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

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ClinicalTrials.gov Identifier: NCT03289338
Recruitment Status : Recruiting
First Posted : September 20, 2017
Last Update Posted : September 20, 2017
Information provided by (Responsible Party):
Ashu Rastogi, Postgraduate Institute of Medical Education and Research

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.

Condition or disease Intervention/treatment Phase
Charcot Arthropathy Diabetes Complications Drug: Zoledronic Acid Drug: Methylprednisolone Drug: Placebos Phase 2 Phase 3

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Zoledronic Acid or Methylprednisolone in the Management of Active Charcot's Neuroarthropathy of Foot in Patients With Diabetes Mellitus: A Randomized, Double-blind, Placebo Controlled Trial
Actual Study Start Date : June 1, 2016
Estimated Primary Completion Date : December 31, 2017
Estimated Study Completion Date : June 1, 2018

Arm Intervention/treatment
Experimental: Zoledronic acid
Bisphosphonate Zoledronic acid
Drug: Zoledronic Acid
Zoledronic acid 5mg intravenous once a month for 3 months
Other Name: Zoledronate
Active Comparator: Methylprednisolone
Glucocorticoid Methylprednisolone
Drug: Methylprednisolone
Methylprednisolone 1gm intravenous once a month for 3 months
Other Name: MPS
Placebo Comparator: Placebos
Placebo normal saline
Drug: Placebos
Normal saline intravenous once a month for 3 months
Other Name: NS

Primary Outcome Measures :
  1. Time for resolution of active Charcot foot [ Time Frame: 6 months ]

Secondary Outcome Measures :
  1. Time for reduction in levels of inflammatory cytokines (>= 50%) [ Time Frame: 6 months ]
  2. Time for radiologic resolution/reduction on MRI [ Time Frame: 6 months ]

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

Patients with Diabetes mellitus with active Charcot neuroarthropathy of foot as per following criteria:

Clinical criteria

  1. Warm, swollen and erythematous foot
  2. 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-

  1. Osteopenia
  2. Joint subluxation
  3. Normal or low normal marrow signal on T1 MRI
  4. Bone marrow edema on T2W MRI
  5. Microfractures
  6. Cortical disruption
  7. Several joints or bones
  8. Preserved periarticular subcutaneous fat

Exclusion Criteria:

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03289338

Contact: Anil Bhansali, DM 01722756583 anilbhansaliendocrine@gmail.com
Contact: Ashu Rastogi, DM 01722756585 ashuendo@gmail.com

Department of Endocrinology, PGIMER Recruiting
Chandigarh, India, 160012
Contact: Anil Bhansali, DM    01722756585    ashuendo@gmail.com   
Contact: Ashu Rastogi, DM    01722756585    ashuendo@gmail.com   
Principal Investigator: Ashu Rastogi, MD, DM         
Sponsors and Collaborators
Postgraduate Institute of Medical Education and Research
Study Director: Anil Bhansali, DM Postgraduate Institute of Medical Education and Research

Responsible Party: Ashu Rastogi, Assistant Professor, Postgraduate Institute of Medical Education and Research
ClinicalTrials.gov Identifier: NCT03289338     History of Changes
Other Study ID Numbers: ZoleMethCNO
First Posted: September 20, 2017    Key Record Dates
Last Update Posted: September 20, 2017
Last Verified: September 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Ashu Rastogi, Postgraduate Institute of Medical Education and Research:
Zoledronic acid
Active Charcot's disease

Additional relevant MeSH terms:
Diabetes Mellitus
Joint Diseases
Diabetes Complications
Arthropathy, Neurogenic
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Musculoskeletal Diseases
Prednisolone acetate
Methylprednisolone acetate
Methylprednisolone Hemisuccinate
Prednisolone hemisuccinate
Prednisolone phosphate
Zoledronic acid
Anti-Inflammatory Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Neuroprotective Agents
Protective Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents