The primary objective is to demonstrate the efficacy using 2 co-primary endpoints (as measured by thechanges from baseline to the end of Week 16 in Western Ontario and McMaster UniversityOsteoarthritis Index [WOMAC] pain and physical function…
ID
Source
Brief title
Condition
- Joint disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Co-primary Efficacy Endpoints: Changes from baseline to the end of the 16-week
double-blind phase in
the WOMAC pain and physical function subscale scores and PGA score (for US FDA
and Health
Canada only).
Secondary outcome
Secondary Efficacy Endpoints: Change from baseline to the end of the 16-week
double-blind phase in
scores in: PGA score (not for US FDA and Health Canada), NRS for the study
joint, WOMAC Stiffness
subscale, Medical Outcomes Study (MOS) sleep scale, Short-Form-36 Health Survey
(SF-36) subscales,
EuroQol, 5 dimensions, 5 levels (EQ-5D-5L) scales, rescue medication use, as
well as responder rates
based on WOMAC pain and physical function subscales and PGA, separately, and
responder rates for
Outcome Measures in Rheumatology initiative/Osteoarthritis Research Society
(OMERACT-OARSI),
Patient Acceptable Symptom State (PASS), Minimal Clinically Important
Improvement (MCII).
Exploratory Efficacy Endpoints: Changes from baseline to the end of the 16-week
double-blind phase in:
Australian/Canadian Osteoarthritis Hand Index (AUSCAN) scales for subjects with
a pre-study
diagnosis of OA of the hand.
Background summary
This Phase 3 study will examine the efficacy, safety, and tolerability of 4
injections of fulranumab compared with placebo as monotherapy in subjects with
signs and symptoms of OA of the hip or knee that are not adequately controlled
by current pain therapy and who have scheduled or who are planning a joint
replacement surgery. The pain experienced by this population can affect
function, therefore, it is appropriate to evaluate the effect of fulranumab on
both pain and physical function. Significant improvement in both areas was
previously shown in Phase 2 studies.
This study will provide data to support a product approval.
The hypothesis is that, as monotherapy, at least 1 of the 2 fulranumab doses is
statistically significantly
more effective than placebo in changes from baseline in each of the 2
co-primary endpoints: WOMAC
pain and physical function subscales scores after 16 weeks of treatment.
This protocol fulfills global health authority requirements. The differences in
the protocol to account for
requirements specific to the US FDA and Health Canada are shown in italics.
Study objective
The primary objective is to demonstrate the efficacy using 2 co-primary
endpoints (as measured by the
changes from baseline to the end of Week 16 in Western Ontario and McMaster
University
Osteoarthritis Index [WOMAC] pain and physical function subscales), safety, and
tolerability of
fulranumab subcutaneous (SC) injections as monotherapy compared with placebo in
subjects with signs
and symptoms of osteoarthritis of the hip or knee that were not adequately
controlled by current pain
therapy and who are planning a joint replacement surgery.
Secondary Objectives
To evaluate the effect of fulranumab on:
* Patient Global Assessment (PGA) (not for US FDA and Health Canada)
* Joint pain using Numerical Rating Scale (NRS)
* Stiffness, sleep, functional status and well-being as measured by the subject
* Additional analgesic medication use
* Pharmacokinetics and immunogenicity of fulranumab
Exploratory Objectives
To investigate the effect of fulranumab on:
* Post-surgery outcome after joint replacement
* Pre-existing hand OA
* Healthcare resource use and productivity
* Biomarker development
Study design
This is a randomized, double-blind, multi-phase, placebo-controlled,
parallel-group efficacy, safety, and tolerability study examining, as
monotherapy, fulranumab compared to placebo in subjects with signs and symptoms
of hip or knee OA that are not adequately controlled by current pain therapy.
Approximately 450 men or women (*18 years of age) will be randomly assigned in
a 1:1:1 ratio, ie, 150 subjects to each double-blind treatment group (placebo
Q4wk (every 4 weeks), fulranumab 1mgQ4wk,fulranumab 3mgQ4wk). Subjects will be
stratified by: study joint type (at least 33% of hip and of knee),baseline body
weight group (<85 kg versus *85 kg), and planned or scheduled joint replacement
surgery.
The study is a total of 67 weeks in duration. The study includes the following
phases: screening phase (3 weeks that includes a 7-day OA analgesic washout
period); double-blind treatment phase (16 weeks);post-treatment follow-up phase
(up to 48 weeks). Subjects who discontinue from the double-blind phase and who
do not enter the post-treatment follow-up phase will be asked to allow limited
safety follow-up
lasting up to 24 weeks after the last injection of study drug. The screening
phase can be extended to document OA analgesic failure or to verify
contraception method if approved by the medical monitor.
Chronic NSAID use and aspirin use (>325 mg/day inclusive of all acetylsalicylic
acid containing products) will be prohibited during the double-blind treatment
phase and for 16 weeks after the last injection of study drug. Chronic NSAID
use of non-selective NSAIDs or selective NSAIDs [COX-2 inhibitors] is defined
as use that lasts for a total of >10 days within each 8-week period, >30 days
for each 6-month period, or >60 days over 1 year.
Acetaminophen/paracetamol (3,000 mg per day inclusive of all
acetaminophen/paracetamol containing products) will be allowed as rescue
medication during the washout and the double-blind phase except for 48 hours
before each clinic visit if an efficacy assessment will be performed.
If subjects discontinue treatment, they will complete the double-blind
treatment phase assessments up to and including the Week 17 visit (except
injection site reaction). Following the completion of the double-blind
assessments, they will enter the post-treatment and/or limited safety follow-up.
A subject who undergoes a joint replacement surgery will discontinue treatment
and be followed for up to 52 weeks in the post-treatment phase that will
include up to 24 weeks of post-surgery assessments.
An unblinded Independent Data Monitoring Committee (IDMC) and 2 blinded
Independent Adjudication Committees (IAC) will be commissioned for safety
oversight.
Intervention
Subjects will receive 4 subcutaneous (SC) injections of study drug during the
double-blind treatment
phase. Fulranumab will be administered as a 1 mg or 3 mg dose every 4 weeks by
SC injection of 0.25 mL using a prefilled syringe (1 mg [4.0 mg/mL] and 3 mg
[12 mg/mL]). Placebo will be administered by SC injection every 4 weeks using a
0.25 mL volume. The SC injection will be
administered into the thigh or abdomen except in the 2-inch area around the
navel.
Study burden and risks
Participation in the study could take up to 67 weeks and longer and could
involve 11 visits to the clinic. The patient will also be contacted by phone in
between the visits. The number of weeks the4 patient will stay in the study is
depending on joint replacement surgery or not and at what stage in the study.
The following procedures will be done during the different visits:
3x physical examination, 11x brief neurological examination, 11x vital signs,
1x medical history including medication history, 7x blood draw,
discussconception methods, 5x urine sample, 4x pregnancy test ( women), 3x ECG,
3x X-rays hips, knees ( and shoulders only at ScR), 11x joint assessments,
discuss/review e-diary, discuss side effects. Different questionnaires:
- 1x OA-medical history
- 1x failure OA-pain medication
- 1x medical history nervous system
- 1x BDI-II (presence and severity of symptoms of depression)
- 2 times daily through e-diary: Numerical rating scale (NRS) of OA pain
- 1 x carpal tunnel syndrome
- 10x WOMAC ( OA pain, stiffness and activity)
- 3x MMSE( thinking, concentration and memory)
- 10x patient global assessment (PGA) ( the treatment has affected the OA)
- 8x EQ-5D-5l ( quality of life)
-4x Short Form- 36 Health Survey (SF-36) (health status, pain and well-being)
- 5x AUSCAN ( only for patients with OA in their hands)
-4x MOS sleep (questions about ( quality of) sleep)
- 2x (subject version- Leeds Assessment of Neuropathic Symptoms and Signs)
(S-LANSS): to monitor the possible development of neuropathic pain after a
joint replacement ( only for patients with a joint replacing surgery)
Most common side effects (affects1 or more users out of 10 users): Arthralgia
(achy joints), Headache, Upper respiratory tract infection (colds, cough,
runny nose)
Common (affects 1 to 9 users out of 100 users): Rapidly progressing
osteoarthritis leading to joint replacement, Carpal Tunnel Syndrome,
Hypoesthesia/paresthesia, Recurrence of oral ulcers (cold sores), Peripheral
edema
Other side effects:
* Injections of fulranumab and blood draw may cause pain, redness, swelling or
bruising at the place where the needle goes into the skin. Fainting, and in
rare cases infection, may occur. The amount of blood taken is a small amount
per visit.
* X-Ray Risks:
* The total amount of radiation for this study is approximately equivalent to
13-18 months of whole body exposure to natural background radiation.
* The risk associated with such an exposure is considered minimal and is
necessary to obtain the research information desired for the study.
* ECG Risk: There is generally no risk with having an ECG. The sticky patches
may pull the skin or cause redness or itching
Please also refer to Protoocl, IB and ICFs
Turnhoutseweg 30
Beerse 2340
BE
Turnhoutseweg 30
Beerse 2340
BE
Listed location countries
Age
Inclusion criteria
The major inclusion criteria are:
1) Man or woman at least 18 years of age;
2) Clinical diagnosis of OA of hip or knee based on criteria defined by the American College of Rheumatology and radiographic evidence of OA (Kellgren-Lawrence class *2) of the study joint;
3) Scheduled joint replacement surgery for the study joint *20 weeks after randomization or planning to undergo a joint replacement surgery for the study joint;
4) Must have an unsatisfactory response (inadequate efficacy or poor tolerability) that includes at least one from each of the following 3 classes of oral analgesic medications (acetaminophen/paracetamol, NSAID, and opioid;
5) Moderate to severe pain and functional impairment based on the NRS, WOMAC pain and physical function subscales, and PGA with specific criteria applied to each scale and subscale. Eligibility criteria will be blinded to subjects, investigators, and site staff to reduce error variance, to improve accuracy of treatment estimates, and to avoid inclusion of subjects who cannot provide interpretable data.
6) During treatment and within 24 weeks after the last injection of study drug: if female of childbearing potential, is not pregnant, breast-feeding, or planning to become pregnant, or if male, will not father a child;
Please refer to the protocol section 4.1 ( page 42-44) for a complete list of inclusion criteria)
Exclusion criteria
The major exclusion criteria are medical history that suggests:
1) Increased risk of osteonecrosis (ON) or rapidly progressive osteoarthritis (RPOA);
2) Sympathetic dysfunction as defined in the protocol
3)Central nervous system abnormalities as defined in the protocol
4) Peripheral neurological deficits as defined in the protocol
5)Viral infections as defined in the protocol
6)Cardiovascular related conditions as defined in the protocol
7) History of inherited disorders associated with or causing hypercoagulopathy
8) History of malignanies within the past 2 years
9)Uncontrolled diabetes
10) any other chronic pain condition that would interfere with the subject's ability to assess their OA pain ( e.g fibromyalgia)
11) Creatinine clearance < 30 mL per minute
12) ALT or AST>- 2.5 times ULN
13) BMI > 39 kg/m2
14) Other as described in the protocol;Please see a complete list of all exclusion criteria in the protocol section 4.2 (page 44-47)
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 | EUCTR2014-002598-13-NL |
| ClinicalTrials.gov | NCT02289716 |
| CCMO | NL51453.100.15 |