A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging, Dose-Loading Study to Evaluate the Efficacy, Safety, and Tolerability of JNJ-42160443 as Adjunctive Therapy in Subjects With Inadequately Controlled, Moderate to Severe, Chronic Low Back Pain

Low back pain is a common cause of nonmalignant, chronic pain and represents
one of the most significant socioeconomic health-related problems in developed
countries.
Unless a diagnosis leading to curative medical or surgical procedures is
established, the management of musculoskeletal nonmalignant chronic pain
(chronic LBP being a predominant disease) remains in most cases symptomatic,
directed primarily towards relief of pain, optimization of function, and
minimization of disability. Pharmacologic treatment includes the following
analgesics: non-steriodal anti-inflammatory drugs (NSAIDs), cyclooxygenase II
(COX-II) inhibitors, acetaminophen (paracetamol), and opioids. Muscle
relaxants, antidepressants, and occasionally sterioids (oral or epidural) are
used. Despite the variety of available pharmacologic treatments for
nonmalignant, chronic pain, many patients with chronic pain do not obtain
adequate relief or experience unacceptable adverse events from existing
treatments.

Nerve growth factor plays an important role in the generation of pain and
hyperalgesia in several acute and chronic pain states, and anti-NGF therapy was
associated with significant improvement in chronic pain from osteoarthritis.
Although anti-NGF therapy for relief of chronic LBP has not been reported, NGF
expression was increased in intervertebral discs associated with pain on
discography and was absent in intervertebral discs not associated with pain.
Therefore, anti-NGF therapy may be effective in the treatment of chronic LBP as
well as other chronic pain states.
This study will evaluate the analgesic efficacy, safety, and tolerability of
several doses and dosage regimens of JNJ-42160443 in subjects with moderate to
severe, chronic LBP that is not adequately controlled with standard pain
therapies. This study will also provide information for dosing recommendations
for future clinical studies.

Primary Objectives
The primary objectives of this study are to evaluate the analgesic effect size
over 12 weeks of several doses and dosage regimens of JNJ-42160443 compared
with placebo in subjects with moderate to severe, chronic, low back pain (LBP)
that is not adequately controlled by standard pain therapy, and to evaluate the
safety and tolerability of multiple SC doses of JNJ-42160443 in this population.
Secondary Objectives
The key secondary objectives of this study are:
• To evaluate the efficacy of JNJ-42160443 compared with placebo as measured by
back pain disability with subscales and total scores of the Oswestry Disability
Index (ODI)
• To evaluate the efficacy of JNJ-42160443 compared with placebo as measured by
the pain severity and pain interference subscales and total scores from the
Brief Pain Inventory (BPI) Short Form
• To evaluate the efficacy of JNJ-42160443 compared with placebo as measured by
the Patient Global Assessment (PGA)
Other secondary objectives are:
• To evaluate the pharmacokinetics of JNJ-42160043 after multiple dose
administrations of JNJ 42160443. A population PK approach will be used to
characterize the disposition characteristics of JNJ 42160443 in this study.
• To evaluate the immunogenicity (antibodies to JNJ-42160443) associated with
JNJ 42160443 treatment
• To evaluate the long-term efficacy, safety, and tolerability of JNJ-42160443
in this subject population during the 92-week double-blind extension phase
Exploratory Objectives
The exploratory objectives of this study are:
• To evaluate the efficacy of JNJ-42160443 compared with placebo as measured by
rescue medication use
• To investigate the effects of JNJ-42160443 on changes in functional status
(including physical functioning) and well-being with subscales of the Short
Form 36 (SF-36*) Health Survey
• To investigate the effects of JNJ-42160443 on dimensions of sleep and daytime
somnolence using a daily sleep interference question and the Medical Outcomes
Study (MOS) Sleep Scale
• To investigate potential biomarker development by biochemical analysis of
blood samples
• To explore PK/pharmacodynamic (PD) modeling using pooled data from other JNJ
42160443 studies

This is a randomized, double-blind, placebo-controlled, dose-ranging,
dose-loading study evaluating the analgesic efficacy, safety and tolerability
of JNJ-42160443 at several doses and dosage regimens in subjects with moderate
to severe, chronic, LBP that is not adequately controlled by standard pain
therapy. The study consists of a 3-week screening phase, a 12 week double blind
efficacy phase, a 92 week double blind extension phase, and a 26 week
posttreatment phase. The screening phase may be extended up to 3 months to meet
the contraception inclusion criteria for women, but baseline safety evaluations
must be performed within 3 weeks before the first dose of study drug.
Approximately 360 subjects will be enrolled and randomly assigned to receive
either placebo or 1 of 4 JNJ 4216043 treatment regimens, 72 subjects in each
treatment group.
The study duration will be approximately 41 weeks (3-week screening phase,
12-week double-blind efficacy phase, and 26-week posttreatment phase for
immunogenicity evaluations) for a subject who does not continue in the
double-blind extension phase. The study duration for a subject who completes
both the double-blind efficacy and extension phases will be approximately 133
weeks (3-week screening phase, 12 week double-blind efficacy phase, 92-week
double blind extension phase, and 26-week posttreatment phase for
immunogenicity evaluations).

Subjects will be randomly assigned to receive placebo or 1 of 4 JNJ-42160443
treatment regimens: 1 mg every 4 weeks, 3 mg every 4 weeks, an initial 6 mg
loading dose followed by 3 mg every 4 weeks, and 10 mg of every 4 weeks. Within
each cohort of approximately 90 subjects, subjects will be randomly assigned to
treatment in a 4:1 ratio to receive placebo or 1 of 4 JNJ 42160443 treatment
regimens (active treatment:placebo 72:18 subjects in each treatment cohort).
Doses of JNJ-42160443 or placebo will be administered as a SC injection into
the thigh. An alternative administration site, to be used only in the event
that the study drug cannot be administered into the thigh, is the abdomen
(avoiding the area 2 inches around the navel). JNJ-42160443 will be provided in
vials containing 1 mL of solution (10 mg/mL). Doses will be administered by
volume (eg, 1 mg=0.1 mL, 3 mg=0.3 mL, 6 mg=0.6 mL, 10 mg=1 mL). Each of the 4
cohorts will have a different dosing volume and the placebo dosing volume will
match its treatment cohort dosing volume. A scheduled PK blood sample must be
collected before administration of any JNJ 42160443 dose of study drug. The
method(s) of contraception used by each subject or their partner must be
documented before administration of any dose of study drug. A pharmacy manual
containing detailed information about the dose preparation and administration
instructions will be provided to each study site.
During the double-blind extension phase, subjects will remain in the same
blinded treatment group to which they were initially randomly assigned, and
will receive the same volume of injection (including placebo subjects).

Burden for the patients
- In the first 3 months, the patient will be asked to complet an e-diary twice
daily to report pain score, score sleep quality and rescue medication.
- Patient visits the site monthly for administration of study medication.
During these visits a number of questionnaires has to be completed and
neurological tests will be done. After administration of study medication, the
patient has to stay in the hospital for another 30 minutes under supervision of
the studystaff. These visits can therefore last about 1.5 to 2 hours.

Possible risks and adverse events : see E9

Benifits : possible pain relief with the study drug