© 2012 American Academy of Neurology IV IMMUNOGLOBULIN IN THE TREATMENT OF NEUROMUSCULAR DISORDERS Report of the Therapeutics and Technology Assessment.

Slides:



Advertisements
Similar presentations
Diuretic Strategies in Patients with Acute Decompensated Heart Failure Diuretic Optimization Strategies Evaluation (DOSE) trial.
Advertisements

Improving The Clinical Care of Children and Adolescents With Mild Traumatic Brain Injury Madeline Joseph, MD, FACEP, FAAP Professor of Emergency Medicine.
天 津 医 科 大 学天 津 医 科 大 学 Clinical trail. 天 津 医 科 大 学天 津 医 科 大 学 1.Historical Background 1537: Treatment of battle wounds: 1741: Treatment of Scurvy 1948:
Clinical Trials Medical Interventions
Accessing Sources Of Evidence For Practice Introduction To Databases Karen Smith Department of Health Sciences University of York.
Clinical Trials Hanyan Yang
By Dr. Ahmed Mostafa Assist. Prof. of anesthesia & I.C.U. Evidence-based medicine.
Gut-directed hypnotherapy for functional abdominal pain or irritable bowel syndrome in children: a systematic review Journal club presentation
1 The Chemoprevention of Sporadic Colorectal Cancer Issues Surrounding a Benefit/Risk Analysis in Clinical Trials Mark Avigan MD CM Medical Officer Division.
Spring 2015 ETM 568 Callier, Demers, Drabek, & Hutchison Carter, E. J., Pouch, S. M., & Larson, E. L. (2014). The relationship between emergency department.
Clinical Trials. What is a clinical trial? Clinical trials are research studies involving people Used to find better ways to prevent, detect, and treat.
DoH IVIG Workshop Update, neurology usage and outcomes measurement
Systematic Reviews.
Study design P.Olliaro Nov04. Study designs: observational vs. experimental studies What happened?  Case-control study What’s happening?  Cross-sectional.
Investigational Drugs in the hospital. + What is Investigational Drug? Investigational or experimental drugs are new drugs that have not yet been approved.
Evidence Based Medicine Meta-analysis and systematic reviews Ross Lawrenson.
Placebo-Controls in Short-Term Clinical Trials of Hypertension Sana Al-Khatib, MD, MHS Assistant Professor of Medicine Division of Cardiology Duke University.
Practice Parameter: Immunotherapy for Guillain-Barré syndrome
Monthly Journal article review: Vimmi Kang PGY 2
Landmark Trials: Recommendations for Interpretation and Presentation Julianna Burzynski, PharmD, BCOP, BCPS Heme/Onc Clinical Pharmacy Specialist 11/29/07.
Critical Appraisal Did the study address a clearly focused question? Did the study address a clearly focused question? Was the assignment of patients.
Clinical Writing for Interventional Cardiologists.
ALI R. RAHIMI, BOBBY WRIGHTS, MD, HOSSEIN AKHONDI, MD & CHRISTIAN M. RICHARD, MSC Clinical Correlation Between Effective Anticoagulants & Risk of Stroke:
CRDAC Questions June 15, 2005 Antihypertensive drugs, with few exceptions, have no outcome claim in their labeling. This is inconsistent with their approval.
What is a non-inferiority trial, and what particular challenges do such trials present? Andrew Nunn MRC Clinical Trials Unit 20th February 2012.
DIVISION OF REPRODUCTIVE AND UROLOGIC PRODUCTS Physician Labeling Rule Lisa Soule, M.D.
EXPERIMENTAL EPIDEMIOLOGY
بسم الله الرحمن الرحيم جامعة أم درمان الإسلامية كلية الطب و العلوم الصحية - قسم طب المجتمع مساق البحث العلمي / الدفعة 21 Basics of Clinical Trials.
Evidence Based Practice RCS /9/05. Definitions  Rosenthal and Donald (1996) defined evidence-based medicine as a process of turning clinical problems.
Pompe Disease Evidence Evaluation Michael Watson, PhD, on behalf of Piero Rinaldo, MD, PhD, and the Decision-Making Workgroup October 1, 2008.
1 Study Design Issues and Considerations in HUS Trials Yan Wang, Ph.D. Statistical Reviewer Division of Biometrics IV OB/OTS/CDER/FDA April 12, 2007.
RELEVANCERELEVANCE Is the objective of the article on harm similar to your clinical dilemma? Yes, the article’s objective is similar to the clinical dilemma.
Evidence Based Advertising Part II Beyond the TMA: From clinical trials to real world evidence.
A Claims Database Approach to Evaluating Cardiovascular Safety of ADHD Medications A. J. Allen, M.D., Ph.D. Child Psychiatrist, Pharmacologist Global Medical.
Sifting through the evidence Sarah Fradsham. Types of Evidence Primary Literature Observational studies Case Report Case Series Case Control Study Cohort.
PTP 661 EVIDENCE ABOUT INTERVENTIONS CRITICALLY APPRAISE THE QUALITY AND APPLICABILITY OF AN INTERVENTION RESEARCH STUDY Min Huang, PT, PhD, NCS.
EBM --- Journal Reading Presenter :呂宥達 Date : 2005/10/27.
Is the conscientious explicit and judicious use of current best evidence in making decision about the care of the individual patient (Dr. David Sackett)
EVALUATING u After retrieving the literature, you have to evaluate or critically appraise the evidence for its validity and applicability to your patient.
Journal Club Alcohol, Other Drugs, and Health: Current Evidence November-December 2012.
Copyright © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins Chapter 18 Systematic Review and Meta-Analysis.
Safety of Albumin Revisited Blood Products Advisory Committee Meeting March 17, 2005 Laurence Landow MD, FRCPC.
Chronic pelvic pain Journal Club 17 th June 2011 Dr Claire Hoxley (GPST1) Dr Harpreet Rayar (GPST2)
©2014 American Academy of Neurology. Report of the Guideline Development Subcommittee of the American Academy of Neurology Systematic Review: Efficacy.
Practice Parameter: Use of Epidural Steroid Injections to Treat Radicular Lumbosacral Pain (An Evidence-Based Review) American Academy of Neurology (AAN)
Practice Parameter: Treatment of Nervous System Lyme Disease (An Evidence-Based Review) American Academy of Neurology (AAN) Quality Standards Subcommittee.
©2015 American Academy of Neurology. Report of the Guideline Development Subcommittee of the American Academy of Neurology and the American Epilepsy Society.
© 2012 AMERICAN ACADEMY OF NEUROLOGY Antiepileptic Drug Selection for People with HIV/AIDS Report of the American Academy of Neurology and the International.
© 2006 American Academy of Neurology Practice Parameter: The diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review) Report.
Practice Parameter: Risk of Recurrent Stroke and Secondary Stroke Prevention in Patients With Interatrial Septal Abnormalities (An Evidence-Based Review)
EBM --- Journal Reading Presenter :黃美琴 Date : 2005/10/27.
Methodological Issues in Implantable Medical Device(IMDs) Studies Abdallah ABOUIHIA Senior Statistician, Medtronic.
© 2011 AMERICAN ACADEMY OF NEUROLOGY Update: Plasmapheresis in Neurologic Disorders Report of the Therapeutics and Technology Assessment Subcommittee of.
© 2011 AMERICAN ACADEMY OF NEUROLOGY Clinical Evaluation and Treatment of Transverse Myelitis Report of the Therapeutics and Technology Assessment Subcommittee.
© 2012 American Academy of Neurology Evidence-based Guideline: Steroids and antivirals for Bell palsy Report of the Guideline Development Subcommittee.
Evidence Report: Neutralizing Antibodies to Interferon: An Assessment of Their Clinical and Radiological Impact American Academy of Neurology Therapeutic.
LSU Journal Club Corticosteroid Therapy for Patients Hospitalized With Community-Acquired Pneumonia A Systematic Review and Meta-analysis Scott Hebert,
Efficacy of Colchicine When Added to Traditional Anti- Inflammatory Therapy in the Treatment of Pericarditis Efficacy of Colchicine When Added to Traditional.
©2016 American Academy of Neurology. Report by: Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.
A quick reference to literature searches
Use of fMRI in the Presurgical Evaluation of Patients with Epilepsy
Division of Cardiovascular Devices
Developing a guideline
CLINICAL PROTOCOL DEVELOPMENT
Donald E. Cutlip, MD Beth Israel Deaconess Medical Center
Supplementary Table 1. PRISMA checklist
Critical Reading of Clinical Study Results
Ethical Considerations for Pediatric Clinical Investigations
What is a review? An article which looks at a question or subject and seeks to summarise and bring together evidence on a health topic. Ask What is a review?
Does cinnamon reduce fasting blood glucose in Type II diabetics?
Presentation transcript:

© 2012 American Academy of Neurology IV IMMUNOGLOBULIN IN THE TREATMENT OF NEUROMUSCULAR DISORDERS Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology

©2012 American Academy of Neurology Authors  Huned S. Patwa, MD  Vinay Chaudhry, MD  Hans Katzberg, MD  Alex D. Rae-Grant, MD  Yuen T. So, MD, PhD

©2012 American Academy of Neurology Sharing this information  The AAN develops these presentation slides as educational tools for neurologists and other health care practitioners. You may download and retain a single copy for your personal use. Please contact to learn about options for sharing this content beyond your personal use.

