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Safety and Efficacy of Subcutaneous Sarilumab in Improving the Quality of Life in People With Indolent Systemic Mastocytosis

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ClinicalTrials.gov Identifier: NCT03770273
Recruitment Status : Recruiting
First Posted : December 10, 2018
Last Update Posted : June 24, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Tracking Information
First Submitted Date  ICMJE December 7, 2018
First Posted Date  ICMJE December 10, 2018
Last Update Posted Date June 24, 2019
Actual Study Start Date  ICMJE June 19, 2019
Estimated Primary Completion Date August 1, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 7, 2018)
  • Frequency and severity of adverse events (AEs) during the randomized double-blinded placebo-controlled treatment period. [ Time Frame: day 0 through week 28 ]
  • QoL at 16 weeks post-initiation of study drug/placebo using the Mastocytosis Quality of Life Questionnaire (MC-QoL). [ Time Frame: 16 weeks post study drug initiation ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03770273 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 14, 2018)
  • Decrease in the allelic frequency of D816V using PCR [ Time Frame: Day 0, week 16 and week 28 for D816V allelic frequency by PCR ]
  • Percent improvement in QoL using MC-QoL, scoring of mastocytosis index (SCORMA), and Memorial Symptom Assessment Scale (MSAS) [ Time Frame: Day 0 through Week 28 ]
  • Reduction in use of medicines for symptomatic relief, reduction in serum levels of tryptase [ Time Frame: Day 0 through Week 28 ]
  • Reduction of percentage infiltrating mast cells in bone marrow [ Time Frame: Day 0 and Week 16 only for bone marrow ]
Original Secondary Outcome Measures  ICMJE
 (submitted: December 7, 2018)
  • Decrease in the allelic frequency of D816V using PCR [ Time Frame: Day 0, week 16 and week 28 for D816V allelic frequency by PCR ]
  • Percent improvement in QoL using MC-QoL, scoring of mastocytosis index (SCORMA), and Memorial Symptom Assessment Scale (MSAS) [ Time Frame: Day 0 through Week 28 ]
  • (MSAS) Day 0 through Week 28 (NotEqual)Yes No Reduction in use of medicines for symptomatic relief, reduction in serum levels of tryptase [ Time Frame: Day 0 through Week 28 ]
  • Reduction of percentage infiltrating mast cells in bone marrow [ Time Frame: Day 0 and Week 16 only for bone marrow ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy of Subcutaneous Sarilumab in Improving the Quality of Life in People With Indolent Systemic Mastocytosis
Official Title  ICMJE A Phase 2 Randomized Double-Blinded Placebo-Controlled Study to Evaluate the Safety and Efficacy of Subcutaneous Sarilumab in Improving the Quality of Life in Subjects With Indolent Systemic Mastocytosis
Brief Summary

Background:

Mast cells help the body fight disease and heal wounds. People with indolent systemic mastocytosis (ISM) make too many mast cells. This causes pain, tiredness, digestive problems, and other symptoms. Researchers think the drug sarilumab could help.

Objective:

To see if sarilumab is a safe and effective treatment for people with ISM.

Eligibility:

Adults ages 18-75 with ISM who are enrolled in NIH study 02-I-0277

Design:

Participants will be screened with:

  • Physical exam
  • Medical history
  • Blood and urine tests
  • Questionnaires
  • Bone marrow removed by a needle inserted into the hip bone
  • Ultrasound of the abdomen
  • Photographs of the skin

Participants will repeat some screening tests at study visits.

Participants will have a baseline visit in the hospital for 3 days. They will:

  • Be assigned to get either the study drug or a placebo. They will not know which one they get.
  • Have a skin punch biopsy: An instrument will remove a small piece of skin.
  • Get their first drug dose injected under their skin

Participants will keep a side effect and medication diary during the study.

Participants will visit the clinic to get a drug dose every 2 weeks, for a total of 8 doses.

Participants will have a visit 2 weeks after their final dose. It will last up to 2 days.

Participants will have another visit 12 weeks later.

Participants may then continue this study for 1 more year. Those who continue will get sarilumab, even if they previously got the placebo, every 2 weeks. They will have visits every 6 weeks, and then every 3 months.

Detailed Description

Systemic mastocytosis is a disorder caused by clonal mast cell proliferation and release of mast cell mediators including tryptase. As a result, mast cell numbers may increase and affect target organs including the dermis (maculopapular cutaneous mastocytosis/urticaria pigmentosa, flushing), gastrointestinal tract (abdominal pain, diarrhea), skeletal system (osteoporosis), hematological system (anemia, thrombocytopenia), and spleen and liver (organomegaly). Patients with indolent (non-aggressive) systemic mastocytosis (ISM) are not candidates for cytoreductive therapy and are generally treated with symptomatic therapy that only partly decreases symptoms. There is, however, a documented association between severity of mastocytosis and elevated serum levels of interleukin (IL)-6. Furthermore, mast cells have been shown to double their rate of division and exhibit increased reactivity and release of mediators when cultured in the presence of IL-6. In addition, in an animal model of mastocytosis, anti-IL-6 has been shown to slow disease progression. In this study, adults with ISM will thus be randomized and treated with sarilumab, a recombinant monoclonal antibody directed against the IL-6 receptor, or receive placebo. Sarilumab is marketed in the United States as Kevzara (Regeneron [Tarrytown, NY, USA]) and is approved by the Food and Drug Administration for the treatment of rheumatoid arthritis. Binding of sarilumab to the IL-6 receptor inhibits IL-6-associated human mast cell signaling and proliferation with a resultant decrease in proliferation and reactivity (decreased mediator release), and therefore is a rational choice for the treatment of ISM.

In this study, participants will be randomized with approximately half of the participants receiving study drug, which will be administered at 200 mg via subcutaneous (SC) injection once every 2 weeks (Q2W) for a total of 16 weeks. The other participants will receive a placebo administered via SC injection Q2W for 16 weeks. Participants will return for a follow-up visit 2 weeks after the final dose (treatment peak), and then again 12 weeks later. Evaluations at study visits will include quality of life and symptom assessments and measurement of serum tryptase levels. Bone marrow examination will be performed at the onset and conclusion of the study. After the week 28 visit, all participants will have the option to continue sarilumab for 52 more weeks, at 200 mg administered via SC injections. Participants will continue to be monitored on a regular basis for safety concerns, as instructed in the study drug s package insert.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Indolent Systemic Mastocytosis
Intervention  ICMJE
  • Other: Placebo
    Placebo
  • Biological: Sarilumab
    Sarilumab is a fully human anti-IL-6R-alpha monoclonal antibody that binds membrane-bound and soluble human IL-6R and has been shown to inhibit IL-6 signaling
Study Arms  ICMJE
  • Active Comparator: 1
    8 subcutaneous (SC) injections of 200 mg/1.14 mL of sarilumab (trade name Kevzara) over 16 weeks
    Intervention: Biological: Sarilumab
  • Placebo Comparator: 2
    8 subcutaneous (SC) injections of placebo, volume 1.14 mL over 16 weeks
    Intervention: Other: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 7, 2018)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 1, 2027
Estimated Primary Completion Date August 1, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:

Participants must meet all of the following criteria to be enrolled in this study:

  1. Male or female participant greater than or equal to 18 and < 75 years of age at screening.
  2. Enrolled on NIAID protocol 02-I-0277.
  3. Documented pathologic diagnosis of ISM.
  4. MC-QoL score of at least 25% (which suggests participant is at least somewhat affected by all McQoL questions).
  5. Willing and able to undergo a bone marrow biopsy and aspirate.
  6. Absolute neutrophil count (ANC) greater than or equal to 2000/mL.
  7. Hemoglobin greater than or equal to 12.0 g/dL (males), greater than or equal to 11 g/dL (females).
  8. Platelet count greater than or equal to 150,000/microliters.
  9. Alanine transaminase (ALT) and aspartate transaminase (AST) < 1.5 times the upper limit of normal (ULN).
  10. Willing to allow storage of blood and bone marrow for future use in medical research.
  11. Willing to allow genetic testing on biospecimens.
  12. Able to provide informed consent.
  13. Participants who can become pregnant must agree to use adequate contraception when engaging in sexual activities that can result in pregnancy. Adequate contraception must be used consistently, beginning at least 1 month before the beginning of dosing and lasting until 3 months after the final dose of study drug. Acceptable methods of contraception include the following:

    • Hormonal contraception (non-oral only).
    • Male or female condom with spermicide.
    • Diaphragm or cervical cap with a spermicide.
    • Intrauterine device.

EXCLUSION CRITERIA:

Individuals meeting any of the following criteria will be excluded from study participation:

  1. Any abnormality that would be scored as a Grade 4 toxicity on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
  2. Infected with HIV or has other known immunodeficiency.
  3. Has an active infection, including localized infection.
  4. Active diverticulitis.
  5. Active or chronic viral hepatitis.
  6. Active or latent tuberculosis.
  7. Use of any other anti-IL-6 or anti-IL-6R agent within 1 year prior to the date informed consent was obtained.
  8. Use of cytoreductive therapy for mastocytosis within 1 year prior to the date informed consent was obtained.
  9. Known lymphoma or advanced and metastatic solid tumors on active therapy (including chemotherapy) within 1 year prior to the date informed consent was obtained
  10. Use of chemotherapy or monoclonal antibodies (experimental or licensed) within 1 year prior to the date informed consent was obtained.
  11. Receipt of any marketed (eg, omalizumab) or investigational biologic within 4 months or 5 half-lives prior to date informed consent was obtained, whichever is longer.
  12. Receipt of intravenous (IV) immunoglobulin within 30 days prior to the date informed consent was obtained.
  13. Receipt of live attenuated vaccines within 30 days prior to the date informed consent was obtained.
  14. History of alcohol or drug/abuse within 12 months prior to date informed consent was obtained.
  15. Is allergic to any component of the sarilumab formulation.
  16. Pregnant or breastfeeding.
  17. Any condition that, in the opinion of the investigator, contraindicates participation in this study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 74 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Robin R. Eisch, R.N. (301) 443-1720 eischar@mail.nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03770273
Other Study ID Numbers  ICMJE 190027
19-I-0027
Has Data Monitoring Committee Not Provided
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  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Hirsh D Komarow, M.D. National Institute of Allergy and Infectious Diseases (NIAID)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date January 11, 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP