Primary Objective:To assess the efficacy potential of GSK3196165 on pain in inflammatory HOA.Secondary endpoints:To evaluate impact of GSK3196165 on average and worst HOA pain, over time.To assess the impact of GSK3196165 on hand pain (on use),…
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Source
Brief title
Condition
- Joint disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary study parameter / outcome:
Change from baseline in 24h average hand pain intensity at Week 6, as measured
by daily pain Numerical Rating Scale (NRS) averaged over the 7
days prior to assessment visit.
Secondary outcome
Secundary study pararmeters / outcomes:
Change from baseline in 24h average hand pain intensity at each visit, measured
by daily pain NRS and averaged over the 7 days prior to each
assessment visit.
Change from baseline of worst hand pain intensity over 24h at each visit,
measured by daily NRS and averaged over the 7 days prior to each assessment
visit.
Proportion of subjects in each treatment group achieving a 30% reduction in 24h
average hand pain intensity at each visit, measured by daily NRS
averaged over the 7 days prior to assessment visit.
Proportion of subjects in each treatment group achieving a 50% reduction in 24h
average hand pain intensity at each visit, measured by daily NRS
averaged over the 7 days prior to assessment visit.
Proportion of subjects in each treatment group achieving a 30% reduction in 24h
worst hand pain intensity at each visit, measured by daily NRS
averaged over the 7 days prior to assessment visit.
Proportion of subjects in each treatment group achieving a 50% reduction in 24h
worst hand pain intensity at each visit, measured by daily NRS
averaged over the 7 days prior to assessment visit.
Change from baseline in Australian Canadian Hand Osteoarthritis Index (AUSCAN)
3.1 NRS, total and domains (pain, morning stiffness, function) scores at each
visit.
Change in number of swollen and tender hand joints at each visit.
Change from baseline in patient global assessment (PtGA) and physician global
assessment (PhGA) of disease activity at Week 6,12 and 22.
Incidence of adverse events and serious adverse events.
Incidence of infections.
Incidence of pulmonary events (cough/dyspnea, PAP and DLCO).
Immunogenicity.
Population pharmacokinetics endpoints such as CL/F, Vss/F, Ka.
Background summary
Hand osteoarthritis (HOA) is the second most common form of osteoarthritis (OA)
which is itself, the most common musculoskeletal disorder. The
presentation of HOA is typically with symptoms reflecting underlying
inflammation in the proximal joints of the hand affecting the synovium,
cartilage and bone.Severe hand pain can significantly impair day to day
activities through functional impairment in the form of stiffness, reduced grip
strength, reduced hand mobility, and difficulty performing dexterous tasks.
Treatment options for both inflammatory and erosive HOA are limited and are
focused on alleviating symptoms through pain medication, local steroid
injections and surgical intervention but provide limited, if any, benefit.
The etiology of OA is likely to be multifactorial, and recent histological
evidence indicates that synovitis is an early feature in OA, even in joints
where it could not be detected clinically, with a mixed inflammatory infiltrate
consisting mainly of macrophages and with pro-inflammatory mediator production.
It has been found that Granulocyte-macrophage colony stimulating factor
receptor (GM-CSFR) is expressed in OA synovium. GM-CSF induces the
proliferation and activation of macrophage lineage cells leading to strongly
increased production of key proinflammatory cytokines. Furthermore, it has been
demonstrated pre-clinically that GM-CSF is linked to the development of
experimental and spontaneous osteoarthritis and it is associated with pain,
function, matrix degrading proteases and structural disease severity.
Importantly, GM-CSF neutralization by a therapeutic monoclonal antibody rapidly
and completely abolished existing arthritic pain and suppressed the degree of
arthritis development in the collagenase induced model of OA.
Taken together, pre-clinical and clinical data suggest that blocking GM-CSF
should interfere with several pathophysiological pathways and significantly
reduce inflammation by inhibiting activation of inflammatory cells within the
OA joint and by blocking the chemotaxis recruitment of such non-resident
inflammatory cells, thus leading to a benefit on inflammatory pain and
inhibiting bone and cartilage destruction. GSK3196165 is a high-affinity
recombinant human monoclonal antibody (mAb) that binds specifically to human
GM-CSF and neutralises its biological function by blocking the interaction of
GM-CSF with its cell surface receptor.