©2012 American Academy of Neurology Guideline Endorsement  Endorsed by the American Association of Neuromuscular and Electrodiagnostic Medicine

©2012 American Academy of Neurology Presentation Objectives  To present analysis of the evidence regarding efficacy of intravenous immunoglobulin (IVIg) to treat neuromuscular disorders  To present evidence-based recommendations

©2012 American Academy of Neurology Overview  Background  Gaps in care  American Academy of Neurology (AAN) guideline process  Analysis of evidence, conclusions, recommendations  Recommendations for future research

©2012 American Academy of Neurology Background  IVIg is used to treat a range of immune- mediated neurologic diseases.  The US Food and Drug Administration (FDA) approved IVIg for use in Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP), but IVIg use for non–FDA-approved indications is common.  Although IVIg appears to be well tolerated in many patients, hypercoagulability and renal failure are of concern.

©2012 American Academy of Neurology Gaps in Care  Given the FDA approved IVIg for use only in GBS and CIDP, understanding what the existing evidence says for IVIg use more broadly would be helpful.  Neurologists are familiar with the use of IVIg for a variety of diseases; this guideline presents the evidence supporting its use in a broad range of neuromuscular diseases.

©2012 American Academy of Neurology AAN Guideline Process  Clinical Question  Evidence  Conclusions  Recommendations

©2012 American Academy of Neurology Clinical Questions  Is IVIg effective in GBS in adults?  Is IVIg effective in GBS in children?  Is IVIg as effective as plasmapheresis in GBS in adults?  Is steroid an effective adjunctive treatment in patients with GBS treated with IVIg?  What is the optimal IVIg dosing for GBS?  Is IVIg effective in CIDP?  Is IVIg effective in myasthenia gravis (MG)?  Is IVIg effective in multifocal motor neuropathy (MMN)?

©2012 American Academy of Neurology Clinical Questions, cont.  Is IVIg effective in neuropathy associated with immunoglobulin M (IgM) paraprotein?  Is IVIg effective in neuropathy associated with dermatomyositis?  Is IVIg effective in inclusion body myositis (IBM)?  Is IVIg effective in postpolio syndrome?  Is IVIg effective in other neuromuscular disorders?

©2012 American Academy of Neurology Literature Search/Review  Rigorous, Comprehensive, Transparent Review abstracts Search Review full text Select articles Relevant Search

©2012 American Academy of Neurology AAN Classification of Evidence  All studies rated Class I, II, III, or IV  Five different classification systems Therapeutic Randomization, control, blinding Diagnostic Comparison with gold standard Prognostic Screening Causation

©2012 American Academy of Neurology AAN Level of Recommendations  A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population  B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population  C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population  U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven Note that recommendations can be positive or negative

©2012 American Academy of Neurology Translating Class to Recommendations  A = Requires at least two consistent Class I studies*  B = Requires at least one Class I study or two consistent Class II studies  C = Requires at least one Class II study or two consistent Class III studies  U = Studies not meeting criteria for Class I through Class III

©2012 American Academy of Neurology Translating Class to Recommendations, cont. *In exceptional cases, one convincing Class I study may suffice for an “A” recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).

©2012 American Academy of Neurology Applying the Process to the Issue  We will now turn our attention to the guidelines.

©2012 American Academy of Neurology Methods  MEDLINE, Web of Science, and EMBASE were searched (1966–2009) Used search term “immunoglobulin” and one of the following: myasthenia gravis, GBS, neuropathy, CIDP, multifocal motor neuropathy, polymyositis, dermatomyositis, diabetic neuropathy, diabetic radiculoplexoneuropathy, postpolio syndrome, paraproteinemic neuropathy, Lambert-Eaton myasthenic syndrome, Miller Fisher syndrome, inclusion body myositis Relevant, fully published, peer-reviewed articles

©2012 American Academy of Neurology Methods, cont.  At least two authors reviewed each article for inclusion  Risk of bias was determined using the classification of evidence scheme for therapeutic articles  Strength of recommendations were linked directly to levels of evidence  Conflicts of interest were disclosed

©2012 American Academy of Neurology Literature Search/Review  Rigorous, Comprehensive, Transparent 32 articles 943 abstracts Inclusion criteria: - Therapeutic articles assessing the efficacy, safety, tolerability, or IVIg mode of use in humans Exclusion criteria: - Case reports

©2012 American Academy of Neurology AAN Classification of Evidence for Therapeutic Interventions  Class I: Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. The following are also required: Concealed allocation Primary outcome(s) clearly defined Exclusion/inclusion criteria clearly defined Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias.

©2012 American Academy of Neurology AAN Classification of Evidence for Therapeutic Interventions, cont. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*: The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective). The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment. The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.

©2012 American Academy of Neurology AAN Classification of Evidence for Therapeutic Interventions, cont.  Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a  e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b  e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.  Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.**

©2012 American Academy of Neurology AAN Classification of Evidence for Therapeutic Interventions, cont.  Class IV: Studies not meeting Class I, II or III criteria including consensus or expert opinion. *Note that numbers 1  3 in Class I, item 5 are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III. **Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer’s (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

©2012 American Academy of Neurology Clinical Question 1a and 1b  Is IVIg effective in GBS in adults?  Is IVIg as effective as plasmapheresis in GBS in adults?

©2012 American Academy of Neurology GBS in Adults: Conclusions  Based on 2 Class I studies, IVIg is as efficacious as plasmapheresis for treating GBS in adults. Because plasmapheresis is established as effective GBS treatment, 1 we conclude that IVIg also has established effectiveness.  Based on one adequately powered Class I study, the combination of plasmapheresis and IVIg is probably not better than either treatment alone.

©2012 American Academy of Neurology GBS in Adults: Recommendations  IVIg should be offered to treat GBS in adults (Level A).  IVIg combined with plasmapheresis should not be considered for treating GBS (Level B).

©2012 American Academy of Neurology Clinical Question 2  Is IVIg effective in GBS in children?

©2012 American Academy of Neurology GBS in Children: Conclusion and Recommendation  Based on conflicting primary outcome measures, IVIg benefit is uncertain in children with GBS.  There is insufficient evidence to support or refute the effectiveness of IVIg in children with GBS (Level U).

©2012 American Academy of Neurology GBS in Children: Clinical Context  Many experts consider it reasonable treatment to use IVIg for GBS in children given its effectiveness in the same disease in adults.

©2012 American Academy of Neurology Clinical Question 3  Is steroid an effective adjunctive treatment in patients with GBS treated with IVIg?

©2012 American Academy of Neurology GBS and Adjunctive Steroid Use: Conclusion and Recommendation  Based on one underpowered Class I study, evidence is insufficient to support or exclude a benefit of adding methylprednisolone (MP) to IVIg in GBS.  Evidence is insufficient to recommend MP in combination with IVIg (Level U).

©2012 American Academy of Neurology Clinical Question 4  What is the optimal IVIg dosing for GBS?

©2012 American Academy of Neurology GBS and Optimal IVIg Dose: Conclusion and Recommendation  Data are insufficient to make a recommendation on optimal IGIV dosing (Level U).

©2012 American Academy of Neurology Clinical Question 5  IVIg effective in CIDP?

©2012 American Academy of Neurology CIDP: Conclusions and Recommendation  Based on 2 Class I studies, IVIg is effective for the long-term treatment of CIDP.  Data are insufficient to address the comparative efficacy of prednisolone and IVIg in treating CIDP.  IVIg should be offered for the long-term treatment of CIDP (Level A).

©2012 American Academy of Neurology CIDP: Clinical Context  Dosing, frequency, and duration of IVIg for CIDP may vary depending on the clinical assessment.  Data are insufficient to address the comparative efficacy of other CIDP treatments (e.g., steroids, plasmapheresis, immunosuppressants).  Experts have identified that there may be overuse of IVIg in long-term care of CIDP. We were unable to evaluate this question using available randomized trial data.

©2012 American Academy of Neurology Clinical Question 6  Is IVIg effective in MG?

©2012 American Academy of Neurology MG: Conclusions and Recommendation  Based on one Class I study, IVIg is probably effective in treating patients with MG.  Evidence is insufficient to compare the efficacy of IVIg and plasmapheresis in treating MG.  IVIg should be considered in the treatment of MG (Level B).

©2012 American Academy of Neurology MG: Clinical Context  This recommendation was based on studies involving primarily moderately or severely affected patients.  The benefits and risks of this medication should be weighed carefully in patients with mild MG.  Further studies of IVIg efficacy in MG are warranted due to the few randomized trials and small study size to date.

©2012 American Academy of Neurology Clinical Question 7  Is IVIg effective in MMN?

©2012 American Academy of Neurology MMN: Conclusion and Recommendation  Based on consistent results from 3 Class II studies, IVIg is probably effective for MMN treatment.  IVIg should be considered for the treatment of MMN (Level B).

©2012 American Academy of Neurology MMN: Clinical Context  MMN is a chronic disease requiring ongoing treatment.  No data are available to address optimal treatment dosing, interval, and duration.

©2012 American Academy of Neurology Clinical Question 8  Is IVIg effective in neuropathy associated with IgM paraprotein?

©2012 American Academy of Neurology IgM Paraprotein‒associated Neuropathy: Conclusion and Recommendation  Based on 1 Class I study and 1 Class II study, IVIg is possibly ineffective for the treatment of IgM paraprotein–associated neuropathy. A modest benefit cannot be excluded due to each study’s small sample size.  Evidence is insufficient to assess the role of IVIg in treating neuropathy associated with IgM paraprotein (Level U).

©2012 American Academy of Neurology Clinical Question 9  Is IVIg effective in neuropathy associated with dermatomyositis?

©2012 American Academy of Neurology Dermatomyositis: Conclusion and Recommendation  Based on 1 Class II study, IVIg is possibly effective for the treatment of nonresponsive dermatomyositis in adults.  IVIg may be considered for the treatment of nonresponsive dermatomyositis in adults (Level C).

©2012 American Academy of Neurology Clinical Question 10  Is IVIg effective in IBM?

©2012 American Academy of Neurology IBM: Conclusion and Recommendation  Two Class I studies and 1 Class II study failed to demonstrate a consistent or significant clinical benefit of IVIg in treating IBM.  Evidence is insufficient to support or refute the use of IVIg in treating IBM (Level U).

©2012 American Academy of Neurology IBM: Clinical Context  There is presently no effective treatment for IBM.

©2012 American Academy of Neurology Clinical Question 11  Is IVIg effective in postpolio syndrome?

©2012 American Academy of Neurology Postpolio Syndrome: Conclusion and Recommendation  One Class I study showed a significant difference, but the difference was not clinically important for IVIg use on the most affected muscle in postpolio syndrome. One underpowered Class I study showed an effect of IVIg for pain in postpolio syndrome but no effect on strength or fatigue.  Evidence is insufficient to support or refute IVIg use in the routine treatment of postpolio syndrome (Level U).

©2012 American Academy of Neurology Postpolio Syndrome: Clinical Context  There is presently no effective treatment for postpolio syndrome.

©2012 American Academy of Neurology Clinical Question 12  Is IVIg effective in other neuromuscular disorders?

©2012 American Academy of Neurology Lambert-Eaton Syndrome: Conclusion and Recommendation  Based on 1 Class II study, IVIg is possibly effective in Lambert-Eaton syndrome (LEMS).  IVIg may be considered in the treatment of LEMS (Level C).

©2012 American Academy of Neurology Other Disorders: Conclusion and Recommendation  There are no controlled studies evaluating the effects of IVIg on polymyositis, diabetic polyradiculoplexoneuropathy, or Miller Fisher syndrome.

©2012 American Academy of Neurology Adverse Effects of IVIg  Eighteen of the 22 prospective studies reviewed recorded the number of serious and minor adverse effects (AEs).  There were no IVIg-related deaths in these studies.  Most studies concluded that IVIg was well- tolerated and AEs were either transient or manageable.  Serious AEs related to IVIg were rare and included aseptic meningitis, urticaria, heart failure, myocardial infarction, and renal failure.

©2012 American Academy of Neurology Adverse Effects: Clinical Context  It is important to assess individual patient risk for AEs when considering IVIg therapy.

©2012 American Academy of Neurology Future Research Recommendations  For most of the diseases examined here, alternative treatment modalities are available. Comparative studies may be helpful.  IVIg benefit is generally short lived; further, long-term studies might be useful.  Studies are needed to explore possible synergistic effects of adjunctive treatments such as immunosuppressants or plasmapheresis.

©2012 American Academy of Neurology Future Research Recommendations, cont.  Few data are available on the optimal IVIg infusion frequency and cumulative dose.  A larger study of IVIg in patients with mild MG may be useful.  The issue of overtreatment of CIDP with IVIg, which may be a clinically significant issue, could be assessed with further observational studies.

©2012 American Academy of Neurology Reference 1. Cortese I, Chaudhry V, So YT, Cantor F, Cornblath DR, Rae-Grant A. Evidence-based guideline update: plasmapheresis in neurological disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2011;76:294–300. For a complete list of references, please access the full guideline at

©2012 American Academy of Neurology  Questions/comments? Question-and-Answer Period

©2012 American Academy of Neurology  To access the complete guideline and related guideline summary tools, visit  Thank you for your participation! Closing