Randomized Control Trials

Question 1

What advantage does a RCT has over an observational trial?

Answer 1

Because RCT’s use random assignment and are often quasi-experimental in nature, you can draw conclusions on causality. This is not allowed in observational research.

Question 2

What are the disadvantages of RCT’s?

Answer 2

1. You can only test very narrow research questions
2. Safety and efficacy need to be balanced; possible harm to pp
3. RCTs are costly and time-consuming

Question 3

What reasons explain the lack of evidence on rehabilitation treatments (compared to medicine)?

Answer 3

1. We often use experience-based treatments, which are complex to measure
2. “Added ingredients” such as interactions in treatment, attention of the therapist, are difficult to take into account.
3. Target outcomes are widely varying, which makes it difficult to quantify them.
4. Difficult to isolate and test the active ingredients in treatments > makes it also difficult to determine to which control conditions the treatment needs to be compared.

Question 4

Which two classes of control groups exist in NP?

Answer 4

1. Active control groups

2. Usual care control groups

Question 5

What are active treatment witheld groups and which forms are there?

Answer 5

Active control groups means that active treatment is withheld in the control group. This is not always ethical, but can be very helpful in matters where there is not much knowledge about the efficacy of a treatment (to see if there is an effect).

1. No treatment: regression to the mean, time effects, effect of repeated testing
2. Waitlist group: expectancy effects, regression to the mean
3. Placebo-analogue conditions; when double-blind very good control on expectancy effects. Also good control for nonspecific treatment effects (professional time, attention, congitive stimulation).

Question 6

What are drawback of the different active treatment withheld control groups?

Answer 6

Overall: ethical concerns. More specifically:

1. No treatment: may not be acceptable for potential participants and can lead to dropouts/independent treatment seeking.
2. Waitlist: can discourage participants
3. Placebo: costly and cannot be applied in a double-blind fashion

Question 7

What are the different forms of usual care control groups?

Answer 7

1. Normal usual care: helps you to find out the “added” value of a new versus old treatment, thereby maximizing equipose.
2. Devised usual care: less intensity/stimuli/frequency of the usual care treatment, to increase the power/need a smaller sample size to detect group differences.

Question 8

What are the different forms of active treatment control groups?

Answer 8

1. Dose control groups: examine the dose-response relationship
2. Dismantling design: giving the same treatment to the groups, but in one group take out one or more “active ingredients” to find out their specific value in the treatment.
3. Equivalence trials: when there are issues with the usual care treatment, you can compare the new treatment in both groups. This makes it very difficult to detect differences, very large sample sizes necessary.

Question 9

What are the drawbacks of active control groups?

Answer 9

1. Dose control: not always possible to try different doses, large sample size needed to detect differences
2. Dismantling design: a priori knowledge on active ingredients necessary, large N
3. Equivalence trials: internal validity is threatened, because the groups are essentially the same so what do you actually conclude when they get different results?

Question 10

What are composite outcome measurements and what is its main drawback?

Answer 10

Composite outcomes are a number of different measures/events in one outcome measures. This leads to higher power, but is less clinically useful. If you find an effect, you still don’t know for which events this effect is true.

Question 11

Why do we need to define entry criteria in our studies?

Answer 11

To maximize power and generalizability AND to determine the sample size (good estimates of ES of the prevalence of the primary outcome in the population.

Question 12

What are mechanisms of change in RCT’s?

Answer 12

1. Predictors
2. Mediators: variables that show how and why treatment is effective; shows the pathways through which there is a causal relationship.
3. Moderators: variables that strengthen or weaken relationships between the predictors and outcome measures.

Question 13

What are important points to monitor during clinical trials?

Answer 13

1. Harm
2. Futility; stopping the trial when there is a very low chance of answering your main research question
3. Stopping when clear benefit has been proved; you already have your answer.

Question 14

Which concepts are used in the data that is considered? and which one is preferred?

Answer 14

1. Intention-to-treat: include every participant that is assigned to the groups. Gives smaller but more realistic effects. In real life also not all people will adhere to protocol.
2. Per protocol: only include participants that adhered to protocol > gives higher effects because you exclude participants that did not (entirely) follow the instructions, thereby causing bias/overestimation of effectiveness.

