Safety and Efficacy Study of MIS416 to Treat Secondary Progressive Multiple Sclerosis

• ClinicalTrials.gov Identifier: NCT02228213
• Recruitment Status: Completed
• First Posted: August 28, 2014
• Last Update Posted: July 14, 2017
• Sponsor: Innate Immunotherapeutics
• Collaborator: Syneos Health
• Information provided by (Responsible Party): Innate Immunotherapeutics

Study Description

Brief Summary:

The purpose of this study is to determine whether MIS416 administered once weekly over 12 months is safe, tolerable, and improves a range of signs and symptoms associated with secondary progressive multiple sclerosis.

Condition or disease	Intervention/treatment	Phase
Secondary Progressive Multiple Sclerosis	Biological: MIS416; Drug: Saline	Phase 2

Detailed Description:

The primary objectives of the study are to:

1. Determine the efficacy of MIS416, relative to placebo, when administered repeatedly via weekly intravenous (IV) administration to subjects with Secondary Progressive Multiple Sclerosis, as assessed by its effect on measures of neuromuscular function.
2. Determine the safety and tolerability of a weekly regimen of MIS416.

The secondary objectives of the study are to:

1. Determine the effect of MIS416 on disease activity and neurodegeneration by assessing changes in Magnetic Resonance Imaging (MRI) markers including lesions, whole brain atrophy (WBA) and Magnetization Transfer Ratio (MTR).
2. Determine the effect of MIS416 on Patient Reported Outcomes (PRO) related to disability and health status.
3. Assess, in a subset of subjects, the pharmacodynamic (PD) effects of MIS416, including effects on serum, Peripheral Blood Mononuclear Cell (PBMC), and Cerebral Spinal Fluid (CSF) cytokine/chemokine levels and expression patterns.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 93 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2B Randomised, Double-Blind, Placebo-Controlled Trial of the Efficacy and Safety of MIS416 in the Treatment of Subjects With Secondary Progressive Multiple Sclerosis
• Study Start Date: October 2014
• Actual Primary Completion Date: May 2017
• Actual Study Completion Date: June 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment; 500 mcg MIS416 500 at 0.2 mg/mL administered i.v. once weekly for 52 weeks	Biological: MIS416; Intravenous administration weekly for 52 weeks
Placebo Comparator: Saline; Saline administered i.v. once weekly for 52 weeks	Drug: Saline; Intravenous administration weekly for 52 weeks; Other Name: Placebo

Outcome Measures

Primary Outcome Measures :

1. Change from baseline of neuromuscular function at 12 months [ Time Frame: Baseline, 3, 6, 9 and 12 months ]

   Neuromuscular function will be assessed using the following test:

   • MS Function Composite (MSFC), comprising the; timed 25 Foot Walk, 9 Hole Peg Test (9HPT), and Paced Auditory Serial Addition Test (PASAT);
   • Jebsen Hand Function Test (JHFT);
   • Grip, tip and key pinch strength;
   • Symbol digit modalities test (SDMT);
   • Sloan low-contrast letter visual acuity (SLCVA);
   • 6-minute walk test (6MWT);
2. Proportion of Participants with Serious and Non-Serious Adverse Events [ Time Frame: Up to 12 months ]
   Safety assessments will be conducted at each study visit and include; characterization of the type, incidence, severity, timing, seriousness, and relationship to treatment of adverse events (AEs); effects on vital signs and clinical laboratory parameters; changes on electrocardiograms (ECGs); and at 3 months and 12 months - the number of gadolinium-enhancing lesions on cranial MRI assessments.

Secondary Outcome Measures :

1. Change from baseline of disability and health status at 12 months [ Time Frame: Baseline, 3, 6, 9, and 12 months ]

   Disability and health status will be assessed using the following assessments and patient reported outcomes:

   • Expanded Disability Status Scale (EDSS)

   • Patient Reported Outcomes (PROs) including;

     • SF-36 and its components;
     • MS Impact Scale (MSIS-29);
     • Neurological Fatigue Index for MS (NFI-MS);
     • Brief Pain Inventory (BPI).
2. Change from baseline of neurodegeneration by assessing changes in Magnetic Resonance Imaging (MRI) markers at 12 months [ Time Frame: Baseline, 3, and 12 months ]
   Disease activity and neurodegeneration will be assessing using Magnetic Resonance Imaging (MRI) markers including lesions, whole brain atrophy (WBA) and Magnetization Transfer Ratio (MTR).
3. Change from baseline of activity of immune biomarkers in serum [ Time Frame: Up to 1 year ]
   The effect on immune biomarkers will include the analysis of serum for some or all of the following markers: IP-10 (CXCL10), MCP-1 (CCL2), MIG (CXCL9), IL-8 (CXCL8), IFNγ, Neopterin, IL-1RA, sTNF-R, IL-12/23, p40, CD62E (E-selectin), CD54 (ICAM-1), and CD106 (VCAM-1).
4. Change from baseline of activity of immune biomarkers in cerebrospinal fluid (CSF) [ Time Frame: Up to 12 months ]
   The effect on immune biomarkers will include the analysis of CSF for some or all of the following markers: IP-10 (CXCL10), MCP-1 (CCL2), MIG (CXCL9), IL-8 (CXCL8), IFNγ, Neopterin, IL-1RA, sTNF-R, IL-12/23, p40, CD62E (E-selectin), CD54 (ICAM-1), and CD106 (VCAM-1).
5. Change from baseline in Peripheral Blood Mononuclear Cell (PBMC) immune biomarkers [ Time Frame: Up to 12 months ]
   Some or all of these biomarkers may be assayed ex vivo: PBMC expression of mRNA encoding proteins involved in myeloid differentiation and immune regulatory function (e.g. VEGF, Arginine, INOS, IL-10, MMP9); PBMC myeloid subset production of IL-10, TGFβ, IL-6, TNFα, IL-1β, IFNγ, IL-17, and GM-CSF in response to stimulation with LPS, LPS/IFNγ or MIS416 ex vivo; and PBMC subset analysis of myeloid and dendritic cell subsets for immunoregulatory cell subset markers.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. A historical or current cranial MRI scan demonstrating T2-hyperintense lesions consistent with MS.
2. Has SPMS as determined by the 2010 Update to the McDonald Criteria
3. An Expanded Disability Status Scale (EDSS) of 3.0 to 6.5 at Screening.
4. Has SPMS which, in the judgment of the investigator, has been clinically active and functionally progressive within the 2 years prior to Screening
5. The absence of MS relapse for at least two years prior to Baseline.
6. Neurologically stable for at least four weeks prior to Screening.

7. Has the following laboratory values within three days prior to initiation of Investigational Product:

   • Absolute neutrophil count (ANC) >= 1 x 109/L;
   • Platelet count >= 100 x 109/L;
   • Serum creatinine =< 1.5 mg/dL;
   • Aspartate aminotransferase (AST) =<2 × upper limit of normal;
   • Alanine aminotransferase (ALT) =< 2 × upper limit of normal.
8. Provided written informed consent to participate.

Exclusion Criteria:

1. Has primary Progressive MS (PPMS), Relapsing Remitting (RRMS), or progressive relapsing MS as determined by the 2010 update to the McDonald Criteria.
2. Has not completed the discontinuation period for approved and/or investigational multiple sclerosis disease modifying therapies prior to screening.
3. Has had any other immunomodulatory drug therapy or immunosuppressive therapy within four weeks prior to Screening, or systemic corticosteroids within the eight weeks prior to Screening.
4. Any previous exposure to investigational MS therapeutic vaccines.
5. Any use of cell-depleting monoclonal antibodies including, but not limited to, Rituximab, or Ocrelizumab.
6. A diagnosis or history of collagen vascular disease (including Sjögren's syndrome and systemic lupus erythematosus), anticardiolipin antibody syndrome, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, sarcoidosis, vasculitis, Behcet's syndrome and/or Lyme disease.
7. Contraindication to MRI (e.g., pacemaker or other contraindicated implanted metal device, allergy to gadolinium, or unmanageable claustrophobia).
8. A history of alcohol or drug abuse (including cannabinoid use) within two years prior to Screening.
9. Has had major surgery or radiation therapy within four weeks prior to Screening.
10. Has an active infection requiring antibiotics within two weeks prior to Screening.
11. Has had active malignancy within two years of Screening, with the exception of basal cell carcinoma and squamous cell carcinoma of the skin.
12. Uncontrolled congestive heart failure, myocardial infarction, cerebrovascular accident, coronary/peripheral artery bypass graft surgery, or transient ischemic attack within twelve weeks prior to Screening.
13. Has angina, other symptomatic coronary artery disease, or known cardiomyopathy.
14. Has symptomatic cardiac dysrhythmias requiring treatment, or persistent prolongation of the QTcF (Fredericia) interval to > 450 msec for males or > 470 msec for females.

Contacts and Locations

Locations

Australia, Queensland

The Wesley-St. Andrew's Research Institute

Brisbane, Queensland, Australia, 4066

Australia, South Australia

PARC Clinical Research

Adelaide, South Australia, Australia, 5000

Australia, Victoria

Nucleus Network - Centre for Clinical Studies

Melbourne, Victoria, Australia, 3004

Australia, Western Australia

Western Australian Neuroscience Research Institute

Perth, Western Australia, Australia, 6009

Neurodegenerative Disorders Research

West Perth, Western Australia, Australia, 6005

New Zealand

Optimal Clinical Trials

Auckland, New Zealand, 1010

P3 Research

Wellington, New Zealand, 6021

Sponsors and Collaborators

Innate Immunotherapeutics

Syneos Health

Investigators

• Study Director: Michael Silverman; Innate Immunotherapeutics

More Information

• Responsible Party: Innate Immunotherapeutics
• ClinicalTrials.gov Identifier: NCT02228213
• Other Study ID Numbers: MIS416-202; U1111-1166-0910 ( Other Identifier: WHO )
• First Posted: August 28, 2014
• Last Update Posted: July 14, 2017
• Last Verified: July 2017

Keywords provided by Innate Immunotherapeutics:

multiple sclerosis; SPMS

Additional relevant MeSH terms:

Neoplasm Metastasis; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Neoplastic Processes; Neoplasms; Chronic Disease; Disease Attributes