NCT03289338

Zoledronic Acid or Methylprednisolone for Active Charcot's Neuroarthropathy of Foot in Patients With Diabetes Mellitus

Completed Phase 2, PHASE3 Last updated 16 July 2019

What this trial tests

Phase 2, PHASE3 trial testing Zoledronic Acid in Charcot Arthropathy in 36 participants. Completed in 31 December 2018.

Timeline

1 June 2016

Primary endpoint
31 December 2018

31 December 2018

Quick facts

Lead sponsor	Post Graduate Institute of Medical Education and Research, Chandigarh
Phase	Phase 2, PHASE3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	triple
Primary purpose	treatment
Enrollment	36
Start date	1 June 2016
Primary completion	31 December 2018
Estimated completion	31 December 2018
Sites	1 location across India

Drugs / interventions tested

• Zoledronic Acid (ZOLEDRONIC ACID) — full drug profile →
• Methylprednisolone (methylprednisolone) — full drug profile →
• Placebos — full drug profile →

Conditions studied

• Charcot Arthropathy — all drugs for Charcot Arthropathy →
• Diabetes Complications — all drugs for Diabetes Complications →

Sponsor

Post Graduate Institute of Medical Education and Research, Chandigarh

Who can join

Adults 18 to 70, any sex, with Charcot Arthropathy or Diabetes Complications. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

Charcot neuropathic osteoarthropathy (CNO) is a progressively destructive process resulting from significant peripheral neuropathy of almost any aetiology. Diabetes mellitus has emerged as the commonest cause of CNO.

The Charcot foot in diabetes poses many clinical challenges in its diagnosis and management. The lacuna primarily lies in delineation of its etio-pathogenesis and consequently in targeted treatment modalities. Although traditional approaches focus on neurotraumatic and neurovascular theories, these fail to explain all the features of CNO, hence, other hypotheses have been put forward.The current belief is that once the disease is triggered in a susceptible individual, it is mediated through a process of uncontrolled inflammation which, in turn, leads to osteolysis, fractures and joint destruction. Of these processes, the involvement of the receptor activator of nuclear factor- кB (RANK) ligand /RANK/osteoprotegerin (OPG) system in the process of acute CNO is particularly appealing and suggests new pharmacological approaches.

Standard modalities of treatment include offloading and casting. Although various trials have analysed the impact of medical agents including bisphosphonates, teriparatide and bone stimulation techniques, the results have been either inconclusive or not translated into clinical practice. Hence, there is no efficacious treatment of active CNO apart from the traditional offloading. In view of recent advances in understanding of the disease process, the target of intervention should, logically, be interruption of the inflammatory cascade and subsequent osteoclast resorption. Zoledronic acid is the most potent bisphosphonate that has been studied in clinical trials to date and has the distinctive profile of strong inhibitory activity on the enzyme farnesyl pyrophosphate synthase, essential for osteoclast function. Methylprednisolone conceivably has a potential benefit by offsetting the RANKL/OPG system involved. There have been conflicting reports with bisphophosphonates in active CNO and Zoledronic acid has been infrequently used despite being the most potent. Glucocorticoids including methylprednisolone have also not been systematically tried in this condition.

We hypothesise that targeting the inflammatory cascade with Methylprednisolone and osteoclast mediated damage by Zoledronic acid will address the basic etiopathogenesis of active CNO and may result in earlier resolution of the disease activity. The above mentioned hypothesis is hence, planned to be tested in a randomised, double-blind, placebo-controlled study.

Publications & conference data

1 peer-reviewed publication reference this trial (live from Europe PMC):

1. Long-term foot outcomes following differential abatement of inflammation and osteoclastogenesis for active Charcot neuroarthropathy in diabetes mellitus.
   Das L, Rastogi A, Jude EB, Prakash M, et al · · 2021 · cited 11× · PMID 34748565 · DOI 10.1371/journal.pone.0259224