–> preferably include both in the analysis

Question 15

Which control groups can you use best when you don’t know much about the efficacy of a treatment?

Answer 15

You can then best use a waitlist control group and after that an active control group, to first maximize group differences (thereby increasing power with only small samples). So, when you have done this and see if a treatment works at all:

1. compare the treatment to usual care; is it better?
2. why does it work/in which doses? Get more specific information in the active ingredients with a dismantling design.

Question 16

Which nonrandomized designs can we use?

Answer 16

1. Between-group designs: very susceptible for confounders
2. Within group designs: participants act as their own control group; low chance on confounders > “time-series design” or “n-of-one trials” (individual patient can alternate between active/inactive versions of a drug to detect his/her specific respons to a drug.
3. Crossover designs: both the HC and treatment group receive both conditions (with a washout in between) > nice in small samples, increases power + minimizes confounding)
4. Factorial design: multiple treatments are tested in one trial > very efficient, two trials for the price of one.
5. Adaptive designs: monitor results from the trial as it progresses and change the design of the trial based on interim analysis of results

Question 17

What are the disadvantages of a within-group design?

Answer 17

1. Learning effects

2. Regression to the mean

Question 18

What are the disadvantages of a cross-over design?

Answer 18

Carry-over effects from treatment 1 to treatment 2 (or vice versa)

Question 19

Why is it important to take the time of measurement in consideration?

Answer 19

Results obtained at post-treatment or at follow-up can differ very much; when you only measure at follow-up; what did participants do in the time between treatment and follow-up? And if you only use post-treatment data; what are the long-term effects?

Question 20

In which measures can intention-to-treat and per-protocol best be used?

Answer 20

1. Intention-to-treat can best be used in assessing efficacy, because it preserves the randomnisation of participants, thereby decreasing bias/overestimation of effect.
2. Per protocol can best be used in assessing possible harm of an intervention; only people that completed the treatment can reliably say something about this.

Question 21

What is the blinded- and unblinded version of the cross-over design?

Answer 21

Blinded: both HC as active group get treatment and the control condition, working as their own control group.
Unblinded: waitlist control group and immediate intervention in both groups

Question 22

How can you improve follow-up procedures/adherence to protocol? Name 6 points.

Answer 22

1. Choose participants who likely adhere to protocol.
2. Make the intervention simple.
3. Make study visits convenient and enjoyable.
4. Make study measurements painless, useful and interesting.
5. Encourage participants to continue in the trial.
6. Find participants who are lost to follow-up.

Question 23

What is the best sequence of control groups when you study a treatment whose efficacy is unknown?

Answer 23

First work with a no treatment waitlist control group to maximize group differences, following that, use an active placebo control group > with these, you assess if a treatment works at all.

When you found an effect, you want to know:
> If the new treatment is better than usual care
> Why it works/in which doses it works: dismantling/in which doses it works

Question 24

Which statistical technique is mostly used in comparing 2 groups in RCT’s?

Answer 24

ANOVA; mostly focus on the interaction effects.

Question 25

What are the 4 reasons why there is a lack of evidence based rehabilitation techniques in CNP?

Answer 25

1. Widely varying target outcomes that are difficult to quantify.
2. Added ingredients/team interactions in treatment that are difficult to take into account
3. Most treatments are experienced-based; complex to measure
4. Active ingredients are difficult to isolate/test them

Question 26

What is adjudication?

Answer 26

Adjudication is finding evidence on that a certain outcome/effect is there/true

Question 27

When is it ethically defensible to use a placebo-control group?

Answer 27

When no effective treatment exists for a given disorder.

Question 28

Which control group is the best one for assessing adverse effects of a treatment?

Answer 28

The placebo-analogue control condition.

Question 29

Which forms of the placebo-analogue conditions exist?

Answer 29

1. Sham treatment, Spurious treatment or Pseudo treatment; plausible treatment that is theoretically irrelevant to the target problem
2. Attentional control; control group receives no intervention but does receive attention from the study personnel > giving too much attention can reduce the power of the study bc you reduce group differences.