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Final Report: Phase III Multi-center clinical trial of Vitex negundo L. (Lagundi) Syrup vs. Placebo among Pediatric Patients with Cough of Moderate Severity

Investigators: Nelia P. Cortes-Maramba, M.D.
Jaime Purificacion, M.D.


INTRODUCTION


Among the causes of morbidity and mortality for all age groups in the Philippines are pneumonias and pulmonary tuberculosis, usually manifesting clinically with cough. In children, the acute respiratory infection (ARI) syndrome continues to cause untold sufferings and even death. In a country with limited financial resources, the available money could be channeled to the purchase of appropriate antibacterial agents since about 62% of the etiologic agents are due to bacteria and 23% are viral in origin. The availability of an effective herbal cough medication for children would therefore provide not only important clinical relief but would also allow easy accessibility and affordability for such a therapeutic agent.

Lagundi tablet and decoction have been proven to be effective and safe anti-cough medications in pediatric and adult patients in comparison to placebo. Clinical studies of the lagundi syrup in phase I and phase II clinical trials among children with mild to moderate cough showed favorable results. The efficacy of lagundi based on reduction of cough frequency was 84% and 90% on Day 4 and 8, respectively, compared with 42% and 50% for placebo. The peak expiratory flow rate (PEFR) values of lagundi-treated patients improved significantly on Day 4 and Day 8 by 12% and 20%, respectively, while those on placebo increased by 4% and 9% only. The phase III clinical trial was originally planned to be concluded by at least two academic research groups in several communities with the general objective of comparing the efficacy, safety and acceptability of lagundi syrup among outpatient pediatric patients with acute cough of moderate severity.

METHODOLOGY

This is a randomized double-blind, placebo-controlled clinical trial conducted by the UP College of Medicine research group in a Pandacan community from September to December 1997. The placebo and syrup preparations of lagundi were formulated by the UP Manila College of Pharmacy, Department of Industrial Pharmacy.

A. Patient Selection

The inclusion criteria admitted children of both sexes of age group 6 to 17 years who were in good general health and nutritional status with manifestation of cough of moderate severity (which would be assessed as non-bacterial). The children and/or their parents or guardians voluntarily agreed to participate with a signed informed consent. Among the exclusion criteria were presence of high fever (greater than or equal to 39°C axillary) and/or signs and symptoms of severe lower respiratory tract disease and/or requiring antibiotic therapy. Patients with systemic diseases involving other organs or with previous use of systemic corticosteroids or anti-asthma medications (within 14 hours of consultation) or presence of pregnancy and lactation were also excluded.

B. Treatment and Assessment

Patients were allocated at random (blocks of 10) to one of the two treatment regimens using lagundi or placebo syrup, identical in appearance, smell and taste.

In this study, acute cough was defined as less than 14 days in duration and of moderate severity if the respiratory rate is less than 30/min for 6-14 years of age and < 25/min for 15-17 years of age, coughing episodes of at least 10 times a day with bronchovesicular sounds and without cyanosis or intercostal retraction. A complete personal, social and medical history was obtained for each patient and baseline complete blood count and PEFR readings were obtained. Lagundi syrup was administered orally at 45 mg/kg/day in three divided doses using standardized spoon or cup, one hour after a meal for a maximum duration of 8 days, with follow-up visits on Day 4 and Day 8.

Case report form (CRF) for each patient was filled up by the physician. Evaluation for efficacy and safety was assessed by each patient using visual cough severity and relief scales and by the physician based on objective lung findings and clinical manifestation of cough.

Patients were considered evaluable if complete baseline and data on at least Day 4 follow-up (if with recovery on that first visit) and Day 8 follow-up. Provisions for patient drop-out, discontinuation of therapy and follow-up treatment with antibiotics or bronchodilators were included in the protocol. A signed free informed consent for voluntary participation was obtained per patient with a guarantee for freedom from assault, confidentiality of records and indemnification and an assurance of medical management in case adverse reactions occur, were also part of the conduct of the clinical trial.

C. Data Analysis

Comparison of the baseline demographic and medical characteristics of the two groups was done using Barlett’s test for homogeneity of variance. Fisher Exact Test or Chi Square was used in comparing the two groups as to frequency of cough, expectoration of phlegm when present, and difficulty of breathing at baseline and follow-up visits. Fisher Exact test was also utilized in the analysis of the patient’s global evaluation and the physician’s evaluation of the patient’s response to therapy at Days 4 and 8.


RESULTS AND DISCUSSIONS


A. Demographic Characteristics

A total of 120 patients were screened and 33 were found qualified to enter the study. A total of 33 patients were evaluable at the beginning and Day 4 and 24 were evaluable at the end (Day 8) of the clinical trial. There were 13 patients in the placebo (39.4%) and 20 (60.6%) in the lagundi group. There were a total of 22 males and 11 females with almost equal distribution in the placebo group and a predominance of male (80%) in the lagundi group. The mean age of patients was 8.6 years, ranging from 6-16 years old. The mean years of schooling of the children was 2.79 years (range of 1-10 years), predominantly in the elementary level (92.3% in the placebo and 90% in the lagundi). The mean weight of the subjects was 47.8± 12.3 pounds for placebo and 48 ± 21.5 pounds for the lagundi group while mean height was 48.2 ± 4.53 inches for placebo and 48.1 ± 5.83 inches in the lagundi group. Statistical analysis (Table 2) showed the two treatment groups to be comparable based on the above parameters.


