Epimedium Prenylflavonoid (EP) Extract for Osteoporosis and Cardiovascular Disease

Study Overview
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Brief Summary
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The primary objective of the trial is to develop Epimedium Prenylflavonoid (EP) extract as a pharmaceutical-quality intervention for post-menopausal osteoporosis and cardiovascular disease. There will be 3 cohorts of 10 healthy men each for the Phase 1 study. In each cohort, 8 men will receive the Epimedium capsules and 2 men will received the matched controls.

Detailed Description
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Prenylflavonoids and its glycoside derivatives isolated from the Traditional Chinese Medicine (TCM), Epimedium, have potent estrogenic properties. The principal bioactive compounds in Epimedium are the prenylflavonoids, icaritin, and their glycosylated derivatives which can enhance osteoblastic differentiation and mineralization, inhibits bone resorption, and induces apoptosis of osteoclasts. Animal experiments indicate that icariin can prevent bone loss induced by ovariectomized (OVX) in rats, through its stimulatory effects on osteoblast growth and function, and inhibitory action on osteoclast cells. Epimedium has also demonstrated significant cardiovascular benefits with positive actions on vascular reactivity, endothelial function and thrombosis in human subjects. Notably, icariin, demonstrated a significant nitric oxide (NO)-dependent vasorelaxation of precontracted coronary arterial rings with intact endothelium in a concentration-dependent manner, via the activation of endothelial nitric oxide synthase protein and NO-cyclic guanidine monophosphate (cGMP) pathway. Epimedium prenylflavonoids (EP) can prevent steroid-associated osteonecrosis in rabbit model and notably, reduce thrombosis incidence and shrink fat-cell-size significantly. This striking combination of properties highlights the immense potential in EP for osteoporosis and cardiovascular health.

Official Title
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Randomized, Double-blind, Placebo-controlled, Phase 1A Clinical Trial to Assess the Safety, Pharmacokinetic and Pharmacodynamic Effects of Single Escalating Doses of a Standardized Epimedium Prenylflavonoids (EP) Extract (HSA Chinese Proprietary Medicine No: 123317) in Healthy Men.

Conditions
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Osteoporosis, Cardiovascular Disease

Intervention / Treatment
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* Drug: Epimedium Prenylflavonoids Extract
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy men. Exclusion Criteria: Hepatitis B patients

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Epimedium Prenylflavonoids Extract<br>Single oral doses of EP (370 mg, 740 mg and 1110 mg) capsules would be orally administered. | Drug: Epimedium Prenylflavonoids Extract<br>* Each Epimedium Prenylflavonoids Extract capsule contains 370 mg of EPIMEDIUM EXTRACT<br>* Other names: EP;|
| Placebo Comparator: Placebo<br>Single oral doses of Placebo (370 mg, 740 mg and 1110 mg) capsules would be orally administered. | Drug: Placebo<br>* Use iron oxide (brown, black and yellow) to mimic Epimedium Prenylflavonoids Extract.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of adverse events/serious adverse events | Incidence and severity of adverse events/serious adverse events based on history, physical examination and vital signs, hematology and clinical chemistry. | 8 to10 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| lcariin | Serum will be extracted from blood samples for measurement of levels of icariin using Liquid chromatography-mass spectrometry (LC/MS). | 3 months | 
| Ex vivo osteoblast and osteoclast activities | Ex vivo assays using human serum to test the effects of EP in bone models of osteoblasts and osteoclasts | 6 to 9 months | 
| Estrogenic biomarkers | The serum will be tested for cell based estrogen receptor bioassays, and its effects on Michigan Cancer Foundation-7 (MCF-7) cell proliferation will also be assessed. | 1 to 2 months | 
| interleukin-6 (IL-6) | IL-6 assays for thrombosis | 1 month | 
| high-sensitivity C-reactive protein (hs-CRP) | hs-CRP assays for thrombosis | 1 month | 
| F2-isoprostanes | F2-isoprostanes assays for thrombosis | 1 month | 
| multiple platelet aggregation | multiple platelet aggregation assays for thrombosis | 1 month | 
| Icaritin (ICT) | Serum will be extracted from blood samples for measurement of levels of ICT using LC/MS. | 3 months | 
| Demethylicaritin (DICT) | Serum will be extracted from blood samples for measurement of levels of DICT using LC/MS. | 3 months | 
| icariside 1 | Serum will be extracted from blood samples for measurement of levels of icariside 1 using LC/MS. | 3 months | 
| icariside II | Serum will be extracted from blood samples for measurement of levels of icariside II using LC/MS. | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epimedium prenylflavonoids, Osteoporosis, Cardiovascular diseases, Phase 1, safety, tolerability