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Clinical Trial Results:
A phase II a , Multicenter, Randomized , Third -party Unblinded , Long- term Extension study to Determine Safety, Tolerability and Immunogenicity of ACC-001 with and without QS21 Adjuvant in Subjects with Mild to Moderate Alzheimzer's Disease

Summary
EudraCT number	2009-010922-21
Trial protocol	DE FR ES
Global end of trial date	17 Dec 2013

Results information
Results version number	v1(current)
This version publication date	23 May 2016
First version publication date	05 Jul 2015
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

3134K1-2203-EU

ISRCTN number

US NCT number

NCT00955409

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer, Inc.

Sponsor organisation address

235 E 42nd St, New York, United States,

Public contact

Pfizer ClinicalTrials.gov Call Center , Pfizer, Inc., 1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center , Pfizer, Inc., 1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

03 Oct 2014

Is this the analysis of the primary completion data?

Yes

Primary completion date

17 Dec 2013

Global end of trial reached?

Yes

Global end of trial date

17 Dec 2013

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objective of the study is to evaluate the long-term safety and tolerability of doses of 3, 10, and 30 µg of ACC-001 (CRM-conjugated A-beta [1-7] antigen alone and in combination with QS-21 adjuvant) in subjects with mild to moderate AD. The Basic Results disclose pooled data from the extension studies 3134K1-2203-EU (B2571007) and 3434K1-2205-US (B2571008).

Protection of trial subjects

These studies were conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation Good Clinical Practice guidelines. Pfizer/Janssen Alzheimer’s Immunotherapy (AI) data monitoring committee (DMC) and external DMC were involved for the ongoing monitoring of participants' safety. The table 'Number of subjects enrolled per age group' below reflects the number of enrolled subjects in the extension study.

Background therapy

Evidence for comparator

Actual start date of recruitment

05 Nov 2009

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 110

Country: Number of subjects enrolled

Spain: 9

Country: Number of subjects enrolled

France: 15

Country: Number of subjects enrolled

Germany: 26

Worldwide total number of subjects

160

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

117

85 years and over

Subject disposition

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Recruitment details

Planned duration was approximately 2 years (including 18 months of treatment + 6 months of follow-up). Participants who completed the lead-in 3134K1-200-EU (B2571004) study through Week 78 (Week 104 for Cohort 1 and 2) had the option to stay in the lead-in study or to roll-over into the extension protocol 3134K1-2203-EU (B2571007).

Screening details

This extension study enrolled participants who completed lead-in study 3134K1-200-EU. All participants received active treatment in this extension study (ACC-001 with QS-21 adjuvant). Basic Results disclose pooled data from extension studies 3134K1-2203-EU (B2571007) and 3134K1-2205-US (B2571008). The row 'completed'=completed study in below table.

Period 1 title

Including treatment and follow up period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

ACC 3 μg+QS-21 /ACC 3 μg+QS-21

Arm description

Participants received 3 μg of ACC-001 and 50 μg of QS-21 in the lead-in study and in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

Arm type

Experimental

Investigational medicinal product name

ACC-001 + QS-21 Adjuvant

Investigational medicinal product code

ACC-001 + QS-21 Adjuvant

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Lead-in study and extension study: ACC-001 3 μg and QS-21 50 μg. Intramuscular use.

QS-21 / ACC 3 μg+QS-21

Arm description

Participants received 50 μg of QS-21 in the lead-in study and 3 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

Arm type

Experimental

Investigational medicinal product name

ACC-001 + QS-21 Adjuvant

Investigational medicinal product code

ACC-001 + QS-21 Adjuvant

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Lead-in study: QS-21 - 50 μg. Extension study: ACC-001 - 3 μg and QS-21 - 50 μg. Intramuscular use.

ACC 10 μg+QS-21 /ACC 10 μg+QS-21

Arm description

Participants received 10 μg of ACC-001 and 50 μg of QS-21 in the lead-in study and in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

Arm type

Experimental

Investigational medicinal product name

ACC-001 + QS-21 Adjuvant

Investigational medicinal product code

ACC-001 + QS-21 Adjuvant

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

In both lead-in study and extension study: ACC-001 - 10 μg and QS-21 - 50 μg. Intramuscular use.

ACC 10 μg / ACC 10 μg+QS-21

Arm description

Participants received 10 μg of ACC-001 in the lead-in study and 10 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

Arm type

Experimental

Investigational medicinal product name

ACC-001 + QS-21 Adjuvant

Investigational medicinal product code

ACC-001 + QS-21 Adjuvant

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Lead-in study: ACC-001 - 10 μg. Extension study: 10 μg ACC-001 and 50 μg QS-21. Intramuscular use.

QS-21 / ACC 10 μg+QS-21

Arm description

Participants received 50 μg of QS-21 in the lead-in study and 10 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

Arm type

Experimental

Investigational medicinal product name

ACC-001 + QS-21 Adjuvant

Investigational medicinal product code

ACC-001 + QS-21 Adjuvant

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Lead-in study: 50 μg QS-21. Extension study: 10 μg ACC-001 and 50 μg QS-21 . Intramuscular use.

PBS / ACC 10 μg+QS-21

Arm description

Participants received Phosphate buffered Saline (PBS) in the lead-in study and 10 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

Arm type

Experimental

Investigational medicinal product name

ACC-001 + QS-21 Adjuvant

Investigational medicinal product code

ACC-001 + QS-21 Adjuvant

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Lead-in study: PBS. Extension study: 10 μg ACC-001 and 50 μg QS-21 . Intramuscular use.

