Control [Weeks 20-24]

   Percentage of participants who discontinue use of OCS during weeks 20-24 while maintaining asthma control. Patients listed as "no" continued to use OCS during weeks 20-24, or who discontinued use of OCS during weeks 20-24 but lost control of their asthma, or discontinued from study drug.

7. Participants With Treatment-Emergent Anti-Drug Antibody (ADA) Responses [Weeks 4, 8, 12, 24 or early withdrawal.]

   Treatment-emergent responses were defined as a positive sample post-baseline (negative baseline) OR a titer increase of >=4-fold relative to a positive baseline sample. Two types of antibody assay were performed, an immunogenicity status assay (ADA) and neutralizing assay (NAb). The ADA assay produces a positive or negative result. For samples with a positive result, a neutralizing assay was performed, which also produces a positive or negative result.

8. Participants With Adverse Events [Day 1 up to Week 24 (end of treatment visit); Data were included between Day 1 and Week 24 for completed patients, and Day 1 and 4 weeks after the last dose of study drug for patients who discontinued treatment early.]

   An adverse event is any untoward medical occurrence in a patient administered a pharmaceutical product, regardless of whether it has a causal relationship with this treatment. In this study, asthma exacerbations (which are efficacy parameters) should not be recorded as adverse events unless assessed by the investigator as more severe than the patient's usual disease course. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes. Treatment-related adverse events or adverse events related to OCS use included events with missing relationship to study drug or OCS use, respectively.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. The patient is male or female, 12 years of age and older, with a previous diagnosis of asthma.

2. Written informed consent is obtained.

3. The patient requires daily maintenance dose of prednisone or equivalent for asthma of between 5 and 40 mg during the 3 months prior to screening.

4. The patient has a documented elevated blood eosinophils at screening or during the previous 12 months.

5. The patient has required high dose ICS plus another asthma controller for at least 6 months prior to screening.

6. The patient has FEV1 reversibility to inhaled SABA or historical reversibility within the previous 24 months.

• Other criteria may apply, please contact the investigator for more information.

Exclusion Criteria:

1. The patient has any clinically significant, uncontrolled medical condition that would interfere with the study schedule or procedures and interpretation of efficacy results or would compromise the patient's safety.

2. The patient has another confounding underlying lung disorder.

3. The patient has a known hypereosinophilic syndrome.

4. The patient has a history of any malignancy within 5 years of the screening visit, except for treated and cured non-melanoma skin cancers.

5. The patient is pregnant or intends to become pregnant during the study or is lactating.

6. The patient required treatment for an asthma exacerbation within 4 weeks of screening.

7. The patient is a current smoker or has a smoking history ≥10 pack-years.

8. The patient is currently using any systemic immunosuppressive or immunomodulatory biologic except maintenance OCS for the treatment of asthma.

9. The patient participated in a clinical study within 30 days or 5 half-lives of the investigational drug before screening, whichever is longer.

