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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03197623
Recruitment Status : Recruiting
First Posted : June 23, 2017
Last Update Posted : June 28, 2018
California Institute for Regenerative Medicine (CIRM)
Information provided by (Responsible Party):
Nancy E. Lane, MD, University of California, Davis

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Osteopenia Osteoporosis Osteonecrosis Drug: LLP2A-ALENDRONATE Drug: Placebo Phase 1

Detailed Description:

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Randomized, Double-Blind, Placebo-Controlled Single and Multiple Ascending Dose Study
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : October 14, 2016
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : June 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Steroids

Arm Intervention/treatment
50, 150, 400 or 750 μg/kg or placebo given as a one time intravenous administration over 120 minutes.
A small molecule, LLP2A-Ale that directs endogenous mesenchymal stem cells (MSCs), the cells that have the potential to grow bone tissue, to the bone surface to form new bone. Single administration of LLP2A-Ale given intravenously over 120 minutes.
Other Name: LLP2A-Ale

Placebo Comparator: Placebo
placebo given as a one time intravenous administration over 120 minutes.
Drug: Placebo
Placebo, one time single administration given intravenously over 120 minutes.

Primary Outcome Measures :
  1. Dose limiting Adverse events [ Time Frame: Duration of the Study, average of 4 years ]
    Incidence of dose limiting or intolerable treatment related adverse events (AEs) including A serious drug-related adverse event in ≥ 1 subject receiving LLP2A-Ale and/or Severe drug related adverse events in ≥ 2 subjects receiving LLP2A-Ale

Secondary Outcome Measures :
  1. Severe infusion reactions [ Time Frame: Duration of the study, average of 4 years ]
    Fever, myalgia, nausea/vomit, headache, flu like symptoms in ≥ 2 subjects receiving LLP2A-Ale

  2. Grade 2 elevated creatinine [ Time Frame: Duration of the study, average of 4 years ]
    serum creatinine greater than 1.5 - 3.0 x baseline; greater than 1.5 - 3.0 x upper limit of normal (CTCAE v4.0) in ≥ 1 patient.

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Ages Eligible for Study:   20 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 procedures)
  5. Prior use or current need for prohibited concomitant medications (Section 5.10)
  6. Rheumatic disease with clinically significant renal or central nervous system involvement
  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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03197623

Contact: Christy Pifer, BS 916-734-4536
Contact: Center for Musculoskeletal Health 916-734-4534

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Sponsors and Collaborators
Nancy E. Lane, MD
California Institute for Regenerative Medicine (CIRM)
Principal Investigator: Nancy E Lane, MD UC Davis Health
Study Director: Nancy E Lane, MD UC Davis Health

Responsible Party: Nancy E. Lane, MD, Professor, University of California, Davis Identifier: NCT03197623     History of Changes
Other Study ID Numbers: 20161825
LLP2A-001 ( Other Identifier: UC Davis )
First Posted: June 23, 2017    Key Record Dates
Last Update Posted: June 28, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Nancy E. Lane, MD, University of California, Davis:

Additional relevant MeSH terms:
Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Metabolic Diseases
Pathologic Processes
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Bone Density Conservation Agents