iMiiN
`
`RiesCSE
`
`UM Libraries
`
`*Merck 2010
`saat AW(orean
`
`Merck 2010
`TWi v Merck
`IPR2023-00050
`
`

`

`Multiple Sclerosis
`The Questions You Have—
`The Answers You Need
`Second Edition
`Edited by Rosalind C. Kalb, Ph.D.
`
`

`

`Demos Medical Publishing, Inc., 386 Park Avenue South,
`New York, New York 10016
`
`© 2000 by Demos Medical Publishing, Inc. All rights reserved. This
`book is protected by copyright. No partofit may be reproduced,
`stored in a retrieval system, or transmitted in any form or by any
`means,electronic, mechanical, photocopying, recording, or other-
`wise, without the prior written permission of the publisher.
`
`Library of Congress Cataloging-in-Publication Data
`
`Multiple sclerosis : the questions you have, the answers you need /
`edited by Rosalind C. Kalb.—2nd ed.
`p.
`cm.
`Includes bibliographical references and index.
`ISBN 1-888799-43-9
`2. Multiple
`1. Multiple sclerosis—Popular works,
`sclerosis—Miscellanea.
`J. Kalb, Rosalind
`RC377.M564
`2000
`616.8’34—dc21
`
`00-035857
`
`Printed in Canada
`
`Annual updatesto this book can be downloaded from our
`Website: demosmedpub.com.Thissite also contains informa-
`
`tion about Demos’s other publications on multiple sclerosis.
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`

`

`viii
`
`CONTENTS
`
`9. Cognition
`Nicholas G. LaRocca, Ph.D., Pam Sorensen, M.A.,
`CCC-SLP. and Jill Fischer, Ph.D.
`10. Psychosocial Issues
`Rosalind C. Kalb, Ph.D.,
`and Deborah M.Miller, Ph.D.
`—11. Stress and Emotional Issues
`Nicholas G. LaRocca, Ph.D., and Jill Fischer, Ph.D.
`12. Sexuality
`Frederick W. Foley, Ph.D.,
`and Michael A. Werner, M.D.
`13. Fertility, Pregnancy, Childbirth,
`and Gynecologic Care
`Kathy Birk, M.D., and Michael A. Werner, M.D.
`14. Employment
`Phillip D. Rumrill, Jr., Ph.D., CRC
`Insurance Issues
`Robert Enteen, Ph.D.
`-16. Long-Term Care
`Debra Frankel, M.S., O.T.R.
`17. Life Planning
`Laura Cooper, Esq.
`Appendixes
`A. Glossary
`—B. Medications Commonly Used in Multiple Sclerosis
`C. National Multiple Sclerosis Society
`Consensus Statement
`D. Additional Readings
`E.
`Resources
`F
`Professional Biographies of the Authors
`Index
`
`15.
`
`193
`
`221
`
`259
`
`281
`
`311
`
`329
`
`357
`
`387
`
`407
`
`425
`
`453
`
`943
`
`947
`
`955
`
`971
`
`987
`
`

`

`Multiple Sclerosis
`The Questions You Have—
`The Answers You Need
`Edited by ROSALIND C. KALB, Ph.D.
`
`“This book is trustworthy! It is factual! It is honest! It is a jumping-off point to
`learning more about MS and with that knowledge developing new and better cop-
`ing skills to deal with the ups and downsof the mysteries of MS."
`.
`From the Foreword by RANDALL T.SCHAPIRO, M.D.,
`Fairview Multiple Sclerosis Center, Minneapolis
`Here is thedefinitive guide for anyone concerned with multiple sclerosis—those
`who have the disease, those who share their lives with someone who hasit,and
`health care professionals involved with its management. Multiple Sclerosis: The
`Questions You Have—The Answers You Need covers a wide range ‘of topics in a.
`question and answer format that is readily accessible and easily understood:
`Experiencedclinicians provide answers to thequestions that they have been asked
`repeatedly. Readers can quickly find information about specific topics and ques-
`tions based ontheir individual needs,
`.
`Each chapter contains a list of references and recommended readings for those
`interested in pursuing more detailed information on a particular topic, The guide
`also contains a comprehensive glossary of all terms commonly used in MS man-
`agement and a list of relevant resources for. individuals with MS and their families.
`The chapter on treatmentsdescribes all medications commonlyused‘in the treat-
`meni of MS and the Managementof its symptoms.
`
`
`
`,
`os
`
`: aCoverDesign Darby Downey
`ce
`:
`I Mos
`DEMOS MEDICAL PUBLISHING _
`1s8N 1-888799-45~9
`386 Park Avenue South, Suite 201
`|
`New York, New York 10016
`$30.98 1-888799-43-9
`
`9"'781888!'799439
`
`
`
`

