Summaries
22nd
February 2010
Session 2.2
Case Study - AIDSVAX: A Prophylactic (Preventative) AIDS
Vaccine
Conventional
theory concerning AIDS views HIV as a virus that causes the onset of AIDS by
inducing immune system suppression and failure. One approach may seek to
prevent AIDS cases by preventing HIV infection, by using a vaccine based on
HIV. Consider the description of clinical trials evaluating the first such a
vaccine,
Vaccine
X1{ VX1tm }.
Sketch
out a clinical trial design for Vaccine VX1.
Describe
the treatments, and the outcome(s) by which the treatments will be evaluated.
The
active treatment is the experimental vaccine, VX1. If there are no proven
vaccines available, then the other treatment is placebo.
Do we
want a basic, or comparative trial ?
Since
VX1 is the first vaccine of its class, we want a basic clinical trial, which
uses a placebo for comparison.
Identify
the subject population for this trial.
Subjects
eligible for this trial must by HIV negative, that is, free of HIV infection.
Subjects eligible for the trial must volunteer and give informed consent in
order to participate in the trial.
Discuss
the assignment of subjects to the treatments in the trial.
Enrolled
subjects are randomly assigned to either VX1 or to its placebo version. Neither
the subjects nor the clinical workers will know which drug has been assigned –
this is called double blinding.
We
will track the trial subjects in both treatment groups for a number of
outcomes:
Safety
– any adverse reactions to the vaccine
Effectiveness – HIV infection status for each treatment group.
Case
Study - Taxol: Terminal Cervical Cancer
Taxol®
was discovered at Research Triangle Institute in 1967 when Dr. Monroe E. Wall
and Dr. Mansukh C. Wani
isolated the compound from the Pacific yew tree, Taxus
brevifolia, and noted its anti-tumor activity in
a broad range of rodent tumors.(1)
Striking
clinical results with advanced ovarian cancer were reported by The Johns
Hopkins University School of Medicine in The Annals of Internal Medicine
in 1989. In 1991 Dr. Samuel Broder, then director of
the National Cancer Institute, hailed Taxol as the
most important new cancer drug in the past 15 years. In December 1992 the FDA
approved Taxol for refractory ovarian cancer.
Today
it is used for a variety of cancers, including ovarian, breast, non-small-cell
lung, and Karposi's sarcoma. The drug is being tested
against a variety of other cancers
Originally,
the only source of Taxol was the Pacific yew; to
treat one patient required the harvest of six, 100-year-old trees. Today, the
drug is made by a semi-synthetic process from Taxus
baccata. 
(1)
M.E. Wall and M.C. Wani, Paper M-006, 153rd National
Meeting, American Chemical Society (1967).
Consider
a clinical trial in which Taxol is evaluated as an
end-stage treatment for Cervical Cancer(2)
Sketch this clinical trial.
(2)
Subjects must be diagnosed with cervical cancer and be assessed with 18 months
or fewer survival time by their oncologist.
Describe
the treatments, and the outcome(s) by which the treatments will be evaluated.
The
active treatment is Taxol. Since these are end stage
patients, the risks associated with conventional cancer treatments are not
worth the dubious possible benefits. We will be using a placebo version of Taxol for comparison.
Do we
want a basic, or comparative trial ?
We
want a basic clinical trial, which uses a placebo for comparison.
Identify
the subject population for this trial.
Subjects
eligible for this trial must be terminal. End stage cervical cancer patients.
Subjects eligible for the trial must volunteer and give informed consent in order
to participate in the trial.
Discuss
the assignment of subjects to the treatments in the trial.
Enrolled
subjects are randomly assigned to either Taxol or to
its placebo version. Neither the subjects nor the clinical workers will know
which drug has been assigned – this is called double blinding.
We
will track the trial subjects in both treatment groups for a number of
outcomes:
Safety
– any adverse reactions to Taxol
Survival
Time and Survival Status
Status
of Cancer
Pain
Quality
of Life
From http://clinicaltrials.gov:
Study Phase (FDA Clinical Trials)
Most clinical trials are designated as phase I, II, or
III, based on the type of questions that study is seeking to answer:
In Phase I clinical trials, researchers test a new drug or treatment in a small
group of people (20-80) for the first time to evaluate its safety, determine a
safe dosage range, and identify side effects.
In Phase II clinical trials, the study drug or treatment is given to a larger
group of people (100-300) to see if it is effective and to further evaluate its
safety.
In Phase III studies, the study drug or treatment is given to large groups of people
(1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to
commonly used treatments, and collect information that will allow the drug or
treatment to be used safely.
These phases are defined by the Food and Drug
Administration in the Code of Federal Regulations.
