International Journal of Clinical Pharmacology and Therapeutics, Vol. 49 – No. 10/2011 (614-621)

Original©2011 Dustri-Verlag Dr. K. Feistle

ISSN 0946-1965

DOI 10.5414/CP201513

ReceivedOctober 21, 2010;acceptedApril 5, 2011

Correspondence to F. Novariska Clinical Study Unit, Departemen Farma-kologi dan Terapeutik, Fakultas Kedokteran Universitas Indonesia, Jl. Salemba 6, Jakarta Pusat, Jakarta, 10430, Indonesia riskapulmo@yahoo.co.id

Key wordsprocaterol – salbutamol – moderate acute asthma – nebulized

The efficacy of nebulized procaterol versus nebulized salbutamol for the treatment of moderate acute asthma: a randomized, double-blind, parallel group studyH. Mangunnegoro1, F. Novariska1, W.H. Wiyono1, A. Setiawati2 and M. Louisa2

1Department of Pulmonology and Respiratory Medicine, Faculty of Medicine University of Indonesia/Persahabatan Hospital, and 2Department of Pharmacology and Therapeutics, Faculty of Medicine University of Indonesia, Jakarta, Indonesia

Abstract. Objective: β2 agonists have been used widely as relievers in asthma man-agement. Procaterol is a selective b2 agonist, claimed to be more selective than salbuta-mol. The present study aimed to compare the efficacy of nebulized procaterol with nebu-lized salbutamol in the treatment of moder-ate acute asthma. Methods: This was a ran-domized, double-blind, parallel group study in 140 patients with moderate acute asthma according to modified GINA 1998 who vis-ited emergency department of Persahabatan Hospital, Jakarta. Patients were randomly as-signed to receive three doses of either nebu-lized procaterol or salbutamol. The primary efficacy variable was the improvement in predicted peak expiratory flow rate (PEFR), while the secondary efficacy variable was the improvement in asthma score and the in-cidence and severity of adverse events. This study is registered at Current Controlled Trials, number ISCTRN25669625. Results: Baseline characteristics were similar in both groups. After treatment, there were signifi-cant improvement of % PEFR (p < 0.001) and asthma score (p < 0.001) in procaterol (n = 68) and salbutamol (n = 69) groups. It was shown that procaterol and salbuta-mol produced similar efficacy in improving % predicted PEFR and decreasing asthma score. Both treatments were well tolerated. Palpitation and sinus tachycardia were found as adverse events with low incidence. Con-clusion: In moderate acute asthma, nebulized procaterol and nebulized salbutamol were both effective in improving PEFR and de-creasing asthma score. Both treatments were well tolerated, adverse reactions were rare.

Introduction

Asthma is a chronic inflammatory dis-order of the airways associated with hyper responsiveness, reversible airflow limitation

and respiratory symptoms [1]. All patients with asthma are at risk of having exacer-bations (acute asthma) characterized by a progressive increase in shortness of breath, cough, wheezing or chest tightness [1,2] and by a decrease in expiratory airflow that can be quantified by simple measures of pulmo-nary function such as peak expiratory flow rate (PEFR) [1, 2, 3, 4]. β2 agonists, even at low doses, produce prompt bronchodilation when administered directly into the bron-chial tree. The conventional mode of admin-istration in acute asthma is nebulization [2].

Procaterol, discovered by Yoshizaki et al. [5] in Japan in 1976, is a long-acting, selec-tive b2 agonist [6, 7], and currently has been marketed in several countries. It is an effec-tive bronchodilator by oral administration and inhalation [6]. Structurally, procaterol is unique with a carbostyril rather than a catecholamine nucleus [5, 6, 8] that makes it highly resistant to enzymatic degradation [8] and have mild cardiovascular effects [7]. Procaterol, like other b2 agonists, stimulates b2 receptor causing an increase in intracel-lular cyclic 3’5’ adenosine monophosphate (cAMP) [9]. Oral procaterol in patients with chronic, stable, mild-to-moderate asthma produced consistently greater improvements in pulmonary function tests (FVC, FEV1 and FEF25–75) than salbutamol and similarly in clinical response [6]. Salbutamol is the stan-dard short-acting b2 agonist that is indicated for relief of acute asthma by MDI or by neb-ulizer [2], while use of procaterol by nebuliz-er has not been adequately studied [10, 11].

The present study was conducted with the aim to compare the efficacy and safety of nebulized procaterol with nebulized salbuta-

Nebulized procaterol for moderate acute asthma 615

mol in the treatment of moderate acute asth-ma. The primary outcome was improvement in PEFR, while the secondary outcomes were improvement in asthma score and the incidence and severity of adverse events.

Methods

Patients

Patients visiting the Emergency Room of Persahabatan Hospital, Jakarta with mod-erate acute asthma according to modified Global Initiative for Asthma (GINA) 1998, male or female, aged 15 – 60 y, were eligible for entry into this study. Excluded from the study were pregnant or lactating women, smokers, patients with chronic obstructive pulmonary disease (COPD), heart disease, hyperthyroidism, diabetes mellitus, severe infections, or other chronic diseases.

Study design and procedure

This was a randomized, double-blind, parallel-group study, nebulized procaterol

versus nebulized salbutamol, performed in patients with moderate acute asthma who visited the emergency room of Persahabatan Hospital, Jakarta. The study protocol was approved by the Ethics Committee of Fac-ulty of Medicine, University of Indonesia, Jakarta and the National Agency of Drug and Food Control of Indonesia, and the study was conducted in compliance with Good Clinical Practice. Informed consent was ob-tained from every patient before screening. This study is registered at Current Controlled Trials, number ISCTRN25669625.

Upon arrival at the emergency room, the patient received explanation about the nature of the study, and when he/she agreed to par-ticipate, informed consent was obtained from him/her. Then, the investigator screened the patient by performing anamnesis, physi-cal examination (vital signs) and assessed his/her asthma score according to modified GINA 1998 criteria (breathlessness, talking, alertness, respiratory rate, accessory muscles and suprasternal retractions, wheezing, heart rate and peak expiratory flow rate). The eli-gible patients were patients with moderate severity, having a total asthma score of 5 to 11, but with modified % predicted PEFR (changed from 60 – 80% to < 80%). This modification was based on a aprevious study by Pramahdi [12] in 2005, who found that most of moderate acute asthma patients visit-ing emergency room in Persahabatan Hospi-tal, Jakarta, had PEFR < 60%. These patients underwent further measurements (blood gas analysis, hematology, ECG and chest X-ray).

The investigational product, ampoules containing 50 µg procaterol in 0.5 ml aque-ous solution (Meptin®, PT Otsuka), and the comparator, ampoules containing 2.5 mg salbutamol in 2.5 ml aqueous solution (Ven-tolin®, Glaxo Smith Kline) were provided by PT Otsuka, Jakarta. Treatment alloca-tion was according to block randomization using random permuted blocks of size 4. Patients received either one ampoule of pro-caterol, diluted with 2 ml of normal saline, or one ampoule of salbutamol 3 times every 20 minutes (at 0, 20 and 40 minutes). Both drugs were administered by other physicians (to keep the investigators blind to the study drug assigned) via jet-type nebulizer (Pul-moaidTM). The dose of salbutamol was the standard dose used internationally, while that

Figure 1. Flow of patients throughout the study.

Mangunnegoro, Novariska, Wiyono et al. 616

of procaterol was the standard dose approved in Japan [13].

The PEFR was measured using a mini-wrights peak expiratory flow meter (Airmed Clement Clarke International, London, Eng-land) at the start of treatment (0 minute) and at 20, 40, 60 and 120 minutes. We calculated % predicted PEFR based on Pneumobile Project Indonesia Table [14]. At the same time, vital signs, asthma score and adverse events were evaluated. At 120 minutes, the

blood gas analysis and the ECG were re-peated. Then, the patient was observed for adverse event(s) that might occur until 280 minutes. All of these measurements were performed by the investigators who were blinded to the study groups. Afterwards, the patient was discharged from the study and received 6 tablets of bronchodilator (salbuta-mol 2 mg/tablet) and 6 tablets of corticoste-roid (methylprednisolone 4 mg/tablet). We gave the patients oral tablets because these were the usual dosage form used.

Patients were withdrawn from the study if the study drug was found not effective at 60 minutes evaluation (wheezing was still significant and asthma score > 4, the patient was then given aminophylline infusion and an intravenous corticosteroid), or the patient underwent serious adverse events, or at the request of the patient.

