HC2: RCT

ReDuCe

ReDuCe is a new diuretic drug for patients with hypertension. Its effect has to be studied → a research question has to be made:

• What is the effect of a new diuretic drug (ReDuCe) versus no diuretic treatment on blood pressure in patients who have an increased blood pressure?
  • Classification: treatment research
  • Patients: subjects with an increased blood pressure
  • Intervention: 40 mg ReDuCe
  • Comparator: no diuretic treatment
  • Outcome: blood pressure reduction

Effect

After 6 weeks of treatment, a patient prescribed with ReDuCe has a normalized blood pressure → the effect. However, this effect can have several causes:

• Start of the pharmacological therapy (ReDuCe)
• Stopping of smoking
• Starting to go to the gym
• More adherence to β-blocker treatment
• Fear of the doctor the first time the blood pressure was measured
  • This is called “white coat hypertension”
• Use of a more precise measurement instrument the second time
• The blood pressure fluctuation over time
  • Regression to the mean has to be applied
  • Sometimes the blood pressure is relatively high, sometimes relatively low
• Et cetera

Outcome

The outcome is a combination of 4 phenomena:

• Treatment (T)
• Natural course (NC)
  • Natural reasons for why the blood pressure goes up or down
• Extraneous factors (EF)
  • E.g. going to the gym
• Error processes (V)
  • Variation of the measurement device

Therefore, outcome = T + NC + EF + V. The interest mainly lies in the effect of the treatment (T):

• Outcome with treatment : T + NC + EF + V
• Outcome without treatment : NC + EF + V

Comparison:

To identify the effect of treatment, 2 (or more) groups need to be compared. These groups should be comparable with respect to NC, EF and V, and differ only with respect to treatment. In this case, an observed difference in the outcome between the groups can be attributed to the only aspects that the 2 groups differ on → the treatment. Comparability is necessary.

Design elements

A randomized controlled trial is the number 1 design to achieve comparability. In order to achieve comparability, an RCT typically has 3 design elements:

• Randomization
  • Concealment of treatment allocation → treatment allocation independent of patient characteristics
    • A remote algorithm that is concealed for both the patient and physician
      • The physician who asked patients to participate does not know what treatment the next patient will receive, nor do the patients themselves
    • The physician can cheat on other processes
• Blinding
  • Participants should not now which treatment they receive → can influence their behavior
    • This also applies to the treating physicians, nurses and relatives
    • Aims to keep the groups comparable during the follow-up
  • Methods
    • Placebo
      • Tastes/looks/smells like the active treatment, but does not contain the active compound
      • Sometimes difficult in case of surgery or physiotherapy
    • Active comparator
      • E.g. ReDuCe (40 mg) versus hydrochlorothiazide (25 mg)
  • Outcome assessment: the one who measures the outcome shouldn’t know about treatment status because that could influence the measurement
    • E.g. blood pressure, quality of life, etc.
    • Exception: all-cause mortality
• Standardization
  • 3 elements need to be standardized
    • Standardization of intervention
      • Administration, frequencies and dosages
    • Standardization of concomitant care
      • What physicians should/should not combine with the treatment
    • Standardization of outcome assessment
      • How the blood pressure should be recorded
  • Aims
    • Minimizing error processes
    • Improving interpretability of treatment effects

In short, several elements are necessary to achieve comparability in 3 stages of treatment:

• Start of treatment → randomization and concealment of allocation
• Follow-up → blinding of the patient and physician
• Outcome assessment → blinding of the outcome assessor

Research questions

Several things can be done to find the answer to the question: “What is the effect of a new diuretic drug (ReDuCe) versus no diuretic treatment on blood pressure in patients who have an increased blood pressure?”. The intervention is ReDuCe, with either a placebo of hydrochlorothiazide as comparators:

• Intervention
  • Patients: subjects with an increased blood pressure
  • Intervention: 40 mg ReDuCe
  • Comparator: no diuretic treatment
  • Outcome: blood pressure after 6 weeks of treatment
• Comparator
  • Placebo
    • Patients: subjects with increased blood pressure
    • Intervention: 40 mg of ReDuCe
    • Comparator: placebo
    • Outcome: blood pressure after 6 weeks of treatment
  • Hydrochlorothiazide
    • Patients: subjects with increased blood pressure
    • Intervention: 40 mg of ReDuCe
    • Comparator: 25 mg of hydrochlorothiazide
    • Outcome: blood pressure after 6 weeks of treatment

Equipoise:

It may not be ethical to compare a new drug with a placebo, especially if it is known that the drug is effective and available → comparison with an effective comparator is necessary. Some comparisons may also not be relevant. Clinical equipoise provides the ethical basis for medical research that involves assigning patients to different treatment arms of a clinical trial.

Primary endpoint, analysis and measure

Primary endpoint:

The primary/clinical endpoint of a clinical trial is the endpoint for which the trial is powered. It is the main result that is measured at the end of a study to see if a given treatment worked.Secondary endpoints are additional endpoints for which the trial may not be powered.

Primary analysis:

The primary analysis is the intention to treat. It is the original analysis of data collected for a research study. In an intention to treat analysis, anyone randomized into one of the study groups must be included in the final analysis in the group to which they were originally randomized, regardless of whether they adhered to the protocol or not.

Primary measure:

The primary outcome measure is the outcome that an investigator considers to be the most important among the many outcomes that are to be examined in the study. The primary outcome needs to be defined at the time the study is designed.

Randomization

Block randomization:

Block randomization is done by the computer and ensures that the disbalance of total numbers in a type of treatment can never be substantial. This is called random permuted blocks (RPBs):

• Sequences can never be more than 2 out of balance
• If there are 4 groups, trials need to consist of 4, 8, 12, etc. patients
  • Are predictable to a certain extent → to prevent this, block length variation is applied (both length 6 blocks and length 4 blocks are used)

Voice response system:

Voice response systems are used to conduct clinical trials and manage the large volumes of data generated. The caller responds to questions, which will be logged into a database and possibly recorded at the same time to confirm authenticity. Applications include patient randomization and drug supply management. They are also used in recording patient diaries and questionnaires. This allows callers to obtain data relatively anonymously, which allows callers to receive anonymous access to test results. The voice response system is used to preserve privacy and avoid potential embarrassment of sensitive information or test results.

Declaration of Helsinki

The declaration of Helsinki provides guidance to physicians engaged in clinical research and focuses on the responsibilities of researchers for the protection of research subjects → in medical research involving human subjects capable of giving informed consent, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study.

Preregistration

Preregistration separates hypothesis-generating (exploratory) from hypothesis-testing (confirmatory) research. Both are important. But the same data cannot be used to generate and test a hypothesis, which can happen unintentionally and reduce the credibility of your results. Addressing this problem through planning improves the quality and transparency of your research. This helps you clearly report your study and helps others who may wish to build on it.