An Adaptive Phase I Study to Evaluate the Safety, Efficacy and Dose Responses of Ronacaleret in Healthy Human Volunteers
Condition: Bone Marrow Transplantation
Study type: Interventional
Phase: Phase 1

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.
    


Intervention name(s): Ronacaleret (100mg tablet); Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 100mg tablet; matching placebo tablet
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Supportive Care