Clinical Trial Worksheet
From here:
Case Two | Clinical Trial
Sketch | Non-small Cell Lung Cancer (NSCLC)
A key ability of malignant cells is the ability to
induce angiogensis, the formation of new blood supply. These cells can release
a substance that stimulates the formation of new blood vessels. This ability is
key in the ability of malignant tumors to survive and
grow.Avastin is a monoclonal antibody that works by attaching to
and inhibiting the action of vascular endothelial growth factor (VEGF) in
laboratory experiments. VEGF is a substance that binds to certain cells to
stimulate new blood vessel formation. When VEGF is bound to Avastin, it
cannot stimulate the formation and growth of new blood vessels. A number of cancers are driven by the
derangement of cells composing the linings (epidermal cells) of various organs
in the body. In particular, these cells lose control of their growth behaviors,
leading to uncontrolled reproduction of cells. This deranged, accelerated cell
reproduction is key to the ability of malignant tumors
to grow.
Tarceva (erlotinib) is an oral anti-cancer drug under
development by OSI Pharmaceuticals, Genentech and Roche. It is a member of the
epidermal growth factor receptor (EGFR) inhibitor class of agents. Two general
types of lung cancer exist: Non-Small Cell Lung Cancer (NSCLC) and
small-cell lung cancer (SCLC). The most common type of lung cancer is NSCLC.
Approximately 85% of all lung cancer cases are NSCLC. Three main types of NSCLC
- General treatment options for each of these are the same: Squamous cell carcinoma. Most
often related to smoking. These tumors may be found in the mucous membrane that
lines the bronchi. Sometimes the tumor spreads beyond the bronchi. Coughing up
blood may be a sign of squamous cell NSCLC.
Adenocarcinoma (including bronchioloalveolar carcinoma).
Most often found in nonsmokers and women. Cancer is usually found near the edge
of the lung. Adenocarcinoma can enter the chest lining. When that happens,
fluid forms in the chest cavity. This type of NSCLC spreads (metastasizes)
early in the disease to other body organs. Large-cell undifferentiated carcinoma.
Rare type of NSCLC. Tumors grow quickly and spread
early in the disease. Tumors are usually larger than 1-1/2 inches.
First-line
Treatments for NSCLC: Surgery:
Removes the tumor. This can be done if the tumor is small and has not spread to
other areas of your body. Radiation: Destroys any leftover cancer cells
not removed by surgery. This may be done before surgery to make it easier to
remove the tumor. Radiation can also be done after surgery. Chemotherapy
may help slow the growth of cancer cells and destroy them. Chemotherapy may be
used with radiation to help shrink the tumor before surgery. It may be used
after surgery or radiation to destroy any cancer cells that may have been left
behind.
Consider
patients with locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC)
after failure of at least one previous chemotherapy regimen. Consider two treatments: Avastin+Tarceva and Tarceva.
Sketch a comparative clinical trial for Avastin+Tarceva versus Tarceva
in the treatment of patients with locally advanced or metastatic
Non-Small Cell Lung Cancer (NSCLC) after failure of at least one previous
chemotherapy regimen.
We recruit subjects with with locally advanced or metastatic
Non-Small Cell Lung Cancer (NSCLC) after failure of at least one previous
chemotherapy regimen. Those who give informed consent and who qualify are enrolled
in the trial.
Enrolled subjects are randomly assigned to either Tarceva + Avastin
(TA) or to Tarceva + PalceboAvastin (T) with double blinding, so that neither
the subjects nor the trial workers know the actual treatment status of the
subjects.
Subjects are followed for safety and toxicity, including kidney or
liver damage.
Subjects are followed for their cancer status – has the cancer
stabilized? Has it spread further? Has it receded? Is the cancer more
treatable?
Subjects are followed for mortality and time-to-death. Do fewer
subjects die in the TA group relative to the T group? Do those who die live
longer in the TA group relative to the T group?
Subjects are followed for quality of life – are subjects in the TA
group better able to live normally and to manage their pain than subjects in
the T group?
From here:
Case Six | Clinical Trial Sketch | Study of Tamoxifen
and Raloxifene (STAR) for the Prevention of Breast Cancer
The purpose of this study is
to examine the performance of the drug Raloxifene
(relative to the drug Tamoxifen) in
reducing the incidence of breast cancer in postmenopausal women1 who are at increased risk
of the disease2.
1. Postmenopausal women at increased risk for
developing invasive breast cancer, who meet one of the following criteria: At least 12 months since spontaneous menstrual
bleeding; Prior documented
hysterectomy and the surgical removal of fallopian tubes and ovaries; At least 55 years of age with prior
hysterectomy with or without surgical removal of the ovaries; Aged 35 to 54 years with a prior
hysterectomy without surgical removal of the ovaries or with a status of
ovaries unknown with documented follicle-stimulating hormone level
demonstrating elevation in postmenopausal range.
2. Women without prior breast cancer, but who are at
elevated risk for breast cancer: Histologically confirmed lobular
carcinoma in situ treated by local excision only or at least 1.66% probability
of invasive breast cancer within 5 years using Breast Cancer Risk Assessment
Profile; No clinical evidence of
malignancy on physical exam within the past 180 days; No evidence of suspicious or malignant disease on bilateral mammogram
within the past year; No bilateral
or unilateral prophylactic mastectomy and No
prior invasive breast cancer or intraductal carcinoma in situ
Objectives: Determine whether Raloxifene is more or less effective than Tamoxifen in significantly reducing the incidence rate of invasive breast cancer in postmenopausal women; Evaluate the effects of Tamoxifen and Raloxifene on the incidence of intraductal carcinoma in situ, lobular carcinoma in situ, endometrial cancer, ischemic heart disease, fractures of the hip and spine, or Colles' fractures of the wrist in these participants; Evaluate the toxic effects of these regimens in these participants and Determine the effect of these regimens on the quality of life of these participants.
Sketch a comparative clinical
trial to evaluate the drug Raloxifene (relative to the drug Tamoxifen) in reducing the incidence of
breast cancer in postmenopausal women1
who are at increased risk of the disease2.
Solution
Purpose
of Treatment: The
purpose of this study is to examine the performance of the drug Raloxifene (relative to the drug Tamoxifen) in reducing the incidence of
breast cancer in postmenopausal women1
who are at increased risk of the disease2.
Eligible subjects
are: 1. postmenopausal women at increased risk for developing invasive breast
cancer, who meet one of the following criteria: At least 12 months since spontaneous
menstrual bleeding; Prior documented
hysterectomy and the surgical removal of fallopian tubes and ovaries; At least 55 years of age with prior
hysterectomy with or without surgical removal of the ovaries; Aged 35 to 54 years with a prior
hysterectomy without surgical removal of the ovaries or with a status of
ovaries unknown with documented follicle-stimulating hormone level
demonstrating elevation in postmenopausal range.
2. Women without prior breast cancer, but
who are at elevated risk for breast cancer: Histologically
confirmed lobular carcinoma in situ treated by local excision only or at least
1.66% probability of invasive breast cancer within 5 years using Breast Cancer
Risk Assessment Profile; No clinical
evidence of malignancy on physical exam within the past 180 days; No evidence of suspicious or malignant
disease on bilateral mammogram within the past year; No bilateral or unilateral prophylactic mastectomy and No prior invasive breast cancer or
intraductal carcinoma in situ. The eligible patients are briefed as to
the details and potential risks and benefits of study participation, and those
who give informed consent and who meet all inclusion and exclusion
requirements are enrolled in the trial.
Study
treatments include Raloxifene and Tamoxifen. Enrolled subjects are randomly
assigned either to Raloxifene with PlaceboTamoxifen or to
Tamoxifen with PlaceboRalixifene. Double-blinding is employed, so that neither the subjects
nor the clinical workers know the actual individual treatment
assignments.
Subjects are then followed for: Incidence of invasive breast cancer in postmenopausal women; Incidence of intraductal carcinoma in situ, Incidence of lobular carcinoma in situ, Incidence of endometrial cancer, Incidence of ischemic heart disease, Incidence of fractures of the hip and spine, and Incidence of Colles' fractures of the wrist, Toxic effects of the medications, and Quality of Life.
Case Study - Gastric
Adenocarcinoma
Case
Study - Myocardial Infarction
Case
Study - Traumatic Brain Injury
Case
Study - Carbon Monoxide Intoxication
Case Study - Ocular
Hypertension
From
http://clinicaltrials.gov: Study Phase
(FDA Clinical Trials)
Most clinical trials are designated as phase I, II, or
III, based on the type of questions that study is seeking to answer:
In Phase I clinical trials, researchers test a new drug or treatment in a small
group of people (20-80) for the first time to evaluate its safety, determine a
safe dosage range, and identify side effects.
In Phase II clinical trials, the study drug or treatment is given to a larger
group of people (100-300) to see if it is effective and to further evaluate its
safety.
In Phase III studies, the study drug or treatment is given to large groups of people
(1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to
commonly used treatments, and collect information that will allow the drug or
treatment to be used safely.
These phases are defined by the Food and Drug
Administration in the Code of Federal Regulations.
Comparative Clinical Trial
Advanced Stomach
Cancer (Gastric Adenocarcinoma)
Use of Combination Chemotherapy
The purpose of this trial is to test the combination
of Gleevec®
(also known as imatinib mesylate) and Taxotere
(also known as docetaxel) in patients with incurable stomach cancer. This
study is being performed to see if the combination of Gleevec and Taxotere is
an effective treatment for incurable stomach cancer with minimal side effects.
Gleevec is a pill form of chemotherapy and is indicated for the treatment of
adult patients with chronic myeloid leukemia (CML) and gastrointestinal stromal
tumors (GIST). It is considered experimental for the treatment of stomach
cancer.
Taxotere is a chemotherapy which is injected into the vein. It is approved for
breast and lung cancer but has been shown to shrink many different types of
tumors. Taxotere has been shown to shrink stomach cancer in about 20% - 30%
of patients treated with Taxotere.
An adenocarcinoma is a cancer that
develops in the glandular lining of an organ. A gastric adenocarcinoma
is a cancer that that develops in the glandular lining of the stomach.
Define advanced gastric adenocarcinoma
for the purposes of this clinical trials as surgically
inoperable gastric adenocarcinoma.
This study is being performed to see if the
combination of Gleevec and Taxotere is an effective treatment for
advanced stomach cancer.
Sketch a comparative clinical trial for
Gleevec+Taxotere versus Taxotere in the treatment of advanced gastric
adenocarcinoma.
Condition of Interest: advanced gastric adenocarcinoma, defined
as surgically inoperable gastric
adenocarcinoma.
Subjects: Adult patients diagnosed with advanced
gastric adenocarcinoma.
Recruitment and Informed Consent: We recruit volunteer candidates who have
been diagnosed with advanced gastric adenocarcinoma, and who meet all requirements
for study inclusion, We exclude all candidates
presenting one or more conditions for exclusion. The volunteers are briefed as
to the requirements, details, potential benefits and risk associated with trial
participation. Those who give informed consent agree to participate and are
enrolled in the trial.
Assignment to Treatment: Enrolled subjects are randomly assigned
to either Gleevec+Taxotere or to Placebo+Taxotere, where Placebo represents a
placebo version of Gleevec. Double-blinding is employed in the trial, so
that neither the study subjects nor their clinical personnel know the actual
assignment status of any subject.
Endpoints and Follow-up: Subjects are followed for toxicity,
safety, effect and quality-of-life.
Toxicity involves severe events such as anaphylaxis
(shock), kidney or liver failure/damage, and the like.
Adverse Events involve lesser events like the things you
read in the package inserts: rashes, “dry mouth”, gastrointestinal effects,
nausea, and the like.
Effect involves the actual effect of the
treatment, measured as change in disease status or progression. In this case,
we’re dealing with progression and stage of the cancer: tumor size, metastasis
(spreading) and the like. We also consider survival time,vital
status and stomach function.
Quality of Life: We consider pain control, basic body
function, ability to work, live and play, ability to maintain cogent
consciousness, ability to live independently or with minimal assistance.
We compare the performance of each treatment
group in these results: Toxicity, Safety, Effect and QoL.
Comparative Clinical Trial
Magnesium
Sulfate versus Nimodipine
Determine the effectiveness of nimodipine
versus magnesium sulfate in the prevention of eclamptic seizures
in patients with severe pre-eclampsia.
Nimodipine: Patients receive nimodipine by mouth every 4
hours. Treatment is continued until 24 hours post-partum.
Magnesium Sulfate: Patients receive a loading dose of magnesium
sulfate IV for 20 minutes, followed by continuous infusion of magnesium
sulfate. Treatment is continued until 24 hours post-partum.
Severe pre-eclampsia involves the onset of hypertension
(high blood pressure) in the late stages of pregnancy, as well as proteinuria
(excessive levels of protein in the urine), thrombocytopenia
(deficiency of blood platelets) and swelling (edema).
This study is being performed to compare the
effectiveness of Magnesium Sulfate and Nimodipine in the treatment of severe
pre-eclampsia.
Sketch a comparative clinical trial for the
comparison of Magnesium Sulfate and Nimodipine in the treatment of severe
pre-eclampsia.
Condition of Interest: severe pre-eclampsia.
Subjects: Pregnant patients diagnosed with
pre-eclampsia.
Recruitment and Informed Consent: We recruit volunteer candidates who have
been diagnosed with severe pre-eclampsia, and who meet all requirements for
study inclusion, We exclude all candidates presenting
one or more conditions for exclusion. The volunteers are briefed as to the
requirements, details, potential benefits and risk associated with trial
participation. Those who give informed consent agree to participate and are
enrolled in the trial.
Assignment to Treatment: Enrolled subjects are randomly assigned
to either magnesium sulfate + placebo
Endpoints and Follow-up: Subjects are followed for toxicity,
safety, effect and quality-of-life.
Toxicity involves severe events such as anaphylaxis
(shock), kidney or liver failure/damage, and the like.
Adverse Events involve lesser events like the things you
read in the package inserts: rashes, “dry mouth”, gastrointestinal effects,
nausea, and the like.
Effect involves the actual effect of the
treatment, measured as change in disease status or progression. In this case,
we’re dealing with the frequency and severity of eclamptic seizures in the
pregnant woman. We will also track the other aspects of pre-eclampsia:
hypertension (high blood pressure) in the late stages of pregnancy, proteinuria
(excessive levels of protein in the urine), thrombocytopenia (deficiency of
blood platelets) and swelling (edema).
We compare the performance of each
treatment group in these results: Toxicity, Safety, Effect.
Basic Clinical Trial
Pre-eclampsia
Sildenafil Citrate
To determine the efficacy and safety of sildenafil
citrate in the treatment of established pre-eclampsia.
Sildenafil Citrate: Better known as Viagra, this drug is a vaso-dilator.
The medication causes blood vessels to dilate, enabling a drop in blood
pressure.
Pre-eclampsia involves the onset of hypertension (high blood
pressure) in the late stages of pregnancy, as well as proteinuria
(excessive levels of protein in the urine), thrombocytopenia (deficiency
of blood platelets) and swelling (edema).
This study is being performed to see if the Sildenafil
Citrate is an effective treatment for pre-eclampsia.
Sketch a basic clinical trial for Sildenafil
Citrate in the treatment of Pre-eclampsia.
Condition of Interest: Pre-eclampsia.
Subjects: Pregnant patients diagnosed with
pre-eclampsia.
Recruitment and Informed Consent: We recruit volunteer candidates who have
been diagnosed with pre-eclampsia, and who meet all requirements for study
inclusion, We exclude all candidates presenting one or
more conditions for exclusion. The volunteers are briefed as to the
requirements, details, potential benefits and risk associated with trial
participation. Those who give informed consent agree to participate and are
enrolled in the trial.
Assignment to Treatment: Enrolled subjects are randomly assigned
to either Sildenafil Citrate or to Placebo. Double-blinding is employed
in the trial, so that neither the study subjects nor their clinical personnel
know the actual assignment status of any subject.
Endpoints and Follow-up: Subjects are followed for toxicity,
safety, effect and quality-of-life.
Toxicity involves severe events such as anaphylaxis
(shock), kidney or liver failure/damage, and the like.
Adverse Events involve lesser events like the things you
read in the package inserts: rashes, “dry mouth”, gastrointestinal effects,
nausea, and the like.
Effect involves the actual effect of the
treatment, measured as change in disease status or progression. In this case,
we’re dealing equally with all aspects of pre-eclampsia. We track the frequency
and severity of eclamptic seizures in the pregnant woman. We track all
aspects of pre-eclampsia: hypertension (high blood pressure) in the late stages
of pregnancy, proteinuria (excessive levels of protein in the urine),
thrombocytopenia (deficiency of blood platelets) and swelling (edema).
We compare the performance of each
treatment group in these results: Toxicity, Safety, Effect.
Old Case Studies
Case Study -
Simvastatin and Heart Attacks
Heart Attacks
The heart
continuously pumps blood enriched with oxygen and vital nutrients through a network
of arteries to all parts of the body's tissues. The heart muscle itself needs a
plentiful supply of oxygen-rich blood, which is provided through a network of
coronary arteries. These arteries carry oxygen-rich blood to the heart's
muscular walls (the myocardium). Coronary artery disease is the most common
cause of heart attacks, which occurs when blood flow to the myocardium is
interrupted. Heart attack occurs when blood flow is blocked and tissue death
occurs from loss of oxygen, severely damaging the heart. Coronary artery
disease is the end result of a complex process commonly called "hardening
of the arteries"). This causes blockage of arteries and prevents
oxygen-rich blood from reaching the heart.
Cholesterol and Lipoproteins. The
story begins with cholesterol and sphere shaped bodies called lipoproteins that
transport cholesterol. Cholesterol is a white, powdery nutrient that is found
in all animal cells and in animal-based foods. The lipoproteins that transport
cholesterol are referred to by their size. The most commonly known are
low-density lipoproteins (LDL) and high density lipoproteins (HDL). In heart
disease, free radicals are released in artery linings and oxidize low-density
lipoproteins (LDL). The oxidized LDL is the basis for cholesterol build-up on
the artery walls. The injuries to the arteries during oxidation signal the
immune system to release white blood cells (particularly those called
neutrophils and macrophages) at the site. These factors initiate the
inflammatory response. Macrophages literally "eat" foreign debris, in
this case oxidized LDL cholesterol. The process converts LDL cholesterol into
foamy cells that attach to the smooth muscle cells of the arteries. The
cholesterol becomes mushy and accumulates on artery walls. Over time the
cholesterol dries and forms a hard plaque, which causes further injury to the
walls of the arteries. Eventually these calcified (hardened) arteries become
narrower. As this narrowing and hardening process continues, blood flow slows
and prevents sufficient oxygen-rich blood from reaching the heart.
Simvastatin is a drug that interferes in the early
stages of cholesterol. This drug actively lowers the levels of serum
cholesterol, and it is thought that this effect may afford protection against heart
attacks.
Sketch
a basic clinical trial of simvastatin that evaluates the effectiveness of
simvastatin in preventing heart attacks.
Describe
the treatments, and the outcome(s) by which the treatments will be evaluated.
The
active treatment is simvastatin. A basic clinical trial is indicated, so there
will be a placebo version of simvastatin.
Do we
want a basic, or comparative trial ?
A basic clinical trial, which uses a placebo for comparison.
Identify
the subject population for this trial.
For the
purpose of this trial, we might focus on subjects who are free of previous
heart attacks, but who do show elevated serum cholesterol. Subjects eligible
for the trial must volunteer and give informed consent in order to participate
in the trial.
Discuss
the assignment of subjects to the treatments in the trial.
Enrolled
subjects are randomly assigned to either simvastatin or to its placebo version.
Neither the subjects nor the clinical workers will know which drug has been
assigned – this is called double blinding.
We
will track the trial subjects in both treatment groups for a number of
outcomes:
Safety
– any adverse reactions to Taxol
Heart
Attack – do the subjects present heart attacks (MI) during follow-up?
Time
to Event – how long does it take the subjects to present MI?
Survival
Status – do the subjects die during followup? Do they die of MI?
Cholesterol
Levels – do subjects show decreased serum cholesterol?
Case Study -
Corticosteroids and Traumatic Brain Injury (TBI)
Traumatic Brain
Injury
Traumatic Brain
Injury (TBI) involves the injury of the brain when it involves sudden or
intense physical force resulting in the presence of Concussion, Skull Fracture,
or Bleeding and Tissue Damage (Contusions, Lacerations, Hemorrhaging) involving
the brain. Tissue damage to the brain results from the
traumatic force of injury, swelling (inflammation) and bleeding.
Consequences of TBI include death, intellectual impairment, social and
emotional impairment and physical disability.
Inflammation
Inflammation is the
response of living tissue to damage. The acute inflammatory response has 3 main
functions. The affected area is occupied by a transient material called the
acute inflammatory exudate. The exudate carries proteins, fluid and cells from
local blood vessels into the damaged area to mediate local defenses. The
damaged tissue can be broken down and partially liquefied, and the debris
removed from the site of damage.
The cause of acute
inflammation may be due to physical damage, chemical substances, micro-organisms
or other agents. The inflammatory response consist of
changes in blood flow, increased permeability of blood vessels and escape of
cells from the blood into the tissues. The changes are essentially the same
whatever the cause and wherever the site.
Acute inflammation
is short-lasting, lasting only a few days. If it is longer lasting however,
then it is referred to as chronic inflammation.
Corticosteroids
Corticosteroids are
drugs that reduce inflammation. Corticosteroids, often referred to as steroids,
are related to cortisol, a naturally produced hormone that controls many
important body functions. In normal amounts, corticosteroids play an important
role in the regulation of blood sugar levels, salt and water, and in metabolism
and growth. They also reduce the activity of the body's immune system and act
to suppress allergic reactions. Corticosteroids are used to decrease the
inflammation that causes the pain, redness and swelling associated with
inflammatory diseases.
Sketch
a basic clinical trial of corticosteroids that evaluates the effectiveness of
corticosteroids in reducing death and disability following TBI.
Describe
the treatments, and the outcome(s) by which the treatments will be evaluated.
The
active treatment is corticosteroid (CS). A basic clinical trial is indicated,
so there will be a placebo version of CS.
Do we
want a basic, or comparative trial ?
A basic clinical trial, which uses a placebo for comparison.
Identify
the subject population for this trial.
Subjects
who qualify for this trial have just suffered a traumatic brain injury (TBI).
Subjects eligible for the trial must volunteer and give informed consent in
order to participate in the trial. Given the altered consciousness that goes
with brain injuries, this trial will utilize the appropriate proxy consent,
in which the subject’s medical agent gives consent.
Discuss
the assignment of subjects to the treatments in the trial.
Enrolled
subjects are randomly assigned to either CS or to its placebo version. Neither the
subjects nor the clinical workers will know which drug has been assigned – this
is called double blinding.
We
will track the trial subjects in both treatment groups for a number of
outcomes:
Safety – any adverse reactions to corticosteroid (CS)?
Physical
Effects – how does post treatment brain tissue damage compare?
Cognitive
Effects – how well does the patient recover cognitive function:
Memory Function
Coordination
Speech
Thought
Emotional Stability
Impulse Control
Life
Effects – how well does the patient recover life function:
Career/Job Function
Social Function
Family Function
Psycho/Sexual Function
Mortality
– how do death rates compare for each treatment group?
Case Study -
Acute Carbon Monoxide Intoxication
Normal Oxygen
versus Normal Oxygen + Hyperbaric Oxygen
Carbon Monoxide
and Hemoglobin
Hemoglobin is a protein that is carried by red cells. Heme is
the prosthetic group that mediates reversible binding of oxygen by hemoglobin.
This mechanism allows the red blood cells to transport oxygen to the cells of
the body. Globin is the protein that surrounds and protects the heme
molecule. It picks up oxygen in the lungs and delivers it to the peripheral
tissues to maintain the viability of cells. Carbon monoxide quickly
binds with hemoglobin with an affinity 200 to 250 times greater than that of oxygen.
