Endothelial Dysfunction Clinical Trial
Official title:
Influence of Nitrates on Bone Remodeling and Endothelial Function in Patients With Type 2 Diabetes Mellitus.
NCT number | NCT02011620 |
Other study ID # | D001 |
Secondary ID | |
Status | Withdrawn |
Phase | Phase 4 |
First received | |
Last updated | |
Start date | October 2014 |
Est. completion date | December 2014 |
Verified date | September 2019 |
Source | Tameside Hospital NHS Foundation Trust |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Withdrawn |
Enrollment | 0 |
Est. completion date | December 2014 |
Est. primary completion date | December 2014 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 40 Years to 75 Years |
Eligibility |
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 |
Country | Name | City | State |
---|---|---|---|
United Kingdom | Tameside General Hospital NHS Foundation Trust | Manchester |
Lead Sponsor | Collaborator |
---|---|
Tameside Hospital NHS Foundation Trust |
United Kingdom,
Jamal SA, Cummings SR, Hawker GA. Isosorbide mononitrate increases bone formation and decreases bone resorption in postmenopausal women: a randomized trial. J Bone Miner Res. 2004 Sep;19(9):1512-7. Epub 2004 Jul 26. — View Citation
Jamal SA, Goltzman D, Hanley DA, Papaioannou A, Prior JC, Josse RG. Nitrate use and changes in bone mineral density: the Canadian Multicentre Osteoporosis Study. Osteoporos Int. 2009 May;20(5):737-44. doi: 10.1007/s00198-008-0727-7. Epub 2008 Sep 18. Retraction in: Osteoporos Int. 2016 Dec 1;:. — View Citation
Mascarenhas JV, Jude EB. Pathogenesis and medical management of diabetic Charcot neuroarthropathy. Med Clin North Am. 2013 Sep;97(5):857-72. doi: 10.1016/j.mcna.2013.05.002. — View Citation
Veves A, Akbari CM, Primavera J, Donaghue VM, Zacharoulis D, Chrzan JS, DeGirolami U, LoGerfo FW, Freeman R. Endothelial dysfunction and the expression of endothelial nitric oxide synthetase in diabetic neuropathy, vascular disease, and foot ulceration. Diabetes. 1998 Mar;47(3):457-63. — View Citation
Wimalawansa SJ. Nitric oxide: new evidence for novel therapeutic indications. Expert Opin Pharmacother. 2008 Aug;9(11):1935-54. doi: 10.1517/14656566.9.11.1935 . Review. — View Citation
Wimalawansa SJ. Rationale for using nitric oxide donor therapy for prevention of bone loss and treatment of osteoporosis in humans. Ann N Y Acad Sci. 2007 Nov;1117:283-97. Review. Erratum in: Ann N Y Acad Sci. 2010 Mar;1192(1):444. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Improvement in endothelial function as measured by laser doppler imaging. | 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). |
6 months | |
Secondary | Improvement in bone metabolism | An improvement in bone formation as measured by serum procollagen type 1 amino terminal propeptide (P1NP) Suppression of bone resorption as assessed by measurement of serum C-terminal crosslinked telopeptide of type 1 collagen (CTX) Improvement in calcaneal bone mineral density |
6 months |
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