10. The patient was previously exposed to benralizumab within 12 months of screening.

11. The patient was previously exposed to reslizumab.

12. The patient has a history of immunodeficiency disorder including human immunodeficiency virus.

13. The patient has current suspected drug and/or alcohol abuse.

14. The patient has had an active helminthic parasitic infection or was treated for one within 6 months of screening.

15. The patient has a history of allergic reactions or hypersensitivity to any component of the study drug.

• Other criteria may apply, please contact the investigator for more information.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Teva Investigational Site 13357	Bakersfield	California	United States	93301
2	Teva Investigational Site 13365	Long Beach	California	United States	90813
3	Teva Investigational Site 13371	Clermont	Florida	United States	73034
4	Teva Investigational Site 13351	Homestead	Florida	United States	33030
5	Teva Investigational Site 13342	Kissimmee	Florida	United States	34741
6	Teva Investigational Site 13344	Miami	Florida	United States	33015
7	Teva Investigational Site 13372	Miami	Florida	United States	33133
8	Teva Investigational Site 13354	Pembroke Pines	Florida	United States	33029
9	Teva Investigational Site 13343	Saint Cloud	Florida	United States	34769
10	Teva Investigational Site 13368	Sebring	Florida	United States	33870
11	Teva Investigational Site 13346	Tampa	Florida	United States	33607
12	Teva Investigational Site 13367	Chicago	Illinois	United States	60612
13	Teva Investigational Site 13363	Normal	Illinois	United States	61761
14	Teva Investigational Site 13345	Michigan City	Indiana	United States	46360
15	Teva Investigational Site 13348	Lenexa	Kansas	United States	66215
16	Teva Investigational Site 13362	Biloxi	Mississippi	United States	39531
17	Teva Investigational Site 13350	Saint Louis	Missouri	United States	63106
18	Teva Investigational Site 13352	Saint Louis	Missouri	United States	63143
19	Teva Investigational Site 13356	New York	New York	United States	10016-9196
20	Teva Investigational Site 13349	Cincinnati	Ohio	United States	45231
21	Teva Investigational Site 13370	Edmond	Oklahoma	United States	73034
22	Teva Investigational Site 13347	Oklahoma City	Oklahoma	United States	73112
23	Teva Investigational Site 13366	Charleston	South Carolina	United States	29414
24	Teva Investigational Site 13377	Dallas	Texas	United States	75225
25	Teva Investigational Site 13369	Houston	Texas	United States	77099
26	Teva Investigational Site 13358	Fairfax	Virginia	United States	22030
27	Teva Investigational Site 20059	Buenos Aires		Argentina	C1028AAP
28	Teva Investigational Site 20058	Buenos Aires		Argentina	C1425BEN
29	Teva Investigational Site 20056	Buenos Aires		Argentina	C1426ABP
30	Teva Investigational Site 20057	Buenos Aires		Argentina
31	Teva Investigational Site 20052	Cordoba		Argentina	X5003DCE
32	Teva Investigational Site 20055	Mendoza		Argentina	5500
33	Teva Investigational Site 20050	Mendoza		Argentina	M5500CCG
34	Teva Investigational Site 20087	Rosario		Argentina	2000
35	Teva Investigational Site 20051	San Miguel de Tucuman		Argentina	T4000CHE
36	Teva Investigational Site 20066	San Rafael		Argentina
37	Teva Investigational Site 78089	Bedford Park		Australia	5042
38	Teva Investigational Site 78092	Box Hill		Australia	3128
39	Teva Investigational Site 78097	Frankston		Australia	3199
40	Teva Investigational Site 78093	Kent Town		Australia	5067
41	Teva Investigational Site 78090	Nedlands		Australia	6009
42	Teva Investigational Site 78091	New Lambton		Australia	2305
43	Teva Investigational Site 37059	Bruxelles		Belgium	1200
44	Teva Investigational Site 37058	Gembloux		Belgium	5030
45	Teva Investigational Site 54133	Breclav		Czechia	690 74
46	Teva Investigational Site 54132	Jindrichuv Hradec		Czechia	377 38
47	Teva Investigational Site 35186	Le Kremlin-bicetre		France	94275 Cedex
48	Teva Investigational Site 35185	Lille Cedex		France	59037
49	Teva Investigational Site 35189	Lyon Cedex 04		France	69317
50	Teva Investigational Site 35187	Strasbourg		France	67091
51	Teva Investigational Site 32621	Bad Worishofen		Germany	86825
52	Teva Investigational Site 32576	Berlin		Germany	10717
53	Teva Investigational Site 32573	Berlin		Germany	12159
54	Teva Investigational Site 32578	Berlin		Germany	13187
55	Teva Investigational Site 32622	Frankfurt		Germany	60389
56	Teva Investigational Site 32579	Hannover		Germany	30173
