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Pharmacological treatment for memory disorder in multiple sclerosis

  1. Dian He1,
  2. Yun Zhang2,
  3. Shuai Dong3,
  4. Dongfeng Wang3,
  5. Xiangdong Gao3,
  6. Hongyu Zhou4,*

Editorial Group: Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group

Published Online: 17 DEC 2013

Assessed as up-to-date: 25 JUL 2013

DOI: 10.1002/14651858.CD008876.pub3


How to Cite

He D, Zhang Y, Dong S, Wang D, Gao X, Zhou H. Pharmacological treatment for memory disorder in multiple sclerosis. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD008876. DOI: 10.1002/14651858.CD008876.pub3.

Author Information

  1. 1

    Affiliated Hospital of Guiyang Medical College, Department of Neurology, Guiyang, Guizhou Province, China

  2. 2

    Jinan No. 6 People's Hospital, Clinical Laboratory, Jinan, Shandong Province, China

  3. 3

    Jinan No. 6 People's Hospital, Department of Neurology, Jinan, Shandong Province, China

  4. 4

    West China Hospital, Sichuan University, Department of Neurology, Chengdu, Sichuan, China

*Hongyu Zhou, Department of Neurology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan, 610041, China. Hyzhou98@yahoo.com.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 17 DEC 2013

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Characteristics of included studies [ordered by study ID]
Krupp 2004

MethodsRandomised, double-blind, placebo-controlled clinical trial with parallel design in a single-centre.

The sample size and power were estimated.

35 patients were randomised to donepezil and 34 to placebo.

Donepezil group: 2 patients discontinued study drug due to AEs. 1 patient did not return at study end and was lost to follow-up.

Placebo group: 3 patients discontinued study drug due to AEs. 1 patient did not return at study end and was lost to follow-up.

34 patients in donepezil group and 33 patients in placebo group completed the 24-week follow-up visits.

35 patients in donepezil group and 34 in placebo group were analysed.

Treatment duration: 24 weeks.

Follow-up period: 24 weeks.

ITT analysis: yes.


ParticipantsInclusion criteria: (1) the diagnosis of definite MS according to Poser's diagnostic criterion; (2) aged 18-55 years; (3) had to exhibit stable neurological functioning for at least 30 days prior to study entry and agree to continue their current medications for the study duration; (4) display at least mild verbal memory impairment, operationally defined as a score at least 0.5 SD below age- and gender-based normative data on the RAVLT; (5) had an absence of severe cognitive impairment on the MMSE (≥ 26); (6) all participants were ambulatory and had EDSS scores of ≤ 6.5; (7) concurrent antidepressants, antispasticity agents and DMTs (interferon-β or glatiramer acetate) were permitted, so long as dosage had been constant for at least 1 month prior to the evaluation.

Exclusion criteria: (1) evidenced severe depressive symptoms on the MADRS (≥ 14); (2) currently taking benzodiazepines were excluded, as these medications may affect cognition; (3) current alcohol or substance abuse, history of head injury or other medical condition known to affect cognition.

260 individuals were initially screened, 81 of whom were confirmed eligible. Potential participants were most commonly excluded because they refused entry (n = 72: scheduling difficulties, transportation issues, or lack of interest) or scored too highly on the RAVLT learning and memory screen (n = 59). Very few of the participants screened were excluded due to severe cognitive impairment, as indicated by low MMSE scores (n = 4). 35 patients were randomised to donepezil and 34 to placebo.

Most of characteristics of patients at baseline were similar except for gender, mean EDSS and MS subtypes.

Summary of patient characteristics at baseline (placebo: G1 (n = 34), donepezil: G2 (n = 35)):

  • Mean age: G1 = 45.85 ± 7.65 years, G2 = 42.49 ± 9.27 years
  • Female: G1 = 27 (79%), G2 = 20 (57%)
  • Mean education: G1 = 14.82 ± 2.32 years, G2 = 14.40 ± 2.37 years
  • Full-time employed: G1 = 14 (41%), G2 = 19 (54%)
  • Mean EDSS: G1 = 4.25 ± 1.62, G2 = 3.14 ± 1.78
  • MS subtypes: RRMS: G1 = 14 (41%), G2 = 24 (69%); SPMS: G1 = 19 (56%), G2 = 9 (26%); PPMS: G1 = 1 (3%), G2 = 2 (6%)
  • Years since symptom onset: G1 = 10.32 ± 6.78, G2 = 9.89 ± 8.50
  • Years since diagnosis: G1 = 9.12 ± 6.89, G2 = 7.09 ± 6.89
  • Concomitant medications: interferon-β: G1 = 23 (68%), G2 = 28 (80%); antidepressant medication: G1 = 13 (38%), G2 = 15 (43%); bladder medication: G1 = 10 (29%), G2 = 6 (17%); antispasticity medication: G1 = 13 (38%), G2 = 8 (23%); anticonvulsant medication: G1 = 10 (29%), G2 = 7 (20%)
  • Mean MADRS: G1 = 6.15 ± 3.62, G2 = 6.51 ± 3.31
  • Mean PANAS positive affect: G1 = 28.43 ± 6.05, G2 = 28.12 ± 8.46
  • Mean PANAS negative affect: G1 = 14.35 ± 5.19, G2 = 13.81 ± 5.10
  • Mean FSS: G1 = 5.06 ± 1.18, G2 = 4.97 ± 1.49
  • Mean MMSE: G1 = 28.44 ± 1.26, G2 = 28.71 ± 1.13
  • Mean WRAT3 Reading: G1 = 48.47 ± 3.29, G2 = 47.26 ± 4.10
  • Mean baseline SRT: G1 = 42.74 ± 8.78, G2 = 42.3 ± 9.03.


InterventionsExperimental intervention: the initial dose of donepezil was 5 mg/day, increasing to 10 mg/day at week 4 (G2)

Control intervention: placebo (G1)


OutcomesPrimary outcome: change score in total recall on the SRT (week 24 to week 0).

Secondary outcomes: (1) the patient self reported impression of memory change and the physician global impression of cognitive change, with a single physician completing all clinical assessments; (2) self reported changes in affect (PANAS) and fatigue (FSS); (3) BRB in MS: the 10/36 SRT total correct, SDMT (oral version) total correct, PASAT total correct sum of the 2 and 3 second forms of the task, and modified version of COWAT (Category Fluency) using mean number of correct words in the categories of animals and fruits/vegetables; (4) mean TOH performance; (5) AEs.


NotesThe study was registered with Clinicaltrials.gov NCT00062972 and approved by Stony Brook University's Committee on Research Involving Human Subjects. Patients were recruited from September 1999 to May 2002, primarily from Suffolk County, NY.

The evaluating physician was the same as the treating physician.

Groups differed at baseline on gender, MS type and EDSS.

Consistent with the selection of people having difficulty on the RAVLT verbal learning/memory test, participants performed most poorly at baseline on the verbal learning/memory measures of the SRT, performing 1.3-2.0 SD below norms, generally consistent with the classification of mild cognitive impairment.

A higher percentage of donepezil patients correctly guessed their medication status, as compared with placebo patients (rate ratio 1.77, 95% CI 1.00 to 3.11; P value = 0.038).

Groups did not differ in relapse rate during the study (P value = 0.329).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "The randomization plan was generated by the study biostatistician using a computerized random number generator. Eligible patients were assigned to groups according to a simple randomization scheme using two blocking constraints. The randomization scheme was modified to a stratified permuted block design by sex randomization."

Comment: sequence generation was adequate.

Allocation concealment (selection bias)Low riskQuote: "The pharmacist was informed of all randomization assignments and was responsible for labelling the study drug and maintaining a master list linking the patients and their treatment assignments. The masking of the active and placebo treatments was preserved by creating treatments that looked identical."

Comment: allocation concealment was adequate.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "All clinical staff and patients were masked regarding treatment assignment. One individual acted as both the evaluating physician and treating physician."

Comment: participants and personnel in this study were blinded to the allocated interventions. However, the evaluating physician was the same person as the treating physician who might have learned about any adverse events that the participant might have experienced due to study medication. This may have resulted in the possibility of detection bias.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAccording to the Subject Flow Figure and the corresponding description, 61 patients were randomly assigned to donepezil and 59 to placebo. 9 patients in donepezil group and 6 in placebo group discontinued study medication, among them, 3 patients in donepezil group and 4 in placebo group lost to follow-up. Finally, 58 in donepezil group and 55 in placebo group completed their final visit and data collection.

Comment: the reasons for drop-out were not carefully recorded; however, the rate of drop-outs (14.8% and 10.2% in donepezil group and placebo group, respectively) and the amounts of missing data were low. The difference in proportions between groups was small. Moreover, a last-observation-carried forward imputation strategy was used for missing data and the ITT principle was used for analyses. The risk for attrition bias was low.

Selective reporting (reporting bias)Low riskAll listed outcomes were reported adequately.

Other biasUnclear riskQuote: "A higher percentage of donepezil subjects correctly guessed their medication status, as compared to placebo subjects (rate ratio, 1.77; 95% CI, 1.00 to 3.11; P=0.038)."

Comment: this may have led to biased results.

Quote: "Two treatment groups differed at baseline on sex, MS type and EDSS."

Comment: this may have led to biased results.

Krupp 2011

MethodsMulticentre, randomised, double-blind, placebo-controlled clinical trial with parallel design.

This study was powered on the basis of the findings for the primary outcome in Krupp 2004 (change in the SRT sum of recall) (sample sizes of 34 for placebo and 35 for donepezil). With actual sample sizes of 61 for donepezil and 59 for placebo, this study had a power of 79.1%.

61 patients were randomly assigned to donepezil and 59 to placebo.

Donepezil group: 9 (14.8%) patients discontinued study medication, among them, 3 patients lost to follow-up. 58 (95.1%) patients completed the study.

Placebo group: 6 (10.2%) patients discontinued study medication, among them, 4 patients lost to follow-up. 55 (93.2%) patients completed the study.

61 patients in donepezil group and 59 in placebo group were analysed.

Treatment duration: 24 weeks.

Follow-up period: 24 weeks.

ITT analysis: yes.

A last-observation-carried-forward imputation strategy was used for missing data.


