Clinical trial NCT01059435: A First-in-human Study Evaluating Romosozumab (AMG 785) in Healthy Men and Postmenopausal Women
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Osteopenia
Keywords: Amgen
First in Human
Postmenopausal
Phase 1
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2010-02-01
Enrollment: 74
Sex: ALL
Minimum age (years): 45
Maximum age (years): 59
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Adverse Events
timeFrame: 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.
measure: Number of Participants Who Developed Anti-romosozumab Antibodies
timeFrame: 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 outcomes:
measure: Maximum Observed Concentration (Cmax) of Romosozumab
timeFrame: 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.
measure: Time to Maximum Observed Concentration (Tmax) of Romosozumab
timeFrame: 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.
measure: Initial Concentration Following IV Administration (C0) of Romosozumab
timeFrame: Day 1 at the end of infusion
measure: Area Under the Serum Concentration-time Curve From Time Zero to Infinity for Romosozumab
timeFrame: 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.
measure: Apparent Clearance (CL/F) / Clearance (CL) for Romosozumab
timeFrame: 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.
measure: Half-life Associated With the Beta (Plateau) Phase of Elimination for Romosozumab
timeFrame: 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.
measure: Half-life Associated With the Gamma (Terminal) Phase of Elimination for Romosozumab
timeFrame: 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.
measure: Maximum Effect for Serum Type 1 Aminoterminal Propeptide (P1NP)
timeFrame: 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.
measure: Time to Maximum Effect of P1NP
timeFrame: 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.
measure: Area Under the Curve From Day 0 to Day 29 (AUC0-29) for P1NP
timeFrame: 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.
measure: Area Under the Curve From Day 0 to the Last Sampling Time Point (AUC0-t) for P1NP
timeFrame: 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,
measure: Maximum Effect for Serum C-telopeptide (sCTX)
timeFrame: 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.
measure: Time to Maximum Effect of sCTX
timeFrame: 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.
measure: Area Under the Curve From Day 0 to Day 29 (AUC0-29) for sCTX
timeFrame: 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.
measure: Area Under the Curve From Day 0 to the Last Sampling Time Point (AUC0-t) for sCTX
timeFrame: 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.
measure: Maximum Effect for Osteocalcin
timeFrame: 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.
measure: Time to Maximum Effect of Osteocalcin
timeFrame: 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.
measure: Area Under the Curve From Day 0 to Day 29 (AUC0-29) for Osteocalcin
timeFrame: 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.
measure: Area Under the Curve From Day 0 to the Last Sampling Time Point (AUC0-t) for Osteocalcin
timeFrame: 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.
measure: Maximum Effect for Bone-specific Alkaline Phosphatase (BSAP)
timeFrame: 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.
measure: Time to Maximum Effect of BSAP
timeFrame: 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.
measure: Area Under the Curve From Day 0 to Day 29 (AUC0-29) for BSAP
timeFrame: 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.
measure: Area Under the Curve From Day 0 to the Last Sampling Time Point (AUC0-t) for BSAP
timeFrame: 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.
measure: Maximum Effect for Intact Parathyroid Hormone (iPTH)
timeFrame: 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.
measure: Time to Maximum Effect of iPTH
timeFrame: 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.
measure: Area Under the Curve From Day 0 to Day 29 (AUC0-29) for iPTH
timeFrame: 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.
measure: Area Under the Curve From Day 0 to the Last Sampling Timepoint (AUC0-t) for iPTH
timeFrame: 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.
measure: Percent Change From Baseline in Sclerostin
timeFrame: Baseline and days 15, 29, 43, 57, 71, and 85
measure: Serum Calcium Over Time
timeFrame: 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
measure: Ionized Calcium Over Time
timeFrame: 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
Other outcomes:
Locations:
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: Padhi D, Jang G, Stouch B, Fang L, Posvar E. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res. 2011 Jan;26(1):19-26. doi: 10.1002/jbmr.173.