Protocol Number: 02-AR-0170

Title:

Suppression of the Growth Hormone/ Insulin-like Growth Factor-1 (GH/IGF-1) Axis in Women with Rheumatoid Arthritis

Number:

02-AR-0170

Summary:

This study has two phases. Phase 1 will examine the role of inflammatory mediators called cytokines on growth hormone levels in women with rheumatoid arthritis (RA). Phase 2 will evaluate the effect of etanercept on these growth hormone levels. Etanercept is approved for the treatment of RA. It lowers the levels of a key inflammatory mediator called tumor necrosis factor-alpha and is very effective in reducing arthritis symptoms.

Growth hormone promotes bone and muscle growth. With aging, people lose muscle mass and bone strength, possibly because of decreased levels of growth hormone. People with RA have bone and muscle changes similar to those in older people, perhaps also due to decreased levels of growth hormone. The first part of this study will see if the inflammatory mediators responsible for joint inflammation (warmth, redness, pain, and swelling) in RA are related to the lowered growth hormone levels in this disease. The second part will evaluate the effect of etanercept treatment on muscle mass and bone density, in addition to growth hormone levels.

Premenopausal women between 18 and 55 years of age with a recent diagnosis of rheumatoid arthritis (less than 3 years) are eligible for this study. Healthy volunteers will also be enrolled in the first phase of the study as control subjects. This study is conducted at two sites, the NIH and the Johns Hopkins Medical Center in Baltimore.

Healthy volunteers enrolled in this study will be interviewed about their health status and will fill out questionnaires on diet and general physical function, including fatigue, energy and well being. In addition, they will be hospitalized once at the NIH Clinical Center for 24-hour blood sampling and will visit to Johns Hopkins Medical Center in Baltimore for a brachial artery reactivity study, as follows:

- 24-hour blood sampling for growth hormone levels. Blood samples (1/2 teaspoon each) will be collected every 20 minutes from 8 AM one day until 8 AM the following day through a plastic tube in an arm vein.

- Dual energy X-ray absorptiometry (DEXA) scan on a small area of the spine, hip and wrist to assess bone density and a total body DEXA scan to assess the amount and distribution of muscle and body fat.

- Blood vessel (brachial artery reactivity) study to measure the ability of the brachial artery to dilate and increase its blood flow. For this procedure, the subject lies on a table with electrocardiogram leads attached to the chest. A blood pressure cuff is inflated for several minutes and a drop of nasal spray of nitroglycerin is given that may cause a headache. Blood pressure and headache are monitored and treated as needed.

Patients with rheumatoid arthritis will be seen at the NIH clinic on six separate visits (weeks 0, 1, 6, 12, 18, and 26) over 26 weeks. Week 0 is a screening visit. At weeks 1 and 26, patients will be admitted to the hospital for 24-hour blood sampling, DEXA scans, and brachial artery reactivity tests, as described above, plus X-rays of the hand and feet. After the first visit, they will start taking etanercept, given by self-injection under the skin (like insulin shots) twice a week. Follow-up visits at weeks 6, 12, and 18 will involve evaluations of disease activity and drug side effects through joint examination, blood tests, and questionnaires.

Sponsoring Institute:

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

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Female

Referral Letter Required: No

Population Exclusion(s): Male

Children

Eligibility Criteria:

INCLUSION CRITERIA - General:

Healthy women, or women with RA, 18-55 year old, with a history of regular menses or who are perimenopausal, have a BMI less than 30, able to provide informed consent to all aspects of the study after full information is provided.

Women must have a negative pregnancy test at screening.

Study participants will be allowed to continue taking medications for chronic, stable conditions, such as hypertension and hypercholesteremia, while in the study.

INCLUSION CRITERIA - for RA Patients:

Active RA as defined by 9 tender and 6 swollen joints; ESR greater than 35 mm/hr OR CRP greater than 2.0 mg/dL; and, morning stiffness greater than 45 min.

Actively menstruating with a normal estrogen level or who are perimenopausal.

Women must be practicing, or willing to practice, an acceptable method of birth control that does not involve use of prescription or OTC estrogen/progesterone preparations during the two weeks prior to screening. Acceptable means of contraception include: abstinence, barrier methods with spermicides, intrauterine devices (IUD's) or surgical sterilization. (phase 2 of the study only)

Current use of nonsteroidal anti-inflammatory drugs (NSAIDs) and/or hydroxychloroquine are permitted. Drug doses must have been stable for at least one month prior to enrollment, and must be held constant during the study unless toxicity requires dose reduction.

Past and/or current use of a disease modifying agent (DMARD) such as methotrexate, sulfasalazine and cyclosporine is allowed.

EXCLUSION CRITERIA - General:

Patients or control subject will be excluded if they exhibit any medical condition that has the potential of placing the candidate at unnecessary risk during the study. Additionally, patients with impaired renal, hepatic, cardiovascular or endocrine-metabolic function, or any immunodeficiency syndrome including HIV infection, will be excluded

Use of systemic corticosteroids in the two weeks before screening and study entry.

Women with a history of cancer, with the exception of limited, resolved skin cancer.

Women who are menopausal. Clinical menopause is defined as the absence of spontaneous menses during the preceding 12 months.

Pregnant women or women who are nursing.

Use of prescription or OTC estrogen/progesterone preparations during the two weeks prior to screening

The patient or control subject has received any investigational drug within 30 days of the start of the study.

History of autoimmune endocrinopathy.

Serious medical illnesses or abnormal laboratory values that would, in the opinion of the P.I., preclude study participation.

EXCLUSION CRITERIA - For RA Patients:

BMI greater than or equal to 30.

Active infection or other contraindication to use of an anti-TNF agent (phase 2 of the study only).

History of untreated tuberculosis, or of a positive PPD without completion of adequate treatment. (phase 2 of the study only)

Live vaccinations in the 3 months prior to study (phase 2 of the study only).

Special Instructions: Currently Not Provided

Keywords:

Cytokines

Exanercept

Cachexia

Body Composition

Vascular Endothelial System

Recruitment Keywords:

Rheumatoid Arthritis

RA

Women

Healthy Volunteer

HV

Normal Control

Conditions:

Rheumatoid Arthritis

Healthy

Investigational Drug(s):

None

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Tak PP, Bresnihan B The pathogenesis and prevention of joint damage in rheumatoid arthritis: advances from synovial biopsyand tissue analysis [PMID: 11145019]

Straub RH, Cutolo M Involvement of the hypothalamic--pituitary--adrenal/gonadal axis and the peripheral nervous system in rheumatoid arthritis: viewpoint based on a systemic pathogenetic role [PMID: 11263762]

Gabriel SE, Crowson CS, O'Fallon WM Mortality in rheumatoid arthritis: have we made an impact in 4 decades? PMID: 10606358

• Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.
• Technical questions regarding the Clinical Center web site, please contact the Department of Networks and Applications, CC.

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Bethesda, Maryland 20892. Last update: 10/23/2004