ParticipantsInclusion criteria: (1) had a clinically definite MS diagnosis according to McDonald's diagnostic criterion (2001 version); (2) aged 18-59 years; (3) had EDSS score ≤ 7.0; (4) participants could not have received steroids within 4 weeks of screening; (5) all MS subtypes were eligible; (6) participants had to score 0.5 SD below age- and gender-corrected normative data on the RAVLT; (7) concurrent use of antidepressants, antispasticity agents and DMTs were permitted; (8) participants had to agree to maintain stable doses of all medications to the extent possible.

Exclusion criteria: (1) benzodiazepine use was a basis for exclusion as these medications can affect cognition; (2) prior use of donepezil; (3) a current diagnosis of major depression; (4) current alcohol or substance abuse; (5) history of any other neurological or medical condition that could adversely affect cognition.

247 people with MS were screened for the study and 120 were enrolled. The most common reasons for not meeting eligibility criteria were (1) RAVLT above cut-off (54%); (2) declined participation (13%); (3) exclusionary medical issue (11%); (4) depression (10%); (5) benzodiazepine use (6%); (6) other (6%). 59 patients were assigned placebo treatment and 61 were assigned donepezil treatment. Of the 120 enrolled participants, 113 completed their final visit and data collection.

Groups did not differ significantly on most demographic or baseline features. However, the donepezil group had more years of education (P value = 0.027), higher reading scores on the WRAT 3 (P value = 0.026), and a longer self reported disease duration as measured from symptom onset (P value = 0.039). Self report on the OFQ indicated that a total of 38% of those on placebo and 44% of those on donepezil were on disability. OFQ responses also indicated that cognitive challenges associated with MS contributed to disability in 76% of the placebo and 65% of the donepezil group. No baseline differences between the donepezil and placebo groups reached significance on any of the neuropsychological test measures or questionnaires.

Summary of patient characteristics at baseline (placebo: G1 (n = 59), donepezil: G2 (n = 61)):

  • Demographics: mean age: G1 = 47.3 ± 8.9 years, G2 = 46.2 ± 7.5 years; women: G1 = 48 (81%), G2 = 45 (74%); mean education: G1 = 13.2 ± 2.0 years, G2 = 14.0 ± 2.2 years
  • MS characteristics: mean EDSS score: G1 = 3.74 ± 1.98%, G2 = 3.96 ± 1.78%; RRMS: G1 = 37 (63%), G2 = 38 (62%); SPMS: G1 = 19 (32%), G2 = 18 (30%); PPMS (%): G1 = 3 (5%), G2 = 5 (8%); years since symptom onset: G1 = 11.8 ± 8.0, G2 = 14.9 ± 8.2; years since diagnosis: G1 = 9.4 ± 7.6, G2 = 11.3 ± 7.7
  • Concomitant medications: interferon-β: G1 = 24 (41%), G2 = 28 (46%); glatiramer acetate: G1 = 9 (15%), G2 = 18 (30%); anticholinergic medications: G1 = 10 (17%), G2 = 14 (23%); non-tricyclic antidepressants: G1 = 26 (44%), G2 = 23 (38%); anticonvulsant medication: G1 = 14 (24%), G2 = 12 (20%)
  • Mean reading score on WRAT 3: G1 = 45.0 ± 6.5, G2 = 47.1 ± 3.5
  • Mean patient total on MSNSQ (SD): G1 = 30.3 ± 10.5, G2 = 30.2 ± 10.8
  • Mean clinician total on MSNSQ (SD): G1 = 25.5 ± 10.3, G2 = 25.7 ± 9.9
  • Mean scores on SRT (SD): G1 = 36.0 ± 9.8, G2 = 38.0 ± 8.7
  • Median scores on SRT (range): G1 = 36.0 (16-60), G2 = 40.0 (19-57)
  • Mean scores on RAVLT (SD): G1 = 37.5 ± 7.3, G2 = 35.6 ± 6.7
  • Median scores on RAVLT (range): G1 = 39.0 (17-49), G2 = 36.0 (18-47)
  • Primary occupational role: paid worker: G1 = 21 (36%), G2 = 15 (25%); disabled: G1 = 26 (44%), G2 = 23 (38%); cognitive challenges contribute to disability: G1 = 20 (76% of disabled), G2 = 15 (65% of disabled)
  • Psychological characteristics: mean mood sum on CMDI: G1 = 17.0 ± 7.7, G2 = 17.5 ± 8.0; mean mood T score on CMDI: G1 = 54.2 ± 14.0, G2 = 55.2 ± 14.5; mean total on FSS: G1 = 4.9 ± 1.5, G2 = 5.3 ± 1.4; mean total on Apathy Evaluation Scale Self Report: G1 = 31.7 ± 7.7, G2 = 31.5 ± 8.6.


InterventionsExperimental intervention: the initial dose was donepezil 5 mg/day, increased to 10 mg/day at week 4 (G2).

Control intervention: placebo (G1)


OutcomesPrimary outcome: (1) change in total recall on the SRT; (2) self reported memory change.

Secondary outcomes: (1) the10/36 Spatial Recall Test; (2) the SDMT total; (3) the PASAT 2 and 3 form total; (4) the COWAT letter fluency total; (5) Judgment of Line Orientation; (6) D-KEFS Sorting Test; (7) participant's impression of overall cognitive (not just memory) change; (8) impressions of memory and cognitive functioning from the perspective of the participant's partner (when available) and the evaluating clinician; (9) the CMDI; (10) the OFQ.


NotesThe clinical trial was registered with clinicaltrials.gov (protocol ID:Teva186557-1).

The mean impairment of enrolled participants was 1.7 ± 0.9 SD below norms on the RAVLT, similar to a prior donepezil study in MS. 42.5% of enrolled participants performed below fifth percentile of published norms (≥ 1.65 SD below the mean).

Missing data and reasons were not carefully recorded.

30% of placebo recipients and 40% of donepezil recipients treated correctly guessed their group assignment.

RCT had a multicentre design and a larger sample size than the earlier positive trial, though it had the same eligibility criteria and primary outcome.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Using a random number generator, participants were assigned by the pharmacist at the Stony Brook University Hospital site to receive either donepezil or placebo in a 1:1 ratio, using a randomization scheme stratified by gender, MS type, and study site."

Comment: sequence generation was adequate.

Allocation concealment (selection bias)Low riskQuote: "The pharmacists at each site were the only individuals informed of the randomization assignments and were responsible for labelling study drug and maintaining a master list linking patients with treatment assignments."

Comment: allocation concealment was adequate.

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Masking of active and placebo treatments was preserved by creating capsules that appeared identical. All other research staff and participants were masked regarding treatment assignment. The treating neurologist assessed each patient during the study visits. A separate evaluating clinician performed a structured interview to assess cognition at baseline and at the end-of-study visit. Medication compliance and adverse events were monitored by telephone at weeks 8, 12, 16, and 20, and in-person visits with the treating neurologist at weeks 4 and 14. The evaluating clinician was allowed only to ask about cognitive functioning and was specifically masked to any adverse events that the participant might have experienced due to study medication."

Comment: participants, personnel and outcomes assessors in this study were blinded to the allocated interventions.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAccording to the Subject Flow Figure and the corresponding description, 61 patients were randomly assigned to donepezil and 59 to placebo. 9 patients in donepezil group and 6 in placebo group discontinued study medication, among them, 3 patients in donepezil group and 4 in placebo group lost to follow-up. Finally, 58 in donepezil group and 55 in placebo group completed their final visit and data collection.

Comment: the reasons for drop-out were not carefully recorded; however, the rate of drop-outs (14.8% and 10.2% in donepezil group and placebo group, respectively) and the amounts of missing data were low. The difference in proportions between groups was small. Moreover, a last-observation-carried forward imputation strategy was used for missing data and the ITT principle was used for analyses. The risk for attrition bias was low.

Selective reporting (reporting bias)Low riskAll listed outcomes were reported adequately.

Other biasUnclear riskQuote: "The donepezil group had more years of education (P= 0.027), higher reading scores on the Wide Range Achievement Test 3 (WRAT 3) (P= 0.026), and a longer self-reported disease duration as measured from symptom onset (P=0.039)."

Comment: this may have led to biased results.

Quote: "A total of 30% of placebo recipients and 40% of donepezil recipients treated correctly guessed their group assignment."

Comment: this may have led to biased results.

Lovera 2007

MethodsRandomised, double-blind, placebo-controlled trial with parallel design.

A formal sample size calculation or power analysis was not done.

21 patients were randomised to GB and 22 to placebo.

GB group: 1 person lost to follow-up for personal reasons.

Placebo group: 2 people lost to follow-up (1 due to pregnancy, 1 because of a traumatic injury and 1 because of a gastrointestinal illness).

20 people in the GB group and 19 in the placebo group completed the study. Available data for 20 people in the GB group (except for UFOV analysis, 1 patient was excluded because of unreliable observation) and 19 in the placebo group (except for Stroop analysis, 1 patient was excluded because they were colour blind) were analysed.

Treatment duration: 12 weeks.

Follow-up period: 17 weeks. (The data from the visit at week 5 served as the baseline. Treatment with GB or placebo was started after the week 5 visit.)

ITT analysis: no.


ParticipantsInclusion criteria: (1) diagnosis of MS by McDonald's criteria; (2) aged 18-60 years; (3) a score 0.5-2.5 SD below the mean on the PASAT or the CVLT-II total score.

Exclusion criteria: (1) history of alcoholism, drug abuse, psychosis, major depression or a score on the BDI-IA > 19; (2) people with severe cognitive impairment who required a permanent carer; (3) any significant medical problem, including insulin-dependent diabetes, uncontrolled hypertension, uncontrolled hypothyroidism, hepatic disease, renal disease, pulmonary disease, congestive heart failure, angina, valvular disease or abnormalities of coagulation; (4) a significant MS exacerbation within the 30 days before screening; (5) current use of anticoagulants; (6) pregnancy; (7) any visual problem that would interfere with testing, such as corrected binocular visual acuity worse than 20/50, nystagmus on primary gaze or impaired colour vision; (8) not speaking English as the native language; (9) any other condition that the investigator thought would make them unsuitable for the study.

68 people were screened and 43 met inclusion/exclusion criteria. Of the 25 who did not meet entry criteria, 19 scored too well on the PASAT and CVLT-II, 4 had BDI scores > 19 and 2 had medical illnesses that excluded them from the trial. Of the 43 who met the inclusion criteria, 21 were randomised to GB and 22 to placebo.

There were no significant differences on the demographic characteristics and the use of psychoactive or sedating medications between groups. There were no differences in performance on any of the tests of the neuropsychological test battery at baseline.

Summary of patient characteristics at baseline: (placebo: G1 (n = 19), GB: G2 (n = 20)):

  • Gender: male: G1 = 6 (32%), G2 = 6 (30%); female: G1 = 13 (68%), G2 = 14 (70%)
  • Race: white: G1 = 19 (100%), G2 = 18 (90%); other: G1 = 0 (0), G2 = 2 (10%)
  • Type of MS: RRMS: G1 = 11 (58%), G2 = 11 (55%); PPMS: G1 = 2 (10%), G2 = 0 (0); SPMS: G1 = 6 (32%), G2 = 9 (45%)
  • Education: high school: G1 = 2 (11%), G2 = 5 (25%); college: G1 = 12 (63%), G2 = 11 (55%); master's degree or higher: G1 = 5 (26%), G2 = 4 (20%)
  • Age: G1 = 50.2 ± 8.0 years, G2 = 47.8 ± 6.7 years
  • Years since MS onset: G1 = 15.6 ± 6.3, G2 = 15.1 ± 8.8
  • EDSS score: G1 = 3.5 ± 1.3, G2 = 3.8 ± 1.6
  • 9-HPT: G1 = 27.2 ± 10.2 s, G2 = 26.4 ± 11.2 s
  • 25 Foot Timed Walk: G1 = 5.8 ± 1.2 s, G2 = 6.8 ± 3.7 s
  • BDI-IA: G1 = 6.9 ± 5.4, G2 = 7.7 ± 5.1.


Number of people using different psychoactive or sedating medications in each group (n):

  • Selective serotonin re-uptake inhibitors: G1 = 6, G2 = 6
  • Tricyclic antidepressants: G1 = 3, G2 = 3
  • Benzodiazepines: G1 = 3, G2 = 3
  • Stimulants: G1 = 6, G2 = 6
  • Anticonvulsants: G1 = 3, G2 = 3
  • Narcotics: G1 = 1, G2 = 1
  • Baclofen: G1 = 4, G2 = 5
  • Anticholinergics: G1 = 4, G2 = 5.


InterventionsExperimental intervention: GB 120 mg twice a day (G2).

Control intervention: placebo (G1).


OutcomesPrimary outcomes: (1) free delayed recall score from the CVLT-II; (2) time for the colour-word interference condition from the Stroop; (3) threshold from an adapted version of the UFOV, (4) scores on the SDMT; (5) scores on the COWAT; (6) scores on the 3 second version of the PASAT.

Secondary outcomes: (1) the other subscores from the tests in the cognitive battery; (2) perceived cognitive deficits assessed by the PDQ; (3) quality of life assessed by the MSQLI); (4) safety (the frequency of side effects).


NotesThis is the first study that evaluated the effects of GB on cognitive performance. The Oregon Health and Science University (OHSU) Institutional Review Board approved the study protocol and informed consent. Recruitment started in July 2002 and ended in June 2004.

41% of people taking GB and 59% taking placebo guessed their treatment allocation correctly.

No information on DMTs was reported.

The GB (120 mg) and placebo capsules were provided by Thorne Research Inc. (Dover, ID, USA).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "The allocation sequence was generated using a random number generator. The sequence was stratified by age and had a block size of six."

Comment: sequence generation was adequate.

Allocation concealment (selection bias)Low riskQuote: "The staff at the OHSU Medical Informatics and Clinical Epidemiology Department generated the allocation sequence, and numbered sequentially the containers provided by the manufacturer accordingly."

Comment: allocation concealment was adequate.

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "The blinding was implemented by using identical containers, instructions and labels. The subjects, physicians and research assistants did not know the treatment allocation at any point until the data analysis was completed. The rest of the study personnel did not have access to the allocation sequence until the study was completed. A neuropsychologist trained the research assistants in the administration of the battery. A research assistant obtained side-effect reports by telephone at four and eight weeks after starting treatment and at exit. One of the study physicians evaluated the side-effect reports and graded them."

Comment: participants, personnel and outcomes assessors in this study were blinded to the allocated interventions.

Incomplete outcome data (attrition bias)
All outcomes
High riskAccording to the Subject Flow Figure and the corresponding description, 21 people were randomised to GB and 22 to placebo. 1 person in GB group lost to follow-up, and 3 people in placebo group lost to follow-up. 20 people in the GB group and 19 in the placebo group completed the study. Available data for 20 participants in the GB group (except for UFOV analysis, 1 patient was excluded because of unreliable observation) and 19 in the placebo group (except for Stroop analysis, 1 patient was excluded because they were colour blind) were analysed.

Comment: the rate of drop-outs (4.8% and 13.6% in the GB and placebo group, respectively) and the amounts of missing data were low, and the reasons for missing outcomes were carefully recorded and balanced between groups. However, the difference in proportions between groups was large; moreover, the ITT principle was not used for analyses. The risk for attrition bias was high.

Selective reporting (reporting bias)Unclear riskAll listed outcomes were reported, but some outcomes were lack of data.

Other biasUnclear riskQuote: "A total of 41% of subjects taking GB and 59% of the subjects taking placebo guessed their treatment allocation correctly."

Comment: this may have led to biased results.

No information was reported on DMTs, this may have led to biased results.

Lovera 2010

MethodsDouble-blind, randomised, placebo-controlled trial in 4 MS centres.

The sample size and power were estimated. With only 2 tests as the primary outcome measure, the subsequent univariate tests with Bonferonni correction had > 80% power.

58 patients were randomly allocated to memantine and 68 to placebo. 4 patients in memantine group did not receive allocated intervention due to (1) protocol violation and history of seizures; (2) decided not to participate; (3) time commitment; (4) not recorded. 3 patients in placebo group did not receive allocated intervention due to (1) not recorded; (2) decided not to participate; (3) did not attend for follow-up visits.

54 patients in memantine group and 65 in placebo group received allocated intervention.

Memantine group: 9 patients discontinued intervention due to (1) somnolence; (2) nausea, root canal treatment; (3) UTI, insomnia; (4) memory changes, insomnia, ataxia, dysarthria; (5) agitation, dizziness; (6) nausea, vomiting; (7) dizziness, MS relapse; (8) rash; (9) headache. 0 lost to follow-up.

Placebo group: 5 patients discontinued intervention due to (1) flatulence; (2) cold; (3) leg fracture; (4) UTI, increased memory problems; (5) unknown. 4 patients lost to follow-up due to (1) mood changes; (2) headaches; (3) headaches; (4) did not return calls.

54 patients were analysed in memantine group, and 60 patients were analysed in placebo group (1 patient had lost baseline PASAT data).

Treatment duration: 16 weeks.

Follow-up period: 16 weeks.

ITT analysis: no.


ParticipantsInclusion criteria: (1) MS as per McDonald's criteria determined by 1 of the study physicians after review of the patient's medical record and imaging (participants with all types of MS were eligible); (2) aged 18-65 years; (3) subjective cognitive complaints and a score on the PASAT or the CVLT-II (LDFR or total recall) worse than 1 SD below the mean from appropriate age- and education-adjusted norms.

Exclusion criteria: (1) history of major depression or psychosis, or a score > 19 on the BDI-IA; (2) corrected binocular visual acuity worse than 20/50 or impairment of binocular colour vision; (3) a primary language different from English; (4) pregnancy; (5) renal insufficiency; (6) seizures; (7) use of medical marijuana or abuse of alcohol or other illegal drugs in the prior 6 months; (8) use of medications that could interact with memantine; (9) an MS relapse in the prior 30 days.

206 people were initially screened, 75 did not meet inclusion criteria due to (1) BDI; (2) PASAT and CVLT; (3) impaired vision; (4) unable to read. 4 refused to participate. 1 was not recorded. 58 patients were randomly allocated to memantine and 68 to placebo.

After allocation, 4 in memantine group did not receive allocated intervention due to (1) protocol violation, history of seizures; (2) decided not to participate; (3) time commitment; (4) not recorded. 3 in placebo group did not receive allocated intervention due to (1) not recorded; (2) decided not to participate; (3) did not attend for follow-up visits.

54 patients received memantine treatment and 65 received placebo treatment.

Groups were well matched on demographic characteristics except for type of MS. There was an imbalance on the z-scores for the CVLT-II LDFR, but well matched on the raw test scores.

Summary of patient characteristics at baseline (placebo: G1 (n = 68), memantine: G2 (n = 58)):

  • Age: G1 = 50.4 ± 7.7 years, G2 = 50.5 ± 8.2 years
  • Female: G1 = 50 (77%), G2 = 45 (83%)
  • Education: G1 = 14.6 ± 2.2 years, G2 = 14.5 ± 2.1 years
  • EDSS: G1 = 4.4 ± 1.9, G2 = 4.5 ± 2.2
  • Disease duration: G1 = 13.3 ± 8.3 years, G2 = 14.0 ± 9.0 years
  • PASAT, # correct: G1 = 33.1 ± 13.1, G2 = 32.8 ± 13.7
  • PASAT, z-score: G1 = -1.7 ± 1.3, G2 = -1.8 ± 1.4
  • CVLT-II free delayed recall, # words: G1 = 8.1 ± 3.6, G2 = 7.2 ± 3.4
  • CVLT-II free delayed recall, z-score : G1 = -1.1 ± 1.2, G2 = -1.5 ± 1.3
  • Race: white: G1 = 61 (94%), G2 = 52 (98%); African-American: G1 = 2 (3%), G2 = 0 (0); other: G1 = 2 (3%), G2 = 2 (2%); Hispanic: G1 = 2 (3%), G2 = 1 (2%)
  • Type of MS: RRMS: G1 = 47 (72%), G2 = 28 (52%); PPMS: G1 = 6 (9%), G2 = 12 (22%); SPMS: G1 = 12 (18%), G2 = 14 (26%).


InterventionsExperimental intervention: memantine 10 mg twice a day (4-week titration followed by 12 weeks on the highest tolerated dose) (G2).

Control intervention: placebo (G1).


