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Efficacy of Teriparatide in Diabetic Inactive Charcot Neuroarthropathy of Foot

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ClinicalTrials.gov Identifier: NCT02023411
Recruitment Status : Completed
First Posted : December 30, 2013
Results First Posted : September 16, 2020
Last Update Posted : September 16, 2020
Sponsor:
Information provided by (Responsible Party):
Ashu Rastogi, Postgraduate Institute of Medical Education and Research

Tracking Information
First Submitted Date  ICMJE December 23, 2013
First Posted Date  ICMJE December 30, 2013
Results First Submitted Date  ICMJE July 2, 2019
Results First Posted Date  ICMJE September 16, 2020
Last Update Posted Date September 16, 2020
Study Start Date  ICMJE January 2014
Actual Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 25, 2020)
SUV Max on PET/CT Scan at 12 Months [ Time Frame: 12 months ]
F18 PET/CT scan of foot was performed at baseline and at 12 months following intervention. Main outcome measure was Standardised Uptake value (SUV max) with intervention. A higher score on the scale suggest better outcome
Original Primary Outcome Measures  ICMJE
 (submitted: December 23, 2013)
Efficacy of teriparatide in improving remodeling of foot bones in diabetic inactive Charcot's neuroarthropathy [ Time Frame: Two years ]
20 diabetic patients , who are Vit.D and calcium sufficient , will be recruited and baseline serum urea, creatinine, calcium, inorganic phosphorus, Alkaline phosphatase, serum 25(OH)- Vit.D, and albumin level will be measured , along with serum iPTH (immunoreactive parathyroid hormone) level. They will undergo baseline X-ray, DEXA (Dual Energy X-Ray Absorptiometry) scan and F18 PET scan of foot with measurement of markers of bone turnover. 10 patients each will receive teriparatide or placebo for 18 months. They will be followed regularly at every 3 months with foot X-ray , serum urea , creatinine, calcium, albumin , inorganic phosphorus and alkaline phosphatase measurement. DEXA scan of foot bones will be done at 12 and 18 months , while F18 PET scan of foot and bone turnover markers will be measured at 3, 12 and 18 months after starting teriparatide therapy. Any side effect will be noted at each visit.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 25, 2020)
Clinical Events [ Time Frame: 12 months ]
Any of the following will be taken as a secondary end point: The number of participants with
  1. new onset fracture
  2. new onset/progression of deformity
  3. amputation
Original Secondary Outcome Measures  ICMJE
 (submitted: December 23, 2013)
Efficacy of teriparatide in improving remodeling of foot bones in diabetic inactive Charcot's neuroarthropathy [ Time Frame: two tears ]
Any of the following will be taken as a secondary end point:
  1. new onset fracture
  2. new onset/progression of deformity
  3. need of amputation
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy of Teriparatide in Diabetic Inactive Charcot Neuroarthropathy of Foot
Official Title  ICMJE To Study the Efficacy of Teriparatide in Improving Remodeling of Foot Bones in Chronic Charcot Neuroarthropathy in Patients With Diabetes Mellitus.
Brief Summary

Diabetic foot represents a major medical , social and economic problem worldwide.

Charcot's neuroarthropathy, being a common cause of diabetic foot, has been an intriguing topic of research for endocrinologists, podiatrists and surgeons. After its first description by JEAN-MARTIN CHARCOT in 1868, many theories have been put forward regarding its pathophysiology , but not much research has been done for its prevention and treatment , specially the inactive stage.

The course of Charcot 's neuroarthropathy is triphasic , with the diagnosis being usually missed in the active stage, henceforth the patients often come to us with a deformed foot. As a consequence , the osteoclastic activity in active stage renders the foot bones demineralized and weak, thus being susceptible to fracture and fragmentation.

Teriparatide is recombinant human (1-34) parathyroid molecule that has been approved for post-menopausal osteoporosis and in men with primary or secondary osteoporosis. It acts by preferentially stimulating osteoblast over osteoclast activity resulting in new bone formation and an increase in the rate of bone remodeling which manifest as an increase in skeletal mass and bone mineral density .

Keeping the pathophysiology of Charcot's foot in mind, teriparatide may be used as potential treatment for inactive Charcot's neuroarthropathy but there are no studies or randomized trials in this setting, till date. We hypothesize that teriparatide may increase the remodeling of foot bones in Charcot's neuroarthropathy, improve bone mineral density, subsequently leading to a reduction in the risk of fractures and progression of deformities. This study plans to compare the effects of teriparatide in diabetes patients with inactive Charcot's foot in a placebo controlled design.

Detailed Description

Charcot neuroarthropathy (CN) was first described by Jean-Martin Charcot in a patient with tabes dorsalis who recognized that peripheral neuropathy could lead to neuropathic joints. This condition has many names, including Charcot osteoarthropathy, neuropathic osteo- arthropathy, and many others. Charcot foot may occur as a complication of neurosyphilis, syringomyelia, leprosy, poliomyelitis, congenital neuropathy and diabetes mellitus , the latter currently being the most common cause of CN. Since the description of CN in 1883, its pathophysiology remains an enigma, and there are no strict guidelines for the treatment of this disorder.

India has more people living with diabetes than any other country of the world and diabetic foot is one of the common diabetic complications found in India. The prevalence of Charcot foot in diabetes is not clearly known (0.1% to nearly 30%), but it is now appreciated that the condition is not as infrequent as might be generally thought. CN is characterized by progressive destruction of bones and joints of the foot with accompanying osteopenia. The current belief is that once the disease is triggered in a susceptible individual, it is mediated through a process of uncontrolled inflammation in the foot. This inflammation leads to osteolysis and is indirectly responsible for the progressive fracture and dislocation that characterizes its presentation.

The pathophysiologic event is cytokine- driven elevation of the receptor activator of nuclear factor kappa B ligand (RANKL), which, in turn, enhances the synthesis of nuclear factor kB (NF-kB). The latter promotes osteoclast maturation and osteoclastic activity, leading to osteoporosis in the affected bones. In parallel , NF-kB enhances the production of osteoprotegerin from osteoblasts, in order to provide an antagonist of RANKL and mitigate its effects. Ultimately, the cascade of all pathophysiologic changes leads to the development of the Charcot's foot and demineralization of bones.

If the condition is correctly diagnosed and the patient is appropriately immobilized, the local inflammation will subside and further bony destruction including progressive loss of mineral density may be prevented. But the diagnosis of CN is frequently missed in the active phase in almost 25% of cases. In the inactive stage, signs of local inflammation progressively recede, redness subsides, and the difference in skin temperature between the two feet diminishes. Most of the patients coming to our diabetes clinic present in the inactive phase with stable foot deformities viz rocker bottom deformity, loss of longitudinal or transverse arches, bony prominence (medial convexity) and significant demineralization of bones. These foot deformities result in abnormal high-pressure areas that are particularly prone to ulceration; a consequence of continued weight bearing.

Recombinant human parathyroid hormone fragment (teriparatide) is an anabolic therapy , that preferentially stimulates osteoblast over osteoclast activity resulting in new bone formation and an increase in the rate of bone remodeling. These effects manifest as an increase in skeletal mass, bone mineral density (BMD) and bone strength, subsequently leading to a reduction in the risk of fractures. It has been well established that teriparatide increases bone remodeling in the skeleton through histomorphometry studies and measurements of bone turnover markers (BTM), and recently direct measurements of the effect of teriparatide on the site-specific metabolic activity of the skeleton has been shown in patients of osteoporosis.

Radionuclide bone scan imaging using the radiopharmaceutical 99Technetium-methylene diphosphonate (MDP) has a useful role in both clinical practice and research to investigate metabolic bone diseases and response to treatment. In clinical practice, bone scans are reported solely on a qualitative visual interpretation of images allowing for the detection of discrete changes in the skeleton in areas of focal tracer uptake. An increased 99mTc-MDP skeletal uptake with teriparatide is seen in patients with osteoporosis indicating an increased bone formation which was supported by BTM increases. Recently, quantitative bone scintigraphy with MDP is described as a more sensitive tool to study the bone-remodeling process even in CN. The potential utility of quantitative bone scanning for the diagnosis and more importantly for CN activity is suggested. However, translating visual assessments into quantitative data with F18 PET/ SPECT CT to study the regions of interest (ROI) and assess the response to teriparatide will be more specific.

The role of teriparatide in diabetes patients with CN has not been studied, till date. Keeping the pathophysiology of CN in mind, the present study plans to assess the efficacy of teriparatide in chronic CN by studying the change in bone remodeling as quantitated by F18 SPECT CT, BMD and markers of bone turnover. We will also assess the benefits of teriparatide, if any, on the foot morbidity i.e incidence of fractures, progression of deformity or need for amputation over the follow up period of 18 months.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Treatment
Condition  ICMJE Diabetic Neuropathic Arthropathy
Intervention  ICMJE
  • Drug: Teriparatide
    recombinant human parathyroid hormone (1-34) subcutaneous every day at 8-9 pm
    Other Names:
    • parathyroid hormone
    • recombinant human parathyroid hormone
  • Other: Placebo
    Placebo
Study Arms  ICMJE
  • Active Comparator: teriparatide
    10 diabetic patients with inactive Charcot's foot who are calcium and Vit.D sufficient will receive 20 microgram of teriparatide , subcutaneous between 8-9 p.m., daily.
    Intervention: Drug: Teriparatide
  • Placebo Comparator: placebo
    10 diabetic patients with inactive Charcot's foot who are calcium and Vit.D sufficient will receive placebo , subcutaneous between 8-9 p.m. , daily.
    Intervention: Other: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 23, 2013)
20
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE December 2018
Actual Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Clinical criteria:

    1. No warmth or redness of foot.
    2. Difference in temperature between two foot < 2 degree Centigrade.
    3. If deformity present , patient able to walk without aid.
    4. History of resolved active Charcot's neuroarthropathy of foot.
  2. Radiological criteria: Plain X-ray foot (weight bearing lateral and oblique) showing at least 3 of the following features -

    1. Foot deformity.
    2. Joint subluxations/dislocations.
    3. Smoothening /Rounding of bone fragments.
    4. Subchondral sclerosis/erosions.
    5. Callus formation.
    6. Joint space collapse.

Exclusion Criteria:

  1. Active inflammatory phase of Charcot's neuroarthropathy.
  2. Active on inactive Charcot's neuroarthropathy.
  3. Osteomyelitis of foot bones.
  4. Peripheral vascular disease.
  5. Osteoporosis (T score less than or equal to -2.5 at lumbar spine or hip).
  6. Renal failure ( estimated Glomerular Filtration Rate < 60 ml/min).
  7. Previous/present bone malignancy.
  8. Previous malignancy with metastases to bone.
  9. Received teriparatide earlier.
  10. Hyperparathyroidism.
  11. Paget's disease of bone.
  12. Pregnant women.
  13. Received bisphosphonates in previous 18 months.
  14. Patients with ulcer on the involved foot.
  15. Patients previously taking Pioglitazone. -
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE India
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02023411
Other Study ID Numbers  ICMJE ABAR-1072013
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Ashu Rastogi, Postgraduate Institute of Medical Education and Research
Study Sponsor  ICMJE Postgraduate Institute of Medical Education and Research
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Anil Bhansali, DM PGIMER, Chandigarh
PRS Account Postgraduate Institute of Medical Education and Research
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP