On- and Off-Label Uses and Clinical Trials of IG
By Ronale Tucker Rhodes, MS, and Kris McFalls
Immune globulin (IG) is used to treat a wide range of disorders. While the most common use of IG therapy is in treating primary immune deficiencies, its efficacy in numerous other disorders is well-documented. It is estimated that for every U.S. Food and Drug Administration (FDA)-approved indication, there are more than 10 non-FDA-approved indications. In certain neurological and dermatological disorders, IG is considered a first-line agent. In other areas, such as renal transplant and cardiology, it has established itself as an integral part of patient therapy. In the future, IG may be a potentially effective treatment for diseases and conditions for which there is currently no cure.
Marketing for IG is currently FDA approved for five indications: primary humoral immunodeficiency (PIDD); immune thrombocytopenia purpura (ITP); chronic inflammatory demyelinating polyneuropathy (CIDP); B-cell lymphocytic leukemia; and Kawasaki syndrome. While all IG products carry an indication for primary immunodeficiency, no one product carries an indication for all five.1
The number of off-label uses for IG far exceeds that of labeled indications. Although IG has been proven useful for many disease states, the likelihood of manufacturers pursuing FDA approval for already treated indications is remote given the high cost of conducting trials without the benefit of increased marketing advantages. The sometimes tenuous and limited supply of IG, combined with the high costs of treatment, require best practice standards be used when deciding to treat with IG. Some diseases commonly treated off label with IVIG are Guillain-Barré syndrome, polymyositis, dermatomyositis, multifocal motor neuropathy, stiff person syndrome, relapsing-remitting multiple sclerosis and pemphigus.2 Anecdotal reports suggest IVIG is effective in treating autoimmune neutropenia, autoimmune hemolytic anemia, Evans syndrome and acquired hemophilia, especially when other therapeutic modalities fail.3
Indications Under Current Research
Many studies are currently being conducted to look at the efficacy of IG in non-FDA-approved indications. Three specific areas that are being explored, for which IG is not used as a standard of care, include Alzheimer’s, secondary recurrent miscarriage and chronic regional pain syndrome.
Alzheimer’s. IVIG appears to have promising effects for both reducing the risk of developing Alzheimer’s, as well as improving the cognitive ability of those suffering from it. Results of a study presented at the International Alzheimer’s Symposium in 2008 showed that the risk of developing Alzheimer’s disease and related disorders (ADRD) may be reduced by about 40 percent in patients previously treated with IVIG.4
As of early 2009, several small clinical trials have shown promising results for treating Alzheimer’s with IVIG.5 In March 2010, results of a Phase 2 clinical trial suggests that treatment with IVIG is associated with a reduction in ventricular enlargement rates and cognitive decline in patients with mild to moderate Alzheimer’s. In the study, uninterrupted treatment with IVIG for 18 months was associated with about half the rate of ventricular enlargement reflecting brain atrophy versus a placebo, along with better scores on neuropsychological testing. A pivotal Phase 3 study is now enrolling patients from 35 sites throughout the United States.6
Secondary recurrent miscarriage. Several clinical trials have been conducted to determine whether IVIG is an effective treatment for recurrent miscarriage. While clinical trials are still ongoing, one particular study consisted of a systematic review of randomized controlled trials, comparing all dosages of IVIG to a placebo or an active control. The study looked at eight trials involving 442 women that evaluated IVIG therapy used to treat recurrent miscarriage. The findings showed that, overall, IVIG did not significantly increase the odds ratio of live birth when compared with a placebo for treatment of recurrent miscarriage. However, there was a significant increase in live births following IVIG use in women with secondary recurrent miscarriage, while those with primary miscarriage did not experience the same benefit.7
Chronic regional pain syndrome (CRPS). Most recently, a small study found IVIG effective for alleviating CRPS, which causes chronic and often intractable pain, usually in the arm or leg, long after recovery from an illness. Researchers at the Pain Research Institute at the University of Liverpool in England administered a half gram of IVIG per kilogram of body weight to 13 people who had been suffering from CRPS between six and 30 months and who reported pain intensity of at least five on an 11-point scale for seven consecutive months. All had failed to achieve significant relief from other conventional treatments. After being treated with IVIG, five of the 12 subjects reported median pain scores at least two points lower, and three of the five reported pain scores at least 50 percent lower.8
Other diseases. There also are case reports and open label trials that show IVIG benefits some patients with rheumatoid arthritis, anti-neutrophil cytoplasmic antibody disorders, systemic sclerosis/scleroderma and Still’s disease.3
The Future of IG
For now, IG continues to be used as a treatment for both FDA-approved and non-FDA-approved indications. But, the future of IG looks promising for its ability to treat a host of disease states.
Ronale Tucker Rhodes, MS, is the editor of IG Living and BioSupply Trends Quarterly magazines, and
Kris McFalls is the full-time patient advocate for IG Living magazine, written for patients who depend upon immune globulin products and their healthcare providers.
- U.S. Food and Drug Administration. Immune Globulin Intravenous (IGIV) Indications.
- Leong, H, Stachnik, J, Bonk, ME, and Matuszewski, KA. Unlabeled uses of intravenous immune globulin. American Journal of Health-System Pharmacy, Oct. 2008; 65: 1815-1824.
- American Academy of Allergy, Asthma & Immunology. Work Group Report on the Appropriate Use of Intravenously Administered Immunoglobulin (IGIV). Accessed at: www.aaaai.org
- Intravenous Immunoglobulin Treatment Is Associated with a Reduced Risk of Developing Alzheimer’s Disease and Related Disorders. Reuters, Feb. 28, 2008. Accessed at: www.reuters.com
- IVIG Use in Alzheimer’s. IVIG Use in Alzheimer’s Frequently Asked Questions. Accessed at: www.ivigforalzheimers.com
- Jeffrey, S. IVIG Slows Ventricular Enlargement, Cognitive Decline in Alzheimer’s. Medscape Today, April 15, 2010.
- BJOG: An International Journal of Obstetrics & Gynaecology. Use of intravenous immunoglobulin for treatment of recurrent miscarriage: A systematic review. Accessed at: login.medscape.com
- Valeo, T. IVIG Shown to Relieve Complex Regional Pain Syndrome: But Study Has Limitations, Experts Say. Neurology Today, March 4, 2010. Accessed at: journals.lww.com