An Adaptive Phase I Study to Evaluate the Safety, Efficacy and Dose Responses of Ronacaleret in Healthy Human Volunteers

Summary

Ronacaleret is an orally administered CaSR antagonist which has previously been demonstrated to transiently increase PTH in both animals and humans. Additional studies in post-menopausal women and patients with distal radial fractures have demonstrated both anabolic and catabolic effects on bone biomarkers and scans of bone density. Based on ronacalerets ability to interact with the CaSR inducing PTH release and activating endogenous bone metabolism of both osteoblasts and osteoclasts, it is our intention to evaluate the impact activation of this pathway has on mobilization of Hematopoietic stem cell (HSCs) into the periphery.

This is an adaptive, phase I, randomized, single centre, double-blind dose finding, parallel-group, multi-cohort placebo controlled study of the efficacy and safety of ronacaleret in up to 45 healthy human volunteers. Cohorts of eligible subjects will be studied for periods up to 28 days. Total daily doses of ronacaleret will range from 100mg, up to 400mg and be administered for a maximum of 28days. The first part of this study will evaluate several doses and schedules of ronacaleret, run in parallel, with respect to their ability to affect mobilization of CD34+ cells into the peripheral circulation. In subsequent cohorts of the study we will utilize information obtained from previous cohorts to further refine and optimise those dosing paradigms which show efficacy. For the first cohort of study participants; the study will commence with 6 days of dosing in an inpatient setting followed by 21 days of continued dosing and evaluation as an outpatient, with a series of regularly scheduled visits, with the final visit on day 28. The study period will include evaluations of pharmacokinetic and pharmacodynamic parameters along with standard laboratory and safety evaluations. The second cohort may be treated with ronacaleret for periods ranging from 14 to 28 days in order to optimise the treatment paradigm with respect to pharmacodynamic efficacy. The PK/PD of each group in cohort one will be utilized to make adjustments in the total daily dose, dose frequency and or duration of dosing investigated in cohort 2. Decisions will be made as to dropping doses based on the PK/PD results and any safety considerations. An initial equal randomization amongst groups within the first cohort may be adjusted to allow for other randomization strategies as various doses and schedules are assessed.

The objective of this study is to characterise the dose-response curve for ronacaleret with respect to safety and efficacy based on changes in peripheral CD34+ cell counts. Results obtained from this study will inform us: of optimized doses, schedules, and durations of treatment for future studies. Additional cohorts may be added to further explore the dose schedule and duration if required. The exact number of cohorts studied will depend on the results obtain from the prior groups and the desire to explore a variety of doses and schedules. The aims of the present study (CR9115166) include an assessment of the pharmacodynamic effects (mobilization of CD34+ cells), safety, tolerability, and pharmacokinetics of ronacaleret in healthy human volunteers.

Conditions

• Bone Marrow Transplantation

Interventions

DRUG

Ronacaleret (100mg tablet)

100mg tablet

DRUG

Placebo

matching placebo tablet

Sponsors & Collaborators

• GlaxoSmithKline

  lead INDUSTRY

Principal Investigators

• GSK Clinical Trials · GlaxoSmithKline

Study Design

Allocation

RANDOMIZED

Purpose

SUPPORTIVE_CARE

Masking

TRIPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

65 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2011-10-27

Primary Completion

2012-03-05

Completion

2012-03-05

Countries

• United States

Study Locations