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

Phase 1

Completed

Conditions: Multiple Sclerosis, Relapsing Forms

Interventions: Drug: MEDI-551 30 MG-IV
Drug: MEDI-551 60 MG-SC
Drug: MEDI-551 100 MG-IV
Drug: MEDI-551 300 MG-SC
Drug: MEDI-551 600 MG-IV
Drug: PLACEBO-IV-SC

Registration Number: NCT01585766

Lead Sponsor: MedImmune LLC

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 56

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
MEDI-551 30 MG-IV	MEDI-551 30 MG-IV	Participants received a fixed IV dose of 30 milligram (mg) MEDI-551 infused on Days 1 and 15.
MEDI-551 60 MG-SC	MEDI-551 60 MG-SC	Participants received SC injection of 60 mg MEDI-551 on Day 1.
MEDI-551 100 MG-IV	MEDI-551 100 MG-IV	Participants received a fixed IV dose of 100 mg MEDI-551 infused on Days 1 and 15.
MEDI-551 300 MG-SC	MEDI-551 300 MG-SC	Participants received SC injection of 300 mg MEDI-551 on Day 1.
MEDI-551 600 MG-IV	MEDI-551 600 MG-IV	Participants received a fixed IV dose of 600 mg MEDI-551 infused on Days 1 and 15.
PLACEBO-IV-SC	PLACEBO-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.

Primary Outcome Measures

Name	Time	Method
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 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 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 Outcome Measures

Name	Time	Method
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.
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.
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.
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 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.
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.
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.
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 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.
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.