Phase I Study of PH100 (Ecklonia Cava Phlorotannins)

Study Overview
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Brief Summary
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The purpose of this study was to determine the safety and tolerability of PH100, a purified phlorotannins from a brown alga Ecklonia cava and the pharmacokinetics of its major compounds 8,8'-bieckol, dieckol, and phlorofucofuroeckol A (PFF-A), after single, ascending, oral doses of PH100 Capsules (over-encapsulated tablets) in healthy adult volunteers.

Detailed Description
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This was a single-center, randomized, double-blind, placebo-controlled, single ascending dose study in healthy volunteers in which subjects received either placebo or a 100 mg, 200 mg, 400 mg, 800 mg, 1200 mg, or 1600 mg dose of PH100 capsules (over-encapsulated tablets containing purified Ecklonia cava phlorotannins as an active ingredient) in escalating dose groups (six cohorts). A total of 48 subjects were enrolled. Each cohort comprised eight subjects. Within each cohort, six subjects received PH100 and two subjects received placebo. The first cohort was dosed as a single group with PH100 (100 mg) or placebo. The subsequent five cohorts were dosed sequentially with 200 mg, 400 mg, 800 mg, 1200 mg, and 1600 mg of PH100 or placebo. Safety and pharmacokinetic data were collected and evaluated following each cohort. Dose escalation occurred after review of the safety and pharmacokinetic data from the preceding cohort(s). Doses were administered with subjects in the fasted condition.

Official Title
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A Double-Blind, Placebo-Controlled, Single Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of PH100 Capsules in Healthy Adult Volunteers

Conditions
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Safety Issues

Intervention / Treatment
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* Drug: Placebo
* Drug: PH100 100mg
* Drug: PH100 200mg
* Drug: PH100 400mg
* Drug: PH100 800mg
* Drug: PH100 1200mg
* Drug: PH100 1600mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or nonpregnant, nonbreastfeeding female; Between 40 and 75 years of age (inclusive); Body mass index (BMI) between 18 and 30 kg/m2 (inclusive), and minimum weight of 50 kg (110 lbs); If female, subject was considered postmenopausal or surgically sterile and had status confirmed by one of the following: Physiologicallypostmenopausalbasedonnomensesforatleast2years(not due to lactational amenorrhea) and follicle stimulating hormone (FSH) levels equal to or greater than 40.0 mIU/mL at screening; or Bilateraloophorectomy,hysterectomy,orbilateraltuballigation(post 6 months). Or If female and of childbearing potential, subject agreed to use one of the following forms of birth control from 3 months prior through 12 days after study drug administration: Vasectomizedpartner(atleast6monthspriortodosing); Doublebarrier(diaphragmwithspermicide;condomswithspermicide); Intrauterinedevice(IUD); Abstinence(agreedtouseadoublebarriermethodiftheybecamesexually active during the study); Implantedorintrauterinehormonalcontraceptives;or Oral,patch,orinjectedcontraceptives,orvaginalhormonaldevice (i.e. NuvaRing®). If male, subject had a documented vasectomy or agreed to use a double-barrier local contraception (i.e., condom with spermicide) when engaging in sexual activity with women of childbearing potential from prior to the first dose of study drug through 28 days after the last dose of study drug; If male, subject agreed to refrain from sperm donation from prior to the first dose of study drug through 28 days after the last dose of study drug; Voluntarily consented to participate in this study and provided their written informed consent prior to start of any study-specific procedures; Able to communicate with the Investigator, and understand and comply with the requirements of the protocol; Willing and able to remain in the study unit for the entire duration of the confinement period and return for an outpatient visit; Had screening blood pressure (measured sitting after 3 minutes rest) 140/90 mmHg. Out-of-range blood pressure could be repeated once; and Willing and able to swallow up to eight size AAA capsules with water at dose administration. Size AAA capsules are 0.642 inches (16.31 mm) in length and 0.450 inches (11.44 mm) in diameter). Exclusion Criteria: History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, GI, endocrine (including thyroid), immunologic, dermatologic, neurologic, oncologic, respiratory, lymphatic, musculoskeletal, genitourinary, infective, inflammatory, connective tissue, or psychiatric disease or disorder or any other condition that, in the opinion of the Investigator, would have jeopardized the safety of the subject or the validity of the study results; Clinically relevant history or presence of cardiac arrhythmia, narrow angle glaucoma, benign prostatic hypertrophy (men only), Hashimoto's thyroiditis, lymphocytic thyroiditis, or uncontrolled diabetes; Had a clinically significant abnormal finding on the physical exam, medical history, ECG, or clinical laboratory results at screening; History or presence of allergic or adverse response to PH100 (product names: Seapolynol, Fibroboost, Fibronol, Seanol Longevity Plus, Circulate, Alginol, PC Ecklonia Cava, Seanol, Seanol-F, Seanol-EX, Seanol-TX, Venusen, Memories with Seanol-P, Astaxanthol, Brilliant Vision with Seanol-P, Gly-Control, Gyne-Andro-Plex, Lipid Balance, Seanol with Broccoraphanin, and Marine D3) or related drugs; Had used PH100 (product names: Seapolynol, Fibroboost, Fibronol, Seanol Longevity Plus, Circulate, Alginol, PC Ecklonia Cava, Seanol, Seanol-F, Seanol-EX, Seanol-TX, Venusen, Memories with Seanol-P, Astaxanthol, Brilliant Vision with Seanol-P, Gly-Control, Gyne-Andro-Plex, Lipid Balance, Seanol with Broccoraphanin, and Marine D3) as a supplement within 30 days prior to the first dose of study medication; Had been on a significantly abnormal diet during the 4 weeks preceding the first dose of study medication; Had donated blood or plasma within 30 days prior to the first dose of study medication; Had participated in another clinical trial (randomized subjects only) within 30 days prior to first dose of study medication; Had used any over-the-counter (OTC) medication, including nutritional supplements, within 5 half-lives or 14 days (whichever was longer) prior to the first dose of study medication; Had used any prescription medication, except hormonal contraceptives for women of childbearing potential or hormone replacement therapy, within 5 half-lives or 14 days (whichever was longer) prior to the first dose of study medication; Had ingested drinks or foods containing grapefruit or St. John's Wort within 14 days prior to the first dose of study medication; Had been treated with any known drugs that are moderate or strong inhibitors/inducers of CYP enzymes such as barbiturates, phenothiazines, cimetidine, carbamazepine, etc., within 30 days prior to the first dose of study medication and that in the Investigator's judgment may have impacted subject safety or the validity of the study results; Had discontinued the use of implanted, intrauterine, or injected hormonal contraceptives less than 6 months prior to the first dose of study medication; Had discontinued the use of oral, patch, or vaginal hormonal contraceptives less than 1 month prior to the first dose of study medication; Had smoked or used tobacco products within 6 months prior to the first dose of study medication; Had a history of substance abuse or treatment (including alcohol); Was a female who had a positive pregnancy test result or was nursing, lactating, or trying to become pregnant; Had a positive urine screen for drugs of abuse (amphetamines, barbiturates, benzodiazepines, cocaine, cannabinoids, opiates), alcohol, or cotinine; Had a positive test for hepatitis B surface antigen (HbSAg), hepatitis C antibody, or human immunodeficiency virus (HIV) at screening or had been previously treated for hepatitis B, hepatitis C, or HIV infection; or Had difficulty swallowing up to eight capsules.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

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: Sequential Assignment
Interventional Model Description: Single-center, randomized, double-blind, placebo-controlled, single ascending dose study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 100mg Dose<br>1 x 100 mg PH100 capsule (n=6) | Drug: PH100 100mg<br>* 1 x 100 mg PH100 oral capsule<br>|
| Placebo Comparator: Control for 100mg Dose<br>1 placebo capsule (n=2) | Drug: Placebo<br>* 1 8 Placebo capsule(s) corresponding to each PH100 dose<br>|
| Active Comparator: 200mg Dose<br>1 x 200 mg PH100 capsule (n=6) | Drug: PH100 200mg<br>* 1 x 200 mg PH100 oral capsule<br>|
| Placebo Comparator: Control for 200mg Dose<br>1 placebo capsule (n=2) | Drug: Placebo<br>* 1 8 Placebo capsule(s) corresponding to each PH100 dose<br>|
| Active Comparator: 400mg Dose<br>2 x 200 mg PH100 capsules (n=6) | Drug: PH100 400mg<br>* 2 x 200 mg PH100 oral capsules<br>|
| Placebo Comparator: Control for 400mg Dose<br>2 placebo capsules (n=2) | Drug: Placebo<br>* 1 8 Placebo capsule(s) corresponding to each PH100 dose<br>|
| Active Comparator: 800mg Dose<br>4 x 200 mg PH100 capsules (n=6) | Drug: PH100 800mg<br>* 4 x 200 mg PH100 oral capsules<br>|
| Placebo Comparator: Control for 800mg Dose<br>4 placebo capsules (n=2) | Drug: Placebo<br>* 1 8 Placebo capsule(s) corresponding to each PH100 dose<br>|
| Active Comparator: 1200mg Dose<br>6 x 200 mg PH100 capsules (n=6) | Drug: PH100 1200mg<br>* 6 x 200 mg PH100 oral capsules<br>|
| Placebo Comparator: Control for 1200mg Dose<br>6 placebo capsules (n=2) | Drug: Placebo<br>* 1 8 Placebo capsule(s) corresponding to each PH100 dose<br>|
| Active Comparator: 1600mg Dose<br>8 x 200 mg PH100 capsules (n=6) | Drug: PH100 1600mg<br>* 8 x 200 mg PH100 oral capsules<br>|
| Placebo Comparator: Control for 1600mg Dose<br>8 placebo capsules (n=2) | Drug: Placebo<br>* 1 8 Placebo capsule(s) corresponding to each PH100 dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment emergent adverse events | Subjects were instructed to inform the study physician and/or research personnel of any AEs that occurred at any time during the study. Subjects were monitored for AEs from the beginning of confinement through the end-of-study visit (96 hours after dose administration). Reported or observed AEs were documented and followed to resolution. | 96 hours postdose | 
| Hematocrit (%) | Safety Assessment in Hematology | 48 hours postdose | 
| Hemoglobin (g/dL) | Safety Assessment in Hematology | 48 hours postdose | 
| Erythrocytes (10^6/uL) | Safety Assessment in Hematology | 48 hours postdose | 
| Leukocytes (10^3/uL) | Safety Assessment in Hematology | 48 hours postdose | 
| Basophils (10^3/uL) | Safety Assessment in Hematology | 48 hours postdose | 
| Basophils/Leukocytes (%) | Safety Assessment in Hematology | 48 hours postdose | 
| Eosinophils (10^3/uL) | Safety Assessment in Hematology | 48 hours postdose | 
| Eosinophils/Leukocytes (%) | Safety Assessment in Hematology | 48 hours postdose | 
| Lymphocytes (10^3/uL) | Safety Assessment in Hematology | 48 hours postdose | 
| Lymphocytes/Leukocytes (%) | Safety Assessment in Hematology | 48 hours postdose | 
| Monocytes (10^3/uL) | Safety Assessment in Hematology | 48 hours postdose | 
| Monocytes/Leukocytes (%) | Safety Assessment in Hematology | 48 hours postdose | 
| Neutrophils (10^3/uL) | Safety Assessment in Hematology | 48 hours postdose | 
| Neutrophils/Leukocytes (%) | Safety Assessment in Hematology | 48 hours postdose | 
| Platelets (10^3/uL) | Safety Assessment in Hematology | 48 hours postdose | 
| Serum Glucose (mg/dL) | Safety Assessment in Serum Chemistry | 48 hours postdose | 
| Sodium (mmol/L) | Safety Assessment in Serum Chemistry | 48 hours postdose | 
| Potassium (mmol/L) | Safety Assessment in Serum Chemistry | 48 hours postdose | 
| Calcium (mg/dL) | Safety Assessment in Serum Chemistry | 48 hours postdose | 
| Chloride (mmol/L) | Safety Assessment in Serum Chemistry | 48 hours postdose | 
| Blood urea nitrogen (mg/dL) | Safety Assessment in Serum Chemistry | 48 hours postdose | 
| Creatinine (mg/dL) | Safety Assessment in Serum Chemistry | 48 hours postdose | 
| Urate (mg/dL) | Safety Assessment in Serum Chemistry | 48 hours postdose | 
| Albumin (g/dL) | Safety Assessment in Serum Chemistry | 48 hours postdose | 
| Alkaline phosphatase (U/L) | Safety Assessment in Serum Chemistry | 48 hours postdose | 
| Aspartate phosphatase (U/L) | Safety Assessment in Serum Chemistry | 48 hours postdose | 
| Alanine transaminase (U/L) | Safety Assessment in Serum Chemistry | 48 hours postdose | 
| Total bilirubin (mg/dL) | Safety Assessment in Serum Chemistry | 48 hours postdose | 
| Lactate Dehydrogenase (U/L) | Safety Assessment in Serum Chemistry | 48 hours postdose | 
| Specific gravity | Safety Assessment in Urinalysis | 48 hours postdose | 
| pH | Safety Assessment in Urinalysis | 48 hours postdose | 
| Glucose (mg/dL) | Safety Assessment in Urinalysis | 48 hours postdose | 
| Nitrite (Negative/Positive) | Safety Assessment in Urinalysis | 48 hours postdose | 
| Leukocyte esterase (/uL) | Safety Assessment in Urinalysis | 48 hours postdose | 
| Occult blood (/uL) | Safety Assessment in Urinalysis | 48 hours postdose | 
| Bilirubin (mg/dL) | Safety Assessment in Urinalysis | 48 hours postdose | 
| Urobilinogen (mg/dL) | Safety Assessment in Urinalysis | 48 hours postdose | 
| Change from Baseline Systolic Blood Pressure (mmHg) | Safety Assessment in Vital Signs | 2, 4, 48, 96 hours postdose | 
| Change from Baseline Diastolic Blood Pressure (mmHg) | Safety Assessment in Vital Signs | 2, 4, 48, 96 hours postdose | 
| Change from Baseline Pulse Rate (bpm) | Safety Assessment in Vital Signs | 2, 4, 48, 96 hours postdose | 
| Change from Baseline Respiration Rate (Breath/Min) | Safety Assessment in Vital Signs | 2, 4, 48, 96 hours postdose | 
| Change from Baseline Body Temperature (degrees C) | Safety Assessment in Vital Signs | 2, 4, 48, 96 hours postdose | 
| ECG heart rate (bpm) | Safety Assessment in ECG | 48 hours postdose | 
| PR interval (ms) | Safety Assessment in ECG | 48 hours postdose | 
| QRS complex (ms) | Safety Assessment in ECG | 48 hours postdose | 
| QT interval (ms) | Safety Assessment in ECG | 48 hours postdose | 
| QTcB interval (ms) | Safety Assessment in ECG | 48 hours postdose | 
| QTcF interval (ms) | Safety Assessment in ECG | 48 hours postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Blood Concentration of 8,8'-bieckol (ng/mL) by HPLC-MS | Pharmacokinetics of 8,8'-bieckol, a major compound of PH100, after single, ascending, oral doses (100 mg, 200 mg, 400 mg, 800 mg, 1200 mg, and 1600 mg) of PH100 in normal healthy volunteers. | at 0, 15, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 96 hours after dosing. | 
| Change in Blood Concentration of dieckol (ng/mL) by HPLC-MS | Pharmacokinetics of 8,8'-bieckol, a major compound of PH100, after single, ascending, oral doses (100 mg, 200 mg, 400 mg, 800 mg, 1200 mg, and 1600 mg) of PH100 in normal healthy volunteers. | at 0, 15, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 96 hours after dosing. | 
| Change in Blood Concentration of PFF-A (ng/mL) by HPLC-MS | Pharmacokinetics of 8,8'-bieckol, a major compound of PH100, after single, ascending, oral doses (100 mg, 200 mg, 400 mg, 800 mg, 1200 mg, and 1600 mg) of PH100 in normal healthy volunteers. | at 0, 15, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 96 hours after dosing. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Safety, Tolerability, Pharmacokinetics, PH100, Ecklonia cava, Phlorotannin