A Follow-up Trial of Proglucamune® in the Treatment of Protective Qi Insufficiency, a TCM Condition

Study Overview
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Brief Summary
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This is a follow-up Phase II study of a previously complete pilot trial (Protocol ID: 201875) with the same goal: evaluating the activity of Proglucamune on Protective Qi (PQi) Insufficiency. According to Traditional Chinese Medicine (TCM) principle, Protective Qi is a one specific concept of Qi that provides the vital energy of the body. It works primarily on the body surface as a defensive barrier. In this context, Protective Qi is analogous to anatomical barriers of the innate immune system located for example, at the skin surface and the mucosal surfaces of the respiratory and digestive tract. Individuals with PQi Insufficiency are predisposed to frequent cold and other symptoms caused by invasion of external pathogens (Wai Xie or external evil in TCM). ß-glucan is a polysaccharide that activates macrophage (Dectin-1) and neutrophil (CR3) receptors, and therefore enhances immune defense at digestive and respiratory mucosa. Clinical trials have shown its immune activity such as preventing upper respiratory tract infection (URTI) and Traveler's diarrhea. Notably, ß-glucan is a component of Ganoderma Luciderm (or Reishi / Lingzhi), one TCM ingredient well-known for improving Qi. Based on this connection, investigators hypothesized that ß-glucan is the active ingredient in Reishi that at least partially accounts for Reishi's activity on Qi. To test our hypothesis, investigators have conducted an uncontrolled pilot trial that investigated the effect of a commercially available, high ß-glucan containing product, Proglucamune®, on PQi status. Proglucamune contains ß-glucan from three different natural sources: Reishi mushroom, Shiitaki mushroom, and Bakers' yeast, each providing ß-glucan that differs slightly in their molecular structure. The data obtained demonstrated a statistically significant effect of Proglucamune on improving PQi in individuals with PQi Insufficiency. The current study is aimed to further determine this effect in a more stringent (placebo-controlled, randomized, and triple-blinded) way.

Detailed Description
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Unlike mainstream Western medicine (WM), alternative medicines (AM) such as Traditional Chinese Medicine (TCM), emphasizes individually-differentiated therapies. As such, AM therapies are normally not tested in clinical studies that statistically demonstrate the efficacy at the populational level for applicable patients, and this makes it difficult to objectively evaluate and compare different therapies. The lack of clinical studies stands as a barrier for the advance of AMs as well as their engagement with WM. In fact, most researchers view AMs primarily as untapped sources of active ingredients/compounds for drug development, but disregard the rationales under which the therapies were developed. A One-Way-Traffic research paradigm is thus created wherein AM therapies are investigated for their efficacy by WM standards, whereas the vast potential of employing WM therapies for AM therapeutics is ignored. In light of this, investigators set up a novel strategy that bridges TCM and WM, i.e., testing a WM-based therapy by TCM standards through clinical trial/statistics- based method. Qi is a central concept in TCM and was first documented in the oldest TCM writings more than 2000 years ago. Generally speaking, Qi refers to the vital energy of the body and is derived from two primary sources: 1) inborn Qi (that may be construed as genetics), and 2) pectoral Qi (can be construed as metabolism). Moreover, Qi manifests itself in two forms: Nutritive Qi and Protective Qi (PQi), which can be understood to reflect an individual's nutritional state and immune health, respectively. Regarding the latter, protective Qi functions to defend the body from the invasion of external pathogens. TCM also emphasizes that Protective Qi works primarily on the body surface as a defensive barrier. In this context, Protective Qi is analogous to anatomical barriers of the innate immune system located for example, at the skin surface and the mucosal surfaces of the respiratory and digestive tract. TCM has developed a number of methods to strengthen the Qi. Prominent among these is the use of Reishi, either alone or in combination with other TCM remedies. The use of Reishi was described in detail in the first TCM pharmacopedia Compendium of Materia Medica published in year 1,600. Nonetheless, although PQi is part of the general Qi, the specific effect of Reishi on Protective Qi is less documented. Anecdotal reports are available that claim significant improvement of Protective Qi with Reishi or Reishi- containing formulas within days. Notably, WM has identified immune-boosting properties of Reishi, which may explain the Qi enhancing effects of this plant. Specifically, beta-glucan - a component of Reishi - has been shown to activate macrophage (large white blood cells in the immune system that destroy bacteria and other harmful substances), neutrophil (a type of white blood cells that are important for protection against infections), and other immunocytes (cells capable of producing an immune response), and may exhibit particular benefits among macrophage-rich organs such as the lung, liver and spleen. In fact, ß-glucans from sources other than Reishi, such as baker's yeast, are able to initiate the same immune response and clinical benefits. The overlap of TCM and western medicine concerning the beneficial effects of Reishi for its Qi enhancing and immune-modulating effects, respectively, has prompted us to investigate whether or not Reishi, in conjunction with other natural products used in TCM, can enhance an individual's Protective Qi. A previous Pilot trial has been conducted that aimed to determine if a commercially available dietary supplement (Proglucamune®, USANA Health Sciences) containing powdered Reishi and Shitake mushrooms as well as baker's yeast extract, and which is comprised of 11% ß-glucans by weight, would improve Protective Qi in subjects diagnosed by practitioners of TCM as having low or insufficient Protective Qi. The data obtained demonstrated a statistically significant effect of Proglucamune on improving PQi. Based on the effect size and variability, investigators have arrived, via statistical methods, at the necessary sample size for a more definitive (placebo-controlled, randomized, and triple-blinded) trial.

Official Title
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A Randomized, Placebo-controlled, Triple-blinded Evaluation of Proglucamune® in the Treatment of Protective Qi

Conditions
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Protective Qi Insufficiency (a Condition Term From TCM)

Intervention / Treatment
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* Dietary Supplement: beta glucan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or females aged 18 to 65 years (inclusive) without regard to race or ethnic background Provide a signed Informed Consent prior to entry in the study. Willing to follow all study instructions and consume the assigned investigational product for 12 weeks. Not currently taking a beta-glucan containing supplement or any other supplement that might interfere with the study design. Ability to swallow tablets and pills. Exhibit an PQi Insufficiency score > 2 (See Primary Outcome Measure) Exclusion Criteria: 1. Persons diagnosed by TCM as having medical conditions other than low Qi. 2. Significant acute or chronic illness or other medical conditions that will prevent or interfere with giving an informed consent, or with participation in the study. 3. Scheduling difficulties or lack of transportation that will prevent or interfere with their ability to attend all of the necessary study visits. 4. Persons medically diagnosed with depression or anxiety disorders. 5. Persons with a history of alcohol abuse or other substance abuse within the previous 2 years. 6. Females who are attempting to become pregnant, pregnant, lactating or who have given birth within 1 year. 7. Persons who have had a medical surgery in the past 4 weeks or have scheduled a surgery during the study period. 8. Persons currently enrolled in a clinical trial, or who have completed a clinical trial within the last 4 weeks. 9. Allergies to mushrooms or other fungi. 10. Significant problems with constipation or diarrhea. 11. A lifestyle or schedule incompatible with the study protocol. 12. Persons who are allergic to yeast products, have autoimmune disease/an immune disorder, or take antidepressants, blood thinners (anticoagulants, acetylsalicylic acid), or immunosuppressant medication

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Individuals with Protective Qi Insufficiency
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Proglucamune treatment<br>Participants were treated with 2 tablets of Proglucamune per day (containing 200mg of beta glucan) for a total duration of 8 weeks. | Dietary Supplement: beta glucan<br>* Following screening and enrollment, participants will be treated with 2 tablets (Proglucamune or placebo) per day for a total duration of 8 weeks. Each Proglucamune tablet contained  100 mg ß-glucan derived from Baker's Yeast extract (Saccharomyces cerevisiae, cell wall), Reishi mushroom powder (Ganoderma lucidum), and Shitake mushroom powder (Lentinula edodes).<br>|
| Placebo Comparator: Placebo<br>Participants were treated with 2 tablets of placebo per day (contain no beta glucan) for a total duration of 8 weeks. | Dietary Supplement: beta glucan<br>* Following screening and enrollment, participants will be treated with 2 tablets (Proglucamune or placebo) per day for a total duration of 8 weeks. Each Proglucamune tablet contained  100 mg ß-glucan derived from Baker's Yeast extract (Saccharomyces cerevisiae, cell wall), Reishi mushroom powder (Ganoderma lucidum), and Shitake mushroom powder (Lentinula edodes).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Protective Qi improvement | The Protective Qi status of participants at baseline and each follow-up visit will be assessed by on-site investigators (licensed TCM practitioners). Each health condition relevant to protective Qi insufficiency (i.e., cold history, symptoms, and signs) will be scored on a 1-10 or 1-5 scale (with higher number indicating more severe insufficiency) based on a set of standardized and specified criteria (see uploaded Study Protocol for specifics). The sub-scores are then weighted (cold history 25%, symptoms 33.3%, signs: 41.7%) to arrive at a final Protective Qi Insufficiency Index. This index is on a 1-5 scale, with 5 being the most severe insufficiency. The change of the score from baseline, indicating the treatment effect, will be calculated and analyzed by statistical means. | The participants will be followed every two weeks for a total of 12 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Generic Qi improvement | The generic Qi status of participants at baseline and each follow-up visit will be assessed by on-site investigators (licensed TCM practitioners). The assessment consists of two parts of health conditions relevant to generic Qi insufficiency (symptoms and signs). Each part will be scored on a 1-5 scale (with 5 being the most severe insufficiency) based on a set of standardized and specified criteria (See uploaded Study Protocol). The sub-scores are then weighted (symptoms 40% and signs 60%) to arrive at a combined generic Qi Insufficiency Index. This index is on a 1-5 scale, with 5 being the most severe insufficiency. The change of the score from baseline, indicating the treatment effect, will be calculated and analyzed by statistical means. | The participants will be followed every two weeks for a total of 12 weeks. | 
| Global Health | The participants' Global Health will be assessed using the established PROMIS® Scale v1.2 (See the link http://www.healthmeasures.net/explore-measurement-systems/promis or the Citation below for detail). This questionnaire consists of 10 global-health related questions. The answer for nine of ten questions are graded on 1-5 scale (with 5 being the best), and one question is graded on 1 to 10 scale (with 10 being the worst grade). The sub-scores are used to obtain a final combined score of Global Health using a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. | The participants will be followed every two weeks for a total of 12 weeks. | 
| Emotional Impact | The participants' Emotional status will be assessed using the ASCO-Me® v2.0 Emotional Impact (Short Form). This questionnaire-based survey was established based on a Sickle-cell patient population (Please see the link http://www.ascq-me.org/Science or the citation below for detail). This questionnaire consists of 5 emotional-status related questions. The answer for each of the questions are graded on five levels from best to worst. A combined score is generated using a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. | The participants will be followed every two weeks for a total of 12 weeks. | 
| Saliva sIgA | The effect of Proglucamune on the participants' immunity will be assessed by the change of saliva secretary IgA. | The participants will be followed every 6 weeks during 12 week trial. | 
| Emotional and Behavioral Dyscontrol - Short Form | Neuro-QoL (Quality of Life in Neurological Disorders) is a measurement system that evaluates and monitors the physical, mental, and social effects experienced by adults and children living with neurological conditions. Please see the link (http://www.healthmeasures.net/explore-measurement-systems/neuro-qol) for details. This questionnaire consists of 8 questions related to emotional and behavioral control. The answers for each of the questions are graded on five levels from best to worst. A combined score is generated using a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. | The participants will be followed every two weeks for a total of 12 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Protective Qi, Immunity