Strictly Confidential Glaxosmithkline Consumer Healthcare Gmbh

Strictly Confidential

GlaxoSmithKline Consumer Healthcare GmbH & Co. KG

Name of the Sponsor: GlaxoSmithKline Consumer Healthcare GmbH & Co. KG Name of the Products: Product 1: GRANU FINK Prosta forte Product 2: Granufink Kürbiskerne

Name of the Active Ingredients: Product 1: Pumpkin seed extract (15-25 : 1), extraction solvent ethanol 92 % (m/m)

Product 2: Pumpkin seed Title of the Clinical Trial: Partially blinded, randomised, placebo-controlled, multi-centre study to determine the efficacy of a pumpkin seed extract and pumpkin seed in patients with benign prostatic hyperplasia (BPH) – Short title: G.R.A.N.U. Study CCI

Trial Protocol Amendments No changes were made after approval of the study by the BfArM (Federal Institute for Drugs and Medical Devices) and the Ethics Commission.

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GlaxoSmithKline Consumer Healthcare GmbH & Co. KG Investigator(s)/Trial Centre: 125 urological practices in Germany: 1. Facharztpraxis Urologie, 041XX Leipzig 2. Facharztpraxis Urologie, 793XX Emmendingen 3. Facharztpraxis Urologie, 475XX Kleve 4. Facharztpraxis Urologie, 507XX Köln 5. Facharztpraxis Urologie, 441XX Dortmund 6. Facharztpraxis Urologie, Landkreis Melsungen 7. Facharztpraxis Urologie, 107XX Berlin 8. Facharztpraxis Urologie, Landkreis Sächsische Schweiz-Osterzgebirge 9. Facharztpraxis Urologie, 405XX Düsseldorf 10. Facharztpraxis Urologie, 470XX Duisburg 11. Facharztpraxis Urologie, 015XX Riesa 12. Facharztpraxis Urologie, 376XX Holzminden 13. Facharztpraxis Urologie, 715XX Backnang 14. Facharztpraxis Urologie, 509XX Köln 15. Facharztpraxis Urologie, 212XX Buchholz 16. Facharztpraxis Urologie, 225XX Hamburg 17. Facharztpraxis Urologie, 126XX Berlin 18. Facharztpraxis Urologie, Landkreis Erzgebirgskreis 19. Facharztpraxis Urologie, 823XX Starnberg 20. Facharztpraxis Urologie, Landkreis Wertingen 21. Facharztpraxis Urologie, 062XX Lutherstadt Eisleben 22. Facharztpraxis Urologie, 180XX Rostock 23. Facharztpraxis Urologie, 410XX Mönchengladbach 24. Facharztpraxis Urologie, 174XX Greifswald 25. Facharztpraxis Urologie, 560XX Koblenz 26. Facharztpraxis Urologie, Landkreis Landsberg am Lech 27. Facharztpraxis Urologie, 107XX Berlin 28. Facharztpraxis Urologie, 790XX Freiburg 29. Facharztpraxis Urologie, Landkreis Aachen 30. Facharztpraxis Urologie, 163XX Schwedt 31. Facharztpraxis Urologie, 795XX Lörrach 32. Facharztpraxis Urologie, Landkreis Emmendingen 33. Facharztpraxis Urologie, 904XX Nürnberg 34. Facharztpraxis Urologie, Landkreis Märkisch-Oderland 35. Facharztpraxis Urologie, 659XX Frankfurt a. M. 36. Facharztpraxis Urologie, 796XX Rheinfelden 37. Facharztpraxis Urologie, Landkreis Main-Taunus-Kreis 38. Facharztpraxis Urologie, 026XX Bautzen 39. Facharztpraxis Urologie, 103XX Berlin 40. Facharztpraxis Urologie, 384XX Wolfsburg 41. Facharztpraxis Urologie, 130XX Berlin 42. Facharztpraxis Urologie, 042XX Leipzig 43. Facharztpraxis Urologie, 181XX Rostock 44. Facharztpraxis Urologie, Landkreis Rostock 45. Facharztpraxis Urologie, 882XX Ravensburg 46. Facharztpraxis Urologie, 121XX Berlin 47. Facharztpraxis Urologie, 502XX Pulheim 48. Facharztpraxis Urologie, Landkreis Limburg-Weilburg 49. Facharztpraxis Urologie, 043XX Leipzig 50. Facharztpraxis Urologie, 311XX Hildesheim 51. Facharztpraxis Urologie, 350XX Marburg 52. Facharztpraxis Urologie, 824XX Garmisch-Partenkirchen

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GlaxoSmithKline Consumer Healthcare GmbH & Co. KG 53. Facharztpraxis Urologie, 861XX Augsburg 54. Facharztpraxis Urologie, Landkreis Aichach-Friedberg 55. Facharztpraxis Urologie, Landkreis Weimarer Land 56. Facharztpraxis Urologie, 091XX Chemnitz 57. Facharztpraxis Urologie, Landkreis Oldenburg 58. Facharztpraxis Urologie, 674XX Neustadt 59. Facharztpraxis Urologie, 120XX Berlin 60. Facharztpraxis Urologie, 819XX München 61. Facharztpraxis Urologie, Landkreis Nordsachsen 62. Facharztpraxis Urologie, 130XX Berlin 63. Facharztpraxis Urologie, Landkreis Mittelsachsen 64. Facharztpraxis Urologie, 301XX Hannover 65. Facharztpraxis Urologie, 350XX Marburg 66. Facharztpraxis Urologie, 445XX Castrop-Rauxel 67. Facharztpraxis Urologie, Kreis Wesel 68. Facharztpraxis Urologie, 190XX Schwerin 69. Facharztpraxis Urologie, 202XX Hamburg 70. Facharztpraxis Urologie, 461XX Oberhausen 71. Facharztpraxis Urologie, 140XX Berlin 72. Facharztpraxis Urologie,026XX Bautzen 73. Facharztpraxis Urologie, 062XX Leuna 74. Facharztpraxis Urologie, 447XX Bochum 75. Facharztpraxis Urologie, 068XX Dessau 76. Facharztpraxis Urologie, 370XX Göttingen 77. Facharztpraxis Urologie, 041XX Leipzig 78. Facharztpraxis Urologie, 821XX Planegg 79. Facharztpraxis Urologie, 043XX Leipzig 80. Facharztpraxis Urologie, 604XX Frankfurt am Main 81. Facharztpraxis Urologie, Landkreis Dachau 82. Facharztpraxis Urologie, 203XX Hamburg 83. Facharztpraxis Urologie, Landkreis Regionalverband Saarbrücken 84. Facharztpraxis Urologie, 904XX Nürnburg 85. Facharztpraxis Urologie, 013XX Dresden 86. Facharztpraxis Urologie, 904XX Nürnberg 87. Facharztpraxis Urologie, 786XX Rottweil 88. Facharztpraxis Urologie, 041XX Leipzig 89. Facharztpraxis Urologie, Landkreis Augsburg 90. Facharztpraxis Urologie, Kreis Mettmann 91. Facharztpraxis Urologie, Landkreis Main-Taunus-Kreis 92. Facharztpraxis Urologie, 531XX Bonn – Bad Godesberg 93. Facharztpraxis Urologie, Landkreis Vorpommern-Rügen 94. Facharztpraxis Urologie, 241XX Kiel-Gaarden 95. Facharztpraxis Urologie, 193XX Parchim 96. Facharztpraxis Urologie, 861XX Augsburg 97. Facharztpraxis Urologie, Landkreis Hochtaunuskreis 98. Facharztpraxis Urologie, 014XX Radebeul 99. Facharztpraxis Urologie, Landkreis Rhein-Lahn-Kreis 100. Facharztpraxis Urologie, 104XX Berlin 101. Facharztpraxis Urologie, 381XX Braunschweig 102. Facharztpraxis Urologie, 245XX Neumünster 103. Facharztpraxis Urologie, 181XX Rostock 104. Facharztpraxis Urologie, 044XX Markkleeberg 105. Facharztpraxis Urologie, Kreis Herzogtum Lauenburg 106. Facharztpraxis Urologie, 126XX Berlin 107. Facharztpraxis Urologie, 041XX Leipzig 108. Facharztpraxis Urologie, 107XX Berlin

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GlaxoSmithKline Consumer Healthcare GmbH & Co. KG 109. Facharztpraxis Urologie, 041XX Leipzig 110. Facharztpraxis Urologie, 531XX Bonn 111. Facharztpraxis Urologie, 163XX Bernau bei Berlin 112. Facharztpraxis Urologie, 126XX Berlin 113. Facharztpraxis Urologie, Landkreis Vogtlandkreis 114. Facharztpraxis Urologie, 350XX Marburg 115. Facharztpraxis Urologie, 453XX Essen 116. Facharztpraxis Urologie, 239XX Wismar 117. Facharztpraxis Urologie, 651XX Wiesbaden 118. Facharztpraxis Urologie, 823XX Starnberg 119. Facharztpraxis Urologie, Landkreis Zwickau 120. Facharztpraxis Urologie, Landkreis Nordsachsen 121. Facharztpraxis Urologie, 126XX Berlin 122. Facharztpraxis Urologie, 855XX Grafing b. München 123. Facharztpraxis Urologie, 131XX Berlin 124. Facharztpraxis Urologie, 043XX Leipzig 125. Facharztpraxis Urologie, Landkreis Würzburg

Publications: None to date.

Duration of the Clinical Trial: 02AUG2005 (First Patient In) to 06AUG2009 (Last Patient Out).

Clinical Phase: IIIb

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Objectives: This study is intended to examine the effectiveness of a well-defined extract from pumpkin seed and the effectiveness of pumpkin seed in the symptomatic treatment of BPH under the conditions in daily practice. Through the 3-arm design, it was possible to compare pumpkin seed - which cannot be blinded - in comparison to placebo. • Primary target outcome criteria were the IPSS responder rate for pumpkin seed extract compared to placebo and the responder rate of pumpkin seed compared to placebo, after 12 months of treatment. Responders were defined as patients with at least a 5 point improvement in the International Prostate Symptom Score IPSS compared to baseline. • Secondary endpoints were the change in IPSS and its individual items, the change of the frequency of nocturia (micturition diary), and the course of the IPSS-related quality of life (IPSS-QoL), the primary reasons for discontinuation, the participant’s actual time in the study and the tolerability. • The evaluation of tolerability of pumpkin seed extract and pumpkin seed was based on the incidence of adverse events (AE), the vital signs, a physical examination, including the determination of residual urinary volume, prostate volume, the peak urinary flow rate (Qmax) and a qualitative urine analysis) and the clinical analysis of laboratory parameters including the serum PSA value.

Method (study design): This was a randomised, multi-centre study with a 12-month treatment phase and 3 parallel treatment groups (2-times daily 1 capsule pumpkin seed extract [500 mg of pumpkin seed extract], 2-times daily 5 grams of pumpkin seed or 2 times daily 1 capsule placebo) to determine the effectiveness of pumpkin seed extract compared to placebo in double-blinded manner, and the efficacy of pumpkin seed compared to placebo in an open design. After patients had undergone a 1-month run-in phase, they were randomly assigned to one of three parallel treatment groups in a 1:1:1 ratio. Regular post-randomisation visits took place every 3 months. At each visit, IPSS data was collected. In addition, patients were asked to complete a micturition diary on 3 consecutive days before each study visit, in which they noted the frequency of nocturia per night.

Number of Patients (planned and analysed): It was planned to screen 1770 patients and to randomise 1590 patients (530 patients per treatment group [pumpkin seed extract, pumpkin seed, placebo]). Patient recruiting for this clinical trial was terminated after more than three year´s duration on 30th June 2008 before achieving the planned number of patients, as recruiting progressed extremely slowly. In fact, of the 1599 initially screened patients 1431 were randomised (481 to the pumpkin seed extract group, 475 to the pumpkin seed group, 475 to the placebo group), 1430 received the study medication. Safety population: 1488 patients (57 non-randomised, 481 pumpkin seed extract, 475 pumpkin seed, 475 placebo) ITT population: 1430 patients (481 pumpkin seed extract, 475 pumpkin seed, 474 placebo). PP population: 908 patients (307 pumpkin seed extract, 291 pumpkin seed, 310 placebo). The treatment groups were similar with regard to demographic and anamnesis data in all populations.

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Diagnosis and main inclusion criteria: Male patients aged 50 to 80 years, who suffered from symptomatic BPH, could be included in the clinical trial if their BPH-related micturition symptoms had existed for at least 6 months, they achieved an IPSS of  13 and  19, an IPSS-QoL of  3, and the frequency of nocturia was at least twice per night. Further important inclusion criteria were: residual urine volume ≤ 100 ml, prostate volume ≤ 40 ml, and a peak urinary flow rate  12 ml/s at a micturition volume of at least 150 ml. Patients with prostate cancer, with disorders associated with micturition disturbances, with neurological diseases, with a PSA value of more than 10 ng/ml (with values above 4 ng/ml exclusion of prostate carcinoma using biopsy was obligatory), and patients, who had been treated with synthetic prostate drugs or phytotherapeutics within the last 6 months before inclusion in this clinical trial for BPH/micturition disorders, were excluded from participation.

Test preparations, dosage and type of application: Pumpkin seed extract (Test preparation 1): GRANU FINK Prosta forte – CCI Capsules for oral administration 2 times daily. Pharmaceutically active constituents: One capsule contained 500 mg pumpkin seed extract (15-25:1) of the cultivated variety Cucurbita pepo L. convar. citrullinina I.GREB var. styriaca I. GREB (extraction solvent ethanol 92% m/m). Batch numbers: 640001, 650001.

Pumpkin seed (Test preparation 2): Granu Fink Kürbiskerne – CCI 2 times daily 5 g whole cleaned pumpkin seed of the cultivated variety Cucurbita pepo L. convar. citrullinina I.GREB var. styriaca I. GREB. for oral administration. Batch numbers: 055003, 075005, 497022.

Duration of treatment: The overall duration of the clinical trial was 13 months. After a 1-month run-in phase, patients were randomised and entered into the 12-month treatment phase, during which regular study visits were intended to take place every 3 months.

Reference therapy, dosage and type of administration, batch numbers: The reference product during the randomised treatment phase was placebo in capsule form for oral administration 2 times daily. Batch numbers: PPD

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GlaxoSmithKline Consumer Healthcare GmbH & Co. KG Evaluation criteria: Primary:

• IPSS responder rate of pumpkin seed extract versus placebo after 12 months treatment, as well as the responder rate of pumpkin seed versus placebo after 12 months treatment. Patients with at least a 5 point improvement in the IPSS in comparison to baseline were defined as responders.

Secondary:

• Change in the IPSS over the study period • Change in the individual IPSS items over the study period • Change in nocturia frequency (micturition diary) • Quality of life (IPSS-QoL) • Period of time spent in trial participation • Reasons for early withdrawal from the trial • Tolerability

The tolerability of pumpkin seed extract and pumpkin seed was evaluated based on the AE incidence, the vital parameters, a physical examination (including the determination of the volume of residual urine, prostate volume, the peak urinary flow rate Qmax and a qualitative urine analysis), and the clinical analysis of laboratory parameters including the serum PSA.

Statistical methods:

Primary analysis: The primary statistical analyses were based on the ITT population. Where IPSS values of the primary endpoint were missing, a progression of the last observed value was made (last observation carried forward, LOCF). As primary efficacy analysis, the IPSS responder rate between the treatment groups placebo and pumpkin seed extract were first compared using the bilateral Mantel-Haenszel- Test at the 0.05 level. The odds ratio including the 95% confidence interval was provided. The homogeneity of the odds ratio with regard to any centre effects was estimated by the Breslow-Day Test with Tarone adjustment. Only if this test was significant the responder rates between placebo and the pumpkin seed group were compared in a second step using the same procedure (due to the rejection of the null hypothesis in the first step). Independent of the outcome of this second test in the hierarchical hypotheses group, the test procedure ended with this test.

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GlaxoSmithKline Consumer Healthcare GmbH & Co. KG Summary of the results and conclusions:

Demographic data and baseline characteristics

A total of 1488 patients were included and analysed in this clinical trial, 1431 of whom were randomised, 57 were not randomised, they dropped out in the run-in phase (run-in drop- outs). One randomised patient did not take any study medication, so that he was excluded from the ITT analysis. The ITT population comprised of 481 patients in the pumpkin seed extract group (Kürbissamen-Dickextrakt, KS-DE), 475 in the pumpkin seed (Kürbissamen, KS) and 474 in the placebo group (PB). In the safety population, 36.2% of patients under KS-DE vs. 38.7% under KS vs. 34.7% under PB showed at least one relevant violation of protocol, for which reason they were excluded from the PP population. The PP population consisted of 307, 291 and 310 patients randomised to KS-DE, KS and PB, respectively.

On average (mean ± SD), patients were 65.3  6.9 years of age (range: 45–82). The treatment groups were homogenous with regard to patient age (Kruskal-Wallis Test). In the randomised treatment groups, prostate volume, residual urine volume, peak urinary flow rate and micturition volume were almost identical, the BPH symptoms had existed on average for at least 4 years. The mean prostate volume was slightly increased with a total of 28.9  7.5 ml. The mean residual urine volume was 30.0 ml. The mean peak urinary flow rate was 9.7  2.5 ml/s at a micturition volume of 236  92 ml (total group). The urine analysis for protein, glucose and blood cells gave a negative result in at least 96% of the randomised patients per treatment group (safety population).

