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Protocol Details

Compassionate Use Treatment Protocol I4V-MC-JAGA; Treatment of Autoinflammatory Syndromes Expected to Benefit from JAK Inhibition

This study is NOT currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

12-AR-8001

Sponsoring Institute

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Recruitment Detail

Type: Completed Study; data analyses ongoing
Gender: Male & Female
Min Age: 1
Max Age: N/A

Referral Letter Required

Yes

Population Exclusion(s)

None

Keywords

JAK Inhibition;
Autoinflammatory Syndrome;
Interferon

Recruitment Keyword(s)

None

Condition(s)

JAK Inhibition;
CANDLE

Investigational Drug(s)

LY3009104

Investigational Device(s)

None

Intervention(s)

Drug: Baricitinib

Supporting Site

National Institute of Arthritis and Musculoskeletal and Skin Diseases

I4V-MC-JAGA (JAGA) is an open-label compassionate-use study. Patients who weigh at least 8.5 kg and who are at least 17.5 months of age are eligible to enter this study. Patients who are enrolled will be hospitalized at the time of initiation of treatment and for a period of time to allow for dose escalation and stabilization. The patient will then be allowed to be discharged from the hospital and continue study drug as an outpatient. The patient s disease severity will be recorded daily by the patient or patient s parent throughout the study on a diary. Average diary scores will define adequate response to therapy and be used to trigger increases in daily doses of LY3009104. Once a patient achieves a low average daily diary score (defined below), the investigator will begin to taper the patient s steroid dose. Patients whose average diary score decreases, but who do not meet the threshold for steroid weaning, may continue in the study, if the investigator determines that the patient has shown response to treatment with LY3009104 and it is in the best interest of the patient to continue treatment.

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Eligibility

INCLUSION CRITERIA:

Patients are eligible for entry into the study (that is, eligible to sign consent) only if they meet all of the following criteria:

1) Have systemic signs and symptoms of inflammation as manifested by the presence of 2 or more of the following symptoms: rash, fever,musculoskeletal pain, headache, fatigue, weakness, respiratory/breathing symptoms, or ulcers/ischemic lesions.

2) Have an average daily diary score of greater than or equal to 0.5 (CANDLE diary) or greater than or equal to1.0 (SAVI or JDM diary) assessed over at least 2 weeks prior to entry, if available. Otherwise, patients can complete the diary after study consent is signed during the screening period and meet the inclusion criteria for enrollment into the study.

3) Are greater than or equal to 17.5 months of age. Patients younger than 17.5 months of age can be considered for enrollment after discussion with the Sponsor.

4) Are greater than or equal to 8.5 kg in body weight. Patients weighing less than 8.5 kg can be considered for enrollment after discussion with the Sponsor.

5) Have been previously treated with at least 1 biologic therapy and, in the opinion of the investigator, did not respond or are no longer responding to therapy. If the patient has been diagnosed with CANDLE, Nakajo-Nishimura syndrome, SAVI, or an equivalent syndrome, the need for previous biologic therapy is not required.

6) Require treatment with oral corticosteroids (greater than or equal to 0.15 mg/kg/day of prednisone or its equivalent) for control of systemic signs and symptoms of their chronic inflammatory disease for at least 2 weeks prior to study entry, or in the opinion of the investigator, have failed an adequate course of steroids.

7) Have had previous documented elevations in acute-phase reactants (for example, high sensitivity C-reactive protein) considered to be the result of the inflammatory disease (patients with CANDLE or CANDLE-related conditions only).

8) Have the ability to provide informed consent or have legal representative who is willing and able to provide written informed consent, provided that assent is obtained from patients at an age-appropriate level.

