Clinical Drug Experience Knowledgebase

Main objective of the study:

To evaluate whether the progression of aortic valve calcification and/or coronary arteries in the group treated with oral InsP6 is smaller than in the placebo group, measured by quantification of calcium (score and mass) by multidetector CT to the inclusion in the study and 24 months.

Secondary:

To observe whether the progression of aortic stenosis severity in the intervention group is smaller than in the placebo group, evaluated by echocardiography.

To compare the clinical events between the intervention and placebo groups, measured as the combined event of death, hospitalization for angina, coronary revascularization (surgical or percutaneous), nonfatal myocardial infarction and stroke of any type.

To compare the adverse effects collected by spontaneous reporting between the two groups.

Main variable of analysis ( multidetector CT measurements): Calcium in aortic valve and/or coronary arteries assessed by Agatston units (AU) on two occasions: before treatment, and 2 years of follow up.

Types of analysis of the main variable:

Percentage of change in quantity of calcium in aortic valve between baseline and study end.
Absolute difference from quantity of calcium in aortic valve between baseline and study end.
Percentage change in coronary calcium quantity between baseline and study end.
Absolute difference in coronary calcium quantity between baseline and study end.
Percentage change of total calcium in aortic valve and coronary artery between baseline and study end.
Absolute difference of total calcium in aortic valve and coronary artery between baseline and study end.

Secondary analysis:

Progression of aortic stenosis severity assessed by gradient and maximum speed, average by echocardiography.

Percentage of clinical events. The event is considered the composite event "death, hospitalization for angina, coronary revascularization (surgical or percutaneous), valvular surgery, nonfatal myocardial infarction or stroke of any type"

Measurements:

Calcium valve by echocardiography: expressed as Rosenhek score at the aortic and coronary calcium CT MD: expressed as Agatston score units and mass determination of calcium. Measurement of emitted radiation .

Demographic variables: age, sex, race, weight, height, and BMI SC, snuff and alcohol habits.

Food Survey: Quality and frequency of feeding in relation to income Ins6P. Conventional hematological and biochemical parameters: blood count. ESR. Urea, Creatinine, Na, K, Ca, P Phytate: determination in urine by InsP6 technique developed at the Universitat Illes Balears. The blind is maintained until final results.

Events qualifiers: death, nonfatal myocardial infarction, hospitalization for angina, coronary revascularization, stroke (score by Events Committee of the study).

Adverse events: Determination of adverse events according to RD 223/2004 (Spanish regulation) Patient Compliance: By counting returned capsules and quantification of phytate in urine.

Withdrawals: If there are withdrawals for any reason the patient is requested authorization for calcium measurement by CT when possible.

Statistical:

Predetermination of sample size:

Assuming the evolution of aortic valve calcification between 21.7% to 32% per year found in the placebo arm of clinical trials with similar methodology and population, and based on a standard deviation of 1100 AU per year, assuming a Type I error of 0.05 and type II of 0.2, to detect a difference of 20% annually between treatments, we need between 124 and 105 patients, respectively, assuming a 10% of losses, and an average Agatston units at baseline, of 1700. We decide to adopt the larger size.

Strategy for statistical analysis: The analysis of data will carry out maintaining the blind and conducted by intention to treat and, as a secondary analysis, per protocol.

The population for the intention to treat analysis, include those randomized patients who have received at least one dose of assigned treatment. The per protocol population will consist of those individuals who finish the study without protocol violation.

A description of the baseline characteristics of the groups, will be carry out, verifying, despite using a system of random assignment, the homogeneity of the two groups for baseline variables. A test for the normality of quantitative variables to select the statistic descriptors, mean (CI95%) or median (RI), and test for comparisons.

The main result will be a change of aortic valve calcification, calculated as the percentage change from baseline divided by the duration of follow up as years. An analysis stratified for each independent variable.

An increment of at least 18% of the basal calcification, will be considered evident progression, by contrast, a lesser progression will be considered response to treatment. Logistic regression will be used to establish the likelihood of response.

Secondary objectives will be analyzed by comparing the ratios between treatment groups.

There will be a descriptive analysis of the side effects listed in both groups.

Ethical considerations: No special ethical problems arise in the trial because of the phytate is considered a safe product (FDA-Title 21 subchapter GRSH E-Part 582) which are a component of the normal diet, and because of the chances of problems with excessive intake of this are nil. Nor is amended nor intervene during the study in routine clinical practice.

The most important aspect is to control the radiation dose that patients receive during the multidetector CT. In any case is lower than the environmental background radiation received during 6 months.

Considering this aspect, intermediate CT study has not been scheduled.

No information is available on the extent of calcium through multidetector-CT to let us build the sample size with great confidence. We have used the values of progressive studies Cowell and Houslay for making this approximation.