Appendix 5. Characteristics of included studies. Study title: NCT

Transcription

1 Appendix 5 Characteristics of included studies Study title: NCT Study design: 'A Randomized, Double-Blind, Placebo-led, Two Dose Arm, Parallel Study of the Safety and Effectiveness of Immune Globulin Intravenous (Human), 10% (IGIV, 10%) for the Treatment of Mild-to-Moderate Alzheimer s Disease' Study Registration number: NCT (Last access December 5, 2014), study ID Country: USA & Canada Centre: Multicentre, 44 locations Ethics Committee Approval: health authorities in the above countries Sponsor: Baxter Healthcare Corporation Study period (study start, study end): December 2008 to December 2012 Patients with mild-to-moderate Alzheimer's disease Age of patients 50 to 89 Sex: Both sexes (M/F unclear) Disease severity: mild-to-moderate (as stated in the title, see above), and 'as determined by a Mini Mental State Examination (MMSE) score of inclusive' (inclusion criterion) AD therapy (cholinesterase inhibitor; memantine): ' On stable doses of FDA approved AD medication(s) for at least 3 months prior to screening. These medications must be continued throughout this study.' (inclusion criterion) IVIG (Gammagard Liquid) 200 mg or 400 mg/kg every 2 weeks (70 weeks) Placebo: Human Albumin 0.25% 4 ml/kg; solution infused at 4 ml/kg/2weeks or 2 ml/kg solution infused at 2 ml/kg/2weeks (70 weeks) Cognitive functions measured by ADAS-Cog Activities of daily living measured by ADCS-ADL

2 No of patients enrolled: 702 participants enrolled; 308 were screen failures; 4 were discontinued before randomization; and 7 were withdrawn after randomization, but prior to receiving investigational product. Therefore 383 participants were randomized, 262 assigned to intervention group (127 to 400 mg/kg regimen; 135 to 200 mg/kg regimen), 121 to placebo (58 to 4 ml/kg regimen; 63 to 2 ml/kg regimen); 302 completed the study: 206 assigned to intervention group (104 to 400 mg/kg regimen; 102 to 200 mg/kg regimen), 96 to placebo (49 to 4 ml/kg regimen; 47 to 2 ml/kg regimen). Number of analysed patients: 302 available for effectiveness data, 383 for safety data;. Results unpublished and posted in clinicaltrial.gov record. Author Disclosure (Conflict of interest): Not applicable

3 Characteristics of excluded studies Randomized controlled trials Study title: Arai 2014 Study design: multiple dose,, randomised, placebo-controlled trial Study Registration number: not reported Country: Japan Centre: 5 research centres in Japan Ethics Committee Approval: Not reported (Quote This study was conducted in accordance with the applicable laws and regulations, including but not limited to the International Conference on Harmonization Guidelines for Good Clinical Practice, the ethical principles that have their origins in the Declaration of Helsinki, and Japan Good Clinical Practice. The institutional review board of each organization reviewed and approved the protocol and the informed consent form before any of the patients were enrolled. Sponsor: Not reported. Study period (study start, study end): Not reported Patients with mild-to-moderate Alzheimer s disease Age of patients: groups 72.9 (9.2) years, placebo group 71.5 (11.3) years Sex: groups 9F/3M, Placebo group 4F/0M Disease severity: MMS score of 16-26, modified Hachinski-Rosen score of less than 5 (as stated in inclusion criteria) AD therapy (cholinesterase inhibitor; memantine): Quote Any therapy appropriate to the subject s condition was permitted during the study. Concomitant medications with the potential to affect cognition, other than cholinesterase inhibitors and/or memantine, were to be maintained on a stable dose regimen for 30 days prior to the baseline evaluations. This included injectable medications such as anxiolytics, sedatives, hypnotics, antipsychotics, antidepressants, over-thecounter sleeping aids, antiallergy medications, thyroid supplements, and vitamin B12 supplements. The use of cholinesterase inhibitors for the symptomatic treatment of AD was allowed when the following conditions were met: (i) the subject s dose regimen had been stable for 120 days prior to baseline; (ii) the subject was free of significant side effects attributable to such drugs; and (iii) the subject and caregiver agreed that, barring unforeseen circumstances, they would continue the advised regimen for the duration of the trial. In contrast, subjects who discontinued the use of cholinesterase inhibitors and/or memantine within 60 days of baseline were excluded from the trial. The use of these drugs was not specified. One of two doses of intravenous immunoglobulin (0 2 g/kg, 0 4 g/kg) every 2 weeks (12 weeks) placebo (50-mL 0.25% human albumin solution (25% human albumin in a sterile nonpyrogenic formation for intravenous injection, mixed with sterile physiological saline (1:99)) every 2 weeks safety and tolerability including adverse events (AE), vital signs, physical and neurological examinations, 12-lead electrocardiogram, clinical laboratory evaluations, and brain MRI scans

4 Other: MMSE No of patients enrolled: assessed for eligibility not reported, 16 randomised, all treated, 12 assigned to intervention groups, 4 to placebo Number of analysed patients 12 per protocol/12 ITT analysis in the intervention group, 4 per protocol/4 ITT analysis in the placebo group. Author Disclosure (Conflict of interest) Yes, p. 165 (Quote All authors declare that they have no conflicts of interest associated with this manuscript). Study title: Dodel 2013 Study design: Phase 2, dose finding, block randomised, placebo-controlled trial Study Registration number: ClinicalTrials.gov (NCT ) and controlled-trials.com (ISRCTN ) Country: USA & Germany Centre: Hospitals, research centres and private clinics, 5 in Germany, seven in the USA Ethics Committee Approval: Yes, by each site's ethics comitteee and the regulatory authorities (FDA and Paul-Ehrlich Institute) Sponsor: Octapharma AG. Study period (study start, study end): February 2009 to March, 2010 Patients with mild-to-moderate Alzheimer s disease Age of patients: group 69.4(7.3) years, placebo group 72.0(10.2) years Sex: group 15F/26M, Placebo group 9F/5M Disease severity: MMS score of 16-26, modified Hachinski-Rosen score of less than 5 (as stated in inclusion criteria) AD therapy (cholinesterase inhibitor; memantine): 'Patients had to have been taking a stable dose of an approved Alzheimer s disease drug for at least 3 monthsbefore screening; use reported in Table 1: intervention group 36(88%), Placebo group 11(79%) One of three doses of intravenous immunoglobulin (0 2 g/kg, 0 5 g/kg, or 0 8 g/kg) every 4 weeks, or half of that dose (0 1 g/kg, 0 25 g/kg, or 0 4 g/kg) every 2 weeks (24 weeks) placebo (0 9% isotonic sodium chloride) every 4 weeks or every 2 weeks Cognitive functions measured by ADAS-Cog, CDR-GS Other: MMSE

5 Activities of daily living measured by ADCS-ADL Variation of biomarkers (decrease of cerebrospinal fluid Aβ1-40/Aβ1-42; increase of serum Aβ1-40/Aβ1-42) Variation of imaging signs (change in ventricular volumetric as measured by MRI) No of patients enrolled: 89 assessed for eligibility, 58 randomised, 2 not treated, 42 assigned to intervention group, 14 to placebo Number of analysed patients 36 per protocol/41 ITT analysis in the intervention group, 9 per protocol/14 ITT analysis in the placebo group. Author Disclosure (Conflict of interest) Yes, p Other designs (interventional prospective non-controlled studies and observational study) Study title: Dodel 2004 Study design Pilot interventional prospective non-controlled study Study Registration number: Not reported in the paper Country: Germany Centre: Unclear; ' Six individuals were recruited from specialised outpatient clinics for cognitive disorders' Ethics Committee Approval: Yes, ' by the local ethical committee of the Philipps-University, Marburg' Sponsor: 'supported in part by the Alzheimer Forschungsinitiative (grant: 00806), Germany'; ' Octapharma (Lagenfeld, Germany) provided the intravenous immunoglobulins and Eli Lilly and Company (Indianapolis, USA) provided the Ab antibodies for this study.' Study period (study start, study end): Not reported in the paper Patient's with Alzheimer's disease (4 mild-to-moderate; 1 moderate-to-severe) Age of patients: years Sex: 3M/2F Disease severity: Unclear AD therapy (cholinesterase inhibitor; memantine): 4 participants on Donepezil 10mg, 1 on Rivastigmine 12mg IVIG (OctagamH) 0.4 g/kg on three consecutive days every 4 weeks (6 months)

6 none Cognitive functions measured by ADAS-Cog Other: MMSE, CERAD neuropsychological test battery Variation of biomarkers (decrease of cerebrospinal fluid Aβ1-40/Aβ1-42; increase of serum Aβ1-40/Aβ1-42) No of patients enrolled: 6 Number of analysed patients:5, 1 refused to get a lumbar puncture at the end of study Author Disclosure (Conflict of interest): Not clearly stated Study title: Devi 2008 Study design Observational retrospective study Study Registration number Not applicable Country: USA Centre: Not clearly reported, probably Lenox Hill Hospital, New York (see below) Ethics Committee Approval: Yes, ' institutional review board of Lenox Hill Hospital in New York, New York' Sponsor: 'This study did not have a sponsor.' Study period (study start, study end): Not reported Patients with Alzheimer's disease Age of patients 74 ±7.5 Sex 5M/5F Disease severity: Unclear AD therapy (cholinesterase inhibitor; memantine): Not reported IVIG 0.4 g/kg every 2 weeks (3-6 months) none

7 Cognitive functions measured by WAIS, WMS, Boston No of patients enrolled. Not applicable Number of analysed patients 18 recieved IVIgs, 10 analysed Author Disclosure (Conflict of interest): The editor in chief has reviewed the conflict of interest checklist provided by the author and has determined that none of the authors have any financial or any other kind of personal conflicts with this letter. Study title Relkin 2009 Study design: Prospective interventional non-controlled 6 months IVIg dose ranging study, followed by a 3 months washout period, and then extension of 9 months of IVIg Study Registration number: Not reported in the paper Country: USA Centre: Unclear (see below) Ethics Committee Approval: Yes, ' by the Weill Cornell Institutional Review Board (IRB) and the Scientific Advisory Committee of the Weill Cornell General Clinical Research Center (GCRC)' Sponsor: in part, by the General Clinical Research Center at the Weill Medical College of Cornell University, NIH/NCRR Grant M01 RR Additional financial supportwas provided by Baxter Bioscience Corporation, by NIH grant AG , and the Stern Family Fund (MW) as well as the gifts from the Hoyt, Chen, and Koplow families (NR). IVIg for the study was also supplied by Baxter Bioscience Corporation.' Study period (study start, study end): Not reported in paper Patients with mild-to-moderate Alzheimer's disease Age of patients: 67 to 86 years (mean 74.3) Sex: 1M/7F Disease severity: mild, 'MMSE scores ranged from 20 to 29 (mean 23.5)? AD therapy (cholinesterase inhibitor; memantine): ' All subjects were receiving stable doses of a cholinesterase inhibitor and in some cases memantine for at least 3 months prior to enrolling in the study.' one of four IVIG (Gammagard S/D) doses (0.4 g/kg/2 weeks, 0.4 g/kg/week, 1 g/kg/2 weeks and 2 g/kg/4 weeks) (6 months + 9 months) none

8 Cognitive functions measured by MMSE Variation of biomarkers (decrease of cerebrospinal fluid Aβ1-40/Aβ1-42; increase of serum Aβ1-40/Aβ1-42) No of patients enrolled: 8, 2 in each dose group Number of analysed patients: 8, 2 in each dose group Author Disclosure (Conflict of interest): Marc E.Weksler, Paul Szabo, and Norman R. Relkin have received grants for research from Baxter Bioscience Corporation. Characteristics of unpublished studies. Randomized controlled trials Study title: NCT Study design: 'A Placebo-controlled, Randomized, Double-Blind Phase II Clinical Study of Gammagard Intravenous Immunoglobulin (IVIg) for Treatment of Mild to Moderate Alzheimer's Disease' Study Registration number: NCT (Last access September 18, 2014), study ID Country: USA Centre: Unclear Ethics Committee Approval: United States Institutional Review Board Sponsor: Weill Medical College of Cornell University, Baxter BioScience, National Institutes of Health (NIH) Study period (study start, study end): February 2006 to April 2010 Patients wth mild-to-moderate Alzheimer's disease Age of patients. 50 and older Sex: Both Disease severity: mild to moderate (as stated in the title, see above), and 'as determined by a Mini Mental State Examination (MMSE) score of inclusive' (inclusion criterion) AD therapy (cholinesterase inhibitor; memantine): 'On stable doses of approved AD medications for at least 3 months.' (inclusion criterion,details not provided)

9 one of four doses of IVIG Gammagard (from 0 2 g/kg every 2 weeks to 0 8 g/kg every month) (6 months) placebo Cognitive functions measured by ADAS-Cog Other: ADCS-CGIC Activities of daily living measured by ADCS-ADL Behavioural changes measured by Neuropsychiatric Inventory (NPI) Variation of biomarkers (decrease of cerebrospinal fluid Aβ1-40/Aβ1-42; increase of serum Aβ1-40/Aβ1-42) Variation of imaging signs (change in SUVR at PIB-PET) Generic health related quality of life Disease specific health related quality of life Activities of daily living measured by ADCS-ADL Behavioural changes measured by Neuropsychiatric Inventory (NPI) Generic health related quality of life Disease specific health related quality of life No of patients enrolled: Estimated enrollment 24 Number of analysed patients. Not applicable, press release and publication documented, but no results posted in clinical.gov record. Author Disclosure (Conflict of interest): Not applicable Other designs Study title: Kountouris 2000 Study design: Open label, non-randomized controlled trial Study Registration number: Not reported Country: Greece

10 Centre: Unclear, Diagnostic Neurological Center, Michalakopoulou 45, Athens Greece? Ethics Committee Approval: Not reported Sponsor: Not reported Study period (study start, study end): Not reported Patients with Alzheimer's disease Age of patients. Not reported Sex: Not reported Disease severity: 'at the initial faze of the disease' AD therapy (cholinesterase inhibitor; memantine): Not reported. ' Both groups received 140 g of peracetam for the 1 year, IVIgG (Octagam) 0,2 g/kg + piracetam (12 months) Piracetam Cognitive functions measured by MMSE No of patients enrolled: 16, 8 in each group Number of analysed patients. Not spceifically reported Author Disclosure (Conflict of interest): Unclear. Octagam von OCTA farma A.G. provided the treatment? Study title: Papatriantafyllou 2006 Study design: A pilot, uncontrolled longitudinal study Study Registration number: Not reported Country: Greece Centre: Unclear, Memory Clinic, Neurology Department, General Hospital of Athens? Ethics Committee Approval: Unclear Sponsor: Unclear

11 Study period (study start, study end): Unclear Patients with mild-to-moderate Alzheimer's disease Age of patients: Sex: 3M/3F Disease severity: Mini Mental State Examination scores AD therapy (cholinesterase inhibitor; memantine): ' The patients were allowed to keep their previous medication which was steady for the last six months.' total dose of 0.4g/Kg IVIG in three consecutive days every 4 weeks (6 months) none Cognitive functions measured by MMSE No of patients enrolled: 6 Number of analysed patients: 5, reasons for withdrawal/drop-out not reported. Author Disclosure (Conflict of interest): None, disclosed by all authors Study title: Hara 2011 Study design: Uncontrolled longitudinal study Study Registration number: Not reported Country: USA Centre: Shankle Clinic, Newport Beach, California? Ethics Committee Approval: Not reported Sponsor: Not reported Study period (study start, study end): Not reported

12 Patients with Alzheimer's disease Age of patients: Not reported Sex: Not reported Disease severity: Not reported AD therapy (cholinesterase inhibitor; memantine): ' All patients also received Exelon and Namenda at all times.' IVIG ( months) none Cognitive functions measured by Memory Performance Index, and the Functional Assessment Staging test No of patients enrolled: 17 Patients (10 Alzheimer s disease, 4 Lewy body disease and 3 mixed Alzheimer s disease) Number of analysed patients.8/17 for cognitive, 16/17 for functional tests, 8/17 for FAST staging Author Disclosure (Conflict of interest): Not reported Study title: Kondo 2011 Study design: Uncontrolled longitudinal study Study Registration number: Not reported Country: Japan Centre: Unclear Ethics Committee Approval: Not reported Sponsor: Not reported Study period (study start, study end): Not reported Patient's with Alzheimer's disease Age of patients: Not reported Sex: Not reported Disease severity: Not reported AD therapy (cholinesterase inhibitor; memantine): Not reported

13 0.4 g/kg of IVIg for 3 consecutive days every month for 3 months none Cognitive functions measured by MMSE No of patients enrolled: 4 Number of analysed patients. 4, full data for 3, one withrew because of generalized seizure after the first session Author Disclosure (Conflict of interest): Unclear Study title: Rovira 2011 Study design: Single centre, open label pilot uncontrolled longitudinal study Study Registration number: Not reported Country: Spain Centre: Single, unclear Ethics Committee Approval: Not reported Sponsor: Not reported Study period (study start, study end): Not reported Patients with mild-to-moderate Alzheimer's disease Age of patients: Not reported Sex: Not reported Disease severity: Mild to moderate AD therapy (cholinesterase inhibitor; memantine): ' receiving stable donepezil treatment who previously had participated in a proof-of-concept study on plasmapheresis with 5% Human Albumin Grifols' 0.5 g/kg of IVIg (Flebogamma DIF, Grifols) every 2 weeks (6 months)

14 none Cognitive functions measured by ADAS-Cog, CDR-GS, MMSE No of patients enrolled: 4 Number of analysed patients.4 Author Disclosure (Conflict of interest): Unclear Study title: Relkin 2012 (open extension of NCT ) Study design: 12 month open label extension of a Phase II, double blind placebo controlled study Study Registration number: original study NCT Country: USA Centre: Unclear Ethics Committee Approval: Institution Review Bord; 'an IRB-approved extension protocol' Sponsor: Unclear Study period (study start, study end): Beginning at post-enrollment month 18 Patients with mild-to-moderate Alzheimer's disease Age of patients: supposedly as in NCT ; 50 and older Sex: supposedly as in NCT ; Both Disease severity: supposedly as in NCT ; mild to moderate (as stated in the title, see above), and 'as determined by a Mini Mental State Examination (MMSE) score of inclusive' (inclusion criterion) AD therapy (cholinesterase inhibitor; memantine): supposedly as in NCT ; 'On stable doses of approved AD medications for at least 3 months.' (inclusion criterion, details not provided) IVIG (Gammagard, Baxter) 0.4g/ kg/2 weeks (36 months) none

15 Cognitive functions measured by ADAS-Cog, ADCS-CGIC Activities of daily living measured by ADCS-ADL Behavioural changes measured by Neuropsychiatric Inventory (NPI) Generic health related quality of life Disease specific health related quality of life No of patients enrolled: 16, 5 in placebo group; 11 in intervention group Number of analysed patients: 16? Unclear Author Disclosure (Conflict of interest): Unclear Characteristics of terminated studies Randomized controlled trials Study title: NCT Study design: ' A Phase 3 Randomized, Double-blind, Placebo-led Study of the Safety and Effectiveness of Immune Globulin Intravenous (Human), 10% Solution (IGIV, 10%) for the Treatment of Mild to Moderate Alzheimer's Disease' Study Registration number: NCT (Last access September 18, 2014) Country: USA, Australia, Belgium, Canada, Japan, Poland, Spain, United Kingdom Centre: Multiple (70 in total) Ethics Committee Approval: Yes, by health authorities in respective countries Sponsor: Baxter Healthcare Corporation Study period (study start, study end): January March 2015 Age of patients: 50 to 89 years Sex: Both, M/F not reported Disease severity: Mild to moderate, as stated in the title (see above), and inclusion criterion 'Dementia of mild to moderate severity defined as Mini-Mental State Examination (MMSE) inclusive at screening' AD therapy (cholinesterase inhibitor; memantine): As stated in inclusion criterion: ' On stable doses of AD medication(s) for at least 12 weeks prior to screening. These medications must be continued throughout this study.'

16 IVIG (unspecified High and Low doses) (18 months) Placebo No of patients enrolled: Estimated enrollment 530 Number of analysed patients: 'The study was terminated because the first Phase 3 did not demonstrate efficacy on the co-primary endpoints. The known safety profile remained unchanged.' Author Disclosure (Conflict of interest): N/A Other designs Study title: NCT Study design: al, parallel groups, non randomized, open label study (' A Study of the Long-Term Safety and Efficacy of Immune Globulin Intravenous (Human), 10% Solution (IGIV, 10%) in Mild to Moderate Alzheimer s Disease') Study Registration number: NCT (Last access September 18, 2014) Country: USA & Canada Centre: Unclear Ethics Committee Approval: Yes, by health authorities in respective countries Sponsor: Baxter Healthcare Corporation Study period (study start, study end): November 2012 to April 2016 (final data collection date) Age of patients: 51 and older Sex: Both Disease severity: mild to moderate (as stated in the title, see above) AD therapy (cholinesterase inhibitor; memantine): Unclear IVIg IVIG (Gammagard Liquid) 200 mg or 400 mg/kg every 2 weeks (3 years)

17 None No of patients enrolled: 6 Number of analysed patients. N/A ' The study was terminated because the first Phase 3 did not demonstrate efficacy on the co-primary endpoints. The known safety profile remained unchanged.' Author Disclosure (Conflict of interest). N/A