The DENOCHARCOT Trial

Official title

Efficacy of Treatment With DENOsumab of an Acute CHARCOT Foot in Patients With Diabetes. A Multicenter, Double-blind, Randomized, Placebo-controlled Trial.

Overview

The aim of the present trial is to assess the efficacy of treatment of acute Charcot foot in diabetes patients with Prolia® on clinical relevant Outcomes in a randomized, double blind, placebo-controlled trial.

Detailed description

After giving informed consent and being enrolled, patients will be randomized to one of two group given either Denosumab treatment or injection with placebo. The patients will then undergo a 52 week follow up with regular controls to asses if clinical signs of Charcot is in remission, which will be verified using relevant radiological modalities. Upon final visit the patients will be examined using radiology, blood samples, biothesiometry and objective examinations, following up on the same examinations being made upon inclusion.

Primary outcome will be time until full remission of the Charcot foot defined as clinical healing (The acute Charcot foot is clinically healed when the temperature difference at the site maximum temperature on the affected Charcot foot is \< 2 degrees Celsius compared to the similar site on the contra-lateral foot, measured using an infrared thermometer, and edema and redness of the skin has subsided) followed up by radiological signs of healing.

Interventions

• Drug Denosumab Injection
  Injections made subcutaneously per standard description

Primary outcome measures

• Time until remission [Time frame: 52 weeks]

Secondary outcome measures (9)

• Fraction of clinical healed participants at each study visit. [Time frame: 52 weeks]
• Fraction of healing on X-rays and MRI (or PET/CT or Scintigram) at the time of clinical healing and at the End of trial. [Time frame: 52 weeks]
• Number of relapses (defined as need for/prescription of off- loading with cast of the Charcot foot again) [Time frame: 52 weeks]
• Time without relapse (the time from clinical healing/remission to the relapse or to End of Trial at 12 months). [Time frame: 52 weeks]
• Number of patients with development of complications to the acute Charcot foot, as well as number of development of foot ulcer, deformity, need for special footwear or surgery and fractures of bones in the foot, respectively. [Time frame: 52 weeks]
• Changes in BMD (lumbar spine, hip) [Time frame: 52 weeks]
• Changes in markers of bone turnover (CTX and P1NP) [Time frame: 52 weeks]
• Changes in markers of glycemic control (HbA1c) [Time frame: 52 weeks]
• Incidence of Adverse Events and Serious Adverse Events [Time frame: 52 weeks]

Eligibility criteria

Inclusion criteria

• Age 18-80 years
• Type 1 or type 2 diabetes (diagnosed diabetes for more than 3 months)
• Diagnosed with acute Charcot foot defined as a unilateral red, swollen and warm foot, with a difference of skin temperature of more than 2 °C compared with the unaffected foot and with sign of Charcot on either x-rays of the foot, MRI, bone scintigram or PET/CT.
• Peripheral neuropathy: Previously diagnosed and/or biothesiometri: > 25 V or lack of sensation of 10 grams monofilament on 1. toe at the acute Charcot foot.

Exclusion criteria

• Duration of the acute Charcot foot for more than 3 months (at the screening visit).
• Existing foot ulcer on the affected foot
• Previous acute or chronic Charcot of the affected foot
• Planned surgery on the acute Charcot foot
• Infection (cellulitis or osteomyelitis) of the affected foot (clinically and/or radiologically proven)
• Previous midfoot or proximal to mid foot amputation of the affected foot
• Hypocalcemia (Serum Calcium <2.1 mmol/L or Calcium ion < 1.12 mmol/L)
• Vitamin D deficiency (Serum 25-hydroxyvitamin D < 50 nmol/L)
• Renal failure (serum creatinine >200 mmol/L or eGFR < 30 ml/min).
• Treatment with Denosumab within the last 12 months. • Have a known hypersensitivity to Denosumab • History of osteonecrosis of the jaw.
• Poor oral hygiene, which is defined as within 3 months of a tooth extraction, dental implants or mandibular surgery
• Planned mandibular surgery or dental implants within the next 12 months.
• Prior non-traumatic vertebral fracture
• Treatment with medication known to affect bones within the last 12 months (such as bisphosphonates, Forsteo®, calcitonin, Protelos®, selective estrogen receptor modulators, glucocorticoids and sex hormones)
• Active or chronic liver disease \*Chronic liver disease is defined as clinical history of decompensated chronic liver disease (ascites, encephalopathy or variceal bleeding) \*Acute Liver disease is defined as an INR of > 1.5 (in the absence of the use of Warfarin) and AST and ALT > 2 x ULN
• History of inflammatory arthropathies (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, autoimmune arthropathy)
• Pre-existing medical condition judged to preclude safe participation in the study
• Current treatment with cytotoxic drugs or with systemically administered glucocorticoids
• Abuse of alcohol or drugs, or presence of any condition that in the Investigators opinion may lead to poor adherence to study protocol
• Pregnancy, breast feeding or planning pregnancy or not using adequate contraceptive methods. The following contraceptive products are considered to be safe: Intrauterine devices or hormonal contraception (oral contraceptive pills, implants, transdermal patches, vaginal rings or long-acting injections).
• Likely inability to comply with the visits because of planned activity
• Use of any investigational product with the last month.
• Use of any drug or any other reason which in the Investigator's opinion could interfere with the outcome of the treatment of the acute Charcot foot.
• Cancer, or any clinically significant disease or disorder, except for conditions associated to the diabetes, which in the Investigator's opinion could interfere with the results of the trial

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

Denmark · 8 centers

• Steno Diabetes Center North — Aalborg
• Steno Diabetes Center Aarhus — Aarhus
• Bispebjerg Hospital — Copenhagen NV
• Steno Diabetes Center Copenhagen — Gentofte Municipality
• Nordsjællands Hospital — Hillerød
• Hvidovre hospital — Hvidovre
• Zealand University Hospital — Køge
• Steno Diabetes Center Odense — Odense

Publications

• Jeffcoate WJ. Charcot foot syndrome. Diabet Med. 2015 Jun;32(6):760-70. doi: 10.1111/dme.12754. Epub 2015 Apr 15. PMID 25818542
• Christensen TM, Gade-Rasmussen B, Pedersen LW, Hommel E, Holstein PE, Svendsen OL. Duration of off-loading and recurrence rate in Charcot osteo-arthropathy treated with less restrictive regimen with removable walker. J Diabetes Complications. 2012 Sep-Oct;26(5):430-4. doi: 10.1016/j.jdiacomp.2012.05.006. Epub 2012 Jun 12. PMID 22699112
• Pitocco D, Ruotolo V, Caputo S, Mancini L, Collina CM, Manto A, Caradonna P, Ghirlanda G. Six-month treatment with alendronate in acute Charcot neuroarthropathy: a randomized controlled trial. Diabetes Care. 2005 May;28(5):1214-5. doi: 10.2337/diacare.28.5.1214. No abstract available. PMID 15855594
• Anderson JJ, Woelffer KE, Holtzman JJ, Jacobs AM. Bisphosphonates for the treatment of Charcot neuroarthropathy. J Foot Ankle Surg. 2004 Sep-Oct;43(5):285-9. doi: 10.1053/j.jfas.2004.07.005. PMID 15480402
• Jude EB, Selby PL, Burgess J, Lilleystone P, Mawer EB, Page SR, Donohoe M, Foster AV, Edmonds ME, Boulton AJ. Bisphosphonates in the treatment of Charcot neuroarthropathy: a double-blind randomised controlled trial. Diabetologia. 2001 Nov;44(11):2032-7. doi: 10.1007/s001250100008. PMID 11719835
• Bem R, Jirkovska A, Fejfarova V, Skibova J, Jude EB. Intranasal calcitonin in the treatment of acute Charcot neuroosteoarthropathy: a randomized controlled trial. Diabetes Care. 2006 Jun;29(6):1392-4. doi: 10.2337/dc06-0376. No abstract available. PMID 16732029
• Pakarinen TK, Laine HJ, Maenpaa H, Mattila P, Lahtela J. The effect of zoledronic acid on the clinical resolution of Charcot neuroarthropathy: a pilot randomized controlled trial. Diabetes Care. 2011 Jul;34(7):1514-6. doi: 10.2337/dc11-0396. Epub 2011 May 18. PMID 21593295
• Petrova NL, Dew TK, Musto RL, Sherwood RA, Bates M, Moniz CF, Edmonds ME. Inflammatory and bone turnover markers in a cross-sectional and prospective study of acute Charcot osteoarthropathy. Diabet Med. 2015 Feb;32(2):267-73. doi: 10.1111/dme.12590. Epub 2014 Oct 17. PMID 25251588

Identifiers

NCT: NCT04547348 · CODIF-008

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