A First Time in Human Study Exploring Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of GSK2618960 in Healthy Volunteers and Patients With Relapsing Remitting Multiple Sclerosis (RRMS)

NCT01808482 | Terminated Phase 1 DMC

• 1 other identifier: 116702
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

This is a 3-part study where Parts A, B (single-blind - investigator and subject blind) will enrol healthy volunteers and Part C (open-label) will enrol RRMS patients. Parts A (single ascending dose) and B (repeat ascending dose) will assess safety, tolerability, PK and PD of GSK2618960. Part C (repeat doses) will assess safety, tolerability, PK, PD, immunogenicity, paraclinical (magnetic resonance imaging \[MRI\] lesion counts) disease activity and markers of Th1 and Th17 mechanisms. Part A: Each of the 24 healthy volunteers (divided in 5 groups), will take part in only 2 of the planned 8 dosing sessions (A-active, P-placebo). Subjects in each group of Part A will be randomized in a 2:1:1 ratio to one of the following sequences: AA, AP or PA such that in each dosing session they will receive study treatment in a 3:1 ratio of active: placebo respectively. Part B: Dosing levels and regimen are dependent upon safety tolerability and PK/receptor occupancy (RO) data from Part A. In Cohort 1, 12 subjects will be randomized in a 3:1 ratio to A or P. Each subject will receive the same study treatment for repeated doses. If the duration of full RO from highest dose in Part A is less than 4 weeks, a second cohort of 12 subjects in Part B may be recruited, based on Dose Escalation Committee (DEC) decision Part C: The 20 RRMS patients will be assigned to active treatments for 2 to 4 repeated doses. Safety/tolerability and PK data monitoring and the decision to proceed to the next dose level of GSK2618960, and the decisions to proceed to Part B and Part C of the study will be made by a dose escalation committee.

Conditions

Multiple Sclerosis, Relapsing-Remitting

Keywords

monoclonal antibody; Multiple Sclerosis; Interleukin-7 Receptor

Outcome Measures

Primary Outcomes (2)

• Safety and tolerability of GSK2618960 as assessed by changes in: vital signs, ECG monitoring, haematology, clinical chemistry, urinalysis, and monitoring of AEs in healthy volunteers and MS patients

  Safety and tolerability parameters will include recording of vital signs, electrocardiogram (ECG)s, safety labs, and adverse event (AE)s, in Part A/B/C of the study in healthy volunteers and Multiple Sclerosis (MS) patients.

  Upto Week 12 pending emerging data and DEC decisions.

• Safety and tolerability of GSK2618960 as assessed by changes in MS relapses: Number, duration, severity in MS patients

  Safety and tolerability parameters will include recording of the number/duration/severity of MS relapses in Part C of the study in MS patients

  Upto Week 12 pending emerging data and DEC decisions

Secondary Outcomes (8)

• Composite of PK parameters of GSK2618960

  Day 1 predose 1,2,4, 8, 24 hour (hr)s post dose (Day 2), 36 hrs (Day 2), Day 3, Day 4, Day 8, Day 15, and post Day 15 every 2 weeks and dependent upon predictions.

• Receptor occupancy by GSK2618960 - Blinding of fluorophore-conjugated competing and non-competing antibody of GSK2618960 following the single and repeat IV doses

  Day 1 predose 1, 4, 8 hrs dose, Day 2, Day 3, Day 4, Day 8, Day 15, and Day 29 onwards visits through final follow up, and dependent upon predictions.

• Relationship between dose and duration of >95% RO of GSK2618960 following single and repeat IV doses in healthy volunteers

  Day 1 predose 1,2,4, 8, 24 hour (hr)s post dose (Day 2), 36 hrs (Day 2), Day 3, Day 4, Day 8, Day 15, and post Day 15 every 2 weeks and dependent upon predictions.

• To characterize the effect of GSK2618960 on IL-7 downstream signalling - Phosphorylation level of stat5 protein upon ex vivo stimulation of IL-7 cytokine, normalized by baseline, maximum receptor blocking controls and unstimulated controls

  Day -1, Day 8, Day 15 and Day 29 onwards through final follow up, dependent upon predictions.

• Presence of antibodies to GSK2618960

  Immunogenicity sampling will be performed at Day1 pre-dose, Day 15 and approximately 2 months after dosing for dosing sessions 1- 5, and performed every 3 months after final dosing for dosing sessions 6-8 and parts B & C.

Study Arms (5)

Part A: GSK2618960

EXPERIMENTAL

Subjects will receive ascending single dose in 3:1 ratio of active:placebo respectively in each dosing session.

Drug: Part A: 100 mg/mL GSK2618960

Part A: Placebo

PLACEBO COMPARATOR

Subjects will receive ascending single dose in 3:1 ratio of active:placebo respectively in each dosing session

Drug: Part A: matching placebo

Part B: GSK2618960

EXPERIMENTAL

Subjects will receive ascending repeat dose (dose decided from Part A) in 3:1 ratio of active:placebo respectively in each cohort.

Drug: Part B: Dose of GSK2618960 decided from Part A

Part B: Placebo

PLACEBO COMPARATOR

Subjects will receive ascending repeat dose (dose decided from Part A) in 3:1 ratio of active:placebo respectively in each cohort.

Drug: Part B: matching placebo

Part C: GSK2618960

EXPERIMENTAL

Subjects will receive active treatments for 2 to 4 repeated doses (dose decided from Part A\& B)

Drug: Part C: Dose of GSK2618960 decided from Part A and B

Interventions

Part A: 100 mg/mL GSK2618960 DRUG

100 mg/mL GSK2618960 solution for IV Infusion up to 1 hr except for the 1st dose (IV bolus) and 2nd dose (IV infusion over 5 min) of Part A

Part A: GSK2618960

Part A: matching placebo DRUG

Matching placebo

Part A: Placebo

Part B: Dose of GSK2618960 decided from Part A DRUG

100 mg/mL GSK2618960 solution for IV Infusion in repeat dose decided from Part A

Part B: GSK2618960

Part B: matching placebo DRUG

Matching placebo

Part B: Placebo

Part C: Dose of GSK2618960 decided from Part A and B DRUG

100 mg/mL GSK2618960 solution for IV Infusion in repeat dose decided from Part A and B

Part C: GSK2618960

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy volunteers
• Healthy as determined by a responsible and experienced physician
• Male between 18 and 55 years of age inclusive, at the time of signing the informed consent.
• Alanine aminotransferase (ALT), alkaline phosphatase (AP) and bilirubin \<=1.5xupper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
• Corrected QT interval using Fridericia's (QTcF) \< 450 milliseconds (msec).
• Body weight \>=50 kilogram (kg), \<=100 kg and body mass index (BMI) within the range 19.0 - 29.9 kg/meter squared (m\^2) (inclusive).
• Subjects with history of current vaccination status for tetanus, diphtheria, pertussis, measles, mumps and rubella (or consent to vaccination at screening). Subjects with history of current vaccination status for influenza or who consent to receive influenza vaccine at screening if study dosing is predicted to result in \>75% RO during Flu season (October - April).
• Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods. This criterion must be followed from the time of the first dose of study.
• MS Patients
• Suitable as determined by the Principal Investigator, based on his/her overall evaluation.
• Must have a confirmed diagnosis of RRMS according to 2010 revisions to McDonald Criteria..
• Must have a history of at least two clinical episodes of demyelination.
• Have demonstrated clinical or paraclinical activity in 12 months prior to screening (which may have occurred whilst on a disease-modifying therapy) by either: One or more documented relapses,OR one or more documented Gd enhancing lesions in the brain or spinal cord,
• Expanded Disability Status Scale (EDSS) score \<=0 at the screening.
• Male or female between 18 and 55 years of age inclusive, at the time of signing the informed consent.

You may not qualify if:

• Healthy Volunteers
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
• A positive test for HIV antibody.
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• A positive pre-study drug/alcohol screen.
• History of smoking within 6 months of screening.
• History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of \>21 units for males. One unit is equivalent to 8 g of alcohol: a half-pint (\~240 milliliter \[mL\]) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
• The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
• Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
• Unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
• History of sensitivity to any of the study medications, or components thereof or a history of drug or other significant allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
• Subjects, who in the investigator's judgement, pose a significant suicide risk. Evidence of serious suicide risk may include any history of suicidal behaviour in the last 6 months and/or any suicidal ideation of type 4 or 5 on the C-SSRS in the last 2 months.
• Previous history of anaphylaxis and severe allergic reaction.
• Receipt of live vaccination within 1 month of screening (excluding flu vaccination) or plan to receive live vaccination during the study.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Cambridge, CB2 2GG, United Kingdom

Location

Related Links

• Results for study 116702 can be found on the GSK Clinical Study Register.
• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

MeSH Terms

Conditions

Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis

Interventions

GSK2618960

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 7, 2013
• First Posted: March 11, 2013
• Study Start: March 13, 2013
• Primary Completion: August 6, 2013
• Study Completion: August 6, 2013
• Last Updated: June 7, 2017

Record last verified: 2017-06

Data Sharing

• IPD Sharing: Will share

Locations

GB (1)