A Phase 2 Study of Atacicept in Subjects With Relapsing Multiple Sclerosis (ATAMS)

• Sponsor: EMD Serono (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00642902
• Collaborator: (none)
• Enrollment: 255
• Locations: 51
• Arms: 4
• Duration (Months): 17
• Patients Per Site: 5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

To evaluate the safety and tolerability of atacicept and to explore if atacicept reduces central nervous system inflammation in subjects with relapsing multiple sclerosis (RMS) as assessed by frequent magnetic resonance imaging (MRI). This study is randomised. Study medication is administered via subcutaneous (under the skin) injections.

Condition or Disease	Intervention/Treatment	Phase
Relapsing Multiple Sclerosis	Drug: Atacicept; Drug: Atacicept; Drug: Atacicept; Drug: Placebo matched to atacicept	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 255 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Four-Arm Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase II Study to Evaluate the Safety, Tolerability and Efficacy as Assessed by Frequent MRI Measures of 3 Doses of Atacicept Monotherapy in Subjects With Relapsing Multiple Sclerosis (RMS) Over a 36 Week Treatment Course
• Study Start Date: Apr 1, 2008
• Actual Primary Completion Date: Sep 1, 2009
• Actual Study Completion Date: Sep 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Atacicept 25 mg	Drug: Atacicept; Atacicept will be administered subcutaneously at a dose of 25 milligram (mg) twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 32 weeks.
Experimental: Atacicept 75 mg	Drug: Atacicept; Atacicept will be administered subcutaneously at a dose of 75 mg twice a week for initial 4 weeks as loading dose, followed by 75 mg once a week for subsequent 32 weeks.
Experimental: Atacicept 150 mg	Drug: Atacicept; Atacicept will be administered subcutaneously at a dose of 150 mg twice a week for initial 4 weeks as loading dose, followed by 150 mg once a week for subsequent 32 weeks.
Placebo Comparator: Placebo	Drug: Placebo matched to atacicept; Placebo matched to atacicept will be administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 32 weeks.

Outcome Measures

Primary Outcome Measures

1. Mean Number of Time Constant 1 (T1) Gadolinium (Gd)-Enhancing Lesions Per Participant Per Scan [Weeks 12 to 36]

   Analysis of T1 Gd-enhancing lesions was done using magnetic resonance imaging (MRI) scans. Only post-baseline scans were included in the calculation of this endpoint (excluding the Study Day 1 scan which had been conducted before first dosing).

Secondary Outcome Measures

1. Number of New T1 Gd-enhancing Lesions Per Participant [Weeks 12, 24, 36]

   Analysis of new T1 Gd-enhancing lesions was done using MRI scans.

2. Percentage of Participants Free From Relapses [Baseline up to Week 36]

   A relapse was defined as the fulfillment of all the following criteria: a) neurological abnormality, either newly appearing or re-appearing, with abnormality specified by both i) neurological abnormality separated by at least 30 days from onset of a preceding clinical event, and ii) neurological abnormality lasting for at least 24 hours; b) absence of fever or known infection (fever with temperature [axillary, orally, or intrauriculary] greater than (>) 37.5 degrees Celsius or 99.5 degrees Fahrenheit); and c) objective neurological impairment, correlating with the participant's reported symptoms, defined as either i) increase in at least 1 of the functional systems of the Expanded Disability Status Scale (EDSS), or ii) increase of the total EDSS score. Percentage of participants free from relapses during 36-week treatment period was reported.

3. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs [From the first dose of study drug administration up to 12 weeks after the last dose of the study drug]

   An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. An SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. Treatment-emergent are events between first dose of study drug up to 12 weeks after the last dose of the study drug that were absent before treatment or that worsened relative to pretreatment state. Number of subjects with TEAEs included subjects with both non serious and serious TEAEs.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of RMS (as per McDonald criteria, 2005) Other protocol-defined inclusion criteria could apply.

Exclusion Criteria:

• Have primary progressive multiple sclerosis (MS)

• Have secondary progressive MS without superimposed relapses

• Relevant cardiac, hepatic and renal diseases as specified in the protocol

• Pretreatment with immunosuppressants and immunomodulating drugs as specified in the protocol

• Clinical significant abnormalities in blood cell counts and immunoglobulin levels as specified in the protocol

• Clinical significant acute or chronic infections as specified in the protocol Other protocol-defined exclusion criteria could apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Phoenix	Arizona	United States
2	Research Site	Atlanta	Georgia	United States
3	Research Site	Northbrook	Illinois	United States
4	Research Site	East Lansing	Michigan	United States
5	Research Site	Dartmouth	New Hampshire	United States
6	Research Site	Cleveland	Ohio	United States
7		Philadelphia	Pennsylvania	United States
8	Research Site	Nashville	Tennessee	United States
9	Research Site	Box Hill		Australia
10	Research Site	Fitzroy		Australia
11	Research Site	New Lambton		Australia
12	Research Site	Woodville		Australia
13	Research Site	Innsbruck		Austria
14	Research Site	Diepenbeek		Belgium
15	Research Site	Sijsele		Belgium
16	Research Site	Calgary	Alberta	Canada
17	Research Site	Ottawa	Ontario	Canada
18	Research Site	Ontario		Canada
19	Research Site	Brno		Czech Republic
20	Research Site	Hradec Kralove		Czech Republic
21	Research Site	Olomouc		Czech Republic
22	Research Site	Caen		France
23	Research Site	Saint-Herblain		France
24	Research Site	Bochum		Germany
25	Research Site	Dusseldorf		Germany
26	Research Site	Beirut		Lebanon
27	Research Site	Beyrouth		Lebanon
28	Research Site	Kaunas		Lithuania
29	Research Site	Breda		Netherlands
30	Research Site	Nieuwegein		Netherlands
31	Research Site	Rotterdam		Netherlands
32	Research Site	Dnipropetrovsk		Russian Federation
33	Research Site	Ekaterinburg		Russian Federation
34	Research Site	Moscow		Russian Federation
35	Research Site	Novosibirsk		Russian Federation
36	Research Site	Saint Petersburg		Russian Federation
37	Research Site	Samara		Russian Federation
38	Research Site	Vladimir		Russian Federation
39	Research Site	Yaroslavl		Russian Federation
40	Research Site	Barcelona		Spain
41	Research Site	Madrid		Spain
42	Research Site	Malaga		Spain
43	Research Site	Stockholm		Sweden
44	Research Site	Basel		Switzerland
45	Research Site	Kharkiv		Ukraine
46	Research Site	Kyiv		Ukraine
47	Research Site	Odessa		Ukraine
48	Research Site	Uzhgorod		Ukraine
49	Research Site	London		United Kingdom
50	Research Site	Sheffield		United Kingdom
51	Research Site	Stoke on Trent		United Kingdom

Sponsors and Collaborators

• EMD Serono

Investigators

• Study Director: Medical Responsible, EMD Serono, an affiliate of Merck KGaA Darmstadt, Germany

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: EMD Serono
• ClinicalTrials.gov Identifier: NCT00642902
• Other Study ID Numbers: 28063
• First Posted: Mar 25, 2008
• Last Update Posted: May 24, 2016
• Last Verified: Apr 1, 2016

• Keywords provided by EMD Serono: Relapsing Multiple Sclerosis; Atacicept
• Additional relevant MeSH terms: Multiple Sclerosis; Sclerosis

Study Results

Participant Flow

Arm/Group Title	Placebo	Atacicept 25 mg	Atacicept 75 mg	Atacicept 150 mg
Arm/Group Description	Placebo matched to atacicept was administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 32 weeks.	Atacicept was administered subcutaneously at a dose of 25 milligram (mg) twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 32 weeks.	Atacicept was administered subcutaneously at a dose of 75 mg twice a week for initial 4 weeks as loading dose, followed by 75 mg once a week for subsequent 32 weeks.	Atacicept was administered subcutaneously at a dose of 150 mg twice a week for initial 4 weeks as loading dose, followed by 150 mg once a week for subsequent 32 weeks.
Period Title: Overall Study
STARTED	63	63	64	65
Treated	63	63	63	65
COMPLETED	23	21	21	25
NOT COMPLETED	40	42	43	40

Baseline Characteristics

Arm/Group Title	Placebo	Atacicept 25 mg	Atacicept 75 mg	Atacicept 150 mg	Total
Arm/Group Description	Placebo matched to atacicept was administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 32 weeks.	Atacicept was administered subcutaneously at a dose of 25 milligram (mg) twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 32 weeks.	Atacicept was administered subcutaneously at a dose of 75 mg twice a week for initial 4 weeks as loading dose, followed by 75 mg once a week for subsequent 32 weeks.	Atacicept was administered subcutaneously at a dose of 150 mg twice a week for initial 4 weeks as loading dose, followed by 150 mg once a week for subsequent 32 weeks.	Total of all reporting groups
Overall Participants	63	63	64	65	255
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.7 (10.5)	37.5 (8.5)	38.0 (10.1)	37.5 (10.5)	37.7 (9.9)
Sex: Female, Male (Count of Participants)
Female	45 71.4%	34 54%	44 68.8%	46 70.8%	169 66.3%
Male	18 28.6%	29 46%	20 31.3%	19 29.2%	86 33.7%

Outcome Measures

1. Primary Outcome

Title	Mean Number of Time Constant 1 (T1) Gadolinium (Gd)-Enhancing Lesions Per Participant Per Scan
Description	Analysis of T1 Gd-enhancing lesions was done using magnetic resonance imaging (MRI) scans. Only post-baseline scans were included in the calculation of this endpoint (excluding the Study Day 1 scan which had been conducted before first dosing).
Time Frame	Weeks 12 to 36

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants.

Arm/Group Title	Placebo	Atacicept 25 mg	Atacicept 75 mg	Atacicept 150 mg
Arm/Group Description	Placebo matched to atacicept was administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 32 weeks.	Atacicept was administered subcutaneously at a dose of 25 milligram (mg) twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 32 weeks.	Atacicept was administered subcutaneously at a dose of 75 mg twice a week for initial 4 weeks as loading dose, followed by 75 mg once a week for subsequent 32 weeks.	Atacicept was administered subcutaneously at a dose of 150 mg twice a week for initial 4 weeks as loading dose, followed by 150 mg once a week for subsequent 32 weeks.
Measure Participants	63	63	64	65
Mean (95% Confidence Interval) [lesions/participant/scan]	3.07	2.26	2.30	2.49

2. Secondary Outcome

Title	Number of New T1 Gd-enhancing Lesions Per Participant
Description	Analysis of new T1 Gd-enhancing lesions was done using MRI scans.
Time Frame	Weeks 12, 24, 36

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants. 'n' signifies participants who were evaluable for this measure at given time points for each group, respectively.

Arm/Group Title	Placebo	Atacicept 25 mg	Atacicept 75 mg	Atacicept 150 mg
Arm/Group Description	Placebo matched to atacicept was administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 32 weeks.	Atacicept was administered subcutaneously at a dose of 25 milligram (mg) twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 32 weeks.	Atacicept was administered subcutaneously at a dose of 75 mg twice a week for initial 4 weeks as loading dose, followed by 75 mg once a week for subsequent 32 weeks.	Atacicept was administered subcutaneously at a dose of 150 mg twice a week for initial 4 weeks as loading dose, followed by 150 mg once a week for subsequent 32 weeks.
Measure Participants	63	63	64	65
Week 12 (n=55, 45, 50, 55)	2.55 (7.95)	2.71 (7.67)	3.20 (6.41)	2.96 (6.58)
Week 24 (n=41, 34, 37, 41)	0.83 (1.70)	1.50 (2.79)	1.54 (2.96)	1.54 (2.94)
Week 36 (n=23, 22, 24, 26)	0.43 (0.90)	1.68 (5.09)	1.38 (1.93)	0.54 (1.07)

3. Secondary Outcome

Title	Percentage of Participants Free From Relapses
Description	A relapse was defined as the fulfillment of all the following criteria: a) neurological abnormality, either newly appearing or re-appearing, with abnormality specified by both i) neurological abnormality separated by at least 30 days from onset of a preceding clinical event, and ii) neurological abnormality lasting for at least 24 hours; b) absence of fever or known infection (fever with temperature [axillary, orally, or intrauriculary] greater than (>) 37.5 degrees Celsius or 99.5 degrees Fahrenheit); and c) objective neurological impairment, correlating with the participant's reported symptoms, defined as either i) increase in at least 1 of the functional systems of the Expanded Disability Status Scale (EDSS), or ii) increase of the total EDSS score. Percentage of participants free from relapses during 36-week treatment period was reported.
Time Frame	Baseline up to Week 36

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants.

Arm/Group Title	Placebo	Atacicept 25 mg	Atacicept 75 mg	Atacicept 150 mg
Arm/Group Description	Placebo matched to atacicept was administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 32 weeks.	Atacicept was administered subcutaneously at a dose of 25 milligram (mg) twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 32 weeks.	Atacicept was administered subcutaneously at a dose of 75 mg twice a week for initial 4 weeks as loading dose, followed by 75 mg once a week for subsequent 32 weeks.	Atacicept was administered subcutaneously at a dose of 150 mg twice a week for initial 4 weeks as loading dose, followed by 150 mg once a week for subsequent 32 weeks.
Measure Participants	63	63	64	65
Number [percentage of participants]	81.0 128.6%	69.8 110.8%	71.9 112.3%	61.5 94.6%

4. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs
Description	An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. An SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. Treatment-emergent are events between first dose of study drug up to 12 weeks after the last dose of the study drug that were absent before treatment or that worsened relative to pretreatment state. Number of subjects with TEAEs included subjects with both non serious and serious TEAEs.
Time Frame	From the first dose of study drug administration up to 12 weeks after the last dose of the study drug

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least 1 dose of treatment (either active or placebo).

Arm/Group Title	Placebo	Atacicept 25 mg	Atacicept 75 mg	Atacicept 150 mg
Arm/Group Description	Placebo matched to atacicept was administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 32 weeks.	Atacicept was administered subcutaneously at a dose of 25 milligram (mg) twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 32 weeks.	Atacicept was administered subcutaneously at a dose of 75 mg twice a week for initial 4 weeks as loading dose, followed by 75 mg once a week for subsequent 32 weeks.	Atacicept was administered subcutaneously at a dose of 150 mg twice a week for initial 4 weeks as loading dose, followed by 150 mg once a week for subsequent 32 weeks.
Measure Participants	63	63	63	65
TEAEs	46 73%	40 63.5%	39 60.9%	52 80%
Serious TEAEs	1 1.6%	3 4.8%	3 4.7%	1 1.5%

