Safety and Tolerability Study of MEDI-551, a B-cell Depleting Agent, to Treat Relapsing Forms of Multiple Sclerosis

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 1 Randomized Study of MEDI-551 in Subjects With Relapsing Forms of Multiple Sclerosis

Conditions
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Multiple Sclerosis, Relapsing Forms

Intervention / Treatment
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* Drug: MEDI-551 30 MG-IV
* Drug: MEDI-551 60 MG-SC
* Drug: PLACEBO-IV-SC
* Drug: MEDI-551 100 MG-IV
* Drug: MEDI-551 300 MG-SC
* Drug: MEDI-551 600 MG-IV


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MEDI-551 30 MG-IV<br>Participants received a fixed IV dose of 30 milligram (mg) MEDI-551 infused on Days 1 and 15. | Drug: MEDI-551 30 MG-IV<br>* Participants received a fixed IV dose of 30 milligram (mg) MEDI-551 infused on Days 1 and 15.<br>|
| Experimental: MEDI-551 60 MG-SC<br>Participants received SC injection of 60 mg MEDI-551 on Day 1. | Drug: MEDI-551 60 MG-SC<br>* Participants received SC injection of 60 mg MEDI-551 on Day 1.<br>|
| Experimental: MEDI-551 100 MG-IV<br>Participants received a fixed IV dose of 100 mg MEDI-551 infused on Days 1 and 15. | Drug: MEDI-551 100 MG-IV<br>* Participants received a fixed IV dose of 100 mg MEDI-551 infused on Days 1 and 15.<br>|
| Experimental: MEDI-551 300 MG-SC<br>Participants received SC injection of 300 mg MEDI-551 on Day 1. | Drug: MEDI-551 300 MG-SC<br>* Participants received SC injection of 300 mg MEDI-551 on Day 1.<br>|
| Experimental: MEDI-551 600 MG-IV<br>Participants received a fixed IV dose of 600 mg MEDI-551 infused on Days 1 and 15. | Drug: MEDI-551 600 MG-IV<br>* Participants received a fixed IV dose of 600 mg MEDI-551 infused on Days 1 and 15.<br>|
| Placebo Comparator: PLACEBO-IV-SC<br>Participants received either a fixed IV dose of placebo matching with MEDI- 551 on Days 1 and 15 or SC injection on Day 1. | Drug: PLACEBO-IV-SC<br>* Participants received either a fixed IV dose of placebo matching with MEDI- 551 on Days 1 and 15 or SC injection on Day 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | From study drug administration (Day 1) through the end of treatment period (Day 169) | 
| 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 | 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). | 
| 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. | From study drug administration (Day 1) through the end of treatment period (Day 169) | 
| 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. | From study drug administration (Day 1) through the end of treatment period (Day 169) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Reach Maximum Observed Serum Concentration (Tmax) of MEDI-551 | The time to reach the maximum observed serum concentration 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 | 
| Maximum Observed Serum Concentration (Cmax) of MEDI-551 | The 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| Clearance of MEDI-551 | Systemic clearance (CL) for MEDI-551 IV cohorts and apparent clearance (CL/F) for MEDI-551 SC cohorts were calculated | 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 | 
| 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. | 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 | 
| 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. | Predose (Day 1) and Days 4, 8, 15, 29, 57, 85, 113, 141, and 169 | 
| Absolute CD20 B-cell Count at Baseline | Baseline absolute CD20 count is measured as the average between screening and predose on Day 1. | Baseline (Days -28 to -1) | 
| 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. | Baseline (Days -28 to -1) to long-term follow-up (LTFU) (Up to 18 months after EDV or 24 Week treatment period) | 
| 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. | Baseline (Days -28 to -1) to LTFU (Up to 18 months after EDV or 24 Week treatment period) | 
| 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. | Baseline (Days -28 to -1) to LTFU (Up to 18 months after EDV or 24 Week treatment period) | 
| 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. | Days 1, 29, 85 and 169 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MAb, B cell, depletion, RMS