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Science Altered Placebo and Drug Labeling Changes the Outcome of Episodic Translational Medicine Migraine Attacks AAAS Slavenka Kam-Hansen et al. Sci Transl Med 6, 218ra5 (2014); DOI: 10.1126/scitranslmed.3006175 Editor's Summary Placebo and Medication Effects in Episodic Migraine Placebo and medication effects are intimately related in clinical practice and drug development. In new work, Kam-Hansen et at investigated how information—ranging from "negative" to "neutral" to "positive"—provided to patients, who received either active drug or placebo, modified their headache pain as measured by patient-reported pain scores. In a randomized order over six consecutive attacks, 66 patients with episodic migraine received either placebo or Maxalt (10-mg rizatriptan) under three information conditions (told placebo, told Maxalt or placebo, told Maxalt). Each participant also reported on an initial no-treatment attack, yielding a total of 459 documented migraine attacks. Maxalt was superior to placebo for pain relief. Increasing information from negative to neutral to positive progressively enhanced the effects of both placebo and Maxalt. The efficacy of open-label placebo was superior to that of no treatment. Relative to no treatment, the placebo, under each information condition, accounted for more than n't 50% of the drug effect. The benefits of placebo persisted even when the placebo was honestly described. Whether E. treatment involves medication or placebo, the information provided to patients and the ritual of pill taking are important " components of medical care. 05 A complete electronic version of this article and other services, including high-resolution figures, can be found at: http://stm.sciencemag.org/content/6/218/218raafull.html Supplementary Material can be found in the online version of this article at: http://stm.sciencemag.org/contentisuppl/2014/01/06/6.218.218ra5.DC1.html Information about obtaining reprints of this article or about obtaining permission to reproduce this article in whole or in part can be found at: http://www.sciencemag.org/about/permissions.dtl Science Translational Medicine (print ISSN 1946-6234; online ISSN 1946-6242) is published weekly, except the last week in December. by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2014 by the American Association for the Advancement of Science; all rights reserved. The title Science Translational Medicine is a registered trademark of AAAS. EFTA01195776 RESEARCH ARTICLE MIGRAINE Altered Placebo and Drug Labeling Changes the Outcome of Episodic Migraine Attacks Slavenka Kam-Hansen,' Moshe Jakubowske John M. Kelley,14's Irving Kirsch,s'6 David C. Hoaglin/ Ted J. Kaptchulcs* Rami Burstein241. Information provided to patients is thought to influence placebo and drug effects. In a prospective, within- subjects, repeated-measures study of 66 subjects with episodic migraine, we investigated how variations in medication labeling modified placebo and drug effects. An initial attack with no treatment served as a control. In six subsequent migraine attacks, each participant received either placebo or Maxalt (10-mg rizatriptan) administered under three information conditions ranging from negative to neutral to positive (told placebo, told Maxalt or placebo, told Maxalt) (N = 459 documented attacks). Treatment order was randomized. Maxalt was superior to placebo for pain relief. When participants were given placebo labeled as (i) placebo, (ii) Maxalt or placebo, and (iii) Maxalt, the placebo effect increased progressively. Maxalt had a similar progressive boost when labeled with these three labels. The efficacies of Maxalt labeled as placebo and placebo labeled as Maxalt were similar. The efficacy of open-label placebo was superior to that of no treatment. Relative to no treatment, 0 the placebo, under each information condition, accounted for more than 50% of the drug effect. Increasing o5 "positive" information incrementally boosted the efficacy of both placebo and medication during migraine L'• attacks. The benefits of placebo persisted even if placebo was honestly described. Whether treatment involves to medication or placebo, the information provided to patients and the ritual of pill taking are important compo- co nents of care. O rn INTRODUCTION and placebo changed under varying information conditions. We used 0) to It is generally thought that placebo and medication efficacies are in- migraine headache as a model because it is a naturally recurring neu- E fluenced by contextual factors such as the expectations embedded in rological disorder of unilateral throbbing headache associated with rot the information clinicians provide (I). Much of the evidence for such variable incidence of aura, nausea, photophobia, allodynia, fatigue, 0) beliefs is based on "balanced placebo design" experiments concerning and irritability (7). The recurring nature of migraine allowed us to mostly addictive or stimulant substances or their placebo controls that compare for each subject the efficacies of treatment and placebo over con- disentangle and reassemble placebo and medication effects by provid- secutive attacks using varying conditions of information. ing subjects with various statements, including true and false informa- E tion. These between-subjects studies have shown that information can significantly modulate the impact of such substances 0-6). RESULTS To ascertain whether these findings apply in a clinical condition, we -o td used a randomized 2 x 3 within-subjects expanded "balanced placebo Study design design" to test the hypothesis that, in acute migraine, clinical outcomes Participants were required to document one untreated attack at the with both placebo and medication treatment would increase progres- beginning of the study and six subsequent attacks randomly as- O sively as information varied from negative (0% chance of receiving signed for treatment with a pill of rizatriptan (10-mg Maxalt) or active medication) to uncertain (50% chance of medication) to positive placebo, each labeled once as "Maxalt," once as "placebo," and once (100% dunce) (ClinicalTrials.gov identifier. NCT00719134). A seventh as "Maxalt or placebo" (Fig. 1 and Table 1). They were asked to session provided a no-treatment baseline As secondary questions, we record one pain score 30 min after the onset of headache (baseline), planned to examine whether medication with negative information was take the study pill at the same baseline time (but not in an untreated different from placebo with positive information and whether open-label attack), and record a second pain score 23 hours after the onset of head- placebo was superior to no-treatment control. In an exploratory fashion. ache. Rescue medications were provided for each attack to be used as we also planned to examine whether the difference between medication needed 25 hours after the onset of headache Baseline pain scores were reported in 459 attacks, whereas the 2.5-hour pain scores were re- ported in 435 attacks. Using additional information available in 'Department of Neurology. Beth Israel Deaconess Medical Center, Harvard Medical the diaries, we were able to impute 18 of the missing pain scores at School. Boston, MA 02215. USA "Depanment of Anesthesia and Critical Care. Beth Israel 2.5 hours, resulting in 453 analyzable attacks (Table 2 and table S1). Deaconess Medical Center. Kinard Medical School. Bosun MA 02215, USA rychialogy Department, Endicott College. Beverly. MA 01915. USA Massachusetts General Hospital Generalized linear mixed models were used to analyze the data as de- Harvard Medical School Boston. MA 02114. USA. 'Program n Placebo Studies and the scribed in detail in Materials and Methods and Supplementary Methods. Therapeutic &counter. Beth luael Deaconess Medical Center. Harvard Medical School, Boston. MA 02215, USA. °School of Psychobgy. Plymouth Unersity, Plymouth PL4 8AA. Participant enrollment and characteristics UK 'Independent consultant. Sectary. MA 01776. USA 'These authors contributed equally to this work Of 98 persons prescreened for eligibility between December 2008 (Corresponding author. E-mail. rbuisleiCohidmclarvardedu and larch 2010, 19 were excluded for reasons listed in table S2, simwSdenceTranslationalMedicine.org 8 January 2014 Vol 6 Issue 218 218raS 1 EFTA01195777 RESEARCH ARTICLE No treatment (first attack) Primary endpoint The primary outcome measure was the Rescue MediCela:il change in headache between the baseline 1 Maxalt and 2 naproxen pain score recorded 30 min after the on- II you we nee pan4roe 2.5 hours alter migrant angel. you may take all 3 set of headache and the pain score recorded pas fl cis antelope al to same lime 2 hours later. Baseline average pain scores, measured on a numerical scale ranging from 0 (no pain) to 10 (maximal pain), at time of treatment were comparable among the six treated migraine attacks (P = 015) Study thug labels (attacks 1-6) (Table 2). Compared with baseline, the typ- ical pain score in the untreated attack was Two attacks Two attacks Two attacks higher after 2 hours (P = 0037) in the trea- Negative information Neutral information Positive information ted attacks, the typical pain score was (-placebo' labeling) (unspecilied labeling) (Waxe' labeling) lower after 2 hours (P 5 0.015). Table 2 provides the means and SDs of pain scores Envelope MI: Study drug Envelope a t: Study drug Envelope II: Study drug at 30 min and 25 hours by experimental O Take pll 30 mn *et migraine onset Take pill 30 min after migraine creel Take pit 30 min after migraine onset condition. 0 This envelope contains: This envelope contests: This envelope contains: Both labeling of the pill ("placebo," Placebo Maxalt or Placebo Malian "Maxalt or placebo," "Maxalt") (P = 0.010) os Irranadive) (act? e) (nosedive) latiNe) and treatment (Maxak placebo) (P < 0.001) to had statistically significant effects on the difference in pain scores between baseline Jr and 2 hours after treatment, but the two Actual pill Actual pill Actual pill Actual pill Actual pill Actual pill factors had no significant interaction (P = O Placebo Maxalt PlaceOo 1.1axalt Placebo Maxall 037). The lack of a significant interaction Fig. 1. Labeling of the "study drug" and optional "rescue medkations" envelopes. The study drug allowed the labeling effect to be summa- 0) td envelope was labeled "placebo" (two attacks), "Maxalt or placebo" (two attacks), or "Maxalt" (two attacks) rized across treatments and the drug effect E to provide negative, neutral, or positive Information, respectively. Subjects were instructed to open the to be summarized across labels. The typ- envelope and take the p11 30 min after onset of headache. They were asked to refrain from taking rescue ical decrease in pain score was 26.1% [con- medications during the first 2.5 hours of each attack, Including attack 1 (no treatment). fidence interval (Cl), 182 to 332161 with "placebo" labeling, 40.1% (CI, 32.1 to 47.0%) with "Maxalt or placebo" label- pi Table 1. Study design combining three types of labeling and two types ing, and 395% (CI, 31/ to 46.5%) with "Maxalt" labeling. The typical E of treatment decrease in pain score was 47.6% (CI, 41.5 to 53.0%) for Maxalt treat- 2 ment versus 20.7% (CI, 14.3 to 26.7%) for placebo treatment. Accuracy of treatment labeling In secondary analyses, we found that even when placebo treat- m Labeling of treatment pill ment was labeled accurately and openly described as placebo, pain .2 Given placebo pill Given Maxalt pill scores typically decreased by 145% (CI, 2.9 to 24.6%). This contrasted Placebo (negative information) Correct Incorrect significantly with the untreated attack (P = 0.001), during which pain scores typically rose by 15.4% (CI, 0.9 to 31.9%). The efficacy of 10-mg Maxalt or placebo Correct Correct (neutral information) Maxalt that was mislabeled as placebo was not significantly different from the efficacy of placebo treatment that was mislabeled as Maxalt Maxalt (positive information) Incorrect Correct (36.1 versus 24.6%, P = 0.127, Fig. 3). Notably, the placebo effect in this experiment was quite robust and more than half as large as the effect of Maxalt treatment. Relative to and 3 declined to participate. The remaining 76 persons signed the the no-treatment condition (15.4% increase in pain), the effect of pla- consent form, but 10 of them dropped out of the study for various cebo under "placebo" labeling (145 + 15.4%) was 60.0% as large as the reasons (Fig. 2). The demographic characteristics of the 66 partici- corresponding effect of Maxalt treatment (36.1 + 15.4%). Similarly, the pants and the 10 dropouts were very similar (table S3). Participants placebo effect was 59.8% as large as the Maxalt effect under "Nlaxalt" had experienced a median of 4 episodic migraine attacks per month labeling and 55.3% as large under "Maxalt or placebo" labeling. [interquartile range (IQR), 2 to 8), cumulatively lasting a median of 4 (IQR, 3 to 8) migraine days per month (table S4); 25% of them used Secondary endpoint migraine prophylactic drugs. Of the 66 participants, 51 provided A secondary measure of attack outcome was based on categorical clas- complete data on all seven attacks, and 15 submitted incomplete data sification of the pain freedom (pain score = 0) 2.5 hours after onset on one to three attacks and complete data on the remaining attacks of headache. The proportion of participants who were pain-free var- (Fig. 2). None of the subjects reported any unexpected adverse event ied significantly among the six treated attacks (P < 0001). Treatment other than the typical side effects listed in the drug information. had statistically significant effects (P < 0.001), but labeling did not wwwScienceTranslationalMedidne.org 8 January 2014 Vol 6 Issue 218 218raS 2 EFTA01195778 RESEARCH ARTICLE Table 2. Mean pain scores in the seven study attacks. (P = 0.053); treatment and labeling had no significant interaction (P = 0.48) (Fig. 4). The typical percentage of participants who were Number of attacks (n) and mean free from pain was 25.5% (CI, 172 to 36.0%) for all Maxalt treatments (SD) pain scores versus 6.6% (CI, 3.4 to 122%) for all placebo treatments. The typical percentage of participants who were pain-free was 16.6% (CI, 9.6 to Available and Pill Label Available Available 27.3%) for "Maxalt" labeling versus 9.2% (CI, 4.7 to 17.2%) for "pla- imputed values values cebo" labeling (P = 0.082). The typical percentage of participants who values were pain-free for "Maxalt or placebo" labeling was 15.5% (CI, 8.8 it 0.5 hour n 2.5 hours n 2.5 hours to 25.9%). Unlike the primary endpoint, the proportion of participants who None No treatment 66 4.6 (12) 63 5.3 (2.4) 66 5.4 (2.4) were pain-free during the no-treatment condition (0.7%) was not sta- Placebo Placebo 65 5.9 (2.1) 57 4.8 (3.0) 63 5.0 (3.0) tistically different from when participants took open-label placebo Maxalt or placebo 66 5.7 (2.0) 63 4.2 (2.6) 66 43 (2.7) (5.7%). As with the primary endpoint, the proportion of participants pain-free after treatment was not statistically different between Maxalt Maxalt 66 5.7 (2.0) 62 4.2 (2.9) 65 42 (2.9) treatment mislabeled as placebo (14.6%) and placebo treatment mis- Maxalt Placebo 65 5.6 (2.1) 63 3.3 (2.9) 65 3.4 (3.0) labeled as Maxalt (7.7%). The resulting therapeutic gain (that is, drug- Maxalt or placebo 65 5.5 (2.0) 64 2.4 (2.8) 65 2.4 (2.8) placebo difference) was 8.8 percentage points under "placebo" labeling n Maxalt 66 5.6 (1.9) 63 2.5 (3.0) 63 23 (3.0) [odds ratio (OR), 2.80j, 26.6 percentage points under "Maxalt or pla- cebo" labeling (OR, 7.19), and 24.6 percentage points under "Ivlaxalt" a Total number of attacks 459 435 453 labeling (OR, 5.70). cci co c to 98 prescreened for eligibility O 40 - Fir) O O) co 22 excluded: 20 - E 19 did not meet inclusion criteria U 3 declined to participate .0) O I -20 — E 76 enrolled to documen seven migraine attacks: 1 untreated attack 6 attacks treated in randomized order 2 En -SO — 9 lost to follow-ups I Sopped out for a personal reasons -60 — O 66 ccatinued as planned Labeling: Treatment: NT Placebo pill Maxalt pill Fig. 3. Changes In headache Intensity as a percentage of the 30-min pain score. The data are estimates for the seven experimental conditions, 51 provided complete intormation tor all 7 attacks with 95% Cis, from the generalized linear mixed model (table 58). The es- IS provided incomplete information on some attacks timates for the three types of information (labeling) are grouped according to whether the treatment was a placebo pill (blue) or a Maxalt pill (red). The Fig. 2. Flow diagram of disposition of patients, after the Consolidated within-subjects design of this study allowed each subject to serve as his or Standards for Reporting of Trials (CONSORT). The steps lead from pre- her own control, whkh substantially increased statistical power. Conse- screening to collection of the data used in the analysis. The diagram shows quently, 95% Cls cannot be Interpreted in the same manner as in a typical the extent of exclusions, loss to follow-up, and missing data. 'Nine subjects between-subjects study. Thus, two groups can differ significantly even submitted no diary (two relocated, three withdrew from the study, and four when the mean for one group falls within the 95% CI for the other group. gave no specific reason). °One subject withdrew after submitting a diary NT, no treatment I), "placebo" label; U, unspecified "Maxalt or placebo" la- for the untreated attack. bel; M, "Maxair label wwwScienceTranslationalMedicine.org 8 January 2014 Vol 6 Issue 218 2l8raS 3 EFTA01195779 RESEARCH ARTICLE SO - difference in pain-free outcome between Maxalt and placebo was re- duced by negative information (9 percentage points) compared with neutral (27 percentage points) or positive information (25 percentage points). The results for the primary endpoint were in the same direction, Pain-free outcome (% of subjects) 40 - but less marked (214 304 and 26.9 percentage points for negative, neu- tral, and positive information, respectively). The reduced therapeutic gain when negative information was provided to patients appeared to 30 - reflect a decrease in the efficacy of the drug rather than an increase in the efficacy of the placebo treatment, a conclusion supported by a re- cent imaging study (10). In the context of triptan therapy for migraine, our data suggest that the therapeutic gains cannot be improved by de- 20 - creasing positive information; in fact, lower expectations may reduce drug-placebo differences. In the placebo literature, expectancy is usually defined as the sub- 10- jective probability of the occurrence of a certain clinical outcome (11). Many placebo researchers would have considered our provision of positive, neutral, and negative information as a method for manipu- ,. lating expectancy (12, B). However, we did not assess expectancies in c 0 our within-subjects experiment because we thought such queries might " cause patients to question the accuracy of the information we provided. oti Labeling: P U M P U M Therefore, we cannot assert with certainty that our manipulation worked c; Treatment: NT Placebo pill Maxalt pill through changes in conscious or nonconscious expectations due to the 2 information provided (14). We also did not Issns blinding to avoid sus- 4 Fig. 4. Percentage of subJeds who reported being pain-free 2.5 hours picions in a within-subjects design. Because our study used deception, its after onset of headache. The data are estimates for the seven experirnen- applicability to routine clinical care is limited, and the present findings °co tat conditions, with 95% Cis, from the mixed•effects logistic regression model (table 513). The estimates for the three types of information (label- are essentially a proof of concept. It would be important to expand our ing) are grouped according to whether the treatment was a placebo pill findings with experimental manipulations of expectancy considered te (blue) or a Maxalt pill (red). NT, no treatment P. 'placebo" labet U, unspe- ethical in clinical practice. cified "Maxalt or placebo" label; M, "Maxalt" label. To our knowledge, only one between-subjects study previously ex- 8 ambled clinical pain responses of placebo under three different infor- tr , mation sets (13). Thoracotomized patients (n = 38), all of whom were "g DISCUSSION treated postsurgically with a fixed dose of buprenorphine, also received a basal intravenous infusion of saline solution for the first 3 days after 15 By manipulating the information provided to patients, our primary surgery. The patients received three kinds of information concerning E analysis showed that the magnitude of headache relief induced by the saline (i) a rehydrating solution (no additional treatment control), ,eg Maxalt (10-mg rizatriptan), as well as that of placebo, was lowest when (u) either a powerful medication or placebo (uncertain information), or la pills were labeled as placebo, and higher when pills had uncertain (iii) a powerful painkiller (positive information). Request for oral pain 1:05 labeling or wee labeled as active medication. Two other findings were medication, the primary outcome measure, was lowest with positive s that (i) placebo treatment mislabeled as 10-mg Maxalt reduced head- information, highest in the no additional treatment condition, and in- ache severity as effectively as did Maxalt mislabeled as placebo, and (ii) open-label placebo treatment was superior to no treatment. We con- termediate in the uncertain condition. Our study improved on this pre- ACAS study by using a within-subjects design, including an uncompromised a dude that raising the likelihood of receiving active treatment for pain no-treatment control, and examining both placebo and active treatment relief significantly contributed to increased success rate of triptan ther- responses. apy for migraine, that open-label placebo treatment may have an im- We were surprised that when Maxalt was labeled "Maxalt or pla- portant therapeutic benefit, and that placebo and medication effects cebo," it had a numerically greater effect on pain (though statistically can be modulated by expectancies. not significant, P = 0385) than when it was labeled "Maxalt" We had Although Maxalt was superior to placebo under each type of expected that greater certainty of receiving active medication would information, we were surprised that the efficacy of Maxalt mislabeled result in greater efficacy (as occurred for the placebo experiment de- as placebo was not significantly better than the efficacy of placebo mis- scribed above and the placebo treatment in our experiment). Very few labeled as Maxalt. We were also surprised to find that open-label pla- experiments have compared medication under different degrees of cebo treatment induced pain relief as compared with the worsening of certainty. Some have found that certainty increases medication ef- pain during the untreated attack. A therapeutic benefit of open-label ficacy in pain and anxiety (15, 16), whereas other studies, for exam- placebo versus no treatment was also recently reported for patients ple, in Parkinson's disease (17) and cancer pain (18), have shown with irritable bowel syndrome in a randomized controlled study (8) that uncertainty enhances medication effects. A related experiment and in a pilot study in depression (9). with asthmatic patients showed that positive expectations selective- One of our exploratory goals was to assess whether information ly affected placebo but not drug responses (19). Furthermore, an- provided to patients can influence the net therapeutic gain of drug thropological investigations have noted that patients assessing treatment (drug efficacy minus placebo efficacy). We found that the whether treatment is helpful report that the increased vigilance that wwwSdenceTranslatIonalMedicine.org 8 January 2014 Vol 6 Issue 218 218raS 4 EFTA01195780 RESEARCH ARTICLE comes with uncertainty may increase therapeutic efficacy (20). This sician anytime (S.K.-H.) to report any adverse event or if they had conflicting evidence suggests that much research is needed in this question& Patients were also told that, if needed, they could use the res- domain. cue medications 2.5 hours after the onset of the attack In conclusion, positive information about active medication con- tributes to successful treatment of episodic migraine. Medication and Intervention information (which presumably influences expectancies) may be equally The study intervention was manipulation of information about study critical for pain relief. The benefits of placebo persist even if placebo pill identity to assess the effects of that information on treatment ef- treatment is honestly described. Whether treatment involves medication ficacy. At the time of study enrollment, patients were informed that or placebo, our study dearly shows that the information provided to the study drug envelope contained 10-mg Maxalt or placebo, that patients and the predictable ritual of pill taking are important compo- Maxalt is a medication for aborting migraine headache, that it works nents of care (21). Further research is warranted to investigate the best when taken 30 min after onset of headache, and that the placebo application of our findings to clinical practice and research design. pill looks and tastes the same as the Maxalt pill but contains no active medication. They were also informed that for the six study migraine attacks after the baseline attack, the brown study drug envelope would MATERIALS AND METHODS be labeled "Maxalt," "placebo," or "Maxalt or placebo" for three ran- domly ordered pairs of treatments. It was not disclosed to them that Study design two of the six study drug envelopes were labeled incorrectly: one en- nr The study followed migraine headache subjects over seven migraine velope containing a placebo tablet was mislabeled as Maxalt (to max- 0 attacks (ClinicalTrials.gov identifier. NCT00719134). Baseline pain in- imize placebo effect), and one envelope containing a tablet of Max.* tensity in the absence of treatment was measured in an untreated first was mislabeled as placebo (to minimize drug effect). Exemption from off attack Then, subjects self-reported response to treatment over the full transparency for the two attacks that involved deception was a'• next six attacks, for which they were given one of two treatments granted by the institutional review board in compliance with the four 2 (Maxalt or placebo) labeled in one of three ways (Maxalt, placebo, criteria specified by Federal Regulation 46.116c (http://wwwits.gov/ Ca Maxalt or placebo) with labels that were true (for four attacks) or false ohrp/humansubjects/guidance/45cfr46.htm1446.116) for Protection (for two attacks) (Fig. 1 and Table 1). of Human Subjects (accessed 31 May 2012) because the deception in- rn volved minimal additional risk, did not adversely affect the rights and wel- Participants fare of the patients, was necessary to practically answer an important tit Participants were recruited from Beth Israel Deaconess Medical Cen- question, and was followed with a full debriefing at the end of the study. E ter outpatient clinics: they signed an informed consent in a prescreen- ing visit and met with investigators (S.IC-H. and R.B.) to determine Randomization eligibility. Participants were eligible if they met the criteria of the Patients were randomly assigned in blocks of eight to eight sequence .g International Headache Classification Committee for Migraine (7), patterns that balanced the order of the two treatments and three types had suffered from episodic migraine attacks (with and without aura) of information (Supplementary Methods: Randomization of Treat- 15 in the past 3 years, and were at least 18 years old. Excluded were non- ment and Treatment Labeling table 55). A table summarizing the ran- E migraine headache, peripheral nervous system injuries, chronic pain domination for each patient was placed in a sealed envelope wg conditions, opioid use, cardiovascular or cerebrovascular disorders, and given to the treating physician (SIC-H.), to be opened in case of -ta cardiac risk factors, or uncontrolled hypertension. Eligible patients unexpected reaction or medical emergency. All study personnel were list were informed that the purpose of the study was to understand the ef- blind to treatment allocation. fects of 10-mg rizatriptan (orally disintegrating melting tablet, brand name Maxalt-MLT, Merck and Co. Inc.) and placebo treatment (micro- Outcomes O crystalline cellulose, Merck) on acute migraine (Supplementary Methods: The primary study outcome was the percentage change from baseline Scripted Information Read to Participants). in headache intensity 2 hours after treatment using self-reported pain assessments obtained from diary entries that subjects completed during Medications each attack at home. The secondary study outcome was the proportion At the end of the prescreening visit, each patient received seven sealed of patients pain-free 2 hours after treatment. Pain level was assessed white envelopes, one for each successive migraine attack The envelope on a discrete numerical scale ranging from 0 (no pain) to 10 (maximal for the first attack ("no treatment") contained a five-page diary concern- pain). Subjects returned completed diaries after each attack ing details of symptomatolog and a small brown envelope containing rescue medications (one 10-mg Maxalt and two 220-mg naproxen for Statistical analysis relief 25 hours after attack onset) (Fig. 1 and Supplementary Methods). Our statistical analysis, detailed methods, and additional supporting Envelopes for the subsequent six attacks contained a four-page diary data can be found in Supplementary Materials and tables S6 to 514. and two small brown envelopes, one labeled "study drug" (to be taken Briefly, our main objective was to assess whether the effect on the pri- 30 min after headache onset) and the other "rescue medication" (con- mary and secondary endpoints differed among the three types of in- taining one 10-mg Maxalt and two 220-mg naproxen, to be taken formation and whether the effect differed between the two treatments. 2.5 hours after headache onset if the study drug was ineffective). Pa- We also made exploratory comparisons. For the primary endpoint, tients were instructed to open only one white envelope at the beginning change in headache intensity from baseline to 2 hours after treatment, of each attack, to do so in the exact order indicated on the envelopes we used generalized linear mixed models with a normal random com- (treatments I through 6 in sequence), and to call the responsible phy- ponent and a logarithmic link function to analyze the pain scores. INWOISdenceTranslationalMedicine.org 8 January 2014 Vol 6 Issue 218 2l8raS 5 EFTA01195781 RESEARCH ARTICLE Because the systematic component of the model is on the logarithmic Table 510. Estimates of cidference (25 hours minus 30 min) on the primary endpoint for key contrasts involving treatment and labeling. scale, estimates of differences in its parameters translate into estimates Table 511. Sensitivity analysis of the main model for the pain scores. of ratios on the pain score scale, which one can interpret as percent- Table 512. Estimates of parameters in the main model kg pain freedom at 25 hours. age increase or decrease. These approximate ratios of averages are not Table 513. Estimated probability of being pain-free 2 hours after treatment under the seven literally ratios of means (or means of ratios). Phrases such as "typical experimental conditions Iftom an analysis that included imputed pan scores at 25 Noun). value" reflect this feature of the analysis; one can interpret "typical Table S14. Estimates of difference (25 hours minus 30 min) ea the secondary endpoint for key contrasts involving treatment and labeling. values" as similar to means. For the secondary endpoint, the propor- tion of patients who were free from pain 2 hours after treatment, we used a mixed-effects logistic regression model to analyze the individual dichotomous outcomes. Its systematic component on the log-odds