`

`Multiple Sclerosis
`The Questions You Have—
`The Answers You Need
`
`Second Edition
`
`Edited by Rosalind C. Kalb, Ph.D.
`
`

`

`Demos Medical Publishing, Inc., 386 Park Avenue South,
`New York, New York 10016
`
`© 2000 by Demos Medical Publishing, Inc. All rights reserved. This
`book is protected by copyright. No part of it may be reproduced,
`stored in a retrieval system, or transmitted in any form or by any
`means, electronic, mechanical, photocopying, recording, or other-
`wise, without the prior written permission of the publisher.
`
`Library of Congress Cataloging-in-Publication Data
`
`Multiple sclerosis : the questions you have, the answers you need /
`edited by Rosalind C. Kalb.—2nd ed.
`.
`cm.
`Includes bibliographical references and index.
`ISBN 1-888799-43-9
`2. Multiple
`1. Multiple sclerosis—Popular works.
`sclerosis—Miscellanea.
`I. Kalb, Rosalind
`RC377.M564
`2000
`616.8’34—dc21
`
`00-035857
`
`Printed in Canada
`
`Annual updatesto this book can be downloaded from our
`Website: demosmedpub.com. This site also contains informa-
`
`tion about Demos’s other publications on multiple sclerosis.
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`

`

`44
`
`TREATMENT ISSUES
`
`focus of day-to-day medical care in MS is symptom manage.
`ment(see Chapter2) and efforts to stabilize the disease course.
`These efforts to stabilize the disease are the main focus ofthis
`chapter.
`In order to understand whyefforts to find an effective treat.
`ment for MS have beenso frustrating, it is important to review
`some of the characteristics of the disease. Although webelieve
`MSto be an autoimmunedisease thatis triggered in genetical-
`ly susceptible individuals by some infectious agent in the envi-
`ronment (see Chapter 2), we do not yet have any definitive
`answers. Not knowing the cause of a disease makes looking for
`its cure significantly more challenging. Additionally, the disease
`tends to progress quite slowly, with a symptom picturethatis
`highly variable from one person to the next. These characteris-
`tics makeit difficult for researchers to know howto evaluate the
`efficacy of any particular treatment. If the disease manifests
`itself differently from one person to the next, what symptom or
`other aspect of the disease should be looked at to determineif a
`treatment is working?
`Furthermore, although a review of treatments used in MS
`over the 15-year period from 1935 to 1950 indicated that 66
`percent of the patients improved, none of these interventions
`has been shown over time to be any more effective than no
`treatment at all. Other studies have demonstrated that 70 per-
`cent of individuals treated for a recent worsening oftheir dis-
`ease will improve, at least temporarily, with a placebo, or inac-
`tive, medication. Thus, treatment of a recent exacerbation in
`MS can only be considered effective if it leads to long-lasting
`improvement in significantly more than 70 percent of people
`whoare givenit.
`This brings us back to the question of measuring the out-
`comes obtained when evaluating experimental
`treatments.
`Recentresearch efforts have targeted the number of exacerba-
`tions, length of exacerbations, length of time between exacer-
`bations, severity of exacerbations, and the total area or vol-
`ume of lesions shown on MRI as reasonable indicators of
`treatment impact in relapsing-remitting multiple sclerosis. In
`1981, at the first international conference on therapeutictri-
`als in MS, it was clear that there had been only one success-
`ful treatmenttrial in MS that met the scientific standards of
`its time.
`In that
`trial of adrenocorticotropic hormone
`
`

`

`MULTIPLE SCLEROSIS: THE QUESTIONS, THE ANSWERS
`
`45
`
`it was demonstrated that ACTH could shorten
`(ACTH),
`attacks even though it had no effect on the ultimate degree of
`recovery or long-term disability.
`since that time, there have been several high-quality drug
`trials in MS. There currently are more trials in progress in
`North America and Europe than at any time in the history of
`the disease. These include small-scale (fewer
`than 20
`patients) and large-scale (several hundred patients)trials, tar-
`geting acute relapses, as well as exacerbating-remitting, sec-
`ondary progressive, and primary progressive MS. They
`involve experimental therapies designed to affect immune
`function, fight infectious agents, restore myelin, and improve
`symptoms. The trials are evaluating new drugs, old drugs,
`and drugs used in various combinations. In addition, treat-
`ments that have already been approved for use in MS are
`beginning to be compared to one another.
`Based on data from recently completed Europeantrials of
`mitoxantrone, an advisory panel for the Food and Drug Admin-
`istration (FDA)
`recommended that
`the FDA approve
`Novantrone® (mitoxantrone for injection concentrate) to slow
`worsening of neurologic disability in secondary progressive and
`relapsing-remitting forms of MS. In recently completed trials of
`oral myelin, cladribine, and sulfasalazine, these agents were
`found notto be of benefit. Roquinimex (linomide) provedto be
`toxic so the trial was stopped. As the results from new or ongo-
`ing trials become available, the information will be incorporat-
`ed into periodic updatesavailable from the publisher.
`This is an exciting time for both individuals with MS and
`their health care providers. Interferon beta-1b (Betaseron®),
`the first drug approved by the FDA for treatment of MS,
`became available for relapsing-remitting MS in the fall of
`1993, Betaseron® has had a noticeable impact on the frequen-
`cy and.severity of attacks in manyof those receiving the drug.
`In 1994, reports were made of successful trials of interferon
`beta-la (Avonex® and Rebif®) and glatiramer acetate (Copax-
`one® formerly known as copolymer 1) for exacerbating-remit-
`ting MS. Avonex® and Copaxone® are now approved and in
`Wide use. In February of 2000, Biogen, Inc. announced the
`early termination of its clinical trial of Avonex® for individu-
`a with initial signs of demyelinating disease whoareatrisk
`Or developing clinically definite MS. When usedat the stan-
`
`

`

`46
`
`TREATMENTISSUES
`
`dard dose of 30 micrograms in once-weekly intramuscular
`injections, Avonex® (in comparison to a placebo treatment)
`significantly delayed development of a second objective sign
`that would signal clinically definite MS. [Publication of these
`data, and their review by the FDA had not yet occurred when
`this book went to print.] Rebif® has already been approvedin
`Canada and Europe, and is expected to becomeavailable in
`the United States within the next few years. While theseoffer
`neither a cure nor any restoration of lost function, they dorep-
`resent a significant advance in our efforts to stabilize the dis-
`ease process.
`
`What makesit so difficult for scientists to find a cure for multi-
`ple sclerosis?
`
`Physicians and researchers have foundit difficult to find a cure
`for MS because the underlying cause ofthe illness is not known.
`Current thinking is that some “environmental”trigger (a viral
`infection, for example) initiates a process in which the individ-
`ual’s immune system inappropriately attacks the myelin in his
`or her own central nervous system. This process probably
`occurs morereadily in people born with a genetic predisposition
`to the disease. Since we do not knowthe exact triggers for the
`initial and ongoing immunological assault,
`it
`is difficult to
`devise specific treatments to preventit.
`The ultimate result of the immunologic process in MS is dam-
`age to the myelin and destruction of nerve fibers or axons. While
`myelin has the potential to regenerate to some degree, and does
`so early in the course of the disease, damaged axons do not
`regenerate. Once this damage has proceeded beyonda certain
`point, there are insufficient nerve fibers left to carry out normal
`functions, and permanent weakness, numbness, or visual loss
`begins to occur. Thus, much of the function lost during acute
`attacks early in the disease tends to be recovered, with the
`remaining fibers compensatingfor those that are lost. As the dis-
`ease progresses, cumulative damage to myelin and nervefibers
`leads to increasing, persistent neurologic dysfunction. Research
`has also demonstrated that some degree of brain atrophy, oF
`shrinkage, occurs in MS, even in the early years of the illness.
`However, the causeor causes of this atrophy remain to be deter-
`mined. At present, we do not know how to repair or restore
`myelin and are, therefore, unable to reverse the neurologic
`
`