This study is designed to investigate whether GSK3196165 may offer a treatment
benefit for subjects with inflammatory hand osteoarthritis.
Study objective
Primary Objective:
To assess the efficacy potential of GSK3196165 on pain in inflammatory HOA.
Secondary endpoints:
To evaluate impact of GSK3196165 on average and worst HOA pain, over time.
To assess the impact of GSK3196165 on hand pain (on use), stiffness and
function, over time.
To assess the impact of GSK3196165 on HOA inflammation
To assess potential impact of GSK3196165 on disease activity in HOA,
To assess safety of GSK3196165 in HOA patients, over the study duration.
To assess population pharmacokinetics of GSK3196165 in HOA.
Study design
This study will be double-blinded (subjects, investigators and sponsor
blinded), however at least one unblinded drug administrator will be required at
each site to administer the study treatment.
For screening, baseline and efficacy assessments, the average pain intensity
over 7 days prior to assessment date will be used. This is calculated from
collected daily pain NRS data over 7 days.
Imaging MRI will be carried out at screening, Week 12 and Week 22. (Note: MRI
at screening will serve as the baseline measurement).
At baseline subjects will be evaluated by pain NRS (average 7 days prior to
visit), AUSCAN 3.1 NRS, PtGA, PhGA, number of tender and swollen joints in
their hands and blood will be collected for safety, biomarker monitoring, and
pharmacokinetics.
Throughout the study treatment period, subjects will be assessed for hand pain
using a daily pain NRS questionnaire (daily from screening to Week 12). In
addition, at the specified time points (see Section 7.1, time and events
table), function and disease state will be assessed using the AUSCAN 3.1 NRS,
PtGA and PhGA. The number of tender and swollen joints in affected hands will
also be assessed and blood samples will be collected for safety, biomarkers
monitoring, and pharmacokinetics.
At the Week 22 follow up visit, blood will again be collected for safety
monitoring as well an assessment of pain NRS (average 7 days prior to visit),
PtGA, PhGA and MRI imaging of the affected hand.
For MRI endpoints the assessments are based on one hand only. In cases where
both hands are affected by HOA and both meet the inclusion criteria, then the
dominant hand will be documented at screening and this hand will be used for
the MRI assessments throughout the study.
Intervention
The Study consists of 2 arms: treatment with GSK3196165 or placebo will be
given as a single subcutaneous injection (shielded to subjects) to the abdomen
or thigh, by an unblinded administrator weekly for 5 injections, from Week 0 to
Week 4 (Days 1, 8, 15, 22, 29), then every other week for 3 further injections,
from Week 6 until Week 10 (Days 43, 57 and 71). In total, each subject will
receive up to 8 doses of study treatment.
Safety should be monitored for 1 hour after the injection, for the first 3
injections, then for 30 minutes thereafter. Such monitoring will include
general safety monitoring including monitoring for systemic hypersensitivity
infusion reactions and local injection site reactions.
Study burden and risks
During the conduct of the study, the subjects will visit the hospital 12 times
and will undergo the following assessments:
12-lead ECG (at screening, baseline and week 12)
Vital signs and physical examination (screening, baseline, week 2, 4, 8 and 12)
Blood draws (at screening, baseline, week 1, 2, 4, 6, 8, 10, 12 and 22):
potential risks associated with local reactions (e.g., swelling, induration,
pain).
Pulmonology assessments (at screening, baseline, week 1, 2, 4, 6, 8, 10, 12 and
22):
Spirometry (at screening, baseline and week 12 and 22)
Swollen and tender joints assessment (at screening, baseline, week 1, 2, 4, 6,
8, 10, 12 and 22):
MRI (week Screening, week 12 and week 22): potential risks associated with
exposure to a high field MRI magnet and Gadolinium (Gd) containing MRI contrast
agents)
Questionnaires: questionnaires (Pain NRS, AUSCAN 3.1 NRS, Patient Global
Assessment of Disease Activity [PtGA]) will be completed at relevant
study visits or at home as described in the Time and Events Table (Section 7.1
of the protocol).
