Influence of Nitrates on Bone Remodeling and Endothelial Function in Patients With Type 2 Diabetes Mellitus

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified December 2013 by Tameside Hospital NHS Foundation Trust
Sponsor:
Information provided by (Responsible Party):
Dr Edward Jude, Tameside Hospital NHS Foundation Trust
ClinicalTrials.gov Identifier:
NCT02011620
First received: November 26, 2013
Last updated: December 13, 2013
Last verified: December 2013
  Purpose

Type 2 diabetes mellitus (DM) is becoming a leading global epidemic. DM affects several systems in the body. Most of the complications encountered in DM are attributed to uncontrolled hyperglycemia or poor glycemic control. Hyperglycemic stress tends to damage the inner lining of the small blood vessels (endothelium). Normally, the endothelium releases a chemical substance called nitric oxide (NO) which relaxes the blood vessels and also prevents blockade of these vessels. Therefore damage to the endothelium (endothelial dysfunction) results in diminished levels of NO which ultimately leads to occlusion of these small blood vessels (microvascular occlusion). Microvascular occlusion of vessels supplying the eyes, kidneys and nerves leads to serious complications like diabetic retinopathy, nephropathy and neuropathy.

Of late, the skeletal system has emerged as another vulnerable target of diabetic microvascular disease. Patients with DM have an increased risk of developing fractures. Certain predisposing factors like diabetic neuropathy and visual disturbances (retinopathy and cataract) increases the likelihood of fractures in DM. More recently, evolving research has demonstrated NO's prospective role in bone preservation. Earlier studies have also validated the use of nitrates (donor of NO) in improving bone strength and reducing the risk of fractures.

So far no study has investigated the effect of nitrates on endothelial function and bone microarchitecture in patients with diabetes. The investigators therefore propose to investigate the influence of nitrates on endothelial dysfunction and bone integrity in patients with type 2 diabetes. 40 patients with type 2 DM will be recruited into the study; 20 patients will receive 20 mg of oral isosorbide mononitrate daily and the other 20 will not receive the study drug. The investigators hope to demonstrate an improvement in endothelial function (by measuring skin blood flow) and bone integrity (by measuring markers of bone formation and bone resorption and bone mineral density - BMD) following 6 months of nitrate therapy.


Condition Intervention Phase
Endothelial Dysfunction
Bone Disease
Other: Isosorbide-5-mononitrate
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Investigator)
Primary Purpose: Treatment
Official Title: Influence of Nitrates on Bone Remodeling and Endothelial Function in Patients With Type 2 Diabetes Mellitus.

Resource links provided by NLM:


Further study details as provided by Tameside Hospital NHS Foundation Trust:

Primary Outcome Measures:
  • Improvement in endothelial function as measured by laser doppler imaging. [ Time Frame: 6 months ] [ Designated as safety issue: No ]

    Assessment of the microcirculation with Laser Doppler Iontophoresis at baseline and 6 months

    A standard measurement of microcirculation is laser Doppler iontophoresis, which is used by several research institutes. In this trial the skin microcirculation will be measured on the ventral aspect of the forearm using a Perimed Laser Doppler imager and iontophoresis system.

    Endothelial-mediated vasodilation will be measured by the iontophoresis of acetylcholine, while sodium nitroprusside will be used to measure endothelium-independent vasodilation. The iontophoresis system consists of an ION chamber (iontophoresis delivery vehicle device) that sticks firmly to the skin and a reference electrode. The response in blood flow will be imaged and quantified using the Perimed Laser Doppler Imager (Sweden).



Secondary Outcome Measures:
  • Improvement in bone metabolism [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    1. An improvement in bone formation as measured by serum procollagen type 1 amino terminal propeptide (P1NP)
    2. Suppression of bone resorption as assessed by measurement of serum C-terminal crosslinked telopeptide of type 1 collagen (CTX)
    3. Improvement in calcaneal bone mineral density


Estimated Enrollment: 40
Study Start Date: February 2014
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Isosorbide-5-mononitrate
Tablet Isosorbide mononitrate 20 mg; 1 tablet to be taken daily at night for a total duration of 6 months.
Other: Isosorbide-5-mononitrate
Tablet Isosorbide mononitrate 20 mg; 1 tablet to be taken daily at night for a total duration of 6 months.
Other Names:
  • Name of the MA holder: TEVA UK LIMITED
  • MA number (if MA granted by a Member State): PL 0289/0287
  • UNITED KINGDOM
No Intervention: Standard care
Standard care - no intervention with nitrates

