Gaudig 2011

·       One non-randomized controlled study progressing from a randomized controlled phase III study

Number of groups: Four groups

Parent study: Five-month randomized controlled study (allocated to groups based on the parent study)

·       Placebo in parent study -> Placebo in current deprescribing study

·       Galantamine 8mg/day in parent study -> Galantamine 8mg/day in current deprescribing study

·       Galantamine 16mg/day in parent study -> Galantamine 16mg/day in current deprescribing study

·       Galantamine 24mg/day in parent study -> Placebo in current deprescribing study

723 participants enrolled, 687 completed

o   Active deprescribing group galantamine 24mg*: 198 enrolled, 189 completed

o   Continued galantamine 8mg group: 104 enrolled, 99 completed

o   Continued galantamine 16mg group*: 202 enrolled, 193 completed

o   Continued placebo group: 219 enrolled, 206 completed

Age: 77.9 years ± 0.48

·

Sex: 462 female, 261 male

·

Participants with dementia: All

·       Mild to moderate Alzheimer’s Disease

§  mean MMSE: 17.9 ± 0.26

§  mean Alzheimer’s Disease Assessment Scale (11-item cognitive sub-scale) score: 28.6 ± 0.75

Inclusion criteria:

·       Diagnosis of probable Alzheimer’s Disease according to the National Institute of Neurological and Communicative Disorders and Stroke, and the Alzheimer’s Disease and Related Disorders Association criteria

·       Remained in good health during the previous clinical trial (‘parent’ trial)

·       Have a responsible caregiver

·       Mild to moderate Alzheimer’s Disease who had completed a previous 5-month trial randomized clinical trial investigating the efficacy and safety of galantamine (‘parent’ trial: GAL-USA-10)

OR

·       US-based patients with mild to moderate Alzheimer’s Disease who had completed a previous 3-month trial randomized clinical trial investigating the efficacy and safety of galantamine (‘parent’ trial: GAL-INT-2)

·       Completed one of two Phase 3 randomized, placebo-controlled, 3- or 5-month clinical trials

Exclusion criteria:

·       Withdrawal from parent trial

·       Development of symptoms of other conditions that might contribute to dementia or cognitive impairment resulting from brain injury

Country: United States of America

Setting: Community

Withdrawal Schedule: Not described

Comparator:

·       Participants who continued from the parent study on the same treatment for the current deprescribing study (placebo, galantamine 8mg, 16mg, 24mg, or 32mg)

·       Participants who continued from the parent study from the galantamine 24mg or 32mg group to placebo in the current deprescribing study.

Safety and tolerability assessments included adverse event monitoring

Physical examinations and laboratory testing

Follow-up duration: 4.5 to 6.5 months total: three to five months parent study and six weeks withdrawal study

“Assistance with writing this manuscript was provided by Andy Lockley of Bioscript Stirling Ltd, UK, and funded by Janssen EMEA Medical Affairs, Beerse, Belgium.”

*Where there are more than two groups, Cochrane Handbook recommends selecting only two groups to include in the analysis.⁵⁵ The groups marked with an asterisks indicate the groups included in the systematic review for analysis.

The groups were inherited from the parent study, and this introduced a risk of bias, particularly in the first study as it was only those participants on the highest dose (24mg) that were assigned to placebo for 6 weeks.

Study One: Discontinued group were those who had been on the highest dose of galantine (24mg) whereas continued doses were 8mg and 16mg. Unclear why only the highest dose stopped.

” On entering Study One, patients were assigned treatment according to the group into which they had previously been randomized. Patients in the placebo, and galantamine 8 or 16 mg/day, groups continued to receive the same treatment (PLA/PLA, GAL8/GAL8 or GAL16/GAL16, respectively). Those who had originally been randomized to galantamine 24 mg/day were assigned to placebo for 6 weeks (GAL24/PLA).”

Additional information from original study: TariotPN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C. A 5-month, randomizedplacebo-controlled trial of galantamine in Alzheimer’s Disease. The Galantamine USA-10 Study Group. Neurology 54: 2269-76 (2000).

“patients were randomized to one of four treatment arms for 5 months, using a computer-generated code (weeks 1 to 21): placebo for 5 months; galantamine 8 mg/day for 5 months; galantamine 8 mg/day for 4 weeks followed by galantamine 16 mg/day for 17 weeks; galantamine 8 mg/day for 4 weeks, then galantamine 16 mg/day for 4 weeks, and then a maintenance dose of galantamine 24 mg/day from weeks 9 to 21.”

Not described in current deprescribing paper.

From Study One: Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C. A 5-month, randomized, placebo-controlled trial of galantamine in Alzheimer’s Disease. The Galantamine USA-10 Study Group. Neurology 54: 2269-76 (2000).
Not described.

Paper states that it is blinded, but no method is described.

From Study One: Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C. A 5-month, randomized, placebo-controlled trial of galantamine in Alzheimer’s Disease. The Galantamine USA-10 Study Group. Neurology 54: 2269-76 (2000).
“Galantamine and placebo were administered as identical single tablets taken orally twice-daily.”

Two deaths occurred within 30 days of the end of Study One—one due to chronic airway obstruction and respiratory insufficiency (in the PLA/PLA group), the other due to advanced Alzheimer’s Disease (in the GAL8/GAL8 group). Neither of these deaths was considered related to the study treatment.

Not clear how many drop-outs. Four discontinuations from adverse drug withdrawal event – no deaths.

Does not report outcomes for all the groups (e.g. no outcomes given for galantamine 8mg continued group).

Interchangeably report the intention-to-treat and observed analysis.

Their statistical analysis is entirely based on change, not absolute numbers and has issues: e.g.
– first study includes intention-to-treat analysis and observed analysis. For this study, they swap between the two without reference, so their figures are inconsistent (i.e. 0.6 = 0.8)

Only reports on the outcomes of ceasing the highest doses of galantamine (24mg and 32mg) without testing for the outcomes of ceasing the lower doses of galantamine 16mg and galantamine 8mg.

·       One randomized controlled study progressing from a randomized controlled phase III study

Number of groups: Three groups

Three-month randomized controlled study (the active galantamine group was re-randomized for the deprescribing study)

·       Placebo in parent study -> Placebo in current deprescribing study

·       Galantamine 24mg or 32mg/day in parent study -> Randomized to placebo or galantamine in current deprescribing study

o   Active deprescribing group*: 39 participants randomized, 39 completed

o   Control deprescribing group*: 32 participants randomized, 31 completed

o   Continued placebo group: 47 enrolled, 41 completed

Age: 76.5 years ± 1.26

Sex: 69 female, 49 male

Participants with dementia: All

·       Mild to moderate Alzheimer’s Disease

§  mean MMSE: 20.0 ± 0.51

§  mean Alzheimer’s Disease Assessment Scale (11-item cognitive sub-scale) score:24.9± 1.45

Inclusion criteria:

·       Diagnosis of probable Alzheimer’s Disease according to the National Institute of Neurological and Communicative Disorders and Stroke, and the Alzheimer’s Disease and Related Disorders Association criteria

·       Remained in good health during the previous clinical trial (‘parent’ trial)

·       Have a responsible caregiver

·       Mild to moderate Alzheimer’s Disease who had completed a previous 5-month trial randomized clinical trial investigating the efficacy and safety of galantamine (‘parent’ trial: GAL-USA-10)

OR

·       US-based patients with mild to moderate Alzheimer’s Disease who had completed a previous 3-month trial randomized clinical trial investigating the efficacy and safety of galantamine (‘parent’ trial: GAL-INT-2)

·       Completed one of two Phase 3 randomized, placebo-controlled, 3- or 5-month clinical trials

Exclusion criteria:

·       Withdrawal from parent trial

·       Development of symptoms of other conditions that might contribute to dementia or cognitive impairment resulting from brain injury

Country: United States of America

Setting: Community

Withdrawal Schedule: Not described

Comparator:

·       Participants who continued from the parent study on the same treatment for the current deprescribing study (placebo, galantamine 8mg, 16mg, 24mg, or 32mg)

·       Participants who continued from the parent study galantamine 24mg or 32mg group to placebo in the current deprescribing study.

Safety and tolerability assessments included adverse event monitoring

Physical examinations and laboratory testing.

Follow-up duration: 4.5 to 6.5 months total: three to five months parent study and six weeks withdrawal study

“Assistance with writing this manuscript was provided by Andy Lockley of Bioscript Stirling Ltd, UK, and funded by Janssen EMEA Medical Affairs, Beerse, Belgium.”

*Where there are more than two groups, Cochrane Handbook recommends selecting only two groups to include in the analysis.⁵⁵ The groups marked with * indicate the groups included in the systematic review for analysis.

The groups were inherited from the parent study, and this introduced a risk of bias, particularly in the first study as it was only those participants on the highest dose (24mg) that were assigned to placebo for 6 weeks.

“On entering Study Two, patients who had previously been assigned placebo continued to receive this. Those previously treated with galantamine were randomized into one of two groups: a withdrawal group, in which galantamine was discontinued,and patients received placebo for 6 weeks (GAL/PLA), or a continuation group, in which galantamine treatment was continued at the same dos- age as in the preceding trial (GAL/GAL).”

Additional information from original study: Rockwood K, Mintzer J, Truyen L, Wessel T, Wilkinson D. Effects of a flexible galantamine dose in Alzheimer’s disease: a randomized, controlled trial. J Neurol Neurosurg Psychiatry 71: 589-95 (2001).
“patients were randomized to receive galantamine or placebo in a 2:1 ratio using a computer-generated code.”

“The assignments were kept in sealed, opaque envelopes until the point of allocation. “

Paper states that it is blinded, but no method is described.

From Study Two: Rockwood K, Mintzer J, Truyen L, Wessel T, Wilkinson D. Effects of a flexible galantamine dose in Alzheimer’s disease: a randomized, controlled trial. J Neurol Neurosurg Psychiatry 71: 589-95 (2001).
References a placebo, but no description of what this may be.

There were no deaths associated with Study Two.

Not clear how many drop-outs. Four discontinuations from adverse drug withdrawal event – no deaths.

Does not report outcomes for all the groups (e.g. no outcomes given for galantamine 8mg continued group).

Interchangeably report the intention-to-treat and observed analysis.

Their statistical analysis is entirely based on change, not absolute numbers and has issues: e.g.
– first study includes intention-to-treat analysis and observed analysis. For this study, they swap between the two without reference, so their figures are inconsistent (i.e. 0.6 = 0.8)

Only reports on the outcomes of ceasing the highest doses of galantamine (24mg and 32mg) without testing for the outcomes of ceasing the lower doses of galantamine 16mg and galantamine 8mg.