Treatment of GSK3196165 might be associated with an increased risk to the
following uncommon side effects:
Increased risk of infection.
Increased risk to the extremely rare condition of PAP (Pulmonary alveolar
proteinosis).
There is a potential risk of hypersensitivity reactions, including anaphylaxis.
Subcutaneous injections may be associated with local reactions (e.g.,
swelling,induration, pain).
Increased risk of neutropenia
Increased risk on malignancies
Huis Ter Heideweg 62
Zeist 3705 LZ
NL
Huis Ter Heideweg 62
Zeist 3705 LZ
NL
Listed location countries
Age
Inclusion criteria
1. Age * 18 years at the time of signing the informed consent.
2. Meets ACR classification of OA and is intolerant to, or has not responded to analgesics (level 1 and 2) or to NSAIDs for at least 10 days in the past 3 months.
3. Must have active disease with at least two swollen and tender PIP and/or DIP joints in the affected hand*.
and tender PIP and/or DIP joints in the affected hand*; with the same two joints
affected at both screening and randomization.
4. Signs of inflammation such as synovitis in the MRI scan of the affected hand*.
5. Must have a patient*s self assessment of 24h average hand pain intensity of at least *5* on an 11-point NRS (0-10), calculated as an average using data from the 7 days prior to assessment date.
6. Body weight <= or > 45 kg.
7. Male or female subjects are eligible to participate so long as they meet and agree to
abide by the contraceptive criteria.
8. Written informed consent prior to any of the screening procedures including
discontinuation of prohibited medications.
9. Diffusing capacity of the lung for carbon monoxide (DLCO) * 70 % predicted and
forced expiratory volume in 1 second (FEV1) * 80 % predicted.
10. No evidence of active or latent infection with Mycobacterium tuberculosis (TB), as
defined by all of the following:
a. No history of active or latent TB infection irrespective of treatment status.
b. A negative diagnostic TB test within 28 days of baseline (Day 1) defined as: a
negative QuantiFERON Gold test or T-spot test (may be performed locally) (NB: 2
successive indeterminate QuantiFERON tests will be considered as a positive
result).
Exclusion criteria
1. Pregnant or lactating females.
2. Significant unstable or uncontrolled acute or chronic disease (e.g., cardiovascular
including uncompensated congestive cardiac failure NYHA III or IV, myocardial
infarction within 12 months, unstable angina pectoris, uncontrolled hypertension,
hypercholesterolemia) pulmonary, hematologic, gastrointestinal (including Crohn*s
Disease or ulcerative colitis), hepatic, renal, neurological, psychiatric, malignancy,
endocrinological, immunologic or infectious diseases, which, in the opinion of the
investigator, could confound the results of the study or put the subject at undue risk.
3. History of any clinically significant inflammatory disease other than inflammatory
HOA, especially, but not limited to, rheumatoid arthritis or spondylarthropathies.
4. Diagnosis of rheumatoid arthritis, fibromyalgia, gout, calcium pyrophosphate
deposition disease CPPD, pseudogout, hemochromatosis or other inflammatory
rheumatological or autoimmune disorders.
5. Clinical suspicion of, or previous investigation for CPPD or pseudogout, or history of
chondrocalcinosis.
6. Any injury, medical or surgical procedure to the affected joint(s) that may interfere
with evaluation of the target HOA joint(s).
7. History of any clinically-significant respiratory disease that required treatment and/or
follow up under the direction of a physician or any respiratory disease which in the
opinion of the Investigator would compromise the ability of the subject to complete
the study (e.g. interstitial lung disease, such as pulmonary fibrosis, chronic
obstructive pulmonary disease [COPD], moderate-severe asthma, bronchiectasis,
pneumonitis, pulmonary alveolar proteinosis (PAP), significant exposure to
pneumotoxins (e.g. inhaled silica).
8. Clinically-significant or unstable (in the opinion of the Investigator) persistent cough
or dyspnea that is unexplained.
9. QTc > 450 msec or QTc > 480 msec in subjects with Bundle Branch Block based on averaged values of triplicate electrocardiograms obtained over a brief (e.g. 5-10 minute) recording period.
* The QTc is the QT interval corrected for heart rate according to Bazett*s formula (QTcB), Fridericia*s formula (QTcF), and/or another method, machine-read or manually over-read.
10. ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if
bilirubin is fractionated and direct bilirubin <35%).
11. Current or chronic history of liver disease, or known hepatic or biliary abnormalities
(with the exception of Gilbert's syndrome or asymptomatic gallstones)
12. A history of malignant neoplasm within the last 10 years or breast cancer within the
last 20 years, except for non-melanoma skin cancers that have been excised and cured
or carcinoma in situ of the uterine cervix.
13. Kidney disease: Current or history of renal disease, or estimated creatinine clearance
<60 mL/min/1.73m2 or serum creatinine >1.5xULN within 28 days of Day 1.
14. Hereditary or acquired immunodeficiency disorder, including immunoglobulin
deficiency.
15. History of infected joint prosthesis at any time, with the prosthesis still in situ.
History of leg ulcers, catheters, chronic sinusitis or recurrent chest or urinary tract
infections.
16. Active infections, or history of recurrent infections (excluding recurrent fungal
infections of the nail bed), or have required management of acute or chronic
infections, as follows:
a. Currently on any suppressive therapy for a chronic infection (such as tuberculosis,
pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical
mycobacteria).
OR
b. Hospitalization for treatment of infection within 26 weeks of Day 1.
OR
c. Use of parenteral (IV or IM) antimicrobials (antibacterials, antivirals, antifungals,
or antiparasitic agents) within 26 weeks of Day 1 or oral antimicrobials within 14
days of Day 1.
17. A vaccination (live or attenuated) within 30 days of Day 1 or BCG vaccination
within 365 days of Day 1, or a live vaccination planned during the course of the
study.
18. Any surgical procedure, including bone or joint surgery/synovectomy within 12
weeks prior to Day 1 or any planned surgery within the duration of the study or
follow-up period.
19. Contraindication to MRI scanning (as assessed by local MRI safety questionnaire)
which includes but not limited to:
a. Intracranial aneurysm clips (except Sugita) or other metallic objects,
b. History of intra-orbital metal fragments that have not been removed by an
medical professional.,
c. Pacemakers or other implanted cardiac rhythm management devices and non-
MR compatible heart valves,
d.Inner ear implants, except MR-conditional implants scanned within manufacturer guidelines,
e. History of claustrophobia which may impact participation
20. Use any of prohibited medications, as listed in Section 6.10.2, throughout the study
until after completion of the week 22 follow-up visit. Prohibited medications must be
discontinued for the stated time in Section 6.10.2 prior to Day 1.
21. Have current drug or alcohol abuse or dependence, or a history of drug or alcohol
abuse or dependence within a year prior to Day 1.
22. History of sensitivity to any of the study treatments, or components thereof or a
history of drug or other allergy that, in the opinion of the investigator or GSK
Medical Monitor, contraindicates their participation.
23. Contraindication to gadolinium contrast agent as assessed by the site.
24. Must have negative titer rheumatoid factor (RF) and anti-CCP antibody.
25. Any Grade 3 or 4 hematology or clinical chemistry laboratory abnormality [CTCAE,
2009 v4.0] within 28 days of Day 1.
26. Hemoglobin *9 g/dL; white blood cell count *3.0 x109/L; platelet count *100 X
109/L; absolute neutrophil count *1.5 x 109/L; lymphocyte count *0.8 x 109/L within
28 days of Day 1.
27. Presence of hepatitis B surface antigen (HBsAg) and/or presence of hepatitis B core
antibody (HBcAb) at screening.
28. Positive hepatitis C antibody test result at screening. Subjects with positive Hepatitis
C antibody due to prior resolved disease can be enrolled only if a confirmatory
negative Hepatitis C RNA PCR test is obtained.
29. Positive serology for human immunodeficiency virus (HIV) 1 or 2 (within 28 days of
Day 1).
30. A positive pre-study drug/alcohol screen.
31. 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).
32. Exposure to more than 4 investigational medicinal products within 12 months prior to
the first dosing day.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-003089-96-NL |
| CCMO | NL55882.100.15 |