Long-term Safety, Tolerability and Effectiveness Study of Ofatumumab in Patients With Relapsing MS (ALITHIOS)

• ClinicalTrials.gov Identifier: NCT03650114
• Recruitment Status: Recruiting
• First Posted: August 28, 2018
• Last Update Posted: February 15, 2021
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: August 17, 2018
• First Posted Date: August 28, 2018
• Last Update Posted Date: February 15, 2021
• Actual Study Start Date: December 28, 2018
• Estimated Primary Completion Date: October 3, 2028 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: August 27, 2018): Number of patients that experience an adverse event or abnormal laboratory, vital and/or ECG results and positive suicidiality outcomes [ Time Frame: Up to 5 years ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 27, 2018)

• Number of relapse rates per year [ Time Frame: Core studies up to 5 years from first dose of ofatumumab (depending on if first dose was in the core or in this extension study or comparator randomization) ]
  Annual Relapse Rate (ARR) time calculated as number of confirmed relapses divided by time in study per year and will also be presented for the entire duration
• Patients with confirmed 3 and 6 month disability worsening [ Time Frame: Duration of the study, approximately 5 years ]
  A confirmed disability worsening is an increase from baseline in Expanded Disability Status Scale (EDSS) score sustained for at last 3, or 6 months EDSS consists of seven functional systems and an ambulation score that are then combined to determine the EDSS steps (ranging from 0 (normal) to 10 (death due to MS)). The functional systems are Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel and Bladder, and Cerebral functions (Fatigue contributes).
• Patients with confirmed 6, 12 and 24 month disability improvement and improvement until end of study [ Time Frame: Duration of the study, approximately 5 years ]
  Confirmed disability improvement is a decrease from baseline in Expanded Disability Status Scale (EDSS) score sustained for at least 6, 12 or 24 months EDSS consists of seven functional systems and an ambulation score that are then combined to determine the EDSS steps (ranging from 0 (normal) to 10 (death due to MS)). The functional systems are Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel and Bladder, and Cerebral functions (Fatigue contributes).
• Patients with changes in Expanded Disability Status Scale (EDSS) scores [ Time Frame: Core studies up to 5 years from first dose of ofatumumab (depending on if first dose was in the core or in this extension study or comparator randomization) ]
  Score changes in Expanded Disability Status Scale (EDSS) over time EDSS consists of seven functional systems and an ambulation score that are then combined to determine the EDSS steps (ranging from 0 (normal) to 10 (death due to MS)). The functional systems are Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel and Bladder, and Cerebral functions (Fatigue contributes).
• Changes in and time to 6 month confirmed worsening of Symbol Digit Modalities Test Scores [ Time Frame: Duration of the study, approximately 5 years ]
  Score changes and confirmed 4-point worsening sustained for 6 months in Symbol Digit Modalities Test (SDMT) scores The Symbol Digit Modalities Test is a neuropsychological, timed test for sustained attention and concentration. 3 versions will be used, alternating at each visit where done. The number of correct responses will be counted for the score.
• Changes in the Magnetic Resonance Image (MRI) related to brain volume loss [ Time Frame: Core studies up to 5 years from first dose of ofatumumab (depending on if first dose was in the core or in this extension study or comparator randomization) ]
  Percent change from baseline in brain volume loss (BVL)
• Changes in the Magnetic Resonance Image (MRI) related to T2 lesions [ Time Frame: Core studies up to 5 years from first dose of ofatumumab (depending on if first dose was in the core or in this extension study or comparator randomization) ]
  Number of new or enlarging T2 lesions
• Changes in the Magnetic Resonance Image (MRI) related to Gd-enhancing lesions [ Time Frame: Core studies up to 5 years from first dose of ofatumumab (depending on if first dose was in the core or in this extension study or comparator randomization) ]
  Total number of Gd-enhancing lesions on all MRI scans adjusted for different time of scan versus follow up time in study
• Changes in neurofilament light change serum concentration [ Time Frame: Core studies up to 5 years from first dose of ofatumumab (depending on if first dose was in the core or in this extension study or comparator randomization) ]
  Extent of neurofilament light change concentration in blood NfL is a component of the neuronal cytoskeleton and is released into the cerebrospinal fluid and into subsequently blood following neuro-axonal damage

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: August 30, 2019)

• Hummoral immune response to TT vaccine [ Time Frame: Pre-vaccination, 4 and 8 weeks post-vaccination ]
  Proportion of subjects with a positive antibody response to TT vaccine measured 4 and 8 weeks after vaccination while treated with ofatumumab

  • 2-fold increase in titer level
  • Tetanus anti-bodies ≥ 0.2 IU/mL
  • Mean titers of anti-tetanus antibody
• Hummoral immune response to 13-valent pneumococcal conjugate vaccine (13-PCV) [ Time Frame: 4 and 8 weeks ]
  Proportion of subjects with a positive antibody response against individual anti-pneumococcal antibody serotypes while treated with ofatumumab

  • 2-fold increase in titer level or a > 1 microgram/mL rise in titer compared with pre-immunization titer
  • Positive anti-body response against at least 2 of the 13 pneumococcal antibody serotypes
  • Positive anti-body response against at least 50% of serotypes
  • Mean titers of anti-pneumococcal antibody
• Hummoral immune response to 13-PCV boosted eight weeks later by 23-valent pneumococcal polysaccharide vaccine (23-PPV) [ Time Frame: Pre-vaccination, 4 and 8 weeks post-vaccination ]
  Proportion of subjects with a positive antibody response against individual anti-pneumococcal antibody serotypes (23 serotypes to be tested individually) measured 4 and 8 weeks after the booster 23-PPV while the subject continues to be treated with ofatumumab

  • 2-fold increase in titer level or a > 1 microgram/mL rise in titer compared with pre-immunization titer
  • Positive anti-body response against at least 2 of the 23 pneumococcal antibody serotypes
  • Positive anti-body response against at least 50% of serotypes
  • Mean titers of anti-pneumococcal antibody
• Humoral immune response to KLH neo-antigen [ Time Frame: Pre-administration, 4, 8, 12 weeks after initial administration and 4 weeks after last administration ]
  Mean titers of anti-KLH antibody measured immediately prior the first administration of KLH and measured immediately prior to the first administration, 4, 8 and 12 weeks after the first administration, and measured 4 weeks post last administration of KLH
• Hummoral immune response to 2020-2021 seasonal quadrivalent influenza vaccine [ Time Frame: Pre-vaccination and 4 weeks post-vaccination ]
  Proportion of subjects fulfilling:

  1. Seroconversion: The pre-vaccination HI antibody titer is < 1:10 and the postvaccination measurement is ≥ 1:40 (this applies to subjects with a pre-vaccination HI titer < 1:10), or
  2. Significant increase in HI antibody titer: The pre-vaccination HI antibody titer is ≥ 1:10 and the increase from the pre- to the post-vaccination measurement is ≥ 4-fold (this applies to subjects with a pre-vaccination HI titer ≥ 1:10)
• Antibody response rate to TT and influenza vaccination as a function of exposure to ofatumumab [ Time Frame: 8 weeks ]
  Immune response to TT and influenza vaccination

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Long-term Safety, Tolerability and Effectiveness Study of Ofatumumab in Patients With Relapsing MS
• Official Title: An Open-label, Single Arm, Multi-center Extension Study Evaluating Long-term Safety, Tolerability and Effectiveness of Ofatumumab in Subjects With Relapsing Multiple Sclerosis

Brief Summary

The purpose of this study is to collect long-term safety, tolerability, effectiveness and health outcomes data in eligible subjects who have participated in a Novartis ofatumumab clinical MS study.

Vaccination sub-study The purpose of this research sub-study is to find out the effects of ofatumumab on the development of antibody responses to selected vaccines and keyhole limpet hemocyanin (KLH) neo-antigen in subjects with relapsing multiple sclerosis (RMS).

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Relapsing Multiple Sclerosis

Intervention

• Biological: Ofatumumab
  subcutaneous injection of 20 mg ofatumumab every 4 weeks
• Biological: Tetanus toxoid (TT) containing vaccine (Td, Tdap)
  0.5mL Vial/Syringe Containing 5 limit of flocculation (LF) tetanus toxoid
• Biological: 13-valent pneumococcal conjugate vaccine (13-PCV)
  0.5mL Vial/Syringe
• Biological: 23-valent pneumococcal polysaccharide vaccine (23-PPV)
  0.5mL Vial/Syringe
• Biological: Seasonal Quadrivalent influenza vaccine
  Seasonal 2020-2021 0.5mL Vial/Syringe (trivalent may be used where quadrivalent is not available)
• Biological: Keyhole limpet hemocyanin (KLH) neo-antigen
  1mg Vial

Study Arms

Experimental: Ofatumumab

Subcutaneous injection

Interventions:

• Biological: Ofatumumab
• Biological: Tetanus toxoid (TT) containing vaccine (Td, Tdap)
• Biological: 13-valent pneumococcal conjugate vaccine (13-PCV)
• Biological: 23-valent pneumococcal polysaccharide vaccine (23-PPV)
• Biological: Seasonal Quadrivalent influenza vaccine
• Biological: Keyhole limpet hemocyanin (KLH) neo-antigen

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 27, 2018): 2010
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 3, 2028
• Estimated Primary Completion Date: October 3, 2028 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Must have completed a selected Novartis MS study which dosed ofatumumab 20 mg sc every 4 weeks
2. Written informed consent

Exclusion Criteria:

• Emergence of any clinically significant condition/disease during the previous ofatumumab study in which study participation might result in safety risk for the subject
• Subjects with active systemic bacterial, viral or fingal infections, or chronic infection (e.g. AIDS)
• Subjects taking medications prohibited by the protocol
• Pregnant or nursing (lactating) women Other protocol-defined inclusion/exclusion criteria may apply

Vaccination sub-study:

Inclusion criteria

1. Informed consent
2. Actively enrolled in the COMB157G2399 Study
3. 12 weeks of continuous treatment within the COMB157G2399 Study
4. prior vaccination history as per protocol-defined

Exclusion criteria

• known hypersensitivity or history of systemic allergic, neurologic or other reactions to vaccines
• allergies to egg or shellfish
• any safety findings including low IgG/IgM requiring ofatumumab interruption within 12 weeks prior to vaccination sub-study start
• any major episode of infection requiring hospitalization or treatment with intravenous antibiotics within 2 weeks of the first vaccination sub-study visit

Other protocol-defined inclusion/exclusion criteria may apply

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Novartis Pharmaceuticals; 1-888-669-6682; Novartis.email@novartis.com

Contact: Novartis Pharmaceuticals; +41613241111

• Listed Location Countries: Argentina, Australia, Austria, Belgium, Bulgaria, Canada, Croatia, Czechia, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, India, Israel, Japan, Latvia, Lithuania, Mexico, Netherlands, Norway, Peru, Poland, Portugal, Russian Federation, Slovakia, South Africa, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT03650114
• Other Study ID Numbers: COMB157G2399
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

• URL: https://www.clinicalstudydatarequest.com

• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Study Sponsor: Novartis Pharmaceuticals
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Novartis
• Verification Date: February 2021