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BSN 2b
RLE Group 4

I. Introduction
Cystic fibrosis is a multi-system disorder of the exocrine glands,
leading to increased production of thick mucus in bronchioles, small
intestines and pancreatic and bile ducts & even causes fertility
problems. It is an autosomal recessive disorder that obstructs small
passageways of these organs:

• Lungs (bronchioles): atelectasis (lung collapse) & Emphysema

(Overinflation of the alveoli)
• Pancreatic ducts become clogged, impairing digestion and
• Small intestine: absence of pancreatic enzymes unable to
absorb fats and protein.
Symptoms of cystic fibrosis are:

In babies and infants,

• persistent diarrhea
• bulky, foul smelling and greasy stools
• pale stools
• frequent wheezing or pneumonia
• chronic cough with thick mucus
• salty-tasting skin
• poor growth
• blockage of the intestine (called meconium ileus)
• abdominal swelling
• gassiness
• vomiting
• dehydration
In children,
• frequent respiratory infections
• fever
• cough
• difficulty in breathing
• abdominal pain and discomfort
• gassiness
• fast respiration
• flaring of the nostrils
• poor appetite
• malnutrition
• poor growth
• a barrel-chested appearance
CF can also cause other medical problems, such as:
• sinusitis (inflammation of the nasal sinuses)
• nasal polyps (fleshy growths inside the nose)
• clubbing (rounding and enlargement of fingers and toes)
• pneumothorax (rupture of lung tissue and trapping of air between
the lung and chest wall)
• coughing up blood
• enlargement of the right side of the heart (called cor pulmonale)
• protrusion of the rectum through the anus (called rectal
• liver, pancreatic and gallbladder problems
• delayed puberty
• reproductive abnormalities (especially male sterility) - Over 90
percent of all males with CF are sterile.

Cystic fibrosis is a common genetic disease within the Caucasian

(white) population in the United States. The disease occurs in 1 in
2,500 to 3,500 Caucasian newborns. Cystic fibrosis is less common in
other ethnic groups, affecting about 1 in 17,000 African Americans and
1 in 31,000 Asian Americans. Cystic fibrosis affects 1: 30 Europeans, 1:
3,000 WHITES, 1: 15,000 BLACKS and, 1: 90,000 ASIANS.

The greatest risk factor for cystic fibrosis is a family history of

the disease. If both come from families with cystic fibrosis, then each
of their children has a one in four chance of having cystic fibrosis.
Risk is also greater if they are under Northern European ancestry. In
that case, they have a one in 29 chance of carrying the gene. Among
other ethnic groups in the United States, Hispanics have a one in 46
chance of carrying the gene, blacks have a one in 65 chance and Asian-
Americans a one in 90 chance.
CF is carried as an autosomal recessive trait by about 3% of the
white population. The responsible gene has been localized on the long
arm of chromosome 7. It encodes a membrane-associated protein
called the cystic fibrosis transmembrane conductance regulator
(CFTR). The most common gene mutation, ΔF508, occurs in about 70% of
CF alleles; > 1500 less common CFTR mutations have been identified.
CFTR seems to be part of a cAMP-regulated Cl channel, regulating Cl
and Na transport across epithelial membranes. A number of additional
functions are considered likely. Disease manifests only in homozygotes.
Heterozygotes may show subtle abnormalities of epithelial electrolyte
transport but are clinically unaffected.

II. Pathophysiology
III. Laboratory Tests
Diagnosis of CF can be determined at three stages - prenatal,
postnatal and early childhood.
In pregnant women, the amniotic fluid surrounding the fetus can
be tested for fetal intestinal enzymes. Using a procedure called an
amniocentesis, a sample of amniotic fluid is extracted from the
amniotic sac (the protective covering around the fetus) and analyzed.
In a fetus with CF, the enzymes are decreased.
• Sweat Chloride Test
The most common test for children and young adults is the
electrolyte sweat test. This test measures the amount of electrolytes
(sodium [salt], potassium and chloride) in a person's sweat. This is done
by applying a chemical (called pilocarpine-used to stimulate sweat
production) to the forearm and using a mild electric current to cause
the area to sweat. It analyzes sodiam and chloride content in sweat and
if this results to higher than normal amounts of sodium and chloride,
CF is present. It is done after 3-4 weeks after birth. Patient often
report that infants taste salty when kissed.
• Immunoreactive Trypsinogen Test (IRT)
In newborn babies who cannot produce enough sweat for a sweat test,
an IRT may be done. An IRT is a blood test that involves drawing blood
a couple of days after birth and evaluating the presence of the protein
trypsinogen. If the test is positive, it should be confirmed by a
mutation analysis (i.e., genetic testing). The combination of an IRT and
a mutation analysis is sensitive 90% to 100% of the time.
• Nasal Potential Difference (NPD) Measurement
As Na+ (sodium) and Cl- ions move across the membranes of the cells
lining the airway, they generate what is called an electric potential
difference (the amount of energy required to move an electrical charge
from one point to another). In the nasal passages, this electric
potential difference is known as the nasal potential difference (NPD),
and it can be easily measured with a surface electrode. Because Na+
and Cl- transport is abnormal in CF patients, NPD measurements are
very different in CF patients than in people who do not have CF.
This test is especially helpful when the sweat electrolyte test and/or
the genetic tests are inconclusive. However, the success of the test is
highly dependent on the skill of the technician, and should be done in a
special center.
• Genetic Testing
A genetic test, also known as a genotype test or mutation analysis, is
designed to analyze DNA for the presence of one of the several
hundred mutations that can cause CF. The test involves collecting a
sample of the patient's blood. The test cannot detect all of the
mutations that can cause CF, however, so its sensitivity is only about
80% to 85%. Genetic testing cannot be used to predict the severity of
symptoms. There is no way to know, based on a person's genotype,
whether CF will be fatal or mild.
Generally, a genetic test is done if a patient's sweat test is negative
and there is still high suspicion that the patient has CF.
• Pulmonary Function Tests
Pulmonary function tests may be done to assess the patient's
respiratory dysfunction and whether the patient is healthy enough to
receive a lung transplant, if necessary.
• 72-hour stool collection (Keep food diary)

Analyzes fat & enzyme content.

• Chest x-ray

To reveal atelectasis & obstructive emphysema

IV. Medical Management

Attempt aggressive medical management prior to surgical
intervention. Patients may report chronic purulent nasal discharge or
cough, but initiate therapy whenever they experience a subjective
increase in nasal obstruction, cough, or drainage. Oral antibiotics
effective against Pseudomonas species and staphylococci, coupled with
aggressive nasal toilet, may improve symptoms.
• Antibiotic choices: The bacteriology of sinonasal disease in
patients with cystic fibrosis (CF) differs from that in patients
without CF. This difference affects antibiotic choices. The most
notable difference is the nearly ubiquitous presence of
Pseudomonas species in patients with CF. As detailed above, sinus
aspirates are important to direct treatment against Pseudomonas
• Nasal toilet: Because mucociliary clearance is chronically
impaired, irrigations are critical and should be a daily routine as
patients begin to develop sinonasal symptoms. Nasal saline
irrigations serve to decrease bacterial colonization, wash away
inspissated secretions that lead to obstruction, and temporarily
aid in vasoconstriction. Irrigation is also required after any
surgical intervention because surgery enlarges sinus ostia but
does not address underlying defects in mucociliary clearance
• Physiotherapy: to help clear the lungs of mucus, which attracts
• Exercise: beneficial as a form of physiotherapy and for general
• Nutrition: enzyme tablets to help digest food and dietetic

V. Surgical Management

• Surgical Therapy

Nasal polypectomy to relieve obstruction is the most common surgical

procedure in CF, and most patients get symptomatic improvement.375
Recurrence of polyps is common, but the incidence of polyposis usually
wanes after the second decade. Gallstones are common, and
symptomatic disease may require elective cholecystectomy in as
many as 5% of CF adults. Lobectomy is occasionally indicated for
massive hemoptysis that is refractory to bronchial
artery embolization. Partial lung resection has been advocated for
apparently localized disease and recurrent severe
exacerbations. However, the generalized lung disease continues to
progress; the limited probability of long-termbenefits dictates caution
in patient selection.
• Transplantation

Lung transplantation has become an accepted treatment for

respiratory failure secondary to CF. Heart-lung transplant
has been largely replaced by sequential double-lung transplant because
of limited organ availability. Patients should be referred when their
prognosis is about equal to the waiting time for donor lungs, currently
about 2 years after acceptance as a lung transplant candidate. More
than 1600 lung transplants have been performed for CF around the
world. The transplanted lungs remain free of CF but are subject to
secondary infection, acute rejection, and chronic rejection
(bronchiolitis obliterans syndrome). The 5-year survival is 48%—as
good as that of lung transplant recipients
with other causes of lung disease. Living lobar transplantation is an
effective alternative to conventional
cadaveric lung transplants.380 The lobe donors must have sufficiently
large lungs that their lower lobe fills the recipient’s
hemithorax. Survival appears to be similar to that following
conventional lung transplantation.

VI. Medications
• Nasal corticosteroids
These agents decrease mucosal edema and promote mucus clearance.

Fluticasone furoate (Veramyst)

Has potent glucocorticoid activity, weak mineralocorticoid activity, and
the least systemic absorption of nasal steroid preparations.
Contraindicated to patients with hypersensitivity to drug.
Mometasone furoate monohydrate (Nasonex)
Has potent glucocorticoid activity, weak mineralocorticoid activity, and
the least systemic absorption of nasal steroid preparations. Decreases
rhinovirus-induced up-regulation in respiratory epithelial cells and
modulates pretranscriptional mechanisms. Reduces intraepithelial
eosinophilia and inflammatory cell infiltration (eg, eosinophils,
lymphocytes, monocytes, neutrophils, plasma cells). Its
contraindications are documented hypersensitivity; nasal septal
perforation; nasal surgery and nasal trauma.

• Systemic corticosteroids
Short-term bursts may be beneficial for acute exacerbations and may
prevent increased intraoperative bleeding in patients with severe

Prednisolone (Delta-Cortef, Econopred)

Suppresses key components of immune system. Widely available in
syrup form; easily dosed for children. Containdicated to patients with
documented hypersensitivity; viral infection; peptic ulcer disease;
hepatic dysfunction; connective tissue infections; fungal or tubercular
skin infections and GI disease.

Prednisone (Deltasone, Meticorten, Orasone)

Suppresses key components of immune system. Widely available in
syrup form; easily dosed for children. Contraindicatd to patients with
documented hypersensitivity; viral infection; peptic ulcer disease;
hepatic dysfunction; connective tissue infections; fungal or tubercular
skin infections and GI disease.
Dexamethasone (Decadron, Dexasone, Solurex)
Can be administered IV at induction of anesthesia; may help immediate
postoperative inflammation. Contraindications include: coadministration
with estrogens may decrease prednisone clearance; concurrent use
with digoxin may cause digitalis toxicity secondary to hypokalemia;
phenobarbital, phenytoin, and rifampin may increase metabolism of
glucocorticoids (consider increasing maintenance dose); monitor for
hypokalemia with coadministration of diuretics.

• Decongestants
These agents are helpful in improving the nasal airway and shrinking
down swollen tissues in some patients.

Pseudoephedrine hydrochloride (Sudafed, Actifed)

Sympathomimetic agent that shrinks swollen nasal mucosa.
Contraindicated to patients with documented hypersensitivity; severe
anemia; postural hypertension or hypotension; closed angle glaucoma;
head trauma and cerebral hemorrhage.
• Anti-inflammatory Therapy With Ibuprofen

A recent study of high-dose ibuprofen over 4 years indicates that

young CF patients (<13 years) with mild lung disease have remarkable
slowing of the decline of lung function (eightfold) compared to placebo
control subjects. No
effect was documented in patients older than 13 years, even among
patients with mild lung disease. There were few side
effects, but most of the patients were taking antacids or H2-receptor

• Topical nasal medications

Some authors advocate irrigations with antipseudomonal antibiotics
such as tobramycin, and these may be effective in decreasing bacterial
colonization. Nebulization of antipseudomonal medications like
tobramycin is clearly beneficial for lung infections in CF patients, but
may not be particularly useful for the sinuses. Serial tobramycin
irrigation of the maxillary sinuses, which can be done in an office
setting in a compliant patient, however, may significantly decrease the
intensity and frequency of infections, especially when done after sinus
Two small studies have shown improvement of postoperative mucosal
edema, pulmonary function testing, and polyp regrowth after sinus
surgery when recombinant human deoxyribonuclease I (dornase alfa or
Pulmozyme) was used via nasal inhalation.28,29

