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Study design and Randomization:
The long-term HT trials are designed today as PROBE(Prospective Randomised,open,blinded end point) studies. Such studies are aimed at comparing a treatment regimen of newer anti-HT drugs (e.g, a CCB) with a traditional regimen (β-blocker and/or a diuretic), like prevention of CHD. The study basically consists of two arms, i.e. the control and the experimental arms, in which appropriate number of patients are entered following a randomization scheme. Because the control arm in such studies consists of receiving an active drug, which is often one of the standard first-line treatments, the trial is often dubbed as an “active control trial,” as mentioned above several times. A schematic representation of a two-arm randomized trial is presented in Figure (1)below.

The total number of patients (sample size) and those in each arm are calculated carefully such that a clinically meaningful effect size can be differentiated between the average outcome measurements for the two arms with adequate statistical power (usually 80%) and significance (usually two-sided 5%). Both the power and the level of significance are prospectively defined and finalized in the detailed protocol before the trial begins. The final sample size includes considerations of drop out patients and all interim analyses (IA)7 Schematic representation of a two-arm randomized clinical trial of new and existing anti hypertension (anti-HT) treatments in HT patients with one or more additional risk factors.

The RCTs for HT and co morbidities are usually large (few thousand patients) multi centric studies.[6]Open label refers to a non concealment of both the active control and the experimental drugs to the patients and investigators, in that they can figure out the difference in physical and organoleptic properties between the two. Sometimes, there could also be a difference in the route of the two administrations.

The investigator or the expert who measures the endpoint, however, is blinded to the randomization codes and allocations to all patients, such that no bias is introduced in the assessment of the endpoint. If dosage titration for the experimental arm is required, the same principle of endpoint blinding should be applied.[7]

There are three basic ways to generate a randomization scheme for an RCT.
Simple randomization
Block randomization
Stratified blocks

Simple randomization: The simple randomization, which is equivalent to tossing a coin for each subject that, enters a trial. The heads get the experimental treatment while the tails receive the placebo. A computerized or tabulated random number generator is generally used. It is simple and easy to implement and treatment assignment is completely unpredictable.

Block randomization: It is very popular and balanced within each block. For a trial of n treatments, the total number patients are divided into m blocks of size 2n. Then, each of the m blocks is randomized such that n patients are allocated to each of the treatments. One can then choose the blocks randomly. The INVEST[15] study followed this scheme of block randomization.

Stratified blocks: , a third approach to randomization involves “stratified blocks.” Because a trial may not be considered valid if it is not well balanced across the prognostic factors, stratification of patients is done to produce comparable groups with regard to certain characteristics (e.g., gender, age, race, disease severity). This approach produces valid statistical tests in all stratified subgroups (e.g., high-risk subgroups in the ALLHAT trial).[13,14

Whatever the mode of randomization is, it is ensured that the pattern of assignment of control or experimental drug within a group of patients cannot be guessed at any point. It is recommended that the statistician who generated the randomization codes does not get involved in the IA or the final analysis of the experimental data. Other study designs can be used in HT trials as long as they are scientifically valid and manageable.[10]

Usually, studies are designed for observation and analysis of the primary outcome on which the sample size calculation is also based. Secondary outcomes, however, can also be validly analyzed if the primary outcome difference is not statistically significant provided that they were declared a prior and are clinically important. Another condition for the valid use of secondary outcomes in the efficacy or endpoint estimation is that the method to capture outcomes was the same in each treatment group and the data are unbiased (randomized). In addition, if the outcomes for secondary endpoints such as heart failure (HF) and CVD are still compelling even after considering the number of comparisons made, then the conclusion based on these outcomes is valid.

Assessment /Analysis of the study:

The primary basis of assessment of efficacy of antihypertensive drugs is the effect of the drug on systolic and diastolic blood pressures. In the past the primary endpoint of most studies was diastolic blood pressure. Although all drugs to date have reduced both systolic and diastolic blood pressures, the recognition of isolated or predominant systolic hypertension as a significant and remediable risk factor demands explicit evaluation of the effect of a drug on systolic blood pressure. Many clinical trials of many interventions (including low and high dose diuretics, reserpine, and beta-blockers, usually as part of combination therapy) have shown consistent beneficial effects on long-term mortality and morbidity, most clearly on stroke and less consistently on cardiovascular events. Whether some drugs or combinations have better effects than others on overall outcomes or on particular outcomes is not yet known. Formal mortality and morbidity outcome studies are not ordinarily required for approval of antihypertensive drugs and the kind of active control mortality and morbidity studies that would be convincing is not well defined. Results of a large number of on-going outcome studies could affect this policy and modify requirements. It should be noted that, even if an antihypertensive effect has been proven, a significant concern about a detrimental effect on mortality and/or cardiovascular morbidity might lead to a need for outcome studies.[11]


2.1 Studies to assess antihypertensive effect:  The primary endpoint of studies to assess antihypertensive effect is the absolute change at the end of the dosing interval (trough) from drug-free baseline blood pressure compared to the change in the control group. As a secondary endpoint effects can also be assessed with respect to pre-defined response criteria. In general, the effect on blood pressure at the end of the study is the primary endpoint, but the time course of the onset of the effect is also of interest; this can be defined by examining trough response each week or every two weeks in some studies. [11] The effect on blood pressure and the relationship of the response to dose should be characterized in short-term studies (4-12 weeks), whose short duration allows for use of a placebo control. Long-term (six months or more) studies should also be carried out to demonstrate maintenance of efficacy and to look for withdrawal effects. Because blood pressure readings are subject to systematic error (bias), because spontaneous changes in blood pressure can be large, and because the effect of active drugs is often small  studies conducted in a blinded fashion and with placebo controls are essential . In general, short-term studies should be placebo-controlled. Dose-response studies and studies using an active control drug as well as placebo are strongly encouraged. Controlled randomized short-term studies of various designs can be useful in demonstrating effectiveness, for example:
A) Single fixed-dose vs. placebo
B) Optional titration (based on response) vs. placebo
C) Forced titration vs. Placebo
D) Fixed-dose, dose-response vs. placebo (can use forced titration to reach the randomly assigned fixed maintenance dose)
E) Any of the above designs with an active control drug

2.2 Pharmacodynamic studies: The Pharmacodynamic properties of antihypertensive drugs should be characterized. Studies should be performed to evaluate such properties as hemodynamic effects, renal effects, and neurohumoral effects.[13] In general, it is useful to characterize the magnitude, dose-response, and time-course of these effects. These studies should usually be placebo-controlled.

2.3 Dose response relationship: The dose-response (D/R) relationship for favorable (blood pressure) and unfavorable effects of anti-hypertensive drugs should be well-characterized through randomized fixed-dose, D/R studies. In these studies, a greater number of dose groups will provide a better D/R assessment. If possible, at least three doses (in addition to placebo) should be used. Although trials usually use a randomized parallel fixed-dose, D/R design (See ICH E-4), some studies could utilize a placebo-controlled titration design, appropriately analyzed, to narrow the range of doses to be studied in fixed-dose studies, and to characterize individual D/R relationships. Either or both of these designs can provide evidence for anti-hypertensive efficacy. These D/R studies should characterize critical parts of the D/R curve, allowing identification of the lowest dose with some useful effect, a dose on the steep part of the D/R curve, and a dose beyond which further effects are absent or small (maximum useful dose). If there is a positive D/R slope, a D/R study can show effectiveness even without a placebo, but it may provide littleinformation on the value of the lower doses (which may then need further study). A D/R study may be uninformative if all doses show equal effects.[14]

2.4 Comparison with standard therapy: The need for studies comparing the new drug with current standard therapy varies among regions but comparative studies are of interest in all regions. In order to assess antihypertensive efficacy, these trials need to document assay sensitivity through a placebo arm or a terminal placebo-controlled randomized withdrawal phase. For the short-term studies, a 3-arm design(test drug, active control drug, and placebo) may be particularly helpful as a study that not only supports efficacy but also makes a comparison with standard therapy. If the effect size (vs.placebo) is unusually small, it can be helpful to know whether this was the result of the study population, or other study features (test and control drugs both have small effect vs. placebo), or the drug (active control drug has a larger effect than test drug compared to placebo). For longer-term  comparative studies, where concurrent placebo-control is not possible.



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