Study Design
A randomized, partially double-blind, placebo-controlled, four-armed trial using a 2 × 2 factorial design with a six week study duration per patient will be performed to test two different hypotheses:
H0: homeopathic medicines = placebo (null hypothesis) vs. H1: homeopathic medicines ≠ placebo (alternative hypothesis)
H0: homeopathic case history type I = case history type II (null hypothesis) vs.H1: homeopathic case history type I ≠ case history type II (alternative hypothesis)
To test these hypotheses, patients will be randomized to one of four groups illustrated in Figure 1.
Participants
We will include male and female patients aged between 18 and 65 years diagnosed with moderately severe (HAM-D 17 to 24) major depression by a psychiatrist, patients must not be currently taking antidepressants or anxiolytic drugs (with the exception of Lorazepam as rescue medication, maximal dose 1.5 mg/day). Capability and willingness to give informed consent and to comply with the study procedures will also be required.
Exclusion criteria include current mild episode of depression (HAM-D < 17), current severe episode of depression (HAM-D > 24); schizophrenia or other psychotic disorders, bipolar affective disorder, schizoaffective disorders, alcohol or other substance abuse, eating disorders, a clinically significant (Diagnostic and Statistical Manual of Mental Disorders)-Axis II disorder; severe depression, which previously motivated a suicide attempt; a score of 4 or 5 in the Columbia-Suicide Severity Rating Scale (C-SSRS) [19], up to three months before screening; a clinically significant acute or chronic disease that would hinder regular participation in the study; treatment with antipsychotics, antidepressants, sedatives/hypnotics or mood stabilizers four weeks prior to the screening; complementary or alternative treatment simultaneously to the study (for example, acupuncture, phytotherapy, etc.); homeopathic treatment eight weeks prior to study entry; psychotherapy; simultaneous participation in another clinical trial (the last participation in a previous clinical trial must be completed at least three months prior to screening); concomitant pregnancy or breastfeeding; patients who are assumed to have a linguistic, intellectual or any other reason for not understanding the meaning of the clinical trial and for not complying with the necessary study procedures; persons who have been institutionalized by a court order; patients with an application for a pension.
Participants will be interviewed and treated by a medical doctor specialized in homeopathy at the CHAMP outpatient clinic of Charité University Medical Center.
Interventions
Homeopathic case history - Type I or II
After inclusion, patients will be randomly assigned to either case history type I or II, according to a randomization number disclosed from sequentially numbered, sealed opaque envelopes. This involves disclosing information using different homeopathic techniques, in order to assess their influence on depression severity. Type I and II differ in the time used for the semi-standardized questionnaire and the onsite patients-doctor interaction and to ensure patients' blinding are not further described here. The content and structure of the questionnaire used in DEP-HOM follows Hahnemann's case history instructions [20], with some additional questions stressing the symptoms of a depressive episode. The questionnaire was developed in consensus with members of the German Homeopathic Doctors Association and pretested.
Individualized homeopathic Q-potencies or placebo
The selection of the individualized remedy (case analysis) will be carried out after the case history, in the absence of the patient, by medical doctor specialized in homeopathy with 20 years experience classical homeopathy based on the the clinical-pharmaceutical protocol [21] developed by Hahnemann, which includes the standardized use of ascending Q-potencies [20]. The investigator is also experienced in case history and analysis under double blind conditions [17].
Q-potencies will be provided from the study pharmacy by Dr. Zinsser Arzneimittel, (Freudenstadt, Germany) and are manufactured according to the methodology described in the 6th edition of the Organon. The prescription of the individualized homeopathic Q-potency will be sent to the Charité pharmacy, together with the patient's randomization number. According to the randomization number, the study pharmacist will dissolve one sucrose globule of the prescribed Q-potency (Q2) or one sucrose globule (placebo) in 10 ml of 20% alcohol-distilled water solvent. The vial will then be labeled and sent to the study center, responsible for dispatching it to the patient within three days from the first case history.
The standard dose will be one drop of the received vial three times per week [21]. Follow-ups will be at two, four and six weeks after the first clinical interview. Blinded medicine, dosage or potency changes will be allowed on a clinical basis. Basal Q-potency medicines stored by the study Pharmacy are listed below (Appendix 1).
Outcomes
The primary endpoint is the mean total depression score using the 17-item version of the Hamilton Depression Rating Scale (HAM-D) [22], after six weeks. Severity of symptoms will be assessed by a blinded investigator (psychologist) from the Clinic for Psychiatry and Psychotherapy, Charité University Medical Center. The secondary end points are the mean HAM-D total scores after two and four weeks, response (decrease of 50% or more from baseline HAM-D score) and remission (HAM-D scores ≤ 7) rates, Beck Depression inventory (BDI) [23] total score and mean SF-12 Health Survey (SF-12) at weeks two, four and six.
Adverse events will be collected during the study and will form part of the secondary endpoint data in determining the safety of homeopathic medicines. Serious adverse effects from homeopathic medicine were not observed on the non-inferiority trial [17] and are not expected during the current study. Participants' treatment expectations at baseline will also be assessed.
Randomization and blinding
A non-stratified block randomization with variable block lengths will be carried out, with a 2:1:1:2 ratio (aiming at exposing a smaller number of participants to placebo treatment) for group 1: group 2: group 3: group 4 (i.e. 76:38:38:76 patients). The randomization list was generated with SAS/BASE Software (SAS Inc., Cary NC, USA), by a statistician not further involved in the study. The patients will be assigned in sequential order to the treatment groups.
The patients, the psychiatrist and the statistician will remain blinded from the identity of the four treatment groups until the end of the study. The study clinical investigator will be unmasked for the case history type I or II. The randomization list will be kept strictly confidential. Only the study pharmacist and the statistician who generated the randomization list have access to the randomization list. During the study, unblinding will only occur in the case of a patient emergency using sealed emergency envelopes.
Data management
Data management services will be performed by the study center at the Institute for Social Medicine, Epidemiology and Health Economics - Charité University in accordance with the ICH-Guidelines for Good Clinical Practice and DIN EN ISO 2001.
Statistical Analysis
The following primary comparisons will be conducted between the following groups: The specific effect of homeopathic medicines compared to placebo (double blind comparison), where essentially the groups 1+3 will be compared to the groups 2+4. The effect of the homeopathic case history (single-blind comparison), where essentially groups 1+2 (case history type I) are compared to the groups 3+4 (case history type II).
Analysis for the primary endpoint
Statistical analysis will be by intention-to-treat, including all patients randomized, regardless whether or not they adhered to the treatment protocol or provided complete data sets. Only patients who withdraw their consent to use their personal data can be excluded from the analysis.
To indicate, whether or not the randomisation process leads to prognostically balanced treatment groups, all baseline parameters will be compared by two sided Chi-square-tests (if nominally scaled) or Kruskal-Wallis-tests (if ordinally or continuously scaled). The respective p-values are descriptive in nature, not confirmative.
The primary endpoint will be analysed by a two-factorial analysis of covariance (ANCOVA), modeling time (3 levels: weeks 2, 4 and 6) as a within-group-factor, type of case history (2 levels: types I and II), type of medicine (2 levels: verum and placebo), and their respective interaction as between-group factors, and baseline value and patient's expectation as linear covariates. Within this model generalized estimation equations (GEE) [24] will be used to estimate the 6-week differences between verum and placebo, and between both types of case history. Two-sided p-values and confidence intervals for both hypotheses will be adjusted by the Bonferoni-Holm procedure [25]. As no interim analyses are planned there is no need for further multiple adjustments. The multiple level of significance is set at α = 0.05 (two-sided).
Sample size calculation
For this study we assumed that the verum treatment is better than placebo by 2.7 ± 6.0 (mean ± standard deviation) HAM-D score points after 6 weeks (corresponding to a SMD = 0.45), that type II case history is better than type I by 2.7 ± 6.0 score points (SMD = 0.45), and that both effects do not interact. If so, a Bonferoni-adjusted F-Test (multiple significance level α = 0.05, two-sided) has a power of 83.5% to detect the difference between verum and placebo and a power of 85.0% to detect the difference in case history taking, if 68 patients are included in groups 1 and 3, and 34 patients are included in groups 2 and 4. This leads to a total number of 228 patients, if one allows for a 10%drop-out rate per group.
Regulatory and Ethical approval
Regulatory approval
Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), EudraCT Nr: 2009-017458-11, Submission-Nr.: 4036175.
Ethical approval
Ethics Committee, Berlin, Landesamt für Gesundheit und Soziales (LaGeSo): ZS EK 15 099/10. This study is in compliance in with the Helsinki Declaration and with the International Conference on Harmonisation (ICH) - Good Clinical Practice.