Table 1.

Summary of hypothetical protocols (to be made supplemental).

Phase III Trial (Lower Risk)	Phase II Trial (Higher Risk)
Study purpose: Determine effectiveness of a new cholinomimetic Design: Randomized, double-blind, placebo-controlled trial; 2 study arms (placebo vs. investigational drug) Primary intervention: once daily oral administration of medication for 6 months, follow-up for another 6 months (total duration 1 year) Study procedures/assessments: medical and psychiatric interviews, repeated laboratory screens (blood draws), electrocardiogram, cognitive and functional capacity testing, and functional MRI Benefits: Preliminary evidence from previous trial of possible disease-slowing over short follow-up period. Increase knowledge of treatment of AD. Possibility of no personal benefit Risks: Most common side effects: fatigue, anorexia, insomnia, nausea, and diarrhea. The following were described as less common: vomiting and muscle cramps. In addition, the following were described as rare: bradycardia and peptic ulcers. Standard risks from MRI, blood draws, and cognitive testing are also described. As with any investigational intervention, there may also be unforeseeable risks State of knowledge: Several approved medications similar in mechanism of action; several previous, earlier-phase research studies with this agent showed it was generally safe and tolerable; preliminary evidence of efficacy; side effects generally not serious	Study purpose: Assess safety/tolerability/efficacy of anti-amyloid immunotherapy Design: Randomized, double-blind, placebo-controlled trial; 3 study arms (placebo vs. 2 possible doses of the investigational treatment) Primary intervention: 5 intramuscular injections (one every 3 months starting at baseline) of experimental agent over 1 year; follow-up for another year (total duration 2 years) Study procedures/assessments: Medical and neurological examinations, repeated laboratory screens (blood and urine samples), electrocardiogram, cognitive and functional capacity tests, and structural and functional neuroimaging (MRI & fMRI) Benefits: Currently unknown whether it has any beneficial effects. Increase knowledge about treatment of AD. Possibility of no personal benefit Risks: The most common side effects that have been observed included: pain or swelling at the injection site, fever, acute headache, dizziness, and muscle aches (described as usually mild and lasting less than two days). Other potential risks include: accelerated brain volume loss, allergic reactions, and changes in kidney function. In addition, the following are mentioned as unlikely but possible risks: death (described in a way that clarifies that, while considered very unlikely, the possibility cannot be ruled out); stroke, vision loss, seizure, bleeding in brain, meningoencephalitis (mentioned in context of the adverse events from previous immunotherapy AD research). The standard risks from MRI, injections, blood draws, and cognitive testing are also described. As with any investigational intervention, there may also be unforeseeable risks State of knowledge: Very little previous research on either benefits or risks (one study ongoing; nothing known yet about results; another immunotherapy study led to serious side effects)

Phase III Trial (Lower Risk)

Phase II Trial (Higher Risk)

Study purpose: Determine effectiveness of a new cholinomimetic
Design: Randomized, double-blind, placebo-controlled trial; 2 study arms (placebo vs. investigational drug)
Primary intervention: once daily oral administration of medication for 6 months, follow-up for another 6 months (total duration 1 year)
Study procedures/assessments: medical and psychiatric interviews, repeated laboratory screens (blood draws), electrocardiogram, cognitive and functional capacity testing, and functional MRI
Benefits: Preliminary evidence from previous trial of possible disease-slowing over short follow-up period. Increase knowledge of treatment of AD. Possibility of no personal benefit
Risks: Most common side effects: fatigue, anorexia, insomnia, nausea, and diarrhea. The following were described as less common: vomiting and muscle cramps. In addition, the following were described as rare: bradycardia and peptic ulcers. Standard risks from MRI, blood draws, and cognitive testing are also described. As with any investigational intervention, there may also be unforeseeable risks
State of knowledge: Several approved medications similar in mechanism of action; several previous, earlier-phase research studies with this agent showed it was generally safe and tolerable; preliminary evidence of efficacy; side effects generally not serious

Study purpose: Assess safety/tolerability/efficacy of anti-amyloid immunotherapy
Design: Randomized, double-blind, placebo-controlled trial; 3 study arms (placebo vs. 2 possible doses of the investigational treatment)
Primary intervention: 5 intramuscular injections (one every 3 months starting at baseline) of experimental agent over 1 year; follow-up for another year (total duration 2 years)
Study procedures/assessments: Medical and neurological examinations, repeated laboratory screens (blood and urine samples), electrocardiogram, cognitive and functional capacity tests, and structural and functional neuroimaging (MRI & fMRI)
Benefits: Currently unknown whether it has any beneficial effects. Increase knowledge about treatment of AD. Possibility of no personal benefit
Risks: The most common side effects that have been observed included: pain or swelling at the injection site, fever, acute headache, dizziness, and muscle aches (described as usually mild and lasting less than two days). Other potential risks include: accelerated brain volume loss, allergic reactions, and changes in kidney function. In addition, the following are mentioned as unlikely but possible risks: death (described in a way that clarifies that, while considered very unlikely, the possibility cannot be ruled out); stroke, vision loss, seizure, bleeding in brain, meningoencephalitis (mentioned in context of the adverse events from previous immunotherapy AD research). The standard risks from MRI, injections, blood draws, and cognitive testing are also described. As with any investigational intervention, there may also be unforeseeable risks
State of knowledge: Very little previous research on either benefits or risks (one study ongoing; nothing known yet about results; another immunotherapy study led to serious side effects)