90-Day Cobalt Supplementation Study to Investigate the Cobalt Body Burden in Ten Healthy Adult Volunteers

Completed

Conditions: Cobalt Biokinetics
Safety of Cobalt Dietary Supplementation

Registration Number: NCT01990794

Lead Sponsor: Cardno ChemRisk

Brief Summary: The purpose of this study is to investigate steady-state cobalt levels following dietary supplementation for 90 days with 1 mg cobalt/day (as cobalt chloride in solution) in healthy adult volunteers.

Detailed Description: Over the counter cobalt (Co) dietary supplements are available for sale in the United States, but little is known regarding their clinical effects and biokinetic distribution and body burden with long-term use. This study assessed blood kinetics, steady-state levels, biochemical responses, and clinical effects in five adult males and five adult females who voluntarily ingested approximately 1.0 mg Co/day of a commercially available Co supplement over a three month period. Volunteers were instructed to take the Co-dietary supplement in the morning according to the manufacturer's label. Blood samples were collected and analyzed for a number of biochemical parameters before, during, and after dosing. Hearing, vision, cardiac, and neurological functions were also assessed in volunteers before, during, and after dosing.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 13

Inclusion Criteria

Subject ≥ 18 years old.
Subject able to understand and willing to sign a written informed consent form for the study.

Exclusion Criteria

Subject is unwilling to discontinue current multivitamins or other types of dietary supplements while on study
Subject has a documented history of an allergy to cobalt
Subject has a documented history of severe cardiac problems (e.g., congestive heart failure, myocardial ischemia within past 12 months, cardiomyopathy)
Subject has a documented history of thyroid, kidney, or liver disease
Subject has insulin-dependent diabetes
Subject has a concurrent illness or personal stressor which in the opinion of the investigator may interfere with the subject's ability to perform the study's requirements.
Subject has a total joint replacement (e.g., knee, hip, shoulder)
Subject is pregnant or breastfeeding
Subject is unwilling to follow protocol requirements
Subject weight is less than 45 kg

Study & Design

Study Type: OBSERVATIONAL

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Cobalt Whole Blood Concentrations	Before, during and after cobalt supplementation	The cobalt concentration in whole blood and serum was determined one to two weeks pre-dosing and on the day of the first day of dosing before taking the supplement. Samples were also analyzed during the dosing period as follows: Day 4/5, Day 8/9, Day 14/16, Day 22/23, Day 29/30, Day 43/44, Day 57/58, Day 71/72, and Day 88/90. Cobalt concentration in whole blood and serum was also determined at one, two, six, ten and 16 weeks post-dosing.
Cobalt Serum Concentrations	Before, during and after cobalt supplementation	The cobalt concentration in whole blood and serum was determined one to two weeks pre-dosing and on the day of the first day of dosing before taking the supplement. Samples were also analyzed during the dosing period as follows: Day 4/5, Day 8/9, Day 14/16, Day 22/23, Day 29/30, Day 43/44, Day 57/58, Day 71/72, and Day 88/90. Cobalt concentration in whole blood and serum was also determined at one, two, six, ten and 16 weeks post-dosing.

Secondary Outcome Measures

Name	Time	Method
Changes in Audiological Function	Baseline, at the study midpoint, and at the study completion	Audiologic assessments including pure tone threshold determination at frequencies ranging from 250 to 16000 Hz were performed with volunteers serving as their own baseline controls for receptive changes during the study (i.e., week 0, \~day 45, \~day 90). Audiologic assessments including a pure-tone threshold determination at frequencies that ranged from 250 to 16000 Hz were performed with volunteers serving as their own baseline controls for receptive changes during the study. Decreases in hearing were considered clinically significant when one of the following 3 American Speech-Language-Hearing Association criteria were met: 1) a ≥20-dB decrease in the pure-tone threshold at one test frequency, 2) a ≥10-dB decrease at 2 adjacent test frequencies, or 3) the loss of 3 consecutive test frequencies where responses were previously obtained.
Effects on the Immune System	0 weeks and three months	Sensitivity to metals before and after cobalt supplementation was assessed by an in vitro lymphocyte transformation test (LTT) performed at week 0 and after three months of cobalt supplementation. The average proliferation rate for each metal treatment was normalized to individual proliferation rates of untreated control cells which generated a stimulation index (SI). According to the manufacture, the SI ranges from 0-15, with an SI from 2 to 4 indicated mild reactivity, from 5 to 8 indicated moderate reactivity, and \>8 indicated high reactivity to the metal. The data is presented as the averaged normalized lymphocyte transformation response to each metal in men and women combined (n = 10).
Albumin Levels After 1, 2 and 3 Months of Dosing	Study volunteers were assessed before, during and after cobalt supplementation (2 wk post)	Blood chemistries assessed during the study included a lipid panel, comprehensive metabolic panel, creatine kinase-myocardial band, thyroid stimulating hormone, free thyroxine, and complete blood count with differential, total iron, and ferritin. Blood chemistries were assessed at one or two week pre-dose, pre-dose/ Day 1 before taking the supplement, Day 29/30, Day 57/58, Day 88/90 and one and two weeks post-dose.
Albumin Bound Cobalt Fraction in Serum	Study volunteers will be followed for the duration of the study, an average of about 8 months for most volunteers	The fraction of albumin bound cobalt in serum was determined one to two weeks pre-dosing and on the day of the first dose before taking the supplement. Samples were also analyzed during the dosing period as follows: Day 4/5, Day 8/9, Day 14/16, Day 22/23, Day 29/30, Day 43/44, Day 57/58, Day 71/72, Day 88/90 and the fraction of albumin bound cobalt in serum was also determined at one and two weeks post-dosing.
Changes in Visual Function	Baseline, at the study midpoint, and at the study completion	Ophthalmology studies included an assessment of visual acuity, slit lamp evaluations, and visual field testing. Retinal nerve fiber layer (RNFL) thickness and optic nerve head (ONH) were assessed using optical coherence tomography (OCT). Volunteers served as their own baseline controls for changes during the study (i.e., week 0, \~day 45, \~day 90).
Hemoglobin Levels After 1, 2 and 3 Months of Dosing	Study volunteers were assessed before, during and after cobalt supplementation (2 wk post)	Blood chemistries assessed during the study included a lipid panel, comprehensive metabolic panel, creatine kinase-myocardial band, thyroid stimulating hormone, free thyroxine, and complete blood count with differential, total iron, and ferritin. Blood chemistries were assessed at one or two week pre-dose, pre-dose/ Day 1 before taking the supplement, Day 29/30, Day 57/58, Day 88/90 and one and two weeks post-dose.
Changes in Neurological Function (Peroneal Motor Amplitude)	Baseline, at the study midpoint, and at the study completion	Values of the sural sensory and peroneal motor variables. Volunteers served as their own baseline controls for changes during the study (i.e., week 0, \~day 45, \~day 90, and \~4-6 post-weeks).
White Blood Cell (WBC) Levels After 1, 2 and 3 Months of Cobalt Dietary Supplementation	Study volunteers were assessed before, during and after cobalt supplementation (2 wk post)	Blood chemistries assessed during the study included a lipid panel, comprehensive metabolic panel, creatine kinase-myocardial band, thyroid stimulating hormone, free thyroxine, and complete blood count with differential, total iron, and ferritin. Blood chemistries were assessed at one or two week pre-dose, pre-dose/ Day 1 before taking the supplement, Day 29/30, Day 57/58, Day 88/90 and one and two weeks post-dose.
Changes in Cardiac Function	Baseline, at the study midpoint, and at the study completion	Two-dimensional and Doppler echocardiographic examinations were used to assess cardiac anatomy, structure, and function during the study with volunteers serving as their own baseline controls for changes during the study (i.e., week 0, \~day 45, \~day 90).
Red Blood Cell (RBC) Levels After 1, 2 and 3 Months of Dosing	Study volunteers were assessed before, during and after cobalt supplementation (2 wk post)	Blood chemistries assessed during the study included a lipid panel, comprehensive metabolic panel, creatine kinase-myocardial band, thyroid stimulating hormone, free thyroxine, and complete blood count with differential, total iron, and ferritin. Blood chemistries were assessed at one or two week pre-dose, pre-dose/ Day 1 before taking the supplement, Day 29/30, Day 57/58, Day 88/90 and one and two weeks post-dose.
Hematocrit Levels After 1, 2 and 3 Months of Dosing	Study volunteers were assessed before, during and after cobalt supplementation (2 wk post)	Blood chemistries assessed during the study included a lipid panel, comprehensive metabolic panel, creatine kinase-myocardial band, thyroid stimulating hormone, free thyroxine, and complete blood count with differential, total iron, and ferritin. Blood chemistries were assessed at one or two week pre-dose, pre-dose/ Day 1 before taking the supplement, Day 29/30, Day 57/58, Day 88/90 and one and two weeks post-dose.
Protein Levels After 1, 2 and 3 Months of Dosing	Study volunteers were assessed before, during and after cobalt supplementation (2 wk post)	Blood chemistries assessed during the study included a lipid panel, comprehensive metabolic panel, creatine kinase-myocardial band, thyroid stimulating hormone, free thyroxine, and complete blood count with differential, total iron, and ferritin. Blood chemistries were assessed at one or two week pre-dose, pre-dose/ Day 1 before taking the supplement, Day 29/30, Day 57/58, Day 88/90 and one and two weeks post-dose.
Ferritin Levels After 1, 2 and 3 Months of Dosing	Study volunteers were assessed before, during and after cobalt supplementation (2 wk post)	Blood chemistries assessed during the study included a lipid panel, comprehensive metabolic panel, creatine kinase-myocardial band, thyroid stimulating hormone, free thyroxine, and complete blood count with differential, total iron, and ferritin. Blood chemistries were assessed at one or two week pre-dose, pre-dose/ Day 1 before taking the supplement, Day 29/30, Day 57/58, Day 88/90 and one and two weeks post-dose.
Creatine Creatine Kinase-Myocardial Band (CK-MB) Levels After 1, 2 and 3 Months of Dosing	Study volunteers were assessed before, during and after cobalt supplementation (2 wk post)	Blood chemistries assessed during the study included a lipid panel, comprehensive metabolic panel, creatine kinase-myocardial band, thyroid stimulating hormone, free thyroxine, and complete blood count with differential, total iron, and ferritin. Blood chemistries were assessed at one or two week pre-dose, pre-dose/ Day 1 before taking the supplement, Day 29/30, Day 57/58, Day 88/90 and one and two weeks post-dose.
Creatinine Levels After 1, 2 and 3 Months of Dosing	Study volunteers were assessed before, during and after cobalt supplementation (2 wk post)	Blood chemistries assessed during the study included a lipid panel, comprehensive metabolic panel, creatine kinase-myocardial band, thyroid stimulating hormone, free thyroxine, and complete blood count with differential, total iron, and ferritin. Blood chemistries were assessed at one or two week pre-dose, pre-dose/ Day 1 before taking the supplement, Day 29/30, Day 57/58, Day 88/90 and one and two weeks post-dose.
Alanine Aminotransferase (ALT) Levels After 1, 2 and 3 Months of Dosing	Study volunteers were assessed before, during and after cobalt supplementation (2 wk post)	Blood chemistries assessed during the study included a lipid panel, comprehensive metabolic panel, creatine kinase-myocardial band, thyroid stimulating hormone, free thyroxine, and complete blood count with differential, total iron, and ferritin. Blood chemistries were assessed at one or two week pre-dose, pre-dose/ Day 1 before taking the supplement, Day 29/30, Day 57/58, Day 88/90 and one and two weeks post-dose.
Aspartate Aminotransferase (AST) Levels After 1, 2 and 3 Months of Dosing	Study volunteers were assessed before, during and after cobalt supplementation (2 wk post)	Blood chemistries assessed during the study included a lipid panel, comprehensive metabolic panel, creatine kinase-myocardial band, thyroid stimulating hormone, free thyroxine, and complete blood count with differential, total iron, and ferritin. Blood chemistries were assessed at one or two week pre-dose, pre-dose/ Day 1 before taking the supplement, Day 29/30, Day 57/58, Day 88/90 and one and two weeks post-dose.
Thyroid-Stimulating Hormone (TSH) Levels After 1, 2 and 3 Months of Dosing	Study volunteers were assessed before, during and after cobalt supplementation (2 wk post)	Blood chemistries assessed during the study included a lipid panel, comprehensive metabolic panel, creatine kinase-myocardial band, thyroid stimulating hormone, free thyroxine, and complete blood count with differential, total iron, and ferritin. Blood chemistries were assessed at one or two week pre-dose, pre-dose/ Day 1 before taking the supplement, Day 29/30, Day 57/58, Day 88/90 and one and two weeks post-dose.
T4 Levels After 1, 2 and 3 Months of Dosing	Study volunteers were assessed before, during and after cobalt supplementation (2 wk post)	Blood chemistries assessed during the study included a lipid panel, comprehensive metabolic panel, creatine kinase-myocardial band, thyroid stimulating hormone, free thyroxine, and complete blood count with differential, total iron, and ferritin. Blood chemistries were assessed at one or two week pre-dose, pre-dose/ Day 1 before taking the supplement, Day 29/30, Day 57/58, Day 88/90 and one and two weeks post-dose.
Total Iron Levels After 1, 2 and 3 Months of Dosing	Study volunteers were assessed before, during and after cobalt supplementation (2 wk post)	Blood chemistries assessed during the study included a lipid panel, comprehensive metabolic panel, creatine kinase-myocardial band, thyroid stimulating hormone, free thyroxine, and complete blood count with differential, total iron, and ferritin. Blood chemistries were assessed at one or two week pre-dose, pre-dose/ Day 1 before taking the supplement, Day 29/30, Day 57/58, Day 88/90 and one and two weeks post-dose.
Glucose Levels After 1, 2 and 3 Months of Dosing	Study volunteers were assessed before, during and after cobalt supplementation (2 wk post)	Blood chemistries assessed during the study included a lipid panel, comprehensive metabolic panel, creatine kinase-myocardial band, thyroid stimulating hormone, free thyroxine, and complete blood count with differential, total iron, and ferritin. Blood chemistries were assessed at one or two week pre-dose, pre-dose/ Day 1 before taking the supplement, Day 29/30, Day 57/58, Day 88/90 and one and two weeks post-dose.
Cobalt Urine Concentrations	During cobalt supplementation	A 24 hr urine collection for cobalt analysis was performed at Day 14/16, Day 43/44 and Day 88/90.
Changes in Cardiac Function (LA Volume Index)	Baseline, at the study midpoint, and at the study completion	Two-dimensional and Doppler echocardiographic examinations were used to assess cardiac anatomy, structure, and function during the study with volunteers serving as their own baseline controls for changes during the study (i.e., week 0, \~day 45, \~day 90).
HDL Cholesterol Levels After 3 Months of Cobalt Supplementation	Study volunteers were assessed before and at the end of cobalt supplementation	Blood chemistries assessed during the study included a lipid panel, comprehensive metabolic panel, creatine kinase-myocardial band, thyroid stimulating hormone, free thyroxine, and complete blood count with differential, total iron, and ferritin. HDL cholesterol levels were assessed before cobalt dietary supplementation and after three months of supplementation.
Total Cholesterol Levels After 3 Months of Cobalt Supplementation	Study volunteers were assessed before and at the end of cobalt supplementation	Blood chemistries assessed during the study included a lipid panel, comprehensive metabolic panel, creatine kinase-myocardial band, thyroid stimulating hormone, free thyroxine, and complete blood count with differential, total iron, and ferritin. Total cholesterol levels were assessed before cobalt dietary supplementation and after three months of supplementation.
Triglyceride Levels After 3 Months of Cobalt Supplementation	Study volunteers were assessed before and at the end of cobalt supplementation	Blood chemistries assessed during the study included a lipid panel, comprehensive metabolic panel, creatine kinase-myocardial band, thyroid stimulating hormone, free thyroxine, and complete blood count with differential, total iron, and ferritin. Triglyceride levels were assessed before cobalt dietary supplementation and after three months of supplementation.
Changes in Visual Function (Average RNFL Thickness)	Baseline, at the study midpoint, and at the study completion	Ophthalmology studies included an assessment of visual acuity, slit lamp evaluations, and visual field testing. Retinal nerve fiber layer (RNFL) thickness and optic nerve head (ONH) were assessed using optical coherence tomography (OCT). Volunteers served as their own baseline controls for changes during the study (i.e., week 0, \~day 45, \~day 90).
Changes in Visual Function (Average C:D Ratio)	Baseline, at the study midpoint, and at the study completion	Ophthalmology studies included an assessment of visual acuity, slit lamp evaluations, and visual field testing. Retinal nerve fiber layer (RNFL) thickness and optic nerve head (ONH) were assessed using optical coherence tomography (OCT). Volunteers served as their own baseline controls for changes during the study (i.e., week 0, \~day 45, \~day 90).
Cobalt Urine Concentrations After Cessation of Cobalt Supplementation	After cobalt supplementation	A 24 hr urine collection for cobalt analysis was performed on three volunteers (two females and one male) at one, two, six and ten weeks post-dosing. The one male volunteer provided three consecutive 24-hr urine samples at the one and two week post-dosing time points; data for individual urine collections were averaged together to give an average one and two week post-dosing data concentration.
Changes in Visual Function (Mean Deviation and PSD)	Baseline, at the study midpoint, and at the study completion	Ophthalmology studies included an assessment of visual acuity, slit lamp evaluations, and visual field testing. Retinal nerve fiber layer (RNFL) thickness and optic nerve head (ONH) were assessed using optical coherence tomography (OCT). Volunteers served as their own baseline controls for changes during the study (i.e., week 0, \~day 45, \~day 90).
Changes in Neurological Function (Sural Sensory Amplitude)	Baseline, at the study midpoint, and at the study completion	Values of the sural sensory and peroneal motor variables. Volunteers served as their own baseline controls for changes during the study (i.e., week 0, \~day 45, \~day 90, and \~4-6 post-weeks).
Changes in Cardiac Function (LVEF)	Baseline, at the study midpoint, and at the study completion	Two-dimensional and Doppler echocardiographic examinations were used to assess cardiac anatomy, structure, and function during the study with volunteers serving as their own baseline controls for changes during the study (i.e., week 0, \~day 45, \~day 90).
Changes in Visual Function (Cup Volume)	Baseline, at the study midpoint, and at the study completion	Ophthalmology studies included an assessment of visual acuity, slit lamp evaluations, and visual field testing. Retinal nerve fiber layer (RNFL) thickness and optic nerve head (ONH) were assessed using optical coherence tomography (OCT). Volunteers served as their own baseline controls for changes during the study (i.e., week 0, \~day 45, \~day 90).
Changes in Visual Function (VFI)	Baseline, at the study midpoint, and at the study completion	Ophthalmology studies included an assessment of visual acuity, slit lamp evaluations, and visual field testing. Retinal nerve fiber layer (RNFL) thickness and optic nerve head (ONH) were assessed using optical coherence tomography (OCT). Volunteers served as their own baseline controls for changes during the study (i.e., week 0, \~day 45, \~day 90).
Changes in Neurological Function (Velocity)	Baseline, at the study midpoint, and at the study completion	Values of the sural sensory and peroneal motor variables. Volunteers served as their own baseline controls for changes during the study (i.e., week 0, \~day 45, \~day 90, and \~4-6 post-weeks).