ACC 30 μg+QS-21/ACC 30 μg+QS-21

Arm description

Participants received 30 μg of ACC-001 and 50 μg of QS-21 in the lead-in study and in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

Arm type

Experimental

Investigational medicinal product name

ACC-001 + QS-21 Adjuvant

Investigational medicinal product code

ACC-001 + QS-21 Adjuvant

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Lead-in study and in extension study: 30 μg ACC-001 and 50 μg QS-21. Intramuscular use.

ACC 30 μg / ACC 30 μg+QS-21

Arm description

Participants received 30 μg of ACC-001 in the lead-in study and 30 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

Arm type

Experimental

Investigational medicinal product name

ACC-001 + QS-21 Adjuvant

Investigational medicinal product code

ACC-001 + QS-21 Adjuvant

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Lead-in study: 30 μg ACC-001. Extension study: 30 μg ACC-001 and 50 μg QS-21. Intramuscular use.

QS-21 / ACC 30 μg+QS-21

Arm description

Participants received 50 μg of QS-21 in the lead-in study and 30 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

Arm type

Experimental

Investigational medicinal product name

ACC-001 + QS-21 Adjuvant

Investigational medicinal product code

ACC-001 + QS-21 Adjuvant

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Lead-in study: 50 μg QS-21. Extension study: 30 μg ACC-001 and 50 μg QS-21. Intramuscular use.

PBS / ACC 30 μg+QS-21

Arm description

Participants received PBS in the lead-in study and 30 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

Arm type

Experimental

Investigational medicinal product name

ACC-001 + QS-21 Adjuvant

Investigational medicinal product code

ACC-001 + QS-21 Adjuvant

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Lead-in study: PBS. Extension study: 30 μg ACC-001 and 50 μg QS-21 . Intramuscular use.

Number of subjects in period 1	ACC 3 μg+QS-21 /ACC 3 μg+QS-21	QS-21 / ACC 3 μg+QS-21	ACC 10 μg+QS-21 /ACC 10 μg+QS-21	ACC 10 μg / ACC 10 μg+QS-21	QS-21 / ACC 10 μg+QS-21	PBS / ACC 10 μg+QS-21	ACC 30 μg+QS-21/ACC 30 μg+QS-21	ACC 30 μg / ACC 30 μg+QS-21	QS-21 / ACC 30 μg+QS-21	PBS / ACC 30 μg+QS-21
Started	21	6	41	25	5	9	27	6	16	4
Completed Treatment	12	5	15	17	3	7	4	3	2	4
Completed	11	5	15	17	3	6	3	2	2	3
Not completed	10	1	26	8	2	3	24	4	14	1
Consent withdrawn by subject	1	-	5	2	-	-	2	-	1	-
Physician decision	-	-	1	-	-	-	-	-	-	-
Adverse Event	2	-	-	-	-	1	2	-	2	-
Discontinuation of Study by Sponsor	-	-	-	-	-	-	-	1	-	-
Caregiver Request	2	-	6	5	-	2	3	1	3	-
Lost to follow-up	2	-	1	-	-	-	1	2	-	-
Retrieval subjects; impacted by sponsor disc.	2	1	13	1	2	-	16	-	8	1
Lack of efficacy	1	-	-	-	-	-	-	-	-	-

Baseline characteristics

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Reporting group title

ACC 3 μg+QS-21 /ACC 3 μg+QS-21

Reporting group description

Reporting group title

QS-21 / ACC 3 μg+QS-21

Reporting group description

Reporting group title

ACC 10 μg+QS-21 /ACC 10 μg+QS-21

Reporting group description

Reporting group title

ACC 10 μg / ACC 10 μg+QS-21

Reporting group description

Reporting group title

QS-21 / ACC 10 μg+QS-21

Reporting group description

Reporting group title

PBS / ACC 10 μg+QS-21

Reporting group description

Reporting group title

ACC 30 μg+QS-21/ACC 30 μg+QS-21

Reporting group description

Reporting group title

ACC 30 μg / ACC 30 μg+QS-21

Reporting group description

Reporting group title

QS-21 / ACC 30 μg+QS-21

Reporting group description

Reporting group title

PBS / ACC 30 μg+QS-21

Reporting group description

Reporting group values	ACC 3 μg+QS-21 /ACC 3 μg+QS-21	QS-21 / ACC 3 μg+QS-21	ACC 10 μg+QS-21 /ACC 10 μg+QS-21	ACC 10 μg / ACC 10 μg+QS-21	QS-21 / ACC 10 μg+QS-21	PBS / ACC 10 μg+QS-21	ACC 30 μg+QS-21/ACC 30 μg+QS-21	ACC 30 μg / ACC 30 μg+QS-21	QS-21 / ACC 30 μg+QS-21	PBS / ACC 30 μg+QS-21	Total
Number of subjects	21	6	41	25	5	9	27	6	16	4	160
Age categorical
Units: Subjects
50 - 64 Years	4	2	14	5	1	3	6	2	3	0	40
≥ 65 years	17	4	27	20	4	6	21	4	13	4	120
Age continuous
Units: years
arithmetic mean (standard deviation)	68.7 ( 6.94 )	67.7 ( 9.52 )	69.7 ( 9.29 )	72.4 ( 9.12 )	75.2 ( 8.23 )	69.6 ( 7.94 )	71.3 ( 9.2 )	66.3 ( 9.42 )	69.5 ( 6.95 )	75.8 ( 7.89 )	-
Gender categorical
Units: Subjects
Female	11	4	21	12	3	8	16	3	14	2	94
Male	10	2	20	13	2	1	11	3	2	2	66
Race/Ethnicity
Units: Subjects
Asian	0	0	0	0	0	0	0	0	0	0	0
Black or African American	0	0	1	0	1	0	1	0	0	0	3
Other	1	0	0	0	0	0	0	0	0	0	1
White	20	6	40	25	4	9	26	6	16	4	156
MMSE Ranges
Units: Subjects
MMSE score >26	0	0	5	3	1	1	1	0	1	0	12
MMSE score 21-26	5	2	9	7	2	3	8	3	6	3	48
MMSE score 16-20	5	2	12	10	2	3	11	2	6	0	53
MMSE score 10-15	10	2	15	5	0	2	7	1	3	1	46
MMSE score <10	1	0	0	0	0	0	0	0	0	0	1
MMSE Score
Units: Score
arithmetic mean (standard deviation)	16.7 ( 4.64 )	18.3 ( 5.61 )	18.4 ( 5.92 )	19.6 ( 5.45 )	21.8 ( 4.21 )	20 ( 6.14 )	18.7 ( 4.98 )	20.5 ( 4.76 )	19.1 ( 4.84 )	20 ( 4.69 )	-

