Apatone-B: Double-Blinded Clinical Trial Using Apatone®B for Symptomatic Postoperative Total Joint Replacements

• Sponsor: IC-MedTech Corporation (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01272830
• Collaborator: Summa Health System (Other), Crystal Clinic Orthopaedic Center LLC (Other)
• Enrollment: 57
• Location: 1
• Arms: 2
• Duration (Months): 62
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

This research study is being conducted to determine if taking oral (by mouth in pill form) Apatone®B (a combination of Vitamins C and K3) will reduce chronic joint discomfort and improve function of non-infected symptomatic postoperative total joint replacements.

Condition or Disease	Intervention/Treatment	Phase
Edematous; Synovitis; Foreign Body Reaction; Osteolysis	Drug: Placebo; Drug: Apatone®B	Phase 2

Detailed Description

To perform a prospective, randomized, double-blind clinical trial to determine if oral Apatone®B, an amalgam of vitamins C and K3, has a therapeutic efficacy beyond the conservative care customarily used to reduce inflammatory synovitis and to increase the functional capacity of proven non-infected symptomatic postoperative total joint replacements.

Study Design

• Study Type: Interventional
• Actual Enrollment: 57 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Prospective Double-Blinded Clinical Trial Using Apatone®B for Care and Treatment of Proven Non-Infected Symptomatic Postoperative Total Joint Arthroplasties
• Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: oral Apatone®B An amalgam of Vitamins C & K3	Drug: Apatone®B; Two capsules taken twice daily with meals
Placebo Comparator: Placebo Oral capsule of similar appearance and taste without Apatone®B	Drug: Placebo; Two capsules taken twice daily with meals

Outcome Measures

Primary Outcome Measures

1. Pain Visual Analog Scale (VAS) [13-weeks]

   Pain Visual Analog Scale (VAS) Scale range (0-100) A higher VAS score indicate worse knee pain

Secondary Outcome Measures

1. Surrogate Endpoint Markers (SEBs) [13 weeks]

   HSS = Hospital for Special Surgery Knee Score , KSS = Knee Society Knee Score. Scale range HSS total: 100-90 Excellent; 80-89 Very Good; 70-79 Good; 60-69 Fair; below 60 Poor Scale range HSS pain walking: No Pain 15; Mild Pain 10; Moderate Pain 5; Severe Pain 0 (**this is an element of the HSS total) Scale range KSS: 80-100 Excellent; 70-79 Good; 60-69 Fair; below 60 Poor

2. TGFBeta Levels [Baseline and 13 Weeks]

   The final synovial aspirates obtained from the symptomatic knee of each subject were analyzed using Quantikine and Pyrilinks-D enzyme-linked immunosorbent assay kits from R&D Systems (Minneapolis, MN) and Metra Biosystems (Mountain View, CA), respectively. Lower TGFBeta concentrations represent a better outcome.

3. Deoxypyridinoline Levels [Baseline and 13 Weeks]

   The final synovial aspirates obtained from the symptomatic knee of each subject were analyzed using Quantikine and Pyrlinks-D enzyme-linked immunosorbent assay kits from R&D Systems(minneapolis, MN) and Metra Biosystems (Mountain View, CA) respectively. Lower DPD concentrations represent a better outcome

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Postoperative Total joint replacement with osteoarthritis as the underlying pathology

• Proven non-infected symptomatic Total Joint Arthroplasty (TJA) (joint implanted for

12 months post-op)

• Age (50 to 85 years of age); based on a 10% trim of the age distribution for Summa Health System TJAs (7/1/08-6/30/2009).

Exclusion Criteria:

• An infection of any kind (prior to, or during the study)

• Rheumatoid arthritis as the underlying pathology

• Cortisone injection received <6 months prior to study enrollment

• Insulin dependent diabetes

• Diagnosed immunodeficiency

• On dialysis or have poor kidney function

• Anti-coagulant medication (e.g., Coumadin or >100mg of Aspirin daily)

• Anti-seizure medication (e.g., Dilantin)

• Steroidal medication (e.g., Prednisone, Advair or Symbicort)

• NSAIDS (e.g., Celebrex or Toradol); a 14-day washout period will be allowed

• bisphosphonates (e.g., Fosamax, Actonel, Aredia, Didronel, Boniva or Reclast)

• hormonal therapy (e.g., Estrogen, Progesterone or Testosterone)

• Cancer (active or in remission)

• Planned concurrent vitamins exceeding a standard daily multivitamin or exceeding the Recommended Daily Allowance (RDA) for individual vitamins if used alone; a 72 hour wash out period will be allowed

• A glucose-6-phosphate dehydrogenase (G6PD) deficiency

• Pregnant or lactating; females who are in their reproductive years must have a negative serum pregnancy

• Lactose intolerant

• Citric acid intolerant

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Summa Health System	Akron	Ohio	United States	44310

Sponsors and Collaborators

• IC-MedTech Corporation
• Summa Health System
• Crystal Clinic Orthopaedic Center LLC

Investigators

• Principal Investigator: Thomas F Bear, MD, Crystal Clinic Orthopaedic Center LLC
• Study Director: Mark W Kovacik, BS, Summa Health System

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: IC-MedTech Corporation
• ClinicalTrials.gov Identifier: NCT01272830
• Other Study ID Numbers: Summa-09136
• First Posted: Jan 10, 2011
• Last Update Posted: Jan 31, 2018
• Last Verified: Oct 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by IC-MedTech Corporation: total joint arthroplasty; synovitis; ALVAL (Aseptic Lymphocyte-Dominant Vasculitis-Associated Lesion); osteolysis; periprosthetic metallosis
• Additional relevant MeSH terms: Synovitis; Osteolysis; Foreign-Body Reaction; Foreign Bodies

Study Results

Participant Flow

Recruitment Details	A total of 57 subjects were consented to participate.
Pre-assignment Detail	Following consenting, 6 subjects did not meet the study inclusion/exclusion criteria, thus never received the study drug. 1 - Abnormal Liver Panel: very low Hemoglobin/Hematocrit levels 1 - Glucose-6-phosphate dehydrogenase (G6PD) deficiency 3 - X-rays revealed loose or mal-positioned component(s) 1 - Prescribed steroids prior to study drug

Arm/Group Title	Oral Apatone®B	Placebo
Arm/Group Description	An amalgam of Vitamins C & K3 Apatone®B: Two capsules taken twice daily with meals	Oral capsule of similar appearance and taste without Apatone®B Placebo: Two capsules taken twice daily with meals
Period Title: Overall Study
STARTED	25	26
COMPLETED	17	21
NOT COMPLETED	8	5

Baseline Characteristics

Arm/Group Title	Oral Apatone®B	Placebo	Total
Arm/Group Description	An amalgam of Vitamins C & K3 Apatone®B: Two capsules taken twice daily with meals	Oral capsule of similar appearance and taste without Apatone®B Placebo: Two capsules taken twice daily with meals	Total of all reporting groups
Overall Participants	17	21	38
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.1 (9.5)	65.4 (9.6)	63.9 (9.7)
Sex: Female, Male (Count of Participants)
Female	9 52.9%	12 57.1%	21 55.3%
Male	8 47.1%	9 42.9%	17 44.7%
Region of Enrollment (Count of Participants)
United States	17 100%	21 100%	38 100%
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	96.7 (20.4)	100 (16.8)	99 (18.5)
Height (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	171.7 (9.9)	169.8 (8.6)	170.6 (9.2)
Time elapsed since TKA (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	2.5 (1.9)	4.0 (3.3)	3.3 (2.9)
Initial Pain Visual Analog Scale (VAS) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	57 (24.1)	46.8 (24.9)	51.4 (25.1)

