Perceived Changes in Anxiety Symptom Burden During Treatment With Bryophyllum Pinnatum and Tolerability

Study Overview
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Brief Summary
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Bryophyllum pinnatum (BP) is a succulent perennial plant from the family Crassulacea (for reviews see Fürer 2016 and Hamburger 2017). Leaf extracts from BP have been used in traditional medicine to treat wounds and ulcers, skin diseases, infections, inflammations, pain, diabetes, hypertension, and cancer. In Europe, BP started to be used at the beginning of the 20th century in Anthroposophic medicine, a form of holistic medicine with an integrative approach. Almost a hundred years later, BP preparations are still often prescribed in Anthroposophic medicine, where it is used in the treatment of a broad spectrum of diagnoses, most often of mental and behavioural disorders (ICD-10 F00-F99), including anxiety, depressive, and sleep disorders (Simões-Wüst 2012). In Switzerland, during the last decade, BP (50 % tablets) started to be used in conventional settings mainly in the treatment of preterm labour (Simões-Wüst 2018, Plangger 2006), overactive bladder (Betschart 2013), sleep disorders (Simões-Wüst 2015), and restless legs syndrome (Von Manitius 2019). Whereas the good effectiveness of BP preparations in the treatment of preterm contractions and overactive bladder is well supported by data obtained using a variety of in vitro models (see e.g. Santos 2018, Bachmann 2017, Simões-Wüst 2010), less is known about possible mechanisms of action that would support their use in the treatment of mental and behavioural disorders. Nevertheless, the observed improvements of sleep disorders are corroborated by animal experiments showing that different fractions of the leaf extract of BP can prolong the pentobarbitone-induced sleeping time (Yemitan 2005 and Pal 1999), indicating a CNS depressant action. Some of the bufadienolides present in Bryophyllum species are thought to be responsible for the sedative effects (Wagner 1986). The aim of the present study is to find out if patients suffering from anxiety symptoms perceive improvements of these symptoms during treatment with Bryophyllum 50% tablets. Since anxiety symptoms are often related to depression, reduced sleep quality, stress, reduced health-related quality of life and the feeling of not being able to control owns life (internal coherence), these aspects will be assessed as well.

Detailed Description
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The present IIT (Investigator-Initiated Trial) study is a prospective, single-group, pre-post study (phase IV). A past study showed that among Anthroposophical physicians the most frequent diagnosis group where BP preparations are prescribed are mental and behavioural disorders such as anxiety and sleep disorders. In the present study, we, therefore, want to investigate the effectiveness of Bryophyllum tablets in patients with anxiety symptoms. Study participants will be recruited among the patients on the waiting list of the Department of Psychiatry and Psychosomatics at the Clinic Arlesheim. Participant recruitment will continue until 60 patients have concluded the study. Recruitment period will probably last 15 months. Duration of the drug administration is 3 weeks. Participants will fill in a questionnaire three times. At baseline, after two and after three weeks of Bryophyllum intake.

Official Title
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Perceived Changes in Anxiety Symptom Burden During Treatment With Bryophyllum Pinnatum and Tolerability: a Prospective, Single-Group Pre-post Observational Study as Investigator-Initiated Trial (IIT)

Conditions
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Anxiety Symptoms

Intervention / Treatment
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* Drug: Bryophyllum 50 % Chewing Tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients referred by their treating physician to the Department of Psychiatry and Psychosomatic of the Clinic Arlesheim waiting for the in-stay Expected waiting time until in-stay is at least two weeks Patients having anxiety symptoms as measured by the GAD-2 questionnaire (cut-off of 3 points) Patients'state of health allows them to complete the questionnaire on their own Signed informed consent No treatment with BP during the last two months No planned doses increase of (conventional) anxiolytics or antidepressants for the duration of the period until in-stay Age over 18 years Good German knowledge (at least level B2 from Common European Framework of Reference for Languages) Exclusion Criteria: Wheat allergies Acute life-threatening conditions Withdrawal of informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bryophyllum pinnatum 50% chewing tablets<br>Bryophyllum is administered for 3 weeks. Bryophyllum is given in form of chewing tablets, 350mg per tablet, 0-2-2-2/d: 2 tablets at midday, 2 tablets in the evening, 2 tablets before bedtime. | Drug: Bryophyllum 50 % Chewing Tablets<br>* Each 350 mg tablet corresponds to 170 mg of leave press juice from Bryophyllum pinnatum, dried down to 17 mg by mixing with lactose; 100 mg dried BP matter in 1 g.<br>* Other names: Bryophyllum pinnatum/Kalanchoe, Bryophyllum pinnatum (Lam.) Oken.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of anxiety symptoms | Assessed with the Beck Anxiety Inventory (BAI, Beckler 2010) score between before treatment and after 2 weeks of treatment. BAI is a 21-question multiple-choice self-report inventory that is used for measuring the severity of anxiety in children and adults. The questions ask about common symptoms of anxiety that the subject has had during the past week (including the day you take it) (such as numbness and tingling, sweating not due to heat, and fear of the worst happening). Each answer to a BAI-question is scored on a scale value of 0 (not at all) to 3 (severely). Higher total scores indicate more severe anxiety symptoms. The standardized cut-offs are: 0-7, minimal anxiety; 8-15, mild anxiety; 16-25, moderate anxiety; 26-63, severe anxiety. | 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of anxiety symptoms | Assessed with the Beck Anxiety Inventory (BAI) score between before treatment and after 3 weeks of treatment. | 3 weeks | 
| Change of anxiety symptoms | Assessed with the Generalized Anxiety Disorder (GAD-7, Williams 2014) questionnaire. GAD-7 is used to measure symptoms and severity of anxiety; scores range from 0 to 21, with higher scores indicating more severe symptoms. Total scores classify symptoms as normal (0-4), mild (5-9), moderate (10-14), and severe (15-21). A total score≥8 is indicative of clinically significant anxiety symptoms. | 2 and 3 weeks | 
| Change of depression symptoms | Assessed with the nine-question depression scale (PHQ-9, Spitzer 1999). PHQ-9 is used to assess the presence and severity of depressive symptoms; scores range from 0 to 27, with higher scores indicating more severe symptoms. Total scores classify depression symptoms as normal (0-4), mild (5-9), moderate (10-14), moderate-severe (15-19) and severe (20-27). A total score ≥10 is indicative of clinically significant symptoms of depression and of a DSM-IV diagnosis of depression. | 2 and 3 weeks | 
| Change of stress symptoms | Assessed with the Perceived Stress Scale (PSS, Klein 2016). Individual scores on the PSS can range from 0 to 40 with higher scores indicating higher perceived stress. Scores ranging from 0-13 would be considered low stress. Scores ranging from 14-26 would be considered moderate stress. Scores ranging from 27-40 would be considered high perceived stress. | 2 and 3 weeks | 
| Change in sleep quality | Assessed with the Pittsburgh Sleep Quality Index (PSQI, Buysse 1989). The PSQI contains 19 self-rated questions and are combined to form seven component scores, each of which has a range of 0-3 points. In all cases, a score o 0 indicates no difficulty, while a score of 3 indicates severe difficulty. The seven component scores are then added to yield one global score, with a range of 0-21 points, 0 indicating no difficulty and 21 indicating severe difficulties in all areas. | 2 and 3 weeks | 
| Change in health-related quality of life questionnaire | Assessed with the Health-related Quality of Life questionnaire (SF-12, Morfeld 2011). The 12 items allow the calculation of two health summary measures, namely physical health summary and mental health summary scales. The scores range from 0 to 60 with higher scores indicating higher degree of difficulty in life. | 2 and 3 weeks | 
| Change in the Sense of Coherence | Assessed with the Internal Coherence Scale (ICS, Kröz 2009). The scores range from 1-50 with higher scores indicating higher degree of internal coherence. | 2 and 3 weeks | 
| Brophyllum Prescription report | It is examined whether and which participants asked for a Bryophyllum 50 % prescription after the study. | 3 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anxiety, Depression, Stress, Sleep Quality, Internal Coherence