PATIENTS WITH JUVENILE DERMATOMYOSITIS

Patients with JDM are eligible for entry into the study (that is, eligible to sign consent) only if they meet all of the previous criteria (1 through 8) and all of the following criteria:

37) Meet definite or probable JDM diagnosis by the criteria of Bohan and Peter (1975) with onset of first symptom prior to 18 years of age

38) Have refractory myositis as defined by the intolerance to, or an inadequate response to, corticosteroids plus an adequate regimen of at least 2 other immunomodulatory or immunosuppressive agents (including at least 1 biologic agent), such as intravenous immune globulin (IVIg), azathioprine, methotrexate, mycophenolate mofetil, cyclophosphamide, tacrolimus, or cyclosporine A. Other immunomodulatory or immunosuppressive agents, such as rituximab, can be considered after discussion with the Sponsor. The definition of intolerance is side effects that require discontinuation of the medication or an underlying condition that precludes the further use of the medication.

-Adequate treatment with corticosteroids or immunosuppressive/immunomodulatory drugs is defined as the lowest of the following doses:

--Corticosteroids: 1.0 mg/kg/d or 60 mg/d for at least 1 month

--Azathioprine: 2 mg/kg/d or 150 mg/d for at least 3 months

--Methotrexate: 0.3 mg/kg or 15 mg/m2/week or 15 mg/week for at least 3 months

--IVIg: 1 g/kg/month or 60 g/month for at least 3 months

--Mycophenolate mofetil: 30 mg/kg/d or 1000 mg twice daily for at least 3 months

--Cyclophosphamide: 1.0 mg/kg/d or 500 mg/m2/month or 500 mg/month intravenously for at least 3 months

--Tacrolimus: 0.1 mg/kg/d or 5 mg/d for at least 3 months

--Cyclosporine: 2.5 mg/kg/d for at least 3 months

39) If receiving hydroxychloroquine, must have been receiving a stable dose for at least 4 weeks prior to screening visit

40) If receiving a statin, must have been receiving a stable dose for at least 8 weeks prior to screening visit

PATIENTS WITH CANDLE-RELATED CONDITIONS

Patients with CANDLE-related conditions are eligible for entry into the study (that is, eligible to sign consent) only if they meet all of the common inclusion criteria (1 through 8) and all of the following criteria:

46) Have organ specific inflammation involving at least one of the following:

vasculopathy (such as hypertension, vascular calcifications such as basal ganglia calcifications, or livedo reticularis), metabolic changes (such as lipodystrophy, dyslipidemia, insulin resistance, or intra-abdominal fat deposition), musculoskeletal manifestations (myositis,

arthralgias or arthritis, and/or panniculitis), hematological manifestations (i.e. cytopenias) and/or interstitial lung disease.

47) Have high IP-10/CXCL10 levels and/or IFN response signature in peripheral blood mononuclear cells being one of the most dysregulated blood signatures.

EXCLUSION CRITERIA:

Patients will be excluded from the study if they meet any of the following criteria:

9) Have received an immunosuppressive biologic agent/monoclonal antibody within 4 half-lives prior to entry, for example, anakinra (4 halflives=18 hours); etanercept (4 half-lives=18 days); infliximab; or adalimumab (4 half-lives=36 days). Use of IVIg is permitted.

10) Are pregnant or nursing at the time of entry

11) Are females of childbearing potential who do not agree to use 2 forms of highly effective birth control when engaging in sexual intercourse with a male partner while enrolled in the study and for at least 4 weeks following the last dose of investigational product

Females of nonchildbearing potential are defined as women greater than or equal to 60 years of age, women greater than or equal to 40 and <60 years of age who have had a cessation of menses for at least 12 months, or women who are congenitally or surgically sterile (that is, have had a hysterectomy or bilateral oophorectomy or tubal ligation).

The following birth control methods are considered highly effective (the patient

should choose 2 to be used with their male partner):

-oral, injectable, or implanted hormonal contraceptives

-condom with a spermicidal foam, gel, film, cream, or suppository

-occlusive cap (diaphragm or cervical/vault caps) with a spermicidal foam, gel, film, cream, or suppository

-intrauterine device

-intrauterine system (for example, progestin-releasing coil)

-vasectomized male (with appropriate post vasectomy documentation of the absence of sperm in the ejaculate)

Note: when local guidelines concerning highly effective methods of

birth control differ from the above, the local guidelines must be

followed.

12) Are males who do not agree to use 2 forms of highly effective birth control (see above) while engaging in sexual intercourse with female partners of childbearing potential while enrolled in the study and for at least 4 weeks following the last dose of investigational product.

13) Have had symptomatic herpes zoster within 12 weeks prior to entry or during the screening period.

14) Have a history of disseminated/complicated herpes zoster (for example, multidermatomal involvement, ophthalmic zoster, central nervous system involvement, postherpetic neuralgia)

[CNS] involvement, postherpetic neuralgia)

15) Have evidence of active infection, at the time of entry or during the screening period, that in the opinion of the investigator, would pose an unacceptable risk for participating in the study.

16) Have a history of active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).

17) Have documented high titer autoantibodies suggestive clinically of autoimmune diseases other than severe JDM.

18) Are immunocompromised and, in the opinion of the investigator, are at an unacceptable risk for participating in the study

19) Have had a serious systemic or local infection (including an infectious mononucleosis-like illness or herpes zoster) within 12 weeks prior to entry or during the screening period. Exceptions include SAVI patients with infected ulcerative skin lesions, which in the opinion of the investigator, would not pose an unacceptable risk for pariticipating in the study.

20) Have been exposed to a live vaccine within 12 weeks prior to entry or are expected to need/receive a live vaccine (including herpes zoster vaccination) during the course of the study

Note: Investigators should review the vaccination status of their patients and follow the local guidelines for vaccination with nonlive vaccines intended to prevent infectious disease prior to entering patients into the study.

21) Have had household contact with a person with active tuberculosis (TB) and did not receive appropriate and documented prophylaxis for TB

22) Have a serious and/or unstable illness that, in the opinion of the investigator, poses an unacceptable risk for the patient s participation in the study

23) Have an estimated glomerular filtration rate (eGFR) based on the most recent available serum creatinine of <40 mL/min/1.73 m2.

24) Have or have had a history of lymphoproliferative disease; or signs or symptoms suggestive of possible lymphoproliferative disease, or active primary or recurrent malignant disease; or been in remission from clinically significant malignancy for <5 years

Note: Patients with resolved cervical dysplasia, or no more than 3 successfully treated basal-cell carcinoma of the skin, may participate in this study.

25) Have a history of chronic alcohol abuse or intraveneous (IV) drug abuse within the 2 years prior to entry

26) Are unable or unwilling to make themselves available for the duration of the study and/or are unwilling to follow study restrictions/procedures

27) Are investigator-site personnel directly affiliated with this study and/or their immediate families. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.

28) Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or nonapproved use of a drug or device (other than the investigational product used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study

PATIENTS WITH JUVENILE DERMATOMYOSITIS

Patients with JDM will be excluded from the study if they meet any of the previous criteria (9 through 28) or any of the following criteria:

41) Have drug-induced myositis (myositis in patients taking medications known to induce myositis-like syndromes, including, but not limited to, statin agents, fibric acid derivatives, colchicine, and hydroxychloroquine)

42) Have a history of juvenile polymyositis, inclusion body myositis, or cancer-associated myositis, defined as the diagnosis of myositis within 2 years of the diagnosis of cancer except basal or squamous cell skin cancer or carcinoma in situ of the cervix if at least 5 years since excision

43) Have myositis in overlap with another connective tissue disease (CTD) that precludes the accurate assessment of a treatment response (for example, difficulty in assessing muscle strength in a scleroderma patient with associated myositis)

44) Have joint disease or other musculoskeletal condition, which precludes the ability to quantitate muscle strength

ENROLLMENT CRITERIA

INCLUSION CRITERIA:

Entered patients are eligible for enrollment into the study (that is, eligible to receive LY3009104) only if they continue to meet all of the inclusion criteria for entry at the time of Visit 2 plus the following requirements.

29) Have a mean daily diary score of greater than or equal to 0.5 (CANDLE diary) or greater than or equal to 1.0 (SAVI or JDM diary) assessed over at least 2 weeks prior to enrollment, including patients who completed the diary after consent was signed.

45) For JDM patients, have severe disease as assessed by core set measures. Severe disease will be assessed as follows: baseline manual muscle testing (within the previous month), with a score no greater than 125 of a possible 150 in conjunction with 2 of the following abnormal core set measures:

-Baseline manual muscle testing (within the previous month) with a

score no greater than 125 out of a possible 150

-Parent/patient global VAS with a minimum value of 2.0 cm on a 10 cm scale

-Physician global VAS with a minimum value of 2.0 cm on a 10-cm scale

-Childhood Health Assessment Questionnaire or Health Assessment Questionnaire disability index of greater than or equal to 0.25

-Elevation of at least one of the muscle enzymes (creatine kinase, aldolase, lactate dehydrogenase, alanine aminotransferase [ALT], and aspartate aminotransferase [AST]) at a minimum level of 1.3 times the upper limit of normal (ULN)

-Global extramuscular disease activity score with a minimum value of 1.0 cm on a 10-cm VAS scale (this measure is the physician s composite evaluation and is based on assessments of activity scores on the constitutional, cutaneous, skeletal, gastrointestinal, pulmonary, and cardiac scales of the Myositis Disease Activity Assessment Tool

EXCLUSION FROM STUDY ENROLLMENT:

Entered patients are ineligible for enrollment (that is, ineligible to receive LY3009104) and should be discontinued from the study if they meet any of the following criteria:

30) Have screening laboratory test values outside the reference range for the population or investigative site that, in the opinion of the investigator, pose an unacceptable risk for the patient s participation in the study

31) Have any of the following specific abnormalities on screening laboratory tests:

- AST or ALT >2 times the upper limit of normal (ULN) unless the hepatitis is confirmed as resulting from the autoinflammatory condition. If autoinflammatory-associated hepatitis is present, AST or ALT cannot exceed 4 times the ULN. If inflammatory myositis is present or suspected, obtain total and direct bilirubin, aldolase, and gammaglutamyl transferase (GGT) if not yet done. Elevation in AST and/or ALT is acceptable if GGT and total and direct bilirubin are less than 1.5 times ULN and an expert independent of the principal investigator (preferably a hepatologist or gastroenterologist) documents that the elevation is secondary to myositis. Even if inflammatory myositis is considered present, AST or ALT cannot exceed 5 times the ULN.

- Hemoglobin <10 g/dL (100 g/L). Patients with CANDLE, CANDLE-related conditions, or SAVI may be enrolled with hemoglobin <10 g/dL if the anemia is considered a result of the underlying disease.

- Total WBC count <2500 cells/microL. Patients with CANDLE, CANDLE-related conditions, or SAVI may be enrolled with WBC count <2500 cells/ L if the low WBC count is considered a result of the underlying disease.

- Neutropenia (absolute neutrophil count [ANC] <1200 cells/microL). Patients with CANDLE, CANDLE-related conditions, or SAVI may be enrolled with an ANC <1200 cells/ L if the low ANC is considered a result of the underlying disease.

- Thrombocytopenia (platelets <100,000/microL). Patients with CANDLE or SAVI may be enrolled with a platelet count <100,000/ L if the low platelet count is considered a result of the underlying disease

- eGFR <40 mL/min/1.73 m(2)

Note: A patient with CANDLE, CANDLE-related condition, or SAVI may be enrolled with any of the above specific abnormalities on screening laboratory tests if these laboratory abnormalities are considered a feature of the disease. An expert independent of the principal investigator (preferably a hematologist) must evaluate the patient and, in conjunction with the principal investigator, document that the laboratory abnormality is a feature of the underlying CANDLE, CANDLE-related condition, or SAVI condition; the investigator must also consult with the Sponsor before the patient can be enrolled.

32) Have screening thyroid-stimulating hormone (TSH) and/or thyroxine (T4) values outside of the laboratory s reference range and are assessed to be clinically significant. If results are available from testing within 1 month, then the patient will not have to be retested. Patients who are receiving T4 as replacement therapy may participate in the study provided stable therapy has been administered for greater than or equal to 3 months and TSH is within the laboratory s reference range.

Note: In the case of any of the aforementioned laboratory abnormalities, laboratory tests may be repeated once within 1 week of the initial values, and values resulting from repeat testing may be

accepted for enrollment eligibility if they meet the eligibility criterion.

