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Trial registered on ANZCTR


Registration number
ACTRN12608000226303
Ethics application status
Approved
Date submitted
29/02/2008
Date registered
1/05/2008
Date last updated
21/07/2009
Type of registration
Retrospectively registered

Titles & IDs
Public title
A double-blind, placebo controlled, randomised trial to prove the therapeutic concept and to determine the pharmacokinetic profile of ATL1102 (VLA-4 antisense oligonucleotide) by subcutaneous injections in patients with relapsing remitting multiple sclerosis.
Scientific title
A double-blind, placebo controlled, randomised trial to prove the therapeutic concept and to determine the pharmacokinetic profile of ATL1102 (VLA-4 antisense oligonucleotide) by subcutaneous injections in patients with multiple sclerosis.
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Sclerosis 2760 0
Condition category
Condition code
Neurological 2890 2890 0 0
Multiple sclerosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients receive 200 mg ATL1102 (VLA-4 antisense oligonucleotide) by subcutaneous injection three times in the first week, then twice weekly for the next seven weeks. The patients are monitored for a further eight weeks following completion of dosing.
Intervention code [1] 2500 0
Treatment: Drugs
Comparator / control treatment
1.3 ml placebo comprising sodium chloride and colorant by subcutaneous injection three times in the first week, then twice weekly for the next seven weeks. The patients are monitored for a further eight weeks following completion of dosing.
Control group
Placebo

Outcomes
Primary outcome [1] 3772 0
Cumulative number of new active lesions on Magnetic Resonance Imaging (MRI), corrected for the number of enhancing lesions at baseline.
Timepoint [1] 3772 0
At 4, 8 and 12 weeks after intervention commencement.
Secondary outcome [1] 6373 0
Cumulative volume of gadolinium-enhancing lesions on MRI, corrected for the volume of enhancing lesions at baseline.
Timepoint [1] 6373 0
At 4, 8 and 12 weeks after intervention commencement.

Eligibility
Key inclusion criteria
Males and females aged 18 to 55 years
Diagnosis of Relapsing Remitting Multiple Sclerosis (RRMS)
At least 9 T2 lesions or at least 4 if one is gadolinium-enhancing
Last relapse in the previous 12 months
No relapse in the previous four weeks
Score of EDSS 0 to 6.0
Reliable contraception (e.g. surgical sterilisation, oral contraceptives)
Written informed consent to participate in the study by signature on the Patients Consent Form
Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Administration of any investigational drug within the previous 2 months before enrolment (4 months if the previous drug was a new chemical entity).
Progressive disease.
Concomitant clinically relevant other findings on MRI that may interfere with outcome assessment.
Previous treatment with VLA-4 antibodies, anti-CD4 antibodies, or other monoclonal antibodies.
Total lymphoid irradiation at any time.
Treatment with immune-modulating drugs in the previous two months or treatment with immune-suppressive drugs in the previous six months.
HIV positive patients.
Detectable levels of JC Virus in the blood measured by quantitative PCR.
Patients with renal impairment with serum creatinine greater than or equal to 2,0 mg/dl.
History of clinically relevant gastrointestinal, hepatic, renal, endocrine, haematological, metabolic, neurologic (other than multiple sclerosis (MS)) and psychiatric disease.
Patients with infections (lymphocytes greater than 3000/microL).
History of any bleeding.
History of coagulation abnormalities.
Concomitant medication acetyl salicylic acid (greater than 300 mg/day) and phenprocoumon.
Clinically relevant abnormalities in physical findings at screening examination if interfering with the study objective.
Pregnant or breast-feeding women.
History of drug or alcohol abuse.
Epileptics.
Suicidal subjects.
History of drug allergy and/or known drug hypersensitivity.
Inability to communicate or cooperate with the Investigator due to language problem, poor mental development or impaired cerebral function.
Any medical condition which, in the judgement of the Investigator, might interfere with the objectives of the study.
Repeated participation in this study.
Contraindication for application of study drug.
Corticoid-treatment in the previous six weeks and during the study period, exceptions are corticoid-treatment before the study period (not in the previous six weeks) and of relapses during the study period: Relapses are characterised by the occurrence of neurological dysfunction symptoms, appearing after a 30-day period of stability or improvement and lasting for more than 24 hours (no infection, no fever).
A 5-day methylprednisolone treatment 1000 mg intravenous (i.v) is allowed in this case followed by a reducing procedure.
Corticoid-treatment if applied locally (e.g. inhaled products) is allowed.
Additionally MRI exclusion criteria: Metal residing in the body (e.g. implants), Cardiac pacemaker, valves, cochlear implants, CNS vascular clips.
Contrast medium allergy Gadolinium Diethylenetriamine Penta-Acetic Acid (Gd-DTPA).
No MRI exclusion criteria but caution is advised in case of: Cardiovascular disease including coronary heart disease, Immune deficiency, Haematologic disorder.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 754 0
Slovakia
State/province [1] 754 0
Country [2] 755 0
Poland
State/province [2] 755 0
Country [3] 756 0
Czech Republic
State/province [3] 756 0
Country [4] 757 0
Romania
State/province [4] 757 0
Country [5] 758 0
Bulgaria
State/province [5] 758 0
Country [6] 759 0
Germany
State/province [6] 759 0

