GAL‐USA‐5 Gaudig.

Study characteristics
Methods	Randomised, double‐blind, placebo‐controlled, 6‐week, parallel arm withdrawal study involving patients who had completed a preceding randomised multicentre clinical trial GAL‐INT‐2
Participants	Setting: USA; 15 sites, conducted between December 1997 and May 1998 Sample size: 118 participants (49 male, 69 female) Age: 75.1 ± 1.01 years Inclusion criteria: Outpatient with a diagnosis of mild to moderate probable AD according to NINDS‐ADRDA (for inclusion in GAL‐INT‐2, participants were required to have an MMSE of between 11 and 24 and a score of ≥2 on the standard cognitive subscale of the ADAS‐Cog) Completion of GAL‐INT‐2 study (3 months of double‐blind medication) Remaining in good health, as determined by medical history, complete physical examination, laboratory tests and echocardiogram Reliable caregiver Informed consent Exclusion criteria: Premature discontinuation from GAL‐INT‐2 Any of the following co‐existing medical conditions: epilepsy or convulsions, peptic ulcer, or clinically significant or unstable hepatic, renal, pulmonary, metabolic or endocrine disturbances Current clinically significant cardiovascular disease Receipt of any drug currently being tested as an antidementia treatment
Interventions	Patients taking placebo in GAL‐INT‐2 were assigned to placebo. This group is not relevant to the review (N = 47 patients) Patients taking galantamine 24 mg/day or 32 mg/day in GAL‐INT‐2 were randomised into a withdrawal group, in which galantamine was discontinued and patients received placebo for 6 weeks (N = 39), or a continuation group, in which galantamine was continued at the same dosage as in GAL‐INT‐2 (24 mg/day or 32 mg/day, in 2 divided doses) (N = 32, 16 at each dose). These two groups are relevant to this review.
Outcomes	1. Cognitive function ADAS‐Cog/11 ADAS‐Cog/13 ADAS‐Cog/10 ADAS‐Cog/mem 2. Safety and tolerability Adverse event monitoring Physical examinations Laboratory testing (haematology, biochemistry and urinalysis) ECG evaluations Efficacy outcomes (cognitive function) were measured at the initial visit and at week 6.
Source of funding	Janssen‐Cilag EMEA, a division of Janssen Pharmaceutica NV
Declaration of interest	Withdrawal study was sponsored by Janssen‐Cilag EMEA, a division of Janssen Pharmaceutica NV. Post hoc analyses were funded by Janssen Pharmaceutica NV. Assistance with writing the manuscript (Gaudig 2011) was provided by Bioscript Stirling Ltd, UK, and funded by Janssen EMEA Medical Affairs, Beerse, Belgium.
Notes	ADAS‐Cog/11: The Alzheimer's Disease Assessment Scale–Cognitive Subscale ADAS‐Cog/13: The Alzheimer's Disease Assessment Scale–Cognitive Subscale plus Concentration and Distractability and Delayed Word Recall items ADAS‐Cog/10: The non‐memory Alzheimer's Disease Assessment Scale–Cognitive Subscale ADAS‐Cog/mem: The memory Alzheimer's Disease Assessment Scale–Cognitive Subscale ECG: Electrocardiogram MMSE: Mini‐Mental State Examination NINCDS‐ADRDA: National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Patients entering GAL‐INT‐2 were randomised to receive galantamine or placebo in a 2:1 ratio using a computer generated code. Of the 111 patients who went on to complete GAL‐USA‐5, 70 patients were included in the withdrawal study: 31 were assigned to continue galantamine 24 mg/day or 32 mg/day, and 39 patients were switched from galantamine to placebo, representing a 1:1 ratio for galantamine:placebo. The Clinical Research Report indicated that 28 patients were randomised out of sequence.
Allocation concealment (selection bias)	Low risk	Assignments were kept in sealed, opaque envelopes until the point of allocation.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The medication was formulated in tablets that were identical in appearance, taste, and smell, and which contained either no active ingredient, or 12 mg or 16 mg of galantamine. For each patient, the investigator was provided with a blinded code containing details of the treatment in the withdrawal phase. This code could only be broken in case of an emergency where further treatment of the patient depended on knowledge of the trial medication he or she had been receiving.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	It was not clear who the assessors were, or whether they were blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	"Patients with missing data for Week 6 were not included in the analysis...3 in the GAL/PLA group, and 1 in the GAL/GAL group, did not have any ADAS data collected at the initial visit...1 in the GAL/PLA group, and 2 in the GAL/GAL group did not have ADAS data collected at week 6." Of the 71 patients randomised (GAL/PLA N = 39, GAL/GAL N = 32), 4 did not have outcome data at the initial visit, and another 3 did not have outcome data at week 6. Therefore, data for the primary outcome (ADAS‐Cog/11) were available for 90% (64/71) of randomised participants (completers).
Selective reporting (reporting bias)	Unclear risk	Efficacy results were presented for comparisons with the baseline of the parent trial GAL‐INT‐2 rather than the start of the withdrawal study. In the post hoc analyses undertaken, changes in ADAS‐Cog/11 score were evaluated over time, from the baseline of the 3‐month parent trial to the end of the 6‐week withdrawal study. Analyses were in accordance with prespecified plans in the Statistical Analysis section of the publication. However, information in the published paper differs from that in the clinical study report. In the clinical study report, it is stated that both Traditional Division of Neuropharmacological Drug Product with Last Observation Carried Forward (Traditional DNDP‐LOCF) and Observed Case (OC) analyses were performed, but in the published paper, it is stated that only OC analyses were performed, and DNDP‐LOCF analyses were not reported.
Other bias	Unclear risk	The post hoc analyses were funded by Janssen Pharmaceutica NV, the drug company which manufactures Reminyl® galantamine. Assistance with the writing of the manuscript was provided by a medical‐writing company and funded by Janssen EMEA Medical Affairs, Beerse, Belgium.