RANKL Antibody for Acute Charcot Neuro-osteoarthropathy
Condition: Charcot Joint of Foot
MeSH terms: Arthropathy, Neurogenic
Study type: Interventional
Phase: Phase 4

Summary: 
      This study's goal was to determine how denosumab 60 mg, combined with total contact casting
      and restricted weightbearing status, would affect the treatment of acute CN with CKD.

      METHODS Participants in the research were those who visited the outpatient foot clinic at
      PGIMER, CHD in India. During the study period, 446 persons with CN were identified, 102 of
      whom met the criteria for the first screening, and 78 of whom were ultimately enrolled in the
      study.

      Aim: To assess the clinico-radiological remission of Acute Charcot-neuroarthropathy in
      patients of CKD.
    

Detailed description: 
      Participants attending the outpatient diabetic foot facility of tertiary care hospital in
      North India were assessed for active CN. An active CN of the foot was considered in the
      presence of localised erythema, edoema, and a temperature differential of more than 20C
      compared to a similar location on the opposite foot. Participants were diagnosed with "active
      on chronic" CN if they met the requirements for active CN in the context of foot deformities
      suggestive of chronic CN (rocker bottom deformity). Those with self-reported diabetes or
      those who were already receiving treatment for diabetes, with an estimated glomerular
      filtration rate (eGFR) <60 ml/min/m2 (CKD-EPI equation) and more than 500 mg of urine
      protein/24 hours were considered as having diabetic CKD. Patients with active pedal ulcer,
      inactive charcot foot, peripheral vascular disease (ankle brachial index ABI <0.9), prior
      exposure to medications affecting bone metabolism particularly bisphosphonates, teriparatide,
      denosumab or steroids in the past 12 months, hypocalcemia, active malignancy, CKD on dialysis
      and pregnancy or lactating women were excluded. The study was conducted in accordance with
      the Declaration of Helsinki and its amendments, the International Conference on Harmonization
      Good Clinical Practice guidelines, and its applicable regulatory requirements. All
      participants provided their signed, fully informed consent and study protocol was approved by
      the institutional Ethics Committee ref INT/IEC/SPE-1664.

      The foot temperature was determined by an infrared dermal thermometry [(FLIR Systems Inc,
      Orlando, USA) with a pixel resolution of 4800 (80*60), thermal sensitivity of 0.15 C, and a
      detection range of -20 C to 250 C] after 30 minutes of removing footwear or cast. X-ray
      and/or magnetic resonance imaging (MRI) were used to confirm the diagnosis of an active CN
      (3T scanner Siemens MagnetromVerio). The involved area of foot was classified anatomically
      for pattern of involvement using the Sanders-Frykberg classification. Clinical information
      was documented, including the duration of the symptoms, duration of diabetes, concomitant
      microvascular and macrovascular complications. Comprehensive neurological testing included
      vibration perception threshold (VPT>25 mV was considered abnormal) by
      biothesiometer-Vibrometer-VPT1 (Diabetik Foot Care, Madras Engineering Service, India),
      perception of 10-g monofilament at 5 standardised plantar locations, and ankle reflex.

      Interventions:

      Participants were randomly assigned in 1:2 ratio to receive either injection denosumab 60 gm
      (Group A) or equal volume of normal saline (Group B) subcutaneous over abdomen as a single
      dose (denosumab and normal saline were provided in similar looking syringe). The investigator
      administering the treatment, radiologist and the patient were blinded to treatment
      allocation. A conventional below knee, non-walking, non-removable fibreglass total contact
      cast (TCC) were provided to all participants irrespective of the group allocation for
      offloading.

      Procedures:

      Participants visited the study site initially during screening, randomization and
      subsequently four weekly for the monitoring of foot temperature. During randomization visit,
      blood samples were drawn for HbA1c, renal functions, calcium, phosphate and vitamin D. An
      average of three temperature readings at the afflicted site of the foot were taken and
      temperature difference (0C) were noted. The study drug or placebo were administered by
      blinded investigator and TCC was provided. Subsequently, during 4-weekly follow up visits the
      cast was removed for 30 minutes and skin temperature (mean of three readings) difference was
      noted. A change of cast was performed four weekly or earlier to avoid "pistoning" effect
      caused by the edema diminution until clinical remission. Patients with vitamin D deficiency
      (25 (OH)D3<30 ng/ml were supplemented with weekly oral cholecalciferol 60,000 IU for 8 weeks
      , then monthly till end of follow up.

      A temperature difference of <2C between the afflicted foot and a similar site on the other
      foot documented twice (four weeks apart) along with the absence of signs of inflammation was
      considered "clinical remission" of active CN.

      Following the clinical remission of active CN, the TCC shall be discontinued, and
      participants received cast walkers or customised footwear. Subsequently, foot examination
      shall be performed to monitor for the recurrence of CN (foot temperature assessment), the
      occurrence of deformities or ulcers (clinical examination), new-onset fractures (radiological
      assessment)or amputation for a minimum duration of 48 weeks following remission.
    

Intervention name(s): Danosumab; Normal Saline
Intervention type(s): Drug; Other
Intervention description(s): 60 mg subcutaneous Danosumab; Placebo comparator arm
Other intervention name(s): Drug Arm; Placebo
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary purpose: Treatment