VII. Health teachings:

If a child has cystic fibrosis, one of the best things family members
can do is to learn as much as possible about the disease. Diet,
medication and early recognition of infection are important.
Also important for most patients is performing daily chest percussion
to drain mucus from child's lungs. Doctor or respiratory therapist can
show the best way to perform this lifesaving procedure.
In addition, the following steps can help aid your child's health:
• Keep child's immunizations up to date. In addition to other
usual childhood vaccines, this includes the pneumococcal and
influenza vaccines. Cystic fibrosis doesn't affect the immune
system, but children with cystic fibrosis are more likely to
develop complications when they become sick.
• Encourage child to lead as normal and active a life as
possible. Exercise is extremely important for people of all ages
who have cystic fibrosis. Regular exercise helps loosen mucus in
airways and strengthens heart and lungs. And for many people
with cystic fibrosis, participating in sports can improve
confidence and self-esteem. It isn't necessary to take part in an
organized sport or take classes at a gym. Anything that gets
moving, including walking and biking, can help.
• Make sure your eats a healthy diet. Be sure to discuss child's
dietary needs with doctor or a nutritionist.
• Use nutrition supplements. Provide the fat-soluble vitamin
supplements and pancreatic enzymes that the child needs to stay
as healthy as possible.
• Emphasize liquids. Encourage child to drink plenty of liquids to
help loosen the mucus. This is especially important in the summer
when children are active and tend to lose a lot of fluids.
• Eliminate smoke. Don't smoke in home or car, and don't allow
other people to smoke around child. Secondhand smoke is harmful
for everyone, but especially for people with cystic fibrosis.
• Encourage hand washing.Teach everyone in family to wash their
hands thoroughly before eating, after using the bathroom, when
coming home from work or school, and after being around a
person who is sick. Hand washing is the best way to protect
against infection.

VIII. Advanced researches:

The Cystic Fibrosis Foundation has built a dynamic "pipeline" for the
development of more new potential CF therapies than ever before. To
treat a complex disease like cystic fibrosis (CF), therapies must target
problems in the airways and the digestive system.
In the cystic fibrosis drug development pipeline, there also are
promising new therapies designed to rectify the cause of CF—a faulty
gene and/or its faulty protein product.

Clinical Trial Descriptions

Because a faulty gene causes cystic fibrosis (CF), adding normal copies
of the gene to cells could correct these cells and ultimately cure the
disease. This approach is exploring ways to introduce normal copies of
the gene into CF airways.
• Compacted DNA (PLASmin™): Using compacted DNA (non-viral)
to introduce normal copies of the gene into CF airways. A Phase 1-
a trial demonstrated chloride current changes in the noses of CF
patients, but no evidence of gene expression. The gene therapy
product is being reformulated prior to additional clinical trials in
an attempt to improve the amount and duration of gene
These therapies are designed to correct the function of the defective
CFTR protein made by the CF gene, allowing chloride and sodium (salt)
to move properly in and out of cells lining the lungs and other organs.
• Ataluren (formerly known as PTC124): PTC Therapeutics – A
novel, small molecule compound, that promotes the read-through
of premature truncation codons in the CFTR mRNA. It has been
demonstrated to be safe, orally available and well tolerated in a
Phase 1 single-dose trial in healthy volunteers. A Phase 2 trial in
CF patients conducted in the United States and Israel
demonstrated safety and encouraging biological results. A
Phase 3 trial is scheduled to begin in summer 2009.
• VX-770: Vertex Pharmaceuticals, supported by CFFT. VX-770 is a
"potentiator" that may act upon the CFTR protein and help to
open the chloride channel in CF cells. Phase 1 dosing has been
completed in healthy volunteers and CF patients. A Phase 2 trial
in CF patients with at least one copy of the G551D mutation in
their CF gene demonstrated improvements in biological measures
of CFTR function (nasal potential difference and sweat chloride)
and clinical measures of pulmonary health (FEV1). Two Phase 3
studies (one for pediatric and one for adolescent/adult patients)
are scheduled to begin in Spring 2009.
• VX-809: Vertex Pharmaceuticals, supported by CFFT. VX-809 is a
“corrector” that helps move defective CFTR protein to the
proper place in the airway cell membrane and improve its function
as a chloride channel. A Phase 2a trial began in spring 2009.
These studies are evaluating drugs for their effectiveness in
preventing, thinning and clearing thick mucus from the airways.
• Pulmozyme: Genentech, approved in 1993 and currently being
used by more than 18,000 patients in the United States. Clinical
trials were conducted in the CFF’s care center network.
In cystic fibrosis, changes in salt transport within cells dehydrate
mucus, causing it to become thick and sticky. This approach targets
proteins other than CFTR to improve the movement of salt in and out
of cells, allowing mucus to be more hydrated and, therefore, cleared
more easily.
• Hypertonic Saline: A CFFT-funded Phase 3 trial in Australia had
beneficial effects on pulmonary health in CF patients. Follow-on
studies are determining if younger patients would benefit from
this inhaled therapy.
• Denufosol: Inspire Pharmaceuticals, supported by a CFFT TDA
and the TDN. Correct the ion transport defect in CF. In June
2008, Inspire announced top-line results from TIGER-1, its first
Phase 3 trial with denufosol for CF. The trial demonstrated
statistical significance for its primary endpoint of change in FEV1
from baseline compared to placebo. Inspire is currently enrolling
patients in TIGER-2, the second pivotal Phase 3 trial with
• Bronchitol: Pharmaxis – A Phase 3 trial of Bronchitol (an inhaled
dry powder mannitol) has begun in the United States and in
Canada. Theoretically, mannitol should help rehydrate CF
secretions, improving airway clearance. Trials in Australia and
Europe support this hypothesis.
• SPI-8811: Sucampo Pharmaceuticals and the TDN. Oral agent
believed to bypass transport defect of chloride ions. Initial Phase
2a trial evaluating safety and efficacy. Thirty patients recruited.
• Moli 1901: Lantibio, supported by a CFFT TDA and the TDN.
Thought to affect the ion transport defect in CF patients. Phase
1 trial demonstrated safety. Placebo-controlled, multi-dose, dose-
ranging Phase 2 trial in Europe demonstrated positive changes in
pulmonary function with highest dose.
• Gilead GS9411: As a follow-on compound from Parion 552 that
was used to demonstrate proof of concept, GS9411 has entered a
Phase 1 CF clinical trial. It acts by blocking sodium absorption.

The drugs in this category are being studied for their ability to reduce
inflammation in CF lungs, which should help decrease chronic damage to
lung tissue.
• Ibuprofen: A four-year CFF-supported high dose ibuprofen trial
completed in 1990 demonstrated less lung function decline in the
treatment group than the control group. This effect was greatest
in 5-13 year-olds.
• Oral N-acetylcysteine: BioAdvantex – An antioxidant, oral N-
acetylcysteine replenishes glutathione levels in neutrophils.
Placebo-controlled 12-week study at Stanford Univ.
demonstrated decreases in inflammatory cells in lung and positive
indications of changes in pulmonary function.
• DHA: Univ. of Massachusetts, CFFT-supported as clinical
research grant. Pilot study to examine effect of infant formula
fortified with DHA on pathogenesis of CF in 120 newly diagnosed
patients at 16 centers began in 2003.
• Sildenafil (Revatio): Based upon prior work by researchers at the
University of New Mexico, clinicians there are examining whether
sildenafil can lower markers of airway inflammation and measures
of airway infection in CF patients, as well as alter the patient's
perception of their own well being.
• Inhaled Glutathione: A Phase 1 trial of inhaled glutathione has
been completed in Germany and a Phase 2b trial is now in
• Pioglitazone, Hydroxychloroquine: These approved therapies
(approved for non-CF indications) are being evaluated in
exploratory Phase 1 trials in CF to determine if they are
tolerated and if anti-inflammatory effects are seen.
• Simvastatin (Zocor™): A HMG-CoA reductase inhibitor that
increases nitric oxide (NO) production in cultured CF epithelial
cells. Investigators are evaluating, in a CFFT-funded trial,
whether simvastatin increases exhaled NO production in CF
patients, synthesis of pro-inflammatory cytokines and whether
measures of inflammation in the upper respiratory tract
correlate with those from the lower respiratory tract.
• HE-3286: Hollis-Eden Pharmaceuticals, supported by a CFFT
TDA. An oral immune-regulating hormone which has replaced
The compounds in this category are being evaluated for their
effectiveness in fighting acute and chronic lung infections by
destroying infection-causing bacteria that enter into the airways and
• TOBI®: Novartis Pharmaceuticals – This CFF/Children’s Hospital,
Seattle-developed aerosol antibiotic was licensed to Chiron and
received FDA approval in 1997. Currently being used by more than
15,000 patients worldwide. Benefit at first sign(s) of
Pseudomonas infection is being evaluated.

• Azithromycin: Pfizer – A large-scale, CFFT-conceived and

supported, TDN-coordinated trial completed in 2002. In patients
with chronic Pseudomonas aeruginosa, this oral antibiotic
improved lung function and weight gain, and decreased
hospitalization rate. Two follow up studies are in progress.

• AZLI: Gilead Sciences, supported by a CFFT TDA and conducted

in the TDN. Multiple Phase 3 trials of the aerosolized form of
aztreonam, a widely used IV antibiotic in CF, have been completed
and the FDA has reviewed all the data. Data from another clinical
trial will be required but further discussions with the FDA are
necessary to determine if ongoing trials will suffice.

• TIP (TOBI Inhaled Powder): Novartis Pharmaceuticals is

developing TOBI as a powder to enable a faster, more convenient
dosing regimen. Dosing of TIP will take a fraction of the time of
liquid TOBI. A Phase 3 trial has completed enrollment.

• ArikaceTM: Transave – A liposomal formulation of the antibiotic

amikacin. Animal model studies have shown it to decrease the
Pseudomonas aeruginosa burden in the lung. A Phase 1/2 trial in
Europe has completed enrollment. A Phase 2 trial began in the
TDN in 2007.

• BAY Q3939: Bayer Schering Pharma is developing an inhaled

version of their antibiotic ciprofloxacin for treatment of airway
infections. A small Phase 2 study in Germany is underway. A U.S.
multicenter Phast 2 trial is currently enrolling patients.

• MP-376: MP-376 is a new formulation of levofloxacin being

developed by Mpex Pharmaceuticals for aerosol administration to
CF patients for management of chronic pulmonary infections due
to Pseudomonas aeruginosa and other bacteria. A U.S. multicenter
Phase 2 trial has completed enrollment.

• KB001: Kalobios Pharmaceuticals has initiated a Phase 1 clinical

trial to test the safety of their antibody approach for treatment
of Pseudomonas aeruginosa lung infections.

• GS 9310/11: Gilead Sciences inhaled combination antibiotic

(fosfomycin and tobramycin) has completed Phase 1 testing in
Australia. A U.S. multicenter Phase 2 trial is currently enrolling
One potential drug is being evaluated for its ability to reduce the
chance of organ rejection, which is common after transplantation.
• Inhaled Cyclosporine: APT Pharmaceuticals – Inhaled formulation
of cyclosporine was tested in a randomized placebo controlled
trial at the Univ. of Pittsburgh. The group treated with inhaled
cyclosporine showed a significant decrease in number of deaths
and the development of chronic rejection. An additional clinical
trial has been requested by the FDA before this drug is approved
for clinical use.
Specially formulated supplements in this category include vitamins, as
well as enzymes that increase both fat and vitamin absorption, allowing
better nutrition for people with CF, who can become malnourished as a
result of thick mucus clogging the pancreas.
• AquADEKs: Yasoo Health – Oral antioxidant vitamin formulation
specifically for CF patients. A Phase 1 trial has been completed. A
clinical trial to assess the safety and ability of this formulation
to increase blood levels of antioxidants, normalize plasma levels
of fat-soluble vitamins, improve pulmonary function and improve
growth parameters began in 2007. AquADEKs is available to

• Pancrelipase Enzyme Products: The FDA has required pancreatic

enzyme products to be reformulated and undergo clinical testing
in order to receive FDA approval. Companies completing this
process include: Axcan Scandipharm (Ultrase), DCI
(PANCRECARB), Eurand (Zentase), McNeil (Pancrease MT) and
Solvay (Creon).

• Liprotomase (formerly Trizytek): Altus Pharmaceuticals,

supported by a CFFT TDA, conducted in the TDN. Non-porcine
pancreatic enzyme replacement. Phase 1 studies have not
identified safety concerns. A Phase 2 trial has been completed,
demonstrating safety and efficacy and a Phase 3 trial also has
ended. Work to complete requirements for FDA submission is

IX. Sources: