The effect of thriphala, a herbal Ayurveda formulation, on serum lipids, in patients on a maintenance dose of atorvastatin for hyperlipidaemia: a randomized controlled trial

Introduction: Thriphala, a herbal medicinal formulation, is a bedrock of Ayurveda therapeutics with many postulated benefits. Objectives: We performed a clinical trial to test the effects of Swastha Thriphala®, a proprietary preparation of thriphala, on serum lipid parameters in patients receiving atorvastatin. Methods: Consenting adults receiving a maintenance dose of atorvastatin 10mg (Atorlip®) daily from a clinic of the Institute of Cardiology, National Hospital of Sri Lanka for lipid regulation, were randomly assigned, after counselling, to receive either the proprietary herbal medicinal product Swastha Thriphala® (Treatment Group, n= 101) or a placebo (Control Group n= 97), at the stipulated dose daily, for three calendar months. Results: In the treatment group (n=101) the addition of a proprietary preparation of thriphala formulated as caplets of Swastha Thriphala®, in the standard daily dosage for three months, as an adjunct to atorvastatin 10mg, had a significant (p<0.0001) reduction in the mean total blood cholesterol, mean cholesterol/HDL ratio (p<0.0001), and mean non- HDL-cholesterol (p<0.0001) when compared to the Control Group (n=97) receiving placebo caplets in the same daily dose, with atorvastatin 10mg, for the same period. In the Treatment Group mean HDL, LDL, HS-CRP, and triglyceride concentrations showed non-significant reductions, and nonsignificant elevations in the Control Group Conclusions: Swastha Thriphala® when used in the stipulated dosage as an adjunct to atorvastatin 10 mg daily, significantly enhances its cholesterol reducing action in patients. The use of Swastha Thriphala® as single therapy for lipid regulation, and the mode of its action deserve investigation.

The effect of a herbal formulation on the incidence and severity of upper respiratory symptoms in healthy volunteers: an open-label, randomised controlled clinical trial.

INTRODUCTION: Many traditional preparations with varying combinations of herbs have been used for over 1500 years to treat upper respiratory ailments, and reduce their incidence and severity. Link Samahan® is a formulation containing the extract of 14 such medicinal plants. OBJECTIVES: To test the efficacy of Link Samahan® in reducing the incidence and severity of upper respiratory symptoms in consenting healthy volunteers. SETTING: MAS Linea Aqua, a factory with over 3000 employees, having its own health care centre with a qualified matron and visiting medical officers. METHODS: 956 healthy volunteers took daily either one sachet of Link Samahan® in hot water (test group,n=465, mean age 29.5 ± 7.7 years, women 418) or only plain tea (control group n=491, mean age 29.7 ± 7.9, women 448), for 84 consecutive days, and recorded the incidence and severity of 15 upper respiratory symptoms daily in a purpose-designed form. RESULTS: At the end of 84 days, when compared to the control group, the average incidence of symptoms in the test group showed highly significant reductions at p<0.001 for 6 symptoms and at p<0.005 for 3 symptoms,and at p<0.05 for the remaining 6. Reduction of average incidence over time also was highly significant (p<0.001) for 2 symptoms and (p<0.005) for 7, and significant (p<0.05) for 4 symptoms, but only marginal for the balance 2. Severity was significantly reduced (p<0.05) for 7 symptoms, and reduced also for the other 8 according to descriptive analysis, though not significant at the 5% level. CONCLUSIONS: The results indicate that Link Samahan® taken as one sachet daily significantly reduces average incidence, incidence over time, and severity of 15 upper respiratory symptoms in healthy adults.

The use of mid-trial reviews for design modifications in small scale clinical studies.

Many clinical studies such as those in the areas of toxicology, early phase clinical trials and bioequivalence studies use small samples due to the high cost of experimentation. These studies test hypotheses based on small samples. These small samples result in low power and therefore even if the alternative hypotheses may be true the chance of it being rejected is low. The sample size is determined in an ad-hoc way and no proper scientific approach is used. Sample size calculations for clinical studies are usually conducted to determine the total number of patients needed to satisfy a specified power requirement, and their validity is dependent on pre-trial knowledge of nuisance parameters and distributional and modelling assumptions. Another short coming is that often hypotheses are tested without checking the assumptions required by the test. This paper looks at design reviews in the context of small samples. It examines several design modifications done with a small internal pilot study. In the past similar techniques have been applied to large scale studies but its performance is yet to be established in small scale clinical studies thus the contribution of this paper is in justifying the validity of these techniques for small samples too. The methodology is illustrated on an uncontrolled observational toxicology study. In this paper simulations will be presented showing that the design modifications would not influence the type-I error rate and that these would be successful in preserving the power, and the implementation of the design review procedure will be described.

Mid-trial design reviews for sequential clinical trials.

When sequential clinical trials are conducted by plotting a statistic measuring treatment difference against another measuring information, power is guaranteed regardless of nuisance parameters. However, values need to be assigned to nuisance parameters in order to gain an impression of the sample size distribution. Each interim analysis provides an opportunity to re-evaluate the relationship between sample size and information. In this paper we discuss such mid-trial design reviews. In the special cases of trials with a relatively short recruitment phase followed by a longer period of follow-up, and of normally distributed responses, mid-trial design reviews are particularly important. Examples are given of the various situations considered, and extensive simulations are reported demonstrating the validity of the review procedure in the case of normally distributed responses.

A method for sequential analysis of survival data with nonproportional hazards.

Two tests are proposed for comparing the survival curves of patients randomised between an experimental treatment and a control treatment when it is anticipated that the two survival curves may not satisfy the assumption of proportional hazards. The tests are particularly useful for the situation in which the survival curves are coincident or cross over early in the follow-up period and then diverge. The tests compare the probabilities of survival for longer than some fixed time since randomisation for the two groups of patients. Both methods take account of the right-censored observations, and both are associated with methods for estimating and setting confidence limits for treatment differences. The first method is a mathematically direct approach based on the derivation of the efficient score statistic and Fisher's information. The second method is simpler, being based on Kaplan-Meier estimates and their variances. Conventional methods of sample size determination require the assumption of proportional hazards. Here a sequential approach is used, as it is difficult to set the sample size in advance without strong assumptions about the relationship between the two survival curves. Simulation results giving information on the size and power of the proposed tests are provided and the tests are applied to data from a clinical trial in breast cancer.

Sample size review in a head injury trial with ordered categorical responses.

Between 1993 and 1996, a total of 452 patients were entered into a randomized trial evaluating eliprodil (a non-competitive NMDA receptor antagonist) in patients suffering from severe head injury. The primary efficacy analysis concerned the Glasgow Outcome Score (GOS), six months after randomization. This outcome was classified into three ordered categories: good recovery; moderate disability, and the worst category made up by combining severe disability, vegetative state and dead. A sample size calculation was performed prior to the commencement of the study, using a formula which depends on the anticipated proportions of patients in the three different outcome categories, the proportional odds assumption and on the relationship between outcome and prognostic factors such as Glasgow Coma Score at entry. Owing to uncertainty about the influence of prognostic factors, and about the proportion of patients in the three GOS categories, a blinded sample size review was planned. This review was performed on the basis of the first 93 patients to respond, and this led to an increase in the sample size from 400 to 450. In this paper the pre-trial simulations showing that the type I error rate would be influenced and the power would be preserved will be presented, and the implementation of the procedure will be described.