33) Have screening electrocardiogram (ECG) abnormalities that, in the opinion of the investigator, are clinically significant and indicate an unacceptable risk for the patient s participation in the study (for example, Bazett s corrected QT interval >450 msec for males and >470 msec for females).

34) Have evidence of active or latent TB as documented by a positive purified protein derivative (PPD) test (greater than or equal to 5 mm in duration between approximately 2 and 3 days after application, regardless of vaccination history), medical history, and chest x-ray at screening. If results are available from testing within 1 month, then the patient will not have to be retested. Exceptions include patients with a history of latent TB who have documented evidence of completing a course of appropriate treatment:

-If the PPD test is positive and the patient has no medical history or chest x-ray findings consistent with active or latent TB, the patient should have a QuantiFERON -TB Gold test. If the test is positive or indeterminate, the patient is excluded from the study.

-The QuantiFERON-TB Gold test may be used instead of the PPD test; patients with positive tests are excluded. If the QuantiFERON-TB Gold test is indeterminate, a retest is allowed. If the retest is also indeterminate, the patient is excluded from the study.

35) Have a positive test for hepatitis B defined as (1) positive for hepatitis B surface antigen, or (2) positive for anti-hepatitis B core antibody, but negative for hepatitis B surface antibody) unless the anti-hepatitis B core antibody is thought to be a false positive result. In the latter case, confirmation of the presence of hepatitis B virus (HBV) by DNA testing is required. An HBV DNA indeterminate result is considered HBV infection.

If results are available from testing within the previous 3 months, then the patient will not have to be retested:

-If any of the hepatitis B tests have an indeterminate result, confirmatory testing will be performed by an alternate method.

36) Have hepatitis C virus (HCV) (positive for anti-hepatitis C antibody with confirmed presence of HCV); have evidence of human immunodeficiency virus (HIV) infection and/or positive HIV antibodies. If results are available from testing within the previous 3 months, then the patient will not have to be retested.

Patients who are entered, but do not meet enrollment criteria, should be discontinued from the study. These patients can be re-entered into the trial (that is, be reconsented) if the investigator believes that the patient might meet enrollment criteria at a future date, taking into consideration the volume of blood required for rescreening.


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Citations:

Dalbeth N, So A. Hyperuricaemia and gout: state of the art and future perspectives. Ann Rheum Dis. 2010 Oct;69(10):1738-43.

Boy MG, Wang C, Wilkinson BE, Chow VF, Clucas AT, Krueger JG, Gaweco AS, Zwillich SH, Changelian PS, Chan G. Double-blind, placebo-controlled, dose-escalation study to evaluate the pharmacologic effect of CP-690,550 in patients with psoriasis. J Invest Dermatol. 2009 Sep;129(9):2299-302. Epub 2009 Feb 19.

Agarwal AK, Xing C, DeMartino GN, Mizrachi D, Hernandez MD, Sousa AB, Mart(SqrRoot)(NotEqual)nez de Villarreal L, dos Santos HG, Garg A. PSMB8 encoding the <=5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome. Am J Hum Genet. 2010 Dec 10;87(6):866-72. doi: 10.1016/j.ajhg.2010.10.031. PMID: 21129723; PMCID: PMC2997366.

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Contacts:

Principal Investigator

Referral Contact

For more information:

Hanna Kim, M.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
NIHBC 10 - CLINICAL CENTER BG RM 12N240
10 CENTER DR
BETHESDA MD 20892
(301) 594-6196
kimh11@mail.nih.gov

Hanna Kim, M.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
NIHBC 10 - CLINICAL CENTER BG RM 12N240
10 CENTER DR
BETHESDA MD 20892
(301) 594-6196
kimh11@mail.nih.gov

Office of Patient Recruitment
National Institutes of Health Clinical Center (CC)
Building 61, 10 Cloister Court
Bethesda, Maryland 20892
Toll Free: 1-800-411-1222
Local Phone: 301-451-4383
TTY: TTY Users Dial 7-1-1
ccopr@nih.gov

Clinical Trials Number:

NCT01724580

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