Work Related Musculoskeletal Disorders

Work Related Musculoskeletal Disorders

Upper Extremity Disorders
* Carpel tunnel syndrome
* Cubital tunnel syndrome
* Thoracic outlet syndrome
* Raynaud’s syndrome (white finger)
* Rotator cuff syndrome
* DeQuervain’s disease
* Tendinitis
* Tenosynovitis
* Trigger finger
* Ganglion cyst

Neurovascular Disorders
* Carpal Tunnel Syndrome
o Impingement of the median nerve caused by irritation and swelling of the tendons in the carpal tunnel
* Cubital Tunnel Syndrome
o Pressure on the ulnar nerve when the elbows are exposed to hard surfaces

Neurovascular Disorders
* Thoracic Outlet Syndrome
o Compression of the blood vessels between the neck and shoulder caused by reaching above shoulder level or carrying heavy objects

* Raynaud’s Syndrome
o Also known as Vibration White Finger ; Blood vessels of the hand are damaged (narrowed) from repeated exposure to vibration for long periods of time

Tendon Disorders
* Rotator Cuff Syndrome
* DeQuervain’s Disease
o Combination of tendinitis and tenosynovitis
* Tendinitis
o Irritation of the tendon
* Tenosynovitis
o Irritation of the synovial sheath
* Ganglion Cyst
o Accumulation of fluid within the tendon sheaths

Tendinitis
Hand and Wrist
Common Occupational CTDs of the Upper Extremities

Carpal Tunnel Syndrome occurs from chronic swelling of the flexor tendons in the wrist.

The median nerve, which feeds the first three fingers and the thumb, can become impaired from pressure in the carpal tunnel in the wrist.

Symptoms include:

# pain in the first three fingers and the thumb
# numbness in these areas
# tingling in these areas

Carpal Tunnel Syndrome
Common Occupational CTDs of the Upper Extremities

Raynaud’s Syndrome is when blood vessels of the hand are damaged (narrowed) from repeated exposure to vibration for long periods of time

This is connected with use of vibrating tools, such as hair clippers and jack hammers.

Raynaud’s Syndrome
Symptoms

o Numbness and tingling in the fingers during vibration exposure; may continue after exposure has been discontinued
o Blanching (whitening) of one fingertip because of a temporary constriction of blood flow
o Other fingers also blanch
o Intensity of pain & frequency of attacks increase in time

Common Occupational CTDs of the Upper Extremities

Cubital Tunnel Syndrome is caused by resting the elbows on hard surfaces such as unpadded tables or armrests.

The ulnar nerve, which feeds the ring and little fingers, can become impaired from pressure near the elbows.

Symptoms include:
+ pain in the ring and little fingers
+ tingling in these areas
+ numbness in these areas


Cubital Tunnel Syndrome
Common Occupational CTDs of the Upper Extremities
Thoracic Outlet Syndrome is caused by frequent reaching above shoulder level, by carrying heavy objects, or poor posture involving a forward head tilt.

A Neurovascular bundle called the brachial plexus, which passes between the collar bone and the top rib, can become impaired from pressure associated with movements that causes these two bones to be positioned close together.

Symptoms include:
+ the arms “falling asleep”
+ weakened pulse
+ numbness in the fingers

Thoracic Outlet Syndrome
Common Occupational CTDs of the Upper Extremities
Rotator cuff syndrome is a disorder involving swelling and pain of tendons comprising the rotator cuff muscle group:

subscapularis, supraspinatus, infraspinatus, & teres minor

Symptoms include:

o Pain when you bend the arm and rotate it outwards against resistance
o Pain on the outside of the shoulder possibly radiating down into the arm
o Pain in the shoulder, which is worse at night
o Stiffness in the shoulder joint.

Rotator Cuff Syndrome Anterior View Posterior View
Common Occupational CTDs of the Upper Extremities

Tendinitis is a common CTD for the wrist, elbow, and shoulder. It occurs when we continually stress the tendon cables, causing them to become irritable and sore.

Lateral Epicondylitis - “Tennis elbow”

Medial Epicondylitis - “Golfer’s elbow”

Symptoms include:

# point tenderness
# swelling
# tennis elbow, pain radiates down to back of hand
# golfer’s elbow, pain radiates down to back of hand

Tendinitis

Tenosynovitis is swelling of the sheath that covers the tendon from constant rubbing against the tendon.

Symptoms include:
swelling
pain
loss of motion
loss of strength
Tenosynovitis
Trigger Finger is a tendon disorder that occurs when there is a groove in the flexing tendon of the finger

If the tendon becomes locked in the sheath, attempts to move the finger cause snapping or jerking movements

Usually associated with using tools that have handles with hard or sharp edges.

Trigger Finger
Ganglion Cyst is a bump under the skin caused by an accumulation of fluid within the tendon sheath. It is commonly found at the hand and wrist.

Ganglion Cyst

De Quervain’s Disease is an inflammation of the tendon sheath of the thumb attributed to excessive friction between two thumb tendons and their common sheath.

It’s a combination of Tendonitis and Tenosynovitis.

May be caused by twisting and forceful gripping

Symptoms include:

* swelling
* pain at the base of the thumb.

De Quervain’s Disease
Prospective Study of Computer Users
Fredric Gerr, et. al., 2002, “A Prospective Study of Computer Users: 1. Study Design and Incidence of Musculoskeletal Symptoms and Disorders”.

o 632 individuals
o Newly hired into jobs requiring  15 hr/week of computer use
o Were followed for up to 3 years

Primary Results
* Hand/Arm (H/A) & Neck/Shoulder (N/S) MSS and MSD were common among computer users
* More than 50% of users reported MSS during the 1st year after starting a new job
* Most common H/A disorder was DeQuervain’s tendonitis
* Most common N/S disorder was somatic pain syndrome

Common Occupational Injuries of the Back

Strains and sprains are damage to the tendons and ligaments caused by one time exertions such as lifting or carrying heavy objects.

These can lead to very noticeable back pain, but the pain usually begins to subside within a few days

Facet joint pain results from irritation of the area where the ribs meet the spinal column.

Typically, there is muscle swelling in the affected area and it can become very painful to sit or stand up straight. In some cases it may also be difficult to breath deeply.

Disk erosion occurs from prolonged pressure on the spinal disks, which causes them to become permanently compressed.

The space between the vertebrae becomes smaller, which can lead to impingement of the nerve roots leading out from the spine.

Sitting puts more pressure on the spinal disks than standing, and sitting with the back unsupported can lead to high levels of disk pressure.

Disc Erosion

Sciatic nerve impingement, also called sciatica, is common for people who sit for prolonged periods of time.

The sciatic nerve runs from your lower back down the back of your leg and into to your feet.
Swelling in certain muscles in the buttocks can put pressure on the sciatic nerve, causing pain down the leg.

Herniated discs occur when the inner portion of the disc protrudes, putting pressure on the nerve roots leading from the spine.

Pain or numbness in the legs is a common symptom of herniated discs in the lower back.

Herniated/Bulging Disc
QUESTIONS?

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Planning, Development of Clinical Trials

Planning of Clinical Trials
Development of a Clinical Trial
Idea
Reviews from the experts(Sponsor or CRO)
First planning meeting (basic design features)
Second planning meeting (draft protocol)
Final protocol (ethical and scientific, signed by a statistician)
Evaluation (scientific review, IRB, funding)
Implementation
Final analysis and publication

Evolution of Trial Structure
* Large cooperative trials (multicenter trials)
* High scientific level protocol
* Well-defined administrative structure
* Control of performance at all levels (SOPs)
* Competent biometric advice (ICH E9)
* Careful ethical considerations

Why Multicenter Trials?
* Small but important effect
* Enhance generalizability of the results
* Bring new treatment to the community

Clinical Trial Protocol
* A detailed plan giving instructions to the study investigators(doctors) about the way

to conduct the study.
o Contributors to the protocol development
+ investigators,
+ medical personnel from the Sponsor or delegated CRO
+ representatives from the study monitoring team
+ project statistician

Crucial Roles of Statisticians
* Design (very important!!!)
* Monitoring
* Analysis
* Reporting
* New statistical methodology

Sophisticated Statistical Techniques
* O’Brien and Fleming Boundaries
* Lan & DeMets “Spending function”
* Equivalence testing
* Repeated measures
* Bayesian methods
* Nonlinear random effect modeling

Functions of Clinical Trial Protocol
* Guideline for the conduct of the trial
* Quality control for all aspects of a clinical trial
* To provide guidelines to the monitoring groups such as: IEC / IDMC.
* Written agreement between:
o the investigator
o the participant,
o and the scientific community
* Legal documents for
o FDA and other regulatory bodies
* To procure funding

Duration of Protocol Development
7days-6months!!!
4-50 pages long!!!

Three Fundamental Aspects
* Which patients are eligible
* Which treatment are to be evaluate
* How each patient’s response is to be assessed

Background
* Rationale
* Unpublished work of the investigators
* Pharmacological and toxicity
* Any new and non standard methods

Specific Objectives
* New treatment
* New indication
* Determine the best of a number of standard treatments
* To provide additional data on safety or efficacy

Methods
o Hypothesis
o Patient population (operational definition)
+ Inclusion Criteria
+ Exclusion Criteria
More homogeneous less generalizable!!

Treatment Regimens
Required procedures for treatment administration, including precise rules for does

determinations

Trial Design
Control groups
+ Define and justify the control group
+ Safety consideration of the placebo group
+ Randomization (verifiable method)
# Method used to generate the allocation schedule
# Method of allocation concealment
* Packing number
* Telephone
* Remote data entry
# Timing of assignment
+ Balance on Prognostic Factors
# Stratification
# Minimization
Blinding
+ Mechanism of treatment blinding
+ Single, double, triple, quadruple blinding
+ Assessment of the effectiveness of blinding

Experimental design
+ Parallel designs
+ Cross-over designs
+ Factorial designs
+ Sequential designs

* Patient management guidelines, including specifications for does reductions, treatment

delays and treatment terminations
* Schedules of required clinical tests and assessments

Follow-up phase
* Schedule of submission of required materials and data, including long-term follow-up
* Data and materials submission procedures

Termination
* Procedures for ending patients’ participation in the trial

Study Flow Diagram
* A flowchart describe how patients progress through the trial
o Initial screening
o Randomization
o Planned schedule
o Follow-up visits
o Early termination

Outcome Measures
* Primary end points
Secondary end points

Statistical Issues
* Power analysis justifying sample size requirements
* Interim monitoring and analysis plans
* Planned time and methodology of final analyses e.g. ITT, PP, NNT, CI
* Methods on secondary aims, compare toxicities

Ethics and Safety
* Protection of the trial patient’s right and safety
o How the patient is approached for entry into the trial
o Regulatory obligations, including informed consent and reporting of adverse

events
o Plan and action if a SAE be detacted

Other Topics in a Study Protocol
* Laboratories
* Compliance
o How compliance is monitored
o Methods used to improve compliance
* Organization
o Roles
o Responsibilities
* Budget
* Study Forms (CRFs) and data handling
* Administrative responsibilities

CRF Design
* Identification data
* Research data
* Administrative data
* Regulatory data

Basic Information in CRF
* Consent dates
* Eligibility checklist
* Baseline assessments
* Dosing of study medications ( incl. compliance)
* Concomitant illness
* Safety
* Effectiveness
* Premature termination of study

Administrative Structure of Multicentre Trials
* Steering Committee
o Leadership body of the investigative group
* Data and Safety Monitoring Committee
o Assess the progress, safety and efficacy
o Recommendations about continue, modify or terminate.

Study Chairman
* Chair steering committee
* Responsible for the overall project
* Overseeing the design and conduct of the trial
* Implementation of SOPs and good clinical practices
* Compliance with international and local regulations.

Coordinating Centre
o Training
o Registration
o Randomization
o Supplying
o Collecting and processing CRFs
o Coordination of accrual sites
o Auditing study sites
o Regulatory reporting

Statistical Centre
o Data entry and processing
o Ongoing monitoring of toxicity data
o Periodical interim analysis of study endpoints
o Final data analyses
o Preparation abstract and manuscripts

Central Laboratory

Other Major Personnel
* Trial statistician
* Clinical research associate
* Data manager
* Randomization specialist
* Quality assurance officer
* Computer support personnel
* Resource Centre Directors
* Training directors
* Field site personnel
* Independent Data Monitoring Committee

Field Site Personnel
* Investigator/Study coordinator
* Research Nurse/
o Participants accrual
o Intervention
o Primary data collection
o Follow-up

Standard Operating Procedures (SOPs)
* To ensure that the specific tasks in the trial are carried out in a consistent manner.
* Topics for SOPs for Investigators:

General Topics
* General quality assurance
* Quality control procedures
* Research personnel qualifications
* Clinical audit
* Regulatory authority inspections

Ethics
* Initial and continuing review by ethics committees
* Informed consent
* Consent forms and information sheets

Study Setup
* Review of:
o investigator brochures
o Protocols
o Protocol amendments
o CRFs
o agreements (e.g. responsibility, financial, confidential, insurance/indemnity

agreement)

Monitoring and Initial Data Review:
* Monitoring visits
* Source data verification
* Data query

Management of Study Medications and Clinical Laboratory Samples:
* Shipment
* Receipt
* Control at study sites
* Dispensing inventory
* Compliance with use of study medication
* Randomization procedures
* Clinical laboratory samples

Safety Event Reporting
* Definitions
* Recording and reporting AEs
* Recording and reporting AEs to ethics committees;

Closing The Study
* Review of clinical study reports
* Premature termination or suspension
* Archiving

Some Important ICH Guidelines
* E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting
* E3 Structure and Content of Clinical Study Report (1995)
* E6 Good Clinical Practice (1996)
* E7 Clinical Trials in Special Populations: Geriatrics (1993)
* E8 General Consideration for Clinical Trials (1997)
* E9 Statistical Principles for Clinical Trials (1998)
* E10 Choice of Control Group in Clinical Trials (TBI)
o ICH home page: http://www.ifpma.org/ich1.html
o FDA guidelines: http://www.fda.gov/cder/regulatory/default.htm

Federal Office for Human Research Protections (OHRP)
* OHRP is responsible for monitoring subject protections at more than 4,000 HHS

(Department of Health and Human Services) funded universities, hospitals and other research

institutions.

Investigational Melanoma Vaccine Research Study (MV)- Oklahoma Case
* OHRP Halts Human Research at University of Oklahoma for Subject Protection Violations
* Suspension Date: June 29 2000
* Suspension of 75 federally funded clinical trials performed though the Tulsa campus

Major OHRP Findings:
* MV failure to meet GMP
* allowed for potential subject exposure to bacterial and viral infections.
* 26 of 96 subjects (vaccine arm) died.
* Investigators failed to ensure that risks to subjects were minimized.

Major OHRP Findings:
* Incomplete informed consent documents
o the purpose of the study
o Procedures
o Foreseeable risks and discomforts
o Any expected benefit from study participation
o Overstated the benefits of the study as capable of preventing the recurrence of

melanoma or reducing existing tumor mass
* IRB failure to meet its federal regulatory obligations.
* Implemented substantive changes to the study without obtaining IRB approval.
* Failure to adhere to the protocol inclusion/exclusion criteria.
* Recruited 96 patients with IRB approved size <=40.
* Directly ship study vaccine to some subject’s homes for self-administration.

