Multiple Sclerosis, Relapsing Forms
Conditions
Keywords
MAb, B cell, depletion, RMS
Brief summary
The purpose of this study is to evaluate the safety and tolerability of ascending intravenous (IV) and subcutaneous (SC) doses of MEDI-551 in adult subjects with relapsing forms of multiple sclerosis (MS).
Detailed description
This is a Phase 1, multicenter, multinational, randomized, blinded, placebo-controlled, dose-escalation study to evaluate the safety and tolerability of IV and SC doses of MEDI-551 in adult subjects with relapsing forms of MS.
Interventions
DRUGMEDI-551 30 MG-IV
Participants received a fixed IV dose of 30 milligram (mg) MEDI-551 infused on Days 1 and 15.
DRUGMEDI-551 60 MG-SC
Participants received SC injection of 60 mg MEDI-551 on Day 1.
DRUGPLACEBO-IV-SC
Participants received either a fixed IV dose of placebo matching with MEDI- 551 on Days 1 and 15 or SC injection on Day 1
DRUGMEDI-551 100 MG-IV
Participants received a fixed IV dose of 100 mg MEDI-551 infused on Days 1 and 15.
DRUGMEDI-551 300 MG-SC
Participants received SC injection of 300 mg MEDI-551 on Day 1.
DRUGMEDI-551 600 MG-IV
Participants received a fixed IV dose of 600 mg MEDI-551 infused on Days 1 and 15.
Sponsors
MedImmune LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Confirmed relapsing form of MS (ie, RRMS, SPMS, PRMS, or CIS) according to revised 2010 McDonald criteria and MRI brain lesions consistent with MS on screening * At least 1 documented relapse within the past 3 years prior to screening * EDSS between 0.0 and 6.5 at screening * Have no more than 20 Gd-enhancing T1 brain lesions detected by cranial MRI scan
Exclusion criteria
* Subjects with impaired renal function * Major surgery within 8 weeks of the screening visit * Subjects who are unable to undergo cranial MRI scan * A history of hypersensitivity to Gd-containing MRI contrast agents * Has received within 1 year prior to screening: monoclonal antibodies, experimental B-cell depleting agents, or treatment with natalizumab (Tysabri) for greater than 3 months * Receiving monthly methylprednisone or equivalent glucocorticoid for disease modification of a relapsing form of MS * Known sensitivity to acetaminophen/paracetamol, diphenhydramine or equivalent antihistamine, methylprednisolone or equivalent glucocorticoid, or to any component of the investigational drug * Diagnosis of PPMS, neuromyelitis optica, or other non-MS variant of neuro-inflammatory or demyelinating diseases * Any history of opportunistic infection or the presence of active infection within two months prior to screening or any herpes zoster infection that has not resolved within 12 weeks prior to screening * Any clinically significant findings during the screening phase, including physical, neurological, laboratory, or ECG examination as per protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | From study drug administration (Day 1) through the end of treatment period (Day 169) | An adverse event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A TEAE were the events between administration of study drug (Day 1) and Day 169 that were absent before treatment or that worsened relative to pre-treatment state. The AEs were summarized using Medical Dictionary for Regulatory Activities version 19.0 |
| Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) | From study drug administration (Day 1) through the long term follow up period (up to 18 months after early discontinuation visit or 24 week treatment period). | A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death, life-threatening, initial or prolonged inpatient hospitalization, persistent or significant disability or incapacity, congenital anomaly or birth defect in the offspring of a participant who received the study drug. The TESAEs were the events between administration of study drug (Day 1) and long term follow up period (up to 18 months after early discontinuation visit or 24-week treatment period) that were absent before treatment or that worsened relative to pre-treatment state. The AEs were summarized using Medical Dictionary for Regulatory Activities version 19.0 |
| Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | From study drug administration (Day 1) through the end of treatment period (Day 169) | Any clinically significant change in laboratory evaluations were recorded as AEs. The following parameters were analyzed for laboratory evaluations: haematology, serum chemistry, and urinalysis. Number of participants with TEAEs related to laboratory evaluations were reported. |
| Number of Participants With Vital Sign Abnormalities Reported as TEAEs | From study drug administration (Day 1) through the end of treatment period (Day 169) | Vital sign parameters included blood pressure, temperature, pulse rate, and respiratory rate. The number of participants with TEAEs related to vital signs in participants were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dose Normalized Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC 0-infinity/D) of MEDI-551 | Predose (Day 1) and Postdose (IV Cohorts only), Days 4 (SC Cohorts only), 8, 15 Predose and Postdose (IV Cohorts only), 29, 57, 85, 113, 141, and 169 | The AUC (0-infinity)/D is the area under concentration-time curve extrapolated to infinity post dose normalized by MEDI-551. |
| Clearance of MEDI-551 | Predose (Day 1) and Postdose (IV Cohorts only), Days 4 (SC Cohorts only), 8, 15 Predose and Postdose (IV Cohorts only), 29, 57, 85, 113, 141, and 169 | Systemic clearance (CL) for MEDI-551 IV cohorts and apparent clearance (CL/F) for MEDI-551 SC cohorts were calculated |
| Terminal Elimination Half-life (t1/2) of MEDI-551 | Predose (Day 1) and Postdose (IV Cohorts only), Days 4 (SC Cohorts only), 8, 15 Predose and Postdose (IV Cohorts only), 29, 57, 85, 113, 141, and 169 | The terminal elimination half-life (t1/2) was estimated based on the plasma concentrations of MEDI-551. |
| Absolute Subcutaneous Bioavailability (F%) of MEDI-551 | Predose (Day 1) and Days 4, 8, 15, 29, 57, 85, 113, 141, and 169 | Bioavailability (F%) is the fraction of the study drug absorbed through non-intravenous administration compared with the corresponding intravenous administration of the same drug. |
| Time to Reach Maximum Observed Serum Concentration (Tmax) of MEDI-551 | Predose (Day 1) and Postdose (IV Cohorts only), Days 4 (SC Cohorts only), 8, 15 Predose and Postdose (IV Cohorts only), 29, 57, 85, 113, 141, and 169 | The time to reach the maximum observed serum concentration of MEDI-551. |
| Time to 90 Percent (%) CD20 B-cell Depletion | Baseline (Days -28 to -1) to long-term follow-up (LTFU) (Up to 18 months after EDV or 24 Week treatment period) | Time in days of first observation where CD20 counts fall to or below 10 percent (%) of baseline. |
| Duration of Suppression Greater Than or Equal to 90 % of CD20 B-cell Count | Baseline (Days -28 to -1) to LTFU (Up to 18 months after EDV or 24 Week treatment period) | Time in days of last observation where CD20 counts remain at or below 10% of baseline. Participants whose samples are available were analyzed for this outcome measure. |
| Maximum Change From Baseline in Absolute CD20 of Peripheral Blood B-cell Count to LTFU | Baseline (Days -28 to -1) to LTFU (Up to 18 months after EDV or 24 Week treatment period) | The maximum degree of depletion (intensity) measured during the course of the study for each participant by subtracting 100 from the lowest observed percent of baseline value. |
| Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Days 1, 29, 85 and 169 | A participant was considered anti-drug antibody positive across the study if they had a positive reading at any time point during the study. |
| Absolute CD20 B-cell Count at Baseline | Baseline (Days -28 to -1) | Baseline absolute CD20 count is measured as the average between screening and predose on Day 1. |
| Maximum Observed Serum Concentration (Cmax) of MEDI-551 | Predose (Day 1) and Postdose (IV Cohorts only), Days 4 (SC Cohorts only), 8, 15 Predose and Postdose (IV Cohorts only), 29, 57, 85, 113, 141, and 169 | The maximum observed serum concentration (Cmax) of MEDI-551. |
| Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC 0-last) of MEDI-551 | Predose (Day 1) and Postdose (IV Cohorts only), Days 4 (SC Cohorts only), 8, 15 Predose and Postdose (IV Cohorts only), 29, 57, 85, 113, 141, and 169 | The area under the concentration time curve from time 0 (dosing time) to the last measurable concentration (AUC 0-last) of MEDI-551. |
| Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC 0-infinity) of MEDI-551 | Predose (Day 1) and Postdose (IV Cohorts only), Days 4 (SC Cohorts only), 8, 15 Predose and Postdose (IV Cohorts only), 29, 57, 85, 113, 141, and 169 | The area under the concentration-time curve from dosing extrapolated to infinity (AUC 0-infinity) of MEDI-551. |
Countries
Poland, Spain, Ukraine, United States
Participant flow
Recruitment details
This study was conducted from 30 Jul 2012 to 20 Jun 2016 in United States, Poland, Spain, and Ukraine.
Pre-assignment details
A total of 56 participants were screened in this study. Out of which 28 participants were enrolled and randomized into the study.
Participants by arm
| Arm | Count |
|---|---|
| PLACEBO-IV-SC Participants received either a fixed IV dose of placebo matching MEDI-551 on Days 1 and 15 or SC injection on Day 1. | 7 |
| MEDI-551 30 Mg-IV Participants received a fixed IV dose of 30 milligram (mg) MEDI-551 infused on Days 1 and 15. | 5 |
| MEDI-551 60 Mg-SC Participants received SC injection of 60 mg MEDI-551 on Day 1. | 3 |
| MEDI-551 100 Mg-IV Participants received a fixed IV dose of 100 mg MEDI-551 infused on Days 1 and 15. | 4 |
| MEDI-551 300 Mg-SC Participants received SC injection of 300 mg MEDI-551 on Day 1. | 3 |
| MEDI-551 600 Mg-IV Participants received a fixed IV dose of 600 mg MEDI-551 infused on Days 1 and 15. | 6 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Death | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | PLACEBO-IV-SC | MEDI-551 30 Mg-IV | MEDI-551 60 Mg-SC | MEDI-551 100 Mg-IV | MEDI-551 300 Mg-SC | MEDI-551 600 Mg-IV | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 43.0 Years STANDARD_DEVIATION 15.9 | 42.4 Years STANDARD_DEVIATION 7.8 | 46.7 Years STANDARD_DEVIATION 16.3 | 46.5 Years STANDARD_DEVIATION 13.8 | 56.0 Years STANDARD_DEVIATION 6.1 | 44.2 Years STANDARD_DEVIATION 10.1 | 45.4 Years STANDARD_DEVIATION 12 |
| Sex: Female, Male Female | 6 Participants | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 3 Participants | 19 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 7 | 3 / 3 | 3 / 4 | 2 / 3 | 4 / 5 | 6 / 6 |
| serious Total, serious adverse events | 1 / 7 | 0 / 3 | 0 / 4 | 1 / 3 | 1 / 5 | 1 / 6 |
Outcome results
Primary
Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs
Any clinically significant change in laboratory evaluations were recorded as AEs. The following parameters were analyzed for laboratory evaluations: haematology, serum chemistry, and urinalysis. Number of participants with TEAEs related to laboratory evaluations were reported.
Time frame: From study drug administration (Day 1) through the end of treatment period (Day 169)
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PLACEBO-IV-SC | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Hematology- Anaemia | 1 Participants |
| PLACEBO-IV-SC | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Hematology- White blood cell count decreased | 0 Participants |
| PLACEBO-IV-SC | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Serum chemistry- Liver function test increased | 0 Participants |
| PLACEBO-IV-SC | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Serum chemistry- Hyponatraemia | 0 Participants |
| MEDI-551 30 Mg-IV | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Hematology- Anaemia | 0 Participants |
| MEDI-551 30 Mg-IV | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Serum chemistry- Liver function test increased | 1 Participants |
| MEDI-551 30 Mg-IV | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Hematology- White blood cell count decreased | 0 Participants |
| MEDI-551 30 Mg-IV | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Serum chemistry- Hyponatraemia | 0 Participants |
| MEDI-551 60 Mg-SC | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Hematology- White blood cell count decreased | 0 Participants |
| MEDI-551 60 Mg-SC | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Hematology- Anaemia | 0 Participants |
| MEDI-551 60 Mg-SC | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Serum chemistry- Hyponatraemia | 0 Participants |
| MEDI-551 60 Mg-SC | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Serum chemistry- Liver function test increased | 0 Participants |
| MEDI-551 100 Mg-IV | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Hematology- White blood cell count decreased | 1 Participants |
| MEDI-551 100 Mg-IV | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Hematology- Anaemia | 0 Participants |
| MEDI-551 100 Mg-IV | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Serum chemistry- Hyponatraemia | 0 Participants |
| MEDI-551 100 Mg-IV | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Serum chemistry- Liver function test increased | 0 Participants |
| MEDI-551 300 Mg-SC | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Serum chemistry- Hyponatraemia | 0 Participants |
| MEDI-551 300 Mg-SC | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Hematology- Anaemia | 0 Participants |
| MEDI-551 300 Mg-SC | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Serum chemistry- Liver function test increased | 0 Participants |
| MEDI-551 300 Mg-SC | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Hematology- White blood cell count decreased | 0 Participants |
| MEDI-551 600 Mg-IV | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Hematology- White blood cell count decreased | 0 Participants |
| MEDI-551 600 Mg-IV | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Hematology- Anaemia | 0 Participants |
| MEDI-551 600 Mg-IV | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Serum chemistry- Liver function test increased | 0 Participants |
| MEDI-551 600 Mg-IV | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Serum chemistry- Hyponatraemia | 1 Participants |
Primary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An adverse event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A TEAE were the events between administration of study drug (Day 1) and Day 169 that were absent before treatment or that worsened relative to pre-treatment state. The AEs were summarized using Medical Dictionary for Regulatory Activities version 19.0
Time frame: From study drug administration (Day 1) through the end of treatment period (Day 169)
Population: Safety Population is defined as all participants who received any amount of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PLACEBO-IV-SC | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 6 Participants |
| MEDI-551 30 Mg-IV | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 5 Participants |
| MEDI-551 60 Mg-SC | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 3 Participants |
| MEDI-551 100 Mg-IV | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 3 Participants |
| MEDI-551 300 Mg-SC | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 3 Participants |
| MEDI-551 600 Mg-IV | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 6 Participants |
Primary
Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs)
A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death, life-threatening, initial or prolonged inpatient hospitalization, persistent or significant disability or incapacity, congenital anomaly or birth defect in the offspring of a participant who received the study drug. The TESAEs were the events between administration of study drug (Day 1) and long term follow up period (up to 18 months after early discontinuation visit or 24-week treatment period) that were absent before treatment or that worsened relative to pre-treatment state. The AEs were summarized using Medical Dictionary for Regulatory Activities version 19.0
Time frame: From study drug administration (Day 1) through the long term follow up period (up to 18 months after early discontinuation visit or 24 week treatment period).
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PLACEBO-IV-SC | Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) | 1 Participants |
| MEDI-551 30 Mg-IV | Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) | 1 Participants |
| MEDI-551 60 Mg-SC | Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) | 0 Participants |
| MEDI-551 100 Mg-IV | Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) | 0 Participants |
| MEDI-551 300 Mg-SC | Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) | 1 Participants |
| MEDI-551 600 Mg-IV | Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) | 1 Participants |
Primary
Number of Participants With Vital Sign Abnormalities Reported as TEAEs
Vital sign parameters included blood pressure, temperature, pulse rate, and respiratory rate. The number of participants with TEAEs related to vital signs in participants were reported.
Time frame: From study drug administration (Day 1) through the end of treatment period (Day 169)
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PLACEBO-IV-SC | Number of Participants With Vital Sign Abnormalities Reported as TEAEs | Blood pressure decreased | 0 Participants |
| PLACEBO-IV-SC | Number of Participants With Vital Sign Abnormalities Reported as TEAEs | Blood pressure increased | 1 Participants |
| PLACEBO-IV-SC | Number of Participants With Vital Sign Abnormalities Reported as TEAEs | Tachycardia | 0 Participants |
| MEDI-551 30 Mg-IV | Number of Participants With Vital Sign Abnormalities Reported as TEAEs | Blood pressure decreased | 0 Participants |
| MEDI-551 30 Mg-IV | Number of Participants With Vital Sign Abnormalities Reported as TEAEs | Blood pressure increased | 0 Participants |
| MEDI-551 30 Mg-IV | Number of Participants With Vital Sign Abnormalities Reported as TEAEs | Tachycardia | 0 Participants |
| MEDI-551 60 Mg-SC | Number of Participants With Vital Sign Abnormalities Reported as TEAEs | Blood pressure decreased | 1 Participants |
| MEDI-551 60 Mg-SC | Number of Participants With Vital Sign Abnormalities Reported as TEAEs | Blood pressure increased | 1 Participants |
| MEDI-551 60 Mg-SC | Number of Participants With Vital Sign Abnormalities Reported as TEAEs | Tachycardia | 1 Participants |
| MEDI-551 100 Mg-IV | Number of Participants With Vital Sign Abnormalities Reported as TEAEs | Blood pressure decreased | 0 Participants |
| MEDI-551 100 Mg-IV | Number of Participants With Vital Sign Abnormalities Reported as TEAEs | Blood pressure increased | 0 Participants |
| MEDI-551 100 Mg-IV | Number of Participants With Vital Sign Abnormalities Reported as TEAEs | Tachycardia | 0 Participants |
| MEDI-551 300 Mg-SC | Number of Participants With Vital Sign Abnormalities Reported as TEAEs | Blood pressure decreased | 0 Participants |
| MEDI-551 300 Mg-SC | Number of Participants With Vital Sign Abnormalities Reported as TEAEs | Blood pressure increased | 0 Participants |
| MEDI-551 300 Mg-SC | Number of Participants With Vital Sign Abnormalities Reported as TEAEs | Tachycardia | 0 Participants |
| MEDI-551 600 Mg-IV | Number of Participants With Vital Sign Abnormalities Reported as TEAEs | Blood pressure increased | 2 Participants |
| MEDI-551 600 Mg-IV | Number of Participants With Vital Sign Abnormalities Reported as TEAEs | Tachycardia | 0 Participants |
| MEDI-551 600 Mg-IV | Number of Participants With Vital Sign Abnormalities Reported as TEAEs | Blood pressure decreased | 0 Participants |
Secondary
Absolute CD20 B-cell Count at Baseline
Baseline absolute CD20 count is measured as the average between screening and predose on Day 1.
Time frame: Baseline (Days -28 to -1)
Population: Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO-IV-SC | Absolute CD20 B-cell Count at Baseline | 190 cells/mcL | Standard Deviation 99.1 |
| MEDI-551 30 Mg-IV | Absolute CD20 B-cell Count at Baseline | 173 cells/mcL | Standard Deviation 36.1 |
| MEDI-551 60 Mg-SC | Absolute CD20 B-cell Count at Baseline | 180 cells/mcL | Standard Deviation 108 |
| MEDI-551 100 Mg-IV | Absolute CD20 B-cell Count at Baseline | 183 cells/mcL | Standard Deviation 65.5 |
| MEDI-551 300 Mg-SC | Absolute CD20 B-cell Count at Baseline | 366 cells/mcL | Standard Deviation 257 |
| MEDI-551 600 Mg-IV | Absolute CD20 B-cell Count at Baseline | 201 cells/mcL | Standard Deviation 91.3 |
Secondary
Absolute Subcutaneous Bioavailability (F%) of MEDI-551
Bioavailability (F%) is the fraction of the study drug absorbed through non-intravenous administration compared with the corresponding intravenous administration of the same drug.
Time frame: Predose (Day 1) and Days 4, 8, 15, 29, 57, 85, 113, 141, and 169
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PLACEBO-IV-SC | Absolute Subcutaneous Bioavailability (F%) of MEDI-551 | 58 Percentage of bioavailability |
| MEDI-551 30 Mg-IV | Absolute Subcutaneous Bioavailability (F%) of MEDI-551 | 46 Percentage of bioavailability |
Secondary
Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC 0-last) of MEDI-551
The area under the concentration time curve from time 0 (dosing time) to the last measurable concentration (AUC 0-last) of MEDI-551.
Time frame: Predose (Day 1) and Postdose (IV Cohorts only), Days 4 (SC Cohorts only), 8, 15 Predose and Postdose (IV Cohorts only), 29, 57, 85, 113, 141, and 169
Population: Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO-IV-SC | Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC 0-last) of MEDI-551 | 436 microgram*day per milliliter(mcg*day/mL) | — |
| MEDI-551 30 Mg-IV | Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC 0-last) of MEDI-551 | 197 microgram*day per milliliter(mcg*day/mL) | Standard Deviation 92.6 |
| MEDI-551 60 Mg-SC | Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC 0-last) of MEDI-551 | 1140 microgram*day per milliliter(mcg*day/mL) | Standard Deviation 278 |
| MEDI-551 100 Mg-IV | Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC 0-last) of MEDI-551 | 788 microgram*day per milliliter(mcg*day/mL) | Standard Deviation 455 |
| MEDI-551 300 Mg-SC | Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC 0-last) of MEDI-551 | 6850 microgram*day per milliliter(mcg*day/mL) | Standard Deviation 1340 |
Secondary
Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC 0-infinity) of MEDI-551
The area under the concentration-time curve from dosing extrapolated to infinity (AUC 0-infinity) of MEDI-551.
Time frame: Predose (Day 1) and Postdose (IV Cohorts only), Days 4 (SC Cohorts only), 8, 15 Predose and Postdose (IV Cohorts only), 29, 57, 85, 113, 141, and 169
Population: Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO-IV-SC | Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC 0-infinity) of MEDI-551 | 440 mcg*day/mL | — |
| MEDI-551 30 Mg-IV | Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC 0-infinity) of MEDI-551 | 201 mcg*day/mL | Standard Deviation 91.5 |
| MEDI-551 60 Mg-SC | Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC 0-infinity) of MEDI-551 | 1150 mcg*day/mL | Standard Deviation 286 |
| MEDI-551 100 Mg-IV | Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC 0-infinity) of MEDI-551 | 794 mcg*day/mL | Standard Deviation 453 |
| MEDI-551 300 Mg-SC | Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC 0-infinity) of MEDI-551 | 6950 mcg*day/mL | Standard Deviation 1430 |
Secondary
Clearance of MEDI-551
Systemic clearance (CL) for MEDI-551 IV cohorts and apparent clearance (CL/F) for MEDI-551 SC cohorts were calculated
Time frame: Predose (Day 1) and Postdose (IV Cohorts only), Days 4 (SC Cohorts only), 8, 15 Predose and Postdose (IV Cohorts only), 29, 57, 85, 113, 141, and 169
Population: Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO-IV-SC | Clearance of MEDI-551 | 139 mL/day | — |
| MEDI-551 30 Mg-IV | Clearance of MEDI-551 | 351 mL/day | Standard Deviation 177 |
| MEDI-551 60 Mg-SC | Clearance of MEDI-551 | 181 mL/day | Standard Deviation 44.5 |
| MEDI-551 100 Mg-IV | Clearance of MEDI-551 | 457 mL/day | Standard Deviation 214 |
| MEDI-551 300 Mg-SC | Clearance of MEDI-551 | 180 mL/day | Standard Deviation 41.5 |
Secondary
Dose Normalized Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC 0-infinity/D) of MEDI-551
The AUC (0-infinity)/D is the area under concentration-time curve extrapolated to infinity post dose normalized by MEDI-551.
Time frame: Predose (Day 1) and Postdose (IV Cohorts only), Days 4 (SC Cohorts only), 8, 15 Predose and Postdose (IV Cohorts only), 29, 57, 85, 113, 141, and 169
Population: Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO-IV-SC | Dose Normalized Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC 0-infinity/D) of MEDI-551 | 7.34 mcg*day/mL/mg | — |
| MEDI-551 30 Mg-IV | Dose Normalized Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC 0-infinity/D) of MEDI-551 | 3.35 mcg*day/mL/mg | Standard Deviation 1.52 |
| MEDI-551 60 Mg-SC | Dose Normalized Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC 0-infinity/D) of MEDI-551 | 5.75 mcg*day/mL/mg | Standard Deviation 1.43 |
| MEDI-551 100 Mg-IV | Dose Normalized Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC 0-infinity/D) of MEDI-551 | 2.65 mcg*day/mL/mg | Standard Deviation 1.51 |
| MEDI-551 300 Mg-SC | Dose Normalized Area Under the Plasma Concentration-time Curve From Zero to Infinity (AUC 0-infinity/D) of MEDI-551 | 5.79 mcg*day/mL/mg | Standard Deviation 1.19 |
Secondary
Duration of Suppression Greater Than or Equal to 90 % of CD20 B-cell Count
Time in days of last observation where CD20 counts remain at or below 10% of baseline. Participants whose samples are available were analyzed for this outcome measure.
Time frame: Baseline (Days -28 to -1) to LTFU (Up to 18 months after EDV or 24 Week treatment period)
Population: Safety Population. No participants were included in placebo-IV-SC group since no participant reached 90% depletion.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| MEDI-551 30 Mg-IV | Duration of Suppression Greater Than or Equal to 90 % of CD20 B-cell Count | 149 Day | Full Range 62.8 |
| MEDI-551 60 Mg-SC | Duration of Suppression Greater Than or Equal to 90 % of CD20 B-cell Count | 100 Day | Full Range 28.3 |
| MEDI-551 100 Mg-IV | Duration of Suppression Greater Than or Equal to 90 % of CD20 B-cell Count | 180 Day | Full Range 39.2 |
| MEDI-551 300 Mg-SC | Duration of Suppression Greater Than or Equal to 90 % of CD20 B-cell Count | 211 Day | Full Range 17.3 |
| MEDI-551 600 Mg-IV | Duration of Suppression Greater Than or Equal to 90 % of CD20 B-cell Count | 254 Day | Full Range 45.3 |
Secondary
Maximum Change From Baseline in Absolute CD20 of Peripheral Blood B-cell Count to LTFU
The maximum degree of depletion (intensity) measured during the course of the study for each participant by subtracting 100 from the lowest observed percent of baseline value.
Time frame: Baseline (Days -28 to -1) to LTFU (Up to 18 months after EDV or 24 Week treatment period)
Population: Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO-IV-SC | Maximum Change From Baseline in Absolute CD20 of Peripheral Blood B-cell Count to LTFU | 25.0 Percentage of cells | Standard Deviation 31.2 |
| MEDI-551 30 Mg-IV | Maximum Change From Baseline in Absolute CD20 of Peripheral Blood B-cell Count to LTFU | 99.8 Percentage of cells | Standard Deviation 0.077 |
| MEDI-551 60 Mg-SC | Maximum Change From Baseline in Absolute CD20 of Peripheral Blood B-cell Count to LTFU | 99.2 Percentage of cells | Standard Deviation 0.787 |
| MEDI-551 100 Mg-IV | Maximum Change From Baseline in Absolute CD20 of Peripheral Blood B-cell Count to LTFU | 99.7 Percentage of cells | Standard Deviation 0.225 |
| MEDI-551 300 Mg-SC | Maximum Change From Baseline in Absolute CD20 of Peripheral Blood B-cell Count to LTFU | 99.8 Percentage of cells | Standard Deviation 0.182 |
| MEDI-551 600 Mg-IV | Maximum Change From Baseline in Absolute CD20 of Peripheral Blood B-cell Count to LTFU | 99.8 Percentage of cells | Standard Deviation 0.237 |
Secondary
Maximum Observed Serum Concentration (Cmax) of MEDI-551
The maximum observed serum concentration (Cmax) of MEDI-551.
Time frame: Predose (Day 1) and Postdose (IV Cohorts only), Days 4 (SC Cohorts only), 8, 15 Predose and Postdose (IV Cohorts only), 29, 57, 85, 113, 141, and 169
Population: Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO-IV-SC | Maximum Observed Serum Concentration (Cmax) of MEDI-551 | 17.9 microgram per milliliter (mcg/mL) | Standard Deviation 13.2 |
| MEDI-551 30 Mg-IV | Maximum Observed Serum Concentration (Cmax) of MEDI-551 | 6.67 microgram per milliliter (mcg/mL) | Standard Deviation 2.88 |
| MEDI-551 60 Mg-SC | Maximum Observed Serum Concentration (Cmax) of MEDI-551 | 43.1 microgram per milliliter (mcg/mL) | Standard Deviation 11.4 |
| MEDI-551 100 Mg-IV | Maximum Observed Serum Concentration (Cmax) of MEDI-551 | 24.7 microgram per milliliter (mcg/mL) | Standard Deviation 9.37 |
| MEDI-551 300 Mg-SC | Maximum Observed Serum Concentration (Cmax) of MEDI-551 | 248 microgram per milliliter (mcg/mL) | Standard Deviation 66.8 |
Secondary
Number of Participants Positive for Anti-Drug Antibodies to MEDI-551
A participant was considered anti-drug antibody positive across the study if they had a positive reading at any time point during the study.
Time frame: Days 1, 29, 85 and 169
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PLACEBO-IV-SC | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 1 (Baseline) | 0 Participants |
| PLACEBO-IV-SC | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 29 | 0 Participants |
| PLACEBO-IV-SC | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 85 | 0 Participants |
| PLACEBO-IV-SC | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 169 | 0 Participants |
| MEDI-551 30 Mg-IV | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 85 | 0 Participants |
| MEDI-551 30 Mg-IV | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 29 | 0 Participants |
| MEDI-551 30 Mg-IV | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 1 (Baseline) | 0 Participants |
| MEDI-551 30 Mg-IV | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 169 | 0 Participants |
| MEDI-551 60 Mg-SC | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 169 | 0 Participants |
| MEDI-551 60 Mg-SC | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 85 | 0 Participants |
| MEDI-551 60 Mg-SC | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 29 | 0 Participants |
| MEDI-551 60 Mg-SC | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 1 (Baseline) | 0 Participants |
| MEDI-551 100 Mg-IV | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 1 (Baseline) | 0 Participants |
| MEDI-551 100 Mg-IV | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 169 | 0 Participants |
| MEDI-551 100 Mg-IV | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 29 | 0 Participants |
| MEDI-551 100 Mg-IV | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 85 | 0 Participants |
| MEDI-551 300 Mg-SC | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 85 | 0 Participants |
| MEDI-551 300 Mg-SC | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 169 | 0 Participants |
| MEDI-551 300 Mg-SC | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 29 | 0 Participants |
| MEDI-551 300 Mg-SC | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 1 (Baseline) | 0 Participants |
| MEDI-551 600 Mg-IV | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 29 | 0 Participants |
| MEDI-551 600 Mg-IV | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 85 | 0 Participants |
| MEDI-551 600 Mg-IV | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 169 | 0 Participants |
| MEDI-551 600 Mg-IV | Number of Participants Positive for Anti-Drug Antibodies to MEDI-551 | Day 1 (Baseline) | 0 Participants |
Secondary
Terminal Elimination Half-life (t1/2) of MEDI-551
The terminal elimination half-life (t1/2) was estimated based on the plasma concentrations of MEDI-551.
Time frame: Predose (Day 1) and Postdose (IV Cohorts only), Days 4 (SC Cohorts only), 8, 15 Predose and Postdose (IV Cohorts only), 29, 57, 85, 113, 141, and 169
Population: Safety Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PLACEBO-IV-SC | Terminal Elimination Half-life (t1/2) of MEDI-551 | 17.7 Day | — |
| MEDI-551 30 Mg-IV | Terminal Elimination Half-life (t1/2) of MEDI-551 | 12.3 Day | Standard Deviation 1.71 |
| MEDI-551 60 Mg-SC | Terminal Elimination Half-life (t1/2) of MEDI-551 | 17.7 Day | Standard Deviation 6.27 |
| MEDI-551 100 Mg-IV | Terminal Elimination Half-life (t1/2) of MEDI-551 | 15.1 Day | Standard Deviation 4.31 |
| MEDI-551 300 Mg-SC | Terminal Elimination Half-life (t1/2) of MEDI-551 | 18.7 Day | Standard Deviation 2.03 |
Secondary
Time to 90 Percent (%) CD20 B-cell Depletion
Time in days of first observation where CD20 counts fall to or below 10 percent (%) of baseline.
Time frame: Baseline (Days -28 to -1) to long-term follow-up (LTFU) (Up to 18 months after EDV or 24 Week treatment period)
Population: Safety Population. No participants in placebo-IV-SC group reached 90% CD20 B-cell depletion.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| MEDI-551 30 Mg-IV | Time to 90 Percent (%) CD20 B-cell Depletion | 15.0 Day | Full Range 1.1 |
| MEDI-551 60 Mg-SC | Time to 90 Percent (%) CD20 B-cell Depletion | 88.0 Day | Full Range 50.3 |
| MEDI-551 100 Mg-IV | Time to 90 Percent (%) CD20 B-cell Depletion | 25.0 Day | Full Range 6.19 |
| MEDI-551 300 Mg-SC | Time to 90 Percent (%) CD20 B-cell Depletion | 15.0 Day | Full Range 4.04 |
| MEDI-551 600 Mg-IV | Time to 90 Percent (%) CD20 B-cell Depletion | 14.5 Day | Full Range 5.65 |
Secondary
Time to Reach Maximum Observed Serum Concentration (Tmax) of MEDI-551
The time to reach the maximum observed serum concentration of MEDI-551.
Time frame: Predose (Day 1) and Postdose (IV Cohorts only), Days 4 (SC Cohorts only), 8, 15 Predose and Postdose (IV Cohorts only), 29, 57, 85, 113, 141, and 169
Population: Safety Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PLACEBO-IV-SC | Time to Reach Maximum Observed Serum Concentration (Tmax) of MEDI-551 | 0.14 Day |
| MEDI-551 30 Mg-IV | Time to Reach Maximum Observed Serum Concentration (Tmax) of MEDI-551 | 2.98 Day |
| MEDI-551 60 Mg-SC | Time to Reach Maximum Observed Serum Concentration (Tmax) of MEDI-551 | 0.07 Day |
| MEDI-551 100 Mg-IV | Time to Reach Maximum Observed Serum Concentration (Tmax) of MEDI-551 | 7.92 Day |
| MEDI-551 300 Mg-SC | Time to Reach Maximum Observed Serum Concentration (Tmax) of MEDI-551 | 0.12 Day |