`

`MULTIPLE SCLEROSIS: THE QUESTIONS, THE ANSWERS
`
`47
`
`symptoms, i.e., cure the disease. One hopeful sign is that we
`have recently come to realize that mammals, including humans,
`do have the capacity for spontaneous repair of central nervous
`em myelin and there is experimental evidence that this
`st: ess can be favorably influenced.
`roc‘itn I have an exacerbation my doctor prescribes intravenous
`steroids (e.g., Solu-Medrol®). Why are steroids prescribed and
`what is the difference between steroids taken orally and those
`taken intravenously?
`Steroids are a group of chemicals, some of whichare naturally
`occurring hormones. They have many important hormonal
`functions but they have various additional effects when admin-
`istered as medications (usually in synthetic preparations).
`Their utility in MS stems from their ability to decrease inflam-
`mation in the central nervous system, at least in part by clos-
`ing the damaged blood-brain barrier. The steroids used in MS
`should not be confused with the anabolic steroids used by ath-
`letes to build muscle; the corticosteroids used in MS suppress
`inflammation.
`Under normal circumstances, many potentially damaging sub-
`stances are prevented by the blood-brain barrier from passing
`out of the blood stream into the brain and spinal cord. During
`attacks of MS, this barrier can break down and begin to allow
`damaging chemicals and cells to leak into the central nervous
`system. Inflammation then ensues, resulting in both acute neu-
`rologic injury—sometimes with accompanying symptoms—and
`chronic damage to myelin and axons. Steroids appear to
`decrease this inflammation.
`Most neurologists caring for MS patients believe that steroids
`work best when given directly into the veins in high doses. We
`do not know whether equivalently high doses given orally
`would be equally effective, but some MScentersare taking this
`approach. In the past, it has been more common to prescribe
`lower doses of steroids orally. However, recent studies in
`patients with optic neuritis, a condition that is often thefirst
`sign of MS, suggestthat this strategy is less effective than high
`doses given intravenously.
`ce have any long-term benefits? I feel much stronger
`while I’m taking steroids but my doctorsays they should not be
`used frequently or for very long periods. Whynot?
`
`

`

`48
`
`TREATMENTIssugsg
`
`Continuous administration of steroids has never been shownty
`provide long-term benefits for people with MS. There is some
`suggestion that short courses of high-dose intravenoussteroids
`may havea longer-term benefit in delaying further diseaseactiy.
`ity. Many people feel better while taking steroids,
`in part
`because these drugs can have a mood-elevating effect. However,
`the chronic useof steroids is fraught with many potentially dan-
`gerousside effects and is currently thought to be unwisein the
`treatment of MS. Their long-term use can be associated with
`such side effects as hypertension, diabetes, bone loss (osteo-
`porosis), cataracts, and ulcers. These potential detrimental
`effects outweigh the possible benefits when steroids are used on
`an extended basis.
`
`WhenI take steroids I get very emotional and have intense
`mood swings.I also feel very down or depressed toward the end
`of the treatment. Why does this happen andis there anythingto
`do aboutit?
`
`Short courses of steroids, even in very high doses, are usually
`well-tolerated. Many people, however, do have some minor
`mood changes, both highs and lows. Others may havedifficulty
`sleeping. A much smaller group of individuals may have more
`severe disturbances in mood or behavior. Lithium, a medication
`often prescribed for people with bipolar disorder (formerly
`called manic-depressive disorder), is sometimes used to prevent
`or manage these mood swings. Carbamazepine (Tegretol®) and
`divalproex (Depakote®) have also been shownto be veryeffec-
`tive. On occasion, antidepressant medications may be pre-
`scribed, but they are seldom needed becausethe “blues” associ-
`ated with a short course of steroids usually disappear sponta-
`neously before the antidepressants would begin to take effect
`(usually a few weeks).
`Once a promising new treatment has been identified, why does
`it take such a long timeforit to be available for patients?
`Unfortunately, the process of new drug development is very
`slow, particularly for a chronic disease like MS. The typical
`sequenceinitially begins with animal studies (see Fig. 3-1). This
`is a crucial first step because an experimental model for MS,
`experimental allergic encephalomyelitis (EAE), exists in |abo-
`ratory rodents (as well as other species). This allows a quick
`
`

`

`MULTIPLE SCLEROSIS: THE QUESTIONS, THE ANSWERS
`
`49
`
`Summarytable of steps involved in the developmentof a
`
`Figure 3-1.
`new drug
`—_—
`© Preclinical Phase
`Animal studies
`© Phase |
`Preliminary humanclinicaltrials
`q» small, unblinded, open labeltrials (for safety)
`<p small, often double-blind, for additional safety
`and efficacy information
`Multicenter, randomized, double-blind, placebo-
`controlled trials needed for FDA approval
`
`© Phase Il
`
`© PhaseIll
`
`© Data Analysis
`© Application for approval of drug by the FDA
`© Pharmaceutical company brings drug to market
`aRLLSscarmmmtiimimaalsa-Raisin
`
`assessment of the possible benefits of a treatment, as well as the
`preliminary evaluation of its safety. A promising agent then
`moves into humanclinicaltrials.
`Human clinical trials begin with very small “open label”
`(unblinded) trials in which the physicians and subjects know
`what drug is being taken.Initially, these are usually donein nor-
`mal individuals without known disease. An unblinded trial is
`aimed at demonstrating the safety of a treatment and maybefol-
`lowed by an open trial in a few patients with known disease.
`These trials are typically of much shorter duration than later
`studies, but still take many monthsto a year or longer becauseof
`the variable nature of MS. The open label trials are then fol-
`lowed by relatively small, usually double-blind, pilot trials
`designed to give stronger evidence suggesting that a new treat-
`ment may be effective as well as safe. “Double-blind” meansthat
`neither the subject nor the investigators know which subjects are
`receiving the real medication and whichare getting the placebo
`(an inactive substance). This procedure is followed in order to
`prevent hopes and expectations on the part of researchers or
`subjects from affecting the course or evaluation ofthe treatment.
`If the drug still appears promising, testing will move into
`Phase III, involving large, multicenter, randomized, placebo-
`controlled, double-blindtrials. In this stage of drug develop-
`ment, typically hundredsof subjects are enteredinto a study in
`which some are randomly assigned to receive the medication
`and others to get placebo. Because MSis a chronic disease in
`Which changes occur relatively slowly in most people, these
`
`

`

`50
`
`TREATMENTISSUE
`
`PhaseIII trials typically last for several years in order to obtain
`enough information on whichto basefair andstatistically valid
`conclusions. These trials are expensive, costing many millions
`of dollars that are essentially wasted if the drug does not work.
`This accounts, in large part, for the high cost of new drugs.
`Following the completion ofthe trial, another six months may
`be necessary to analyze the large quantity of data and prepare
`submission of documents to the Food and Drug Administration
`(FDA). The FDA, which is ultimately responsible for the
`approval of new drugs, carefully reviews both the data andthe
`methodology ofthe trial. This agency must be convincedofboth
`the effectiveness and safety of the treatment before givingits
`approval. The review process typically takes another six to
`twelve months. Finally, after approval of a drug, the pharmaceu-
`tical companytypically needs a few more monthsto get the drug
`to market.
`Thus, the process is extremely long and arduous, as well as
`very frustrating for people with MS andtheir families. However,
`it is a process designed to assure that everyone receivessafe
`treatments and that no one misses out on the opportunityto take
`other, potentially useful treatments while taking something that
`is ineffective. The problem with manyof the publicly acclaimed
`“treatments” that receive so much attention in the press(e.g.,
`snake venom and the removal of tooth amalgams)is that they
`have not been through this process. In other words, they have
`not been proven to be safe or effective in a clinical trial and can
`sometimes be quite harmful.
`Whatis the “placeboeffect?”
`A placebo is a non-active substance that is designed to look just
`like the drug that is being evaluated in a research protocol.
`Investigators repeatedly find that a substantial proportion of
`patients with a variety of diseases experience somebenefit even
`when they are treated with a placebo. This phenomenonis
`knownasthe placeboeffect. Although this effect may occur in
`part
`through unconscious psychological mechanisms,
`some
`studies have also demonstrated the production of certain chem-
`icals in such individuals that may contribute to this improve
`ment. Even though the benefits are not usually sustained, this
`short-lived effect confounds the study of new drugs. Random-
`ized, placebo-controlled, double-blind trials are used in order to
`
`

`

`MULTIPLE SCLEROSIS: THE QUESTIONS, THE ANSWERS
`
`o1
`
`determine the advantage (if any) that the new drug shows over
`o effects. Thus, to demonstrate the value of a newtreat-
`laceb
`:
`t must be proven to have a benefit superiorto that offered
`ment, i
`by a placebo.
`;
`;
`It is important to rememberthat being treated with a placebo
`‘5 not the same as receiving no treatment. Taking the placebofos-
`ters certain expectations for improvementthat are not present
`when no treatment is given. That is why new drugsare always
`compared with a placebo rather than with no treatmentatall.
`The drug must demonstrate a specific benefit beyond the place-
`bo effect or the improvement that might occur spontaneously
`with no treatment, or with an existing treatment. Now,with the
`availability of several treatments for relapsing-remitting MS,
`many future trials will probably compare a new drug with an
`existing drug rather than with placebo.
`If alternative treatments like bee stings and cobra venom work
`well for some people, why aren’t they more widely prescribed?
`Alternative treatments for MS suchas beestings are often tout-
`ed as helping people with MS. The problem is that these reports
`are always “anecdotal”; they consist mostly of individual claims
`of success, without any scientific study. It is well-known that
`MS often undergoes spontaneous improvement or remission.
`Furthermore, as discussed previously, virtually every study of
`MSindicates a significant placebo effect, whereby people taking
`placebo (non-active substance) do better than they would with
`no treatment. Therefore, claims of success with any therapy,
`including alternative treatments, must be regarded with consid-
`erable skepticism unless controlled clinical
`trials are done.
`Additionally, some of these treatments, such as beestings, carry
`potentially severe risks. Specifically, fatal allergic reactions can
`occur in some individuals receiving bee stings. These comments
`are not to suggest that there might not be merit to somealterna-
`live treatments, but rather to emphasize the importance of prop-
`er scientific investigation under controlled and safe conditions.
`Who designs clinical trials and decides when and where they
`will take place, and who can participate?
`oe trials may originate from several different sources. Early
`Oe are often initiated by investigators interested in MS,
`whereas more definitive trials of promising new treatments are
`
`

`

`52
`
`TREATMENTIssugs
`
`generally undertaken by pharmaceutical companiesinteresteq
`in marketing a product. Although these companiesoften haye
`physicians and basic scientists in their direct employment,they
`usually recruit outside investigators to help planaclinicaltriaj.
`Then, depending on the size of the study, additional investiga-
`tors are invited to participate in the trial in order to enterthe
`required number of subjects as quickly as possible. The lead
`investigators design the protocol or formatfor thetrial, deciding
`how thetrial will be carried out and who will beeligible to par-
`ticipate. The design of thetrial is then submitted to the Food and
`Drug Administration for approval before thetrial is begun.
`How canIgetinto a clinical trial?
`Various sources of information aboutclinical trials are available.
`The best placeto start is with your own physician, whowill often
`be able to direct you to a particular trial. The National Multiple
`Sclerosis Society can also provide information aboutthesites par-
`ticipating in particular clinical trials. Some of the local chapters of
`the National Multiple Sclerosis Society publish newsletters in
`which they announcetrials in their area. Many of the member
`centers of the Consortium of Multiple Sclerosis Centers (see
`Appendix E, Resources) participate in one or moreclinicaltrials.
`It is important to rememberthat eachtrial has a very specific pro-
`tocol that details the types of patients whoareeligible to partici-
`pate. For sometrials, the eligibility criteria are quite restrictive; for
`others, the criteria are more liberal. Your willingness to participate
`in a Clinical trial is greatly appreciated by investigators because
`successful completion of such studies is the only waythat we will
`definitively identify effective new treatments. Do not be discour-
`aged if you do not meetthe entrancecriteria for a particular trial.
`Keep informed—thenext one might be right for you.
`Whyshould I participate in a clinicaltrial if I have a significant
`chanceof getting the placebo instead of the real drug?
`There are several reasonsto participate in clinical trials.
`
`© It has been demonstrated repeatedly in MStrials that even
`those subjects who receive the placebo usually do better
`than they would have done without any intervention. The
`quality of medical care in trials tends to be very high, and
`is provided withoutcost to the participants.
`
`

`

`MULTIPLE SCLEROSIS: THE QUESTIONS, THE ANSWERS
`
`53
`
`© Clinical trials are the best mechanism currently available to
`identify effective treatments; therefore, your participation
`ultimately helps investigators answer important questions.
`© Standard, accepted treatments continue to be allowed
`under the research protocols of most placebo-controlled
`trials. For example, acute exacerbations could be treated
`with steroids in the interferon beta-1b (Betaseron®) and
`interferon beta-1a (Avonex®)trials.
`© With Betaseron®. Avonex®, and Copaxone® currently
`available in the United States, Rebif® available in Cana-
`da and Europe, and Novantrone® recommended for
`approval by the FDA, it is likely that we will shift away
`from placebo-controlled trials to drug comparisontrials
`in which a proposed new drug will be compared with the
`most effective available drug. Thus, any proposed new
`drug would have to demonstrate its superiority over
`those that have already been approved for use. Partici-
`pants in this type of drug comparison trial would there-
`fore be randomly assigned to either the proposed drug or
`one that has already been shownto beeffective in treat-
`ing MS.
`
`Whydo so manyclinical trials require that participants be able
`to walk?
`
`The entrancecriteria for particular trials are very specific. Many
`of the trials require that subjects be able to walk, sometimes
`without the use of aids. This requirement is made becauseit is
`oiten more difficult to detect changes in disease activity in indi-
`viduals whose illness is more advanced, and the inclusion of
`people with more advanced disease might cause investigatorsto
`discard potentially useful treatments because they erroneously
`failed to detect a benefit.
`Why were the disease-modifying agents (Betaseron®, Avonex®,
`Copaxone®, and Rebif® [not available in U.S.]) originally tested
`on people with relapsing-remitting disease?
`These agents (see Appendix B) were originally tested on people
`with telapsing-remitting MS becauseinvestigators thought those
`with milder disease would be more likely to show a benefit from
`the treatment. Also, previous studies had shownthat it might be
`
`

`

`54
`
`TREATMENT ISSUES
`
`easier to demonstrate an effect by measuring a reduction jn
`attack rate than by showing a reduction in disease progression.
`How does Copaxone® differ from the interferon medications,
`Betaseron®, Avonex®, and Rebif® [not available in U.S]?
`Betaseron®, Avonex®, and Rebif® are interferons, a group of
`immunesystem proteins, produced andreleased bycells infect.
`ed by a virus, which inhibit viral multiplication and modify the
`body’s immune response. Copaxone® is unrelated to the inter.
`ferons. It is a synthetic polypeptide (like a protein) that mayact
`by fooling the immunesystem, and by suppressing the immune
`attack on myelin that is believed to occur in MS.
`Copaxone® is administered by daily subcutaneous (underthe
`skin) injection. Unlike Betaseron®, Avonex®, and Rebif®,it does
`not cause flu-like reactions. Injection-site reactions are general-
`ly minor. Depression, which has been associated with all inter-
`ferons administered in high doses for human disease, does not
`occur with Copaxone®. However, people whoare taking Copax-
`one® should be aware of one peculiar reaction that, although
`infrequent, can be quite alarming. On rare occasions (perhaps
`once in 800 to 1,000 injections), a person taking Copaxone® may
`experience an immediate post-injection reaction involving sen-
`sations of tightness in the chest and flushing of the face, perhaps
`accompanied by palpitations, shortness of breath, or anxiety.
`This reaction passes within 15 to 30 minutes and has never
`provedto beserious.
`Table 3-1 compares the four drugs currently approved for the
`treatmentof relapsing-remitting MS. Note: Betaseron®, Avonex®,
`and Copaxone® have been approved in the United States and
`Canada. Betaseron® is approved in Canada and Europefor both
`relapsing-remitting and secondary-progressive MS. To date,
`Rebif® has been approved only in Canada and Europe.
`At a recent MS educational meeting, sponsored by mylocal
`chapter of the National Multiple Sclerosis Society, I heard
`about a drug named Rebif®. Whatis it, and whyisn’t it avail-
`able in the United States?
`Rebif®, like Avonex®, is beta interferon-1a. In a multicentertrial
`in Canada, Europe, and Australia, for relapsing-remitting dis-
`ease, Rebif® was found to reduce the number and frequency of
`MSattacks, slow the progression of disability, and reduce the
`
`

`

`MULTIPLE SCLEROSIS: THE QUESTIONS, THE ANSWERS
`
`55
`
`number of brain lesions as measured by magnetic resonance
`imaging (MRI). It also reduced the number of hospitalizations
`and steroid use. The drug was tested in two dose strengths,
`administered subcutaneously three times per week.
`In this
`study, amounts of interferon beta-1a were higher on a weekly
`basis (by weight) at each dose than the weekly amount of
`Avonex®that has been approvedbythe FDAforusein relapsing
`forms of MS. In addition, people with a broader range of dis-
`abilities were studied, and shownto benefit.
`In a separate, three-year, controlled clinicaltrial of (Rebif®)
`for secondary progressive MS, twodosesof the drug were com-
`pared to placebo. Compared to placebo, neither dose of Rebif®
`delayed progression of disability (the primary goal of the
`study). However, both treated groups had significantly fewer
`and less severe relapses, fewer hospitalizations, reduced use of
`steroids, and fewertotal lesions and newlesions in the brain as
`detected by MRI. The manufacturer of the drug has suggested
`that the failure to delay progression of disability in these sec-
`ondary-progressive patients (in contrast to their positive find-
`ings in relapsing-remitting disease) may be dueto thefact that
`the patients in this study started with higher levels of disabili-
`ty and had had the disease longer than the patients in previous
`studies.
`Rebif® is now available for use in some countries. Thetrial
`sponsor, Ares Serono, has applied to the FDA for approval to
`market Rebif® in the United States as a treatment for relapsing-
`remitting MS. The FDA ruled that Rebif® was notsufficiently
`different from Avonex® to be marketed in the United States at
`this time. Under the provisions of the U.S. Orphan Drug Act,
`which provides financial incentives to the developers of drugs
`for rare diseases, Rebif® may not be allowed to compete with
`Avonex® on