Funding & Sponsors
Funding source category [1] 3143 0
Commercial sector/Industry
Name [1] 3143 0
Antisense Therapeutics Limited
Address [1] 3143 0
10 Wallace Avenue, Level 1
Toorak
Country [1] 3143 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Antisense Therapeutics Limited
Address
10 Wallace Avenue, Level 1
Toorak
Vic 3142
Country
Australia
Secondary sponsor category [1] 2718 0
None
Name [1] 2718 0
Address [1] 2718 0
Country [1] 2718 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 5044 0
Ethics Committee of the Faculty of Medicine, University of Duisburg-Essen, University Clinic Essen
Ethics committee address [1] 5044 0
Robert-Koch-Str. 9-11 45147 Essen
Ethics committee country [1] 5044 0
Germany
Date submitted for ethics approval [1] 5044 0
Approval date [1] 5044 0
05/08/2004
Ethics approval number [1] 5044 0
Idnr: 04-2508
Ethics committee name [2] 5045 0
Ethics Committee of the State Chamber of Physicians of the Federal State of Hessen
Ethics committee address [2] 5045 0
Im Vogelsang 3 60488 Frankfurt am Main
Ethics committee country [2] 5045 0
Germany
Date submitted for ethics approval [2] 5045 0
Approval date [2] 5045 0
12/10/2004
Ethics approval number [2] 5045 0
E 258/2004MC
Ethics committee name [3] 5046 0
Ethics Committee of the Chamber of Physicians of the Federal State of Lower Saxony, Corporation under Public Law
Ethics committee address [3] 5046 0
Berliner Allee 20 30175 Hannover
Ethics committee country [3] 5046 0
Germany
Date submitted for ethics approval [3] 5046 0
Approval date [3] 5046 0
05/10/2004
Ethics approval number [3] 5046 0
Grae 212/2004
Ethics committee name [4] 5047 0
Ethics Committee of the Chamber of Physicians of the Federal State of Mecklenburg-West Pomerania at the University of Rostock, Institute of Forensic Medicine
Ethics committee address [4] 5047 0
Postfach 100888 18055 Rostock
Ethics committee country [4] 5047 0
Germany
Date submitted for ethics approval [4] 5047 0
Approval date [4] 5047 0
20/10/2004
Ethics approval number [4] 5047 0
II SV 68/2004
Ethics committee name [5] 5048 0
Ethics Committee of the State Chamber of Physicians of Thuringia, Corporation under Public Law
Ethics committee address [5] 5048 0
Im Semmicht 33 07751 Jena
Ethics committee country [5] 5048 0
Germany
Date submitted for ethics approval [5] 5048 0
Approval date [5] 5048 0
21/10/2004
Ethics approval number [5] 5048 0
kl/1117/04112
Ethics committee name [6] 5049 0
Ethics Committee of the Chamber of Physicians of Berlin, Corporation under Public Law
Ethics committee address [6] 5049 0
Friedrichstrasse 16 10969 Berlin
Ethics committee country [6] 5049 0
Germany
Date submitted for ethics approval [6] 5049 0
Approval date [6] 5049 0
19/01/2005
Ethics approval number [6] 5049 0
Eth-012/05
Ethics committee name [7] 5050 0
Ethics Committee of the Medical University of Hannover
Ethics committee address [7] 5050 0
Carl-Neuberg-Str. 1 30625 Hannover
Ethics committee country [7] 5050 0
Germany
Date submitted for ethics approval [7] 5050 0
Approval date [7] 5050 0
21/03/2005
Ethics approval number [7] 5050 0
Nr. 3884
Ethics committee name [8] 5051 0
Ethics Committee of the State Chamber of Physicians of Rhineland-Palatinate, Corporation under Public Law
Ethics committee address [8] 5051 0
Postfach 2926 55019 Mainz
Ethics committee country [8] 5051 0
Germany
Date submitted for ethics approval [8] 5051 0
Approval date [8] 5051 0
19/09/2006
Ethics approval number [8] 5051 0
837.253.06 (5351)
Ethics committee name [9] 5052 0
Ethics Committee of the Chamber of Physicians of Hamburg, Corporation under Public Law
Ethics committee address [9] 5052 0
Postfach 760109 22051 Hamburg
Ethics committee country [9] 5052 0
Germany
Date submitted for ethics approval [9] 5052 0
Approval date [9] 5052 0
22/08/2006
Ethics approval number [9] 5052 0
M-206/06
Ethics committee name [10] 5053 0
Ethics Committee of the Faculty of Medicine, University of Witten/Herdecke
Ethics committee address [10] 5053 0
Alfred-Herrhausen-Str.50 D58448 Witten
Ethics committee country [10] 5053 0
Germany
Date submitted for ethics approval [10] 5053 0
Approval date [10] 5053 0
24/04/2006
Ethics approval number [10] 5053 0
Antragsnr. 33/2006
Ethics committee name [11] 5055 0
MHAT "Tzaritza Ioanna" Ltd Local Ethics Committee
Ethics committee address [11] 5055 0
Byalo more Str. Sofia 1504, 8
Ethics committee country [11] 5055 0
Bulgaria
Date submitted for ethics approval [11] 5055 0
Approval date [11] 5055 0
31/10/2006
Ethics approval number [11] 5055 0
231/25.10.2006
Ethics committee name [12] 5056 0
Local Ethics Committee at SHATNP "Sv. Naum
Ethics committee address [12] 5056 0
4 km Tsarigradsko shose Blvd.1113 Sofia
Ethics committee country [12] 5056 0
Bulgaria
Date submitted for ethics approval [12] 5056 0
Approval date [12] 5056 0
18/10/2006
Ethics approval number [12] 5056 0
10/18.10.2006
Ethics committee name [13] 5057 0
Local Ethics Committee at SHATCVD
Ethics committee address [13] 5057 0
Sofia, 65 Konyovitsa Str
Ethics committee country [13] 5057 0
Bulgaria
Date submitted for ethics approval [13] 5057 0
Approval date [13] 5057 0
18/10/2006
Ethics approval number [13] 5057 0
10/18.10.2006
Ethics committee name [14] 5058 0
MHAT "St. Marina" Ltd. Varna Local Ethics Committee
Ethics committee address [14] 5058 0
1 Hristo Smirnenski Str. 9010 Varna
Ethics committee country [14] 5058 0
Bulgaria
Date submitted for ethics approval [14] 5058 0
Approval date [14] 5058 0
10/10/2006
Ethics approval number [14] 5058 0
17/10.10.2006
Ethics committee name [15] 5059 0
Ethics Committee FN Olomouc
Ethics committee address [15] 5059 0
I.P. Pavlova 6 77520 Olomouc
Ethics committee country [15] 5059 0
Czech Republic
Date submitted for ethics approval [15] 5059 0
Approval date [15] 5059 0
11/12/2006
Ethics approval number [15] 5059 0
174/06 MEK 44
Ethics committee name [16] 5060 0
Ethics Committee of Slezska Nemocnice Opava
Ethics committee address [16] 5060 0
Olomoucka 86 Opava, 74601
Ethics committee country [16] 5060 0
Czech Republic
Date submitted for ethics approval [16] 5060 0
Approval date [16] 5060 0
03/05/2007
Ethics approval number [16] 5060 0
Ethics committee name [17] 5061 0
Ethics Commitee of FNKV
Ethics committee address [17] 5061 0
Scrobarova 50 100 34 Praha 10
Ethics committee country [17] 5061 0
Czech Republic
Date submitted for ethics approval [17] 5061 0
Approval date [17] 5061 0
05/01/2007
Ethics approval number [17] 5061 0
Ethics committee name [18] 5062 0
Ethics Committee of District Hospital Pardubice
Ethics committee address [18] 5062 0
Kyjevska 44 53203 Pardubice
Ethics committee country [18] 5062 0
Czech Republic
Date submitted for ethics approval [18] 5062 0
Approval date [18] 5062 0
17/01/2007
Ethics approval number [18] 5062 0
Ethics committee name [19] 5063 0
Ethics Committee at FNsP Bratislava Ruzinov Facility
Ethics committee address [19] 5063 0
Ruzinovska 6 82606 Bratislava
Ethics committee country [19] 5063 0
Slovakia
Date submitted for ethics approval [19] 5063 0
Approval date [19] 5063 0
14/11/2006
Ethics approval number [19] 5063 0
2006-004736-79
Ethics committee name [20] 5064 0
Ethics Committee at FNsP BratislavaSt.cyril and Method Hospital pracovisko Petrzalka
Ethics committee address [20] 5064 0
Antolska 11 85107 Bratislava
Ethics committee country [20] 5064 0
Slovakia
Date submitted for ethics approval [20] 5064 0
Approval date [20] 5064 0
14/11/2006
Ethics approval number [20] 5064 0
Ethics committee name [21] 5065 0
Ethics committee at University Hospital Nitra
Ethics committee address [21] 5065 0
Spitalska 6 PP41C 95001 Nitra
Ethics committee country [21] 5065 0
Slovakia
Date submitted for ethics approval [21] 5065 0
Approval date [21] 5065 0
20/12/2006
Ethics approval number [21] 5065 0
Ethics committee name [22] 5066 0
Bioethical Committee of Medical University of Lodz
Ethics committee address [22] 5066 0
Al. Kosciuszki 4 90-419 Lodz
Ethics committee country [22] 5066 0
Poland
Date submitted for ethics approval [22] 5066 0
Approval date [22] 5066 0
16/01/2007
Ethics approval number [22] 5066 0
RNN/4/07KE
Ethics committee name [23] 5067 0
Ministry of Health National Ethics Committee
Ethics committee address [23] 5067 0
Av. Sanatescu 48 sector 1 Bucharest
Ethics committee country [23] 5067 0
Romania
Date submitted for ethics approval [23] 5067 0
Approval date [23] 5067 0
14/11/2006
Ethics approval number [23] 5067 0
Nr. 4302

Summary
Brief summary
Background: Antisense oligonucleotides (ASOs) are an innovative new class of drugs that inhibit the expression of proteins by sequence-specific binding to the protein’s mRNA. ATL1102 is a 2nd generation antisense inhibitor of CD49d, a subunit of Very Late Antigen 4 (VLA-4) which plays a key role in cell adhesion to vessel walls. VLA-4 blockade, as shown by monoclonal antibodies such as natalizumab, prevents activated lymphocytes from migrating into the CNS and significantly reduces disease activity in MS.

Objective: To evaluate VLA-4 Antisense (ATL1102) in the treatment of RR-MS

Methods: Randomized, double-blind, placebo-controlled multicenter Phase-IIa trial. 77 patients with RR-MS were treated for 8 weeks with either 200mg of ATL1102 or placebo subcutaneously twice weekly and evaluated for 16 weeks. MRI scans were performed at screening, and then monthly over 16 weeks. Primary efficacy variable: cumulative number of new active lesions (CNNAL; new gadolinium-enhancing T1 lesions (T1-Gd), new or enlarging T2 lesions) on MRIs taken at weeks 4, 8 and 12. Secondary efficacy variable: cumulative volume of T1-Gd lesions (CVT1L) on MRIs taken at weeks 4, 8 and 12.

Results: ITT population: 74 patients with a valid baseline MRI and at least one post-baseline MRI scan after first injection of study medication (n=39 placebo, n=35 ATL1102). ATL1102 showed a significant reduction, 54.4%, in CNNAL (6.2 placebo, 3.0 ATL1102; p=0.01). A reduction of 66.7% (p=0.002) was observed in the cumulative number (weeks 4,8,12) of new T1-Gd lesions with ATL1102. A reduction in CVT1L was also observed under ATL1102 but did not reach significance (589.4 mm3 placebo, 358.0 mm3 ATL1102; p=0.1068). Adverse events that were more frequent under ATL1102 included mild to moderate injection site reactions and a tendency for decreased platelet counts which were reversible after treatment interruption.

Conclusions: This proof-of-concept study of a drug designed to inhibit VLA-4 mRNA showed a significant reduction of the cumulative number of new active lesions in RR-MS patients following 8 weeks of treatment. These promising results warrant further investigation.
Trial website
Trial related presentations / publications
VLA-4 Antisense – An Oligonucleotide targeting VLA-4 mRNA (ATL1102) significantly reduces new active lesions in patients with RR-MS. Volker Limmroth, Frederik Barkhof, Nuket Desem, for the ATL1102 Study Group
Presented at the World Congress on Treatment and Research in Multiple Sclerosis in Montreal Canada on 20 September 2008 and at the American Academy of Neurology (AAN) 61st Annual Meeting in Seattle, Washington USA on 29 April 2009 by the Principal Investigator of the trial, Volker Limmroth MD PhD.

ATL/TV1102, an oligonucleotide targeting VLA-4 mRNA, significantly reduces new active lesions in patients with relapsing remitting multiple sclerosis.
Volker Limmroth, Frederik Barkhof, Nuket Desem
Presented at the New York Academy of Sciences Annual Meeting of the Oligonucleotide Therapeutics Society, Boston Massachusetts, USA on 18 October 2008 by Dr Christopher Wraight, Research Director, Antisense Therapeutics Ltd.

ATL1102, an Antisense Drug Targeting VLA-4, Significantly Reduces the Development of Active Lesions in Relapsing-Remitting Multiple Sclerosis.
Volker Limmroth, Frederik Barkhof, Nuket Desem
Presented at the Keystone Symposia scientific conference entitled ‘Therapeutic Modulation of RNA Using Oligonucleotides’, in Alberta Canada on 13 February 2009 by Nuket Desem, Development Director, Antisense Therapeutics Ltd.
Public notes

Contacts
Principal investigator
Name 28325 0
Address 28325 0
Country 28325 0
Phone 28325 0
Fax 28325 0
Email 28325 0
Contact person for public queries
Name 11482 0
Mark Diamond
Address 11482 0
10 Wallace Avenue, Level 1, Toorak, Vic 3142
Country 11482 0
Australia
Phone 11482 0
+61 3 9827 8999
Fax 11482 0
+61 3 9827 1166
Email 11482 0
mark.diamond@antisense.com.au
Contact person for scientific queries
Name 2410 0
Nuket Desem
Address 2410 0
10 Wallace Avenue, Level 1, Toorak, Vic 3142
Country 2410 0
Australia
Phone 2410 0
+61 3 9827 8999
Fax 2410 0
+61 3 9827 1166
Email 2410 0
nuket.desem@antisense.com.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary