Longjohn Amgen Study - Effect of Denosumab...

EXPERIMENTAL PLAN Study Design The proposed study is a Phase 3, double-blinded, randomized
controlled study. All of the 80 patients, both placebo and denosumab groups, will adhere to
the same protocol. Patient screening will be performed by the orthopaedic surgeons (Donald
Longjohn, MD and Daniel Oakes, MD) during the preoperative clinical appointments, based on
the Inclusion and Exclusion Criteria. If the patient is deemed appropriate for the study,
consent for participation in the proposed study will be obtained prior to hip replacement
surgery.

Two doses of denosumab will be given, 60 mg each. Study Day 1 will be defined as the day of
injection, with the first 60 mg dose of denosumab or the placebo administered within 7-14
days following hip replacement surgery. The second injection (60 mg) of either denosumab or
the placebo will be administered 6 months after Study Visit #1 . DEXA will be performed on
the treated femur using the 7 Gruen radiographic zones of interest, and on the contralateral
femur, using traditional analysis protocol, as well as the acetabulum on the treated side
using the 3 zones of interest . This will be performed at (1) Study Visit #1, date of first
injection; (2) 3 months after injection; (3) 6 months after injection, immediately prior to
injection #2; and (4) 12 months after Study Visit #1. Bone mineral density in all patients
will be assessed utilizing a Hologic Bone Densitometer with software for metal subtraction
on the treated femur. As well, bone turnover markers will be determined base line from blood
drawn: (1) at Study Visit #1, date of first injection; (2) 1 month after injection; (3) 3
months after injection; (4) 6 months after injection 1, date of injection 2; (5) 12 months
after injection #1 (same as 6 months after injection 2).

Number of Centers

(1) - Orthopaedic Institute for Children (Orthopaedic Hospital), 403 W. Adams Boulevard, Los
Angeles, CA

Number of Subjects Number of Subjects = 80

Estimated Study Duration Twenty four (24) months. The study duration for individual
participants will be twelve (12) months: Enrollment will take place over the course of the
first 12 months of the study and each patient will be followed for 12 months following joint
replacement surgery, for a total duration of 24 months. If the study enrollment is not
complete by the end of the first 12 months, the enrollment period will be extended an
additional 6 months.

SUBJECT ELIGIBILITY Inclusion Criteria Inclusion criteria will allocate patients undergoing
elective total hip replacement due to osteoarthritis. The prosthetic device will be a
standard, non-cemented tapered total hip replacement, such as an Alloclassic® (Zimmer, Inc.,
Warsaw, IN) or a similarly shaped implant of the same material (titanium alloy) such as the
Summit Hip (Depuy, Inc., Warsaw, IN). Subjects will be between 55 and 75 years of age. Both
genders will be included. Prior to surgery, creatinine clearance, calcium, and vitamin D
will be checked. Creatinine clearance rates must be above 30 ml/min, vitamin D serum levels
must be greater than 12 ng/ml, and patients cannot be hypocalcemic. If vitamin D serum
levels are below normal (30ng/ml) the 1000 mg of calcium and at least 1000 Units of vitamin
D, recommended by the surgeon at the time of operation will likely be sufficient to correct
this problem.

Exclusion Criteria Current use of medications that may affect bone and mineral metabolism
(e.g., glucocorticoids, diuretics, estrogen, oral contraceptives, tamoxifen,
bisphosphonates, raloxifene, calcitonin, PTH, anticonvulsants, immunosuppressants), and
subjects with a history of any disease that affects bone and mineral metabolism (e.g.,
thyrotoxicosis, hyperparathyroidism, hypocalcemia hypoparathyroidism, chronic renal failure,
Cushing's disease, rheumatoid arthritis, hematological disease, alcohol abuse > 3 drinks a
day), cancer. Additionally, patients who are taking immunosuppressants will be excluded.
Patients who have been treated with anti-TNF in the past 3 months will be excluded. Patients
with hypocalcemia or patients who have used bisphosphonates in the 2-3 years prior to the
surgery will be excluded. Additionally, patients with creatinine clearance rates below 30
ml/minwill be excluded, as will patients with severe vitamin D deficiencies (<12 ng/ml).
Patients with decreased hepatic function as measured by AST, ALT, Alkaline Phosphatase or
Total Bilirubin will be excluded from the study. Patients who have had any solid organ or
bone marrow transplants will be excluded. Patients who have a history of malignancy within
the past 5 years, with the exception of basal cell carcinoma or cervical carcinoma in situ,
will be excluded. Additionally, as the incidence of serious infections may be higher in
patients treated with denosumab, patients with poorly controlled diabetes/HbA1C will be
excluded.

SUBJECT ENROLLMENT AND TREATMENT ASSIGNMENT A total of 80 subjects (N=80) will be enrolled
over the first twelve months of the proposed study.

40 of the patients will randomly receive the placebo treatment, and 40 will receive the
denosumab treatment. All individuals interacting with patients, including operating surgeons
and the patients, will be blinded, with the exception of the Orthopaedic Hospital pharmacist
who will be un-blinded. The pharmacist will be in charge of receiving and maintaining the
drug until the time of administering to the patient.

TREATMENT PROCEDURES Amgen Investigational Product Denosumab

Dosage, Administration, and Schedule On postoperative day 7-14 (Study Visit #1), and at 6
months following Study Visit #1 (date of first injection, DEXA, and blood draw), the
patients will receive either 60 mg denosumab or placebo.

Dose Escalation and Stopping Rules There will be no dose escalation. Therapy will be
evaluated if the subject develops symptomatic hypocalcemia, serious skin infections,
osteonecrosis of the jaw, or pancreatitis. The subjects will be advised to seek prompt
medical attention if they develop any of these signs or symptoms. If Adverse Events develop
as defined in section 9.1., if there is suspicion that it may be related to the drug, the
case(s) will be investigated and, if deemed necessary, then the patient and doctors may be
un-blinded for the purposes of treatment. If symptoms develop after Study Visit #6 (date of
second and final injection), even if un-blinding occurs for treatment purposes, patient will
be asked to come back for final Study Visit (#5) for 12 month DEXA and blood draw, if
willing. If serious side effects occur prior to second injection (Study Visit #4), patient
may not receive second injection if there are serious medical concerns.

Dosage Adjustments There will be no dose adjustments.

Concomitant Therapy Subjects will be instructed to take 1000 mg of calcium and at least 1000
Units of vitamin D per day.

Prescribed Therapy during Study Period No use of the medications as listed in the exclusion
criteria.

Other Treatment Procedures None

Inclusion Criteria:

- Inclusion criteria will allocate patients undergoing elective total hip replacement
due to osteoarthritis. The prosthetic device will be a standard, non-cemented tapered
total hip replacement, such as an Alloclassic® (Zimmer, Inc., Warsaw, IN) or a
similarly shaped implant of the same material (titanium alloy) such as the Summit Hip
(Depuy, Inc., Warsaw, IN). Subjects will be between 55 and 75 years of age. Both
genders will be included. Prior to surgery, creatinine clearance, calcium, and
vitamin D will be checked. Creatinine clearance rates must be above 30 ml/min,
vitamin D serum levels must be greater than 12 ng/ml, and patients cannot be
hypocalcemic. If vitamin D serum levels are below normal (30ng/ml) the 1000 mg of
calcium and at least 1000 Units of vitamin D, recommended by the surgeon at the time
of operation will likely be sufficient to correct this problem.

Exclusion Criteria:

- Current use of medications that may affect bone and mineral metabolism (e.g.,
glucocorticoids, diuretics, estrogen, oral contraceptives, tamoxifen,
bisphosphonates, raloxifene, calcitonin, PTH, anticonvulsants, immunosuppressants),
and subjects with a history of any disease that affects bone and mineral metabolism
(e.g., thyrotoxicosis, hyperparathyroidism, hypocalcemia hypoparathyroidism, chronic
renal failure, Cushing's disease, rheumatoid arthritis, hematological disease,
alcohol abuse > 3 drinks a day), cancer. Additionally, patients who are taking
immunosuppressants will be excluded. Patients who have been treated with anti-TNF in
the past 3 months will be excluded. Patients with hypocalcemia or patients who have
used bisphosphonates in the 2-3 years prior to the surgery will be excluded.
Additionally, patients with creatinine clearance rates below 30 ml/minwill be
excluded, as will patients with severe vitamin D deficiencies (<12 ng/ml). Patients
with decreased hepatic function as measured by AST, ALT, Alkaline Phosphatase or
Total Bilirubin will be excluded from the study. Patients who have had any solid
organ or bone marrow transplants will be excluded. Patients who have a history of
malignancy within the past 5 years, with the exception of basal cell carcinoma or
cervical carcinoma in situ, will be excluded. Additionally, as the incidence of
serious infections may be higher in patients treated with denosumab, patients with
poorly controlled diabetes/HbA1C will be excluded.