Sample size determination

The sample size was calculated based on the improvement of PEFR with a statistical power of 90% and a 2-sided significance lev-el of 0.05. The minimum difference which was considered by the investigators as clini-cally significant in PEFR increase between procaterol and salbutamol group was 5% (from previous studies). The total number of patients required for this study was 126 (63 patients per group).

Statistical analysis

The primary analysis was intent-to-treat (ITT) on all randomized patients who received at least one dose of the test drug, had at least one evaluation afterwards, and did not have any major violation of the en-try criteria. The secondary analysis was per protocol (PP) on patients who completed the study. The increase in PEFR from baseline in each group was compared using paired-t test or Wilcoxon matched pairs test depending on the data distribution. The increased PEFR from baseline between the two groups were analyzed using unpaired t-test or Mann-Whitney U-test depending on the distribu-tion of the data. The decrease in asthma score from baseline were analyzed using Wilcoxon

Table 1. Demographics and baseline characteristics of the intent-to-treat (ITT) population.

Procaterol (n = 68)

Salbutamol (n = 69)

DemographicsGender: male, n (%) 19 (27.9) 22 (31.9) female, n (%) 49 (72.1) 47 (68.1)Age (y), mean (SD) 41.0 (11.60) 40.7 (10.65)Weight (kg), mean (SD) 57.7 (10.09) 58.5 (11.04)Height (cm), mean (SD) 156.3 (6.76) 156.7 (7.18)Vital signs temperature (°C), mean (SD) 36.9 (0.36) 36.8 (0.48) heart rate (beats/min), mean (SD) 104.2 (11.7) 102.9 (12.7) blood pressure (mm Hg), mean (SD) systolic diastolic respiratory rate (resp/min), mean (SD)

121.5 (10.8)77.9 (8.9)27.3 (2.6)

120.0 (9.7)75.2 (7.0)27.4 (2.2)

Physical examinations, n (%) normal abnormal (hyperemic pharynx)

64 (94.1) 5 (5.9)

66 (95.7)3 (4.3)

Asthma score, mean (SD) 8.8 (1.5) 8.4 (1.6)PEFR, median (range) PEFR value (l/min) % predicted < 25%, n (%)

125 (70 - 300) 30.5 (12 - 57)

19 (27.9)

120 (80 - 320)26.0 (15 - 64)

32 (46.4)Arterial blood gas analyses, mean (SD) PaO2 (mm Hg) PaCO2 (mm Hg) SaO2 (%) HCO3

- (mEq/l) pH

75.8 (16.28) 33.9 (6.67) 94.4 (4.37) 22.4 (3.84)7.4 (0.06)

79.8 (22.18)32.8 (5.46)95.3 (2.66)21.8 (2.64)7.4 (0.06)

Laboratory abnormalities, n (%) 23 (33.8) 23 (33.3)ECG abnormalities, n (%) 18 (26.5) 14 (20.3)

Table 2. Concomitant medications within 24 h prior to study.

Procaterol (n = 68)

Salbutamol (n = 69)

Drug therapy within 24 h no 26 (38.2%) 31 (44.9%) yes 42 (61.8%) 38 (55.1%) bronchodilators 39 (57.4%) 34 (49.3%) corticosteroids 16 (23.5%) 10 (14.5%) others 3 (4.4%) 3 (4.3%)

Nebulized procaterol for moderate acute asthma 617

matched pairs test in each group and Mann-Whitney U-test between the two groups.

Results

Patients

A total of 156 patients were screened and 140 were randomized to receive either pro-caterol or salbutamol. Three patients were found to have diabetes mellitus (random blood glucose ≥ 200 mg/dl), and hence were exclud-ed from evaluation of efficacy. One patient from procaterol group withdrew consent after the first dose but this patient was still evalu-ated at 20 minutes. Three patients were dis-continued from treatment at 60 minutes due to treatment failure (2 subjects in the procaterol group, 1 subject in the salbutamol group). Therefore, there were 140 patients eligible

for safety evaluation, 137 patients eligible for ITT evaluation and 133 patients eligible for PP analysis (Figure 1). The demograph-ics of the Intent-to-Treat (ITT) population are presented in Table 1. Treatment groups were well matched for the demographics of subjects. The other baseline characteristics of the ITT population are also listed in Table 1. Most patients took drug therapy prior to the study (Table 2). The most common drugs taken in both treatment groups were bron-chodilators and corticosteroids. Chest X-ray abnormalities in both groups are shown in Table 3.

PEFR (% predicted) improvements in each group

Mean PEFR (% predicted) was markedly improved compared with baseline value at every timepoint (20, 40, 60 and 120 min-utes) in both groups (Figure 2). Procaterol was statistically better in improving PEFR value at 120 minutes compared with salbu-tamol but not clinically significant (Table 4). The minimum clinically significant differ-ence in PEFR improvements between pro-caterol and salbutamol groups according to the investigators’ judgment as defined in the protocol was 5%. At other timepoints, PEFR improvements by procaterol were similar to salbutamol (Table 4).

Asthma score improvements from baseline in procaterol and salbutamol groups

The asthma scores in procaterol and sal-butamol groups were markedly improved at every timepoint (20, 40, 60 and 120 minutes) (Figure 3). At 120 minutes, mean asthma score in procaterol group was 2.0 and in salbutamol group was 2.1. Asthma score im-provements in procaterol group were com-pared with those in salbutamol group (Table 5). It was shown that procaterol gave greater improvements in asthma scores at the first 40 minutes (20 and 40 minutes, p < 0.001 and p < 0.002, respectively). At 60 and 120 minutes, the asthma scores were consistently lower in procaterol group but not significant-ly different.

Figure 2. PEFR (% predicted) values at different timepoints in procaterol and salbutamol groups, ITT population. The improvements from baseline were significant at all timepoints (**p < 0.001). A statistical difference between both groups was found at 120 minutes (p = 0.023).

Table 3. Chest X-ray abnormalities at baseline.

Procaterol (n = 68)

Salbutamol (n = 69)

Hyperinflation 8 (11.8%) 3 (4.3%)Hypervascular 8 (11.8%) 1 (1.4%)Pneumonia 10 (14.7%) 10 (14.5%)Pulmonary TB + post TB

7 (10.3%) 6 (8.7%)

Bronchiectasis – 8 (11.6%)Others 2 (2.9%) 1 (1.4%)Total 33 (48.5%) 28 (40.6%)

Mangunnegoro, Novariska, Wiyono et al. 618

Arterial blood gas analyses

Arterial blood gas analyses at 120 min-utes are summarized in Table 6. Number of patients analyzed for blood gas was 62 pa-tients in procaterol group and 65 patients in salbutamol group. Six patients in procaterol group and 3 patients in salbutamol group could not be included in the blood gas analy-sis due to the missing data on either at base-line or at 120 minutes. Overall, PaO2 in pro-caterol group was slightly increased, while it was slightly decreased in salbutamol group. SaO2 was unchanged in procaterol group and slightly decreased in salbutamol group, whilst PaCO2 slightly decreased in both pro-caterol and salbutamol groups.

Adverse events

There were 140 patients eligible for safe-ty evaluation in the present study, 70 patients in each group. Incidences of adverse events were very low in the present study. Adverse events recorded were sinus tachycardia and palpitation, which were common after b2 agonist administration. Palpitation was recorded as a subjective symptom. There were 2 subjects in salbutamol group experi-enced palpitation, and no one in procaterol group. The palpitation was considered as mild. Sinus tachycardia was found during electrocardiography at 120 minutes, which was recorded and analyzed for any changes from baseline. There were 2 (2.9%) cases of changes in ECG recordings in procater-ol group and 6 (8.6%) cases in salbutamol group. No serious adverse event was found in the present study.

Discussion

The present randomized double-blind study compared nebulized procaterol 50 mg to nebulized salbutamol 2.5 mg in the treat-ment of moderate acute asthma in the emer-gency room. Our study population consisted of many more women than men, in the ratio of around 3 : 1. This finding was consistent with previous studies of asthma conducted in Jakarta [15, 16, 17].

The results of the present study showed that the efficacy of nebulized procaterol 50 mg was comparable to nebulized salbutamol 2.5 mg. In the present study, the % predicted PEFR at baseline ranged from 12 to 64% with a mean

Table 4. Mean PEFR (% predicted) differences from baseline at 20, 40, 60 and 120 minutes in procaterol and salbutamol groups. Comparison between groups, ITT and PP analysis.

ITT Analysis PP analysisTime (min)

Procaterol Salbutamol

Diff

eren

ce b

etw

een

proc

ater

ol a

nd

salb

utam

ol

(95%

CI)

p va

lue

(Man

n W

hitn

ey

U-te

st)

Procaterol Salbutamol

Diff

eren

ce b

etw

een

proc

ater

ol a

nd

salb

utam

ol (9

5% C

I)

p va

lue

(M

ann

Whi

tney

U

-test

)

Mea

n P

EFR

(%

pre

dict

ed)

Mea

n di

ffere

nce

from

bas

elin

e

Mea

n P

EFR

(%

pre

dict

ed)

Mea

n di

ffere

nce

from

bas

elin

e

Mea

n P

EFR

(%

pre

dict

ed)

Mea

n di

ffere

nce

from

bas

elin

e

Mea

n P

EFR

(%

pre

dict

ed)

Mea

n di

ffere

nce

from

bas

elin

e

0 31.9 29.8 32.7 29.820 40.1 8.2 36.3 6.5 1.7 (0.75; 2.71) NS 41.2 8.5 36.3 6.5 2.0 (1.00; 3.00) NS40 44.9 13.0 40.9 11.1 1.9 (0.56; 3.24) NS 46.1 13.4 41.0 11.2 2.2 (0.83; 3.57) NS60 49.5 17.6 44.6 14.8 2.8 (1.24; 4.36) NS 50.9 18.2 44.6 14.8 3.4 (1.81; 4.99) 0.027120 54.6 22.7 48.6 18.8 3.9 (2.10; 5.70) 0.023 56.2 23.5 48.6 18.8 4.7 (2.92; 6.48) 0.005

Figure 3. Asthma scores at several timepoints in procaterol and salbutamol groups, ITT population. The improvements from baseline were significant at all timepoints (**p < 0.001).

Nebulized procaterol for moderate acute asthma 619

(SD) of 30.8 (11.16). The improvements of % predicted PEFR at 20, 40, 60 and 120 min-utes from baseline in each group were sig-nificant (p < 0.001) (Figure 2), but the differ-ences of the improvements between groups were not clinically significant (Table 4). The minimum clinically significant difference was 5%, as determined by the investigator.

The set-up of the present study was sim-ilar to the study set-up of Ferres et al. [8]. Both studies performed in acute asthma, us-ing procaterol versus salbutamol on a ran-dom basis. The differences were the patients (adults in the present study and children in Ferres’s study), the dosage regimen (50 mg procaterol and 2,500 mg salbutamol at 0, 20 and 40 minutes in the present study, and 50 mg procaterol and 500 mg salbutamol at 0 and 30 minutes in Ferres’s study), and the mode of administration (nebulization in the pres-ent study, and MDI with spacer in Ferres’s study). In fact, nebulization and metered-dose inhalers combined with spacers were equally effective as the optimal mode of administration for acute asthma [18]. The % predicted PEFR increase between groups

at 15, 30 and 60 minutes were significant in Ferres’s study [8], but in the present study, the % predicted PEFR increase between groups was not clinically significant. This might be due to the high dose of salbutamol used in the present study.

The improvements of asthma score were substantial, the improvements at 20, 40, 60 and 120 minutes from baseline in each group were highly significant (p < 0.001) (Figure 3). The differences of the improvements be-tween groups were also statistically signifi-cant at 20 and 40 minutes, but not at 60 and 120 minutes (Table 5).

In the study of Ferres et al. [8], the clini-cal evaluation yielded similar results in both groups. However, more patients in the salbu-tamol group required additional treatment at discharge (90 minutes after the first admin-istration).

PaO2 at 120 minutes slightly decreased after salbutamol (from 80.0 to 76.2 mm Hg, NS), but slightly increased after procaterol (from 76.8 to 81.4 mm Hg, NS) adminis-tration. This phenomenon can be explained as follows. In bronchial asthma, the venti-lation to blood flow ratio )Q/V( decreases due to obstruction in the airway, leading to hypoxemia, causing hypoxic pulmonary vasoconstriction (HPVC). Bronchodilators in general, including salbutamol, cause not only bronchodilation, but also vasodilation, producing an inhibitory effect on HPVC, in other words, an increasing effect on pulmo-nary blood flow. The nonselective b agonists, for example isoproterenol, also stimulate the heart and cause increased cardiac output, leading to increased pulmonary blood flow.

