Calcific Aortic Stenosis | Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis.
Calcific Aortic Stenosis research study
What is the primary objective of this study?
Aortic stenosis is a condition whereby one of the heart valves (aortic valve) becomes narrowed, due to calcium deposition, over time. This can lead to chest pain, heart failure and sudden death. It is the commonest valve disease requiring surgery in the developed world and as the population becomes increasingly older, it is predicted that the prevalence of aortic stenosis will double in the next 20 years. Currently the only treatment is replacement of the aortic valve. Whilst this is excellent treatment, not everyone is suitable for it. The primary objective of our study is to determine whether 2 drugs used in the treatment of osteoporosis (a condition of bone thinning) can halt/retard the progression of aortic stenosis. This is on the basis that studies have suggested that altered regulation of calcium metabolism may be an important mechanism perpetuating the disease. Both drugs work by reducing calcium release into the bloodstream from bones and therefore calcification of the aortic valve. 150 patients will therefore be randomly allocated to either of the trial drugs which are denosumab,the bisphosphonate (alendronic acid), or a placebo. Positron Emission Tomography (PET) scanning is a technique where biochemically active molecules are injected and are taken up at sites of ongoing calcification activity where they emit radiation and can be detected by the PET scanner. We have previously shown that this technique can demonstrate areas of newly developing calcification on an aortic valve. We therefore propose that patients receiving bisphosphonates or denosumab will have reduced evidence of active calcification and slower progression of their disease at two years as assessed by Echocardiography (ultrasound) and a change in their calcium score (quantity of calcium on the aortic valve measured using Computed Tomography [CT] ). The data from this study will then be used to design a larger trial.
Who is eligible to participate?
Inclusion Criteria: 1. age >50 years 2. peak aortic jet velocity of >2.5 m/s on Doppler echocardiography 3. grade 2-4 calcification of the aortic valve on echocardiography Exclusion Criteria: 1. Anticipated or planned aortic valve surgery in the next 6 months, 2. Life expectancy <2 years, 3. Inability to undergo scanning 4. Treatment for osteoporosis with bisphosphonates or denosumab. 5. Long-term corticosteroid use. 6. Abnormalities of the oesophagus or conditions which delay oesophageal/gastric emptying, 8) Inability to sit or stand for at least 30 minutes, 9) Known allergy or intolerance to alendronate or denosumab, or any of their excipients, 10) Hypocalcaemia, 11) Maintenance calcium supplementation, 12) Dental extraction within 6 months, 13) History of osteonecrosis of the jaw, 14) Major or untreated cancers, 15) Poor dental hygiene, 16) Women of child-bearing potential who have experienced menarche, are pre-menopausal, have not been sterilised or who are currently pregnant, 17) Women who are breastfeeding, 18) Renal failure (estimated glomerular filtration rate of <30 mL/min), 19) Allergy or contraindication to iodinated contrast, 20) Inability or unwilling to give informed consent, 21) Likelihood of non-compliance to treatment allocation or study protocol
Which medical condition, disease, disorder, syndrome, illness, or injury is researched?
Calcific Aortic Stenosis
Interventions can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available or noninvasive approaches such as surveys, education, and interviews.
Drug:Denosumab Placebosubcutaneous injection of 0.9%Saline at baseline, 6 months, 12 months and 18 months
Drug:Alendronic Acid PlaceboInert Capsule containing lactose monohydrate manufactured and labelled by Investigational Supplies Group (ISG) University of Edinburgh.
Research studies and clinical trials typically have two or more research arms. An arm is a group of people who receive the same treatment in the study.
Alendronic Acid50 patients will receive once weekly Alendronic Acid tablets (70mg).
Alendronic Acid placebo25 patients will receive alendronic acid placebo tablets.
Denosumab50 patients will receive 6 monthly denosumab injections
Denosumab Placebo25 patients will receive a 6 monthly placebo injection.
Start Date: November 2014
Completed Date: August 2017
Phase: Phase 2
Primary Outcome: Change in aortic valve calcium score
Secondary Outcome: Change in aortic valve 18F-NaF uptake
Study sponsors, principal investigator, and references
Principal Investigator: Tania A Pawade, MbChB
Lead Sponsor: University of Edinburgh
Collaborator: NHS Lothian
Dweck MR, Jenkins WS, Vesey AT, Pringle MA, Chin CW, Malley TS, Cowie WJ, Tsampasian V, Richardson H, Fletcher A, Wallace WA, Pessotto R, van Beek EJ, Boon NA, Rudd JH, Newby DE. 18F-sodium fluoride uptake is a marker of active calcification and disease progression in patients with aortic stenosis. Circ Cardiovasc Imaging. 2014 Mar;7(2):371-8. doi: 10.1161/CIRCIMAGING.113.001508. Epub 2014 Feb 7.