Outcome Measures

1. Primary Outcome

Title	Pain Visual Analog Scale (VAS)
Description	Pain Visual Analog Scale (VAS) Scale range (0-100) A higher VAS score indicate worse knee pain
Time Frame	13-weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Oral Apatone®B	Placebo
Arm/Group Description	An amalgam of Vitamins C & K3 Apatone®B: Two capsules taken twice daily with meals	Oral capsule of similar appearance and taste without Apatone®B Placebo: Two capsules taken twice daily with meals
Measure Participants	17	21
Baseline	57 (24.1)	46.8 (24.9)
13 Weeks	39.7 (27.4)	39.1 (29.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Apatone®B
	Comments	Change from baseline data.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0063
	Comments	Significance threshold p<0.05
	Method	paired t-test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	Changes from baseline data
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	Significant threshold p<0.05
	Method	paired t-test
	Comments

2. Secondary Outcome

Title	Surrogate Endpoint Markers (SEBs)
Description	HSS = Hospital for Special Surgery Knee Score , KSS = Knee Society Knee Score. Scale range HSS total: 100-90 Excellent; 80-89 Very Good; 70-79 Good; 60-69 Fair; below 60 Poor Scale range HSS pain walking: No Pain 15; Mild Pain 10; Moderate Pain 5; Severe Pain 0 (**this is an element of the HSS total) Scale range KSS: 80-100 Excellent; 70-79 Good; 60-69 Fair; below 60 Poor
Time Frame	13 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Oral Apatone®B	Placebo
Arm/Group Description	An amalgam of Vitamins C & K3 Apatone®B: Two capsules taken twice daily with meals	Oral capsule of similar appearance and taste without Apatone®B Placebo: Two capsules taken twice daily with meals
Measure Participants	17	21
HSS Pain Walking- Baseline	5.9 (5.4)	6.9 (4.3)
HSS Pain Walking-13 Weeks	9.1 (6.2)	7.9 (4.4)
HSS Total-Baseline	69.6 (14.3)	71.9 (11.6)
HSS Total-13 Weeks	76.6 (16.7)	74.5 (11.1)
KSS Total Pain-Baseline	56.2 (19.4)	59.0 (14.0)
KSS Total Pain-13 Week	65.3 (20.1)	63.0 (18.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Apatone®B
	Comments	Change from baseline data (HSS pain walking)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0226
	Comments	Significance threshold p<0.5
	Method	paired
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Oral Apatone®B
	Comments	Change from baseline data (HSS total score)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0375
	Comments	Significance threshold P<0.05
	Method	paired t-test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Oral Apatone®B
	Comments	Change from baseline data (KSS knee pain)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0391
	Comments	Significance threshold p<0.05
	Method	paired t-test
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	Changes from baseline data (HSS pain walking)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2137
	Comments
	Method	paired t-test
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	Change from baseline data (HSS total score)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1312
	Comments
	Method	paired t-test
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	Change from baseline data (KSS knee pain)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1578
	Comments
	Method	paired t-test
	Comments

3. Secondary Outcome

Title	TGFBeta Levels
Description	The final synovial aspirates obtained from the symptomatic knee of each subject were analyzed using Quantikine and Pyrilinks-D enzyme-linked immunosorbent assay kits from R&D Systems (Minneapolis, MN) and Metra Biosystems (Mountain View, CA), respectively. Lower TGFBeta concentrations represent a better outcome.
Time Frame	Baseline and 13 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Oral Apatone®B	Placebo
Arm/Group Description	An amalgam of Vitamins C & K3 Apatone®B: Two capsules taken twice daily with meals	Oral capsule of similar appearance and taste without Apatone®B Placebo: Two capsules taken twice daily with meals
Measure Participants	17	21
Baseline	3197.4 (2793.5)	2089.2 (2879.7)
13 Weeks	2572.2 (2879.7)	1572.2 (1803.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Apatone®B
	Comments	Changes from baseline data
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0083
	Comments	Significance threshold p<0.05
	Method	t-test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	Change from baseline data
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	Significant threshold p<0.05
	Method	paired t-test
	Comments