B. Cough Profile at Initial Consultation

In both treatment groups, majority had duration of cough of 4-9 days (60.6%) and frequency of 10-15 /day. Expectoration of phlegm was generally mild for both groups and mild to moderate difficulty of breathing was only noted in 2 patients of the lagundi group. Table 3 shows the distribution of the patients as to cough profile on initial consultation. Statistical analysis (Fisher Exact test) did not show any significant differences.

C. Vital Signs

Vital signs consisting of pulse, heart and respiratory rates, temperature and PEFR were within normal limits. However, a statistically significant difference (p=0.03) was noted when comparing the values of the respiratory rate in the placebo group (Mean± S.D. = 18.2± 1.7) with the lagundi group (16.8±1.6) with a wider range (14-20) noted for the lagundi group (Table 4-A).

D. Follow-up Data

1. Vital Signs and PEFR Table 4-B shows that in the placebo group, pulse, heart and respiratory rates remained stable with no statistically significant change on the 1st (Day 4) and 2nd (Day 8) follow-up. There was a 3% and an 8.6% increase in PEFR on Day 4 & 8, respectively, but these were not statistically significant. The lagundi group also showed no statistically significant change in the pulse, heart and respiratory rates, on follow-up. However, there is noticeable increase in the mean PEFR especially on Day 4 (14.6%) and also increased on Day 8 (12.3%), but not statistically significant when compared with baseline values. Comparison of the values obtained for the two treatment groups (Table 4-B) showed that a p-value of 0.009 was obtained for respiratory rate on 1st follow-up of the patients while no significant difference was obtained with the other parameters, including PEFR. It should be noted, however, that the 2 patients with mild and moderate difficulty in breathing at baseline belonged to the lagundi group.

2. Cough frequency, ease of expectoration and breathing difficulty

In the placebo group, all 13 patients had cough frequency of 10-15 per day at baseline and at Day 4 follow-up, cough was reduced to once a day in 3 patients while 10 patients did not improved. By Day 8, 3 patients were cough-free, one worsened to 16-20 coughs per day and one patient’s cough frequency remained unchanged while 5 had cough reduction to once a day only. Among the lagundi-treated children, 19 had cough frequency of 10-15/day and one patient with frequency of 16-20/day. By Day 4, only 15 (out of 19) had 10-15 coughs/day 2 had reduced cough to once daily and one was fully recovered (no cough) but these improvements were not statistically significant. By Day 8, twelve children out of 14 who followed-up were free from cough and one had only 1 cough/day. Within patient analysis in the lagundi-treated group showed a highly significant improvement in cough frequency (p=0.002) by Day 8. Comparison of the two treatment groups also showed a significant difference (p=0.002) favoring the lagundi group by Day 8 (Tables 5-A and 5-B).

Assessment of the ease of expectoration and difficulty of breathing in the placebo group showed no significant change on follow-up. This was not surprising since patients in this group had very mild or easy expectoration and no difficulty in breathing. In the lagundi group, all patients remained without problem of expectoration and two patients with difficulty of breathing became asymptomatic by day 4. However, this improvement was not reflected as statistically significant (p=0.24). Comparison of the placebo and lagundi groups did not differ significantly based on ease of expectoration and breathing difficulty on follow-up.

3. Pulmonary and Medical examinations

Two parameters were assessed by the examining physician regarding the pulmonary status of each patient at baseline and follow-up. At baseline, all patients in the placebo group had clear breath sounds and only two had adventitious sounds (1 with wheezing and another with rales). In the lagundi group at baseline, 18 had clear breath sounds and 2 with harsh breath sounds based on breath sound quality. Rales were recorded in 1 child. On follow-up at Day 4, all patients had normal lung findings. However, on Day 8, one patient in the placebo group demonstrated harsh breath sounds and as to adventitious lung sound, one patient had rales. Statistical tests showed no significant difference between the placebo and the lagundi groups at baseline and on Days 4 and 8 when the criteria were quality of breath sounds and presence of adventitious lung sound. One patient in the placebo group worsened by Day 8 (Table 6a 6b).


E. Evaluation of Efficacy of Treatment

1. Patient’s Evaluation Based on Severity of Complaints

The efficacy of treatment was evaluated by the patients using the cough visual analog scale for severity of complaints and another one based on feelings of improvement. At baseline in the placebo group, 6 children (46%) assessed themselves as having infrequent cough, 5 (38.46%) with frequent cough and 2 (15.38%) with very frequent cough. In the lagundi group, 8 (40%) assessed themselves as having infrequent cough, 10 (50%) with frequent cough and only 2 (10%) with very frequent cough. On Day 4, three children treated with lagundi syrup had no more cough, while 9 remained with infrequent cough and only 1 had very frequent cough. By Day 8, of the 10 patients on placebo who followed-up, only one remained unimproved for an over-all improvement rate of 92% on Day 4 and 90% on Day 8. In the lagundi group, all patients were improved by Days 4 and 8. However, on statistical analysis (Fisher Exact test), there was no significant difference in the two treatment groups based on cough frequency (Table 7).

2. Feeling of Improvement

Evaluation of response to treatment based on feelings of improvement was also conducted among the patients using another cough visual analog scale. In the placebo group, by Days 4 and 8, the percentage of positive responders was only 85% and 80%, respectively, lower than the efficacy rate using severity of complaints based on cough frequency only. In the lagundi group, the percentage of positive responders was 100% by Day 4 with a larger number feeling much better (35% vs. 25%) when cough frequency was the only basis and the rest (65%) assessed themselves as feeling somewhat better. All patients were much better in the lagundi group by Day 8 (Table 7). The p-value, however, did not correspond to a statistically significant difference in response between the two treatments.

3. Physician’s Evaluation of Patient’s Response to Therapy

The physician’s evaluation of patient’s response to treatment was assessed based on 5 degrees of responses. In the 1st follow-up of the placebo-treated group, 77% were either very much improved (23%) or much improved (54%) while 2 were either minimally improved or unchanged. One patient was evaluated as being much worse with placebo. In contrast, the lagundi treatment resulted in 100% improvement (25% very much improved and 75% much improved) on Days 4 and 8 of follow-up (Table 8a 8b).

4. Over-all Global Evaluation as to Response to Therapy

Patient assessment using the evaluation criteria of either fair to excellent response or poor to no response showed that on Day 4 or 1st follow-up, there was agreement between the patients and physician’s evaluation. In the placebo group, the fair to excellent response was 84.6% for Day 4 and 80% for Day 8, whereas with the lagundi therapy, the positive response was 100% for Days 4 and 8 follow-up visits. Statistically, however, these differences in response favoring lagundi were not significant with p-value of 0.148 for Day 4 and 0.163 for Day 8 (Table 9).
F. Terminal Report

At the end of the study, all patients in the lagundi group terminated their participation by Day 8 because of 100% good response. In the placebo group, 2 patients required additional medical management because of worsened condition. Both patients were treated for 7 days with amoxicillin and expectorant for severe cough.

G. Adverse Effects

All patients did not complain of any adverse effect on Day 4 or 8 of follow-up in both treatment groups. The syrup was also found to be acceptable by the children.


CONCLUSIONS

1. Comparison of the effects of lagundi treatment on respiratory rate and frequency of cough showed statistically significant difference by Day 4 based on respiratory rate of the placebo and lagundi groups and decreased frequency of cough with the lagundi treatment vs. placebo when evaluated on Day 8 (p=0.002)

2. Lagundi syrup, at a dose of 45 mg/kg/day, given orally in 3 divided doses 1 hour after each meal resulted in an efficacy rate of 100% based on severity of complaints (frequency of cough) by 1st follow-up visit on Day 4 of therapy. The same favorable response (100%) by Day 4 was attained when the criterion was clinical feelings of improvement.

Placebo treatment effected 92% and 90% improvement on Days 4 and 8, respectively. There was no statistically significant difference based on patient’s assessment of the severity of complaints and findings of improvement over time.

3. Assessment of patient’s response to treatment conducted by the physician showed 84.6% fair to excellent response with placebo and 100% for lagundi on Day 4 and 80% vs. 100% on Day 8 for placebo and lagundi, respectively. However, p-value was above 0.05.

4. At termination of the study, all lagundi patients were deemed completed while 2 of the placebo-treated patients became worse and required antibiotic and expectorant therapy.

5. There were no adverse effects secondary to lagundi treatment for the duration of 8 days administration. The syrup was found acceptable by the children.


Table 3 Distribution of Pediatric patients on their Initial Consultation According
to Duration of Cough, Frequency of Cough, Expectoration of Phlegm
and Difficulty of Breathing

Table 4 A Vital Signs, PEFR and Results of T-test Comparing Placebo and Lagundi at baseline and follow-up Visits

Table 4 B Comparison of Vital Signs, PEFR, Mean Rates at Baseline and During Follow-up Visits within Placebo and Lagundi Groups
PLACEBO LAGUNDI



Table 5 B Comparison of Effects at Baseline and During Follow-up Visits and Results of Fisher Exact Test (See also following graph )





Table 6 Findings on Pulmonary Examination in the Two Treatment Groups at Baseline and Follow-up Visits


Table 8 Physician’s Evaluation of Patient’s Response to Therapy at Follow-up Visits

 

 

 

 

 

 

 

 

 

 

 

 

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