The mean baseline IPSS was in total 16.0 ± 2.0 points, which corresponded to moderately severe BPH symptoms. The mean IPSS-QoL at baseline was 3.5  0.7 points. The frequency of nocturia according to the micturition diary was on average 2.6  0.8 per night. The mean value of IPSS (Kruskal-Wallis Test), IPSS-QoL and the frequency of nocturia were almost identical at baseline in the 3 treatment groups (ITT- population).

Concomitant diseases were documented for 73.6% of patients. Almost half of all patients (42.2%) had accompanying diseases of the primary systemic organ class (SOC) "Vascular disorders". The SOC "Metabolism and nutrition disorders" was in 24.3%, "Cardiac disorders" in 15.2%, "Reproductive system and breast disorders" in a total of 14.8% of those affected; 11.1%, respectively, had accompanying diseases from the SOC’s "Gastrointestinal disorders" and "Renal and urinary disorders" (most frequently accompanying diseases at the Preferred Term (PT) level: "Renal cyst" [87 patients, 6.1%] and "Nephrolithiasis" [44 patients, 3.1%]). There were no relevant differences regarding prevalence of accompanying diseases in the treatment groups, neither at the level of the primary SOC’s, nor at the level of the PT’s (ITT population).

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GlaxoSmithKline Consumer Healthcare GmbH & Co. KG Efficacy: The analysis of the primary efficacy parameter (IPSS responder rate after 12 months treatment) showed in the 1st step of the test procedure (PB vs. KS-DE) that 218 of 471 patients (46.3%) in the KS-DE group vs. 223 out of 467 patients (47.8%) in the PB group were IPSS responders after 12 months (last observation carried forward, LOCF), which corresponded to an odds ratio PB vs. KS-DE of 1.06 (p = 0.65, Mantel-Haenszel-2 Test). The null hypothesis could thus not be refuted, the proof of efficacy for KS-DE vs. PB in the double-blind comparison could not be provided.

The secondary descriptive sensitivity analyses in the PP population showed a numerically higher responder rate for KS-DE than for placebo (50.5% vs. 49.0%). In the results "as observed" (without carrying forward the last observation), the responder rate in the KS- DE group was more than 2% higher (52.2%) than in the PB group (49.8%); nevertheless, the difference was not significant. Based on the results of the 1st step of the test procedure, comparison of the IPSS responder rates with the KS group in the 2nd step was purely descriptive.

In the open KS group, both in the ITT population as well as in the PP population, a clearly higher IPSS responder rate could be achieved after 12 months treatment than in the other treatment groups. In the ITT population, 275 of 470 patients (58.5%) of the KS group achieved IPSS response (LOCF). Test centre effects with regard to the IPSS responder rate could neither be determined in the ITT nor in the PP population (Breslow-Day Test with Tarone adjustment). All results of the 2-step test procedure are presented for the ITT and the PP populations in Tables A and B.

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Table A: IPSS responder rate after 12 months (ITT and PP populations)

Treatment group IPSS responder rate ITT population PP population N* n (%) 95% CI** N* n (%) 95% CI** Pumpkin seed extract Visit 6 (LOCF) 471 218 (46.3) [41.7; 50.9] 307 155 (50.5) [44.8; 56.2] Pumpkin seed Visit 6 (LOCF) 470 275 (58.5) [53.9; 63.0] 291 171 (58.8) [52.9; 64.5] Placebo Visit 6 (LOCF) 467 223 (47.8) [43.1; 52.4] 310 152 (49.0) [43.3; 54.7] * In several patients, details of the baseline-IPSS are missing. This led to the fact that the theoretical case numbers for the ITT population could not be achieved exactly for the calculation of the IPSS responder rates. * * The confidence intervals were calculated according to the method of Clopper and Pearson. IPSS response definition: decrease in IPSS by at least 5 points versus baseline. IPSS = International Prostate Symptom Score; CI = Confidence Interval; LOCF = Last Observation Carried Forward.

Table B: Odds ratio analyses IPSS responder rates - LOCF (ITT and PP populations)

Comparison groups Odds ratio p-value**

Value 95% CI*

ITT population Placebo vs. pumpkin seed extract 1.06 [0.82; 1.37] 0.65 Placebo vs. pumpkin seed† 0.65 [0.50; 0.84] <0.01 Pumpkin seed vs. pumpkin seed extract† 1.64 [1.26; 2.12] <0.01 PP population Placebo vs. pumpkin seed t extract 0.94 [0.69;1.29] 0.72 Placebo vs. pumpkin seed† 0.68 [0.49; 0.93] 0.02 Pumpkin seed vs. pumpkin seed extract† 1.40 [1.0; 1.93] 0.04 * The confidence intervals were calculated according to the method of Clopper and Pearson. ** Bilateral Mantel-Haenszel-2 Test at the 0.05 level. † The results of the 2nd step of the test procedure are to be interpreted purely descriptively. IPSS = International Prostate Symptom Score; CI = Confidence Interval.

The secondary efficacy parameters ( total IPSS, individual IPSS items, nocturia [micturition diary] and IPSS-QoL) showed that the most distinct improvement (reduction) was achieved early on within the first 3 months of treatment and the values had stabilised after approx. 9 months. Up to the end of treatment, the open KS-group recorded on average a distinctly stronger reduction than in the two blinded groups KS-DE and PB. Table C shows the results after 12 months for overall IPSS, nocturia [micturition diary] and IPSS-QoL for the ITT population; the results in the PP population were very similar.

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Table C: Changes in secondary efficacy parameters over 12 months (ITT population)

Parameter KS-DE group KS group PB group

Point in time N Mean ± SD N Mean ± SD N Mean ± SD

(Median) (Median) (Median) IPSS* Visit 2 (Baseline) 471 16.0 ± 2.1 (16.0) 470 16.0 ± 2.1 (16.0) 467 16.1 ± 1.9 (16.0) Visit 6 (Month 12) 480 11.7 ± 5.5 (12.0) 475 10.6 ± 5.2 (10.0) 474 12.1 ± 5.6 (12.0)

Difference** 471 -4.2 ± 5.4 (-4.0) 470 -5.4 ± 5.1 (-6.0) 467 -4.0 ± 5.5 (-4.0)

Nycturia† Visit 2 (Baseline) 481 2.6 ± 0.7 (2.3) 474 2.6 ± 0.7 (2.3) 472 2.7 ± 0.7 (2.7) Visit 6 (Month 12) 426 1.7 ± 0.9 (1.7) 434 1.6 ± 1.0 (1.5) 428 1.9 ± 1.0 (2.0)

Difference** 426 -0.9 ± 0.9 (-1.0) 434 -1.0 ± 0.9 (-1.0) 428 -0.8 ± 1.0 (-1.0)

IPSS-QoL‡ Visit 2 (Baseline) 472 3.5 ± 0.7 (3.0) 466 3.5 ± 0.7 (3.0) 469 3.5 ± 0.7 (3.0) Visit 6 (Month 12) 404 2.3 ± 1.1 (2.0) 428 2.2 ± 1.1 (2.0) 408 2.5 ± 1.2 (2.0)

Difference** 398 -1.2 ± 1.2 (-1.0) 421 -1.3 ± 1.1 (-1.0) 405 -1.0 ± 1.2 (-1.0) * Range of values: 0 to 35. Values at Visit 6 with error value replacement (LOCF). ** Difference = Visit 6 – Baseline. † Nocturia: Recorded using micturition diary; mean of 3 nights. Values at Visit 6 "as observed". ‡ Value range: 0 to 6 points. Values at Visit 6 "as observed". IPSS = International Prostate Symptom Score; IPSS-QoL= IPSS related quality of life; KS-DE = pumpkin seed extract; KS = pumpkin seed; PB = placebo; SD = standard deviation.

The median length of study participation was the same in all 3 treatment groups (365 days). Between 9.5% (KS group) and 13.1% (KS-DE group) of the patients terminated the study prematurely. The most frequent reason for termination was insufficient efficacy, where the open KS group (9 p atients, 1.9%) numerically showed a somewhat lower termination rate due to insufficient efficacy than the two blinded treatment groups (KS-DE: 20 patients [4.2%], PB: 17 patients [3.6%]).

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The mean duration of treatment was the shortest under KS-DE (337.7 ± 85.3 days) and the longest under KS (347.1 ± 73.5 days); under PB it lay at 340.8 ± 77.2 days between these two values. The median duration of treatment, however, was the same in all treatment groups: it amounted to 365 days (safety population). In total, 1265 patients (88.4%) completed the study regularly.

