The DENOCHARCOT Trial

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Charcot Foot, Diabetes Mellitus

Intervention / Treatment
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* Drug: Denosumab Injection


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Denosumab treated group<br>Participants will receive a 60 mg subcutaneous injection of Prolia upon randomization and on week 28 after the first injection provided remission of the Charcot foot has not been achieved by then | Drug: Denosumab Injection<br>* Injections made subcutaneously per standard description<br>|
| Placebo Comparator: Placebo treated group<br>Participants will receive an injection of placebo produced by the same provider as the prolia drug of equivalent volume at the same time points as the treated group | Drug: Denosumab Injection<br>* Injections made subcutaneously per standard description<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time until remission | Time from first injection of IP until the time point where the acute Charcot foot is clinically healed/in remission, ie. 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 - at two subsequent visits 4 weeks apart. The off-loading regime will be continued until the second visit. The first of the two visits is the timepoint of healing of the acute Charcot foot. | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fraction of clinical healed participants at each study visit. |  | 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. |  | 52 weeks | 
| Number of relapses (defined as need for/prescription of off- loading with cast of the Charcot foot again) |  | 52 weeks | 
| Time without relapse (the time from clinical healing/remission to the relapse or to End of Trial at 12 months). |  | 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. |  | 52 weeks | 
| Changes in BMD (lumbar spine, hip) |  | 52 weeks | 
| Changes in markers of bone turnover (CTX and P1NP) |  | 52 weeks | 
| Changes in markers of glycemic control (HbA1c) |  | 52 weeks | 
| Incidence of Adverse Events and Serious Adverse Events |  | 52 weeks |