Introduction

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A thorough evaluation of homoeopathic treatment for asthma is needed because homoeopathy is increasing in popularity ^{1 2} and because uncontrolled studies (without placebo control) have reported that such treatments are efficacious. ^{3 4} Several organisations have called for further research. ^{5 6} A recent review of the limited number of placebo controlled homoeopathic clinical trials in general concluded that the effects of treatment cannot be attributed entirely to a placebo response but that there was insufficient evidence to support the use of homoeopathic treatment for any single disease.⁷

We examined the clinical efficacy of homoeopathic potencies of house dust mite (homoeopathic immunotherapy) in asthmatic people allergic to house dust mite with a placebo controlled, randomised, double blind trial to evaluate whether we could differentiate between homoeopathy and placebo using homoeopathic immunotherapy as a model.^8-10

	Methods

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Design
The study took place from September to April (outside the pollen season). After a run-in period of four weeks participants received homoeopathic immunotherapy or placebo orally on three occasions over 24 hours. We then assessed participants for 16 weeks.

We collected data on clinic assessments at the start and end of the run-in period (that is, at randomisation) and at the start of the sixth, 12th, and 16th week after randomisation. Participants completed diaries in the first and third weeks of run-in (two diaries of seven days) and in the first and every other week (eight diaries of seven days) after randomisation. Concurrent medication for all disorders, including asthma, was unchanged. Any participants who needed oral corticosteroids were withdrawn from the study and any available data used in the intention to treat analysis.

Recruitment of participants
We received lists of patients with asthma from 38 general practices. We wrote to those aged 18-55 years on headed notepaper from each practice. If patients did not respond to the first letter we sent a reminder letter. Over 1000 patients subsequently underwent skin prick tests for nine common allergens. Those eligible and prepared to consent to this prolonged clinical trial were then entered into the baseline recording period. Throughout the study all participants were seen in their own general practitioner's surgery. We included only those people with a positive result to house dust mite (wheal diameter 3 mm greater than the negative control 15 minutes after test) that was greater than for other aeroallergen extracts tested.

We considered patients to have asthma if they had a 15% improvement in forced expiratory volume in one second (FEV₁) or peak expiratory flow 15 minutes after a 200 µg inhalation of salbutamol before randomisation and two of three criteria of an asthma symptom diary score of >1 (that is, any activity limited by asthma) on at least seven of the 14 baseline days during the run-in period or a diurnal variation in peak expiratory flow of >15% on at least seven of the 14 baseline days or need for inhaled salbutamol on at least seven of the 14 baseline days.

View larger version (44K): [in this window] [in a new window]   Fig 1.   Patients entered, randomised, and withdrawn from trial

Some variability in the participants' asthma was essential if we were to observe improvement or deterioration during the trial. We excluded participants if they recorded no impairment in quality of life in their diaries during the run-in period or if they filled in their diaries on fewer than 10 days during that period. We also excluded participants if they had taken part in another drug trial within the previous 30 days, had previously been treated with homoeopathic immunotherapy, were pregnant or lactating, were unlikely to comply with the trial requirements, had experienced a respiratory tract infection within the last three weeks, or had changed their concurrent medication in the two weeks before entry.

Treatment, blinding, and randomisation
Homoeopathic immunotherapy and placebo were prepared by Laboratoire Boiron, Lyons, France, using the same method of multiple dilutions with shaking (homoeopathic potentisation) to produce an ultramolecular dose of house dust mite as a 30C potency (30 dilutions of 1:100) as described by Reilly et al.⁸ The placebo was made with the same method of dilution but without the house dust mite. The indistinguishable preparations were sent directly to the pharmacy at Southampton General Hospital, along with a sealed code indicating which package contained active or placebo treatment. The vials were stored in a secure area in accordance with the standard operating procedures of good clinical practice. The individual treatment vials were recoded as A or B by an independent researcher not involved with the study and not aware whether a vial contained active or placebo treatment.

We randomised the first 10 participants to treatment A or to B using a sealed envelope. All subsequent participants were allocated to A or B by a process of minimisation according to age, sex, smoking status, and severity of asthma, with severity assessed from the diaries (see below). The participants and research nurses recorded whether treatment A or B had been given the day after dosing. The randomisation codes were broken only after the study had been completed.

Measures
We recorded measures taken in the clinic and those noted by the participant on diary cards.

Clinic based measures
At baseline we recorded results of skin prick tests, concentration of total serum IgE, concentration of IgE specific for house dust mite, the participant's attitude to complementary and alternative medicine, ^{11 12} and results of routine blood screening for undetected systemic illness. As a check for blinding, one day after randomisation we asked participants and investigators separately to guess whether the treatment was homoeopathic immunotherapy or placebo. At randomisation we recorded FEV₁ as the maximum of three blows. We calculated predicted FEV₁ from standard tables.¹³ At randomisation and during clinic visits after treatment participants completed questionnaires on negative and positive trait mood^14-16 and quality of life specific to asthma (the asthma bother profile).¹⁷

Diary measures
In the diaries participants recorded morning and evening peak expiratory flow as the best of three attempts; perceived asthma severity on a visual analogue scale with high scores indicating worse asthma; and perceived mood on a bipolar scale with high scores indicating better mood. We calculated mean scores for the run-in period and for each of the eight weeks of assessment after randomisation. We calculated variability in mood by the variance of mood within each participant in each of the assessment periods and variability in peak expiratory flow by taking the difference between previous evening and morning peak expiratory flow and dividing by previous evening peak expiratory flow multiplied by 100.¹⁸

	Results

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Sample characteristics at baseline and blinding.
Figure 1 shows details of participant flow. Diary completion decreased over the course of the study, and only 186 participants completed all diary assessments. Those who withdrew from the study were more troubled by their asthma (P=0.033), had worse scores on the visual analogue scale (P=0.048), and had worse morning peak flows (P=0.042) at baseline. No participant reported an adverse drug reaction due to homoeopathic immunotherapy during the course of the study.

Baseline details of the two groups were similar (table). Forty six participants were not taking inhaled steroids (25 in the homoeopathy group and 21 in the placebo group). Neither participants nor investigators were better than chance at guessing treatment (114 (47%) participants and 116 (48%) investigators guessed correctly).

Clinical efficacy of homoeopathy
There was a significant increase from baseline in FEV₁ (P=0.006) and a significant decrease in asthma bother score (P=0.001) in both groups. There were also significant improvements in many of the diary measures. However, there was no significant difference between the groups in either of the two primary outcome variables. Improvement in FEV₁ from baseline was 0.414 l/sec for placebo and 0.136 l/sec for active treatment (95% confidence interval for difference 0.136 to 0.693), and mean improvement for diary quality of life was 0.117 for placebo and 0.090 for active treatment (0.096 to 0.150). There were no significant differences for any of the secondary outcome variables at the end of the study. Figure 2 shows mean values over time of testing.

View larger version (43K): [in this window] [in a new window]   Fig 2.   Variables measured at clinic visits (FEV1) and from diaries (asthma visual analogue score (VAS), peak expiratory flow (PEF), mood, symptoms, use of bronchodilator). Error bars for each graph are same because of method of analysis used. Baseline figures are averages of two recordings for each variable

Diary assessments

Secondary statistical analysis
We found significant interactions between the treatments and week of assessment for three secondary outcome variables (morning peak expiratory flow (P=0.025); asthma visual analogue scale (P=0.017); mood (P=0.035)), indicating differences between the two groups over the course of the study. There were no significant differences for the remaining variables. As the data for mood variability and bronchodilator use deviated from criteria for parametric testing (no suitable transformation was found) the inference of non-significance in these two cases may be invalid. There was no evidence of significant change in bronchodilator use in either group, although participants in the homoeopathy group were using less bronchodilator than the placebo group in the last four weeks of the study. There was no evidence that homoeopathic immunotherapy was better at treating asthma than placebo. There was no significant correlation between attitudes to complementary and alternative medicine and improvement on any of the outcome variables.

	Discussion

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This randomised placebo controlled trail shows that homoeopathic immunotherapy is no better than placebo for the treatment of people with asthma who are allergic to house dust mite. Previous studies have suggested that homoeopathy is efficacious in the treatment of rhinitis and possibly asthma. ^{8 9 20} Our study was substantially larger than any of the earlier studies and included a wider range of outcome measures. We found no evidence of difference measures between placebo and homoeopathy in our primary outcome at the end of the study but in both arms there were large treatment effects. This "trial effect" remains unexplained.

Although there was some evidence of difference between treatments during the course of the study in three outcome variables from the diaries, these results should be treated with caution. Overall, differences between the treatments failed to achieve significance. However, there was a different pattern of response within the homoeopathy group, characterised by alternating deterioration and improvement. This pattern is inconsistent with homoeopathic theory and with previous reports of data in related studies, in which there was aggravation of symptoms or mid-study improvement. ^{9 10 21} The cause of this significant oscillating pattern is unknown, but we cannot exclude a type 1 error arising from the use of the multiple outcome variables.

We used a similar homoeopathic intervention to that used in an earlier asthma study and used the same outcome variable that previously indicated a significant difference (that is, visual analogue scale).⁸ Although we measured diary outcome on only alternate weeks, it is unlikely that this could explain the difference between results. Perhaps differences in patient recruitment or other unknown factors may explain the inconsistency of the results between these two studies.

The purpose of clinical trials involving homoeopathic immunotherapy has been to demonstrate differences between homoeopathic immunotherapy, involving ultramolecular homoeopathic dilutions, and placebo rather than to prove its clinical efficacy.²¹ We did not observe the same response as that described by Reilly et al and Taylor et al, but there were some differences between homoeopathic immunotherapy and placebo for which we have no explanation. ^{8 9 20} In conclusion, in this double blind, randomised controlled trial of homoeopathic immunotherapy we have failed to confirm that this treatment is therapeutically efficacious in allergic asthma in an assessment that used previously validated objective and subjective outcome measures.

	Acknowledgments

We thank the general practices involved; the doctors who helped us to screen patients for the study; Lorraine Low, Philip Prescott, and Michael Campbell for their statistical input; David Coggon for his advice on the manuscript; Jackie Burnham for her secretarial and administrative help; and Philippe Belon of Boiron for the homoeopathic medicines and placebo. We also thank the medical homoeopathic research community, in particular David Reilly from Glasgow.

Contributors: See bmj.com

	Footnotes

Funding: Smith's Charity, NHS Executive South and West Research and Development Directorate, Boiron. GTL's post is funded by a grant from the Maurice Laing Foundation.

Competing interests: None declared.

The full version of this article appears on bmj.com

	References

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1.	National Association of Health Authorities and Trusts. Complementary therapies in the NHS. Birmingham: NAHAT, 1993 (research paper 10).
2.	Fisher P, Ward A. Complementary medicine in Europe. BMJ 1994; 309: 107-111[Full Text].
3.	Eizayaga FX, Eizayage J, Eizayaga F. Homoeopathic treatment of bronchial asthma. Br Homeopath J 1996; 85: 28-33.
4.	Nolleveaux MA. Interet de la prescription d'APP (Apis 15 cH, Pulmo-Histaminum 15 cH, Pollantinum 30 cH) dans la rhinite allergique. Observations cliniques en pratique journaliere. Homeopathie Francaise 1992; 80: 24-33.
5.	Office of Technology Assessment. Unconventional cancer treatments. Washington DC: Government Printing Office, 1990 (OTA-H-405).
6.	House of Lords Select Committee on Science and Technology. Complementary and alternative medicine. 6th report. London: Science and Technology Committee Publications, 2000.
7.	Linde K, Clausius N, Ramirez G, Melchart D, Eitel F, Hedges LV, et al. Are the clinical effects of homoeopathy placebo effects? A meta-analysis of placebo-controlled trials. Lancet 1997; 350: 834-843[Medline].
8.	Reilly D, Taylor MA, Beattie NGM, Campbell JH, McSharry C, Aitchison TC, et al. Is evidence for homoeopathy reproducible? Lancet 1994; 344: 1601-1606[Medline].
9.	Reilly DT, Taylor MA, McSharry C, Aitchison T. Is homoeopathy a placebo response? Controlled trial of homoeopathic potency, with pollen in hayfever as model. Lancet 1986; 2: 881-886[Medline].
10.	Homoeopathy versus placebo in perennial allergic rhinitis [letters]. BMJ 2001; 322: 169-171.
11.	Finnigan MD. Complementary medicine: attitudes and expectations, a scale for evaluation. Complement Med Res 1991; 5: 79-82.
12.	Finnigan MD. The Centre for the Study of Complementary Medicine: an attempt to understand its popularity through psychological, demographic and operational criteria. Complement Med Res 1991; 5: 83-87.
13.	Working party of the European Community for Coal and Steel. "Standardization of lung function tests": predicted values for lung function. Bull Eur Physiopathol Respir 1983; 19(suppl 5): 1-23.
14.	Watson D, Clark LA, Tellegen A. Development and validation of brief measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol 1988; 54: 1063-1070[Medline].
15.	Watson D, Tellegen A. Toward a consensual structure of mood. Psychol Bull 1985; 98: 219-235[Medline].
16.	Watson D. Intraindividual and interindividual analyses of positive and negative affect: their relation to health complaints, perceived stress, and daily activities. J Pers Soc Psychol 1988; 54: 1020-1030[Medline].
17.	Hyland ME, Ley A, Fisher DW, Woodward V. Measurement of psychological distress in asthma and asthma management programmes. Br J Clin Psychol 1995; 34: 601-611[Medline].
18.	Higgins BG, Britton JR, Chinn S, Cooper S, Burney PGJ, Tattersfield AE. Comparison of bronchial reactivity and peak expiratory flow variability measurements for epidemiologic studies. Am Rev Respir Dis 1992; 145: 588-593[Medline].
19.	Hyland ME, Crocker GR. Validation of an asthma quality of life diary in a clinical trial. Thorax 1995; 50: 724-730[Abstract].
20.	Taylor MA, Reilly D, Llewellyn-Jones RH, McSharry C, Aitchison TC, Lancaster T, et al. Randomised controlled trial of homoeopathy versus placebo in perennial allergic rhinitis with overview of four trial series. BMJ 2000; 321: 471-476[Abstract/Full Text].
21.	Aabel S. No beneficial effect of isopathic prophylactic treatment for birch pollen allergy during a low-pollen season: a double-blind, placebo-controlled clinical trial of homeopathic Betula 30c. Br Homeopath J 2000; 89: 169-173[Medline].

(Accepted 27 September 2001)