Adverse Events

Time Frame	From the first dose of study drug administration up to 12 weeks after the last dose of the study drug
Arm/Group Title	Placebo		Atacicept 25 mg		Atacicept 75 mg		Atacicept 150 mg
Arm/Group Description	Placebo matched to atacicept was administered subcutaneously twice a week for initial 4 weeks, followed by once a week for subsequent 32 weeks.		Atacicept was administered subcutaneously at a dose of 25 milligram (mg) twice a week for initial 4 weeks as loading dose, followed by 25 mg once a week for subsequent 32 weeks.		Atacicept was administered subcutaneously at a dose of 75 mg twice a week for initial 4 weeks as loading dose, followed by 75 mg once a week for subsequent 32 weeks.		Atacicept was administered subcutaneously at a dose of 150 mg twice a week for initial 4 weeks as loading dose, followed by 150 mg once a week for subsequent 32 weeks.
All Cause Mortality
	Placebo		Atacicept 25 mg		Atacicept 75 mg		Atacicept 150 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Atacicept 25 mg		Atacicept 75 mg		Atacicept 150 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/63 (1.6%)		3/63 (4.8%)		3/63 (4.8%)		1/65 (1.5%)
Cardiac disorders
Myocardial infarction	1/63 (1.6%)		0/63 (0%)		0/63 (0%)		0/65 (0%)
Endocrine disorders
Hypothyroidism	0/63 (0%)		0/63 (0%)		1/63 (1.6%)		0/65 (0%)
General disorders
Asthenia	0/63 (0%)		0/63 (0%)		1/63 (1.6%)		0/65 (0%)
Infections and infestations
Lung abscess	0/63 (0%)		0/63 (0%)		1/63 (1.6%)		0/65 (0%)
Pyothorax	0/63 (0%)		0/63 (0%)		1/63 (1.6%)		0/65 (0%)
Pneumonia	0/63 (0%)		0/63 (0%)		1/63 (1.6%)		0/65 (0%)
Otitis media acute	0/63 (0%)		0/63 (0%)		0/63 (0%)		1/65 (1.5%)
Injury, poisoning and procedural complications
Hip fracture	0/63 (0%)		1/63 (1.6%)		0/63 (0%)		0/65 (0%)
Humerus fracture	0/63 (0%)		1/63 (1.6%)		0/63 (0%)		0/65 (0%)
Investigations
Body temperature decreased	0/63 (0%)		0/63 (0%)		1/63 (1.6%)		0/65 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Parathyroid tumour benign	0/63 (0%)		0/63 (0%)		1/63 (1.6%)		0/65 (0%)
Psychiatric disorders
Acute psychosis	0/63 (0%)		1/63 (1.6%)		0/63 (0%)		0/65 (0%)
Anxiety	0/63 (0%)		0/63 (0%)		1/63 (1.6%)		0/65 (0%)
Respiratory, thoracic and mediastinal disorders
Pleurisy	0/63 (0%)		0/63 (0%)		1/63 (1.6%)		0/65 (0%)
Bronchopleural fistula	0/63 (0%)		0/63 (0%)		1/63 (1.6%)		0/65 (0%)
Pneumothorax	0/63 (0%)		0/63 (0%)		2/63 (3.2%)		0/65 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Atacicept 25 mg		Atacicept 75 mg		Atacicept 150 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/63 (52.4%)		30/63 (47.6%)		34/63 (54%)		44/65 (67.7%)
Gastrointestinal disorders
Diarrhoea	1/63 (1.6%)		1/63 (1.6%)		3/63 (4.8%)		5/65 (7.7%)
Nausea	2/63 (3.2%)		3/63 (4.8%)		1/63 (1.6%)		4/65 (6.2%)
General disorders
Injection site reaction	8/63 (12.7%)		19/63 (30.2%)		24/63 (38.1%)		32/65 (49.2%)
Fatigue	0/63 (0%)		1/63 (1.6%)		3/63 (4.8%)		4/65 (6.2%)
Injection site pain	2/63 (3.2%)		2/63 (3.2%)		0/63 (0%)		4/65 (6.2%)
Infections and infestations
Nasopharyngitis	6/63 (9.5%)		4/63 (6.3%)		7/63 (11.1%)		13/65 (20%)
Urinary tract infection	3/63 (4.8%)		4/63 (6.3%)		7/63 (11.1%)		3/65 (4.6%)
Upper respiratory tract infection	3/63 (4.8%)		1/63 (1.6%)		4/63 (6.3%)		8/65 (12.3%)
Bronchitis	1/63 (1.6%)		2/63 (3.2%)		1/63 (1.6%)		5/65 (7.7%)
Influenza	5/63 (7.9%)		1/63 (1.6%)		1/63 (1.6%)		2/65 (3.1%)
Musculoskeletal and connective tissue disorders
Back pain	4/63 (6.3%)		0/63 (0%)		3/63 (4.8%)		3/65 (4.6%)
Pain in extremity	4/63 (6.3%)		3/63 (4.8%)		1/63 (1.6%)		1/65 (1.5%)
Nervous system disorders
Headache	11/63 (17.5%)		8/63 (12.7%)		3/63 (4.8%)		6/65 (9.2%)

Limitations/Caveats

Sponsor voluntarily decided to prematurely terminate this trial due to an increase in multiple sclerosis (MS) disease activity observed in atacicept arms as compared to placebo during a routine independent data monitoring committee (IDMC) review.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Prior to publishing results, Institution and Principal Investigator (PI) must first provide Sponsor with a copy of proposed publication for review at least 30 days prior to submission. If Institution and PI do not agree to modification, they shall so notify Sponsor and postpone submission for additional 60 days to allow Sponsor to seek legal remedies or file patent applications. There is a need for coordinated approach to any publication of results from sites for any multi-site study.