NHR Oct-Dec 2018: Original Research: An open-label randomized pragmatic exploratory pilot trial to compare the effectiveness of Echinacea angustifolia 200cH against individualized homoeopathic medicines in hypothyroidism

An open-label randomized pragmatic exploratory pilot trial to compare the effectiveness of Echinacea angustifolia 200cH against individualized homoeopathic medicines in hypothyroidism


Ruma Debbarma*1, Chintamani Nayak2, Abhijit Chattopadhyay3

  1. Postgraduate Trainee, Dept. of Homoeopathic Materia Medica, National Institute of Homoeopathy, Govt. of India
  2. Lecturer, Dept. of Homoeopathic Materia Medica, National Institute of Homoeopathy, Govt. of India
  3. Professor and Head, Dept. of Homoeopathic Materia Medica, National Institute of Homoeopathy, Govt. of India

*Correspondence: rdebbarma45@gmail.com


Abstract

Background: Thyroid disorders are common across the world and also in India. Among these, hypothyroidism is one of the commonest. In hypothyroidism, deficiency of thyroid hormones occur which produces various signs and symptoms. Homoeopathic medicines are claimed to have promising treatment effect in hypothyroidism. Homoeopathic medicine Echinacea angustifolia (EA) has its probable effect on thyroid gland, but its action on hypothyroidism has not yet been evaluated systematically. We aimed to compare the effectiveness of EA 200cH against individualized homoeopathy (IH) in treatment of hypothyroidism.

Method: An open-label, randomized (1:1), two parallel arms, exploratory, pilot pragmatic trial was conducted on 40 hypothyroid patients. Blood T3, T4 and TSH were used as the outcome measures; and were assessed at baseline and after 3 months. Comparative analysis was done on the protocol-compliant sample to detect group differences.

Results: Groups were comparable at baseline (all P > 0.01). After 3 months of intervention, all the outcome measures changed significantly in both the groups (all P < 0.01). Though the changes were higher in the IH group, there were no significant group differences after 3 months (all P > 0.01) of treatment.

Conclusion: Both treatments seemed to be equally effective. Further rigorous independent replications are warranted.

Keywords: Homoeopathy; Echinacea angustifolia; Hypothyroidism; Randomized controlled trial


INTRODUCTION

Thyroid diseases are common worldwide. In India too, there is a significant burden of thyroid diseases. According to a projection from various studies on thyroid diseases, it has been estimated that about 42 million people in India suffer from thyroid disorders. The common thyroid diseases in India are hypothyroidism, hyperthyroidism, goiter and iodine deficiency disorders, Hashimoto’s thyroiditis, and thyroid cancer [1]. In hypothyroidism, there is an impaired production of thyroid hormones which is usually due to a primary abnormality of thyroid gland or iodine deficiency; occasionally it is secondary to pituitary or hypothalamic disorders. When the TSH is elevated and the free thyroid hormone levels are normal this state is subclinical hypothyroidism [2]. The symptomatology includes tiredness, weakness, dry skin, feeling cold, hair loss, difficult concentration and poor memory, constipation, weight gain with poor appetite,  dyspnea, hoarse voice, menorrhagia (later oligomenorrhoea or amenorrhoea), paresthesia,  impaired hearing, dry coarse skin, cold peripheral extremities puffy face, hands and feet (myxedema), diffuse alopecia, bradycardia, peripheral oedema, delayed tendon reflex relaxation, carpal tunnel syndrome, and serous cavity effusions [3]. The prevalence of hypothyroidism in India is 11%, compared with only 2% in the UK and 4·6% in the USA [4]. Among the adult population in India, the prevalence of hypothyroidism is 3.9%. Subclinical hypothyroidism is also as high as 9.4%. In women, the prevalence is even higher, at 11.4%, when compared with men, in whom the prevalence is 6.2% [1]. The highest prevalence of hypothyroidism (13·1%) is noted in people aged 46-54 years, with people aged 18-35 years being less affected (7·5%) [4]. Among all the cities in India, Kolkata recorded the highest prevalence of hypothyroidism (21.67%), while others showed comparable ranging from 8.88% (Hyderabad) to 11.07% (Delhi) [5]. The standard treatment of hypothyroidism is hormone replacement therapy with levothyroxine sodium (LT4) [6].

The homoeopathic literature is having examples of successful treatment of thyroid diseases; but has remained mostly anecdotal as evidence by paucity of published peer-reviewed research papers. A double blind, randomized, placebo-controlled trial was conducted to evaluate whether an ultra-molecular dilution of homoeopathic medicine Thyroidinum 30cH has an effect over placebo on weight reduction in fasting patients in so-called ‘fasting crisis’. It was found that patients receiving verum had less weight reduction on day 2 after treatment than those receiving placebo. However, no significant differences were found in other outcomes [7]. In an exploratory, randomized, placebo controlled, two parallel arms, single blind trial involving 194 children suffering from subclinical hypothyroidism (SCH) with or without autoimmune thyroiditis (AIT), statistically significant decline in serum TSH values and antiTPOab titers was observed indicating that the homoeopathic intervention had not only the potential to treat SCH with or without antiTPOab but might also prevent progression to overt hypothyroidism [8]. Two non peer-reviewed papers were also identified; one suggesting homoeopathic medicine Natrum muriaticum [9] and another suggested various IH medicines [10] as effective therapy of hypothyroidism. We hypothesized that the homoeopathic medicine Echinacea angustifolia (EA) 200cH, selected on the basis of common symptoms could produce equivalent treatment effect to individualized homoeopathic medicines (IH), based on characteristic symptoms in hypothyroidism.

METHODS

Trial design: This open-label, randomized, prospective, exploratory, pilot, pragmatic, two parallel arms clinical trial was conducted at the Homoeopathic Materia Medica out-patient departments of National Institute of Homoeopathy (NIH). Institutional Ethical Committee (IEC) approved the protocol [Ref. No. 5-023/NIH/PG/Ethical Comm. 2009/Vol. III/1977 (A/S); dated March 27, 2017]. The trial protocol (unpublished) and full dissertation was submitted as the postgraduate thesis of the corresponding author to The West Bengal University of Health Sciences.

Participants: Inclusion criteria were the patients suffering from primary hypothyroidism (ICD 10 code E03.9) and symptomatic for at least last 3 months, both sexes, age 10-65 years, and patients willing to participate in the study and giving written informed consent. Exclusion criteria were the patients suffering from suspected or diagnosed thyroid malignancy, overt hypothyroidism, patients who were too unwell to take part, inability to read patient information sheets and/or denied consent to take part, diagnosed cases of unstable psychiatric complaints or other systemic diseases affecting quality of life, currently receiving standard therapy for hypothyroidism and/or homoeopathic treatment for any chronic condition(s), pregnant and lactating women, self-reported immune compromised conditions, and substance abuse and/or dependence.

Intervention: Each dose was consisted of 4 cane globules no. 30, moistened adequately with EA 200cH, kept preserved in 90% v/v ethanol. Repetition was dependent upon individual requirement of the cases and as judged appropriate by the homoeopaths. The medicine was obtained from a Good Manufacturing Practice (GMP) certified firm – SBL Pvt. Ltd. The medicine was directed to be taken orally on clean tongue with empty stomach. Such intervention continued for 3 months. The participants were assessed by the three homoeopaths every month in every follow-up. Irrespective of the allocated codes, provision was kept for prescribing ‘acute medicines’ based on ‘acute totality’ to meet adverse or serious adverse events as per homoeopathic principles.

Control: Control was planned as administering individualized homoeopathic medicines in centesimal scale potencies as detailed above and in individualized dosage, as decided appropriate to the case or condition. As in the experimental arm, instructions were given to take each dose orally on clean tongue with empty stomach. Duration of treatment was 3 months. On each occasion, single individualized medicine was prescribed considering symptom totality, clinical history details, constitutional traits, miasmatic features, repertorization as and when required, consultation with Materia Medica, and agreement among the three prescribing homoeopaths. Individualized dose was used based on the three homoeopaths’ judgment of susceptibility and agreement. Subsequent prescriptions were produced in accord with Kent’s observations and Hering’s law. Two of the prescribers possessed masters’ degree in homoeopathy and had been practicing ‘classical’ homoeopathy for more than 20 years. The corresponding author was a postgraduate trainee at NIH with 2 years of experience. All the homoeopaths involved were affiliated with respective state councils.

Outcomes: Blood thyroid profile – T3, T4 and TSH, measured at baseline and after 3 months.

Sample size: Formal effect size calculation was not possible on account of absence of any open randomized trial on hypothyroidism comparing effectiveness of EA with IH. As the designed trial was equivalence or non-inferior in type, and EA was considered as one of the recommended homoeopathic medicines for the said condition, we presumed very small difference and small effect size in favor of either of the therapies and considered both the therapeutic options as equally effective (H0). Hence assuming a small effect size (d) of 0.1, and fixing α at 0.01, power (1 – β) = 80% (minimum recommended) and allocation ratio of 1.1, in order to identify a significant difference between two independent means of muscle strength grading scores (primary outcome measure) of the two groups by unpaired t test (two tailed), we would have required 3142 patients, i.e. 1571 in each arm. However, keeping in mind the exploratory nature of the trial, feasibility issues, and time constraints, we targeted to achieve 46 patients, i.e. 23 in each arm. Given β/α ratio of 4, effect size of 0.1 and sample size of 23 in each arm, post hoc analysis revealed a compromised power (1-β) = 22%. The final analysis was restricted on the protocol-compliant sample (n=40) only; thus further compromising the study power up to 21.7%. This indicated the need for cautious interpretation while extrapolating the results to general population.

Randomization: Intervention (EA) or comparator (IH) was implemented as per the random number chart created by using the random number generator at StatTrek. The chart was generated using 4 blocks of size restricted to 10 (4 × 10 = 40) plus another block of size 6 to maintain alike allocation between groups and 1:1 ratio easily; thus the same numbers of patients were randomized to either code 1 or 2, either of intervention or control.

Blinding: The prescribing homoeopaths and the patients – both were aware (i.e. open-label) of the generated allocation codes all through the study. Allocated codes were maintained till the end of the trial. This open list of random numbers with allocated codes was made available with the pharmacist, and he was instructed for dispensing of either EA or IH to the patients according to the chart.

Statistical methods: The protocol-compliant sample was analyzed in the end. Both descriptive and inferential statistics were applied. Baseline comparability of the groups was tested using chi-square (for categorical data) or unpaired t test (for continuous data). Outcome data obtained at baseline and after 3 months were compared by paired t test. Mean group differences after 3 months were compared by unpaired t test. P values for two-tailed tests were set at less than 0.01 as statistically significant. No interim and subgroup analyses were planned. Statistical Package for the Social Sciences, version 20 (IBM Corp., IBM SPSS Statistics for Windows, Armonk, NY:USA) was used for statistical analysis of data. Reporting adhered to the CONSORT [11] and RedHot [12] guidelines for reporting trials, Mathie’s criteria for evaluating the model validity of homoeopathic treatment [13, 14] (MVHT) and Saha’s criteria for reporting quality of individualization in clinical trials of homoeopathy [15].

RESULTS

Study flow: As per the pre-specified inclusion and exclusion criteria, 73 patients suffering from primary hypothyroidism were screened; 27 were excluded on account of various reasons; 46 met the eligibility criteria and were enrolled into the trial. Following that, baseline socio-demographic and outcome data were obtained and were randomized to either EA (n=23) or IH (n=23). After 3 months of intervention, outcome data were recorded again. During course of treatment, 6 dropped out (3 in each group); 40 completed the trial and entered into the analysis. (Figure 1)

Figure 1: Study flow diagram

 Recruitment: The study continued for 15 months; started in April 2017 and continued up to June 2018.

Baseline data: Distribution of socio-demographics features including age, gender, residence, religion, and socio-economic status were similar between the EA and IH group (all P > 0.01, Table 1) ensuring comparability of the two groups. Distribution of the outcome measures at baseline was also similar between the two groups with no significant differences (all P > 0.01). It implied that the groups were comparable at baseline. (Table 2)

Numbers analyzed: Outcomes from 20/23 from each group was complete respectively; rest dropped out of the trial. Only the protocol-compliant patients (i.e. 20 in each group) entered into the final analyses.

Outcomes and estimation:

  • Within group changes over 3 months: All the outcomes in both the groups showed statistically significant improvement except T4 in the EA group. (Tables 3 and 4)
  • Group differences over 3 months: Though the intra-group changes were higher in the IH group over the EA group, still there were no significant group differences in any of the outcomes (all P > 0.01) (Table 5)

Table 1: Socio-demographic features of the participants at baseline (N=40)

Characteristics EA group (n=20);

n (%)

IH group (n=20); n (%) P value
Age groups (yrs):

  •   11 – 20
  •  21 – 30
  •  31 – 40
  •  41 – 50
  •   51 – 60
3 (15)

2 (10)

9 (45)

5 (25)

1 (5)

2 (10)

6 (30)

9 (45)

2 (10

1 (5)

0.480
Gender:

  •  Male
  •  Female
2 (10)

18 (90)

3 (15)

17 (85)

0.632
Residence:

  • Urban
  • Rural
8 (40)

12 (60)

7 (35)

13 (65)

0.744
Religion

  •  Hindu
  •  Islam
13 (65)

7 (35)

5 (25)

15 (75)

0.011
Socio-economic status

  • Lower class
  • Middle class
  • Upper class
5 (25)

14 (70)

1 (5)

5 (25)

14 (70)

1 (5)

1.000

Chi-square test; P values less than 0.01 considered as statistically significant

Table 2: Distribution of thyroid profile at baseline (N=40)

Outcomes EA group (n=20) IH group (n=20) Mean difference ±SE (95% CI) P value
TSH 14.3 (10.3) 16.7 (9.3) 2.4 ± 3.1 (-3.9 to 8.7) 0.442
T3 78.6 (29.9) 83.4 (23.9) 4.7 ± 8.6 (-12.7 to 22.0) 0.587
T4 5.2 (1.9) 5.6 (1.7) 0.4 ± 0.6 (-0.7 to 1.5) 0.491

Unpaired t test; P less than 0.01 two-tailed considered as statistically significant

Table 3: Intra-group changes in the EA group (n=20)

Outcomes Pre-treatment; mean (sd) Post-treatment; mean (sd) Change; mean (95% CI) P value
TSH 14.3 (10.3) 9.5 (5.2) 4.8 (0.7 to 8.9) < 0.001*
T3 78.6 (29.9) 86.0 (27.7) -7.4 (12.7 to -2.0) 0.009*
T4 5.2 (1.9) 5.9 (1.8) -0.7 (-1.4 to -0.0) 0.043

*Paired t test; P values less than 0.01 two-tailed considered as statistically significant

Table 4: Intra-group changes in the IH group (n=20)

Outcomes Pre-treatment; mean (sd) Post-treatment; mean (sd) Change; mean (95% CI) P value
TSH 16.7 (9.3) 9.2 (5.8) 7.5 (4.7 to 10.3) < 0.001*
T3 83.4 (23.9) 96.2 (28.7) -12.8 (18.5 to -7.1) < 0.001*
T4 5.6 (1.7) 6.8 (2.0) -1.2 (-1.6 to -.8) < 0.001*

*Paired t test; P values less than 0.01 two-tailed considered as statistically significant

Table 5: Group differences after 3 months of treatment (N=40)

Outcomes Post-test values in EA group (n=20) Post-test values in IH group (n=20) Mean difference ± SE

(95% CI)

P value
TSH 9.5 (5.2) 9.2 (5.8) -0.2 ± 1.7 (-3.8 to 3.3) 0.891
T3 86.0 (27.7) 96.2 (28.7) 10.2 ± 8.9 (-7.9 to 28.3) 0.260
T4 5.9 (1.8) 6.8 (2.0) 0.8 ± 0.6 (-0.4 to 2.1) 0.175

Unpaired t test; P less than 0.01 two-tailed considered as statistically significant

 

 

 

Medicines used in the IH group: The most frequently indicated medicines in the IH group were Natrium muriaticum (n=4, 20%), Calcarea carbonica and Sulphur (n=3 each, 15%), Medorrhinum and Thuja occidentalis (n=2 each, 10%), and Ignatia amara, Lachesis mutans, Lycopodium clavatum, Spongia tosta, Pulsatilla nigricans, and Sepia succus (n=1 each, 5%).

Adverse events: No harms, unintended effects, serious adverse events, and untoward homoeopathic aggravations were reported from either group during the study period.

DISCUSSION

Empirically selected EA seemed to be non-inferior and equally effective to IH in treatment of hypothyroidism, as evidenced from blood thyroid profile T3, T4, and TSH; however, the trial being underpowered, cautious interpretation is warranted. Further exploration is necessary.

One of the major strengths of the study was randomization; i.e. each number had the same chance of being allocated to either of the two arms. It was a “gold standard” for proof of efficacy/effectiveness. The advantages of randomization included equipoise across groups, enhanced internal validity due to homogenous study groups, minimized selection bias, unbiased allocation, generation of two comparable groups, balancing among possible confounders, facilitating simple analysis, and to declare evidently that the difference was because of the treatment. Prospective study design allowed causal inference to be drawn. No placebo control was used; rather all the randomized patients received medicine – either EA or IH. Hence, ethically the study was less vulnerable. In the study design, we kept provision for pair-wise comparisons using rigorous parametric tests, namely t test.

The study was the very first of its kind in homoeopathy; hence exploratory in nature. Effect size could not be calculated on account of absence of any study of similar design; hence sample size was based on assumption only. The trial was open; no blinding was used. Thus, patient selection bias, treatment assignment bias, patient evaluation bias, and data analysis bias may have affected the outcomes of the study. Duration of follow-up of 3 months might be considered as insufficient in hypothyroidism. The two trial arms had no significant difference at baseline ensuring comparability; still the difference in distribution of religion reached near significance (P = 0.011), so adjusted analysis would have been more appropriate. Besides, our analysis was restricted to protocol-compliant sample only. Imputation of missing values using appropriate statistical techniques and an intention-to-treat analysis would have generated more proper results than this. Further studies are suggested on similar or more rigorous design with validated clinical scoring system and questionnaire focusing on quality of life issues.

CONCLUSION

This prospective, open, randomized, two parallel arms, exploratory, pilot, pragmatic trial was carried out at National Institute of Homoeopathy, India on 40 patients suffering from primary hypothyroidism. Over 3 months of intervention, blood thyroid profile improved significantly in both the EA and IH groups without any significant differences in between, suggesting EA as an equally effective treatment option as that of IH in hypothyroidism. However, being an underpowered trial, results should be interpreted cautiously and further research in multi-centric design is required on larger sample size before making any firm recommendations.

Conflict of interest statement: The authors declare that they have no competing interests. The trial was carried out as the postgraduate thesis of the corresponding author under guidance of CN and AC, who were permanent teaching faculty of the institute.

Funding: We received no funding for the study. Funding required for the project was borne by the authors themselves.

Authors’ contributions: RD and CN conceived and designed the study. RD, CN and AC collected data. CN ran the statistical analyses and interpreted the data. RD prepared the manuscript. All the authors reviewed and approved the final manuscript.

Acknowledgements: We thank Dr. Subhranil Saha, Independent Researcher for his valuable inputs in statistical analysis and drafting of the manuscript. The authors are grateful to institutional heads, both academic and hospital section for their cooperation. We thank the fellow postgraduate trainees, staff, pharmacists, and the patients for their sincere participation in the study.

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Cite this article as: Debbarma R, Nayak C, Chattopadhyay A. An open-label randomized pragmatic exploratory pilot trial to compare the effectiveness of Echinacea angustifolia 200cH against individualized homoeopathic medicines in hypothyroidism. National Homoeo Recorder 2018;14(4):17-24.

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