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

NCT03289338 | Completed Phase 2 DMC

• 1 other identifier: ZoleMethCNO
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Charcot Arthropathy; Diabetes Complications

Keywords

Zoledronic acid; Methylprednisolone; Active Charcot's disease

Outcome Measures

Primary Outcomes (1)

• Time for resolution of active Charcot foot

  6 months

Secondary Outcomes (2)

• Time for reduction in levels of inflammatory cytokines (>= 50%)

  6 months

• Time for radiologic resolution/reduction on MRI

  6 months

Study Arms (3)

Zoledronic acid

EXPERIMENTAL

Bisphosphonate Zoledronic acid

Drug: Zoledronic Acid

Methylprednisolone

ACTIVE COMPARATOR

Glucocorticoid Methylprednisolone

Drug: Methylprednisolone

Placebos

PLACEBO COMPARATOR

Placebo normal saline

Drug: Placebos

Interventions

Zoledronic Acid DRUG

Zoledronic acid 5mg intravenous once a month for 3 months

Also known as: Zoledronate

Zoledronic acid

Methylprednisolone DRUG

Methylprednisolone 1gm intravenous once a month for 3 months

Also known as: MPS

Methylprednisolone

Placebos DRUG

Normal saline intravenous once a month for 3 months

Also known as: NS

Placebos

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with Diabetes mellitus with active Charcot neuroarthropathy of foot as per following criteria:
• Clinical criteria
• Warm, swollen and erythematous foot
• Skin temperature exceeding 2°C at the clinically suspected site of the affected foot compared with a similar site on the contralateral foot (infrared thermometer)
• Radiologic criteria MRI suggestive of acute CNO-
• Osteopenia
• Joint subluxation
• Normal or low normal marrow signal on T1 MRI
• Bone marrow edema on T2W MRI
• Microfractures
• Cortical disruption
• Several joints or bones
• Preserved periarticular subcutaneous fat

You may not qualify if:

• Infected foot ulcer
• Osteoporosis at lumbar spine or hip
• Gouty arthritis
• Active peptic ulcer disease
• Any prior long term steroid intake for asthma, SLE, RA or IBD in the last 3 months
• eGFR 45 ml/min or less
• Active dental caries
• Active upper gastrointestinal disease
• Uncorrected Vitamin D deficiency
• Peripheral vascular disease (ABI 0.9 or less)

Sponsors & Collaborators

• Post Graduate Institute of Medical Education and Research, Chandigarh: lead

Study Sites (1)

Department of Endocrinology, PGIMER

Chandigarh, 160012, India

Location

Related Publications (1)

• Das L, Rastogi A, Jude EB, Prakash M, Dutta P, Bhansali A. Long-term foot outcomes following differential abatement of inflammation and osteoclastogenesis for active Charcot neuroarthropathy in diabetes mellitus. PLoS One. 2021 Nov 8;16(11):e0259224. doi: 10.1371/journal.pone.0259224. eCollection 2021.

  PMID: 34748565 DERIVED

MeSH Terms

Conditions

Arthropathy, Neurogenic; Diabetes Complications

Interventions

Zoledronic Acid; Methylprednisolone

Condition Hierarchy (Ancestors)

Joint Diseases; Musculoskeletal Diseases; Diabetes Mellitus; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Diphosphonates; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Anil Bhansali, DM

  Post Graduate Institute of Medical Education and Research, Chandigarh

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: September 18, 2017
• First Posted: September 20, 2017
• Study Start: June 1, 2016
• Primary Completion: December 31, 2018
• Study Completion: December 31, 2018
• Last Updated: July 16, 2019

Record last verified: 2019-07

Data Sharing

• IPD Sharing: Will not share

Locations

IN (1)