Only those events which occurred after the administration of the study medication were to be documented as adverse events (AE) according to the instructions in the study protocol.

During the randomised treatment phase a total of 439 AEs occurred in 284 patients (19.1%). In most patients, the AEs were at most of mild (123 patients) or moderate intensity (119 patients). At the end of the trial, the outcome was given as "recovered" for the large majority of events (272 events, 62.0%), in 58 events (13.2%), the patients were "recovering". In 87 events (19.8%) the outcome was "not recovered", of 14 events (3.2%) it was "recovered with sequelae", 5 events had a fatal outcome, thereof two events were reported for one patient approx. 3 months after his withdrawal from the trial, for 3 events (3.6%) there were no details concerning the outcome.

Table D gives an overview of the AE incidence in the treatment groups.

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Table D gives an overview of the AE incidence in the treatment groups.

Table D: Incidence of AEs under study medication (safety population)

Number of patients Non-randomised KS-DE group KS group PB group N=57 N=481 N=475 N=475 n (%) n (%) n (%) n (%)

With AEs 0 (0.0) 102 (21.2) 89 (18.7) 93 (19.6) With AE with an association 0 (0.0) 2 (0.4) 3 (0.6) 3 (0.6) With SAE (including 0 (0.0) 27 (5.6) 21 ( 4.4) 19 (4.0)

fatal events) With SAE (without fatal 0 (0.0) 26 (5.4) 20 ( 4.2) 18 (3.8)

events) With SAE with suspected 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

causal relationship With AEs which led to the discontinuation of the study 0 (0.0) 10 (2.1)* 10 (2.1) 12 (2.5)

medication With fatal SAE 0 (0.0) 1 (0.2) 2 (0.4)** 1 (0.2)

* One patient PPD , who was diagnosed with PPD shortly after entering the trial, terminated the study prematurely due to this event. The primary reason for the withdrawal was, however, the subsequent PPD , which was correspondingly considered in the evaluation. ** Patient PPD died approx. 3 months after he had terminated the clinical trial due to another event PPD Within the scope of the follow-up process to this preceding event, 2 further events with fatal outcome were reported: PPD and PPD . Thus, a total of 5 fatal events with 4 deaths were included in the evaluation. KS = pumpkin seed; KS-DE = pumpkin seed extract; PB = Placebo.

The highest AE incidences were determined for AEs of the primary SOCs "Infections and infestations" (60 patients, 4.0%), "Gastrointestinal disorders" (55 patients, 3.7%), and "Musculoskeletal and connective tissue disorders" (39 patients, 2.6%), whereby no relevant differences resulted between the treatment groups. The highest AE incidence on the PT level resulted for: "Hypertension" (1.1%), "Prostatic specific antigen increased" (1.0%), "Back pain" (0.7%), "Nasopharyngitis" (0.7%), "Urinary tract infection" (0.7%), "Haematuria" (0.5%) and "Prostatitis" (0.5%). Also, the AE incidence in the 3 treatment groups was similar at the PT level.

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The type and frequency of the AEs showed no particularities. They corresponded to the average age of the patients (65 years), which is associated with a high prevalence of accompanying diseases for this age group (mostly vascular, metabolic or musculoskeletal type), as well as a relatively long treatment period of 12 months.

In a total of 8 patients (0.5%), at least one AE occurred, for which the investigating physician assumed a possible connection with the study medication; this involved almost exclusively events of the SOC’s "Gastrointestinal disorders" (KS-DE: 2 patients [0.4%] vs. KS: 3 patients [0.6%] vs. PB: 3 patients [0.6%]), affected were the PTs "Nausea", "Abdominal pain upper", "Diarrhoea", "Flatulence" and "Stomach discomfort". In addition, a possible connection with the study medication was assumed in 1 case of "Aversion" (KS) and for 1 case of "Pruritus" (PB). In 3 patients, the severity of the AE was given as severe and the event was considered to be associated (2 cases of "Flatulence", both under KS, as well as 1 case of "Nausea" under PB).

A total of 64 patients (4.3%) experienced at least one serious AE (SAE), with the exception of cases of fatal outcome. The highest SUE incidence was found in the primary SOCs "Cardiac disorders" (11 patients, 0.7%) and "Injury, poisoning and procedural complications" (10 patients, 0.7%). There were no relevant differences between the treatment groups with regard to the SAE incidence. Urological (ad hoc) SAEs were "Calcus urinary", "Renal colic", "Prostatitis" and "Prostate cancer"1 (1 patient for each, all KS-DE). There were no occurrences of SAE with a suspected causal association to the study medication.

PPD

AEs, which led to discontinuation of treatment and occurred in ≥ 1 patient were "Abdominal pain upper" (1 patient KS-DE, 1 patient KS), "Nausea" (1 patient KS-DE, 1 patient KS, 2 patients PB), "Cerebrovascular accident" (1 patient KS-DE, 1 patient PB), "Myocardial infarction" (1 patient KS, 1 patient PB), "Pancreatitis acute" (1 patient KS-DE, 1 patient KS) and "Stomach discomfort" (2 patients PB).

Laboratory values: During the 13-month study phase, neither the average change in haematological laboratory parameters nor the average change in laboratory parameters for clinical chemistry were of any clinical relevance: the average PSA value increased minimally in all 3 groups (0.1 ng/ml under KS-DE and KS; 0.2 ng/ml under PB). Also, the average vital parameters were unchanged.

1 This patient (PPD had been diagnosed with PPD shortly after being enrolled in the trial and terminated the study prematurely due to this event. The primary reason for dropping out, however, was the subsequent PPD

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Urological examination:

The peak urinary flow rate, Qmax increased on average in all treatment groups (3.6 ± 6.3 ml/s under KS-DE and PB, 4.3 ± 6.8 ml/s under KS), the median residual urine volume remained unchanged. The mean prostate volume increased minimally, whereby the median increase under PB (2.0 ml) was somewhat greater than under active treatment (1.0 ml each). In a few patients, changes in the parameters for the urine analysis (protein, glucose, blood cells) were observed, the incidence of which was similar across the treatment groups.

Conclusion:

In this 3-arm, partially blinded, randomised, multi-centre clinical trial with a 12-month treatment period in patients suffering from moderately severe BPH symptoms, it was not possible to demonstrate the efficacy of a pumpkin seed extract (500 mg pumpkin seed extract) versus placebo in the double-blind comparison. IPSS responder rates of pumpkin seed extract vs. placebo showed no significant difference. Due to the 2-step design of the study, the confirmatory proof of efficacy for pumpkin seed was similarly therefore also not possible, although the IPSS-responder rate of the pumpkin seed group was approx. 10% higher than placebo. Testing at the descriptive level led to a p-value of < 0.01, with a confidence interval for the odds ratio of [0.50 – 0.84]. According to the WHO Consensus Criteria, the improvements in both “active substance” groups are within the range of the "fair" response, whereby in the case of the pumpkin seed group they came close to a "good" response. Clinical improvement (IPSS, frequency of nocturia and IPSS-QoL) was shown in all 3 treatment groups, whereby at descriptive level the pumpkin seed group treated openly in parallel was distinctly superior to the two blinded groups pumpkin seed extract and placebo; only slight numerical differences could be established between the latter two groups. The incidence of adverse events was at the placebo level in both active substance groups. Only individual adverse events arose which the investigating physician assumed to be connected to the trial medication, of which none was serious. These events were almost exclusively all of a gastrointestinal nature. The parameters prostate volume, peak urinary flow rate Qmax and residual urinary volume confirm the safety of the phytotherapy. Both treatments with pumpkin seed as well as that with pumpkin seed extract were safe and well tolerated.

Date of the Report: The final report of the study was prepared on 28th May 2010.

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Appendix I – List of Abbreviations:

BfArM Bundesinstitut für Arzneimittel und Medizinprodukte (Federal Institute for Drugs and Medical Devices) BPH Benign prostate hyperplasia

CRF Case Report Form

GCP Good Clinical Practice

IPSS International Prostate Symptom Score

IPSS-QoL IPSS-related Quality of Life

ITT Intent-to-treat

CI Confidence Interval

KS Kürbissamen; pumpkin seed

KS-DE Kürbissamen-Dickextrakt, pumpkin seed extract

LOCF Last observation carried forward

MedDRA Medical dictionary of drug regulatory activities

PB Placebo

PP Per-protocol

PSA Prostate Specific Antigen

PT Preferred Term

Qmax Peak urinary flow rate (Uroflow) QoL Quality of Life SD Standard deviation

SDV Source data verification

SGOT Serum glutamate-oxalacetate transaminase SGPT Serum glutamate-pyruvate transaminase SOC System organ class (System-Organ-Klasse) SAE Serious adverse event AE Adverse event vs. versus WHO World Health Organization