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`THALIDOMIDE FOR THE TREATMENT OF ORAL APHTHOUS ULCERS IN PATIENTS WITH HIV INFECTION
`
`THALIDOMIDE FOR THE TREATMENT OF ORAL APHTHOUS ULCERS
`IN PATIENTS WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION
`
`N
`
`G
`
`.D.,
`, S
` S
`.D., J
`, B.D.S., P
` S. G
`, M.D., J
` M. J
`J
`C
`PRITZLER
`OHN
`H
`REENSPAN
`OHN
`ACOBSON
`EFFREY
`.D.,
` K
`, M.D., J
` L. F
`, M.D., J. B
` J
`, M.D., L
` F
`, M.D., P
`ACKSON
`ROOKS
`AHEY
`OHN
`ZEERA
`ETTER
`AWRENCE
`OX
`H
`M
` C
`, P
`.D., A
` W. W
`, M.D., M.P.H., L
` A. M
`P
`, D.M.D., P
`.D.,
`IRIAM
`HERNOFF
`H
`LBERT
`U
`AURIE
`AC
`HAIL
`H
` J. V
`, M.D.,
` D
` A. W
`, M.D.,
`
` N
` I
`
` A
`UILLERMO
`ASQUEZ
`AND
`AVID
`OHL
`FOR
`THE
`ATIONAL
`NSTITUTE
`OF
`LLERGY
` I
` D
` AIDS C
` T
` G
`*
`AND
`NFECTIOUS
`ISEASES
`LINICAL
`RIALS
`ROUP
`
`
`
`A
`BSTRACT
`Background
`In patients with advanced human
`immunodeficiency virus (HIV) infection, aphthous ul-
`ceration of the mouth and oropharynx can become
`extensive and debilitating. Preliminary reports sug-
`gest that thalidomide may promote the healing of
`oral aphthous ulcers.
`Methods
`We performed a double-blind, random-
`ized, placebo-controlled study of thalidomide as
`therapy for oral aphthous ulcers in HIV-infected pa-
`tients. The patients received a four-week course of
`either 200 mg of thalidomide or placebo orally once
`per day. They were evaluated weekly for the condi-
`tion of the ulcers, their quality of life, and evidence
`of toxicity. Assays were performed for plasma tumor
`necrosis factor
`(TNF-
`), soluble TNF-
` receptors,
`a
`a
`a
`and HIV RNA.
`Results
`Sixteen of 29 patients in the thalidomide
`group (55 percent) had complete healing of their
`aphthous ulcers after four weeks, as compared with
`only 2 of 28 patients in the placebo group (7 per-
`cent; odds ratio, 15; 95 percent confidence interval
`after adjustment for group sequential testing, 1.8 to
`⬍
`499; unadjusted P
`0.001). Pain diminished and the
`ability to eat improved with thalidomide treatment.
`The adverse effects noted with thalidomide included
`somnolence and rash (7 patients each), and 6 of the
`29 patients discontinued treatment because of toxic-
`ity. Thalidomide treatment increased HIV RNA levels
`(median increase, 0.42 log
` copies per milliliter; in-
`10
`⫽
`0.04). With thalido-
`crease with placebo, 0.05; P
`mide treatment there were unexpected increases in
` and soluble
`the plasma concentrations of TNF-
`a
`TNF-
` receptors.
`a
`Conclusions
`Thalidomide is an effective treat-
`ment for aphthous ulceration of the mouth and
`oropharynx in patients with HIV infection. (N Engl J
`Med 1997;336:1487-93.)
`©1997, Massachusetts Medical Society.
`
`A
`
`PHTHOUS ulceration of the mouth,
`though painful and annoying, is usually a
`self-limited problem in immunocompe-
`tent persons.
` In patients with human
`1
`immunodeficiency virus (HIV) infection, however,
`aphthous ulcers frequently become progressive, de-
` Extremely painful, en-
`structive, and debilitating.
`1-4
`larging necrotic lesions can develop, resembling the
`large aphthous ulcers often seen in patients with Beh-
`çet’s syndrome. The hypopharynx and esophagus may
`
`be involved. Aphthous ulcers can interfere with eat-
`ing and lead to malnutrition and wasting. Even when
`the ulcers regress, they tend to recur.
`Available treatments for aphthous ulcers in HIV-
`infected patients are unsatisfactory. Some success
`has been reported with topical, intralesional, and
`systemic corticosteroids, but the responses are not
`uniform and the relapse rate is high.
` No controlled
`2
`studies of this treatment have been performed, and
`long-term treatment with systemic corticosteroids
`may cause further immunosuppression in already im-
`munocompromised patients.
`Several groups have suggested that thalidomide,
`-N
`-phthalimidoglutarimide, is effective for the se-
`
`a
`vere forms of aphthous ulceration in HIV-infected
`and other patients.
` As part of AIDS Clinical Trials
`3-15
`Group (ACTG) protocol 251 of the National Insti-
`tute of Allergy and Infectious Diseases (NIAID), we
`performed a multicenter, double-blind, randomized,
`placebo-controlled study of the usefulness of thalid-
`omide in treating oral aphthous ulcers in HIV-
`infected persons. In addition, since thalidomide has
`been reported to inhibit the production of tumor
`(TNF-
`),
` a substance known to
`necrosis factor
`16-20
`a
`a
`induce the expression of HIV by infected cells,
` we
`21
`also evaluated the activity of the drug against TNF-
`a
`and HIV.
`
`METHODS
`
`Study Population
`We enrolled patients in the study if they met the following cri-
`teria: an age of at least 13 years; documented HIV infection; oral
`aphthous ulceration of at least two weeks’ duration, as confirmed
`by a biopsy that revealed no infectious, neoplastic, or other spe-
`
`From the Departments of Medicine, Bronx Veterans Affairs Medical
`Center and Mount Sinai School of Medicine, New York (J M.J.); the De-
`partment of Stomatology, University of California at San Francisco, San
`Francisco (J.S.G., L.A.M.); the Statistical and Data Analysis Center, Har-
`vard School of Public Health, Boston (J.S., M.C.); the Division of AIDS,
`National Institute of Allergy and Infectious Diseases, Bethesda, Md. (N.K.,
`L.F.); the Department of Medicine, University of California at Los Angeles,
`Los Angeles (J.L F.); the Departments of Pathology (J.B.J.) and Medicine
`(A.W.W.), Johns Hopkins University School of Medicine, Baltimore; the
`Department of Medicine, University of Puerto Rico Medical School, San
`Juan (G.J.V.); and the Department of Medicine, University of North Caro-
`lina, Chapel Hill (D.A.W.). Address reprint requests to Dr. Jacobson at the
`Bronx Veterans Affairs Medical Center, 130 W. Kingsbridge Rd., Bronx,
`NY 10468.
`*Additional investigators who participated in this trial are listed in the
`Appendix.
`
`Volume 336 Number 21
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`ⴢ
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`The New England Journal of Medicine
`
`cific diagnosis; a surface diameter of at least 5 mm for the largest
`ulcer; a negative culture of the ulcer for herpes simplex virus; a
`hemoglobin concentration greater than 8 g per deciliter; an ab-
`solute neutrophil count greater than 500 per cubic millimeter; a
`platelet count greater than 50,000 per cubic millimeter; a serum
`bilirubin concentration no higher than 2.5 times the upper limit
`of normal; serum concentrations of aspartate aminotransferase
`and alkaline phosphatase less than 5 times the upper limit of nor-
`mal; and a serum creatinine concentration of less than 2.5 mg per
`deciliter (221
`mol per liter).
`m
`Patients were excluded from the study if they had bilateral pe-
`ripheral neuropathy more severe than grade 1 or a history of such
`neuropathy, a known allergy to thalidomide, or prior treatment
`of aphthous ulcers with thalidomide; if they were pregnant or lac-
`tating; if they were receiving short-term therapy for opportunistic
`infections; if they were receiving radiation to the head or neck; if
`they had been treated with systemic or oral topical corticosteroids
`within one week before the first set of blood tests; if they were
`treated with other putative immunomodulators within the two
`weeks before entry into the study and during the study; if they
`were undergoing systemic cancer chemotherapy; if they were
`treated with antiinfective mouthwashes; and if they were receiving
`zalcitabine, pentoxifylline, methotrexate, trimetrexate, or antine-
`oplastic alkylating agents. If a patient had received any of the lat-
`ter group of medications within eight weeks before entering the
`study, the patient’s aphthous ulcers had to have persisted for at
`least four weeks after the medication was discontinued. Anti-HIV
`therapy was held constant beginning four weeks before study
`entry. Antimicrobial prophylaxis against opportunistic infections
`was permitted.
`Patients were recruited at 19 sites in the United States. The
`study was approved by the institutional review board of each
`medical center. The patients gave written informed consent to par-
`ticipate. Precautions were taken to prevent and detect pregnancy,
`as described in the Discussion section.
`
`Treatment Regimens
`The patients were randomly assigned to receive a four-week
`course of either two 100-mg capsules of thalidomide or two pla-
`cebo capsules orally once a day at bedtime (the study medications
`were kindly provided by Andrulis Pharmaceuticals, Beltsville,
`Md.). Patients whose aphthous ulcers had not completely healed
`by the end of the four weeks were offered the option of taking
`two 100-mg capsules of open-label thalidomide daily for the next
`four weeks. If the healing was still not complete after that period,
`200 mg of thalidomide could be given twice a day for an addi-
`tional four weeks as tolerated.
`As specified in the study protocol, in the event of sedation or
`other adverse effects, depending on their nature and grade (as de-
`fined according to the NIAID criteria), the dose was reduced, the
`study medication was permanently discontinued, or the medica-
`tion was withheld until the adverse effect had resolved, at which
`point the treatment was resumed at a reduced dose.
`
`Criteria for Response
`One end point of the study was the complete absence of oral
`aphthous ulcers after four weeks of study treatment (a complete
`response). If a patient discontinued the study treatment before
`the end of four weeks because of toxicity, the response was not
`considered complete unless there was complete healing at the
`time of the discontinuation and the complete healing lasted until
`the four-week visit. A partial response at week 4 was defined as a
`decrease of 50 percent or more in the combined surface area of
`the three largest ulcers, as compared with the area of the three
`largest ulcers at base line, with no formation of new ulcers. (The
`surface area was defined as the product of the ulcer’s largest sur-
`face diameter and its largest perpendicular surface diameter.) A
`lack of response was defined as a decrease of less than 50 percent
`or the occurrence of a new ulcer.
`An additional, independent end point was the change in the
`
`1488
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`ⴢ
`
`May 22, 1997
`
`HIV load, as measured by the plasma HIV RNA level, from base
`line to week 4.
`
`Evaluation of Patients and Follow-up
`After the screening and base-line evaluations, the patients were
`seen weekly by site investigators unaware of the patients’ treat-
`ment status and the results of measurements of TNF-
` and the
`a
`HIV load, in order to assess the healing of oral ulcers and toxic
`effects of the study medication. At base line and at each weekly
`visit, a quality-of-life questionnaire was administered to assess pain
`and eating ability; neuropathy was assessed; and there were labo-
`ratory evaluations of blood cells, serum chemistries, serum thalid-
`omide levels, and hepatic and renal function. Plasma samples for
`the measurement of TNF-
`, soluble TNF-
` receptor type II, and
`a
`a
`HIV RNA were obtained at base line and every two weeks. CD4
`and CD8 lymphocyte counts were performed at base line and
`week 4. A pregnancy test for the
` subunit of human chorionic
`b
`gonadotropin in serum was performed weekly on women with
`childbearing potential and was repeated four weeks after the dis-
`continuation of the study medication.
`
`Quality-of-Life Measurements
`The quality-of-life questionnaire contained 15 items that meas-
`ured general health, pain, and eating ability during the study.
`Two of the items, from the Medical Outcomes Study: HIV,
` as-
`22
`sessed general perceptions of health and pain; they were supple-
`mented by an item assessing the patient’s pain while eating. Two
`scales with six items each assessed discomfort while eating and the
`actual consumption of food (the latter scale was modified from
`the Sickness Impact Profile
`). The responses to these questions
`23
`were scored on scales ranging from 1 to 5 or 1 to 6, with higher
`numbers indicating poorer health or more severe symptoms.
`
`TNF Measurements and Virologic Assays
`The laboratory assays for TNF-
`, soluble TNF-
` receptor type
`a
`a
`II, and HIV-1 RNA were performed at the end of the study. Plas-
`ma levels of TNF-
` were measured with TNF-
` enzyme ampli-
`a
`a
`fied-sensitivity immunoassay kits (Medgenix, Incstar, Stillwater,
`Minn.), and levels of soluble TNF receptor II were measured with
`HyCult enzyme-linked immunosorbent assay kits (Caltag, San
`Francisco). The assays were performed in an ACTG Advanced
`Technology Laboratory (University of California at Los Angeles).
`The samples from each patient were batch-tested in a single run.
`For quality control, 15 percent of the samples were retested in a
`subsequent run to confirm the results of the first run.
`HIV-1 RNA levels in plasma collected in acid–citrate–dextrose
`were determined in a single ACTG-certified laboratory by the
`HIV-1 Amplicor Monitor assay (Roche Diagnostics, Branchburg,
`N.J.)
` with the Viral Quality Assurance Program standards of the
`24
`National Institutes of Health. Each patient’s samples were batch-
`tested in a single run with detection on the same microtiter plate
`to minimize variability.
`
`Statistical Analysis and Interim Data Monitoring
`The study was designed to have 80 percent power and type I
`error rates of 0.05 for the independent end points of complete
`ulcer resolution and change in HIV load at week 4. The study
`was not designed for the formal testing of hypotheses about other
`end points; we present those findings for exploratory purposes
`only, without adjusting the type I error rates for multiple testing.
`All the analyses were performed on an intention-to-treat basis, ex-
`cept that three patients who did not begin the study treatment
`were excluded.
`For continuous and ordinal variables, appropriate two-tailed
`Wilcoxon nonparametric rank-sum or signed-rank tests were
`used.
` Two-by-two classifications of ulcer-related and other di-
`25
`chotomous end points were tested by Fisher’s exact test.
` The
`26
`strength of the association between the variables used in the anal-
`ysis was estimated with Spearman’s rank-correlation coefficient.
`25
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`THALIDOMIDE FOR THE TREATMENT OF ORAL APHTHOUS ULCERS IN PATIENTS WITH HIV INFECTION
`
`
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`The distributions of the time to ulcer healing were estimated by
`the Kaplan–Meier product-limit method.
`27
`The study design included a group sequential interim analysis
`of the ulcer-healing end point for the first 45 of 82 intended pa-
`tients, with an O’Brien–Fleming stopping boundary.
` The re-
`28
`sults of the interim analysis were presented to an ad hoc interim-
`review committee. On the basis of these findings, enrollment in
`the placebo group was closed, by which time 12 more patients
`had completed four weeks of randomized study treatment. Re-
`sults for all 57 patients (which were virtually identical to the re-
`sults of the interim analysis) are presented here.
`
`RESULTS
`
`Study Population
`Between February 1994 and October 1995, 60
`patients were enrolled. Three patients were excluded
`from the analysis because they never received treat-
`ment according to the study protocol. The ulcers of
`two of the three patients healed between the time
`of the screening visit and the time the study treat-
`ment was scheduled to begin; the third patient was
`found after randomization to be ineligible for the
`study. Of the 57 patients included in the analysis, 28
`were randomly assigned to receive placebo and 29
`were assigned to receive thalidomide. The patients in
`the two groups had similar base-line characteristics
`(Table 1). Almost all had substantial pain that im-
`paired their eating and overall health. Only one pa-
`tient in each group missed the final study visit at
`week 4.
`
`Clinical Data
`Among the 29 patients in the thalidomide group,
`16 (55 percent) had responded to therapy complete-
`ly at week 4, as compared with 2 of the 28 patients
`in the placebo group (7 percent; odds ratio, 15;
`95 percent confidence interval after adjustment for
`group sequential testing, 1.8 to 499; unadjusted
`P
`0.001) (Fig. 1). For the patients in the thalido-
`⬍
`mide group who had complete responses, the medi-
`an time to complete ulcer healing was 3.5 weeks (95
`percent confidence interval, 2 to 4). Once the pa-
`tients randomly assigned to placebo were offered
`open-label thalidomide after week 4, their rate
`of complete response was similar to the initial rate
`of complete response in the thalidomide group
`(Fig. 2).
`If one combines complete and partial responses,
`the results show a similar pattern. Of the 29 patients
`in the thalidomide group, 26 (90 percent) had com-
`plete or partial responses at the end of week 4, as
`compared with only 7 of 28 patients in the placebo
`group (25 percent; odds ratio, 24; 95 percent con-
`0.001).
`fidence interval, 5.2 to 162; P
`⬍
`Seven patients received the higher dose of thalido-
`mide (200 mg twice a day) because their ulcers were
`still present. Five of these patients had complete
`healing.
`The quality-of-life data showed that the patients
`
`-L
` B
` C
`
`OF 57 HIV-INFECTED
`T
` 1.
`INE
`ASE
`HARACTERISTICS
`ABLE
`PATIENTS WITH APHTHOUS ULCERS TREATED WITH
`THALIDOMIDE OR PLACEBO.*
`
`CHARACTERISTIC
`
`Age — yr
`Weight — kg
`Sex — no. (%)
`Male
`Female
`Race or ethnic group — no. (%)
`Non-Hispanic white
`Non-Hispanic black
`Hispanic
`Asian or Pacific Islander
`American Indian
`CD4 cells
`No./mm3
`Median
`Interquartile range
`Percentage†
`Median
`Interquartile range
`Copies of HIV RNA — ⫻10⫺3/ml‡
`Median
`Interquartile range
`Area of ulcers — mm2
`Mean quality-of-life score§
`
`PLACEBO
`(Nⴝ28)
`
`34.4⫾1.3
`61.9⫾2.1
`
`24 (86)
`4 (14)
`
`10 (36)
`6 (21)
`10 (36)
`2 (7)
`0
`
`27.8
`16.8, 83.5
`
`4.3
`1.8, 8.0
`
`THALIDOMIDE
`(Nⴝ29)
`
`36.2⫾1.5
`66.2⫾3.0
`
`26 (90)
`3 (10)
`
`9 (31)
`7 (24)
`9 (31)
`2 (7)
`2 (7)
`
`17.0
`6.0, 80.0
`
`2.0
`1.0, 8.0
`
`83.3
`37.1, 254.1
`194.3⫾43.5
`3.0⫾0.2
`
`120.6
`67.6, 206.0
`193.6⫾41.5
`3.1⫾0.2
`
`SE.
`*Plus–minus values are means
`⫾
`†Percentages shown are percentages of all lymphocytes.
`‡Data are based on 26 patients in each group.
`§Data are based on 27 patients in the placebo group and 28 patients in
`the thalidomide group.
`
`in the thalidomide group succeeded much more than
`those in the placebo group in attaining a relatively
`problem-free status (responses of
`2 on all meas-
`⭐
`ures [P
`0.03] except general health). The improve-
`⬍
`ment was greatest with regard to the patients’ dis-
`0.001).
`comfort while eating (P
`⬍
`The patients in the thalidomide group gained a
`median of 1.8 kg (4 lb) during the first four weeks
`of the study, whereas there was no weight gain in
`the placebo group (P
`0.07). The study had only
`⫽
`27 percent power to detect a difference of 1.8 kg.
`
`Immunologic Data
`The median plasma levels of TNF-
` and soluble
`a
`TNF-
` receptor type II were elevated in both groups
`a
`before the study treatment began (Table 2). After
`two weeks of treatment, both levels increased signif-
`icantly more in the thalidomide group than in the
`placebo group (Table 2). The increases in plasma
`TNF-
` levels correlated with the increases in levels
`a
`of soluble TNF-
` receptor type II from base line to
`a
`week 2 (r
`0.64, P
`0.001) and from base line to
`⫽
`⫽
`week 4 (r
`0.47, P
`0.005). There were no impor-
`⫽
`⫽
`tant changes in CD4 or CD8 lymphocyte counts or
`percentages from base line to week 4.
`
`Volume 336 Number 21
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`ⴢ
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`The New England Journal of Medicine
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`A
`
`B
`
`Figure 1. Major Aphthous Ulcer of Six Weeks’ Duration on the Palatopharyngeal Arch of a 30-Year-Old
`Man with the Acquired Immunodeficiency Syndrome (AIDS).
`AIDS was diagnosed on the basis of CD4 cell counts of less than 200 per cubic millimeter. The ulcer
`healed completely, with little scarring, after four weeks of thalidomide therapy. In the photograph in
`Panel A, obtained at the start of the study, the arrows indicate the location of the upper and lower
`ulcer margins. In the photograph in Panel B, obtained after four weeks’ treatment with thalidomide,
`the arrows indicate where the ulcer margins had been at the start of the study.
`
`Virologic Data
`The patients in the thalidomide group had a sig-
`nificantly greater increase in HIV RNA from base
`line to week 4 than the patients in the placebo group
`(median increase in the thalidomide group, 0.42
`log10 copies per milliliter; in the placebo group, 0.05;
`P⫽0.04). During the same interval, the increases in
`HIV RNA were weakly associated with the increases
`in plasma levels of TNF-a (r⫽0.34, P⫽0.05) and
`soluble TNF-a receptor type II (r⫽0.42, P⫽0.01).
`
`Safety
`Six patients in the thalidomide group discontin-
`ued the study medication because of toxic effects of
`treatment. One of the 28 patients assigned to place-
`bo requested an early discontinuation of treatment.
`The estimated probability of remaining in the study
`to day 28 without a dose reduction was 52 percent
`in the thalidomide group and 89 percent in the pla-
`cebo group.
`Twelve patients assigned to thalidomide and 11
`
`1490 ⴢ May 22, 1997
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`THALIDOMIDE FOR THE TREATMENT OF ORAL APHTHOUS ULCERS IN PATIENTS WITH HIV INFECTION
`
`P⫽0.052). Other adverse events in the thalidomide
`group, each observed in three patients or fewer, in-
`cluded chest pain, respiratory difficulties, fever, con-
`fusion, headaches, fatigue, dizziness, irregular heart-
`beat, lethargy, nausea, syncope, elevated levels of
`hepatic aminotransferases, and elevated levels of al-
`kaline phosphatase. In the placebo group, the ad-
`verse events included headaches, anemia, elevated
`levels of g-glutamyltransferase, elevated levels of he-
`patic aminotransferases, fever, diarrhea, fatigue, and
`hallucinations. Seven patients in the thalidomide
`group and five in the placebo group had new or
`worsened peripheral sensory neuropathy.
`During the first four weeks of study treatment,
`there were no deaths or new episodes of opportun-
`istic infections. No pregnancies occurred.
`
`DISCUSSION
`This double-blind, randomized, placebo-con-
`trolled study shows that thalidomide is effective in
`healing aphthous ulceration of the mouth and oro-
`pharynx in HIV-infected patients. The ulcers healed
`completely by week 4 in 55 percent of the patients
`in the thalidomide group, as compared with 7 per-
`cent of the patients in the placebo group. Almost all
`the patients taking thalidomide (90 percent) had at
`least partial healing. There was complete resolution
`in some patients within as little as one week after the
`start of therapy, but the median time to complete
`healing among the patients who responded was 3.5
`weeks. Quality-of-life measures clearly showed that
`thalidomide reduced the pain from the aphthous le-
`sions and improved the ability to eat.
`There were no significant differences between the
`groups in the incidence of serious adverse events,
`
`Placebo
`
`Thalidomide
`
`0
`
`2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
`
`Weeks
`
`1.0
`0.9
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`0.1
`0.0
`
`Probability of Unhealed Ulcers
`
`Figure 2. Estimated Distribution of the Time Needed for Com-
`plete Healing of Aphthous Ulcers in the 57 Patients, According
`to Treatment Group.
`Open-label thalidomide was offered at week 4.
`
`patients assigned to placebo had new adverse events
`of grade 3 or higher (as classified according to the
`NIAID criteria) during the four weeks of random-
`ized treatment. Grade 4 neutropenia occurred in
`two thalidomide-treated patients who had severe
`neutropenia before therapy. One patient in the tha-
`lidomide group and two patients in the placebo
`group had grade 3 neutropenia. Somnolence was re-
`ported in seven patients in the thalidomide group
`(24 percent) and two patients in the placebo group
`(7 percent, P⫽0.144). Seven patients in the thalid-
`omide group (24 percent) had rashes, as compared
`with one patient in the placebo group (4 percent,
`
`TABLE 2. CHANGES IN PLASMA LEVELS OF TNF-a AND SOLUBLE TNF-a RECEPTOR TYPE II, ACCORDING TO
`TREATMENT GROUP.*
`
`VARIABLE AND GROUP
`
`NO. OF
`PATIENTS
`
`BASE-LINE
`VALUE
`
`P
`VALUE
`
`NO. OF
`PATIENTS
`
`CHANGE, BASE LINE
`TO WEEK 2†
`
`P
`VALUE
`
`NO. OF
`PATIENTS
`
`CHANGE, BASE LINE
`TO WEEK 4†
`
`P
`VALUE
`
`median
`(interquartile range)
`
`median
`(interquartile range)
`
`median
`(interquartile range)
`
`TNF-a (pg/ml)
`Placebo
`Thalidomide
`Soluble TNF-a receptor
`type II (ng/ml)
`Placebo
`Thalidomide
`
`22
`20
`
`22
`20
`
`37.09 (22.32, 75.85) 0.870
`36.97 (25.97, 48.62)
`
`3.60 (2.81, 5.59)
`3.75 (2.85, 5.12)
`
`0.890
`
`20
`16
`
`20
`16
`
`⫺0.31 (⫺5.60, 3.55) 0.001‡
`12.16§ (5.63, 22.98)
`
`20 ⫺0.91 (⫺9.49, 6.66) 0.090
`14
`4.04 (0.14, 8.83)
`
`⫺0.17 (⫺0.43, 0.27)
`1.46§ (0.53, 1.87)
`
`0.002‡
`
`20
`14
`
`⫺0.05 (⫺0.50, 0.28)
`0.53§ (0.31, 1.06)
`
`0.007‡
`
`*P values are for the difference between groups.
`†Positive values indicate that the level increased from base line to the week shown; negative values indicate that the level decreased. The levels during a
`specified period around the date of the visit were averaged (in the case of base-line values, the measurements considered were made at or before the base-
`line visit). Changes from base line are the differences between the average values. Mean (⫾SD) normal values for TNF-a are 9.5⫾5.7 pg per milliliter; and
`for soluble TNF-a receptor type II, 2 1⫾0.7 ng per milliliter. Data on 42 of the 57 patients were used in the analysis.
`‡P⬍0.05 by the two-sample Wilcoxon rank-sum test for the comparison of the difference in changes between groups.
`§P⬍0.05 by the Wilcoxon signed-rank test for the comparison of the base-line and post–base-line values within the group.
`
`Volume 336 Number 21
`
`ⴢ 1491
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`The New England Journal of Medicine
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`but not all the patients could tolerate the initial
`therapeutic regimen (200 mg per day) for the entire
`four weeks of the randomized study. Approximately
`half the patients either discontinued the study med-
`ication permanently or had their doses reduced be-
`fore the four-week course ended. Half of these treat-
`ment changes were due to rash or excessive sedation.
`Peripheral sensory neuropathy was not found with
`greater frequency in the thalidomide group. How-
`ever, such neuropathy is a known complication of
`longer-term thalidomide treatment.29 Given the oth-
`er neuropathic insults to which HIV-infected pa-
`tients are exposed, patients receiving thalidomide
`must be monitored carefully for this potential toxic
`effect.
`Thalidomide is notorious for its teratogenic ef-
`fects.30-32 During the period of pregnancy when
`there is known sensitivity to the effects of thalido-
`mide (21 to 35 days after conception), even a single
`dose of thalidomide is dangerous.31 If thalidomide is
`given to women with childbearing potential, the
`treatment should be accompanied by cautionary
`measures, including careful informed-consent proce-
`dures, a requirement that effective birth control be
`used, testing for pregnancy every two weeks, warn-
`ing labels on packages and vials, and preestablished
`procedures for counseling and monitoring in the
`event of pregnancy. We believe that this approach
`should be used so that women with childbearing po-
`tential can receive this treatment and other poten-
`tially beneficial therapies of known or uncertain ter-
`atogenic risk.
`Recently, the immune-modulating and angiogen-
`esis-inhibiting activities of thalidomide have been
`recognized.33-35 The drug has shown evidence of ef-
`fectiveness in treating graft-versus-host disease in
`transplant recipients34 and in treating erythema no-
`dosum leprosum.35 Most descriptions of the use of
`thalidomide to treat aphthous ulcers in HIV-infect-
`ed patients and others have been case reports and
`retrospective series.3-14 However, one placebo-con-
`trolled, double-blind, crossover trial with no wash-
`out period reported success with 100 mg of thalid-
`omide per day in presumably non–HIV-infected
`subjects.15 End points related to both prophylaxis
`and treatment were combined in that trial.
`The cause of aphthous ulceration has not been es-
`tablished. Viral, immunologic, hormonal, and stress-
`related factors have all been suggested.36 Evidence of
`HIV RNA or protein has been found in some mac-
`rophages at the bases of esophageal ulcers in some
`patients with the acquired immunodeficiency syn-
`drome (AIDS).37 However, it is likely that the direct
`cause of aphthous ulceration is immunologic36,37
`and that the mechanism of action of thalidomide,
`like that of corticosteroids, is based on its immune-
`modulating properties.
`Our study failed to elucidate the putative immuno-
`
`1492 ⴢ May 22, 1997
`
`logic mechanism, however. Although thalidomide was
`reported to inhibit the production of TNF-a,16-20,38,39
`our data did not show that TNF-a was inhibited, at
`least not systemically. Plasma levels of both TNF-a
`and soluble TNF-a receptor type II increased in the
`thalidomide-treated patients as compared with those
`receiving placebo. This suggests either that TNF-a
`is not important in the pathogenesis of aphthous ul-
`cers or that if it is, the effect may occur locally in the
`tissues. It is more likely that other mechanisms are
`involved.
`Our data suggest that thalidomide enhances the
`production of HIV. This contradicts in vitro find-
`ings18 but is consistent with the results of our meas-
`urements of TNF-a and lends support to the pro-
`posed relation between the activation of TNF-a and
`viral expression from HIV-infected cells.21 TNF-a
`induces the expression of HIV from chronically in-
`fected cell lines by stimulating nuclear factor-kB, a
`cellular transcription factor used by HIV.21 Because
`of the effect of thalidomide on the HIV load and on
`the levels of soluble TNF-a receptor type II, two
`measures associated with the clinical progression of
`HIV disease,40-43 we urge caution in using thalido-
`mide in HIV-infected persons after the two to four
`weeks of short-term treatment.
`Our data indicate that when large, nonhealing
`aphthous ulcers of the gastrointestinal tract develop
`in HIV-infected patients, the patients usually have
`advanced immunosuppression. The median absolute
`CD4 cell count in our patients was 25 cells per cubic
`millimeter; 89 percent had CD4 counts of less than
`200 cells per cubic millimeter. Thus, such ulceration
`should probably be considered an AIDS-defining
`event.
`Few data are available on the incidence of severe
`aphthous ulcers among HIV-infected patients. They
`are certainly uncommon, but when they do occur
`they are often devastating. Our study shows that tha-
`lidomide is clearly effective in treating this condition.
`
`Supported in part by the ACTG, NIAID; and in part by the General
`Clinical Research Center Units funded by the National Center for Research
`Resources.
`
`We are indebted to Susan Stehn and Jana Parson for technical
`support, to Evangeline Leash for editorial assistance, to Carmen Al-
`icea for secretarial assistance, to the clinicians who referred patients
`to the study, and to the patients who participated in it.
`
`APPENDIX
`
`In addition to the study authors, the ACTG protocol 251 team included:
`D. Greenspan and F. Aweeka, University of California, San Francisco;
`C. Trapnell and L. Purdue, Division of AIDS, NIAID; J. McFarland and
`W. Levy, ACTG Operations Center, Social and Scientific Systems, Rock-
`ville, Md ; G. Jones, Data Management Center, Frontier Science Technol-
`ogy and Research Foundation, Amherst, N.Y.; D. Simpson, Mount Sinai
`School of Medicine, New York; A. Bardequez, New Jersey Medical School,
`Newark; R. Clark, Tulane University, New Orleans; N. Quesada, University
`of California, Los Angeles; and P.J. Andrulis, Jr., and M.W. Drulak, Andru-
`lis Pharmaceuticals, Beltsville, Md.
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`IPR2018-00685
`Celgene Ex. 2023, Page 6
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`

`

`THALIDOMIDE FOR THE TREATMENT OF ORAL APHTHOUS ULCERS IN PATIENTS WITH HIV INFECTION
`
`Other investigators at participating sites were as follows: L. Bessen and
`K. Luykx, Mount Sinai Medical Center, New York; S. Forstat, University of
`California, San Francisco; M. Cruz-Ortiz, University of Puerto Rico, San
`Juan; C. van der Horst, University of North Carolin