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Multiple Sclerosis, Relapsing-RemittingPhase 1NCT01808482

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)

A Phase 1 study testing Part A: 100 mg/mL GSK2618960, Part B: Dose of GSK2618960 decided from Part A and Part C: Dose of GSK2618960 decided from Part A and B in people with Multiple Sclerosis, Relapsing-Remitting, run by GlaxoSmithKline at 1 site in United Kingdom.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 55 years, men onlyHealthy volunteers can take part
Conditions the study is for
Multiple Sclerosis, Relapsing-Remitting
What is being tested?
Part A: 100 mg/mL GSK2618960, Part B: Dose of GSK2618960 decided from Part A and Part C: Dose of GSK2618960 decided from Part A and B
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
16 participants
Where
1 siteUnited Kingdom
Study dates
13 Mar 2013to 6 Aug 2013
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 55 years
  • Men only
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • 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).
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  • 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).

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

1 site in 1 country.

United Kingdom1 site

  • GSK Investigational Site

    Cambridge, CB2 2GG

Other trials in United Kingdom

About this study

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

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.

Read more

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.

Being tested
Part A: 100 mg/mL GSK2618960, Part A: matching placebo, Part B: Dose of GSK2618960 decided from Part A, Part B: matching placebo, Part C: Dose of GSK2618960 decided from Part A and B
Keywords
monoclonal antibody, Multiple Sclerosis, Interleukin-7 Receptor
Medical subject headings
Multiple Sclerosis, Relapsing-Remitting, Multiple Sclerosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Part A: 100 mg/mL GSK2618960Drug

    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: matching placeboDrug

    Matching placebo

  • Part B: Dose of GSK2618960 decided from Part ADrug

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

  • Part B: matching placeboDrug

    Matching placebo

  • Part C: Dose of GSK2618960 decided from Part A and BDrug

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

Study groups in NCT01808482
Study groupRoleWhat they receive
Part A: GSK2618960ExperimentalSubjects will receive ascending single dose in 3:1 ratio of active:placebo respectively in each dosing session.
Receives: Drug: Part A: 100 mg/mL GSK2618960
Part A: PlaceboPlacebo comparatorSubjects will receive ascending single dose in 3:1 ratio of active:placebo respectively in each dosing session
Receives: Drug: Part A: matching placebo
Part B: GSK2618960ExperimentalSubjects will receive ascending repeat dose (dose decided from Part A) in 3:1 ratio of active:placebo respectively in each cohort.
Receives: Drug: Part B: Dose of GSK2618960 decided from Part A
Part B: PlaceboPlacebo comparatorSubjects will receive ascending repeat dose (dose decided from Part A) in 3:1 ratio of active:placebo respectively in each cohort.
Receives: Drug: Part B: matching placebo
Part C: GSK2618960ExperimentalSubjects will receive active treatments for 2 to 4 repeated doses (dose decided from Part A\& B)
Receives: Drug: Part C: Dose of GSK2618960 decided from Part A and B

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Upto Week 12 pending emerging data and DEC decisions.

  2. 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

    Measured: Upto Week 12 pending emerging data and DEC decisions

Secondary outcomes (8)

  1. Composite of PK parameters of GSK2618960

    The following pharmacokinetic (PK) data will be calculated: maximum concentration (Cmax), area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration [AUC(0-tau)] and AUC from zero to infinity [AUC(0-inf)], percentage of AUC(0-inf) obtained by extrapolation (%AUC(ex)), clearance (CL), volume of distribution (Vss), time from administration to Cmax (tmax) and elimination half life (t½) of GSK2618960.

    Measured: 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.

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

    The total receptor levels will be measured by counting the binding of fluorophore-conjugated competing antibody (PE-GSK2618960) to unoccupied GSK2618960 binding sites, normalized by baseline and maximum blocking controls, in addition to non-competing antibody binding.

    Measured: 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.

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

    The PK/RO relationship of GSK2618960 following single and repeat IV doses in Part A and B of the study.

    Measured: 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.

  4. 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

    Blood from 7 distinct healthy donors was incubated ex vivo with 0.003 to 100 microgram/mL GSK2618960 and then stimulated with 5ng/mL human IL-7 STAT5 phosphorylation as well as unbound GSK2618960 and total IL-7R levels were assayed by flow cytometry.

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

  5. Presence of antibodies to GSK2618960

    Presence of antibodies to GSK2618960 will be assessed in serum samples using validated ECL assays.

    Measured: 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.

  6. Changes in numbers and relevant ratios of lymphocyte subsets

    Lymphocyte subsets will include B cells, CD3+ T cells, NK cells, regulatory T cells, and recent thymic emigrants, and may include, CD4+T cell, CD8+ T cells, naïve CD4+ T cells, effect memory CD4+ T cells, and central memory CD4+ T cell, etc. For Part A, blood sampling for lymphocyte subset is not required for dosing sessions 1-3. For part A, after day 29, a maximum of 3 blood samples will be drawn, each separated by 2 weeks, at time points spanning the predicted end of full RO. For parts B and C, blood sampling is limited to Day -1, and 3 blood samples separated by 2 weeks.

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

  7. Markers of serum inflammatory mediators in blood.

    Serum inflammatory mediators, including some or all, but not limited to: IL-1β, IL-6, IL-8, MCP-1, TNF-α and IFN-γ blood sampling for serum inflammatory mediators will be performed for dose sessions 1, 2, 3, 6; optional for other dose sessions in part A, Part B and Part C pending emerging data

    Measured: Day 1 predose and 1 h and 4 h post dose, Day 2 and Day 3

  8. Cumulative number of new brain lesions

    Cumulative number of new brain lesions will be assessed in Part C of the study using magnetic resonance imaging (MRI). New lesion is defined as enhancing in the presence of Gadolinium contrast agent.

    Measured: 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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 Mar 2013 (estimated)
  2. Study start13 Mar 2013
  3. Primary completion6 Aug 2013
  4. Study completion6 Aug 2013

Why it stopped: GSK confirmed misrepresentation of preclinical data that supported the rationale for GSK2618960 in MS. This decreased benefit assessment for MS

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Participant
Enrolment
16 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01808482
Sponsor's protocol ID
116702
Status last verified
Jun 2017
First submitted
7 Mar 2013
Last updated
7 Jun 2017
Results posted
No
Data monitoring committee
Yes
Individual data sharing
Yes: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Part A: 100 mg/mL GSK2618960, Part B: Dose of GSK2618960 decided from Part A and Part C: Dose of GSK2618960 decided from Part A and B in people with Multiple Sclerosis, Relapsing-Remitting, run by GlaxoSmithKline at 1 site in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 21 inclusion and 36 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 7 Jun 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: GSK confirmed misrepresentation of preclinical data that supported the rationale for GSK2618960 in MS. This decreased benefit assessment for MS). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome 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 (time frame: Upto Week 12 pending emerging data and DEC decisions.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01808482.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Jun 2017; AzTrials last refreshed its copy on 27 Oct 2026.

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