Study No.: Title: Rationale: Phase: Study Period: Study Design: Centers: Indication: Treatment: Objectives: Endpoints:

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: TRX Title: An Open Label, Single Dose, Parallel Group Pilot Study to Evaluate Absorption and Transit Characteristics of TREXIMA* and Relpax in Patients Inside and Outside of an Acute Migraine Attack *currently known as TREXIMET (sumatriptan and naproxen sodium) Rationale: A single combination (sumatriptan and naproxen sodium) contains sumatriptan 85mg (as the succinate salt) formulated with RT Technology and naproxen sodium 500mg (referred to as sumatriptan/naproxen sodium or ). The RT Technology formulation of the sumatriptan portion of the absorbs water more quickly and disintegrates in the stomach allowing for faster dissolution than a conventional sumatriptan. There is reason to believe that liquids have a faster transition time through the stomach even in presence of significant gastric stasis. And hence, a triptan formulated to rapidly dissolve into a liquid state might reach the small intestine, and get absorbed, much faster than a triptan in a conventionally formulated. Phase: III Study Period: 29 August November 2006 Study Design: Open Label, Single Dose, Parallel Group Pilot Study Centers: One study center in the United States. Indication: Acute Treatment of Migraine Treatment: Study medication (either sumatriptan/naproxen sodium or eletriptan) was given orally as a. Each of the administration occasions was separated by > 7 days. Subjects received either sumatriptan/naproxen sodium or eletriptan but not both. All subjects received study medication when they were not experiencing an active migraine attack and the first 5 of the ten subjects in each treatment group who experienced a migraine attack and could come to the clinic for dosing received study medication when they were experiencing an acute migraine attack. A radioactive isotope (indium-111 chloride, approximately 25 microcuries in a 1 microliter volume) was incorporated into the naproxen half of the bilayer sumatriptan/naproxen sodium while the sumatriptan side of the was radiolabeled with technetium (Tc)-99m diethylenetriaminepentaacetate (DTPA) (approximately 50 microcuries in a 1 microliter volume). The eletriptan was radiolabeled with a single isotope (technetium [Tc]-99m DTPA). Since the radioactive isotopes were not absorbed, the process of disintegration and transit through the gastrointestinal (GI) tract could be monitored using a gamma camera that captured images at frequent intervals after ingestion of the dose. Objectives: The primary objective of this study was to evaluate the rate of dispersion, gastric transit time and relative onset of absorption of sumatriptan and naproxen when delivered from sumatriptan/naproxen sodium in migraineurs (International Classification of Headache Disorders [ICHD] II 1.1 and ICHDII 1.2.1) with and without the presence of active (moderate to severe) migraine. Endpoints: The following endpoints were measured in the presence and absence of a migraine attack: Pharmacokinetic parameters for sumatriptan and naproxen, specifically, AUC(0-2), AUC(0-24), AUC(0- ), Cmax, and tmax Pharmacokinetic parameters for eletriptan, specifically, AUC(0-2), AUC(0- ), Cmax, and tmax Time to 10%, 50%, and 90% of the radioactive markers representing sumatriptan, naproxen and eletriptan Time to complete of the radioactive markers representing sumatriptan, naproxen and eletriptan 1

2 Time to complete dispersion of the sumatriptan and naproxen portions of the and the eletriptan Time to first appearance of sumatriptan, naproxen and eletriptan at the proximal small intestine. Small intestine transit and residence of the radioactive markers representing sumatriptan, naproxen and eletriptan. Statistical Methods: Pharmacokinetic parameters, AUC(0-2), AUC(0- ), Cmax and tmax, of sumatriptan, naproxen and eletriptan were summarized descriptively by means of n, arithmetic mean, standard deviation, minimum, median, maximum, 95% confidence intervals about the arithmetic mean. Additionally, AUC (0-24) of sumatriptan and naproxen were summarized in the same manner. Geometric means, 95% confidence intervals and between-subject coefficients of variation (CVb) were derived for log e-transformed parameters, AUC(0-2), AUC(0- ), Cmax and AUC(0-24) for sumatriptan and naproxen. The geometric means and coefficients of variation were calculated. Scintigraphic images were analyzed in a time-lapse format and regions of interest (ROI) were drawn to include the stomach and small intestine. If applicable, regions of interest could also be drawn for the early and distal small intestine and colon. Each image was corrected for radioactive decay, compton scatter and background radiation. The following parameters were determined as necessary: time for the tracer to leave the stomach (T10%, T50% and T90% ), small intestine transit time (SITT50%, if applicable), and time for half of the tracer to arrive at the colon (T50% colon arrival, if applicable). Safety data were summarized using descriptive statistics. Study Population: Male and female subjects, years of age inclusive, who had at least a 6- month history of migraine with or without aura according to the International Headache Society (IHS) criteria ICHD-II 1.1 and Number of Subjects: Total Planned, N Enrolled, N Completed, n (%) 10 (100%) 10 (100%) 20 (100%) Total Number Subjects Withdrawn, N (%) Demographics Total N (All Subjects) Females: Males 10 : 0 9 : 1 19 : 1 Mean Age, years (SD) 30.6 (7.50) 33.3 (7.17) 32.0 (7.27) White/Caucasian/European Heritage, n 10 (100%) 10 (100%) 20 (100%) (%) Pharmacokinetic Results: (PK Population) Geometric Mean (CVb%) Pharmacokinetic Parameters Migraine status N Cmax (ng/ml) non migraine (33.0) migraine (30.8) 1. (range) 2. n = 9 3. n = 4 tmax (hr) ( ) 1.50 ( ) AUC(0-2) (nghr/ml) AUC(0-24) (nghr/ml) AUC(0- ) (nghr/ml) 65.2 (36.2) 232(25.6) 232 (24.8) (22.3) 166 (38.0) 158 (41.7) 3 2

3 Geometric Mean (CVb%) Pharmacokinetic Parameters Migraine status N Cmax tmax AUC(0-2) AUC(0-24) AUC(0- ) (μg/ml) (hr) 1 (μghr/ml) (μghr/ml) (μghr/ml) non migraine (25.5) 4.50 ( ) 23.2 (79.3) 571 (15.0) 901 (21.9) 2 migraine (28.1) 4.00 ( ) 24.4 (117) 627 (20.6) 978 (23.4) 1. (range) 2. n = 9 Geometric Mean (CVb%) Pharmacokinetic Parameters Migraine status N Cmax tmax AUC(0-2) AUC(0- ) (ng/ml) (hr) 1 (nghr/ml) (nghr/ml) non migraine (61.2) 2.50 ( ) 70.2 (97.3) 541 (78.7) 2 migraine (74.8) 2.00 ( ) 78.1 (121) 571 (94.2) 1. (range) 2. n = 9 3

4 Pharmacodynamic Results: (Scintigraphy or PD Population): Time to endpoint Treatment Component Non-Migraine Time to 10% Time to 50% Time to 90% Time to start of (0.1706) ( ) (0.4939) ( ) (0.1833) ( ) (0.5143) ( ) (0.6497) ( ) (0.8381) ( ) (0.8632) ( ) (1.0913) ( ) (1.5014) ( ) (0.1679) ( ) (0.5474) ( ) (0.2028) ( ) Migraine N= (0.2618) ( ) (0.7529) ( ) (0.2888) ( ) (0.5855) ( ) (1.1297) ( ) (0.9052) ( ) (0.9016) ( ) (2.3349) ( ) (1.8197) ( ) (0.1304) ( ) (0.8442) ( ) (0.2909) ( ) 4

5 Time to complete Time to Start of Dispersion Time to Complete Dispersion Time to First Appearance at the Proximal Small Intestine (50% to arrive in the cecum) (1.0397) ( ) (1.7192) ( ) (2.6615) ( ) (0.0169) ( ) (0.5353) ( ) (0.1874) ( ) (0.0738) ( ) (1.1399) ( ) (0.2320) ( ) (1.4415) ( ) (1.1711) ( ) (3.4274) ( ) (1.9445) ( ) (2.6148) ( ) (2.0519) ( ) (0.0626) ( ) (0.6174) ( ) (0.1945) ( ) (0.0671) ( ) (0.9354) ( ) (0.3125) ( ) (0.8894) ( ) (0.9973) ( ) (1.3040) ( ) 5

6 Small Intestine Transit and Residence (Time to 50% through small intestine) (1.4956) ( ) (1.1572) ( ) (3.6643) ( ) (1.1777) ( ) (0.6377) ( ) (1.7037) ( ) Safety Results (Safety population): Adverse events were collected during the study period. Due to the small number of subjects with AEs, all AEs reported in the study are tabulated below, rather than just the most frequent AEs. Most Frequent Adverse Events Subjects with any AE(s), n (%) 8 (80) 3 (30) Joint stiffness 3 (30) 0 Muscle tightness 3 (30) 0 Paresthesia 3 (30) 0 Musculoskeletal pain 1 (10) 1 (10) Diarrhea 2 (20) 0 Nausea 2 (20) 0 Dissociation 1 (10) 1 (10) Arthralgia 1 (10) 0 Flank pain 1 (10) 0 Neck pain 1 (10) 0 Abdominal pain 0 1 (10) Toothache 1 (10) 0 Dizziness 0 1 (10) Pharyngitis streptococcal 1 (10) 0 Nephrolithiasis 1 (10) 0 Swelling face 0 1 (10) Flushing 1 (10) 0 Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] Subjects with non-fatal SAEs, n (%) 0 0 Subjects with fatal SAEs, n (%) 0 0 Conclusion: See publications below. Publications: Kori S, Byrd S, Doll W, Page R, and Sandefer E. Gastroscintigraphic Evaluation of Gastric Emptying and Absorption of Another Conventionally Formulated Triptan. Cephalalgia 2007; Vol 27; 730. Kori S, Byrd S, Doll W, Page R, and Sandefer E. Gastric Emptying and Absorption of a with RT Technology 85mg and Sodium 500mg Tablet. Cephalalgia 2007; Vol 27; 649. Kori S, Doll WJ, Page RC, Byrd SC, Sandefer EP. Gastric Transit and Absorption of, 6

7 another Conventionally Formulated Triptan, in Migraineurs both During and Outside a Migraine Attack: Evaluation by Gastric Scintigraphy. Headache 2007; 47(5):752. Kori S, Byrd SC, Doll WJ, Page RC, and Sandefer EP. Gastric Transit and Absorption of and from a Fixed Single-Tablet RT Technology 85mg and Sodium 500mg in Migraineurs both During and Outside a Migraine Attack: Evaluation by Gastric Scintigraphy. Headache 2007; 47(5):751. 7