A Study of Oral Recombinant Salmon Calcitonin (rsCT) to Prevent Postmenopausal Osteoporosis

A Randomized, Double-blind, Placebo-controlled Clinical Trial Evaluating the Safety and Efficacy of Oral Recombinant Salmon Calcitonin (rsCT) in the Prevention of Postmenopausal Osteoporosis in Women at Increased Risk of Fracture

The primary purpose of this study was to evaluate the efficacy of oral calcitonin (rsCT)tablets in the prevention of bone loss in postmenopausal women with lower bone mineral density at increased risk of fracture. The secondary purpose of this study was to determine if there is any food effect by comparing the efficacy and safety of oral calcitonin tablets administered at dinner or at bedtime.

This was a randomized, double-blind, placebo-controlled Phase 2 study conducted entirely in the US. The subjects were all post-menopausal women whose 10-year risk of major osteoporotic fracture was assessed using the World Health Organization (WHO) Fracture Risk Assessment Tool (FRAX®) algorithm within the first 3 visits. Eligible, consenting subjects were then enrolled and began a 2- week single-blind placebo run-in phase to determine tolerability. After the run-in phase, continuing subjects were randomized in a 2:1 ratio to receive oral calcitonin or placebo. All subjects took 600 mg calcium citrate and 1000 IU vitamin D once daily with breakfast beginning with the run-in phase. The duration of treatment including the run-in phase was 54 weeks. Bone mineral density (BMD) and C-terminal telopeptide of type 1 collagen (CTx-1) were determined at Baseline and Weeks 28 and 54 after randomization. The % change from baseline in lumbar spine BMD was calculated and compared: active to placebo. The change from baseline in plasma CTx-1 was also calculated and compared likewise.

To confirm that there is no effect of meal timing on this product, subjects in both arms were further randomized to take the active or placebo on an empty stomach at bedtime or with the meal at dinnertime.

Inclusion Criteria:

• Female and at least 45 years of age.

• Must have undergone the onset of spontaneous or surgical menopause more than 5 years prior to entry. Spontaneous menopause is defined as 12 months of spontaneous amenorrhea. Surgical menopause is defined as ≥ 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.

• Serum follicle-stimulating hormone (FSH) levels must be ≥ 30 mIU/mL.

• A body mass index (BMI) of not greater than 35 (BMI

  =weight [kg]/height[m]2).

• Bone mineral density (BMD) T-score between -1.0 and - 2.5 at the total hip, femoral neck, trochanter, or lumbar spine.

• Additional risk factors such that the 10 year risk of a major osteoporotic fracture or hip fracture risk is at least as great as a 65-year-old woman of the same race and BMI of 25 kg/m2 as determined by the FRAX algorithm .

• No clinically significant abnormal findings in the medical history or physical exam that would preclude participation in the investigator's opinion.

• No clinically significant abnormal laboratory values at the screening assessment.

• Subjects must give written informed consent after reading the Subject Information and Consent Form and having had the opportunity to discuss the study with the investigator.

Exclusion Criteria:

• History of an osteoporotic fracture, defined as a fracture at the wrist, hip, or humerus occurring from a fall at standing height or less.
• BMD T-Score at any site ≤ -2.5.
• Current treatment (or within 3 months prior to randomization) with hormone replacement therapy.
• History of metabolic and other bone diseases, including osteogenesis imperfecta, osteomalacia, and Paget's disease.
• Vitamin D insufficiency defined as a 25 hydroxyvitamin D level < 20 ng/mL (50 nmol/L).
• Prior use of calcitonin, ever.
• Prior use of any bisphosphonate, ever.
• Prior use of denosumab, fluoride, or strontium, ever.
• Prior use of parathyroid hormone analogs, ever.
• Any condition or disease that may interfere with the ability to have a dual energy x-ray absorptiometry (DXA) scan or to evaluate a DXA scan, for example, severe osteoarthritis of the spine, spinal fusion, pedicle screws, history of vertebroplasty, or degenerative disease that results in insufficient number of evaluable lumbar vertebrae, bilateral hip replacements.
• Use of anabolic steroids or androgens within 6 months preceding randomization.
• Use of vitamin D metabolites and analogs, (e.g., calcitriol) within 3 months preceding randomization). Note: Vitamin D supplementation is not exclusionary.
• Use of estrogen or estrogen-related drugs (including selective estrogen receptor molecules), for example, tamoxifen, tibolone, or raloxifene within 3 months preceding randomization.
• Chronic systemic treatment with glucocorticoids.
• Clinically relevant abnormal history, physical findings, or laboratory values at the pre-study screening assessment that could interfere with the objectives of the study or the safety of the subject.
• Presence of acute or chronic illness or history of chronic illness which, in the judgment of the investigator, makes participation in the study medically inappropriate.
• Known acquired immune deficiency syndrome (AIDS) or human immunodeficiency virus (HIV) seropositivity.
• Uncontrolled hypertension, significant gastrointestinal abnormalities, uncontrolled diabetes mellitus, significant coronary heart disease, any psychotic mental illness, chronic allergic rhinitis, asthma, uncorrected endocrine dysfunction, or significantly impaired hepatic, respiratory, or renal function.
• Participation in any other clinical study within the previous month.
• History of drug or alcohol abuse, or intake of more than 30 units of alcohol weekly.
• Possibility that the subject will not cooperate with the requirements of the protocol.
• Known sensitivity to sCT.
• Shift workers-individuals who are at work during overnight hours.