57	Teva Investigational Site 32574	Leipzig		Germany	4275
58	Teva Investigational Site 32580	Rostock		Germany	18057
59	Teva Investigational Site 51254	Csorna		Hungary	9300
60	Teva Investigational Site 51232	Dombovar		Hungary	7200
61	Teva Investigational Site 51233	Hatvan		Hungary	3000
62	Teva Investigational Site 51253	Szombathely		Hungary	9700
63	Teva Investigational Site 80085	Haifa		Israel	3436212
64	Teva Investigational Site 80083	Jerusalem		Israel	91120
65	Teva Investigational Site 80091	Kfar Saba		Israel	44281
66	Teva Investigational Site 80084	Petah Tikva		Israel	49100
67	Teva Investigational Site 80082	Rehovot		Israel	76100
68	Teva Investigational Site 30152	Catanzaro		Italy	88100
69	Teva Investigational Site 30154	Genova		Italy	16132
70	Teva Investigational Site 87020	Goyang-si		Korea, Republic of	411-706
71	Teva Investigational Site 87024	Jeonju		Korea, Republic of	561-712
72	Teva Investigational Site 87025	Seongnam-si		Korea, Republic of	463-707
73	Teva Investigational Site 87023	Seoul		Korea, Republic of	137-701
74	Teva Investigational Site 87022	Seoul		Korea, Republic of	138-736
75	Teva Investigational Site 87021	Seoul		Korea, Republic of	143-729
76	Teva Investigational Site 21106	Chihuahua		Mexico	31203
77	Teva Investigational Site 21102	Distrito Federal		Mexico	07020
78	Teva Investigational Site 21104	Durango		Mexico	34080
79	Teva Investigational Site 21094	Guadalajara		Mexico	44100
80	Teva Investigational Site 21091	Guadalajara		Mexico	44130
81	Teva Investigational Site 21100	Guadalajara		Mexico	44160
82	Teva Investigational Site 21093	Guadalajara		Mexico	44220
83	Teva Investigational Site 21090	Mexico City		Mexico	06700
84	Teva Investigational Site 21103	Monterrey		Mexico	64460
85	Teva Investigational Site 21101	Monterrey		Mexico	64718
86	Teva Investigational Site 21105	Queretaro		Mexico	76800
87	Teva Investigational Site 38084	Leeuwarden		Netherlands	8901 BR
88	Teva Investigational Site 38085	Zwolle		Netherlands	8025-AB
89	Teva Investigational Site 53316	Gdansk		Poland	80-952
90	Teva Investigational Site 53318	Krakow		Poland	31-624
91	Teva Investigational Site 53319	Lodz		Poland	90-153
92	Teva Investigational Site 53321	Lodz		Poland	90-153
93	Teva Investigational Site 53322	Lubin		Poland	59-300
94	Teva Investigational Site 53320	Ostrow Wielkopolski		Poland	63-400
95	Teva Investigational Site 53358	Rzeszow		Poland	35-612
96	Teva Investigational Site 53317	Tarnow		Poland	33-100
97	Teva Investigational Site 53323	Wroclaw		Poland	54-239
98	Teva Investigational Site 50356	Barnaul		Russian Federation	656024
99	Teva Investigational Site 50417	Chelyabinsk		Russian Federation	454021
100	Teva Investigational Site 50419	Ekaterinburg		Russian Federation	620039
101	Teva Investigational Site 50385	Kemerovo		Russian Federation	650002
102	Teva Investigational Site 50382	Kemerovo		Russian Federation	650099
103	Teva Investigational Site 50384	Moscow		Russian Federation	129090
104	Teva Investigational Site 50383	Novosibirsk		Russian Federation	630091
105	Teva Investigational Site 50386	Novosibirsk		Russian Federation	630099
106	Teva Investigational Site 50357	St. Petersburg		Russian Federation	197089
107	Teva Investigational Site 50418	Tomsk		Russian Federation	634050
108	Teva Investigational Site 50358	Tomsk		Russian Federation	634063
109	Teva Investigational Site 31159	Barcelona		Spain	?08025
110	Teva Investigational Site 31161	Girona		Spain	17004
111	Teva Investigational Site 31160	Valencia		Spain	46017
112	Teva Investigational Site 31158	Valencia		Spain	46026
113	Teva Investigational Site 58245	Dnepropetrovsk		Ukraine	49044
114	Teva Investigational Site 58238	Dnipropetrovsk		Ukraine	49074
115	Teva Investigational Site 58240	Ivano-Frankivsk		Ukraine	76018
116	Teva Investigational Site 58244	Kharkiv		Ukraine	61002
117	Teva Investigational Site 58235	Kharkiv		Ukraine	61007
118	Teva Investigational Site 58239	Kharkiv		Ukraine	61035
119	Teva Investigational Site 58241	Kharkiv		Ukraine	61039
120	Teva Investigational Site 58249	Kremenchuk		Ukraine	39617
121	Teva Investigational Site 58248	Kyiv		Ukraine	03680
122	Teva Investigational Site 58251	Kyiv		Ukraine	2091
123	Teva Investigational Site 58237	Kyiv		Ukraine	3049
124	Teva Investigational Site 58250	Kyiv		Ukraine	?03680
125	Teva Investigational Site 58243	Sumy		Ukraine	40022
126	Teva Investigational Site 58246	Vinnytsya		Ukraine	21001
127	Teva Investigational Site 58242	Zhaporizhzhya		Ukraine	69035