OutcomesPrimary outcome: the change from baseline to exit on (1) PASAT; (2) CVLT-II LDFR.

Secondary outcomes: (1) COWAT; (2) the Stroop Test (Victoria Version); (3) SDMT; (4) D-KEFS Sorting Test, self reports measures on (5) cognitive deficits using the PDQ; (6) quality of life using the SF-36; (7) fatigue using the MFIS and FSS; (8) depression using the BDI-IA; reports from the participant's closest family member or carer using (9) the MSNSQ and (10) the MNPI; (11) adverse events.


NotesPeople were recruited from 4 MS centres in the US (Oregon Health & Science University, Portland, OR; Evergreen Healthcare Medical Center, Kirkland, WA; University of Texas Southwestern Medical Center, Dallas, TX; and University of Southern California (USC), Los Angeles, CA). Recruitment started in August 2004 and ended in October 2007. The study was registered with Clinicaltrials.gov NCT00300716 and IRB's at each site approved the study.

No information on DMTs was reported.

There were no comparisons at baseline between groups for the scores on the BDI, FSS and MFIS.

Group sizes were slightly imbalanced, which can occur when using several strata and blocking in the allocation sequence. There was 1 protocol violation where 1 person was administered the alternate forms of the PASAT in the incorrect order but this participant's data were still used.

The initial protocol required 3 visits over 3 weeks prior to starting therapy.

The baseline data for the PASAT on 1 of the people in the placebo group were lost.

A violation occurred where 1 person with history of seizures was randomised but the study team found the mistake prior to starting him on the study drug.

Participants were wrong regarding their treatment assignment more frequently than expected by chance (61%; P value = 0.05 binomial test) because they were more likely to think they had received placebo.

Two MS exacerbations occurred during the study, 1 in each group. There was no significant difference between the groups on the change on the EDSS. The proportion of people experiencing progression defined as 1 point worsening for EDSS > 4.5 and 0.5 points for EDSS 4.5 was not significantly different between the groups.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "An independent biostatistician at OHSU (Cynthia Morris, PhD) used EXCEL's random number generator to create the assignment sequence with a block size of six; stratification by centre, age, and score on the CVLT-II LDFR; and equal probability of assignment to either arm."

Comment: sequence generation was adequate.

Allocation concealment (selection bias)Low riskQuote: "The independent statistician's staff would receive a fax with the subject's study ID, randomize the subject, and then send a fax to the pharmacy indicating the treatment allocation.

Comment: allocation concealment was adequate.

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Only the independent statistician's staff and the research pharmacists had access to the allocation sequence until the analysis was completed. Evaluating research assistants and physicians administered the cognitive and behavioural questionnaires and disability scales while treating physicians and research assistants evaluated adverse events and managed dose titration. The subjects and the evaluating team were instructed not to discuss any health related matters to maintain the evaluating team's blinding. The questionnaires administered at the end of the study indicate that blinding of the subjects, evaluating physicians and evaluating research assistants was successful."

Comment: participants, personnel and outcomes assessors in this study were blinded to the allocated interventions.

Incomplete outcome data (attrition bias)
All outcomes
High riskAccording to the CONSORT flow chart, 54 patients received memantine, and 65 patients received placebo. 9 patients in memantine group discontinued intervention and 5 patients in placebo group discontinued intervention. 0 patients in memantine group and 4 in placebo group lost to follow-up. 45 patients in memantine group and 56 in placebo group completed the study. 54 patients in memantine group were analysed, and 60 were analysed in placebo group because 1 person lost baseline PASAT data).

Comment: the rate of drop-outs (22.4% and 17.6% in the memantine and placebo group, respectively) and the amounts of missing data were high. Moreover, the reasons for drop-out were carefully recorded but differed between groups. The study authors excluded the patients who were lost to follow-up and did not use the ITT principle for analyses. The risk for attrition bias was high. Generally, the potential impact of missing continuous outcomes increases with the proportion of participants with missing data.

Selective reporting (reporting bias)Unclear riskAll listed outcomes were reported, but some outcomes lacked data.

Other biasUnclear riskQuote: "The groups were well matched on demographic characteristics except for type of MS. Although the groups were well matched on the raw test scores, there was an imbalance on the z-scores for the CVLT-II LDFR."

Comment: this may have led to biased results.

Quote: "Subjects were wrong regarding their treatment assignment more frequently than expected by chance (61%; P=0.05 binomial test) because they were more likely to think they had received placebo."

Comment: this may have led to biased results.

Lovera 2012

MethodsRandomised, double-blind, placebo-controlled clinical trial with parallel design.

The sample size and power were estimated. The researchers estimated needing 110 people with complete observations to have 80% to detect a difference as low as 0.5 on the z-scores on any of the tests at both the multivariate level and the univariate levels at an α level of 0.05 (2-sided). However, the researchers stopped enrolment after 121 participants had been enrolled because the dropout rate was less than 5% and more than 110 participants had completed the study.

61 patients were randomly allocated to GB and 60 to placebo. 1 patient in placebo group did not receive allocated intervention because of a randomisation error, the patient did not meet inclusion criteria as he refused to complete the PASAT.

61 patients in GB group and 59 in placebo group received allocated intervention.

GB group: 3 patients lost to follow-up (1 did not return telephone calls, 2 discontinued intervention due to AE (myocardial infarction and psychiatric hospitalisation) and did not complete exit visit). 1 discontinued intervention due to AE (nausea and heartburn) but completed exit visit.

Placebo group: 1 patient lost to follow-up (developed pruritus and discontinued intervention and did not complete exit visit).

61 patients were analysed in GB group, and 59 of patients were analysed in placebo group because 1 person lost baseline PASAT data.

Treatment duration: 12 weeks.

Follow-up period: 12 weeks.

Modified ITT analysis: yes.


ParticipantsInclusion criteria: people (1) with MS by McDonald's criteria (2001 version); (2) had EDSS score 0-7.5; (3) were stable for at least 30 days; (4) scored ≥ 1 SD below the mean of established normative samples on ≥ 1 of the 4 tests in the neuropsychological test battery (Stroop (Victoria Version); COWAT; long-delay free-recall portion of the CVLT-II; and the 2 second version of the PASAT); (5) did not have contraindications for GB; (6) did not have problems that would interfere with testing.

173 individuals with MS were screened for the study and 121 were enrolled. The reasons for not meeting eligibility criteria were (1) cognitive scores too high (1 on second screening here) (n = 35); (2) BDI-Ⅱ scores too high (n = 7); (3) failed colour vision (n = 4); (4) had medications that were contraindicated (n = 2); (5) other (n = 3); (6) decided not to participate after qualifying (n = 1). Of the 121 enrolled participants, 61 patients were randomly allocated to GB and 60 to placebo.

Groups did not differ significantly on most demographic or baseline features except for gender.

Summary of patient characteristics at baseline (placebo: G1 (n = 59), GB: G2 (n = 61)):

  • Age: mean (SD) G1 = 53 ± 9.5 years, G2 = 51.3 ± 8.6 years; median (range) G1 = 56 (24-65) years, G2 = 53 (27-65) years
  • Female: G1 = 37 (63%), G2 = 29 (48%)
  • Education: did not complete high school: G1 = 1 (2), G2 = 0 (0); high school diploma or General Educational Development: G1 = 2 (3%), G2 = 4 (7%); some college: G1 = 26 (44%), G2 = 33(54%); college graduate: G1 = 17 (29%), G2 = 10 (16%); some graduate school: G1 = 3 (5%), G2 = 5 (8%); master's degree or higher: G1 = 10 (17%), G2 = 9 (15%)
  • Race: white: G1 = 59 (100%), G2 = 55 (90%); non-white: G1 = 0(0), G2 = 6 (10%)
  • Ethnicity: Hispanic or Latino: G1 = 2 (3%), G2 = 2 (3%)
  • EDSS score: mean (SD) G1 = 4 ± 2, G2 = 4 ± 2; median (range) G1 = 4 (1-7.5), G2 = 4 (0-7.5)
  • Disease duration: mean (SD) G1 = 19.3 ± 11.8 years, G2 = 20.9 ± 11.8 years; median (range) G1 = 18 (1-45) years, G2 = 20 (4-47) years
  • Type of MS: PPMS G1 = 4 (7%), G2 = 5 (8%); PRMS G1 = 1 (2%), G2 = 0 (0); RRMS G1 = 35 (59%), G2 = 42 (69%); SPMS G1 = 19 (32%), G2 = 14 (23%)
  • Centre: Seattle: G1 = 27 (46%), G2 = 29 (48%); Portland: G1 = 32 (54%), G2 = 32 (52%)
  • DMT: glatiramer acetate: G1 = 13 (22%), G2 = 20 (33%); no DMT: G1 = 16 (27%), G2 = 17 (28%); interferon β-1a 30 μg once a week: G1 = 9 (15%), G2 = 10 (16%); interferon β-1a 44 μg 3 times a week: G1 = 10 (17%), G2 = 5 (8%); natalizumab: G1 = 4 (7%), G2 = 3 (5%); interferon β-1b 0.25 mg every other day: G1 = 3 (5%), G2 = 2 (3%); mitoxantrone G1 = 1 (2%), G2 = 1 (2%); azathioprine G1 = 0 (0%), G2 = 1 (2%); interferon β-1a 30 μg/week changed to glatiramer acetate: G1 = 0 (0%), G2 = 1 (2%); mycophenolate: G1 = 1 (2%), G2 = 0 (0%); interferon β-1a 44 μg and methotrexate: G1 = 1 (2%), G2 = 0 (0%); interferon β-1a 44 μg and glatiramer acetate: G1 = 0 (0%), G2 = 1 (2%); interferon β-1a 44 μg and glatiramer acetate: G1 = 1 (2%), G2 = 0 (0%).


InterventionsExperimental intervention: GB 120 mg twice a day (G2).

Control intervention: placebo (G1).


OutcomesPrimary outcomes: z-scores based on healthy, age-matched control norms for (1) the time on Color-Word portion of the Stroop Test (Victoria Version); (2) COWAT; (3) LDFR portion of the CVLT-II; (4) the 2 second version of the PASAT.

Secondary outcomes: (1) perceived cognitive deficits assessed by the PDQ; (2) the MSNSQ; (3) CIQ; (4) fatigue assessed by the MFIS; (5) depression assessed by the BDI-II; (6) safety; (7) relapses.


NotesThe study was registered with clinicaltrials.gov (NCT00841321) and performed at 2 sites, the Portland and Seattle VA Medical Centers. The full protocol of the study can be accessed at www.ohsu.edu/ms/ginkgoprotocol (last accessed 10 December 2013).

GB: EGb-761, Willmar Schwabe GmbH & Co, Germany. The GB tablets contained 29.7 mg of flavoglycosides and 7.3 mg of terpene lactones.

The sample had mild impairment overall and mainly were impaired on the PASAT and mostly below average on the CVLT-II.

No comparisons at baseline between groups for the scores on the MFIS and the BDI-II.

Pill counts indicated that 88% of participants took 80% or more of their treatment.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "The Portland VA research pharmacist generated the allocation sequence in Excel with alternating random blocks of 4 or 6 subjects stratified by disease duration and study site and a 1:1 ratio."

Comment: sequence generation was adequate.

Allocation concealment (selection bias)Low riskQuote: "The Portland VA research pharmacist generated the allocation sequence in Excel with alternating random blocks of 4 or 6 subjects stratified by disease duration and study site and a 1:1 ratio. Only the research pharmacists had access to the allocation sequence."

Comment: allocation concealment was adequate.

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "The research pharmacists assigned the participants to either ginkgo or matching placebo tablets and dispensed the tablets to them in matching identical containers. One research assistant assessed adverse events and another administered the neuropsychological tests. They were instructed not to discuss adverse events between them to ensure that the cognitive test assessments would be masked."

Comment: participants, personnel and outcomes assessors in this study were blinded to the allocated interventions.

Incomplete outcome data (attrition bias)
All outcomes
Low riskAccording to the CONSORT flow chart, 61 patients were randomly allocated to GB and 60 to placebo. 1 patient in placebo group did not receive allocated intervention because he refused to complete the PASAT. 3 patients in GB group and 1 in placebo group were lost to follow-up. 1 in GB group discontinued intervention due to AE. 61 patients were analysed in GB group, and 59 patients were analysed in placebo group because 1 patient lost baseline PASAT data.

Comment: the reasons for drop-out differed between groups; however, the rate of drop-outs (6.6% and 3.3% in GB group and placebo group, respectively) and the amounts of missing data were low, the difference in proportions between groups was small. Moreover, the modified ITT principle was used for analyses. The attrition bias was low.

Selective reporting (reporting bias)Low riskAll listed outcomes were reported adequately.

Other biasUnclear riskQuote: "The patients were enrolled based on scoring 1 SD or more below the mean of established normative samples on one or more of the 4 tests in the neuropsychological test battery (the Stroop Color-Word Test; the COWAT; the CVLT-II; and the PASAT).The sample had mild impairment overall and mainly were impaired on the PASAT and mostly below average on the CVLT-II."

Comment: COWAT is used to measure language, therefore, selection of targeted sample is not specific for memory impairment.

Quote: "The randomization balanced the groups well except for gender."

Comment: this may have led to biased results.

Mäurer 2013

MethodsRandomised, placebo-controlled, multicentre trial used a double-blind, parallel groups design.

The sample size and power were estimated. Assuming a similar improvement in the placebo arm but a mean change of 4.59 with an SD of 8.7 in the active treatment group, a sample size of 90 in each group would have had 80% power to detect a difference in means of 3.02, using a 2-group Satterthwaite t test with a 0.05 2-sided significance level. Assuming a 10% drop-out, 100 patients needed to be randomised to each treatment arm. However, the study was prematurely terminated after the recruitment of 86 patients because of slow recruitment, with this recruitment the actual power of the study is 49%.

45 patients were randomised to rivastigmine and 41 to placebo. 18 of 86 patients enrolled (20.9%) prematurely discontinued the study:

Rivastigmine group: 11 (24.4%) patients prematurely discontinued the study due to AEs (n = 8), condition no longer required study drug (n = 1), withdrew consent (n = 1), lost to follow-up (n = 0), administrative problems (n = 1). 34 patients completed the double-blind study phase at week 16.

Placebo group: 7 (17.1%) patients prematurely discontinued the study due to adverse (n = 3), condition no longer required study drug (n = 0), withdrew consent (n = 2), lost to follow-up (n = 1), administrative problems (n = 1). 34 patients completed the double-blind study phase at week 16.

43 patients in rivastigmine group and 38 in placebo group were analysed.

Treatment duration: 68 weeks (including 4-week titration period and 12-week maintenance period (double-blind study phase), and 12-month open-label treatment phase).

Follow-up period: 68 weeks.

Modified ITT analysis: yes.


ParticipantsInclusion criteria: individuals (1) had diagnosis of MS (subtypes RRMS, SPMS or clinically isolated syndrome, but not stratified a priori) as defined by the 2005 revised McDonald criteria; (2) aged 18-65 years; (3) had cognitive impairment as defined by a FST score ≥ 3.0, a MUSIC score of ≤ 19 at screening, or both (4) participants were eligible if they had received interferonβ-1b therapy for at least 60 days before baseline.

Exclusion criteria: patients (1) used medication for Alzheimer's disease; (2) started taking psychoactive medication; (3) used muscle relaxants or lithium at different time points before randomisation; (4) pregnant or breastfeeding; (5) with diabetes mellitus, malignancy, any cognition-affecting medical condition; (6) had drug addiction, alcohol abuse; (7) had depression as indicated by a MADRS score ≥ 14 at screening; (8) had been subjected to cognitive testing with BRB-N within the last year before randomisation; (9) had attended any cognitive rehabilitation study or program in the 3 months prior to the screening visit. During the study, centrally acting anticholinergics and medication for Parkinson's disease were not permitted.

86 of 125 MS patients screened were enrolled and randomised to either rivastigmine (n = 45) or placebo (n = 41). Of the 86 patients enrolled, 72 had RRMS, 13 SPMS and 1 had been diagnosed with clinically isolated syndrome. Of the 86 patients, 60 satisfied the criteria of cognitive impairment based on the results of the MUSIC and the FST test combined, 11 satisfied the criteria based only on the results of the MUSIC test, and 15 based only on the results of the FST test.

There were no statistically significant differences in baseline characteristics between the rivastigmine and placebo groups.

Summary of patient characteristics at baseline (placebo: G1 (n = 38), rivastigmine: G2 (n = 43)):

  • Mean age: G1 = 44.0 ± 7.3 years, G2 = 44.6 ± 9.4 years
  • Female: G1 = 20 (52.6%), G2 = 23 (53.5%)
  • Score on the MSFC: G1 = -0.03 ± 0.76, G2 = 0.11 ± 0.67
  • Score on the SRT total recall: G1 = 48.21 ± 10.32, G2 = 43.93 ± 10.67
  • Score on SRT long-term storage: G1 = 36.89 ± 13.69, G2 = 31.95 ± 14.41
  • Score on the MADRS: G1 = 8.21 ± 4.99, G2 = 6.63 ± 4.49
  • Score on the FST: G1 = 3.56 ± 1.14, G2 = 3.70 ± 1.17
  • Score on the MFIS: G1 = 37.89 ± 17.21, G2 = 35.74 ± 18.58
  • Score on Multiple Sclerosis Inventarium Cognition: G1 = 16.14 ± 5.29, G2 = 15.28 ± 5.29.


InterventionsExperimental intervention: rivastigmine patches of 5 cm2 (4.6 mg/day), increased to 10 cm2 (9.5 mg/day) at week 4 (G2).

Control intervention: placebo (G1).


OutcomesPrimary outcomes: (1) improvement in memory performance, as assessed by the total recall on the SRT; (2) safety.

Secondary outcomes: (1) improvement in activities of daily living, as assessed by a subscale of the PRIMuS and improvement in the score of the CGI scale; (2) additional BRB-N subtests (the SDMT; PASAT-3 seconds; 10/36 Spatial Recall Test); (3) changes in cognitive functioning, as assessed by subscales of the BRB, BRB-N composite index score, MFIS, MADRS, FST and MSFC.


NotesThe study started in January 2009, and participants were enrolled at 30 investigational sites in Germany. However, the study was terminated in January 2010 because of slow recruitment.

The study is registered in the clinicaltrials.gov database (protocol ID: NCT00881205) and supported by Novartis Pharma GmbH.

After a screening period of 6 weeks, participants were randomised to either rivastigmine or placebo in a 1:1 ratio. Participants then entered a 4-week titration period, followed by a 12-week maintenance period and an optional 12-month open-label treatment phase.

Results were presented for the modified ITT population. The modified ITT population consisted of all patients randomised who received at least 1 dose of study drug and had at least 1 baseline and post-baseline efficacy assessment. Safety was assessed in patients who received at least 1 dose of study drug and had at least 1 post-baseline safety assessment.

During the study, 4 of 35 (8.9%) rivastigmine-treated patients and 6 of 27 (14.6%) placebo-treated patients had an MS relapse.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Randomisation lists were generated by an external clinical research organisation (CRO) using a validated system that automates the random assignment of the treatment arms under the responsibility of the GCP officer."

Comment: sequence generation was adequate.

Allocation concealment (selection bias)Low riskQuote: "Randomisation lists were generated by an external clinical research organisation (CRO) using a validated system that automates the random assignment of the treatment arms under the responsibility of the GCP officer. The investigator enrolled the subjects and assigned participants to treatment according to the randomisation list."

Comment: allocation concealment was adequate.

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Patients, investigator staff, persons performing the assessments and data analysts remained blinded throughout the entire study period. Study drugs were identical in packaging, labelling, schedule of administration, appearance and odour."

Comment: participants, personnel and outcomes assessors in this study were blinded to the allocated interventions.

Incomplete outcome data (attrition bias)
All outcomes
High riskAccording to the Subject Flow and the corresponding description, 45 patients were randomised to rivastigmine and 41 to placebo. 18 of 86 patients enrolled (20.9%) prematurely discontinued the study. 11 (24.4%) patients in rivastigmine group prematurely discontinued the study due to AEs, condition no longer required study drug, withdrew consent and administrative problems (n = 1). 34 patients completed the double-blind study phase at week 16. 7 (17.1%) patients in placebo group prematurely discontinued the study due to AEs, withdrew consent, lost to follow-up and administrative problems. 34 patients completed the double-blind study phase at week 16. 43 patients in rivastigmine group and 38 in placebo group were analysed.