Table 5. Asthma score differences from baseline at 20, 40, 60 and 120 minutes in procaterol and salbutamol groups. Comparison between groups, ITT and PP analysis.

ITT Analysis PP analysis

Time (min)

Procaterol Salbutamol

Diff

eren

ce b

etw

een

proc

ater

ol a

nd

salb

utam

ol (9

5% C

I)

p va

lue

(Man

n W

hitn

ey U

te

st)

Procaterol Salbutamol

Diff

eren

ce b

etw

een

proc

ater

ol a

nd

salb

utam

ol (9

5% C

I)

p va

lue

(Man

n W

hitn

ey U

te

st)

Mea

n as

thm

a sc

ore

Mea

n di

ffere

nce

from

bas

elin

e

Mea

n as

thm

a sc

ore

Mea

n di

ffere

nce

from

bas

elin

e

Mea

n as

thm

a sc

hore

Mea

n di

ffere

nce

from

bas

elin

e

Mea

n as

thm

a sc

ore

Mea

n di

ffere

nce

from

bas

elin

e

0 8.8 8.4 8.7 8.420 5.3 –3.5 5.8 –2.7 0.8 (0.57; 1.03) 0.001 5.2 –3.5 5.8 –2.6 0.9 (0.62; 1.18) < 0.00140 3.2 –5.6 3.6 –4.9 0.7 (0.44; 0.96) 0.002 3.0 –5.7 3.6 –4.8 0.9 (0.57; 1.23) 0.00160 2.4 –6.4 2.5 –5.9 0.5 (0.23; 0.77) NS 2.2 –6.5 2.5 –5.9 0.6 (0.26; 0.94) NS

120 2.0 –6.8 2.1 –6.3 0.5 (0.21; 0.79) NS 2.0 –6.7 2.0 –6.4 0.3 (–0.06; 0.66) NS

Table 6. Mean PaO2, PaCO2 and O2 saturation (SaO2) before and after treat-ment (120 minutes) in procaterol and salbutamol groups: PP analysis.

Blood gas analysis PP analysis Procaterol(n = 62)

Salbutamol(n = 65)

PaO2 (mm Hg) 0 minutes120 minutes

76.881.4

80.076.2

SaO2 (%) 0 minutes 120 minutes

95.095.0

95.394.3

PaCO2 (mm Hg) 0 minutes120 minutes

33.431.6

32.831.7

Mangunnegoro, Novariska, Wiyono et al. 620

Therefore, bronchodilator administration may lead to decreased or unchanged PaO2, depending on the unbalance of the V֗ /Q֗ it causes. A decrease in PaO2 occurs when an increasing effect on pulmonary blood flow into the insufficient ventilation area is pre-dominantly observed [10, 19, 20].

The improvement in PaO2 after nebuli-zation of procaterol (not statistically signifi-cant) was caused by improvement of the V֗ / Q֗ ratio due to increased ventilation volume resulting from a dilating effect on the large and small airways by procaterol [21, 22] and less inhibition of HPVC [10]. Chapman [23] investigated the changes in blood gases asso-ciated with 6 different aerosol bronchodila-tors, including isoproterenol and salbutamol. All bronchodilators tested caused a signifi-cant decrease in PaO2, except a combination of isoproterenol and phenylephrine. The fall in PaO2 is due to the powerful vasodilating properties of the bronchodilators, particular-ly around hypoxic areas of the lung, whereas phenylephrine is an a agonist, it causes vaso-constriction or prevents vasodilatation.

In the present study, the incidence of ad-verse effects caused by procaterol was very low, lower than that caused by salbutamol, and the adverse effects were effects on the heart. This was in accordance with previous studies [8, 10, 19]. This finding demonstrated the high b2-receptor selectivity of procater-ol, with higher selectivity on the bronchial smooth muscle than the cardiac muscle [24].

Conclusion

In moderate acute asthma, nebulized pro-caterol and nebulized salbutamol were both effective in improving PEFR and decreas-ing asthma score. Procaterol and salbutamol showed similar efficacy at all timepoints un-til 120 minutes. Both treatments were well tolerated, and adverse reactions were rare.

Acknowledgment

We thank the study patients for their participation, the study personnel for their commitment, and PT Otsuka Indonesia for providing the test drugs and for funding the study.

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