Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis.
Information source: University of Edinburgh
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Calcific Aortic Stenosis
Intervention: Denosumab (Drug); Alendronic Acid (Drug); Denosumab Placebo (Drug); Alendronic Acid Placebo (Drug)
Phase: Phase 2
Status: Recruiting
Sponsored by: University of Edinburgh Official(s) and/or principal investigator(s): Tania A Pawade, MbChB, Principal Investigator, Affiliation: University of Edinburgh David Newby, Ba BSc PhD BM DM FRCP DSc FRSE, Study Chair, Affiliation: University of Edinburgh Dweck Marc, MbChb, Phd, Principal Investigator, Affiliation: University of Edinburgh
Overall contact: Tania A Pawade, MbChB, Phone: 07805 306 564, Email: tania.pawade@ed.ac.uk
Summary
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.
Clinical Details
Official title: SALTIRE II and RANKL Inhibition in Aortic Stenosis
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: Change in aortic valve calcium score
Secondary outcome: Change in aortic valve 18F-NaF uptakeChange in aortic-jet velocity Change in thoracic aortic and coronary artery calcium score Change in thoracic spine bone mineral density Change in quality of life determined by Short Form 36 Questionnaire
Detailed description:
BACKGROUND Aortic Stenosis is a common cause of valvular heart disease in which the valve
cusps become progressively calcified. The only available treatment is aortic valve
replacement and previous attempts at providing medical therapies to modify the disease
process have proved unsuccessful.
Pathophysiology of Aortic Stenosis. The initiating event is believed to be caused by
mechanical damage to the cells lining the valve in a process similar to that which occurs in
atherosclerosis. However the propagating mechanism is more likely to be that of active
calcification. In support of this, a growing body of pre-clinical and clinical data
indicates that treatments for osteoporosis, which work by preventing the breakdown of bone
and therefore calcium release into the blood, can reduce calcium deposition (calcification)
of the blood vessels. These agents therefore hold considerable promise as novel therapies
for aortic stenosis.
Denosumab in Aortic Stenosis Denosumab is a drug which prevents bone cells called
osteoclasts from breaking down bone and releasing calcium into the blood. For this reason
it is used to treat osteoporosis. It works on a specific pathway which we believe to be
important in regulating calcium release from bone. Mice engineered with defects within this
pathway were found to have increased bone breakdown and blood vessel calcification.
Furthermore there have been two studies to assess the role of this pathway in patients with
aortic valve disease. Both studies have also demonstrated altered regulation within this
pathway
Bisphosphonates in Aortic Stenosis Bisphosphonates are a group of drugs widely used for the
treatment of osteoporosis and also prevent bone breakdown by osteoclasts. They have also
been shown to have important cardiovascular effects with a consistent reduction in
calcification of blood vessels and the aortic valve. This in part appears to be a
consequence of their inhibition of bone breakdown but also by reducing the production of key
inflammatory substances implicated in the early stages of aortic stenosis. We plan on using
alendronic acid which is a bisphosphonate commonly used in the management of osteoporosis.
PET CT scanning in Aortic Stenosis. 18F-NaF (Sodium Fluoride) is biochemical compound which
preferentially binds to regions of newly developing calcification and emits radiation. When
used in combination with Computed Tomography (CT) it enables it to be localized. This way
we are able to identify areas of newly developing calcification on an aortic valve.
In previous studies in our institution, we demonstrated we could quantify 18F-NaF uptake in
the aortic valve and that there was a progressive rise in activity with increasing disease
severity. We found that at At 1 year, the baseline 18F-NaF uptake emerged as a powerful
predictor of the progression in aortic valve calcification. Following analysis of 2 year
follow up data, 18F-NaF emerged as an independent predictor of aortic valve replacement and
cardiovascular mortality
Therefore these findings have led us to propose that
1. Calcification is the key driver to Aortic Stenosis Progression
2. We want to reduce calcification activity using Denosumab and Biphosphonates
3. We predict that this will reduce the 18F-NaF signal and disease progression on
Echocardiography and CT.
STUDY DESIGN This will be a double-blind, randomized, placebo-control trial of denosumab and
alendronic acid in patients with aortic stenosis.
Study population and randomization
We aim to recruit 170 patients in total with non-rheumatic calcific aortic stenosis.
20 patients will only participate in scan-rescan reproducibility studies. They will not
proceed to the randomization stage.
Of the remaining 150 patients, 75 subjects will be randomized (2: 1) to either subcutaneous
denosumab 60 mg (n=50) or matched placebo (n=25) every 6 months; and a further 75 will be
randomized (2: 1) to oral alendronate 70 mg (n=50) or matched placebo (n=25) once weekly
Assessment and follow up
All subjects will undergo a standardized clinical assessment at baseline and every six
months. Data will be collected with respect to symptomatic status, the trial safety
endpoints, routine biochemical profiling, biomarkers, quality of life questionnaires and
electrocardiography.
Aortic stenosis severity will be assessed at baseline and every 6 months by echocardiography
performed by a single, dedicated sonographer to maximize reproducibility. Severity will be
assessed using the peak and mean aortic valve pressure gradients (this technique is used to
monitor aortic stenosis severity; the higher the pressure gradient across the aortic valve
the more severe the narrowing). We will also calculate the aortic valve area and
calcification score.
PET CT and CT calcium scoring.
Both will be performed using a combined PET and 128-multidetector CT scanner (Biograph 128,
Siemens).
CT calcium scoring measures the amount of calcium in the valve and will be assessed at
baseline, 6 months and 2 years. It will act as an additional marker of disease severity and
progression alongside Echocardiography. Those with a heart rate of >65 /min will be given
heart-slowing medication (beta blockers) if deemed safe. The region of the aortic valve will
be then be scanned during a breath hold.
18F-NaF PET uptake will be measured at baseline, and 6 months to assess the early impact of
the intervention on valvular calcification activity. PET images on their own are difficult
to interpret as they do not tell you where the radiation is coming from. For this reason
the PET needs to be performed alongside CT which gives us images of the aortic valve. By
superimposing the two images we are able to identify where the 'PET signal' is originating
from.
To ensure optimal image quality patients will be required to adhere to a high fat, low
carbohydrate diet for 48 hours prior to the scan. The subject will then be cannulated to
enable injection of the 18F-NaF tracer. They will then rest in a quiet environment for 60
minutes to enable the tracer to reach the valve before transfer to the imaging suite. Those
with a heart rate of >65 /min will be given beta-blockade if it is deemed suitable and safe.
This is routine practice in cardiac CT. A scout CT will be performed to allow optimal
alignment of the PET and CT scanners (so we can be sure the radiation we are detecting is
coming from the aortic valve). The patient will then be asked to lie still for 30 minutes
so that the PET data can be acquired.
Finally a 'CT angiogram' will be performed of the aortic valve. This involves image
acquisition following injection of a radio opaque dye into the aorta. This again allows
more accurate localization of our PET signal.
The additional twenty patients will only undergo repeat PET/CT imaging within 2 weeks of
their baseline scan to investigate scan-rescan reproducibility of the 18F-NaF PET signal.
They will not proceed with the trial beyond this stage to avoid facing increased radiation
exposure.
Eligibility
Minimum age: 50 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
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
Locations and Contacts
Tania A Pawade, MbChB, Phone: 07805 306 564, Email: tania.pawade@ed.ac.uk
Clinical Research Facility University of Edinburgh, Edinburgh EH16 4SA, United Kingdom; Recruiting
Additional Information
Related publications: 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. Dweck MR, Khaw HJ, Sng GK, Luo EL, Baird A, Williams MC, Makiello P, Mirsadraee S, Joshi NV, van Beek EJ, Boon NA, Rudd JH, Newby DE. Aortic stenosis, atherosclerosis, and skeletal bone: is there a common link with calcification and inflammation? Eur Heart J. 2013 Jun;34(21):1567-74. doi: 10.1093/eurheartj/eht034. Epub 2013 Feb 7. Dweck MR, Joshi FR, Newby DE, Rudd JH. Noninvasive imaging in cardiovascular therapy: the promise of coronary arterial ¹⁸F-sodium fluoride uptake as a marker of plaque biology. Expert Rev Cardiovasc Ther. 2012 Sep;10(9):1075-7. doi: 10.1586/erc.12.104. Dweck MR, Jones C, Joshi NV, Fletcher AM, Richardson H, White A, Marsden M, Pessotto R, Clark JC, Wallace WA, Salter DM, McKillop G, van Beek EJ, Boon NA, Rudd JH, Newby DE. Assessment of valvular calcification and inflammation by positron emission tomography in patients with aortic stenosis. Circulation. 2012 Jan 3;125(1):76-86. doi: 10.1161/CIRCULATIONAHA.111.051052. Epub 2011 Nov 16.
Starting date: November 2014
Last updated: December 2, 2014
|