Trial Outcomes & Findings for Safety and Efficacy Study of Healos as a Bone Replacement to Treat Degenerative Disc Disease (NCT NCT00316121)

Last Updated: 2011-03-03

Results Overview

Success is bridging bone, slip of study level versus adjacent levels less than 3 millimeters, angulation less than 5 degrees, 15 point increase in Oswestry Disability Index (ODI) (how back/leg trouble affects activities of daily living), no new problems in motor strength in legs, presence/absence of pain on leg raise, sensation intact on thigh/leg/foot reflexes of the knees/ankles, no permanent/serious complications, no revision/removal/reoperation/supplemental fixation. The ODI is on a 6 point scale from 0 (no pain/no impact on duties) to 5 (worst pain ever/unable to perform duties).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

138 participants

Primary outcome timeframe

24 months

Results posted on

2011-03-03

Participant Flow

Subjects were enrolled from 3Apr06 to 31Dec07. Subjects were seen at medical clinics/hospitals, usually by their regular doctor and not found through ads. Subjects were asked to enroll if they were having back surgery for back pain. Enrollment was stopped for administrative reasons at 138 subjects; the per protocol plan was at least 350 subjects.

220 subjects were screened and 82 were excluded (59 did not meet criteria and 23 refused participation).Use of non-steroidal anti-inflammatory medications or cyclooxygenase-II (COX-2) inhibitors (a non-steroidal anti-inflammatory drug that directly targets COX-2, an enzyme responsible for inflammation and pain) at time of surgery were exclusionary.

Participant milestones

Participant milestones
Measure	HEALOS HEALOS is a synthetic bone graft material made of collagen (a fibrous protein) and hydroxyapatite (a natural mineral structure). The collagen is a bovine derivative (obtained from cows). HEALOS is similar to what is found in natural bone and has the clearance of the U.S. Food and Drug Administration for use in filling bony voids or gaps of the skeletal system. It is combined with bone marrow (a vascular or vessel-like tissue found in the cavity of bone) to form new bone. HEALOS with bone marrow aspirate is currently available for use in a procedure where rods and screws are placed in the back with graft material to fuse the vertebrae. The Leopard cage is a spinal implant made of a material called carbon fiber. HEALOS, when used with the Leopard Cage is an investigational device. An investigational device is one that is being tested and has not yet received approval from the Food and Drug Administration for the use in which it is being tested.	Control Autograft is bone taken from the subject's own hip and placed in and around the spinal implant and spinal instrumentation. Local bone (bone from the area of surgery and placed in the fusion site) may be used in combination with autograft.
Overall Study STARTED	92	46
Overall Study COMPLETED	70	37
Overall Study NOT COMPLETED	22	9

Reasons for withdrawal

Reasons for withdrawal
Measure	HEALOS HEALOS is a synthetic bone graft material made of collagen (a fibrous protein) and hydroxyapatite (a natural mineral structure). The collagen is a bovine derivative (obtained from cows). HEALOS is similar to what is found in natural bone and has the clearance of the U.S. Food and Drug Administration for use in filling bony voids or gaps of the skeletal system. It is combined with bone marrow (a vascular or vessel-like tissue found in the cavity of bone) to form new bone. HEALOS with bone marrow aspirate is currently available for use in a procedure where rods and screws are placed in the back with graft material to fuse the vertebrae. The Leopard cage is a spinal implant made of a material called carbon fiber. HEALOS, when used with the Leopard Cage is an investigational device. An investigational device is one that is being tested and has not yet received approval from the Food and Drug Administration for the use in which it is being tested.	Control Autograft is bone taken from the subject's own hip and placed in and around the spinal implant and spinal instrumentation. Local bone (bone from the area of surgery and placed in the fusion site) may be used in combination with autograft.
Overall Study Death	1	0
Overall Study Lost to Follow-up	14	8
Overall Study Withdrawal by Subject	2	0
Overall Study Reason is missing	1	0
Overall Study Subject relocated	1	1
Overall Study Subject refused to return	1	0
Overall Study Subject no show for visit x 3	1	0
Overall Study Subject did not have 24 month visit	1	0

Baseline Characteristics

Safety and Efficacy Study of Healos as a Bone Replacement to Treat Degenerative Disc Disease

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	HEALOS n=92 Participants HEALOS is a synthetic bone graft material made of collagen (a fibrous protein) and hydroxyapatite (a natural mineral structure). The collagen is a bovine derivative (obtained from cows). HEALOS is similar to what is found in natural bone and has the clearance of the U.S. Food and Drug Administration for use in filling bony voids or gaps of the skeletal system. It is combined with bone marrow (a vascular or vessel-like tissue found in the cavity of bone) to form new bone. HEALOS with bone marrow aspirate is currently available for use in a procedure where rods and screws are placed in the back with graft material to fuse the vertebrae. The Leopard cage is a spinal implant made of a material called carbon fiber. HEALOS, when used with the Leopard Cage is an investigational device. An investigational device is one that is being tested and has not yet received approval from the Food and Drug Administration for the use in which it is being tested.	Control n=46 Participants Autograft is bone taken from the subject's own hip and placed in and around the spinal implant and spinal instrumentation. Local bone (bone from the area of surgery and placed in the fusion site) may be used in combination with autograft.	Total n=138 Participants Total of all reporting groups
Age Continuous	47.4 Years n=5 Participants	49.5 Years n=7 Participants	48.45 Years n=5 Participants
Sex: Female, Male Female	57 Participants n=5 Participants	27 Participants n=7 Participants	84 Participants n=5 Participants
Sex: Female, Male Male	35 Participants n=5 Participants	19 Participants n=7 Participants	54 Participants n=5 Participants

PRIMARY outcome

Timeframe: 24 months

Population: Safety Population:All subjects treated. Full Analysis Set(FAS):Subset of Safety Pop. w/follow up. All effectiveness measures were to be assessed on FAS. FAS is intent-to-treat pop. Per Protocol: Subset of FAS who complete study, treated as randomized w/no major protocol deviations. All analyses were to be on this subset.

Outcome measures

Outcome measures
Measure	HEALOS n=71 Participants HEALOS is a synthetic bone graft material made of collagen (a fibrous protein) and hydroxyapatite (a natural mineral structure). The collagen is a bovine derivative (obtained from cows). HEALOS is similar to what is found in natural bone and has the clearance of the U.S. Food and Drug Administration for use in filling bony voids or gaps of the skeletal system. It is combined with bone marrow (a vascular or vessel-like tissue found in the cavity of bone) to form new bone. HEALOS with bone marrow aspirate is currently available for use in a procedure where rods and screws are placed in the back with graft material to fuse the vertebrae. The Leopard cage is a spinal implant made of a material called carbon fiber. HEALOS, when used with the Leopard Cage is an investigational device. An investigational device is one that is being tested and has not yet received approval from the Food and Drug Administration for the use in which it is being tested.	Control n=39 Participants Autograft is bone taken from the subject's own hip and placed in and around the spinal implant and spinal instrumentation. Local bone (bone from the area of surgery and placed in the fusion site) may be used in combination with autograft.
Subject Success (Success is Defined Only if All of These Criteria Are Fulfilled)	0 Subjects Interval 0.0 to 5.1	0 Subjects Interval 0.0 to 9.0

Adverse Events

HEALOS

Serious events: 23 serious events

Other events: 77 other events

Deaths: 0 deaths

Control

Serious events: 13 serious events

Other events: 43 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Manny Lazaro, Director, Clinical Affairs

Advanced Technologies and Regenerative Medicine, LLC

Phone: 508-828-2741

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The PI cannot publish the results without consent of Sponsor. The results must be given to Sponsor 60 days prior to use. This review is not meant to curtail distribution of data, but to identify confidential material and/or to review the content for conformance to regulations. The Sponsor has the right to edit materials to preserve confidentiality of proprietary information. If requested, the Institution and PI will withhold publication for 60 days to allow for filing of a patent application.
Publication restrictions are in place

Restriction type: OTHER

Measure	HEALOS n=92 participants at risk HEALOS is a synthetic bone graft material made of collagen (a fibrous protein) and hydroxyapatite (a natural mineral structure). The collagen is a bovine derivative (obtained from cows). HEALOS is similar to what is found in natural bone and has the clearance of the U.S. Food and Drug Administration for use in filling bony voids or gaps of the skeletal system. It is combined with bone marrow (a vascular or vessel-like tissue found in the cavity of bone) to form new bone. HEALOS with bone marrow aspirate is currently available for use in a procedure where rods and screws are placed in the back with graft material to fuse the vertebrae. The Leopard cage is a spinal implant made of a material called carbon fiber. HEALOS, when used with the Leopard Cage is an investigational device. An investigational device is one that is being tested and has not yet received approval from the Food and Drug Administration for the use in which it is being tested.	Control n=46 participants at risk Autograft is bone taken from the subject's own hip and placed in and around the spinal implant and spinal instrumentation. Local bone (bone from the area of surgery and placed in the fusion site) may be used in combination with autograft.
Cardiac disorders Acute Myocardial Infarction	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Cardiac disorders Arrhythmia	0.00% 0/92 • 4 years and 7 months Regular assessments made via study visits.	2.2% 1/46 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.
Cardiac disorders Myocardial Infarction	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Cardiac disorders Supraventricular Tachycardia	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Congenital, familial and genetic disorders Spondylolisthesis	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Gastrointestinal disorders Abdominal Pain	2.2% 2/92 • Number of events 2 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Gastrointestinal disorders Constipation	0.00% 0/92 • 4 years and 7 months Regular assessments made via study visits.	2.2% 1/46 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.
Gastrointestinal disorders Ileus	0.00% 0/92 • 4 years and 7 months Regular assessments made via study visits.	2.2% 1/46 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.
Gastrointestinal disorders Nausea	0.00% 0/92 • 4 years and 7 months Regular assessments made via study visits.	2.2% 1/46 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.
Gastrointestinal disorders Pancreatitis	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Gastrointestinal disorders Vomiting	0.00% 0/92 • 4 years and 7 months Regular assessments made via study visits.	2.2% 1/46 • Number of events 2 • 4 years and 7 months Regular assessments made via study visits.
General disorders Implant Site Pain	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Infections and infestations Diverticulitis	1.1% 1/92 • Number of events 2 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Infections and infestations Osteomyelitis	0.00% 0/92 • 4 years and 7 months Regular assessments made via study visits.	2.2% 1/46 • Number of events 2 • 4 years and 7 months Regular assessments made via study visits.
Infections and infestations Pneumonia	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Infections and infestations Postoperative Wound Infection	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Infections and infestations Urinary Tract Infection	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Injury, poisoning and procedural complications Facial Bones Fracture	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Injury, poisoning and procedural complications Overdose	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Injury, poisoning and procedural complications Postoperative Ileus	4.3% 4/92 • Number of events 4 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Injury, poisoning and procedural complications Wound Secretion	0.00% 0/92 • 4 years and 7 months Regular assessments made via study visits.	2.2% 1/46 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.
Musculoskeletal and connective tissue disorders Back Pain	0.00% 0/92 • 4 years and 7 months Regular assessments made via study visits.	2.2% 1/46 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.
Musculoskeletal and connective tissue disorders Fracture Nonunion	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Musculoskeletal and connective tissue disorders Intervertebral Disc Degeneration	0.00% 0/92 • 4 years and 7 months Regular assessments made via study visits.	2.2% 1/46 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.
Musculoskeletal and connective tissue disorders Intervertebral Disc Disorder	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Musculoskeletal and connective tissue disorders Intervertebral Disc Protrusion	2.2% 2/92 • Number of events 4 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Musculoskeletal and connective tissue disorders Intervertebral Discitis	0.00% 0/92 • 4 years and 7 months Regular assessments made via study visits.	2.2% 1/46 • Number of events 2 • 4 years and 7 months Regular assessments made via study visits.
Musculoskeletal and connective tissue disorders Lumbar Spinal Stenosis	0.00% 0/92 • 4 years and 7 months Regular assessments made via study visits.	2.2% 1/46 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.
Musculoskeletal and connective tissue disorders Osteoarthritis	4.3% 4/92 • Number of events 5 • 4 years and 7 months Regular assessments made via study visits.	2.2% 1/46 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.
Musculoskeletal and connective tissue disorders Pain In Extremity	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	2.2% 1/46 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.
Musculoskeletal and connective tissue disorders Pseudarthrosis	0.00% 0/92 • 4 years and 7 months Regular assessments made via study visits.	2.2% 1/46 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Endometrial Cancer	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung Adenocarcinoma	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate Cancer	0.00% 0/92 • 4 years and 7 months Regular assessments made via study visits.	2.2% 1/46 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.
Nervous system disorders Cervicobrachial Syndrome	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Nervous system disorders Myelopathy	0.00% 0/92 • 4 years and 7 months Regular assessments made via study visits.	2.2% 1/46 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.
Pregnancy, puerperium and perinatal conditions Pregnancy	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Psychiatric disorders Conversion Disorder	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	2.2% 1/46 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.
Renal and urinary disorders Cystocele	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Reproductive system and breast disorders Ovarian Cyst	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Respiratory, thoracic and mediastinal disorders Asthma	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Respiratory, thoracic and mediastinal disorders Chronic Obstructive Pulmonary Disease	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Vascular disorders Deep Vein Thrombosis	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Vascular disorders Hypotension	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.

Measure	HEALOS n=92 participants at risk HEALOS is a synthetic bone graft material made of collagen (a fibrous protein) and hydroxyapatite (a natural mineral structure). The collagen is a bovine derivative (obtained from cows). HEALOS is similar to what is found in natural bone and has the clearance of the U.S. Food and Drug Administration for use in filling bony voids or gaps of the skeletal system. It is combined with bone marrow (a vascular or vessel-like tissue found in the cavity of bone) to form new bone. HEALOS with bone marrow aspirate is currently available for use in a procedure where rods and screws are placed in the back with graft material to fuse the vertebrae. The Leopard cage is a spinal implant made of a material called carbon fiber. HEALOS, when used with the Leopard Cage is an investigational device. An investigational device is one that is being tested and has not yet received approval from the Food and Drug Administration for the use in which it is being tested.	Control n=46 participants at risk Autograft is bone taken from the subject's own hip and placed in and around the spinal implant and spinal instrumentation. Local bone (bone from the area of surgery and placed in the fusion site) may be used in combination with autograft.
Blood and lymphatic system disorders Anaemia	7.6% 7/92 • Number of events 7 • 4 years and 7 months Regular assessments made via study visits.	8.7% 4/46 • Number of events 5 • 4 years and 7 months Regular assessments made via study visits.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/92 • 4 years and 7 months Regular assessments made via study visits.	6.5% 3/46 • Number of events 3 • 4 years and 7 months Regular assessments made via study visits.
Gastrointestinal disorders Constipation	3.3% 3/92 • Number of events 3 • 4 years and 7 months Regular assessments made via study visits.	6.5% 3/46 • Number of events 3 • 4 years and 7 months Regular assessments made via study visits.
Gastrointestinal disorders Diarrhoea	4.3% 4/92 • Number of events 4 • 4 years and 7 months Regular assessments made via study visits.	6.5% 3/46 • Number of events 4 • 4 years and 7 months Regular assessments made via study visits.
Gastrointestinal disorders Nausea	10.9% 10/92 • Number of events 10 • 4 years and 7 months Regular assessments made via study visits.	17.4% 8/46 • Number of events 10 • 4 years and 7 months Regular assessments made via study visits.
Gastrointestinal disorders Vomiting	3.3% 3/92 • Number of events 3 • 4 years and 7 months Regular assessments made via study visits.	8.7% 4/46 • Number of events 5 • 4 years and 7 months Regular assessments made via study visits.
General disorders Asthenia	4.3% 4/92 • Number of events 5 • 4 years and 7 months Regular assessments made via study visits.	10.9% 5/46 • Number of events 5 • 4 years and 7 months Regular assessments made via study visits.
General disorders Chest Pain	6.5% 6/92 • Number of events 7 • 4 years and 7 months Regular assessments made via study visits.	2.2% 1/46 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.
General disorders Oedema Peripheral	3.3% 3/92 • Number of events 3 • 4 years and 7 months Regular assessments made via study visits.	10.9% 5/46 • Number of events 8 • 4 years and 7 months Regular assessments made via study visits.
General disorders Pain	1.1% 1/92 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.	6.5% 3/46 • Number of events 4 • 4 years and 7 months Regular assessments made via study visits.
General disorders Pyrexia	8.7% 8/92 • Number of events 8 • 4 years and 7 months Regular assessments made via study visits.	15.2% 7/46 • Number of events 7 • 4 years and 7 months Regular assessments made via study visits.
Infections and infestations Upper Respiratory Tract Infection	1.1% 1/92 • Number of events 2 • 4 years and 7 months Regular assessments made via study visits.	10.9% 5/46 • Number of events 5 • 4 years and 7 months Regular assessments made via study visits.
Infections and infestations Urinary Tract Infection	4.3% 4/92 • Number of events 4 • 4 years and 7 months Regular assessments made via study visits.	8.7% 4/46 • Number of events 6 • 4 years and 7 months Regular assessments made via study visits.
Injury, poisoning and procedural complications Anaemia Postoperative	0.00% 0/92 • 4 years and 7 months Regular assessments made via study visits.	6.5% 3/46 • Number of events 3 • 4 years and 7 months Regular assessments made via study visits.
Injury, poisoning and procedural complications Back Injury	3.3% 3/92 • Number of events 3 • 4 years and 7 months Regular assessments made via study visits.	6.5% 3/46 • Number of events 3 • 4 years and 7 months Regular assessments made via study visits.
Injury, poisoning and procedural complications Fall	3.3% 3/92 • Number of events 4 • 4 years and 7 months Regular assessments made via study visits.	17.4% 8/46 • Number of events 10 • 4 years and 7 months Regular assessments made via study visits.
Injury, poisoning and procedural complications Post Laminectomy Syndrome	2.2% 2/92 • Number of events 2 • 4 years and 7 months Regular assessments made via study visits.	8.7% 4/46 • Number of events 5 • 4 years and 7 months Regular assessments made via study visits.
Injury, poisoning and procedural complications Road Traffic Accident	4.3% 4/92 • Number of events 4 • 4 years and 7 months Regular assessments made via study visits.	8.7% 4/46 • Number of events 4 • 4 years and 7 months Regular assessments made via study visits.
Metabolism and nutrition disorders Hypokalaemia	5.4% 5/92 • Number of events 5 • 4 years and 7 months Regular assessments made via study visits.	4.3% 2/46 • Number of events 2 • 4 years and 7 months Regular assessments made via study visits.
Musculoskeletal and connective tissue disorders Arthralgia	12.0% 11/92 • Number of events 16 • 4 years and 7 months Regular assessments made via study visits.	17.4% 8/46 • Number of events 9 • 4 years and 7 months Regular assessments made via study visits.
Musculoskeletal and connective tissue disorders Back Pain	32.6% 30/92 • Number of events 34 • 4 years and 7 months Regular assessments made via study visits.	45.7% 21/46 • Number of events 28 • 4 years and 7 months Regular assessments made via study visits.
Musculoskeletal and connective tissue disorders Bursitis	6.5% 6/92 • Number of events 8 • 4 years and 7 months Regular assessments made via study visits.	4.3% 2/46 • Number of events 2 • 4 years and 7 months Regular assessments made via study visits.
Musculoskeletal and connective tissue disorders Buttock Pain	4.3% 4/92 • Number of events 5 • 4 years and 7 months Regular assessments made via study visits.	10.9% 5/46 • Number of events 6 • 4 years and 7 months Regular assessments made via study visits.
Musculoskeletal and connective tissue disorders Intervertebral Disc Protrusion	5.4% 5/92 • Number of events 6 • 4 years and 7 months Regular assessments made via study visits.	2.2% 1/46 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.
Musculoskeletal and connective tissue disorders Muscle Spasms	7.6% 7/92 • Number of events 7 • 4 years and 7 months Regular assessments made via study visits.	8.7% 4/46 • Number of events 4 • 4 years and 7 months Regular assessments made via study visits.
Musculoskeletal and connective tissue disorders Neck Pain	2.2% 2/92 • Number of events 2 • 4 years and 7 months Regular assessments made via study visits.	10.9% 5/46 • Number of events 6 • 4 years and 7 months Regular assessments made via study visits.
Musculoskeletal and connective tissue disorders Osteoarthritis	5.4% 5/92 • Number of events 5 • 4 years and 7 months Regular assessments made via study visits.	2.2% 1/46 • Number of events 1 • 4 years and 7 months Regular assessments made via study visits.
Musculoskeletal and connective tissue disorders Pain In Extremity	19.6% 18/92 • Number of events 20 • 4 years and 7 months Regular assessments made via study visits.	30.4% 14/46 • Number of events 23 • 4 years and 7 months Regular assessments made via study visits.
Nervous system disorders Cervicobrachial Syndrome	6.5% 6/92 • Number of events 7 • 4 years and 7 months Regular assessments made via study visits.	0.00% 0/46 • 4 years and 7 months Regular assessments made via study visits.
Nervous system disorders Headache	4.3% 4/92 • Number of events 4 • 4 years and 7 months Regular assessments made via study visits.	6.5% 3/46 • Number of events 3 • 4 years and 7 months Regular assessments made via study visits.
Nervous system disorders Hypoaesthesia	8.7% 8/92 • Number of events 11 • 4 years and 7 months Regular assessments made via study visits.	17.4% 8/46 • Number of events 12 • 4 years and 7 months Regular assessments made via study visits.
Nervous system disorders Hyporeflexia	3.3% 3/92 • Number of events 3 • 4 years and 7 months Regular assessments made via study visits.	8.7% 4/46 • Number of events 7 • 4 years and 7 months Regular assessments made via study visits.
Nervous system disorders Paraesthesia	12.0% 11/92 • Number of events 15 • 4 years and 7 months Regular assessments made via study visits.	8.7% 4/46 • Number of events 4 • 4 years and 7 months Regular assessments made via study visits.
Nervous system disorders Sensory Loss	8.7% 8/92 • Number of events 9 • 4 years and 7 months Regular assessments made via study visits.	8.7% 4/46 • Number of events 4 • 4 years and 7 months Regular assessments made via study visits.
Psychiatric disorders Anxiety	4.3% 4/92 • Number of events 4 • 4 years and 7 months Regular assessments made via study visits.	6.5% 3/46 • Number of events 3 • 4 years and 7 months Regular assessments made via study visits.
Psychiatric disorders Depression	7.6% 7/92 • Number of events 7 • 4 years and 7 months Regular assessments made via study visits.	10.9% 5/46 • Number of events 5 • 4 years and 7 months Regular assessments made via study visits.
Psychiatric disorders Insomnia	4.3% 4/92 • Number of events 4 • 4 years and 7 months Regular assessments made via study visits.	10.9% 5/46 • Number of events 7 • 4 years and 7 months Regular assessments made via study visits.
Skin and subcutaneous tissue disorders Pruritus	2.2% 2/92 • Number of events 2 • 4 years and 7 months Regular assessments made via study visits.	10.9% 5/46 • Number of events 5 • 4 years and 7 months Regular assessments made via study visits.
Skin and subcutaneous tissue disorders Rash	0.00% 0/92 • 4 years and 7 months Regular assessments made via study visits.	6.5% 3/46 • Number of events 3 • 4 years and 7 months Regular assessments made via study visits.