Clinical trial NCT01808482: 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)
Official title: A First Time in Human Study Exploring Preliminary Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2618960 in Healthy Volunteers and Patients With Relapsing Remitting Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Multiple Sclerosis, Relapsing-Remitting
Keywords: monoclonal antibody
Multiple Sclerosis
Interleukin-7 Receptor
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-03-11
Enrollment: 16
Sex: MALE
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

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.
* A female subject is eligible to participate as follows: Non-childbearing potential, females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods and women of childbearing potential should have used one of the contraception methods.
* Male subjects must agree to use one of the contraception methods.
* Subjects with history of current vaccination status for tetanus, diphtheria, pertussis, measles, mumps and rubella (or who consent to vaccination at screening). Subjects with expected study participation during Flu season (October - April) only, with history of current vaccination status for influenza or consent to receive influenza vaccine at screening.
* Body weight \>=50 kg.
* On ECG, QTcF interval \<450 msec; or QTcF \<480 msec in subjects with bundle branch block.
* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form, and authorisation of the release and use of protected health information (PHI).

Exclusion Criteria:

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.

MS Patients

* Intolerant, or unwilling, to undergo MRI scanning.
* Contraindications for administration of Gd-contrast agents i.e. history of allergy to gadolinium.
* 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.
* History of, or laboratory findings indicative of any clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic (other than MS), dermatologic, psychiatric, renal, and/or other major disease or of known drug sensitivity that would preclude the administration of a recombinant humanized antibody or the use of systemic steroids during the course of the study.
* Abnormal baseline blood tests exceeding any of the limits defined below: ALT or aspartate transaminase (AST) \>1.5 x the ULN, AP and bilirubin \>1.5X ULN (isolated bilirubin \>1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%), total white blood cell count \<2,500/millimetre cube (mm\^3), if lymphocyte count is less than the Lower Limit of Normal (LLN), maybe included only if PI and GSK Medical Monitor agree that doesn't introduce additional risk, platelet count \< 95,000/mm3, creatinine \>2 x ULN, calculated creatinine clearance \<60 ml/min (per Cockcroft \& Gault) at Screening, International Normalised Ratio (INR) larger than upper limit of the normal reference range (0.9 - 1.3).

A subject with a clinical abnormality or laboratory parameters significantly outside the above reference range for the population being studied may be included only if the Investigator and the GlaxoSmithKline Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.

* Treatment with methylprednisolone or any other systemic steroid, for a relapse or otherwise, within 30 days of dosing.
* Treatment with first line disease modifying therapies for RRMS, such as glatiramer acetate or beta-interferons within 6 weeks prior to screening.
* Treatment within the past 12 months or currently with any of the following agents: cyclosporine, cladribine, natalizumab (Tysabri) or other monoclonal antibodies, murine protein, T-cell vaccination, plasmapheresis, intravenous (IV) Immunoglobulin G (IgG), stem cell transplantation.
* Treatment in the past 6 months with any of the following agents: Fingolimod (Gilenya), methotrexate, mitoxantrone, azathioprine, or other small molecule immunosuppressants.
* History of intolerance to paracetamol, ibuprofen, naproxen or other non-steroidal anti-inflammatory agents which would preclude use of at least one of these during the study.
* Previous history of anaphylaxis, severe allergic reaction, generation of neutralizing antibodies, or hypersensitivity to albumin or a protein-based therapeutic, including natalizumab (Tysabri) or any other monoclonal antibody.
* A positive pre-study hepatitis B surface antigen or positive hepatitis C antibody result.
* Known diagnosis or history consistent with human immunodeficiency virus (HIV) positivity
* Subjects with evidence of dementia or psychiatric illness which, in the Investigator's opinion, is likely to prevent them from a full understanding of and/or compliance with the study requirements and procedures. .
* Blood donation (1 unit or more) within 3 months prior to investigational drug administration.
* History of regular alcohol consumption within 6 months of the study defined as:

Average weekly intake of \>21 units for males or \>14 units for females. One unit is equivalent to 8 gram (g) of alcohol: a half-pint (\~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.

* Subjects who have received live vaccinations 1 month prior to screening (excluding flu vaccination) or plan to receive live vaccination during the study.
* Smokers unable to abstain from smoking while on the clinical unit.

Primary outcomes:
measure: 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
timeFrame: Upto Week 12 pending emerging data and DEC decisions.
measure: Safety and tolerability of GSK2618960 as assessed by changes in MS relapses: Number, duration, severity in MS patients
timeFrame: Upto Week 12 pending emerging data and DEC decisions
Secondary outcomes:
measure: Composite of PK parameters of GSK2618960
timeFrame: 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.
measure: Receptor occupancy by GSK2618960 - Blinding of fluorophore-conjugated competing and non-competing antibody of GSK2618960 following the single and repeat IV doses
timeFrame: 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.
measure: Relationship between dose and duration of >95% RO of GSK2618960 following single and repeat IV doses in healthy volunteers
timeFrame: 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.
measure: 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
timeFrame: Day -1, Day 8, Day 15 and Day 29 onwards through final follow up, dependent upon predictions.
measure: Presence of antibodies to GSK2618960
timeFrame: 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.
measure: Changes in numbers and relevant ratios of lymphocyte subsets
timeFrame: Day -1, Day 8, Day 15 and Day 29 onwards through final follow up, will be dependent upon predictions.
measure: Markers of serum inflammatory mediators in blood.
timeFrame: Day 1 predose and 1 h and 4 h post dose, Day 2 and Day 3
measure: Cumulative number of new brain lesions
timeFrame: 1st MRI baseline at -8weeks, 2nd MRI baseline at -4 weeks, 3rd MRI baseline on Day -1, and at Week 6, Week 10, Week 14 and Week 18 after first dose
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: