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

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Ascending Single-dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 785 in Healthy Men and Postmenopausal Women

Conditions
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Osteopenia

Intervention / Treatment
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* Drug: Romosozumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 59 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants were randomized to receive a single dose of matching placebo administered by subcutaneous or intravenous injection. | Drug: Placebo<br>* Administered subcutaneously or intravenously<br>|
| Experimental: Romosozumab<br>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. | Drug: Romosozumab<br>* Administered subcutaneously or intravenously<br>* Other names: EVENITY™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | 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?' | 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. | 
| Number of Participants Who Developed Anti-romosozumab Antibodies | 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. | 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). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 
| Initial Concentration Following IV Administration (C0) of Romosozumab |  | Day 1 at the end of infusion | 
| 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. | 
| 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 | 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. | 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 Gamma (Terminal) Phase of Elimination for 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). | 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) | Defined as the maximum value postdose. | 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 Effect of P1NP | Defined as the time to maximum value postdose. | 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 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) | Defined as the minimum value postdose. | 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 Effect of sCTX | Defined as the time to minimum value postdose. | 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 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 | Defined as the maximum value postdose. | 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 Effect of Osteocalcin | Defined as the time to maximum value postdose. | 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 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) | Defined as the maximum value postdose. | 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 Effect of BSAP | Defined as the time to maximum value postdose. | 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 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) | Defined as the maximum value postdose. | 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 Effect of iPTH | Defined as the time to maximum value postdose. | 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 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amgen, First in Human, Postmenopausal, Phase 1