The resulting bonding of carbon monoxide and hemoglobin is called carboxyhemoglobin
(COHb).
Effects of Carbon
Monoxide Intoxication
Carbon monoxide
inhibits the blood's ability to carry oxygen to body tissues including vital
organs such as the heart and brain. When CO is inhaled, it combines with the oxygen
carrying hemoglobin of the blood to form carboxyhemoglobin. Once combined with
the hemoglobin, that hemoglobin is no longer available for transporting oxygen.
Symptoms of carbon
monoxide intoxication vary with the degree of intoxication, and the nature of
damage caused to affected organs. For the purposes of this trial, let us focus
on the neurological aspects: Cognitive Skills, Memory Impairment, Coordination,
Headaches.
Normal Oxygen
Therapy
A nonrebreather mask
supplies 100% oxygen at the usual atmospheric pressure to quickly clear COHb
from the blood. This frees up the hemoglobin for oxygen uptake and transport.
Hyperbaric Oxygen
Hyperbaric oxygen
involves delivering oxygen to a patient under higher levels of atmospheric
pressure. Once a patient with acute carbon monoxide poisoning has received
initial treatment and is in stable condition, the physician must decide whether
to initiate hyperbaric oxygen therapy. Hyperbaric oxygen may allow more rapid
clearance of COHb.
Sketch a
comparative clinical trial of normal versus enhanced oxygen therapies in the
treatment of acute carbon monoxide intoxication.
Describe
the treatments, and the outcome(s) by which the treatments will be evaluated.
The
standard treatment is oxygen therapy (OT). The experimental treatment is OT
followed by hyper-baric oxygen therapy (OT+HOT).
Do we
want a basic, or comparative trial ?
A comparative clinical trial, which compares the oxygen treatments.
Identify
the subject population for this trial.
Subjects
who qualify for this trial have just suffered acute carbon monoxide
intoxication. Subjects eligible for the trial must volunteer and give informed
consent in order to participate in the trial. Given the altered consciousness
that goes with brain injuries, this trial may utilize both direct consent and proxy
consent, in which the subject’s medical agent gives consent, depending on
the state of the subject.
Discuss
the assignment of subjects to the treatments in the trial.
Enrolled
subjects are randomly assigned to either OT or to OT+HOT. Neither the subjects
nor the clinical workers will know which drug has been assigned – this is
called double blinding.
We
will track the trial subjects in both treatment groups for a number of outcomes:
Safety – any adverse reactions to either treatment?
Physical
Effects – how does post treatment brain tissue damage compare?
Cognitive
Effects – how well does the patient recover cognitive function:
Memory Function
Coordination
Speech
Thought
Emotional Stability
Impulse Control
Physical
Effects – how often do patients persist in certain effects after treatment?
Headaches
Balance/Coordination
Mortality – how do
death rates compare for each treatment group?
Case Study - Nephrogenic Diabetes Insipidus
Nephrogenic
Diabetes Insipidus is a disease in
which the patient’s kidneys are resistant to the diuretic hormone vasopressin.
Vasopressin is a hormone produced by the hypothalamus, and among other
things, stimulates the kidneys to preserve water and concentrate urine. In NDI,
the kidneys are not responsive to normal amounts of vasopressin.
Symptoms of NDI
include:
Excessive Thirst – polydipsia
Excessive and Dilute
Urine – polyuria
Complications
of NDI include:
Acute
Hyperosmolar Dehydration – excessively high blood plasma concetration
Low
Blood Pressure – hypotension
Shock
Poor
Nutrition and Growth
In
NDI, the problem isn’t a lack of vasopressin, it is a
lack of response to vasopressin. Suppose that we have a new treatment for NDI
cases who have normal levels of vasopressin, but whose
kidneys do not respond adequately to the vasopressin – let’s call it ActiVasex. The purpose of ActiVasex is
to enable the kidneys to respond to the body’s levels of vasopressin. Suppose
further that the only effective intervention for cases of NDI is that of
hydration – maintaining a steady supply of water to replace the outgoing urine.
Assume that all subjects will continue to drink as much water as they need,
regardless of treatment group.
Sketch a basic
clinical trial that evaluates the
experimental treatment ActiVasex in the treatment of NDI cases,
following the examples from class and in the course files. For full credit, discuss
completely.
Solution:
Population
of Interest: Cases of Nephrogenic Diabetes Insipidus;
Treatments:
ActiVasex, and Placebo* ;
We
begin with a set of possible subjects for our study. Those who present with NDI
are briefed as to the particulars of the study, including information about the
possible treatments to be assigned, the methods of assigning treatments and the
potential risks and benefits of the treatments. Those who give informed
consent and join the trial are then randomly assigned to
either Activasex or to Placebo. Neither the
assigned subjects nor their clinical workers are aware of the treatment
assignments (double blinding).
The
subjects are then tracked for the following:
Degree of Thirst
Frequency
of Urination
Concentration
of Urine
Acute
Hyperosmolar Dehydration – excessively high blood plasma concentration
Low Blood
Pressure – hypotension
Shock
Poor
Nutrition and Growth
Medication
Toxicity or Allergic Reactions
We
also track the occurrence of side effects and toxicity.
Case Study
- Ocular Hypertension / Early Prevention of Glaucoma
The eye
is filled with a fluid – there are mechanisms, which provide for the
replacement and draining of this fluid. There is a certain amount of intra-ocular
pressure exerted by the fluid in the eye. A condition called ocular
hypertension (OHT) involves excessive pressures exerted by the
fluid in the eye – sustained OHT can cause damage to the optic nerve, which can
then cause the onset of glaucoma. Glaucoma involves loss of
visual acuity and visual fields due to optic nerve damage. These losses include
loss of visual acuity and loss of peripheral vision.
It is thought that
individuals with OHT are at high risk of developing glaucoma. The purpose of
this clinical trial is the early prevention of glaucoma in individuals who are
glaucoma-free but exhibit ocular hypertension. There is a standard suite of
medications that are used in treating OHT in glaucoma patients. The purpose
of this trial is the evaluation of this suite of medications in the early prevention
of glaucoma.
Sketch a basic
clinical trial that evaluates the
standard OHT suite in the early prevention of glaucoma in OHT subjects,
following the examples from class and in the course files. For full credit,
discuss completely.
Solution:
The treatments:
Placebo/Close
Observation – Placebo version of standard OHT medication
suite. Watch these subjects for progression of OHT and Glaucoma.
Standard
Suite of Glaucoma/OHT Drugs – The usual suite of meds given to glaucoma patients
in reducing intra-ocular hypertension.
Primary
Outcome to be observed is the progression of glaucoma from OHT. The basic
issues are whether the OHT case progresses to Glaucoma, and the extent to which
the onset of Glaucoma is delayed.
Secondary
Outcomes to be observed are Adverse Events and Toxicity
We
require individuals who are currently free of Glaucoma, but who exhibit
excessive intra-ocular pressure – Ocular Hypertension (OHT).
Subjects
who meet all requirements for study admission and who give informed consent are
then randomly assigned to either Placebo/Observation or
Standard Glaucoma/OHT Suite. Double blinding is employed – neither the
subjects nor the clinical workers know the treatment status of the
subjects.
We also
track the occurrence of side effects and toxicity.
Case
Study - Nephrogenic Diabetes Insipidus
Nephrogenic
Diabetes Insipidus is a disease in
which the patient’s kidneys are resistant to the diuretic hormone vasopressin.
Vasopressin is a hormone produced by the hypothalamus, and among other
things, stimulates the kidneys to preserve water and concentrate urine. In NDI,
the kidneys are not responsive to normal amounts of vasopressin.
Symptoms of NDI
include:
Excessive Thirst – polydipsia
Excessive and Dilute
Urine – polyuria
Complications
of NDI include:
Acute
Hyperosmolar Dehydration – excessively high blood plasma concetration
Low
Blood Pressure – hypotension
Shock
Poor
Nutrition and Growth
In
NDI, the problem isn’t a lack of vasopressin, it is a
lack of response to vasopressin. Suppose that we have a new treatment for NDI
cases who have normal levels of vasopressin, but whose
kidneys do not respond adequately to the vasopressin – let’s call it ActiVasex. The purpose of ActiVasex
is to enable the kidneys to respond to the body’s levels of vasopressin.
Suppose further that the only effective intervention for cases of NDI is that
of hydration – maintaining a steady supply of water to replace the outgoing
urine. Assume that all subjects will continue to drink as much water as they
need, regardless of treatment group.
Sketch a basic
clinical trial that evaluates the
experimental treatment ActiVasex in the treatment of NDI cases,
following the examples from class and in the course files. For full credit,
discuss completely.
Solution:
Population
of Interest: Cases of Nephrogenic Diabetes Insipidus;
Treatments:
ActiVasex, and Placebo* ;
We
begin with a set of possible subjects for our study. Those who present with NDI
are briefed as to the particulars of the study, including information about the
possible treatments to be assigned, the methods of assigning treatments and the
potential risks and benefits of the treatments. Those who give informed
consent and join the trial are then randomly assigned to
either Activasex or to Placebo. Neither the
assigned subjects nor their clinical workers are aware of the treatment
assignments (double blinding).
The
subjects are then tracked for the following:
Degree
of Thirst
Frequency
of Urination
Concentration
of Urine
Acute
Hyperosmolar Dehydration – excessively high blood plasma concentration
Low Blood
Pressure – hypotension
Shock
Poor
Nutrition and Growth
Medication
Toxicity or Allergic Reactions
We
also track the occurrence of side effects and toxicity.