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This trial will study three doses of reslizumab versus placebo in children with eosinophilic esophagitis (EE). The objectives of the trial will be to study the effectiveness of reslizumab in improving the clinical signs and symptoms and reducing esophageal eosinophils as well as assessing the safety profile compared to placebo.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Reslizumab 1 mg/kg | Experimental | reslizumab 1 mg/kg intravenous (IV) on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles |
|
| Reslizumab 2 mg/kg | Experimental | reslizumab 2 mg/kg IV on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles |
|
| Reslizumab 3 mg/kg | Experimental | reslizumab 3 mg/kg IV on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles |
|
| Placebo | Placebo Comparator | saline placebo IV on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Reslizumab | Biological |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Mean Percent Change From Baseline to End of Treatment in Peak Esophageal Eosinophil (EE) Levels | Participants underwent esophagogastroduodenoscopy (EGD) with biopsy (2 biopsies each at proximal and distal esophageal locations, plus any inflamed or abnormal areas) per standard clinical practice for the determination of esophageal eosinophils. | Baseline, End of Treatment (up to 15 weeks [+/- 4 days]) |
| Mean Change From Baseline in Physician's Esophageal Eosinophil (EE) Global Assessment At The End-of-Treatment Visit (or at Early Withdrawal) | The investigator completed the Physician's EE Global Assessment based upon the participant's reporting of symptoms, weight, dietary status, and overall well-being. The assessment rated severity on a five-point scale (0=none to 4=very severe), taking into account physical findings, vital signs, the Subject's Predominant EE Symptom Assessment, the subject's diary data, and dietary questions. The Subject's Predominant EE Symptom was the EE symptom (vomiting/regurgitation, abdominal/chest pain, or dysphagia) that had the greatest negative impact on the subject based on patient diary data as of the baseline visit. The full range for change from baseline values is -4 (very severe at baseline, none at end of study) to 4 (none at baseline, severe at end of study). Negative change from baseline scores in the Physician's EE Global Assessment indicate improvement in EE status. | Baseline (Day 1, pre-treatment), End of Treatment (Week 15, 3 weeks [± 4 days] after the last dose of study drug, or at early withdrawal) |
| Measure | Description | Time Frame |
|---|---|---|
| Mean Change From Baseline to End of Treatment in EE Predominant Symptom Assessment | Participants rated the severity of each EE symptom (vomiting/regurgitation, abdominal/chest pain, and dysphagia) based on the previous week's daily diary as none (=0), mild, moderate, severe, or very severe (=4). The predominant symptom was selected at the baseline visit and remained the same throughout the trial. The predominant symptom was defined as the EE symptom that had the greatest negative impact on the participant. The full range for change from baseline values is -4 (very severe at baseline, none at end of study) to 4 (none at baseline, severe at end of study). Negative change from baseline scores in the Patient's EE Predominant Symptom Assessment indicate improvement in the selected symptom. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Sponsor's Medical Expert, MD | Cephalon (Ception) | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Children's Hospital of Alabama | Birmingham | Alabama | 35233 | United States | ||
| University of Arizona Dept. of Pediatrics |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22206777 | Result | Spergel JM, Rothenberg ME, Collins MH, Furuta GT, Markowitz JE, Fuchs G 3rd, O'Gorman MA, Abonia JP, Young J, Henkel T, Wilkins HJ, Liacouras CA. Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2012 Feb;129(2):456-63, 463.e1-3. doi: 10.1016/j.jaci.2011.11.044. Epub 2011 Dec 28. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Reslizumab 1 mg/kg | reslizumab 1 mg/kg intravenous (IV) on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles |
| FG001 | Reslizumab 2 mg/kg | reslizumab 2 mg/kg IV on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Saline | Other |
|
| Baseline (Day 1, pre-treatment), End of Treatment (Week 15, 3 weeks [± 4 days] after the last dose of study drug, or at early withdrawal) |
| Mean Percent Change From Baseline to End of Treatment in the Child Health Questionnaire (CHQ) | CHQ is a quality-of-life (QoL), observer-rated (the parent in this study) instrument designed to assess the general health and well-being of pediatric subjects aged 5 to 18 years. The instrument comprises 50 items that cover 14 unique physical and psychological concepts. Each item was scored separately following different scales and timeframes for response. Proprietary scoring algorithms are used. This outcome reports the two CHQ Summary Scores (Physical Summary Score and the Psychosocial Summary Scores) which are indexed to a 0 (poorest quality of life) to 100 (best quality of life) scores. The two summary scores are subsequently combined (via proprietary algorithm) to create the Global Health Summary Score (also on a 0-100 scale). Percent change from baseline values range from 100% (poorest QoL at baseline, best QoL at end of treatment) to -100% (best QoL at baseline, poorest QoL at end of treatment). Higher percent change from baseline values indicate improved QoL. | Baseline, End of Treatment (up to 15 weeks +/- 4 days) |
| Tucson |
| Arizona |
| 85724 |
| United States |
| Arkansas Children's Hospital/University of Arkansas for Medical Sciences | Little Rock | Arkansas | 72202 | United States |
| Kaiser Permanente Hospital- Pediatric Gastroenterology | Hayward | California | 94545 | United States |
| Children'S Hospital of Orange County Pediatric Subspecialty Faculty Division of Allergy and Asthma | Orange | California | 92868 | United States |
| Pediatric Allergy/Immunology | Palo Alto | California | 94305 | United States |
| Children's Hospital of San Diego | San Diego | California | 92123 | United States |
| Denver Childrens At Aurora, Colorado | Aurora | Colorado | 80045 | United States |
| 1st Allergy and Clinical Research Center | Centennial | Colorado | 80112 | United States |
| Thomas Jefferson University Medical College | Wilmington | Delaware | 19803 | United States |
| Children's Center for Digestive Health Care | Atlanta | Georgia | 30342 | United States |
| University of Chicago | Chicago | Illinois | 60637 | United States |
| Children'S Memorial Hospital Division of Gastroenterology Hepatology & Nutrition | Chicago | Illinois | 66014 | United States |
| Riley Hospital for Children | Indianapolis | Indiana | 46202 | United States |
| Sinai Hospital of Baltimore | Baltimore | Maryland | 21215 | United States |
| Tuft's Floating Hospital | Boston | Massachusetts | 02111 | United States |
| Minnesota Gastroenterology | Plymouth | Minnesota | 55446 | United States |
| Saint Louis University | St Louis | Missouri | 63104 | United States |
| Creighton University Medical Center | Omaha | Nebraska | 68131 | United States |
| Las Vegas Pediatric Gastroenterology Associates | Las Vegas | Nevada | 89109 | United States |
| South Jersey Pediatric Gastroenterology | Mays Landing | New Jersey | 08330 | United States |
| Mount Sinai School of Medicine, Pediatrics | New York | New York | 10029 | United States |
| State University of New York (SUNY) | Syracuse | New York | 13210 | United States |
| Center for Digestive Allergic and Immunologic Diseases | Williamsville | New York | 14221 | United States |
| Pediatric Allergy and Immunology of Duke Medical Center | Durham | North Carolina | 27720 | United States |
| Cincinnati Children's | Cincinnati | Ohio | 45229 | United States |
| Nationwide Children's Hospital | Columbus | Ohio | 43205 | United States |
| Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | 19104 | United States |
| Greenville Health System | Greenville | South Carolina | 29615 | United States |
| University of Texas Southwest Medical Center | Dallas | Texas | 75390 | United States |
| University of Utah School of Medicine | Salt Lake City | Utah | 84113 | United States |
| Virginia Commonwealth University | Richmond | Virginia | 23219 | United States |
| Carilion Medical Center for Children | Roanoke | Virginia | 24013 | United States |
| Medical College of Wisconsin | Milwaukee | Wisconsin | 53226 | United States |
| Pediatric Allergy and Immunology | Edmonton | Alberta | T6G 2C8 | Canada |
| Pediatric Allergy & Immunology | Edmonton | Alberta | T6G2C8 | Canada |
| University of Montreal | Montreal | Quebec | H3T 1C5 | Canada |
| FG002 | Reslizumab 3 mg/kg | reslizumab 3 mg/kg IV on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles |
| FG003 | Placebo | saline placebo IV on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles |
| Intent-to-treat (ITT) Population |
|
| COMPLETED |
|
| NOT COMPLETED |
|
ITT population: all randomized participants who received any amount of study drug.
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| ID | Title | Description |
|---|---|---|
| BG000 | Reslizumab 1 mg/kg | reslizumab 1 mg/kg intravenous (IV) on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles |
| BG001 | Reslizumab 2 mg/kg | reslizumab 2 mg/kg IV on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles |
| BG002 | Reslizumab 3 mg/kg | reslizumab 3 mg/kg IV on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles |
| BG003 | Placebo | saline placebo IV on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles |
| BG004 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Age, Customized | Number | participants |
| ||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Mean Percent Change From Baseline to End of Treatment in Peak Esophageal Eosinophil (EE) Levels | Participants underwent esophagogastroduodenoscopy (EGD) with biopsy (2 biopsies each at proximal and distal esophageal locations, plus any inflamed or abnormal areas) per standard clinical practice for the determination of esophageal eosinophils. | ITT population: all randomized participants who received any amount of study drug. | Posted | Mean | Standard Deviation | percentage change in eosinophils/hpf | Baseline, End of Treatment (up to 15 weeks [+/- 4 days]) |
|
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary | Mean Change From Baseline in Physician's Esophageal Eosinophil (EE) Global Assessment At The End-of-Treatment Visit (or at Early Withdrawal) | The investigator completed the Physician's EE Global Assessment based upon the participant's reporting of symptoms, weight, dietary status, and overall well-being. The assessment rated severity on a five-point scale (0=none to 4=very severe), taking into account physical findings, vital signs, the Subject's Predominant EE Symptom Assessment, the subject's diary data, and dietary questions. The Subject's Predominant EE Symptom was the EE symptom (vomiting/regurgitation, abdominal/chest pain, or dysphagia) that had the greatest negative impact on the subject based on patient diary data as of the baseline visit. The full range for change from baseline values is -4 (very severe at baseline, none at end of study) to 4 (none at baseline, severe at end of study). Negative change from baseline scores in the Physician's EE Global Assessment indicate improvement in EE status. | ITT population: all randomized participants who received any amount of study drug with both a baseline and an End of Treatment assessment. | Posted | Mean | Standard Deviation | units on a scale | Baseline (Day 1, pre-treatment), End of Treatment (Week 15, 3 weeks [± 4 days] after the last dose of study drug, or at early withdrawal) |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Mean Change From Baseline to End of Treatment in EE Predominant Symptom Assessment | Participants rated the severity of each EE symptom (vomiting/regurgitation, abdominal/chest pain, and dysphagia) based on the previous week's daily diary as none (=0), mild, moderate, severe, or very severe (=4). The predominant symptom was selected at the baseline visit and remained the same throughout the trial. The predominant symptom was defined as the EE symptom that had the greatest negative impact on the participant. The full range for change from baseline values is -4 (very severe at baseline, none at end of study) to 4 (none at baseline, severe at end of study). Negative change from baseline scores in the Patient's EE Predominant Symptom Assessment indicate improvement in the selected symptom. | ITT population: all randomized participants who received any amount of study drug with both a baseline and an End of Treatment assessment. | Posted | Mean | Standard Deviation | units on a scale | Baseline (Day 1, pre-treatment), End of Treatment (Week 15, 3 weeks [± 4 days] after the last dose of study drug, or at early withdrawal) |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Mean Percent Change From Baseline to End of Treatment in the Child Health Questionnaire (CHQ) | CHQ is a quality-of-life (QoL), observer-rated (the parent in this study) instrument designed to assess the general health and well-being of pediatric subjects aged 5 to 18 years. The instrument comprises 50 items that cover 14 unique physical and psychological concepts. Each item was scored separately following different scales and timeframes for response. Proprietary scoring algorithms are used. This outcome reports the two CHQ Summary Scores (Physical Summary Score and the Psychosocial Summary Scores) which are indexed to a 0 (poorest quality of life) to 100 (best quality of life) scores. The two summary scores are subsequently combined (via proprietary algorithm) to create the Global Health Summary Score (also on a 0-100 scale). Percent change from baseline values range from 100% (poorest QoL at baseline, best QoL at end of treatment) to -100% (best QoL at baseline, poorest QoL at end of treatment). Higher percent change from baseline values indicate improved QoL. | ITT population: all randomized participants who received any amount of study drug with both a baseline and an End of Treatment assessment; n=number of participants with a response in the given category. | Posted | Mean | Standard Deviation | percentage change in score | Baseline, End of Treatment (up to 15 weeks +/- 4 days) |
|
Baseline through Safety Follow-up (Week 16)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Reslizumab 1 mg/kg | reslizumab 1 mg/kg intravenous (IV) on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles | 1 | 55 | 38 | 55 | ||
| EG001 | Reslizumab 2 mg/kg | reslizumab 2 mg/kg IV on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles | 1 | 57 | 29 | 57 | ||
| EG002 | Reslizumab 3 mg/kg | reslizumab 3 mg/kg IV on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles | 1 | 57 | 39 | 57 | ||
| EG003 | Placebo | saline placebo IV on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles | 2 | 57 | 40 | 57 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| ABDOMINAL PAIN | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
| |
| GASTROINTESTINAL INFLAMMATION | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
| |
| ANAPHYLACTIC REACTION | Immune system disorders | MedDRA 11.0 | Systematic Assessment |
| |
| GASTROENTERITIS VIRAL | Infections and infestations | MedDRA 11.0 | Systematic Assessment |
| |
| SYNCOPE | Nervous system disorders | MedDRA 11.0 | Systematic Assessment |
| |
| RESPIRATORY DISTRESS | Respiratory, thoracic and mediastinal disorders | MedDRA 11.0 | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| ABDOMINAL PAIN | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
| |
| ABDOMINAL PAIN UPPER | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
| |
| DIARRHOEA | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
| |
| NAUSEA | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
| |
| VOMITING | Gastrointestinal disorders | MedDRA 11.0 | Systematic Assessment |
| |
| CHEST PAIN | General disorders | MedDRA 11.0 | Systematic Assessment |
| |
| FATIGUE | General disorders | MedDRA 11.0 | Systematic Assessment |
| |
| PYREXIA | General disorders | MedDRA 11.0 | Systematic Assessment |
| |
| GASTROENTERITIS VIRAL | Infections and infestations | MedDRA 11.0 | Systematic Assessment |
| |
| INFLUENZA | Infections and infestations | MedDRA 11.0 | Systematic Assessment |
| |
| NASOPHARYNGITIS | Infections and infestations | MedDRA 11.0 | Systematic Assessment |
| |
| OTITIS MEDIA | Infections and infestations | MedDRA 11.0 | Systematic Assessment |
| |
| PHARYNGITIS STREPTOCOCCAL | Infections and infestations | MedDRA 11.0 | Systematic Assessment |
| |
| SINUSITIS | Infections and infestations | MedDRA 11.0 | Systematic Assessment |
| |
| UPPER RESPIRATORY TRACT INFECTION | Infections and infestations | MedDRA 11.0 | Systematic Assessment |
| |
| VIRAL INFECTION | Infections and infestations | MedDRA 11.0 | Systematic Assessment |
| |
| PROTEIN URINE | Investigations | MedDRA 11.0 | Systematic Assessment |
| |
| RED BLOOD CELLS URINE POSITIVE | Investigations | MedDRA 11.0 | Systematic Assessment |
| |
| URINARY CASTS | Investigations | MedDRA 11.0 | Systematic Assessment |
| |
| URINE OXALATE INCREASED | Investigations | MedDRA 11.0 | Systematic Assessment |
| |
| WHITE BLOOD CELLS URINE POSITIVE | Investigations | MedDRA 11.0 | Systematic Assessment |
| |
| ARTHRALGIA | Musculoskeletal and connective tissue disorders | MedDRA 11.0 | Systematic Assessment |
| |
| DIZZINESS | Nervous system disorders | MedDRA 11.0 | Systematic Assessment |
| |
| HEADACHE | Nervous system disorders | MedDRA 11.0 | Systematic Assessment |
| |
| COUGH | Respiratory, thoracic and mediastinal disorders | MedDRA 11.0 | Systematic Assessment |
| |
| NASAL CONGESTION | Respiratory, thoracic and mediastinal disorders | MedDRA 11.0 | Systematic Assessment |
| |
| PHARYNGOLARYNGEAL PAIN | Respiratory, thoracic and mediastinal disorders | MedDRA 11.0 | Systematic Assessment |
| |
| ECZEMA | Skin and subcutaneous tissue disorders | MedDRA 11.0 | Systematic Assessment |
| |
| RASH | Skin and subcutaneous tissue disorders | MedDRA 11.0 | Systematic Assessment |
|
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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Director, Clinical Research | Teva Branded Pharmaceutical Products, R&D Inc. | 215-591-3000 |
| ID | Term |
|---|---|
| D057765 | Eosinophilic Esophagitis |
| D005764 | Gastroesophageal Reflux |
| ID | Term |
|---|---|
| D004941 | Esophagitis |
| D004935 | Esophageal Diseases |
| D005767 | Gastrointestinal Diseases |
| D004066 | Digestive System Diseases |
| D005759 | Gastroenteritis |
| D004802 | Eosinophilia |
| D007960 | Leukocyte Disorders |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D006969 | Hypersensitivity, Immediate |
| D006967 | Hypersensitivity |
| D007154 | Immune System Diseases |
| D015154 | Esophageal Motility Disorders |
| D003680 | Deglutition Disorders |
Not provided
Not provided
| ID | Term |
|---|---|
| C515492 | reslizumab |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |
Not provided
Not provided
| 12 to < 19 years |
|
| Male |
|
adjustment for stratification factor and for variable at Baseline |
| < 0.0001 |
| Adjusted mean difference |
| -73.03 |
| Standard Error of the Mean |
| 11.29 |
| 2-Sided |
| 95 |
| -95.28 |
| -50.78 |
| No |
| Superiority or Other |
| ANCOVA | adjustment for stratification factor and for variable at Baseline | < 0.0001 | Adjusted mean difference | -64.69 | Standard Error of the Mean | 11.28 | 2-Sided | 95 | -86.93 | -42.45 | No | Superiority or Other |
reslizumab 2 mg/kg IV on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles |
| OG002 | Reslizumab 3 mg/kg | reslizumab 3 mg/kg IV on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles |
| OG003 | Placebo | saline placebo IV on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles |
|
|
|
| OG002 |
| Reslizumab 3 mg/kg |
reslizumab 3 mg/kg IV on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles |
| OG003 | Placebo | saline placebo IV on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles |
|
|
|
reslizumab 2 mg/kg intravenous (IV) on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles |
| OG002 | Reslizumab 3 mg/kg | reslizumab 3 mg/kg IV on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles |
| OG003 | Placebo | saline placebo IV on Day 0 of each 28-day (+/-7 days) cycle, for up to 4 cycles |
|
|
|