Study to evaluate the safety and efficacy of NU100 in patients with relapsing forms of multiple sclerosis
Scientific Title of Study
A phase 3, multicenter, double-blind, randomized, placebo controlled, parallel-group study to evaluate the safety and efficacy of NU100 in patients with relapsing forms of multiple sclerosis
Trial Acronym
RRMS
Secondary IDs if Any
Secondary ID
Identifier
CP-NU100-01.00
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Dr Krishnan Vijayan
Designation
Consultant Neurologist
Affiliation
Kovai Medical Center and Hospital Ltd
Address
Kovai Medical Center and Hospital Ltd
3209, Avanashi road, Coimbatore- 641014
Tamilnadu, India
Coimbatore TAMIL NADU Coimbatore- 641014 India
Phone
09842155101
Fax
Email
kalyani_vijayan@rediffmail.com
Details of Contact Person Scientific Query
Name
Dr Krishnan Vijayan
Designation
Consultant Neurologist
Affiliation
Kovai Medical Center and Hospital Ltd
Address
Kovai Medical Center and Hospital Ltd
3209, Avanashi road, Coimbatore- 641014
Tamilnadu, India
Coimbatore TAMIL NADU Coimbatore- 641014 India
Phone
09842155101
Fax
Email
kalyani_vijayan@rediffmail.com
Details of Contact Person Public Query
Name
Dr Krishnan Vijayan
Designation
Consultant Neurologist
Affiliation
Kovai Medical Center and Hospital Ltd
Address
Kovai Medical Center and Hospital Ltd
3209, Avanashi road, Coimbatore- 641014
Tamilnadu, India
Coimbatore TAMIL NADU Coimbatore- 641014 India
Phone
09842155101
Fax
Email
kalyani_vijayan@rediffmail.com
Source of Monetary or Material Support
Nuron Biotech Inc
Primary Sponsor
Name
Nuron Biotech Inc
Address
1 East Uwchlan Avenue, 302
Exton, PA 19341 USA
Phone: 1.610.968.6700
Fax: 1.610.968.6550
Type of Sponsor
Other [Biotechnology company ]
Details of Secondary Sponsor
Name
Address
Semler Research Center Pvt Ltd
75A, 15th Cross, I Phase J.P.Nagar, Bangalore 560 078, INDIA
Countries of Recruitment
Belarus Bulgaria Croatia France Georgia India Italy Poland Russian Federation Serbia Spain Ukraine
Sites of Study
No of Sites = 12
Name of Principal
Investigator
Name of Site
Site Address
Phone/Fax/Email
Dr Radhakrishnan Suresh Kumar
Amrita Institute of Medical Sciences
Ponekkara PO Kochi 682 026 Kerala
Ernakulam KERALA
919447708161
rsureshkumar@aims.amrita.edu
Dr Yashpal singh
Christian Medical College and Hospital Â
Room No: 5063, Ground Floor, Department of Neurology
Brown Rd
Ludhiana 141008 Punjab India
"
Ludhiana PUNJAB
919814814044
neuroyash@yahoo.co.in
Dr Rahul Kulkarni
Deenanath Mangeshkar Hospital and Research Centre
Off Karve Road,
Erandwane,
Pune-411004,
Maharashtra,India
Pune MAHARASHTRA
919822012588
rahulneuro@gmail.cpm
Dr Joy Desai
Jaslok Hospital and Research CentreÂ
Room No: 224, Department of Neurology, 15, Dr. G. Deshmukh Marg,Mumbai-400026,India
Mumbai MAHARASHTRA
919820009850
desaijoy@gmail.com
Dr Lekha Pandit
Justice K. S. Hegde Charitable Hospital (JKSH)
Room No 57, Neurology research room, 2nd Floor, PG Block, Department of Neurology, Deralakatte, Mangalore, Karnataka- 575 018
Dakshina Kannada KARNATAKA
919845084343
panditmng@gmail.com
Dr Sangeeta Ravat Hasmukh
K E M Hospital
Seth G S Medical College & KEM Hospital, Parel, Mumbai-400012, Maharashtra, India
Mumbai MAHARASHTRA
919820310850
ravatsh@yahoo.com
Dr Krishnan Vijayan
Kovai Medical Centre and Hospital Limited (KMCH)Â
Room No. 110A, First Floor, 3209 Avanashi Road Coimbatore 641014 Tamil Nadu India Coimbatore TAMIL NADU
919842155101
kalyani_vijayan@rediffmail.com
Dr Rangashetty Srinivasa
M. S. Ramaiah Memorial Hospital (MSRMH)
Suite: 102, Ist floor, Department of Neurology, New Bel Road MSRIT Post Bangalore 560054 Karnataka India Bangalore KARNATAKA
919448040589
drrsrinivasa@hotmail.com
Dr Hemant Madhukar Sant
Sahayadri Speciality Hospital
30 C Erandwane, Karve Road,Near Vimlabai Garware High School,Pune 411004
Pune MAHARASHTRA
919823968620
hmsant@gmail.com
DrAnshu Rohatgi
Sir Gangaram Hospital
Room No:1439, 4th Floor, Department of Neurology, Rajinder Nagar
New Delhi-110060
New Delhi DELHI
919810159046
rohatgianshu@gmail.com
Dr G R K Sarma
St. Johns Medical College Hospital
Department of Neurology, 3rd Floor, Sarjapur Road, Koramangala 2nd block Bangalore-560034,India
Bangalore KARNATAKA
08022065707
grk_sarma@yahoo.com
Dr Shamsher Dwivedee
VIMHANS (Vidyasagar Institute of Mental Health & Nuero Sciences)
Room No. 2B, Ground floor, Department of Neurology, 1 Institutional Area Nehru Nagar
Delhi-110065
Central DELHI
Amrita Institutional ethics commitee,Ponekkara PO Kochi 682 026 Kerala,India
Approved
Central Ethical committee of NItte University, University Enclave, Medical Sciences Complex, Deralakatte, Mangalore-575018, Karnataka, India
Submittted/Under Review
Ethics Committee Christian Medical College and Hospital, Brown Road, Ludhiana-141008, Punjab, India
Submittted/Under Review
Ethics committee for research on human subjects seth GS Medical college and KEM Hospital,Room no.46, 2nd floor, old building, Next to medicine seminar hall,Acharya Dhonde Marg,Parel, Mumbai -400012
Submittted/Under Review
Ethics committee Jaslok hospital and research center,Dr. G. Deshmukh Marg,Mumbai-400026,India
Approved
Ethics Committee Sir Gangaram Hospital,Rajinder Nagar New Delhi-110060, India
Submittted/Under Review
Ethics Committee VIMHANS Hospital,1 Institutional Area Nehru Nagar, Delhi-110065,India
Approved
Institutional Ethics Committee, Lata Mangeshkar medical foundations Deenanath Mangeshkar hospital and research centreOff Karve Road, Erandwane, Pune-411004, Maharashtra,India
Submittted/Under Review
KMCH Ethics Committee,Kovai Medical Centre and Hospital Limited, No 3209 Avanashi Road Coimbatore 641014 Tamil Nadu India
Approved
M S Ramaiah Medical College and hospitals Ethical Review Board, New Bel Road MSRIT Post Bangalore 560054 Karnataka India
Approved
Sahyadri Hospitals Ethics Committee,Sahyadri clinical research and devolopment center a unit of Sahyadri Hospitals limited,30 C Erandwane, Karve Road,Near Vimlabai Garware High School,Pune 411004, India
Approved
St Johns medical college and hospital institutional ethical review board,Sarjapur Road, Koramangala 2nd block Bangalore-560034,India
Patients with relapsing forms of multiple sclerosis
Diagnosis of RRMS according to McDonald’s Criteria – revision 2010 (Polman et al., 2011)
,
Intervention / Comparator Agent
Type
Name
Details
Comparator Agent
interferon beta-1b (Betaferon)
The drug Betaferon® (known as Betaseron® in the United States) is a non-glycosylated recombinant human IFN beta-1b (rhIFN beta-1b) approved for high-frequency subcutaneous (SQ) administration to treat MS. It is formulated with human serum albumin (HSA) and contains about 40% monomeric rhIFN beta-1b with the remainder as aggregates or HSA complexes.Dose: 0.25 mg, Route of administration: Sub Cutaneous, Frequency: e.o.d (once in two days), Duration: 12 months
Intervention
recombinant human interferon beta-1b (rhIFN beta-1b) product
The active pharmaceutical ingredient (rhIFN beta-1b) in NU100 is chemically identical (i.e. the same amino acid sequence) to the active pharmaceutical ingredient in Betaferon. Betaferon is formulated with human serum albumin (HSA) and contains only 40% monomeric rhIFN beta-1b with the remainder as aggregates or HSA complexes [7]. NU100 does not contain HSA and is 99% monomeric rhIFN beta-1b. It is expected that the absence of significant rhIFN beta-1b aggregates in NU100 will result in significantly lower immune responses in patients compared to Betaferon. By reducing or eliminating the immune response to rhIFN beta-1b, NU100 should provide the clinical benefits of prolonged efficacy and safety for RRMS patients who presently require high dose therapy with Betaferon.
Dose: 0.25mg
Route of administration: Sub cutaneous
Frequency: Once in two days
Duration: 12 Months
Inclusion Criteria
Age From
18.00 Year(s)
Age To
60.00 Year(s)
Gender
Both
Details
1. Female or male patients, aged between 18 and 60 years, inclusive
2. Signed and dated statement of informed consent
3. Diagnosis of RRMS according to McDonald’s Criteria – revision 2010 (Polman et al., 2011)
4. Interferon (IFN) beta-1b naïve
5. Expanded Disability Status Scale (EDSS) score of < 5.5
6. At least 1 documented relapse in the past year (defined as the appearance of a new clinical sign/symptom [one that had been stable for at least 30 days] that persisted for a minimum of 24 hours in the absence of fever)
---or---
a subclinical sign/symptom (defined as a Gd enhancing lesion or a new T2 lesion demonstrated on MRI examination on a prior MRI that has been completed within 1 year of the screening MRI). The Screening (V-1) MRI should not be used for this determination.
7. No relapse in the 4 weeks prior to the screening visit (V-1).
8. Must be in a clinically stable or improving neurological state 4 weeks preceding the screening visit (V-1).
ExclusionCriteria
Details
1. Relapse at the baseline visit (V0) or occurring within 4 weeks prior to the screening visit (V-1)
2. Intake of glatiramer acetate within 3 months prior to the screening (V-1) visit
3. Intake of previous immunotherapy or immunosuppressant treatment, within 4 months prior to the screening (V-1) visit
4. Intake of or previously received therapy with cladribine or alemtuzumab
5. An active viral, bacterial, or systemic fungal infection within 1 week of baseline (V0)
6. Use of systemic steroids within 3 weeks prior to the screening (V-1) MRI
7. Progressive disease
8. Level of liver enzymes 2.5 x the upper limit of normal
9. Abnormal renal function (estimated Glomerular Filtration Rate [eGFR] 60 ml/min/1.73 m2 )
10. Positive serology or history for Hepatitis B, C, or human immunodeficiency virus (HIV)
11. Serious or acute coronary diseases, defined by at least 1 of the following conditions:
a. Clinical symptoms of ischemic heart disease
b. ST elevation or depression 2 mm on the electrocardiogram (ECG)
c. Clinical symptoms of cardiac failure and/or current medical treatment for cardiac failure
d. Severe ventricular arrhythmia (frequent premature ventricular beats)
e. Atrioventricular block at third level
12. Chronic use of non-steroidal anti-inflammatory drugs
13. History of any of the following:
a. Severe depression or suicide attempt
b. Uncontrolled seizure disorder
c. Cancer, excluding adequately treated basal cell carcinoma of the skin or adequately treated in situ carcinoma of the cervix
d. Previous contrast reaction to gadolinium or any other contraindications to MRI (e.g., metal in the eye, pacemakers, aneurysm clip)
14. Allergy to human albumin or to mannitol
15. Excessive alcohol use or illicit drug use
16. Women who are breast feeding, pregnant, or planning to become pregnant, or are unwilling to use an effective birth control method while on study
17. Medical, psychiatric, or other conditions that compromise the patients ability to understand the patient information, to give informed consent, to comply with the trial protocol, or to complete the study
18. Participation in any other study involving investigational or marketed products, concomitantly or within 30 days prior to entry in the study
Current participation in other clinical trials
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Centralized
Blinding/Masking
Participant and Investigator Blinded
Primary Outcome
Outcome
TimePoints
To evaluate the safety and efficacy of NU100 in patients with relapsing remitting multiple sclerosis (RRMS) as compared to placebo and an active comparator.
The cumulative number of new combined unique active lesions (CALs; defined as new gadolinium T1-weighted lesions and non enhancing new and newly enlarging T2-weighted lesions) on magnetic resonance imaging (MRI) scans over the course of 4 and 12 months of treatment to demonstrate the superiority of NU100 to placebo and the non-inferiority of NU100 to Betaferon®, respectively.
Secondary Outcome
Outcome
TimePoints
The rates of reduction for a non-inferiority trial require several assumptions: an expected difference between the 2 active therapies, a tolerable difference and the variation found in the treatment groups along with Type I and Type II errors. If we assume that the 2 drugs are truly equivalent, then our expected difference is zero.
Incidence of annualized relapse rates
Proportion of relapse-free patients at 12 months
Incidence and severity of all drug related flu-like symptoms during the first 4 months of study participation in all patients
Incidence of antibody formation against IFN beta-1b
Changes from baseline in the EDSS score after 3, 4, 6, 9, and 12 months of treatment
Sustained change in EDSS measured for at least 3 months
Target Sample Size
Total Sample Size="500" Sample Size from India="110" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
As a multicenter trial, Nuron Biotech, Inc. may publish clinical data from all centers participating in the investigation. A publication committee selected by Nuron Biotech, Inc. will submit draft manuscripts to all participating Investigators for their comments. In conformity with the uniform requirements for manuscripts submitted to biomedical journals published by the International Committee of Medical Journal Editors (see discussion in Kassirer and Angell, 1991),
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
To evaluate the safety and efficacy of NU100 in patients with relapsing remitting multiple sclerosis (RRMS) as compared to placebo and an active comparator.
The primary clinical objective selected for this Phase 3 study, the cumulative number of new combined unique active lesions (CALs; defined as new gadolinium T1-weighted lesions and non��’enhancing new and newly enlarging T2-weighted lesions) on magnetic resonance imaging (MRI) scans over the course of 4 and 12 months of treatment to demonstrate the superiority of NU100 to placebo and the non-inferiority of NU100 to Betaferon®, respectively.
The study will include 3 treatment arms (NU100, Betaferon, and placebo) with 2 cohorts (7 and 5 MRIs) within each arm. Five hundred patients will be randomized to 1 of the following treatments in a 2:9:2:9:2:1 ratio:
·Group A Cohort 1 (n=40): NU100 0.25 mg by subcutaneous (SQ) injection, every other day (e.o.d.) for 12 months
·Group A Cohort 2 (n=180): NU100 0.25 mg SQ, e.o.d. for 12 months
·Group B Cohort 1 (n=40): Betaferon 0.25 mg SQ, e.o.d. for 12 months
·Group B Cohort 2 (n=180): Betaferon 0.25 mg SQ, e.o.d. for 12 months
·Group C Cohort 1 (n=40): Placebo SQ, e.o.d. for 4 months then NU100 0.25 mg SQ, e.o.d. for 8 months
Group C Cohort 2 (n=20): Placebo SQ, e.o.d. for 4 months then NU100 0.25 mg SQ, e.o.d. for 8 months
Within each arm patients are randomized to one of 2 MRI cohorts.Patients randomized to Cohort 1 undergo 7 MRIs (at screening and Months 2, 3, 4, 6, 9, and 12).Patients randomized to Cohort 2 undergo 5 MRIs (at screening and Months 3, 6, 9, and 12).