4. Secondary Outcome

Title	Deoxypyridinoline Levels
Description	The final synovial aspirates obtained from the symptomatic knee of each subject were analyzed using Quantikine and Pyrlinks-D enzyme-linked immunosorbent assay kits from R&D Systems(minneapolis, MN) and Metra Biosystems (Mountain View, CA) respectively. Lower DPD concentrations represent a better outcome
Time Frame	Baseline and 13 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Oral Apatone®B	Placebo
Arm/Group Description	An amalgam of Vitamins C & K3 Apatone®B: Two capsules taken twice daily with meals	Oral capsule of similar appearance and taste without Apatone®B Placebo: Two capsules taken twice daily with meals
Measure Participants	17	21
Basline	8.0 (6.0)	5.9 (1.3)
13 Weeks	6.4 (1.5)	6.1 (1.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Apatone®B
	Comments	Change from baseline data
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments	Significance threshold p<0.05
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	Changes from baseline data
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	paired t-test
	Comments	Significant threshold p<0.05

Adverse Events

Adverse Event Reporting Description	All adverse events (AEs) were classified by the investigator with respect to severity (mild, moderate, severe and potentially life threatening). No AEs classified as potentially life threatening were reported during the course of this study, nor were there any deaths.
Arm/Group Title	Oral Apatone®B		Placebo
Arm/Group Description	An amalgam of Vitamins C & K3 Apatone®B: Two capsules taken twice daily with meals		Oral capsule of similar appearance and taste without Apatone®B Placebo: Two capsules taken twice daily with meals
All Cause Mortality
	Oral Apatone®B		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/21 (0%)
Serious Adverse Events
	Oral Apatone®B		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/17 (5.9%)		0/21 (0%)
Musculoskeletal and connective tissue disorders
Knee pain - hospitalization	1/17 (5.9%)	1	0/21 (0%)	0
Other (Not Including Serious) Adverse Events
	Oral Apatone®B		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/17 (82.4%)		7/21 (33.3%)
Blood and lymphatic system disorders
13th week elevated PT, PTT	0/17 (0%)	0	1/21 (4.8%)	1
Repeated PT, PTT one week later	0/17 (0%)	0	1/21 (4.8%)	1
Injury, poisoning and procedural complications
Fall outdoors, hit head	1/17 (5.9%)	1	0/21 (0%)	0
Pulled muscle right knee	1/17 (5.9%)	1	0/21 (0%)	0
Slipped on ice; cracked rib	1/17 (5.9%)	1	0/21 (0%)	0
Musculoskeletal and connective tissue disorders
Knee pain	1/17 (5.9%)	1	1/21 (4.8%)	1
Knee discomfort left and right	2/17 (11.8%)	2	1/21 (4.8%)	1
Entire body ached	1/17 (5.9%)	1	0/21 (0%)	0
Extreme knee pain	1/17 (5.9%)	1	0/21 (0%)	0
Muscle aches	1/17 (5.9%)	1	0/21 (0%)	0
Painful knee aspiration	1/17 (5.9%)	1	0/21 (0%)	0
Right knee pain	1/17 (5.9%)	1	0/21 (0%)	0
Swelling of knees	1/17 (5.9%)	1	0/21 (0%)	0
Knee discomfort right	0/17 (0%)	0	1/21 (4.8%)	1
Knee pain left	0/17 (0%)	0	2/21 (9.5%)	2
Respiratory, thoracic and mediastinal disorders
Asthma attack	1/17 (5.9%)	1	0/21 (0%)	0
Vascular disorders
Right calf pain, possible blood clot	1/17 (5.9%)	1	0/21 (0%)	0

Limitations/Caveats

limited accrual due to meeting stringent study inclusion/exclusion criteria.Stringent inclusion/exclusion created to allow SEB analyses w/o interference or artifacts,& not due to study drug issues,interaction or limitations.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Published articles to be reviewed/approved by IC-MedTech prior to publication.