A Study of MHAA4549A in Combination With Oseltamivir Versus Oseltamivir in Participants With Severe Influenza A Infection
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| ClinicalTrials.gov Identifier: NCT02293863 |
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Recruitment Status :
Completed
First Posted : November 18, 2014
Results First Posted : June 18, 2018
Last Update Posted : June 18, 2018
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Sponsor:
Genentech, Inc.
Information provided by (Responsible Party):
Genentech, Inc.
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Brief Summary:
This is a randomized, double-blind, placebo-controlled study that will investigate the safety and clinical activity of a single intravenous (IV) dose of MHAA4549A in adult participants hospitalized with severe influenza A in combination with oseltamivir versus a comparator arm of placebo with oseltamivir.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Influenza | Drug: MHAA4549A Drug: Oseltamivir Drug: Placebo | Phase 2 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 168 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Double (Participant, Investigator) |
| Primary Purpose: | Treatment |
| Actual Study Start Date : | January 14, 2015 |
| Actual Primary Completion Date : | May 23, 2017 |
| Actual Study Completion Date : | May 23, 2017 |
Resource links provided by the National Library of Medicine
Drug Information available for:
Oseltamivir
| Arm | Intervention/treatment |
|---|---|
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Experimental: A: MHAA4549A 3600 mg + Oseltamivir
Participants will receive a single low IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
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Drug: MHAA4549A
Participants will receive a single dose of MHAA4549A by IV infusion on Day 1 Drug: Oseltamivir Participants will receive oseltamivir capsule either 75 mg or 150 mg BID orally for minimum of 5 days. Dosage and administration should follow local prescribing information for oseltamivir.
Other Name: Tamiflu |
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Experimental: B: MHAA4549A 8400 mg + Oseltamivir
Participants will receive a single high IV dose of MHAA4549A on Day 1 and standard oseltamivir therapy for minimum of 5 days.
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Drug: MHAA4549A
Participants will receive a single dose of MHAA4549A by IV infusion on Day 1 Drug: Oseltamivir Participants will receive oseltamivir capsule either 75 mg or 150 mg BID orally for minimum of 5 days. Dosage and administration should follow local prescribing information for oseltamivir.
Other Name: Tamiflu |
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Placebo Comparator: C: Placebo + Oseltamivir
Participants will receive a single IV dose of placebo matched to MHAA4549A on Day 1 and standard oseltamivir therapy (75 or 150 mg BID) for minimum of 5 days.
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Drug: Oseltamivir
Participants will receive oseltamivir capsule either 75 mg or 150 mg BID orally for minimum of 5 days. Dosage and administration should follow local prescribing information for oseltamivir.
Other Name: Tamiflu Drug: Placebo Participants will receive a single IV dose of placebo matched to MHAA4549A on Day 1 |
Primary Outcome Measures :
- Percentage of Participants With Adverse Events [ Time Frame: From randomization up to 60 days ]An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
- Number of Participants With Anti-Therapeutic Antibodies (ATA) to MHAA4549A During and Following Administration of MHAA4549A [ Time Frame: From randomization up to 60 days ]Reported are the number of participants positive for ATAs at baseline, the number of participants with treatment-induced ATAs and the number of participants with treatment-enhanced ATAs.
- Time to Normalization of Respiratory Function [ Time Frame: From randomization up to 60 days ]The time to normalization of respiratory function was defined as the time to removal of the participant from oxygen (O2) supplementation in order to maintain a blood oxygen saturation level (SpO2) equal to or greater than 95% as measured by pulse oximetry.
Secondary Outcome Measures :
- Percentage of Participants by Clinical Status Using a Categorical Ordinal Outcome [ Time Frame: Days 1-7, 14 and 30 ]The clinical status of participants was defined by five mutually exclusive categories: 1. Death; 2. In the Intensive Care Unit (ICU); 3. Non-ICU hospitalization, requiring supplemental oxygen (O2); 4. Non-ICU hospitalization, not requiring supplemental oxygen (O2); 5. Not hospitalized.
- Percentage of Participants With Clinical Failure [ Time Frame: 24 hours after end of infusion (infusion duration = approximately 120 minutes) up to Day 60 ]Clinical failure after 24 hours post-infusion of study drug was defined as progression to increased O2 requirement defined by an increase in oxygen supplementation from low flow oxygen (i.e., 2-6 liters per minute [L/min]) to high flow oxygen (i.e., > 6 L/min) or from oxygen supplementation alone to any positive pressure ventilation (PPV) or extracorporeal membrane oxygenation (ECMO), progression to ICU, prolonged ventilation or O2 support defined by > 2 weeks, or death.
- Percentage of Participants With Clinical Resolution of Abnormal Vital Signs [ Time Frame: From randomization up to 60 days ]Description: Clinical resolution of abnormal vital signs was defined as meeting three out of five of the following criteria: 1. SpO2 ≥ 95% without supplemental O2; 2. Respiratory rate < 24 breaths per minute without supplemental O2; 3. Core temperature < 37.2 Celsius (C) immediately prior to receipt of any antipyretic drug, and at least 6-8 hours from the last dose of antipyretic or core temperature > 36 C in participants who are initially hypothermic; 4. Heart rate (HR) < 100 beats/minute; 5. Systolic blood pressure (SBP) >90 mmHg. Reported here is the percentage of participants who had clinical resolution of at least three out of five abnormal vital signs by the end of study.
- Percentage of Participants Who Died Due to Any Cause [ Time Frame: Days 14, 30 and 60 ]
- Area Under Viral Load-Time Curve (AUEC ) of Influenza A Virus [ Time Frame: Immediately prior to MHAA4549A infusion and oseltamivir dosing on Day 1, immediately prior to oseltamivir dosing on Days 2 to 10, Days 14, 20, 25, 30, on day of discharge from hospital (up to Day 60), and at study completion (Day 60) ]Influenza A viral load was measured by quantitative polymerase chain reaction (qPCR) in nasopharyngeal samples at multiple time points during the study. AUEC is the area under the viral load-time curve expressed as log10 (viral particles/milliliter x hour) = log10 (vp/mL x hour).
- Peak Influenza A Viral Load [ Time Frame: Immediately prior to MHAA4549A infusion and oseltamivir dosing on Day 1, immediately prior to oseltamivir dosing on Days 2 to 10, Days 14, 20, 25, 30, on day of discharge from hospital (up to Day 60), and at study completion (Day 60) ]Influenza A viral load was measured by qPCR in nasopharyngeal samples at multiple time points during the study. Reported here is the peak Influenza A viral load expressed as log10 vp/mL.
- Duration of Viral Shedding [ Time Frame: Immediately prior to MHAA4549A infusion and oseltamivir dosing on Day 1, immediately prior to oseltamivir dosing on Days 2 to 10, Days 14, 20, 25, 30, on day of discharge from hospital (up to Day 60), and at study completion (Day 60) ]Influenza A viral load was measured by qPCR in nasopharyngeal samples at multiple time points during the study. Reported here is the duration of viral shedding.
- Duration of Hospitalization [ Time Frame: From randomization up to 60 days ]
- Duration of Intensive Care Unit (ICU) Stay [ Time Frame: From randomization up to 60 days ]
- Percentage of Participants Using Antibiotics for Respiratory Infections [ Time Frame: From randomization up to 60 days ]
- Percentage of Participants With Secondary Complications of Influenza [ Time Frame: From randomization up to 60 days ]The following were considered secondary complications of influenza: pneumonia, including hospital-acquired pneumonia (HAP) and ventilation-acquired pneumonia (VAP), exacerbations of chronic lung disease, myocarditis, acute respiratory distress syndrome (ARDS), otitis media, or other related complications.
- Percentage of Participants Readmitted to Hospital Due to Any Cause [ Time Frame: Days 30 and 60 ]
- Duration of Ventilation [ Time Frame: From randomization up to 60 days ]
- Area Under Serum Concentration-Time Curve From Time 0 to Infinity (AUC ) of MHAA4549A [ Time Frame: 30 minutes (min) before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60) ]AUC0-inf is reported as day*microgram/milliliter (day*mcg/mL).
- Maximum Serum Concentration (Cmax ) of MHAA4549A [ Time Frame: 30 min before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60) ]
- Elimination Half-Life (Terminal t1/2) of MHAA4549A [ Time Frame: 30 min before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60) ]
- Observed Clearance (CL-obs) of MHAA4549A [ Time Frame: 30 min before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60) ]
- Observed Steady State Volume of Distribution (Vss_obs) of MHAA4549A [ Time Frame: 30 min before & 60 min after end of MHAA4549A infusion (infusion duration = 120 min) on Day 1; immediately prior to oseltamivir dose on Days 2, 3, 5, 7; on Days 14, 30; on day of discharge (up to Day 60); at study completion (Day 60) ]
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Diagnosis of influenza A where a Sponsor-approved influenza test is used as an aid in diagnosis. A Sponsor-approved influenza test includes: Influenza antigen test or Influenza polymerase chain reaction (PCR) test
- One of the following markers of severity within 24 hours of admission: requirement for O2 supplementation to maintain SpO2 greater than (>) 92 %; or requirement for Positive Pressure Ventilation (PPV)
- A negative urine or serum pregnancy test for women of childbearing potential within 2 days prior to study treatment
- Participants of reproductive potential must agree to use acceptable contraceptive measures as per the protocol as a minimum, and local guidelines, if more stringent
Exclusion Criteria:
- Pregnant or lactating women, or women who intend to become pregnant during the study
- Hypersensitivity to monoclonal antibodies or any constituents (sodium succinate, sucrose, polysorbate 20) of study drug
- Hypersensitivity to the active substance or to any excipients of oseltamivir
- Investigational therapy within the 30 days prior to study treatment
- Received prior therapy with any anti-influenza monoclonal antibody therapy (including MHAA4549A) within 8 months prior to study treatment
- Current treatment (within 7 days of dosing) with probenecid, amantadine or rimantidine
- Participants who have taken more than a total of 6 doses (3 doses for peramivir) of anti-influenza therapy (e.g., oseltamivir, zanamivir, laninamivir, peramivir) in the period from onset of symptoms and prior to study treatment
- Admission >48 hours prior to study treatment
- Onset of influenza symptoms (including fever, chills, malaise, dry cough, loss of appetite, myalgias, coryza, or nausea) >5 days prior to study treatment
- Positive influenza B or influenza A + B infection within 2 weeks prior to study treatment
- High probability of mortality in the next 48 hours as determined by the investigator
- Participants requiring home or baseline oxygenation therapy
- Participants with history of chronic lung disease with a documented SpO2 less than (<) 95% off oxygen
- Participants on chronic dose of corticosteroids exceeding 10 milligrams per day (mg/day) of prednisone or equivalent steroid dose for duration of greater than 14 days within 30 days of entry into study
- Participants with the following significant immune suppression: bone marrow or solid organ transplant in the previous 12 months; cancer chemotherapy in the previous 12 months, HIV infection with most recent Cluster of Differentiation 4 (CD4) <200 cells per milliliter (cells/mL), or other significant immune suppression as determined by the investigator in discussion with the Sponsor Medical Monitor
- Participants on extracorporeal membrane oxygenation (ECMO) at time of randomization
- Any disease or condition that would, in the opinion of the site investigator or Sponsor, place the participant at an unacceptable risk of injury or render the participant unable to meet the requirements of the protocol
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02293863
Locations
Show 171 study locations
Sponsors and Collaborators
Genentech, Inc.
Investigators
| Study Director: | Clinical Trials | Hoffmann-La Roche |
Study Documents (Full-Text)
Documents provided by Genentech, Inc.:
Documents provided by Genentech, Inc.:
Study Protocol and Statistical Analysis Plan [PDF] May 16, 2016
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Genentech, Inc. |
| ClinicalTrials.gov Identifier: | NCT02293863 |
| Other Study ID Numbers: |
GV29216 2014-000461-43 ( EudraCT Number ) |
| First Posted: | November 18, 2014 Key Record Dates |
| Results First Posted: | June 18, 2018 |
| Last Update Posted: | June 18, 2018 |
| Last Verified: | May 2018 |
Additional relevant MeSH terms:
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Influenza, Human Respiratory Tract Infections Infections Orthomyxoviridae Infections RNA Virus Infections Virus Diseases |
Respiratory Tract Diseases Oseltamivir Antiviral Agents Anti-Infective Agents Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |