Safety and Tolerability of Intravenous LLP2A-Alendronate for Osteopenia Secondary to Glucocorticoids

Conditions:Osteoporosis, Orthopedic, Gastrointestinal
Therapuetic Areas:Gastroenterology, Rheumatology, Orthopedics / Podiatry
Age Range:20 - 75
Start Date:October 14, 2016
End Date:June 2020
Contact:Christy Pifer, BS

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A Phase 1, Randomized, Double-Blind, Placebo-Controlled Single and Multiple Ascending Dose Study of the Safety and Tolerability of Intravenous LLP2A-Alendronate in Adult Men and Women With Osteopenia Secondary to Glucocorticoids

A Phase 1 Randomized, Double-Blind, Placebo-Controlled Single and Multiple Ascending Dose
Study of the Safety and Tolerability of Intravenous LLP2A-Alendronate in Adult Men and Women
with Osteopenia Secondary to Corticosteroids.

The study is designed to evaluate safety and tolerability of LLP2A-Ale beginning with a
single ascending dose (SAD) cohort followed by multiple ascending dose (MAD) cohorts with
matching placebo in each cohort. The population in this study includes patients with low bone
density (osteopenia with a T score ≤ -1.0) in the femoral neck, total hip or lumbosacral
spine who are taking Corticosteroids. Up to 50 patients will be enrolled, 32 in the SAD and
18 in the MAD.

LLP2A-Ale is a novel anabolic agent. It appears that LLP2A-Ale may have utility in a variety
of conditions where new bone formation is required. Non-traumatic osteonecrosis (ON) has been
selected as the first indication for LLP2A-Ale because of the high unmet need, absence of
treatments besides surgical joint replacement, and the clear need to attract and stimulate
differentiation of stem cells into the region of necrotic bone. However, osteonecrosis is a
rare, sporadic disease. Therefore, the Phase 1 study is being performed in people at risk for
osteonecrosis, as a population representative of people with osteonecrosis, who will be the
participants in any subsequent Phase 2 and 3 studies.

Non-traumatic ON may also be caused by a variety of underlying medical conditions.
Glucocorticoid use, alcohol, and smoking contribute to up to 80% of cases of nontraumatic ON.
The relationship to GC is the strongest in people receiving relatively long term therapy,
with risk increasing with cumulative exposure over three or more months. Vasculitis from
autoimmune diseases predisposes to ON and ON is particularly associated with Systemic Lupus
Erythematous (SLE), possibly due to coexistence of vasculitis and chronic GC treatment. In
different series, symptomatic ON is reported in about 5-30% of SLE patients. Because many
foci of ON are asymptomatic, rates based on MRI surveillance are higher, in the range of 30 -
50%, and often are multifocal. Because of the particularly high incidence of ON in SLE we
anticipate that SLE patients will be a significant component of the population in later
trials. Therefore investigators in this Phase 1 trial include rheumatologists in order to
increase the likelihood of inclusion of lupus patients in this first study.

Inclusion Criteria:

Subjects must meet all of the following criteria to be included in the study.

1. 20 - 75 years old

2. Receiving 5 - 40 mg/day prednisone, or equivalent of another GC (methylprednisolone 4
mg/day, or prednisone 10 mg every other day) for a minimum of 4 consecutive weeks
prior to enrollment

3. Anticipated to continue to receive at least 5 mg/day prednisone or equivalent
throughout study participation

4. T score ≤ -1.0 in the femoral neck, total hip or lumbosacral spine.

5. Must be ambulatory and able to attend all appointments

6. Women of child-bearing potential (i.e., non-postmenopausal women or women who are not
surgically sterile) must agree to use one of the following methods of birth control
for the duration of the clinical trial: systemic hormonal contraceptive (oral,
injected, transdermal), intrauterine device, double barrier (e.g., cervical cap or
diaphragm with condom or spermicide). Men with female partners must agree to use
double barrier contraception, unless their partner is using systemic hormonal
contraceptives or has an intrauterine device.

7. In the opinion of the investigator, the concurrent medical conditions of the study
subject are stable.

Exclusion Criteria:

Subjects who meet any of the following criteria will be excluded from the study:

1. Weight greater than the limit of the DXA table at the clinical site

2. History of bone disease (besides osteopenia), skeletal injury at sites of DXA/QCT
examination, skeletal radiation, or conditions that interfere with the ability to have
an accurate DXA/QCT scan at any site

3. History or concurrent conditions that might place the patient at increased risk, such
as renal insufficiency (CKD 4 or 5), glomerulonephritis, atypical infections due to
impaired immunity, hypersensitivity to multiple IV medications

4. History of or concurrent presence of medical conditions which might interfere with
ability to participate for the duration of the study, such as clinically significant
cardiovascular disease, uncontrollable hypertension, uncontrolled asthma, symptomatic
pulmonary fibrosis, recent GI bleeding requiring transfusion, psychosis, substance
abuse or hospital admission within 6 months of enrollment (except for elective

5. Prior use or current need for prohibited concomitant medications (Section 5.10)

6. Rheumatic disease with clinically significant renal or central nervous system

7. History of deep vein thrombosis (DVT) or taking any prophylaxis/treatment within the
last 5 years

8. History of clinically significant atrial fibrillation and/or taking medications for
its treatment and prevention

9. Unable or unwilling to comply with restrictions on alcohol, smoking

10. Previous hypersensitivity to alendronate.

11. Any of the following on Screening laboratory tests:

- Total calcium values outside the normal range (corrected if albumin < lower limit
of normal (LLN))

- Phosphate level < LLN

- 25-hydroxyvitamin D (25-OH Vitamin D) below 10ng/mL

- TSH > upper limit of normal (ULN)

- Hepatic enzymes (ALT, AST, GGT) > 1.5 X ULN

- Creatinine clearance (eGFR)< 35 mL/min/1.73 m2 using the Modification of Diet in
Renal Disease (MDRD) formula

- Hemoglobin < 10 g/dL

- Positive serology for HIV, Hepatitis B or C

- Positive pregnancy test

- Prolonged QTc interval (> 450 ms) (QTcF (Fredericia) of > 450 msec for men, > 470
msec for women)

- Any other clinically significant laboratory value as judged by the investigator
We found this trial at
Duncansville, Pennsylvania 16635
Principal Investigator: Alan Kivitz, MD
Phone: 814-696-7053
Duncansville, PA
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5630 West Cerritos Avenue
Cypress, California 90630
Principal Investigator: Bonnie Bock, MD
Phone: 714-252-0700
Cypress, CA
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Dallas, Texas 75231
Principal Investigator: Roy Fleischmann, MD
Phone: 214-879-6737
Dallas, TX
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Walnut creek, California 94598
Principal Investigator: Mark Christiansen, MD
Phone: 925-930-7267
Walnut creek, CA
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