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   40 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Females and males aged between 40-75 years
  • A diagnosis of type 2 DM based on one of the following criteria (ADA - 2010):
  • Fasting plasma glucose (FPG) >= 126 mg/dL (7.0 mmol/L) or
  • 2-h plasma glucose >= 200 mg/dl (11.1 mmol/L) during an OGTT or
  • Classic symptoms of hyperglycemia or hyperglycemic crisis with a random plasma glucose >= 200 mg/dL (11.1 mmol/L).
  • Known history of type 2 diabetes mellitus on treatment

Exclusion Criteria:

  • At screening, age below 40 years and above 75 years.
  • Pregnancy or lactation
  • Type 1 diabetes mellitus (patients with a history of ketoacidosis, age of onset of DM before 25 years of age, BMI <21 kg/m2 and use of insulin without a concomitant oral hypoglycemic agent)
  • Patients with uncontrolled hypertension (systolic blood pressure [SBP] > 160/90 mmHg) or hypotension (SBP of <=100 mm Hg) at screening.
  • History of hypersensitivity to nitrates
  • History of low blood pressure
  • History of raised intracranial pressure (from cerebral haemorrhage or head trauma)
  • History of cardiovascular disease (ischaemic heart disease, previous stroke and severe peripheral vascular disease [Ankle brachial pressure index - ABPI< 0.7])
  • History of acute circulatory failure (shock), circulatory collapse, cardiogenic shock
  • History of hypertrophic obstructive cardiomyopathy, constrictive pericarditis, cardiac tamponade, low cardiac filling pressures, aortic/ mitral valve stenosis
  • History of general systemic illness including cardiac, hepatic or renal insufficiency
  • Patients with clinical nephropathy (24 hour protein > 0.5g or dipstix protein +) or renal failure (serum creatinine > 130 µmol/l).
  • History of anaemia
  • History of closed angle glaucoma
  • History of migraine headaches
  • History of hypothyroidism
  • History of hypothermia
  • History of malnutrition
  • History of Paget's disease and other metabolic bone disorders
  • History of coeliac or inflammatory bowel disease
  • History of multiple myeloma or cancer
  • History of nitrate use for cardiac conditions
  • History of treatment with phosphodiesterase type-5 inhibitors
  • History of foot ulcers
  • History of active foot deformities e.g. Charcot foot
  • History of glucocorticoid intake within the last 3 months
  • History of hormone replacement therapy in the last 12 months
  • History of treatment with SERM (selective estrogen receptor modulator)
  • History of treatment with thiazolidinedione
  • History of anticonvulsant use
  • History of past or current treatment for osteoporosis
  • History of bisphosphonate therapy within the last 3 years
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02011620

Contacts
Contact: Edward Jude, MD, MRCP 01619226964 edward.jude@tgh.nhs.uk
Contact: John Goodenough 01613316006 john.goodenough@tgh.nhs.uk

Locations
United Kingdom
Tameside General Hospital NHS Foundation Trust Not yet recruiting
Manchester, United Kingdom, OL6 9RW
Contact: Edward Jude, MD, MRCP    01619226964    edward.jude@tgh.nhs.uk   
Contact: John Goodenough    01613316006    john.goodenough@tgh.nhs.uk   
Sponsors and Collaborators
Tameside Hospital NHS Foundation Trust
Investigators
Principal Investigator: Edward Jude, MD, MRCP Tameside General Hospital NHS Foundation Trust
  More Information

Publications:
Responsible Party: Dr Edward Jude, Consultant Diabetologist and Endocrinologist, Tameside Hospital NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT02011620     History of Changes
Other Study ID Numbers: D001
Study First Received: November 26, 2013
Last Updated: December 13, 2013
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Additional relevant MeSH terms:
Bone Diseases
Diabetes Mellitus
Diabetes Mellitus, Type 2
Musculoskeletal Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Isosorbide
Isosorbide-5-mononitrate
Isosorbide Dinitrate
Diuretics, Osmotic
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Cardiovascular Agents
Therapeutic Uses
Vasodilator Agents
Nitric Oxide Donors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 21, 2014