Investigating Mechanism of Action of DAC HYP in the Treatment of High-Inflammatory Multiple Sclerosis (MS)

NCT01143441 | Completed Phase 1

• 2 other identifiers: 10012510-N-0125
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

Objective: The primary goal of this study is to investigate the mechanism of action (MOA) of CD25-blocking therapies in high inflammatory multiple sclerosis (HI-MS). The secondary goal of this study is to assess long-term safety and efficacy of CD25-blocking therapies in HI-MS. Study population: Two cohorts of patients will be enrolled:

• Long-term daclizumab therapy cohort: Up to 15 daclizumab-treated patients with relapsing-remitting (RR-MS) or secondary-progressive MS (SP-MS) previously classified as HI-MS based on MRI/clinical criteria, who have been treated with IV daclizumab for a minimum of 1 year and responded to this therapy with significant (\>70%) decrease in contrast-enhancing lesions (CEL) or stabilization/improvement of disease activity (\>60% decrease in MS relapses and stable or improved EDSS disability score).
• New treatment cohort: Up to 15 HI-MS patients (RR- or SP-MS) with inadequate therapeutic response to first-line, FDA-approved immunomodulatory therapies for MS or who cannot, for any reason, be treated with first-line, FDA-approved immunomodulatory therapies for MS. Design: This is an open label, Phase I trial of 150 mg of daclizumab high yield process (DAC HYP) administered subcutaneously (SC) every 4 weeks for a total of 3 years. Outcome measures: Because the main goal of this study is to investigate the MOA of CD25-blocking therapies in MS, the primary outcomes are mechanistic immunological studies performed on clinical samples (peripheral blood mononuclear cells (PBMC), cerebrospinal fluid (CSF) cells and skin biopsies) derived from DAC HYP-treated patients. The secondary outcome measure is long-term safety and tolerability of subcutaneous DAC HYP in HI-MS patients.

Conditions

Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting

Keywords

Multiple Sclerosis; Daclizumab

Outcome Measures

Primary Outcomes (3)

• Expansion of CD56bright NK cells.

• Contraction of lymphoid tissue inducer cells (LTi) cells.

• Expansion of double negative T cells.

Secondary Outcomes (2)

• Long-term safety and tolerability of DAC HYP in high-inflammatory multiple sclerosis (HI-MS) patients who were either previously successfully treated with Zenapax (registered trademark) or without any previous exposure to DC25-targeting therapie...

  Study Completion

• Secondary Outcome Measure: MRI outcomes Inhibition of the number of contrast-enhancing lesions. T2 lesion load and development of new MS lesions. Clinical/functional outcomesChange in EDSS. Change in Scripps NRS. Change in MSFC.Change in S...

  Study Completion

Study Arms (3)

Cohort A

EXPERIMENTAL

Long-Term daclizumab cohort

Biological: DAC-HYP

Cohort B

EXPERIMENTAL

New Treatment Cohort

Biological: DAC-HYP

Cohort C

NO INTERVENTION

MS Controls

Interventions

DAC-HYP BIOLOGICAL

Cohort A; Cohort B

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• MS as defined by the modified McDonald criteria (Polman, Reingold et al. 2005)
• HI-MS (RR-MS or SP-MS) before initiation of daclizumab therapy, defined as:
• greater than or equal to 3 CEL on a single pre-daclizumab MRI or
• greater than or equal to 1 MS exacerbation per year before initiation of daclizumab therapy or
• progression of sustained disability by greater than or equal to 1.0 point on the expanded disability status scale (EDSS) in the year preceding daclizumab therapy
• Age 18-60, inclusive
• EDSS 0 to 6.0, inclusive
• Able to provide informed consent
• Willing to participate in all aspects of trial design and follow-up
• Females of childbearing potential are willing to commit to the use of a reliable method of birth control (i.e., hormonal contraception including birth control pills, injected hormones or vaginal ring; intrauterine device; barrier methods with spermicide, specifically diaphragms or condoms they have undergone surgical sterilization, such as hysterectomy or tubal ligation) for the duration of the study and continued 4 months after conclusion of the study.
• IV daclizumab therapy for at least 1 year with a treatment response consisting of:\<TAB\>
• greater than or equal to 70% reduction of CEL after starting daclizumab; or
• stabilization or improvement of sustained neurological disability on daclizumab.

You may not qualify if:

• PP-MS or low-inflammatory SP-MS
• Alternative diagnoses that can explain neurological disability and MRI findings (e.g., ischemia/gliosis, CNS lyme disease, SLE, sarcoidosis, etc.)
• History of malignancy, with the following exceptions: excised or treated basal cell carcinoma or fewer than 3 squamous cell carcinomas, grade 1 endometrial carcinomas treated with total hysterectomy and without evidence for recurrence for greater than or equal to 3 years
• positive HIV or HTLV-1 serology;
• positive hepatitis B or C serology;
• pregnant or breastfeeding female;
• known history of severe allergic or anaphylactic reactions;
• known hypersensitivity to study drug or its excipients;
• varicella or herpes zoster virus infection or any severe viral infection within the 6 weeks prior to screening; or
• exposure to varicella zoster virus within 21 days before screening.
• Abnormal screening/baseline blood tests exceeding any of the limits defined below:
• serum alanine aminotransferase/serum glutamate pyruvate transaminase (ALT/SGPT), aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT), or gamma-glutamyl-transferase greater than or equal to 2 times the upper limit of normal (ULN);
• total white blood cell count \<3,000/mm(3);
• hemoglobin greater than or equal to 9.0 g/dL;
• platelets greater than or equal to 100 x 10(9)/L;

Sponsors & Collaborators

• National Institute of Neurological Disorders and Stroke (NINDS): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Bielekova B, Howard T, Packer AN, Richert N, Blevins G, Ohayon J, Waldmann TA, McFarland HF, Martin R. Effect of anti-CD25 antibody daclizumab in the inhibition of inflammation and stabilization of disease progression in multiple sclerosis. Arch Neurol. 2009 Apr;66(4):483-9. doi: 10.1001/archneurol.2009.50.

  PMID: 19364933 BACKGROUND

• Hanssen LE, Schrumpf E, Kolbenstvedt AN, Tausjo J, Dolva LO. Recombinant alpha-2 interferon with or without hepatic artery embolization in the treatment of midgut carcinoid tumours. A preliminary report. Acta Oncol. 1989;28(3):439-43. doi: 10.3109/02841868909111219.

  PMID: 2742781 BACKGROUND

• Bielekova B, Catalfamo M, Reichert-Scrivner S, Packer A, Cerna M, Waldmann TA, McFarland H, Henkart PA, Martin R. Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5941-6. doi: 10.1073/pnas.0601335103. Epub 2006 Apr 3.

  PMID: 16585503 BACKGROUND

MeSH Terms

Conditions

Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Bibiana Bielekova, M.D.

  National Institute of Neurological Disorders and Stroke (NINDS)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 11, 2010
• First Posted: June 14, 2010
• Study Start: May 13, 2010
• Primary Completion: August 11, 2017
• Study Completion: August 11, 2017
• Last Updated: November 1, 2019

Record last verified: 2017-08-11

Locations

US (1)