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Ustekinumab (Anti-IL-12/23p40 Monoclonal Antibody) in Patients With Leukocyte Adhesion Deficiency Type 1 (LAD1) Who Have Inflammatory Pathology

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ClinicalTrials.gov Identifier: NCT03366142
Recruitment Status : Recruiting
First Posted : December 8, 2017
Last Update Posted : July 6, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Brief Summary:

Background:

The disease leukocyte adhesion deficiency type 1 (LAD1) affects white blood cells. Those are immune system cells. In people with LAD1, white blood cells do not properly communicate with the rest of the body. This causes uncontrolled inflammation, particularly in the gums. People with LAD1 can get frequent infections and tend to lose their teeth before adulthood. Researchers want to see if a drug called ustekinumab helps people with LAD1.

Objective:

To study the safety and tolerability of ustekinumab in treating gum inflammation in people with LAD1.

Eligibility:

People ages 12 65 with LAD1

Design:

Participants will be screened with:

  • Medical history
  • Physical exam
  • Oral exam
  • A scan of the chest, abdomen, and pelvis for possible infection
  • Blood and urine tests

The baseline visit will take 2 days. Participants will:

  • Repeat most screening tests
  • Have a skin exam
  • Have small pieces of their gums removed (biopsy)
  • Have mouth fluids collected
  • Get the study drug injected under the skin of the abdomen, thigh, or elsewhere on the body. They will be watched for at least 2 hours.

Participants will be instructed on tracking how they are feeling and any side effects.

Participants will have 4 more visits over 40 weeks. They will get the study drug and repeat the baseline tests.

Participants may have up to 5 more tissue biopsies.

Participants will be called between visits to discuss how they are feeling and side effects.

Participants will have a final visit 52 weeks after the baseline. They will repeat most of the baseline tests.

Participants will answer questions about their oral ulcers.


Condition or disease Intervention/treatment Phase
Leukocyte Adhesion Deficiency Type 1 Biological: Ustekinumab Phase 2

Detailed Description:

Lymphocyte adhesion deficiency type 1 (LAD1) is an autosomal recessive disorder of leukocyte function. Decreased expression of the <=2 subunit of leukocyte integrins results in abnormal cell-cell and cell extracellular matrix adhesion. This disease is characterized by recurrent bacterial infections, impaired wound formation, and other aberrations of adhesion-dependent functions. The severe phenotype can be fatal, but patients with even moderate phenotypes are prone to infection and lose their teeth despite treatment.

Ustekinumab is a monoclonal antibody directed against the p40 subunit of human interleukins IL-12 and IL-23. It is approved for treatment of moderate-to-severe plaque psoriasis, active psoriatic arthritis, and moderate-to-severe Crohn s disease. By binding the shared p40 subunit of IL-12 and IL-23, ustekinumab exerts clinical effects through interruption of the TH1 and TH17 cytokine pathways. Previous work at the NIH suggests that blockade of IL-17, which is highly expressed in the gingiva of people with LAD1, can reduce bacterial load and resolve inflammatory gingival disease. We have treated one patient with ustekinumab for 1 year; during this time, he had no serious infections and there was a dramatic resolution of his inflammatory lesions. Our goal is to explore the potential of ustekinumab as treatment for LAD1 inflammatory disease.

The objective of this open-label, proof-of-concept study is to evaluate the safety and tolerability of ustekinumab in 10 patients with LAD1. Participants will receive 5 doses of ustekinumab via subcutaneous injection over the course of 1 year. They will be evaluated for adverse events, as well as the effect of the drug on inflammatory lesions and biomarker expression.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Ustekinumab (Anti-IL-12/23p40 Monoclonal Antibody) in Patients With Leukocyte Adhesion Deficiency Type 1 (LAD1) Who Have Inflammatory Pathology
Actual Study Start Date : July 2, 2018
Estimated Primary Completion Date : January 31, 2021
Estimated Study Completion Date : May 31, 2021


Arm Intervention/treatment
Experimental: 1
Weights up to 60 kg will receive 0.75 mg/kg, more than 60kg up to 100kg will receive 45 mg, and more than 100kg will receive 90mg via subcutatneious injection once every 12 weeks for a total of 5 doses.
Biological: Ustekinumab
Participants who weight up to 60kg will receive 0.75 mg/kg, those more than 60kg up to 100kg will receive 45 mg and those more than 100 kg will receive 90 mg. If there has been no clinical improvement after the second dose but the participant tolerates the study drug, then subsequent doses will be increased from 45 to 90mg. A dose of 0.75 mg/kg will be increased to 45 mg, and a dose of 45 mg will be increased to 90 mg. The dose will not be escalated more than once, and it will not be increased above 90 mg.




Primary Outcome Measures :
  1. Safety and tolerability of ustekinumab in treating LAD1 affected patients who have gingival inflammation. [ Time Frame: First dose, Weeks 4, 16, 28, 40 and 52 ]

Secondary Outcome Measures :
  1. To evaluate the efficacy of ustekinumab via the assessment of oral inflammation, via full-mouth gingival bleeding on probing measurements. [ Time Frame: Screening, Baseline (day -1), Weeks 4, 16, 28, 40 and 52 ]
  2. Local gingival cytokine expression [ Time Frame: Baseline (day-1), Weeks 4, 16, 28, 40 ]
  3. Changes in serum markers of inflammation and cytokine expression (blood) [ Time Frame: Baseline (day-1), Weeks 4, 16, 28, 40 and 52 ]
  4. Percent of decrease or increase in the incidence, size, and severity (symptoms) of oral ulcers. [ Time Frame: Screening, Baseline (day -1), Weeks 4, 16, 28, 40 and 52 ]
  5. Clinical response of any cutaneous wounds (if present) [ Time Frame: Weeks 4, 16, 28, 40 and 52 ]
  6. Correlation of IL-12 and IL-12 binding levels with clinical response. [ Time Frame: Screening, Baseline (day -1), Weeks 4, 16, 28, 40 and 52 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   12 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION CRITERIA:
  • Age 12-65 years.
  • Molecularly and cellularly confirmed LAD1 with inflammatory gingival lesions.
  • Willing to allow storage of biological samples for future research.
  • Willing to allow genetic testing of blood samples.
  • Able to provide informed consent.
  • Participants who can get pregnant or impregnate a partner must agree to use adequate contraception when engaging in sexual activities that can result in pregnancy. Adequate contraception must be used consistently starting at screening and lasting through the final study visit. Appropriate forms of contraception include the following:

    1. Intrauterine device or equivalent.
    2. Hormonal contraceptive (eg, consistent, timely, and continuous use of contraceptive pill, patch, ring, implant, or injection) that has reached full efficacy before dosing.
    3. A double barrier method (eg, male/female condom, cap, or diaphragm plus spermicide).
    4. Be in a stable, long-term monogamous relationship, per assessment of the principal investigator (PI), with a partner who does not pose any potential pregnancy risk, eg, has undergone a vasectomy at least 6 months before the first dose of study agent or is of the same sex as the participant.
    5. Have had a hysterectomy and/or a bilateral tubal ligation or both ovaries removed.

EXCLUSION CRITERIA:

  • History of malignancy (except for basal cell) within the previous 3 years.
  • Infected with HIV.
  • Active uncontrolled bacterial, viral, or fungal infection.
  • Active or chronic viral hepatitis.
  • Active or latent untreated tuberculosis.
  • Received Bacillus Calmette-Guerin vaccine within the last year.
  • Received live attenuated vaccines within 15 weeks before the first dose.
  • Allergy to any component of the ustekinumab formulation.
  • Pregnant or breastfeeding.
  • No presence of teeth.
  • Any condition that, in the opinion of the investigator, contraindicates participation in this study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03366142


Contacts
Contact: Dawn Shaw, R.N. (301) 435-6169 dawn.shaw2@nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
Principal Investigator: Beatriz E Marciano, M.D. National Institute of Allergy and Infectious Diseases (NIAID)

Additional Information:
Publications:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT03366142     History of Changes
Other Study ID Numbers: 180022
18-I-0022
First Posted: December 8, 2017    Key Record Dates
Last Update Posted: July 6, 2018
Last Verified: November 29, 2017

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

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):
Autosomal Recessive Disorder
Bacterial Infections
Gingival
Oral Ulcer
Cytokine Expression

Additional relevant MeSH terms:
Tissue Adhesions
Leukocyte-Adhesion Deficiency Syndrome
Cicatrix
Fibrosis
Pathologic Processes
Immunologic Deficiency Syndromes
Immune System Diseases
Antibodies
Antibodies, Monoclonal
Ustekinumab
Immunologic Factors
Physiological Effects of Drugs
Dermatologic Agents