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.

Investigators

• Study Director: Teva Medical Expert, MD, Teva Branded Pharmaceutical Products R&D, Inc.

Study Documents (Full-Text)

• Study Protocol - Jul 18, 2016
• Statistical Analysis Plan - Mar 8, 2017

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT02501629
• Other Study ID Numbers: C38072-AS-30027; 2015-001580-39
• First Posted: Jul 17, 2015
• Last Update Posted: Nov 9, 2021
• Last Verified: Nov 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Teva Branded Pharmaceutical Products R&D, Inc.: Asthma; Elevated Blood Eosinophils; Oral corticosteroid dependence; Reslizumab
• Additional relevant MeSH terms: Asthma; Reslizumab

Study Results

Participant Flow

Pre-assignment Detail	A total of 273 patients with OCS-dependent severe eosinophilic asthma were screened, and 180 of these patients (at 78 centers) were considered eligible for enrollment. Three of the eligible patients were not randomized due to failure to meet randomization criteria.

Arm/Group Title	Placebo	Reslizumab 110 mg
Arm/Group Description	Matching placebo was administered by subcutaneous injection (sc) 1.0 mL every 4 weeks for a total of six doses.	Reslizumab was administered by subcutaneous injection (sc) in a dosage of 110 mg (1.0 mL) every 4 weeks for a total of six doses.
Period Title: Overall Study
STARTED	89	88
COMPLETED	84	81
NOT COMPLETED	5	7

Baseline Characteristics

Arm/Group Title	Placebo	Reslizumab 110 mg	Total
Arm/Group Description	Matching placebo was administered by subcutaneous injection (sc) 1.0 mL every 4 weeks for a total of six doses.	Reslizumab was administered by subcutaneous injection (sc) in a dosage of 110 mg (1.0 mL) every 4 weeks for a total of six doses.	Total of all reporting groups
Overall Participants	89	88	177
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.1 (11.99)	55.5 (12.72)	54.3 (12.38)
Sex: Female, Male (Count of Participants)
Female	57 64%	60 68.2%	117 66.1%
Male	32 36%	28 31.8%	60 33.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	16 18%	22 25%	38 21.5%
Not Hispanic or Latino	72 80.9%	65 73.9%	137 77.4%
Unknown or Not Reported	1 1.1%	1 1.1%	2 1.1%
Race/Ethnicity, Customized (Count of Participants)
White	80 89.9%	72 81.8%	152 85.9%
Black or African American	1 1.1%	3 3.4%	4 2.3%
Asian	3 3.4%	2 2.3%	5 2.8%
American Indian or Alaska Native	1 1.1%	3 3.4%	4 2.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Other	4 4.5%	8 9.1%	12 6.8%
Age Group (Count of Participants)
12 to <18 years	1 1.1%	0 0%	1 0.6%
18 to <65 years	74 83.1%	63 71.6%	137 77.4%
>=65 years	14 15.7%	25 28.4%	39 22%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	82.69 (18.949)	79.58 (21.390)	81.14 (20.202)
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	29.859 (6.3499)	29.389 (8.0105)	29.625 (7.2067)
Region Group (Count of Participants)
US/Canada	10 11.2%	9 10.2%	19 10.7%
Europe	58 65.2%	47 53.4%	105 59.3%
Other	21 23.6%	32 36.4%	53 29.9%
Oral Corticosteroid (OCS) Dose at Baseline (mg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg]	10.37 (6.435)	10.37 (6.807)	10.37 (6.604)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Reduction In Daily Oral Corticosteroid (OCS) Dose During Weeks 20-24 As Compared to the Optimized Dose At Baseline
Description	The primary endpoint was the 5-level categorized percent reduction in OCS dose during weeks 20 to 24 compared with the optimized dose at baseline. The primary analysis incorporated data from all randomized patients. Analysis of the primary and secondary variables related to categorical OCS dose reduction incorporated missing data as non-responders. No decrease indicates there was no decrease in OCS, loss of baseline asthma control during weeks 20 to 24, or discontinuation from study drug.
Time Frame	Baseline (Day 1), Weeks 20-24

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) Analysis set; missing data are included as non-responders (no decrease).

Arm/Group Title	Placebo	Reslizumab 110 mg
Arm/Group Description	Matching placebo was administered by subcutaneous injection (sc) 1.0 mL every 4 weeks for a total of six doses.	Reslizumab was administered by subcutaneous injection (sc) in a dosage of 110 mg (1.0 mL) every 4 weeks for a total of six doses.
Measure Participants	89	88
90% to 100%	20 22.5%	18 20.5%
75% to <90%	4 4.5%	8 9.1%
50% to <75%	8 9%	13 14.8%
>0% to <50%	9 10.1%	7 8%
No decrease	48 53.9%	42 47.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reslizumab 110 mg
	Comments	The proportional odds ratio (reslizumab/placebo) was estimated from this model, representing the ratio of the odds of a patient outcome being in a higher OCS dose reduction category for reslizumab compared to placebo.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.468
	Comments	Significance at 0.05.
	Method	proportional odds model
	Comments	factors for treatment group and randomization strata (age and OCS dose); baseline OCS dose and duration of OCS use prior to study were covariates.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.23
	Confidence Interval	(2-Sided) 95%; 0.702 to 2.157
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Participants Achieving a >=50% Reduction in OCS Dose at Weeks 20-24 Compared to Baseline While Maintaining Asthma Control
Description	Percentage of patients whose OCS dose at weeks 20-24 was reduced >=50% compared to baseline while maintaining asthma control. Patients listed as "no" did not achieve the 50% reduction in baseline OCS dose goal, or did achieve that goal but lost asthma control during weeks 20 to 24, or discontinued from study drug.
Time Frame	Baseline (Day 1), Weeks 20-24

Outcome Measure Data

Analysis Population Description

ITT Analysis set; missing data are included as non-responders (No).

Arm/Group Title	Placebo	Reslizumab 110 mg
Arm/Group Description	Matching placebo was administered by subcutaneous injection (sc) 1.0 mL every 4 weeks for a total of six doses.	Reslizumab was administered by subcutaneous injection (sc) in a dosage of 110 mg (1.0 mL) every 4 weeks for a total of six doses.
Measure Participants	89	88
Yes	36 40.4%	44 50%
No	64 71.9%	56 63.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reslizumab 110 mg
	Comments	As the analysis of the primary efficacy endpoint did not meet criteria for statistical significance (p≤0.05), the secondary efficacy endpoints were not interpreted inferentially according to the pre-defined hierarchy. P-values are nominal, meaning they were obtained from the analysis without adjustments to protect family-wise errors and should be interpreted with caution. Nominal p-values do not indicate treatment differences.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.234
	Comments	significance at 0.05.
	Method	Regression, Logistic
	Comments	logistic regression model adjusted for treatment, stratification factors (age group and OCS dose group), duration of OCS use, and baseline value.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.45
	Confidence Interval	(2-Sided) 95%; 0.786 to 2.683
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants Achieving an OCS Dose of <=5 mg at Weeks 20-24 While Maintaining Asthma Control
Description	Percentage of participants whose OCS dose at weeks 20-24 was <=5 mg and they maintained asthma control. Patients listed as "no" had a week 20-24 OCS dose > 5 mg, or whose OCS dose was <=5 mg at weeks 20-24 but did not maintain asthma control, or they discontinued from study drug.
Time Frame	Weeks 20-24

Outcome Measure Data

Analysis Population Description

ITT Analysis set; missing data are included as non-responders (No).

Arm/Group Title	Placebo	Reslizumab 110 mg
Arm/Group Description	Matching placebo was administered by subcutaneous injection (sc) 1.0 mL every 4 weeks for a total of six doses.	Reslizumab was administered by subcutaneous injection (sc) in a dosage of 110 mg (1.0 mL) every 4 weeks for a total of six doses.
Measure Participants	89	88
Yes	38 42.7%	42 47.7%
No	62 69.7%	58 65.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reslizumab 110 mg
	Comments	As the analysis of the primary efficacy endpoint did not meet criteria for statistical significance (p≤0.05), the secondary efficacy endpoints were not interpreted inferentially according to the pre-defined hierarchy. P-values are nominal, meaning they were obtained from the analysis without adjustments to protect family-wise errors and should be interpreted with caution. Nominal p-values do not indicate treatment differences.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.596
	Comments	significance at 0.05.
	Method	Regression, Logistic
	Comments	logistic regression model adjusted for treatment, stratification factors (age group and OCS dose group), duration of OCS use, and baseline value.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.19
	Confidence Interval	(2-Sided) 95%; 0.631 to 2.229
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percent Change From Baseline in Daily Oral Corticosteroid (OCS) Dose During Weeks 20-24 Using a Mixed Model for Repeated Measures
Description	The baseline OCS dose is the prescribed optimized OCS dose following the OCS optimization period. Endpoint data are presented using an on-treatment approach. In this context, 'endpoint' was defined as the last observation obtained at a scheduled or qualified early termination visit during the treatment period. Weeks 20-24 data is included between the Week 20 dose and Week 24 for completed patients; last dose of study drug to 4 weeks after the last dose of study drug for patients who discontinued treatment early. Measurements collected outside of these defined timeframes are excluded from the analyses. The mixed model repeated measures (MMRM) included fixed effects for treatment, visit, treatment by visit interaction, age group, and OCS dose group, duration of OCS use and baseline value as covariates, and patient as a random effect. Unstructured covariance was assumed for the repeated measures.
Time Frame	Baseline (Day 1), Weeks 20-24

Outcome Measure Data

Analysis Population Description

ITT analysis population with available data using the on-treatment approach.

Arm/Group Title	Placebo	Reslizumab 110 mg
Arm/Group Description	Matching placebo was administered by subcutaneous injection (sc) 1.0 mL every 4 weeks for a total of six doses.	Reslizumab was administered by subcutaneous injection (sc) in a dosage of 110 mg (1.0 mL) every 4 weeks for a total of six doses.
Measure Participants	83	84
Least Squares Mean (Standard Error) [percent change]	-40.34 (17.318)	-58.08 (17.633)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reslizumab 110 mg
	Comments	Mixed model repeated measures (MMRM) with fixed effects for treatment, visit, treatment by visit interaction, age group, and OCS dose group, duration of OCS use and baseline value as covariates, and patient as a random effect. Unstructured covariance was assumed for the repeated measures.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.101
	Comments
	Method	mixed model repeated measures (MMRM)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-17.75
	Confidence Interval	(2-Sided) 95%; -38.986 to 3.494
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.759
	Estimation Comments	Reslizumab - Placebo

5. Secondary Outcome

Title	Percentage of Participants Achieving a >=5 mg Reduction in OCS Dose at Weeks 20-24 Compared to Baseline While Maintaining Asthma Control
Description	Percentage of participants whose OCS dose at weeks 20-24 was reduced by at least 5mg from baseline and maintained asthma control. Patients listed as "no" had a week 20-24 OCS dose that did not meet the threshold of a 5mg reduction, or whose OCS dose met the threshold but did not maintain asthma control, or discontinued from study drug.
Time Frame	Baseline (Day 1), Weeks 20-24

Outcome Measure Data

Analysis Population Description

ITT Analysis set; missing data are included as non-responders (No).

Arm/Group Title	Placebo	Reslizumab 110 mg
Arm/Group Description	Matching placebo was administered by subcutaneous injection (sc) 1.0 mL every 4 weeks for a total of six doses.	Reslizumab was administered by subcutaneous injection (sc) in a dosage of 110 mg (1.0 mL) every 4 weeks for a total of six doses.
Measure Participants	89	88
Yes	35 39.3%	41 46.6%
No	65 73%	59 67%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reslizumab 110 mg
	Comments	As the analysis of the primary efficacy endpoint did not meet criteria for statistical significance (p≤0.05), the secondary efficacy endpoints were not interpreted inferentially according to the pre-defined hierarchy. P-values are nominal, meaning they were obtained from the analysis without adjustments to protect family-wise errors and should be interpreted with caution. Nominal p-values do not indicate treatment differences.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.341
	Comments	significance at 0.05.
	Method	Regression, Logistic
	Comments	logistic regression model adjusted for treatment, stratification factors (age group and OCS dose group), duration of OCS use, and baseline value.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.36
	Confidence Interval	(2-Sided) 95%; 0.722 to 2.562
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Annualized Rate of Clinical Asthma Exacerbations (CAEs)
Description	The annual exacerbation rate is based on clinical asthma exacerbations reported by the investigator in the eCRF.
Time Frame	Day 1 through Week 24

Outcome Measure Data

Analysis Population Description

ITT Analysis Set

Arm/Group Title	Placebo	Reslizumab 110 mg
Arm/Group Description	Matching placebo was administered by subcutaneous injection (sc) 1.0 mL every 4 weeks for a total of six doses.	Reslizumab was administered by subcutaneous injection (sc) in a dosage of 110 mg (1.0 mL) every 4 weeks for a total of six doses.
Measure Participants	89	88
Number (95% Confidence Interval) [CAEs / year]	1.86	1.51

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reslizumab 110 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.407
	Comments
	Method	Negative binomial regression model
	Comments	Negative binomial regression model adjusted for stratification factors (OCS dose group), age, number of prior exacerbations, and an offset variable.
Method of Estimation	Estimation Parameter	CAE rate ratio
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.504 to 1.321
	Parameter Dispersion	Type: Value:
	Estimation Comments	reslizumab vs placebo

7. Secondary Outcome

Title	Percentage of Participants Achieving an OCS Dose of 0 mg at Weeks 20-24 While Maintaining Asthma Control
Description	Percentage of participants who discontinue use of OCS during weeks 20-24 while maintaining asthma control. Patients listed as "no" continued to use OCS during weeks 20-24, or who discontinued use of OCS during weeks 20-24 but lost control of their asthma, or discontinued from study drug.
Time Frame	Weeks 20-24

Outcome Measure Data

Analysis Population Description

ITT Analysis set; missing data are included as non-responders (No).

Arm/Group Title	Placebo	Reslizumab 110 mg
Arm/Group Description	Matching placebo was administered by subcutaneous injection (sc) 1.0 mL every 4 weeks for a total of six doses.	Reslizumab was administered by subcutaneous injection (sc) in a dosage of 110 mg (1.0 mL) every 4 weeks for a total of six doses.
Measure Participants	89	88
Yes	22 24.7%	20 22.7%
No	78 87.6%	80 90.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Reslizumab 110 mg
	Comments	As the analysis of the primary efficacy endpoint did not meet criteria for statistical significance (p≤0.05), the secondary efficacy endpoints were not interpreted inferentially according to the pre-defined hierarchy. P-values are nominal, meaning they were obtained from the analysis without adjustments to protect family-wise errors and should be interpreted with caution. Nominal p-values do not indicate treatment differences.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.628
	Comments	significance at 0.05.
	Method	Regression, Logistic
	Comments	logistic regression model adjusted for treatment, stratification factors (age group and OCS dose group), duration of OCS use, and baseline value.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.371 to 1.818
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Participants With Treatment-Emergent Anti-Drug Antibody (ADA) Responses
Description	Treatment-emergent responses were defined as a positive sample post-baseline (negative baseline) OR a titer increase of >=4-fold relative to a positive baseline sample. Two types of antibody assay were performed, an immunogenicity status assay (ADA) and neutralizing assay (NAb). The ADA assay produces a positive or negative result. For samples with a positive result, a neutralizing assay was performed, which also produces a positive or negative result.
Time Frame	Weeks 4, 8, 12, 24 or early withdrawal.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Reslizumab 110 mg
Arm/Group Description	Matching placebo was administered by subcutaneous injection (sc) 1.0 mL every 4 weeks for a total of six doses.	Reslizumab was administered by subcutaneous injection (sc) in a dosage of 110 mg (1.0 mL) every 4 weeks for a total of six doses.
Measure Participants	89	88
Positive ADA samples	0 0%	11 12.5%
Positive Nab samples	0 0%	0 0%

9. Secondary Outcome

Title	Participants With Adverse Events
Description	An adverse event is any untoward medical occurrence in a patient administered a pharmaceutical product, regardless of whether it has a causal relationship with this treatment. In this study, asthma exacerbations (which are efficacy parameters) should not be recorded as adverse events unless assessed by the investigator as more severe than the patient's usual disease course. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes. Treatment-related adverse events or adverse events related to OCS use included events with missing relationship to study drug or OCS use, respectively.
Time Frame	Day 1 up to Week 24 (end of treatment visit); Data were included between Day 1 and Week 24 for completed patients, and Day 1 and 4 weeks after the last dose of study drug for patients who discontinued treatment early.

Outcome Measure Data

Analysis Population Description

Safety analysis set

Arm/Group Title	Placebo	Reslizumab 110 mg
Arm/Group Description	Matching placebo was administered by subcutaneous injection (sc) 1.0 mL every 4 weeks for a total of six doses.	Reslizumab was administered by subcutaneous injection (sc) in a dosage of 110 mg (1.0 mL) every 4 weeks for a total of six doses.
Measure Participants	89	88
Any AE	47 52.8%	57 64.8%
Treatment-related AE	3 3.4%	7 8%
Serious AE (SAE)	4 4.5%	10 11.4%
Treatment-related SAE	0 0%	0 0%
SAE resulting in death	0 0%	1 1.1%
AE leading to treatment discontinuation	1 1.1%	0 0%
AE related to OCS withdrawal	2 2.2%	3 3.4%
AE related to OCS use	2 2.2%	5 5.7%

Adverse Events

Time Frame	Day 1 to Week 24
Arm/Group Title	Placebo		Reslizumab 110 mg
Arm/Group Description	Matching placebo was administered by subcutaneous injection (sc) 1.0 mL every 4 weeks for a total of six doses.		Reslizumab was administered by subcutaneous injection (sc) in a dosage of 110 mg (1.0 mL) every 4 weeks for a total of six doses.
All Cause Mortality
	Placebo		Reslizumab 110 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/89 (0%)		1/88 (1.1%)
Serious Adverse Events
	Placebo		Reslizumab 110 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/89 (4.5%)		10/88 (11.4%)
Gastrointestinal disorders
Inguinal hernia	0/89 (0%)	0	1/88 (1.1%)	1
General disorders
Sudden death	0/89 (0%)	0	1/88 (1.1%)	1
Immune system disorders
Drug hypersensitivity	0/89 (0%)	0	1/88 (1.1%)	1
Infections and infestations
Cellulitis	0/89 (0%)	0	1/88 (1.1%)	1
Influenza	0/89 (0%)	0	1/88 (1.1%)	1
Pneumonia	0/89 (0%)	0	1/88 (1.1%)	1
Pneumonia bacterial	1/89 (1.1%)	1	0/88 (0%)	0
Injury, poisoning and procedural complications
Contusion	1/89 (1.1%)	1	0/88 (0%)	0
Facial bones fracture	1/89 (1.1%)	1	0/88 (0%)	0
Fibula fracture	1/89 (1.1%)	1	0/88 (0%)	0
Foot fracture	1/89 (1.1%)	1	0/88 (0%)	0
Head injury	1/89 (1.1%)	1	0/88 (0%)	0
Rib fracture	1/89 (1.1%)	1	0/88 (0%)	0
Nervous system disorders
Syncope	0/89 (0%)	0	1/88 (1.1%)	1
Respiratory, thoracic and mediastinal disorders
Asthma	2/89 (2.2%)	2	3/88 (3.4%)	3
Other (Not Including Serious) Adverse Events
	Placebo		Reslizumab 110 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/89 (22.5%)		20/88 (22.7%)
Infections and infestations
Bronchitis	4/89 (4.5%)	4	6/88 (6.8%)	6
Upper respiratory tract infection	5/89 (5.6%)	5	1/88 (1.1%)	1
Viral upper respiratory tract infection	5/89 (5.6%)	5	11/88 (12.5%)	13
Respiratory, thoracic and mediastinal disorders
Asthma	4/89 (4.5%)	6	5/88 (5.7%)	6
Vascular disorders
Hypertension	5/89 (5.6%)	5	1/88 (1.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.