A First-in-human Study Evaluating Romosozumab (AMG 785) in Healthy Men and Postmenopausal Women

Phase 1

Completed

Conditions: Osteopenia

Interventions: Drug: Placebo
Drug: Romosozumab

Registration Number: NCT01059435

Lead Sponsor: Amgen

Brief Summary: The primary objective of this study is to assess the safety and tolerability of romosozumab following single dose subcutaneous (SC) or intravenous (IV) administration in healthy men and postmenopausal women.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 74

Inclusion Criteria

Healthy males or female between 45 to 59 years of age, inclusive
Postmenopausal females defined as 12 continuous months of spontaneous amenorrhea confirmed by a serum follicle-stimulating hormone (FSH) result > 40mIU/mL, or 6 weeks postsurgical bilateral oophorectomy (with or without hysterectomy)
Males must agree to use a condom during sexual intercourse with female partners who are of reproductive potential and to have their female partners use an additional effective means of contraception or to abstain from sexual intercourse for the duration of the study
Has no history or evidence of a clinically significant disorder, condition or disease that would pose a risk to subject safety or interfere with the study evaluation, procedures or completion

Exclusion Criteria

Diagnosed with any condition that will affect bone metabolism
Administration of the following medications within 6 months before study drug administration:
Hormone replacement therapy [Infrequent use of estrogen vaginal creams (< 3 times per week) is allowed.]
Calcitonin
Parathyroid hormone (or any derivative)
Supplemental Vitamin D > 1,000 IU/day
Glucocorticosteroids (inhaled or topical corticosteroids administered more than 2 weeks before the enrollment date are allowed)
Anabolic steroids
Calcitriol, and available analogues
Administration of the following medications within 12 months before study drug administration:
Bisphosphonates
Fluoride for osteoporosis
Administration of herbal medications within 2 weeks or 5 half-lives (whichever is longer) before study drug administration
Greatly differing levels of physical activity or constant levels of intense physical exercise during the 6 months before study drug administration
Routine alcohol intake of > 2 drinks per day, on average, within 6 months of study drug administration
Known sensitivity to mammalian-derived drug preparations
Known to be hepatitis B surface antigen, hepatitis C virus, or human immunodeficiency virus (HIV) positive, or a known diagnosis of acquired immunodeficiency syndrome (AIDS)
Any organic or psychiatric disorder which may pose a risk to subject safety and may prevent the subject from completing the study or interfere with the interpretation of the study results
Unavailable for follow-up assessment or any concerns for subject's compliance with the protocol procedures
Any other condition that might reduce the chance of obtaining data required by the protocol or that might compromise the ability to give truly informed consent
Has a history of drug or alcohol abuse with the last 12 months and/or a positive urine test result at screening or admission
Has any clinically significant abnormality during the screening physical examination, electrocardiogram (ECG), or laboratory evaluation
Has participated in another clinical study within 4 weeks of screening or within 5 times the half-life of the investigational agent in the other clinical study, if known
Weight ≥ 98 kilograms (216 pounds) and/or height ≥ 78 inches
Has donated or lost 400 milliliters or more of blood or plasma within 8 weeks of study drug administration

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Participants were randomized to receive a single dose of matching placebo administered by subcutaneous or intravenous injection.
Romosozumab	Romosozumab	Participants were randomized to receive a single dose of romosozumab administered by subcutaneous or intravenous injection. The starting dose was 0.1 mg/kg, with sequential escalation up to 10 mg/kg.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events	Adverse events were collected from the first dose of treatment up until day 29 for the 0.1 mg/kg and 0.3 mg/kg SC treatment groups, up to 57 days for the 1 mg/kg and 3 mg/kg IV/SC groups and for up to 85 days for the 5 mg/kg and 10 mg/kg SC/IV groups.	Serious adverse events were any events that were fatal, were life-threatening (placed the participant at immediate risk of death), required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, were congenital anomalies or birth defects, or were other significant medical hazards. Relatedness to investigational product was assessed by the investigator by means of the question: "Is there a reasonable possibility that the event may have been caused by the investigational product?'
Number of Participants Who Developed Anti-romosozumab Antibodies	Day 29 (all participants), day 57 (1, 3, 5, and 10 mg/kg treatment groups only) and at day 85 (5 and 10 mg/kg teatment groups only).	Binding anti-romosozumab antibody titers were assessed using a validated electrochemiluninescence (ECL) immunoassay. The limit of detection for this assay was 3.91 ng/mL of anti-romosozumab antibody in neat serum. Samples found to be positive for binding antibodies were further tested using a validated bioassay to determine if the antibodies were able to neutralize the activity of romosozumab. The limit of detection for this assay was ≥ 0.75 μg/mL.

Secondary Outcome Measures

Name	Time	Method
Area Under the Serum Concentration-time Curve From Time Zero to Infinity for Romosozumab	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.
Initial Concentration Following IV Administration (C0) of Romosozumab	Day 1 at the end of infusion
Apparent Clearance (CL/F) / Clearance (CL) for Romosozumab	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.
Half-life Associated With the Beta (Plateau) Phase of Elimination for Romosozumab	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.	The plateau (beta, β) phase half-life (t½,β) was calculated from the natural log of 2 divided by the beta phase rate constant (λβ). λβ for a subject was estimated by linear regression of at least 3 contiguous time points that followed the Cmax and constituted a distinct phase that preceded the terminal phase.
Half-life Associated With the Gamma (Terminal) Phase of Elimination for Romosozumab	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.	The terminal (gamma, γ) phase half-life (t½,γ) was calculated from the natural log of 2 divided by the terminal rate constant (λz).
Maximum Observed Concentration (Cmax) of Romosozumab	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.
Time to Maximum Observed Concentration (Tmax) of Romosozumab	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.
Maximum Effect for Serum Type 1 Aminoterminal Propeptide (P1NP)	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.	Defined as the maximum value postdose.
Time to Maximum Effect of P1NP	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.	Defined as the time to maximum value postdose.
Area Under the Curve From Day 0 to Day 29 (AUC0-29) for P1NP	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.
Area Under the Curve From Day 0 to the Last Sampling Time Point (AUC0-t) for P1NP	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab,
Maximum Effect for Serum C-telopeptide (sCTX)	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.	Defined as the minimum value postdose.
Time to Maximum Effect of sCTX	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.	Defined as the time to minimum value postdose.
Area Under the Curve From Day 0 to Day 29 (AUC0-29) for sCTX	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.
Area Under the Curve From Day 0 to the Last Sampling Time Point (AUC0-t) for sCTX	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.
Maximum Effect for Osteocalcin	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.	Defined as the maximum value postdose.
Time to Maximum Effect of Osteocalcin	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.	Defined as the time to maximum value postdose.
Area Under the Curve From Day 0 to Day 29 (AUC0-29) for Osteocalcin	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.
Area Under the Curve From Day 0 to the Last Sampling Time Point (AUC0-t) for Osteocalcin	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.
Maximum Effect for Bone-specific Alkaline Phosphatase (BSAP)	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.	Defined as the maximum value postdose.
Time to Maximum Effect of BSAP	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.	Defined as the time to maximum value postdose.
Area Under the Curve From Day 0 to Day 29 (AUC0-29) for BSAP	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.
Area Under the Curve From Day 0 to the Last Sampling Time Point (AUC0-t) for BSAP	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.
Maximum Effect for Intact Parathyroid Hormone (iPTH)	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.	Defined as the maximum value postdose.
Time to Maximum Effect of iPTH	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.	Defined as the time to maximum value postdose.
Area Under the Curve From Day 0 to Day 29 (AUC0-29) for iPTH	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.
Area Under the Curve From Day 0 to the Last Sampling Timepoint (AUC0-t) for iPTH	Predose up to day 29 for participants receiving 0.1 or 0.3 mg/kg romosozumab, up to day 57 for participants receiving 1 or 3 mg/kg romosozumab, and up to day 85 for participants receiving 5 or 10 mg/kg romosozumab.
Percent Change From Baseline in Sclerostin	Baseline and days 15, 29, 43, 57, 71, and 85
Serum Calcium Over Time	Dday 1 predose and at 4, 6, 8, 10, and 12 hours, days 2, 3, 4, 5, 6, 8, 11, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85
Ionized Calcium Over Time	Day 1 predose and at 4, 6, 8, 10, 12 hours, days 2, 3, 4, 5, 6, 8, 11, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and 85