Clinical trial NCT04547348: 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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Charcot Foot
Diabetes Mellitus
Lead sponsor: Bispebjerg Hospital
Sponsor class: OTHER
First posted: 2020-09-14
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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

Primary outcomes:
measure: Time until remission
timeFrame: 52 weeks
Secondary outcomes:
measure: Fraction of clinical healed participants at each study visit.
timeFrame: 52 weeks
measure: 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.
timeFrame: 52 weeks
measure: Number of relapses (defined as need for/prescription of off- loading with cast of the Charcot foot again)
timeFrame: 52 weeks
measure: Time without relapse (the time from clinical healing/remission to the relapse or to End of Trial at 12 months).
timeFrame: 52 weeks
measure: 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.
timeFrame: 52 weeks
measure: Changes in BMD (lumbar spine, hip)
timeFrame: 52 weeks
measure: Changes in markers of bone turnover (CTX and P1NP)
timeFrame: 52 weeks
measure: Changes in markers of glycemic control (HbA1c)
timeFrame: 52 weeks
measure: Incidence of Adverse Events and Serious Adverse Events
timeFrame: 52 weeks
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: Steno Diabetes Center North
city: Aarhus
country: Denmark
facility: Steno Diabetes Center Aarhus
city: Copenhagen NV
country: Denmark
facility: Bispebjerg Hospital
city: Gentofte
country: Denmark
facility: Steno Diabetes Center Copenhagen
city: Hillerød
country: Denmark
facility: Nordsjællands Hospital
city: Hvidovre
country: Denmark
facility: Hvidovre hospital
city: Køge
country: Denmark
facility: Zealand University Hospital
city: Odense
country: Denmark
facility: Steno Diabetes Center Odense
Study officials:
affiliation: Region Hovedstadens Apotek
name: Ole Lander Svendsen, MD
role: STUDY_CHAIR
References:
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citation: 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.
citation: 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.
citation: Jansen RB, Christensen TM, Bulow J, Rordam L, Jorgensen NR, Svendsen OL. Markers of Local Inflammation and Bone Resorption in the Acute Diabetic Charcot Foot. J Diabetes Res. 2018 Aug 2;2018:5647981. doi: 10.1155/2018/5647981. eCollection 2018.
citation: Busch-Westbroek TE, Delpeut K, Balm R, Bus SA, Schepers T, Peters EJ, Smithuis FF, Maas M, Nieuwdorp M. Effect of Single Dose of RANKL Antibody Treatment on Acute Charcot Neuro-osteoarthropathy of the Foot. Diabetes Care. 2018 Mar;41(3):e21-e22. doi: 10.2337/dc17-1517. Epub 2017 Dec 22. No abstract available.
citation: Tsourdi E, Langdahl B, Cohen-Solal M, Aubry-Rozier B, Eriksen EF, Guanabens N, Obermayer-Pietsch B, Ralston SH, Eastell R, Zillikens MC. Discontinuation of Denosumab therapy for osteoporosis: A systematic review and position statement by ECTS. Bone. 2017 Dec;105:11-17. doi: 10.1016/j.bone.2017.08.003. Epub 2017 Aug 5.