End points

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Reporting group title

ACC 3 μg+QS-21 /ACC 3 μg+QS-21

Reporting group description

Reporting group title

QS-21 / ACC 3 μg+QS-21

Reporting group description

Reporting group title

ACC 10 μg+QS-21 /ACC 10 μg+QS-21

Reporting group description

Reporting group title

ACC 10 μg / ACC 10 μg+QS-21

Reporting group description

Reporting group title

QS-21 / ACC 10 μg+QS-21

Reporting group description

Reporting group title

PBS / ACC 10 μg+QS-21

Reporting group description

Reporting group title

ACC 30 μg+QS-21/ACC 30 μg+QS-21

Reporting group description

Reporting group title

ACC 30 μg / ACC 30 μg+QS-21

Reporting group description

Reporting group title

QS-21 / ACC 30 μg+QS-21

Reporting group description

Reporting group title

PBS / ACC 30 μg+QS-21

Reporting group description

Subject analysis set title

ACC 3 μg+QS-21 / ACC 3 μg+QS-21

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who received at least one dose of the study drug were included in the safety population. Subjects in this group received 3 μg of ACC-001 and 50 μg of QS-21 in the lead-in study and in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

Subject analysis set title

QS-21 / ACC 3 μg+QS-21

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who received at least one dose of the study drug were included in the safety population. Subjects in this group received 50 μg of QS-21 in the lead-in study and 3 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

Subject analysis set title

Active / ACC 10 μg+QS-21

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who received at least one dose of the study drug were included in the safety population. Subjects in this group received 10 μg of ACC-001 and 50 μg of QS-21 or 10 μg of ACC-001 alone in the lead-in study and 10 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

Subject analysis set title

Control / ACC 10 μg+QS-21

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who received at least one dose of the study drug were included in the safety population. Subjects received 50 μg of QS-21 or PBS in the lead-in study and 10 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

Subject analysis set title

Active / ACC 30 μg+QS-21

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who received at least one dose of the study drug were included in the safety population. Subjects received 30 μg of ACC-001 and 50 μg of QS-21 or 30 μg of ACC-001 alone in the lead-in study and 30 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

Subject analysis set title

Control / ACC 30 μg+QS-21

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who received at least one dose of the study drug were included in the safety population. Subjects in this group received 50 μg of QS-21 or PBS in the lead-in study and 30 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

Primary: Percentage of Participants With Treatment-emergent adverse events (AEs) or serious adverse events (SAEs)

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End point title

Percentage of Participants With Treatment-emergent adverse events (AEs) or serious adverse events (SAEs) ^[1]

End point description

An AE was any untoward, undesired, or unplanned clinical event in the form of signs, symptoms, disease, or laboratory or physiologic observations occurring in a person given study drug or in a sponsor's clinical study. The event did not need to be causally related to the study drug or the clinical studies. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.

End point type

Primary

End point timeframe

24 months

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was performed for this endpoint.

End point values	ACC 3 μg+QS-21 / ACC 3 μg+QS-21	QS-21 / ACC 3 μg+QS-21	Active / ACC 10 μg+QS-21	Control / ACC 10 μg+QS-21	Active / ACC 30 μg+QS-21	Control / ACC 30 μg+QS-21
Number of subjects analysed	21	6	65	14	33	20
Units: Percentage of participants
number (not applicable)
With TEAEs	100	100	93.8	92.9	78.8	90
With serious TEAEs	28.6	0	24.6	14.3	12.1	20

No statistical analyses for this end point

Other pre-specified: Geometric Mean Titers (GMTs) of Anti-A-beta Immunoglobulin G (IgG) Total Using an Enzyme-linked Immunosorbent Assay (ELISA) at Weeks 0, 4, 12, 24, 30, 36, 50, 56, 66, 76, 82, and 104

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End point title

Geometric Mean Titers (GMTs) of Anti-A-beta Immunoglobulin G (IgG) Total Using an Enzyme-linked Immunosorbent Assay (ELISA) at Weeks 0, 4, 12, 24, 30, 36, 50, 56, 66, 76, 82, and 104

End point description

The lower limit of quantification (LLOQ) was 100 U/mL and when the assay result was below LLOQ (100 U/mL), 50 U/mL was imputed for IgG.

End point type

Other pre-specified

End point timeframe

Weeks 0, 4, 12, 24, 30, 36, 50, 56, 66, 76, 82, and 104

End point values	ACC 3 μg+QS-21 /ACC 3 μg+QS-21	QS-21 / ACC 3 μg+QS-21	ACC 10 μg+QS-21 /ACC 10 μg+QS-21	ACC 10 μg / ACC 10 μg+QS-21	QS-21 / ACC 10 μg+QS-21	PBS / ACC 10 μg+QS-21	ACC 30 μg+QS-21/ACC 30 μg+QS-21	ACC 30 μg / ACC 30 μg+QS-21	QS-21 / ACC 30 μg+QS-21	PBS / ACC 30 μg+QS-21
Number of subjects analysed	21	6	41	24	5	9	27	6	16	4
Units: U/ml
geometric mean (confidence interval 95%)
Screening Lead-in (N:21,6,41,24,5,9,27,6,16,4)	50 (-99999 to 99999)	50 (-99999 to 99999)	50 (-99999 to 99999)	50 (575.1 to 3808.2)	50 (-99999 to 99999)	50 (-99999 to 99999)	50 (-99999 to 99999)	50 (-99999 to 99999)	58.8 (41.6 to 83.3)	50 (-99999 to 99999)
Screening Extension (N:21,6,41,24,5,9,27,6,16,4)	836.5 (362.2 to 1932.3)	50 (-99999 to 99999)	1623.4 (1015.3 to 2595.7)	180.2 (-99999 to 99999)	50 (-99999 to 99999)	50 (-99999 to 99999)	1718.3 (1101.2 to 2681.3)	424.2 (70.9 to 2539.4)	59.5 (41 to 86.3)	50 (-99999 to 99999)
Week 4 (N:21,6,41,24,5,9,27,5,16,4)	4523.7 (2070.2 to 9885)	50 (-99999 to 99999)	6219.3 (3853.2 to 10038.2)	517.9 (76.4 to 425.3)	50 (-99999 to 99999)	60.6 (38.9 to 94.4)	8436.2 (5569.8 to 12778)	4223 (185 to 96408.3)	144.7 (67.9 to 308)	100.1 (11 to 912.6)
Week 12 (N:21,6,41,23,4,9,27,5,16,4)	2540.3 (1060.5 to 6084.8)	50 (-99999 to 99999)	4251 (2709.7 to 6669.2)	425.4 (166.8 to 1607.6)	50 (-99999 to 99999)	62 (37.8 to 101.7)	3604.3 (2009.6 to 6464.5)	761.6 (33.2 to 17472.9)	89.3 (43.7 to 182.5)	87.9 (14.6 to 529.8)
Week 24 (N:21,6,39,24,4,9,27,5,15,3)	1466.6 (607.2 to 3542.4)	50 (-99999 to 99999)	3058.1 (1887.1 to 4955.9)	280.3 (137 to 1320.6)	50 (-99999 to 99999)	57.5 (41.7 to 79.2)	2146.4 (1309 to 3519.7)	541.1 (31.3 to 9362.1)	78.9 (42.6 to 146.1)	50 (-99999 to 99999)
Week 30 (N:18,6,38,20,4,6,24,5,14,3)	3780.6 (1941.7 to 7360.9)	477.1 (85.4 to 2664.5)	8682 (5670.1 to 13293.8)	1574.5 (100.2 to 784.4)	552.2 (37.8 to 8075.8)	317 (27.5 to 3654.9)	12939.5 (8634.4 to 19391.2)	1374.9 (54.4 to 34722.9)	1889.4 (570.8 to 6254.5)	4360.1 (30.3 to 627361.8)
Week 36 (N:18,6,36,20,4,9,25,5,14,3)	2927.8 (1368.7 to 6262.8)	267.1 (53.6 to 1331.2)	5946.6 (3807.1 to 9288.6)	1029.4 (568.2 to 4363.1)	282.9 (43.5 to 1838.7)	428 (83.8 to 2186.8)	6228.9 (3794.3 to 10225.7)	706.7 (33.6 to 14852.3)	1018.5 (297.8 to 3483.6)	1164.2 (23.4 to 57811.5)
Week 50 (N:17,6,37,20,4,8,20,5,13,3)	1843.8 (776.1 to 4380)	141.3 (24.5 to 813.2)	3146.6 (1945.8 to 5088.4)	512.4 (346.4 to 3059.1)	169.6 (35.8 to 804.5)	333.6 (63 to 1767)	2439 (1369.5 to 4343.8)	527.7 (33.4 to 8348.8)	651.3 (189.9 to 2233.5)	401.4 (4.5 to 35461.1)
Week 56 (N:17,6,32,19,4,8,12,4,5,3)	4958.8 (2257.8 to 10891)	1441.4 (159.3 to 13045.1)	10412.4 (6365.4 to 17032.7)	4562.2 (176.5 to 1487.4)	1720 (108.1 to 27356.9)	3451 (478.9 to 24871.3)	5241.2 (2459.3 to 11170.1)	2216.1 (38 to 129086.9)	578.3 (26.6 to 12559.5)	8033.5 (584.5 to 110404.7)
Week 66 (N:17,6,30,19,4,7,8,5,3,3)	2765 (1190.8 to 6420.3)	701.5 (86 to 5719.3)	6627.7 (3946.1 to 11131.5)	2049.2 (2233.3 to 9319.8)	891 (32.6 to 24385.5)	1989.2 (152.1 to 26014.2)	4341.1 (1677.8 to 11232.1)	1315.8 (117.1 to 14780.6)	968.4 (43 to 21784.1)	5403.5 (171.1 to 170698.5)
Week 76 (N:14,5,23,19,4,7,5,5,3,3)	2802.1 (1334.8 to 5882.6)	842.5 (107.7 to 6592.3)	3373.8 (1763.5 to 6454.6)	1479.9 (852.2 to 4927.5)	628.5 (26.6 to 1478.7)	1235.3 (116.5 to 13096.6)	2030.7 (576.9 to 7147.4)	875 (94.7 to 8083.3)	494.1 (1.2 to 198416.2)	2042.8 (107.4 to 38841.8)
Week 82 (N:13,5,16,18,3,7,4,4,2,3)	6831.1 (3436.2 to 13579.9)	5104.3 (540.8 to 48180.8)	12261.1 (6635.8 to 22655.2)	5771.4 (587.2 to 4172.5)	2768.5 (79 to 97040.9)	4779.6 (706.4 to 32339.3)	1902 (35 to 103340.7)	3736.1 (594.2 to 23491.3)	1617.1 (3 to 868223.9)	9922.5 (2059.8 to 47798.6)
Week 104 (N:12,5,14,17,2,5,5,2,2,3)	2951.6 (1259.3 to 6918.3)	1061 (77.8 to 14476)	6644.4 (2583.6 to 17088.1)	1565.2 (3264.4 to 10203.5)	1128.4 (0.1 to 25253974)	832.4 (56.5 to 12268.2)	1447.6 (548.5 to 3820.9)	3654.5 (11.3 to 1181935)	321.9 (0 to 12636639)	1340.5 (421.5 to 4263.3)

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Approximately 24 months, starting from Day 1, inclusive 18 months of dosing and 6 months of follow-up after the last dose.

Adverse event reporting additional description

Treatment emergent SAEs and non-SAEs are presented. Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another participant, or 1 participant may have experienced both a serious and nonserious event during the study.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

ACC 3 μg+QS-21 / ACC 3 μg+QS-21

Reporting group description

Reporting group title

QS-21 / ACC 3 μg+QS-21

Reporting group description

Reporting group title

Active / ACC 10 μg+QS-21

Reporting group description

Participants received 10 μg of ACC-001 and 50 μg of QS-21 or 10 μg of ACC-001 alone in the lead-in study and 10 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

Reporting group title

Control / ACC 10μg+QS-21

Reporting group description

Participants received 50 μg of QS-21 or PBS in the lead-in study and 10 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

Reporting group title

Active / ACC 30 μg+QS-21

Reporting group description

Participants received 30 μg of ACC-001 and 50 μg of QS-21 or 30 μg of ACC-001 alone in the lead-in study and 30 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

Reporting group title

Control / ACC 30 μg+QS-21

Reporting group description

Participants received 50 μg of QS-21 or PBS in the lead-in study and 30 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

Serious adverse events	ACC 3 μg+QS-21 / ACC 3 μg+QS-21	QS-21 / ACC 3 μg+QS-21	Active / ACC 10 μg+QS-21	Control / ACC 10μg+QS-21	Active / ACC 30 μg+QS-21	Control / ACC 30 μg+QS-21
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 21 (28.57%)	0 / 6 (0.00%)	16 / 65 (24.62%)	2 / 14 (14.29%)	4 / 33 (12.12%)	4 / 20 (20.00%)
number of deaths (all causes)	2	0	1	0	0	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gallbladder cancer metastatic
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	1 / 33 (3.03%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral vascular disorder
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Raynaud's phenomenon
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device dislocation
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	1 / 33 (3.03%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic mass
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	1 / 33 (3.03%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Abnormal behaviour
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	1 / 14 (7.14%)	1 / 33 (3.03%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Agitated depression
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	1 / 14 (7.14%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Agitation
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	1 / 14 (7.14%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Liver function test abnormal
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Forearm fracture
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hand fracture
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bradyarrhythmia
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cyanosis
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mitral valve prolapse
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral haemosiderin deposition
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dementia Alzheimer's type
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysarthria
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Partial seizures
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	1 / 14 (7.14%)	2 / 33 (6.06%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vasogenic cerebral oedema
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Biliary colic
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Drug eruption
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Petechiae
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin exfoliation
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin fissures
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin haemorrhage
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Calculus ureteric
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	1 / 33 (3.03%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	ACC 3 μg+QS-21 / ACC 3 μg+QS-21	QS-21 / ACC 3 μg+QS-21	Active / ACC 10 μg+QS-21	Control / ACC 10μg+QS-21	Active / ACC 30 μg+QS-21	Control / ACC 30 μg+QS-21
Total subjects affected by non serious adverse events
subjects affected / exposed	19 / 21 (90.48%)	6 / 6 (100.00%)	55 / 65 (84.62%)	13 / 14 (92.86%)	23 / 33 (69.70%)	17 / 20 (85.00%)
Vascular disorders
Haematoma
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	1	0	3	0	0	1
Haemorrhage
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	1	0	0	0	0	1
Hypertension
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	3 / 65 (4.62%)	0 / 14 (0.00%)	2 / 33 (6.06%)	0 / 20 (0.00%)
occurrences all number	1	0	3	0	2	0
Hypotension
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	5 / 65 (7.69%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	5	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	3 / 21 (14.29%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	3	0	0	0	0	0
Face oedema
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Fatigue
subjects affected / exposed	2 / 21 (9.52%)	1 / 6 (16.67%)	4 / 65 (6.15%)	0 / 14 (0.00%)	1 / 33 (3.03%)	0 / 20 (0.00%)
occurrences all number	2	1	7	0	1	0
Induration
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	1	0	0	1
Inflammation
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	1 / 14 (7.14%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0
Injection site bruising
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	2 / 33 (6.06%)	1 / 20 (5.00%)
occurrences all number	1	0	2	0	2	1
Injection site erythema
subjects affected / exposed	4 / 21 (19.05%)	0 / 6 (0.00%)	5 / 65 (7.69%)	1 / 14 (7.14%)	5 / 33 (15.15%)	4 / 20 (20.00%)
occurrences all number	8	0	5	1	9	6
Injection site haemorrhage
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	1 / 14 (7.14%)	0 / 33 (0.00%)	3 / 20 (15.00%)
occurrences all number	1	0	0	1	0	4
Injection site hypersensitivity
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Injection site induration
subjects affected / exposed	3 / 21 (14.29%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	4	0	1	0	0	0
Injection site inflammation
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	2 / 65 (3.08%)	0 / 14 (0.00%)	1 / 33 (3.03%)	1 / 20 (5.00%)
occurrences all number	0	0	3	0	1	1
Injection site pain
subjects affected / exposed	4 / 21 (19.05%)	0 / 6 (0.00%)	11 / 65 (16.92%)	2 / 14 (14.29%)	5 / 33 (15.15%)	6 / 20 (30.00%)
occurrences all number	7	0	15	2	9	8
Injection site pruritus
subjects affected / exposed	1 / 21 (4.76%)	4 / 6 (66.67%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	4	0	0	0	0
Injection site swelling
subjects affected / exposed	3 / 21 (14.29%)	0 / 6 (0.00%)	5 / 65 (7.69%)	0 / 14 (0.00%)	4 / 33 (12.12%)	1 / 20 (5.00%)
occurrences all number	3	0	6	0	7	1
Immune system disorders
Seasonal allergy
subjects affected / exposed	2 / 21 (9.52%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	0	0	0	0	0
Reproductive system and breast disorders
Testicular pain
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 21 (9.52%)	1 / 6 (16.67%)	3 / 65 (4.62%)	0 / 14 (0.00%)	1 / 33 (3.03%)	0 / 20 (0.00%)
occurrences all number	3	1	3	0	1	0
Hiccups
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Oropharyngeal pain
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	1 / 14 (7.14%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0
Psychiatric disorders
Abnormal behaviour
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	1 / 14 (7.14%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0
Aggression
subjects affected / exposed	1 / 21 (4.76%)	1 / 6 (16.67%)	2 / 65 (3.08%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	1	1	5	0	0	1
Agitation
subjects affected / exposed	3 / 21 (14.29%)	4 / 6 (66.67%)	5 / 65 (7.69%)	2 / 14 (14.29%)	3 / 33 (9.09%)	1 / 20 (5.00%)
occurrences all number	5	4	7	2	3	1
Anxiety
subjects affected / exposed	2 / 21 (9.52%)	0 / 6 (0.00%)	4 / 65 (6.15%)	1 / 14 (7.14%)	1 / 33 (3.03%)	0 / 20 (0.00%)
occurrences all number	2	0	5	1	3	0
Confusional state
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	4 / 65 (6.15%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	4	0	0	0
Delirium
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Delusional perception
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	1 / 14 (7.14%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0
Depression
subjects affected / exposed	3 / 21 (14.29%)	0 / 6 (0.00%)	3 / 65 (4.62%)	3 / 14 (21.43%)	2 / 33 (6.06%)	0 / 20 (0.00%)
occurrences all number	3	0	3	3	2	0
Irritability
subjects affected / exposed	0 / 21 (0.00%)	1 / 6 (16.67%)	1 / 65 (1.54%)	0 / 14 (0.00%)	1 / 33 (3.03%)	0 / 20 (0.00%)
occurrences all number	0	1	1	0	1	0
Nightmare
subjects affected / exposed	0 / 21 (0.00%)	1 / 6 (16.67%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	3	0	0	0	0
Investigations
Bartonella test positive
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	1 / 14 (7.14%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0
Urine output decreased
subjects affected / exposed	0 / 21 (0.00%)	1 / 6 (16.67%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0
Vitamin B1 decreased
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Weight decreased
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	1	0	0	1
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Contusion
subjects affected / exposed	3 / 21 (14.29%)	1 / 6 (16.67%)	2 / 65 (3.08%)	1 / 14 (7.14%)	2 / 33 (6.06%)	1 / 20 (5.00%)
occurrences all number	4	1	2	1	2	1
Corneal abrasion
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	1 / 14 (7.14%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0
Eye contusion
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Fall
subjects affected / exposed	4 / 21 (19.05%)	1 / 6 (16.67%)	7 / 65 (10.77%)	2 / 14 (14.29%)	2 / 33 (6.06%)	2 / 20 (10.00%)
occurrences all number	6	1	8	2	2	6
Hip fracture
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Laceration
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	3 / 65 (4.62%)	1 / 14 (7.14%)	2 / 33 (6.06%)	1 / 20 (5.00%)
occurrences all number	0	0	3	1	2	1
Limb injury
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	1	0	0	0	0	1
Periorbital contusion
subjects affected / exposed	0 / 21 (0.00%)	1 / 6 (16.67%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0
Cardiac disorders
Bradycardia
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	1 / 14 (7.14%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	1	0	0
Nervous system disorders
Balance disorder
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	1	0	0	0	0	1
Cognitive disorder
subjects affected / exposed	1 / 21 (4.76%)	1 / 6 (16.67%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	2 / 20 (10.00%)
occurrences all number	1	1	0	0	0	2
Dementia Alzheimer's type
subjects affected / exposed	0 / 21 (0.00%)	1 / 6 (16.67%)	1 / 65 (1.54%)	0 / 14 (0.00%)	1 / 33 (3.03%)	0 / 20 (0.00%)
occurrences all number	0	1	1	0	1	0
Dizziness
subjects affected / exposed	2 / 21 (9.52%)	0 / 6 (0.00%)	5 / 65 (7.69%)	2 / 14 (14.29%)	2 / 33 (6.06%)	2 / 20 (10.00%)
occurrences all number	2	0	6	2	2	2
Headache
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	6 / 65 (9.23%)	1 / 14 (7.14%)	3 / 33 (9.09%)	1 / 20 (5.00%)
occurrences all number	1	0	9	1	4	1
Hyperreflexia
subjects affected / exposed	0 / 21 (0.00%)	1 / 6 (16.67%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	1	0	0	0	1
Hypoaesthesia
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	1 / 14 (7.14%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0
Lethargy
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Myoclonus
subjects affected / exposed	1 / 21 (4.76%)	1 / 6 (16.67%)	2 / 65 (3.08%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	1	2	0	0	0
Syncope
subjects affected / exposed	2 / 21 (9.52%)	0 / 6 (0.00%)	2 / 65 (3.08%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	0	2	0	0	0
Tremor
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	0 / 65 (0.00%)	1 / 14 (7.14%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	1	0	0	1	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 21 (0.00%)	1 / 6 (16.67%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0
Ear and labyrinth disorders
Hearing impaired
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	1 / 14 (7.14%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0
Eye disorders
Cataract
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	1 / 14 (7.14%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0
Glaucoma
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Heterophoria
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Retinal degeneration
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Gastrointestinal disorders
Constipation
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	2 / 65 (3.08%)	0 / 14 (0.00%)	2 / 33 (6.06%)	2 / 20 (10.00%)
occurrences all number	0	0	2	0	2	2
Dental caries
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	1 / 33 (3.03%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1	1
Diarrhoea
subjects affected / exposed	4 / 21 (19.05%)	1 / 6 (16.67%)	3 / 65 (4.62%)	1 / 14 (7.14%)	2 / 33 (6.06%)	0 / 20 (0.00%)
occurrences all number	5	1	3	1	2	0
Faeces soft
subjects affected / exposed	0 / 21 (0.00%)	1 / 6 (16.67%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0
Inguinal hernia
subjects affected / exposed	0 / 21 (0.00%)	1 / 6 (16.67%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0
Nausea
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	3 / 65 (4.62%)	0 / 14 (0.00%)	0 / 33 (0.00%)	3 / 20 (15.00%)
occurrences all number	2	0	3	0	0	3
Periodontal disease
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Vomiting
subjects affected / exposed	3 / 21 (14.29%)	0 / 6 (0.00%)	1 / 65 (1.54%)	1 / 14 (7.14%)	1 / 33 (3.03%)	1 / 20 (5.00%)
occurrences all number	4	0	1	1	1	4
Skin and subcutaneous tissue disorders
Ecchymosis
subjects affected / exposed	2 / 21 (9.52%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	2	0	0	0	0	1
Erythema
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	2 / 65 (3.08%)	1 / 14 (7.14%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	2	1	0	0
Pruritus
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	3 / 65 (4.62%)	0 / 14 (0.00%)	1 / 33 (3.03%)	1 / 20 (5.00%)
occurrences all number	1	0	4	0	1	1
Rash
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	4 / 65 (6.15%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	5	0	0	0
Rosacea
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	1 / 14 (7.14%)	1 / 33 (3.03%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	1	0
Skin lesion
subjects affected / exposed	2 / 21 (9.52%)	0 / 6 (0.00%)	1 / 65 (1.54%)	2 / 14 (14.29%)	1 / 33 (3.03%)	1 / 20 (5.00%)
occurrences all number	2	0	1	2	1	1
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	1 / 14 (7.14%)	1 / 33 (3.03%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	2	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	4 / 65 (6.15%)	0 / 14 (0.00%)	1 / 33 (3.03%)	1 / 20 (5.00%)
occurrences all number	0	0	6	0	1	1
Back pain
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	4 / 65 (6.15%)	1 / 14 (7.14%)	1 / 33 (3.03%)	2 / 20 (10.00%)
occurrences all number	0	0	5	2	1	2
Muscle spasms
subjects affected / exposed	0 / 21 (0.00%)	1 / 6 (16.67%)	4 / 65 (6.15%)	1 / 14 (7.14%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	4	1	0	0
Musculoskeletal pain
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	1 / 65 (1.54%)	1 / 14 (7.14%)	1 / 33 (3.03%)	1 / 20 (5.00%)
occurrences all number	1	0	1	1	1	1
Neck pain
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	4 / 65 (6.15%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	4	0	0	0
Pain in extremity
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	3 / 65 (4.62%)	1 / 14 (7.14%)	1 / 33 (3.03%)	0 / 20 (0.00%)
occurrences all number	1	0	3	1	1	0
Infections and infestations
Bronchitis
subjects affected / exposed	3 / 21 (14.29%)	0 / 6 (0.00%)	1 / 65 (1.54%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	3	0	1	0	0	1
Conjunctivitis
subjects affected / exposed	0 / 21 (0.00%)	2 / 6 (33.33%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	2	0	0	0	0
Gastrointestinal infection
subjects affected / exposed	1 / 21 (4.76%)	1 / 6 (16.67%)	2 / 65 (3.08%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	1	2	0	0	0
Infected bites
subjects affected / exposed	0 / 21 (0.00%)	1 / 6 (16.67%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0
Influenza
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Localised infection
subjects affected / exposed	0 / 21 (0.00%)	1 / 6 (16.67%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0
Lyme disease
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	1 / 14 (7.14%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0
Nasopharyngitis
subjects affected / exposed	2 / 21 (9.52%)	1 / 6 (16.67%)	6 / 65 (9.23%)	0 / 14 (0.00%)	1 / 33 (3.03%)	0 / 20 (0.00%)
occurrences all number	4	1	9	0	1	0
Onychomycosis
subjects affected / exposed	1 / 21 (4.76%)	1 / 6 (16.67%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	1	0	0	0	0
Pneumonia
subjects affected / exposed	0 / 21 (0.00%)	1 / 6 (16.67%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0
Rhinitis
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	2 / 65 (3.08%)	0 / 14 (0.00%)	1 / 33 (3.03%)	1 / 20 (5.00%)
occurrences all number	0	0	3	0	1	1
Sinusitis
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	1 / 65 (1.54%)	1 / 14 (7.14%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	4	0	1	1	0	0
Subcutaneous abscess
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	1 / 14 (7.14%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0
Upper respiratory tract infection
subjects affected / exposed	1 / 21 (4.76%)	0 / 6 (0.00%)	3 / 65 (4.62%)	2 / 14 (14.29%)	1 / 33 (3.03%)	0 / 20 (0.00%)
occurrences all number	1	0	3	2	1	0
Urinary tract infection
subjects affected / exposed	1 / 21 (4.76%)	4 / 6 (66.67%)	9 / 65 (13.85%)	1 / 14 (7.14%)	2 / 33 (6.06%)	1 / 20 (5.00%)
occurrences all number	2	4	10	1	2	3
Vulvovaginal mycotic infection
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Wound infection
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	0 / 21 (0.00%)	0 / 6 (0.00%)	1 / 65 (1.54%)	1 / 14 (7.14%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	1	0	0
Glucose tolerance impaired
subjects affected / exposed	0 / 21 (0.00%)	1 / 6 (16.67%)	0 / 65 (0.00%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0
Vitamin D deficiency
subjects affected / exposed	0 / 21 (0.00%)	1 / 6 (16.67%)	3 / 65 (4.62%)	0 / 14 (0.00%)	0 / 33 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	3	0	0	0

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Were there any global substantial amendments to the protocol? Yes

04 Feb 2010

The following major changes were made in protocol amendment 1: - Study design was revised to clarify the study population, inclusion/exclusion criteria, concomitant medications, and procedures. - Protocol inconsistencies, omissions and errors were corrected.

30 Jun 2010

The following major changes were made in protocol amendment 2: - Study design was revised to clarify the study population, inclusion/exclusion criteria, concomitant medications, and procedures. - Protocol inconsistencies, omissions and errors were corrected.

13 Jan 2012

Protocol amendment 3 was made to update: - Exclusion criteria, inclusion of suicidality assessment, addition of direct and indirect bilirubin testing, and to update information and instructions pertaining to retrieval subjects, CSF sample collection, AEs/SAEs, discontinuation of investigational product due to injection site reactions, and reporting of safety issues.

14 Jun 2012

Protocol amendment 4 was made to update: - Adverse events, adverse events of special interest, concomitant treatments, and to add cerebral hemorrhage as an adverse drug reaction.

17 Dec 2013

The following major changes were made in protocol amendment 5: - CSF assays for anti-A-beta antibodies and IgG subtype analysis were listed as exploratory objectives and it was clarified that the analysis will not be conducted. - Specific protocol section was revised to clarify the inconsistency with the Investigator Brochure regarding the adverse events of special circumstance.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
12 Jul 2013	This study was prematurely terminated. In July 2013 the Alliance made a decision that ACC-001 would not be further developed in mild to moderate AD. Consequently, on 12 July 2013, dosing in the long-term extension studies was terminated and all remaining subjects were followed for safety for up to 6 months following their last administration of investigational product in accordance with the study protocols.	-

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

The following endpoints are not presented as these were not analyzed: GMTs of Anti-A-beta IgM and IgG Subtypes (where an IgG total response was measurable) using ELISA at Weeks 0, 4, 12, 24, 30, 36, 50, 56, 66, 76, 82, and 104.

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Clinical trials

Clinical Trial Results:
A phase II a , Multicenter, Randomized , Third -party Unblinded , Long- term Extension study to Determine Safety, Tolerability and Immunogenicity of ACC-001 with and without QS21 Adjuvant in Subjects with Mild to Moderate Alzheimzer's Disease

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants With Treatment-emergent adverse events (AEs) or serious adverse events (SAEs)

Primary: Percentage of Participants With Treatment-emergent adverse events (AEs) or serious adverse events (SAEs)

Other pre-specified: Geometric Mean Titers (GMTs) of Anti-A-beta Immunoglobulin G (IgG) Total Using an Enzyme-linked Immunosorbent Assay (ELISA) at Weeks 0, 4, 12, 24, 30, 36, 50, 56, 66, 76, 82, and 104

Other pre-specified: Geometric Mean Titers (GMTs) of Anti-A-beta Immunoglobulin G (IgG) Total Using an Enzyme-linked Immunosorbent Assay (ELISA) at Weeks 0, 4, 12, 24, 30, 36, 50, 56, 66, 76, 82, and 104

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A phase II a , Multicenter, Randomized , Third -party Unblinded , Long- term Extension study to Determine Safety, Tolerability and Immunogenicity of ACC-001 with and without QS21 Adjuvant in Subjects with Mild to Moderate Alzheimzer's Disease

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants With Treatment-emergent adverse events (AEs) or serious adverse events (SAEs)

Primary: Percentage of Participants With Treatment-emergent adverse events (AEs) or serious adverse events (SAEs)

Other pre-specified: Geometric Mean Titers (GMTs) of Anti-A-beta Immunoglobulin G (IgG) Total Using an Enzyme-linked Immunosorbent Assay (ELISA) at Weeks 0, 4, 12, 24, 30, 36, 50, 56, 66, 76, 82, and 104

Other pre-specified: Geometric Mean Titers (GMTs) of Anti-A-beta Immunoglobulin G (IgG) Total Using an Enzyme-linked Immunosorbent Assay (ELISA) at Weeks 0, 4, 12, 24, 30, 36, 50, 56, 66, 76, 82, and 104

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A phase II a , Multicenter, Randomized , Third -party Unblinded , Long- term Extension study to Determine Safety, Tolerability and Immunogenicity of ACC-001 with and without QS21 Adjuvant in Subjects with Mild to Moderate Alzheimzer's Disease