Actions Taken
* Independent accreditation of a newly formed Tulsa IRB
* Require that sponsor use DSMB as a condition for approval;
* Mandatory certification in human subject protection for those involved in the conduct

of clinical studies
* Educational program specially for clinical investigators, research staffs and IRB

members

Consequences
* Director of the Office of Research resigned
* Chair of IRB retired
* PI (Former Vice Chairman of the University’s dept. of Surgery) has been relieved of

all his administrative duty at the University, which in process of terminating his

appointment as a tenured faculty member.
* Federal lawsuit against
o study’s PI,
o its corporate co-sponsor
o and its IRB members,
* Violations of
o human subject protection regulations,
o international recognized ethical standards for research conduct
o and civil rights laws.

Controlled Clinical Trial
A Journal
* An official journal for the Society for Clinical Trials
* The first issue was published in the May of 1980.
* Aim and scope:
o Basic Design
o Operating features
o Organization
o Analysis

Other Useful Journals
* Applied Clinical Trials
* Statistical Methods in Medical Research
* Statistics in Medicine
* Biometrics

Statistical Principles for Clinical Trials ICH E9
* Considerations for overall clinical development
* Trial design considerations
* Trial conduct considerations
* Data analysis considerations
* Evaluation of safety and Tolerability
* Reporting

Scope of Trials (ICH E9)
* Population
* Primary and Secondary Variables
* Composite variables
* Global Assessment variables
* Multiple Primary Variables
* Surrogate Variables
* Categorized Variables

Design Techniques to Avoid Bias (ICH E9)
* Blinding
* Randomization

Trial Design Considerations (ICH E9)

* Design Configuration
* Parallel Group Design
* Cross-over Design
* Factorial Design
* Mulitcentre Trials

Trial Design Considerations (ICH E9)

* Type of Comparison
o Trials to show superiority
o Trials to show Equivalence or Non-inferiority
o Trials to show Does-response Relationship
* Group sequential designs
* Sample Size
* Data capture and Processing

Trial Conduct Considerations
(ICH E9)
* Trial Monitoring and Interim Analysis
* Changes in Inclusion and Exclusion Criteria
* Accrual Rates
* Sample Size Adjustment
* Interim Analysis and Early stopping
* Role of IDMC

Data Analysis Considerations
(ICH E9)
* Prespecification of the Analysis
* Analysis Sets
o Full Analysis Set
o Per Protocol Set
o Roles of the Different Analysis Sets
* Missing Values and Outliers

Data Analysis Considerations
(ICH E9)
* Data Transformation
* Estimation, CIs and Hypothesis Testing
* Adjustment of Significance and Confidence Levels
* Subgroups, Interactions and Covariates
* Integrity Data and Computer Software Validity

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A Randomized Clinical Trial to Prevent Type 2 Diabetes

A Randomized Clinical Trial to Prevent Type 2 Diabetes in Persons at High Risk

The DPP Research Group
Institutions and Investigators
Abbas Kitabchi
U. of Tennessee

Steven Kahn
U. of Washington
Edward Horton
Joslin Diabetes Center

Richard Hamman
U. of Colorado Health Sciences Center

Steven Haffner
U. of Texas Health Science Center and many others

* There is a long period of glucose intolerance that precedes the development of

diabetes
* Screening tests can identify persons at high risk
* There are safe, potentially effective interventions that can address modifiable risk

factors

Feasibility of Preventing
Type 2 Diabetes

Modifiable Risk Factors for
Type 2 Diabetes
* Obesity
* Body fat distribution
* Physical inactivity
* Elevated fasting and 2 hr glucose levels
* To prevent or delay the development of type 2 diabetes in persons with impaired

glucose tolerance (IGT)

DPP Primary Goal
DPP Secondary Goals
* Reduce cardiovascular disease (CVD) events
* Reduce CVD risk factors
* Reduce atherosclerosis

Study Design
* 3-group randomized clinical trial
* 27 clinical sites
* Standardized across clinics:
o Common protocol and procedures manual
o Staff training
o Data quality control program
Eligibility Criteria
Screening and Recruitment
Step 1 screening
Step 2 OGTT
Step 3 start run-in
Step 4 randomization
Number of participants
Step 3 end run-in

The DPP Research Group, Controlled Clin Trials (in press)
Study Interventions
Eligible participants
Randomized
Standard lifestyle recommendations
Intensive Metformin Placebo
Lifestyle
Primary Outcome: Diabetes

* Annual fasting plasma glucose (FPG) and 75 gm Oral Glucose Tolerance Test
o FPG > 126 mg/dL (7.0 mmol/L) or
o 2-hr > 200 mg/dL (11.0 mmol/L),
o Either confirmed with repeat test
* Semi-annual FPG
o > 126 mg/dL, confirmed

Lifestyle Intervention
An intensive program with the following specific goals:
* > 7% loss of body weight and maintenance of weight loss
o Dietary fat goal -- <25% of calories from fat
o Calorie intake goal -- 1200-1800 kcal/day
* > 150 minutes per week of physical activity

Lifestyle Intervention Structure
* 16 session core curriculum (over 24 weeks)
* Long-term maintenance program
* Supervised by a case manager
* Access to lifestyle support staff
o Dietitian
o Behavior counselor
o Exercise specialist

The Core Curriculum
* 16 session course conducted over 24 weeks
* Education and training in diet and exercise methods and behavior modification skills
* Emphasis on:
o Self monitoring techniques
o Problem solving
o Individualizing programs
o Self esteem, empowerment, and social support
o Frequent contact with case manager and DPP support staff

Post Core Program
* Self-monitoring and other behavioral strategies
* Monthly visits
o Must be seen in person at least every two months
* Supervised exercise sessions offered
* Periodic group classes and motivational campaigns
* Tool box strategies
o Provide exercise videotapes, pedometers
o Enroll in health club or cooking class

DPP Study Interventions:
Criteria for Drug Treatment
* Efficacy
* Safety
* Tolerability - minimal side effects
* Acceptability - dose frequency
Metformin- 850 mg per day escalating after
4 weeks to 850 mg twice per day
Placebo- Metformin placebo adjusted in
parallel with active drugs

Interventions:
Medications
DPP Population
Retention and Participation
Lifestyle Intervention: Physical Activity Results
Mean Change in Leisure Physical Activity
Placebo
Metformin
Lifestyle
Effect of Treatment on Incidence of Diabetes
Diabetes Incidence Rates by Age
Diabetes Incidence Rates by Ethnicity
Diabetes Incidence Rates by BMI
Body Mass Index (kg/m2)
Diabetes Incidence Rates by Fasting Glucose
Fasting Plasma Glucose: mg/dl (mmol/l)
Diabetes Incidence Rates by 2-hr Glucose
2-Hour Plasma Glucose (mg/dl)
Consistency of Treatment Effects
Normal Fasting Glucose
Placebo Metformin Lifestyle
Summary-1
* Both interventions were well accepted and safe
* Intensive lifestyle resulted in weight loss and increased activity level for the

duration of the study

Summary-2
* Both interventions were effective in men and women and all ethnic groups
* Intensive lifestyle intervention was effective in all age groups, including those > 60 years of age

Summary-3
* Intensive lifestyle intervention reduced the development of diabetes by 58%
* Metformin reduced the development of diabetes by 31%
* Lifestyle was more effective than metformin

Lipids by Sex and Ethnicity

A Randomized Clinical Trial to Prevent Type 2 Diabetes.ppt

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