Comment: although the modified ITT principle was used for analyses, the rate of drop-outs and the amounts of missing data were high and the reasons for drop-out differed between groups. Attrition bias was high. Generally, the potential impact of missing continuous outcomes increases with the proportion of participants with missing data.

Selective reporting (reporting bias)Low riskAll listed outcomes were reported adequately.

Other biasUnclear riskThe study was supported by Novartis Pharma GmbH.

Comment: this may have led to biased results.

The patients were enrolled based on cognitive impairment as defined by a FST score of ≥ 3.0, a MUSIC score of ≤ 19, or both at screening.

Comment: selection of targeted sample is not specific for memory impairment.

Shaygannejad 2008

MethodsSingle-centre, double-blind, placebo-controlled, randomised clinical trial.

The sample size and power were estimated. On the basis of previous estimates of SD of recall change score 0.9, the researchers calculated that 30 patients per treatment group would be required to provide the study with 90% power to detect (with a 2-sided α of 0.05) a mean difference in general memory score on the WMS from baseline of 2.5.

All patients completed treatment without interruption and were available for follow-up at 12 weeks.

Treatment duration: 12 weeks.

Follow-up period: 12 weeks.

ITT analysis: yes.


ParticipantsInclusion criteria: (1) men and women aged 15-55 years with a clinical or laboratory-supported diagnosis of definite MS according to Poser's diagnostic criteria; (2) stable neurological functioning for at least 1 month prior to study entry and have an EDSS score ≤ 6 and a willingness to continue current medications for the duration of the study; (3) displayed at least mild verbal memory impairment as indicated by a WMS; (4) concurrent antidepressants, antispasticity agents, anticholinergic drugs frequently taken for urinary problems, and DMTs were permitted, as long as dosage had been constant for at least 1 month prior to the evaluation; (5) women of childbearing potential had to practice a clinically accepted method of contraception.

Exclusion criteria: (1) patients currently taking benzodiazepines were excluded, as these medications may affect cognition; (2) current alcohol or substance abuse, history of head injury or other medical condition known to affect cognition.

71 patients were eligible for the study. 11 patients were excluded because they refused entry.

60 patients were assigned randomly and equally to 1 of the 2 self administered treatment groups.

Most of characteristics of patients in the 2 treatment groups were generally well matched at baseline except for the subtests of digit span and visual reproduction in WMS (rivastigmine group scored slightly but significantly lower).

Summary of patient characteristics at baseline (placebo: G1 (n = 30), rivastigmine: G2 (n = 30)):

  • Mean age: G1 = 31.6 ± 7.6 years, G2 = 33.4 ± 9.6 years, difference 1.8 years (95% CI -2.7 to 6.2)
  • Gender: men G1 = 12 (40.0%), G2 = 15 (50.0%), difference 10.0% (95% CI -15.0% to 35.0%);women: G1 = 18 (60.0%), G2 = 15 (50.0%)
  • Duration of MS: G1 = 4.5 ± 3.2 years, G2 = 6.3 ± 4.1 years, difference 1.8 years (95% CI -0.8 to3.7)
  • EDSS: G1 3.9 (1.1), G2 4.0 (1.2), difference0.1 (95% CI -0.5 to 0.7)
  • Education: primary or below G1 = 7 (23.3%), G2 = 11 (36.7%), difference 13.3% (95% CI -9.6% to 36.3%); secondary: G1 = 13 (43.3%), G2 = 11 (36.7%), difference 6.7% (95% CI -31.4% to 18.1%); post-secondary: G1 = 10 (33.3%), G2 = 8 (26.7%), difference -6.7% (95% CI -29.8% to 16.5%)
  • Marital status: married: G1 = 19 (63.3%), G2 = 19 (63.3%), difference 0.0% (95% CI -24.4% to 24.4%); single: G1 = 11 (36.7%), G2 = 11 (36.7%)
  • Score on the Wechsler Memory Scale Subtests: information: G1 = 5.8 ± 0.4, G2 = 5.6 ± 0.6, difference -0.2 (95% CI -0.4 to 0.1); orientation: G1 = 4.9 ± 0.3, G2 = 4.9 ± 0.3, difference 0.0 (95% CI -0.1 to 0.1); mental control: G1 = 7.2 ± 1.0, G2 = 7.6 ± 1.0, difference 0.4 (95% CI -0.1 to 0.9); logical memory: G1 = 15.2 ± 2.5, G2 = 16.1 ± 1.8, difference 0.9 (95% CI -0.2 to 2.0); digit span: G1 = 5.0 ± 1.0, G2 = 4.6 ± 0.7, difference -0.9 (95% CI -1.3 to -0.5); visual reproduction: G1 = 9.7 ± 1.4, G2 = 8.1 ± 1.0, difference -1.6 (95% CI -2.2 to -1.0); associative learning: G1 = 12.0 ± 2.0, G2 = 13.0 ± 2.8, difference 1.0 (95% CI -0.3 to 2.2); general memory score: G1 = 60.5 ± 4.9, G2 = 60.0 ± 4.2, difference -0.5 (95% CI -2.9 to 1.9)
  • MS subtypes: RRMS: G1 = 11 (36.7%), G2 = 9 (30.0%), difference -6.7 (95% CI -30.5 to 17.1); SPMS: G1 = 16 (53.3%), G2 = 15 (50.0%), difference -3.3 (95% CI -28.6 to 21.9); PPMS: G1 = 3 (10.0%), G2 = 6 (20.0%), difference 10.0 (95% CI -7.9 to 27.9)
  • Concomitant medications: interferon-β: G1 = 22 (73.3%), G2 = 19 (63.3%), difference -10.0 (95% CI -33.4 to 13.4); antidepressant: G1 = 29 (96.7%), G2 = 25 (83.3%), difference -13.3 (95% CI -28.1 to 1.5); bladder drug: G1 = 19 (63.3%), G2 = 19 (63.3%), difference 0.0 (95% CI -24.4 to 24.4); antispasmodic: G1 = 20 (66.7%), G2 = 22 (73.3%), difference 6.7 (95% CI -16.5 to 29.8).


InterventionsExperimental intervention: rivastigmine 1.5 mg once daily increment over 4 weeks to 3 mg twice daily for a total of 12 weeks (G2).

Control intervention: placebo (G1).


OutcomesPrimary outcome: general memory score on the WMS and its subtests.

Secondary outcome: frequency of AEs.


Notes60 patients who sought treatment for MS at a neurology clinic in Al-Zahra Hospital affiliated to Isfahan University of Medical Sciences, Iran, between October 2005 and February 2007.

This is the first study that assessed effectiveness of rivastigmine in treatment of cognitive dysfunction in MS.

No information on depression and fatigue at baseline was reported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Patients were randomized according to a preexisting list produced by a computer program that differed from a random number generator only in that it assigned equal numbers of patients into each treatment group."

Comment: sequence generation was adequate.

Allocation concealment (selection bias)Low riskQuote: "The hospital pharmacist was informed of all randomization assignments and was responsible for labelling the study drug and maintaining a master list linking the patients and their treatment assignments."

Comment: allocation concealment was adequate

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "The trial was double-blinded in that both patient and physician who assessed the outcome were not aware of treatment type that the patient was received. The masking of the active and placebo treatments was preserved by creating treatments that looked identical. Patients were evaluated at baseline and 12 weeks after the start of the therapy by a qualified neurologist to evaluate the development of side effects of the medications, compliance of the patients, and efficacy parameters. Efficacy assessments of all patients were administered by a single rater (NZ) in the same sequence, and did not know which patients had received which treatment."

Comment: participants, personnel and outcomes assessors in this study were blinded to the allocated interventions.

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "The 60 patients who completed treatment were available for follow-up at 12 weeks."

Comment: outcome data were complete.

Selective reporting (reporting bias)Low riskAll listed outcomes were reported adequately.

Other biasUnclear riskMost of characteristics of patients in the treatment groups were generally well matched at baseline except for the subtests of digit span and visual reproduction in WMS (rivastigmine group scored slightly but significantly lower). No information on depression at baseline was reported.

Comment: this may have led to biased results.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Aragona 2009Cross-over study with administration duration < 12 weeks.

Barak 1999Without memory scales in outcomes.

Barak 2002(1) Non-randomised study; (2) control group were untreated MS patients.

Benedict 2008Administration duration < 12 weeks.

Bever 1996Cross-over study with administration duration < 12 weeks.

Bosca 2004The participants did not meet the inclusion criteria for memory impairment prespecified in the protocol.

Bruce 2012Cross-over study with administration duration < 12 weeks.

Cabrera-Gomez 2003Participants did not meet the inclusion criteria for memory impairment prespecified in the protocol.

Christodoulou 2006Based primarily on a study previously published that was included in this review.

Cohen 1989Cross-over study with administration duration < 12 weeks.

Cohen 2002Participants did not meet the inclusion criteria for memory impairment prespecified in the protocol.

Cohen 2010Participants did not meet the inclusion criteria for memory impairment prespecified in the protocol.

Comi 2012Participants did not meet the inclusion criteria for memory impairment prespecified in the protocol.

Decoo 2004Cross-over study.

Fischer 1994Participants did not meet the inclusion criteria for memory impairment prespecified in the protocol.

Fischer 2000Participants did not meet the inclusion criteria for memory impairment prespecified in the protocol.

Flechter 2007Non-randomised and open-label study without control group.

Geisler 1996Single-blind study with administration duration < 12 weeks.

Greene 2000Non-randomised, non-controlled, open-label study.

Harel 2009Administration duration < 12 weeks.

Havrdova 2006Participants did not meet the inclusion criteria for memory impairment prespecified in the protocol.

Honarmand 2011Cross-sectional study.

Huolman 2011(1) Non-randomised study; (2) control group were healthy people.

Iaffaldano 2012Non-randomised, non-controlled, open-label, observational cohort study.

Jeffery 2011Without memory scales in outcomes.

Kappos 2010Participants did not meet the inclusion criteria for memory impairment prespecified in the protocol.

Krause 2012(1) Non-randomised study; (2) control group were healthy people.

Krupp 1999Open-label trial.

Lacy 2013Non-randomised, open-label study.

Lang 2012Non-randomised, non-controlled, open-label, prospective cohort study.

Lange 2009Administration duration < 12 weeks.

Mattioli 2011a(1) Non-randomised and single-blind (assessor-blind) study; (2) quasi controls (MS patients administering immunomodulatory drugs).

Mattioli 2011bNon-randomised, non-controlled, observational study.

Melanson 2010Non-randomised, open-label study.

Miller 2011Participants did not meet the inclusion criteria for memory impairment prespecified in the protocol.

Montalban 2009Participants did not meet the inclusion criteria for memory impairment prespecified in the protocol.

Morrow 2009Administration duration < 12 weeks.

Morrow 2013Administration duration < 12 weeks.

Möller 2011Administration duration < 12 weeks.

Oliveri 1998(1) Non-randomised study; (2) control group were healthy people.

Panitch 2004Participants did not meet the inclusion criteria for memory impairment prespecified in the protocol.

Patti 2009Non-randomised, non-controlled, open-label, observational cohort study.

Patti 2010Non-randomised, non-controlled, open-label, observational cohort study.

Pliskin 1994Participants did not meet the inclusion criteria for memory impairment prespecified in the protocol.

Pliskin 1996Participants did not meet the inclusion criteria for memory impairment prespecified in the protocol.

Portaccio 2013Non-randomised study.

Rorie 2001Cross-over study.

Rossini 2011Cross-over study.

Rudick 2006Participants did not meet the inclusion criteria for memory impairment prespecified in the protocol.

Sailer 2000Cross-over study.

Schröder 2011Observational study with an open-label retrospective analysis.

Schwid 2007Open-label trial.

Selby 1998(1) Non-randomised study; (2) control group were healthy people.

Selmaj 2012Without memory scales in outcomes.

Smits 1994Cross-over study with administration duration < 12 weeks.

Sumowski 2011Based primarily on a study previously published that was excluded in this review.

Uttner 2005(1) Administration duration < 12 weeks; (2) untreated control group consisted of healthy people.

Villoslada 2009Cross-over study.

Wade 2004Administration duration < 12 weeks.

Weinstein 1999Participants did not meet the inclusion criteria for memory impairment prespecified in the protocol.

Weinstock-Guttman 2012bParticipants did not meet the inclusion criteria for memory impairment prespecified in the protocol.

Weinstock-Guttman 2012aParticipants did not meet the inclusion criteria for memory impairment prespecified in the protocol.

Wilken 2004Not a double-blind study.

Wilken 2008Not a double-blind study.

Zéphir 2005(1) Non-randomised study; (2) control group were healthy subjects.

Zéphir 2008(1) Non-randomised study; (2) control group were healthy subjects.

 
Characteristics of studies awaiting assessment [ordered by study ID]
NCT01074619

MethodsStudy on Cognitive Disorders of Multiple Sclerosis.

ParticipantsInclusion criteria:

(1) Aged 18-60 years, both genders

(2) Remitting multiple sclerosis defined by McDonald 2001

(3) Patient with authorised immunomodulator treatment or oral immunosuppressive therapy for > 3 months: interferon-β, glatiramer acetate, azathioprine, methotrexate, mycophenolate mofetil, treatment by monoclonal antibody IV or anti-VLA4, natalizumab (Tysabri)

(4) Patient having benefited, possibly, of following treatments: mitoxantrone, cyclophosphamide, cyclosporine, general-purpose immunoglobulins, only if the treatment is ended > 6 months before the inclusion

(5) EDSS score ≤ 5.5 and DRS score ≥130

(6) PASAT 3s score > 15 and < median/control subjects according to 2 age brackets, gender, school level

(7) Signed the informed consent form

(8) Effective contraception for women in age to procreate

Exclusion criteria:

(1) Progressive form MS

(2) MS relapse of less of 4 weeks

(3) IV or oral corticoid treatment in the month preceding the screening

(4) Medicinal treatments or non-medicinal in cognitive or psychology-stimulant aim in the 3 months before the screening

(5) Tumoural form MS visible by MRI

(6) Depressive syndrome (MADRS score >19)

(7) Quite other diagnosed psychiatric pathology

(8) Known allergy or quite contraindication in memantine: renal or hepatic insufficiency, turned out epileptic disease, treatment by ketamine, amantadine, dextromethorphan, L-dopa, dopaminergic agonist, barbiturates, neuroleptic, 3,4-diaminopyridine, lithium, cimetidine, ranitidine, procainamide, quinine, nicotine, hydrochlorothiazide and ally, phenytoin, modafinil

(9) Recent treatment (< 4 weeks) by antidepressants, anxiolytics, or both

(10) Pregnancy or breastfeeding

(11) Minor or major "protected by the law" patient

(12) Uncontrolled diet

(13) Patient having benefited of 1 psychometric assessment (including in particular tests planned in the protocol) within 1 year.

InterventionsIntervention group: memantine, 5 mg the first week, then 10 mg the second week, 15 mg the third week and 20 mg the fourth week until the end of the study (t0 + 1 year).

Control group: placebo, 5 mg the first week, then 10 mg the second week, 15 mg the third week and 20 mg the fourth week until the end of the study (t0 + 1 year).

OutcomesPrimary outcome measures: PASAT.

NotesOfficial title: Effects of Memantine on Cognitive Disorders of Relapsing-remitting Multiple Sclerosis.

This trial started in September 2005 and was completed in November 2011, but we could not find a formal publication. We wrote to the principal investigator requesting information about this trial, but we received no reply.

Contact information: Defer Gilles, Professor, 02.31.06.46.20 ext +33, Email address: defer-gi@chu-caen.fr.

Sponsor: University Hospital, Caen, Collaborators: Ministry of Health, France, H. Lundbeck A/S.

clinicaltrials.gov/ct2/show/NCT01074619.

 
Characteristics of ongoing studies [ordered by study ID]
NCT01466114

Trial name or titleEstriol Treatment in Multiple Sclerosis (MS): Effect on Cognition.

MethodsRandomised, double-blind (participant, investigator, outcomes assessor), parallel assignment.

ParticipantsInclusion criteria:

(1) Diagnosis of clinically definite or MacDonald criteria relapsing-remitting multiple sclerosis, secondary-progressive multiple sclerosis or primary-progressive multiple sclerosis

(2) No relapse within 30 days before day of trial enrolment (month 0 visit). If steroids given for relapse, then the month 0 visit must be 30 days after last steroid dose.

(3) Females aged 18-50 years, and EDSS = 0.0-6.0

(4) Screening PASAT (3-second) score 25-50, inclusive

(5) Must be mentally competent enough to comply with study guidelines and give informed consent and must be willing and able to travel to the study centre at frequencies in the protocol for a total period of 12 months

(6) Patients must be on a stable dose of 1 of the following agents for a minimum of 3 months prior to the month 0 visit: Copaxone®, Betaseron® (or Extavia®), Rebif®, or Avonex®, Gilenya®, Aubagio® or BG-12. The time spent in the screening period may serve as part of this 3-month period

(7) Patients who are currently being treated with adrenocorticotropic hormone, corticosteroids, intravenous immunoglobulins, plasma exchange, Lipitor® or minocycline may be included

(8) Patients who are not currently treated with 1 of the above treatments may only be included if they plan to start Copaxone® or an interferon (Betaseron® (or Extavia®), Rebif®, Avonex®) or an oral agent (Gilenya®, Aubagio® or BG-12) and then they must be on for at least 3 months prior to month 0 (as above).

Exclusion criteria:

(1) Males

(2) Participant on oral contraceptives, hormone replacement therapy, progesterone intrauterine devices or other sex hormones during screening and during the 12-month study period

(3) Females who are pregnant or who plan to become pregnant during the 12 months of enrolment, who wish to become pregnant within 3 months following completion of the study, or who will be within 6 months postpartum at the day of first enrolment visit (month 0)

(4) Females who plan to breastfeed after first enrolment visit (month 0)

(5) Fertile sexually active women who are unwilling to practice reliable barrier methods of contraception other than oral contraceptives

(6) Patients with surgical ovariectomy with no hormone replacement for ≥ 1 year

(7) Menopause with no hormone replacement for ≥ 3 years prior to the first enrolment visit

(8) Patients who smoke at any time during screening or during the 12-month study period

(9) Patients who have serious pulmonary, renal, gastrointestinal, hepatic, immunological, infectious, neoplastic, major psychiatric disease (major depression, schizophrenia), endocrine disease (including major diabetes, thyroid disease), or gynaecological disease

(10) Vitamin B12 level < 200 pg/mL or drug abuse within the past 5 years

(11) > 130% or < 80% of their ideal body weight based on Metropolitan Life Tables

(12) Conditions that would interfere with assessing neurological functions such as deforming arthritis or a major amputation

(13) Have at any time been treated with total lymphoid irradiation, monoclonal antibody, T-cell vaccination, cladribine, bone marrow transplantation, azathioprine, cyclophosphamide, methotrexate, mitoxantrone, cyclosporine, Tysabri

(14) Positive titres to HIV in the past

(15) Previous serious adverse effects with oestrogen treatment

(16) Patients with MS-disease duration (since onset of symptoms) of > 15 years.

InterventionsExperimental group (group A): estriol (Synapause), 2 capsules of 2 mg (total of 8 mg) PO QD; norethindrone (progestin), starting at month 6, and at months 9 and 12: women who are on estriol (group A) take 0.7 mg PO QD for 2 weeks.

Placebo comparator (group B): placebo, 4 capsules PO QD; progestin placebo, starting at month 6 and at months 9 and 12: women who are on placebo (group B) take a second progestin placebo pill PO QD for 2 weeks.

OutcomesPrimary outcome measures: change from baseline in cognitive function assessed by PASAT.

Secondary outcome measures:

(1) Change from baseline in cognitive function as assessed by cognitive evoked potentials, measured in milliseconds

(2) Change from baseline in standard MS outcome measures (relapses, EDSS, 25-foot walk test, 9-hole peg test, low contrast visual acuity, MS Quality of Life, Modified Fatigue Impact Score, Beck Depression Inventory)

(3) Determine safety by assessing the number of women with adverse events with combination treatment compared with placebo

(4) Change from baseline in MRI measurements of whole brain volume, T2 lesion volume and number of enhancing lesions. Whole brain atrophy, T2 lesion volume, gadolinium enhancing lesion number and volume will be assessed on brain MRI at baseline and conclusion in each woman

(5) Change from baseline in cognitive function as assessed by a brief battery of cognitive tests (Processing speed: SDMT; Visual Memory: 7/24 Spatial Recall Test, Benton Forms F & G; Verbal memory: Buschke Selective Reminding Test, Verbal Paired Associates; Language: Word List Generation.

Starting dateOctober 2011.

Contact informationContact: Jenny Bardens, (310)206-2176, jbardens@mednet.ucla.edu; Janet Yau, (310)794-4020, jyau@mednet.ucla.edu.

NotesOfficial Title: A Double-Blind, Placebo Controlled Trial of Estriol Treatment in Women With Multiple Sclerosis: Effect on Cognition.

clinicaltrials.gov/ct2/show/NCT01466114.

 
Comparison 1. Subgroup analysis for donepezil versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 The mean change of total recall on the Selective Reminding Test (SRT) from baseline2189Mean Difference (IV, Random, 95% CI)1.68 [-2.21, 5.58]

 2 The mean total recall on the Selective Reminding Test (SRT) at exit2189Mean Difference (IV, Random, 95% CI)1.23 [-3.07, 5.53]

 3 The mean change of total correct score on the 10/36 Spatial Recall Test (10/36 SRT) from baseline2189Mean Difference (IV, Random, 95% CI)-0.93 [-3.18, 1.32]

 4 The mean total correct score on the 10/36 Spatial Recall Test (10/36 SRT) at exit2189Mean Difference (IV, Random, 95% CI)0.29 [-2.64, 3.23]

 5 The mean change of total correct score on the Symbol Digit Modalities Test (SDMT) from baseline2189Mean Difference (IV, Fixed, 95% CI)-1.27 [-3.15, 0.61]

 6 The mean total correct score on the Symbol Digit Modalities Test (SDMT) at exit2189Mean Difference (IV, Fixed, 95% CI)1.15 [-2.71, 5.01]

 7 The mean change of total correct score on the Paced Auditory Serial Addition Test (PASAT) (2+3 sec) from baseline2189Mean Difference (IV, Random, 95% CI)2.23 [-1.87, 6.33]

 8 The mean total correct score on the Paced Auditory Serial Addition Test (PASAT) (2+3 sec) at exit2189Mean Difference (IV, Fixed, 95% CI)5.41 [-1.42, 12.23]

 9 The number of patients experiencing diarrhoea2189Risk Ratio (M-H, Fixed, 95% CI)3.88 [1.66, 9.05]

 10 The number of patients experiencing diarrhoea2189Odds Ratio (M-H, Fixed, 95% CI)4.84 [1.87, 12.51]

 11 The number of patients experiencing nausea2189Risk Ratio (M-H, Fixed, 95% CI)1.71 [0.93, 3.18]

 12 The number of patients experiencing nausea2189Odds Ratio (M-H, Fixed, 95% CI)1.94 [0.92, 4.12]

 13 The number of patients experiencing abnormal dreams2189Risk Ratio (M-H, Fixed, 95% CI)2.91 [1.38, 6.14]

 14 The number of patients experiencing abnormal dreams2189Odds Ratio (M-H, Fixed, 95% CI)3.55 [1.50, 8.37]

 
Summary of findings for the main comparison. Donepezil for memory disorder in multiple sclerosis

Donepezil for memory disorder in multiple sclerosis

Patient or population: Patients with memory disorder in multiple sclerosis
Settings: USA
Intervention: Donepezil

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlDonepezil

The mean change of total recall on the SRT from baseline
Scale from: 0 to 72
Follow-up: median 24 weeks
The mean change of total recall on the SRT from baseline ranged across control groups from 0.7 to 1.7 The mean change of total recall on the SRT from baseline in the intervention groups was 1.68 higher (2.21 lower to 5.58 higher)-189
(2 studies)
⊕⊕⊕⊝
moderate1
-

The mean change of total correct score on the 10/36 SRT from baseline
Scale from: 0 to 40
Follow-up: median 24 weeks
The mean change of total correct score on the 10/36 SRT from baseline ranged across control groups from
1.2 to 16
The mean change of total correct score on the 10/36 SRT from baseline in the intervention groups was 0.93 lower (3.18 lower to 1.32 higher)-189
(2 studies)
⊕⊕⊕⊝
moderate1
-

The mean change of total correct score on the SDMT from baseline
Scale from: 0 to infinity
Follow-up: median 24 weeks
The mean change of total correct score on the SDMT from baseline in the control groups was 2 The mean change of total correct score on the SDMT from baseline in the intervention groups was 1.27 lower (3.15 lower to 0.61 higher)-189
(2 studies)
⊕⊕⊕⊝
moderate1
-

The mean change of total correct score on the PASAT (2+3 sec) from baseline
Scale from: 0 to 120
Follow-up: median 24 weeks
The mean change of total correct score on the PASAT (2+3 sec) from baseline ranged across control groups from 0.8 to 3.5 The mean change of total correct score on the PASAT (2+3 sec) from baseline in the intervention groups was 2.23 higher (1.87 lower to 6.33 higher)-189
(2 studies)
⊕⊕⊕⊝
moderate1
-

The number of patients experiencing diarrhoea
Follow-up: median 24 weeks
LowRR 3.88
(1.66 to 9.05)
189
(2 studies)
⊕⊕⊕⊝
moderate1
-

65 per 1000252 per 1000
(108 to 588)

The number of patients experiencing nausea
Follow-up: median 24 weeks
LowRR 1.71
(0.93 to 3.18)
189
(2 studies)
⊕⊕⊕⊝
moderate1
-

140 per 1000239 per 1000
(130 to 445)

The number of patients experiencing abnormal dreams
Follow-up: median 24 weeks
LowRR 2.91
(1.38 to 6.14)
189
(2 studies)
⊕⊕⊕⊝
moderate1
-

86 per 1000250 per 1000
(119 to 528)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
10/36 SRT: 10/36 Spatial Recall Test;CI: confidence interval; PASAT: Paced Auditory Serial Addition Test;RR: risk ratio; SDMT: Symbol Digit Modalities Test; SRT: Selective Reminding Test;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Both studies had a small sample size and a power of test lower than 80%.
 
Table 1. Data of the primary outcomes reported in each study

StudyPrimary outcomesGroupsNumberPre mean values at baselinePost mean values at exitThe mean

change from

baseline
Mean difference

(95% CI) between groups
P valueNotes

Krupp 2004Total recall on SRTDonepezil3542.3 ± 9.046.8 ± 9.34.6 ± 9.13.9 (0.13 to 7.66)*0.043Mean ± SD

*exit-baseline difference

Placebo3442.7 ± 8.843.2 ± 9.20.7 ± 6.3

Krupp 2011Total recall on SRTDonepezil6138.0 ± 8.7

(35.7 to 40.2)
39.6 ± 8.7

(37.4 to 41.8)
1.6 ± 7.5

(0.3 to 3.6)
0.54*-Mean ± SD (95% CI)

*exit-baseline difference

Placebo5936.0 ± 9.8

(33.5 to 38.6)
37.7 ± 11.5

(34.7 to 40.7)
1.7 ± 7.2

(0.2 to 3.6)
-

Lovera 2007LDFR on CVLT-IIGB209.4 ± 1.08.9 ± 0.7--1.2 (-3.2 to 0.8)*-Mean ± SEM

*Exit group difference

Placebo1910.2 ± 0.710.1 ± 0.7-

SDMTGB2047.7 ± 2.843.4 ± 1.3--0.8 (-3.0 to 4.6)*-

Placebo1945.4 ± 2.844.1 ± 1.3-

PASATGB2042.4 ± 3.148.9 ± 1.1-1.1 (-3.1 to 4.2)*-

Placebo1943.9 ± 3.047.8 ± 1.1-

Lovera 2010LDFR on CVLT-IIMemantine54--0.9

(-0.3 to 2)
-0.6 (-2 to 0.8)*0.4Mean change (95% CI)

*Exit-baseline difference

Placebo65--0.2

(-0.9 to 1.3)

PASATMemantine54--3.6

(0.7 to 6.4)
-0.0 (-3.3 to 3.4)*0.9

Placebo65--3.6

(0.9 to 6.3)

Lovera 2012LDFR on CVLT-IIGB61-0.5 ± 1.2-0.4 ± 1.2-0.0 (-0.3 to 0.3)*-z-scores, mean ± SD

*Exit group difference, mean (95% CI)

Placebo59-0.5 ± 1.2-0.4 ± 1.2-

PASATGB61-1.4 ± 0.8-1.3 ± 0.9--0.2 (-0.5 to 0.1)*-

Placebo59-1.2 ± 0.9-1.0 ± 1.1-

Mäurer 2013Total recall on SRTRivastigmine4343.93 ± 10.67-1.35*(-5.8 to 1.6)0.2576**Exit-baseline difference of adjusted LS-means

Placebo3848.21 ± 10.32--0.76*

Shaygannejad 2008WMSRivastigmine3060.0 ± 4.264.9 ± 5.34.9

(3.8 to 6.0)
0.4 (-0.2 to 2.8)*-Mean ± SD

*Exit group difference

Placebo3060.5 ± 4.964.5 ± 3.74.0

(3.0 to 5.0)

Logical MemoryRivastigmine3016.1 ± 1.818.0 ± 2.01.9

(1.4 to 2.4)
1.6 (0.4 to 2.8)*-

Placebo3015.2 ± 2.516.4 ± 2.51.2

(0.7 to 1.7)

Digit SpanRivastigmine304.6 ± 0.74.6 ± 0.70.0

(-0.3 to 0.3)
-1.3 (-1.7 to -0.9)*-

Placebo305.5 ± 1.05.9 ± 0.90.4

(0.2 to 0.5)

 CI: confidence interval; CVLT-II: California Verbal Learning Test II; GB: Ginkgo biloba; LDFR: Long Delay Free Recall; LS: least square; PASAT: Paced Auditory Serial Addition Test; SD: standard deviation; SDMT: Symbol-Digit Modalities Test; SEM: standard error of the mean; SRT: Selective Reminding Test; WMS: Wechsler Memory Scale.