Novel Therapeutic Approaches for Treatment of CF Patients With W1282X Premature Termination Codon Mutations
Phase: PHASE4
Conditions: Cystic Fibrosis
Sponsor: University of Alabama at Birmingham

 
 
 
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Novel therapeutic approaches for treatment of CF patients with 
W1282X premature termination codon mutations 
 
 
Study Protocol & Statistical Analysis Plan 
 
 
 
 
September 19 2020 
 
Steven Rowe, MD, Principal Investigator 
University of Alabama at Birmingham 
Birmingham, AL 35294 
 
 

 
 
 
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Title:                                       
UAB Principal 
Investigator:  
Novel therapeutic approaches for treatment of CF patients with 
W1282X premature termination codon mutations 
Steven M. Rowe, M.D. MSPH 
University of Alabama 
1900 University Blvd 
MCLM 821 
Birmingham, AL 35249-0005 
Email: smrowe@uab.edu 
NCT: 
Date  
Version Number  
NCT03624101 
September 19,2020 
Version 1.0 
 
Background and Significance 
Cystic Fibrosis is an autosomal recessive genetic disorder that most critically affects the lungs, but also 
the pancreas, liver, and intestine.1–3 It is characterized by abnormal transport of chloride and sodium 
across the epithelium, leading to thick, viscous secretions and results from mutations in the gene for the 
protein cystic fibrosis transmembrane conductance regulator (CFTR).3,4 This protein functions as a 
channel that transports chloride ions across the membrane of cells and is required to regulate the 
production and/or secretion of mucus, sweat, saliva, tears, and digestive enzymes. Most CF patients 
develop severe, chronic lung disease partly due to increased levels of sulfated mucins, inflammation, 
and recurrent bacterial infections that are eventually lethal; the median predicted survival age in the US 
in 2014 is 39.3 years.5,6 There are approximately 30,000 individuals affected in the US and 70,000 
worldwide.1,5–8 Incidence varies widely according to country and ethnicity. In the US, estimates of 
incidence range from 1 in 1,900-3,700 white Americans.1,7 CF is present, but less frequent, in other US 
groups: estimated incidences in Hispanic, Asian, and Black American populations have been reported to 

 
 
 
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be 1 in 9,200, 1 in 31,000, and 1 in 15,000, respectively.9 There is wide country variability within Europe, 
ranging from 1 in 1,800 in Ireland to 1 in 25,000 in Finland.10 CF is uncommon in Africa and Asia, with 
an incidence of 1 in 350,000 reported in Japan.3  
Symptoms of CF often appear in infancy and childhood, the most frequent of which are respiratory 
symptoms, followed by failure to thrive, steatorrhea, and meconium ileus.1,3 The lungs of individuals 
with CF are colonized and infected by bacteria from an early age. This leads to chronic airway infection 
and inflammation, progressing to bronchiectasis, gas trapping, hypoxemia, and hypercarbia. Pulmonary 
insufficiency is responsible for 70.5% of CF-related deaths in the US.6 In the initial stage, common 
bacteria such as Staphylococcus aureus and Haemophilus influenzae colonize and infect the lungs. 
Eventually, Pseudomonas aeruginosa (and sometimes Burkholderia cepacia) dominates. Once within 
the lungs, these bacteria adapt to the environment and develop resistance to commonly used antibiotics.  
Non-pulmonary complications of CF result from blockages of affected organs with thickened mucosal 
secretions. These blockages cause damage in the pancreas, liver, and intestines leading to exocrine 
pancreatic insufficiency, malabsorption, and recurrent pancreatitis; CF-related diabetes; chronic 
hepatobiliary disease and cirrhosis; and meconium ileus and distal intestinal obstructive syndrome.1,3 
Male infertility due to azoospermia secondary to congenital absence of the vas deferens is also a common 
complication of CF.    
 
Specific Aims 
Approximately 11% of CF patients have premature termination codons (PTC), causing truncated 
CFTR with little to no function. No approved therapies exist for patients with PTC mutations including 
W1282X, a unique mutation exhibiting partial CFTR activity even in its truncated form. CFTR 
modulators alone enhanced CFTR function in patient cells from W1282X/G542X CFTR. Several 
published studies including ours have shown CFTR modulators alone and/or in combination with 
readthrough (RT) agents benefit W1282X CFTR. Clinical studies further support an aspect of this 
notion, where two W1282X patients showed beneficial effect to Ivacaftor treatment.  This sets the 
stage for studies to combine CFTR correctors, to improve truncated but partially active W1282X 
CFTR to the cell surface, with the CFTR potentiator ivacaftor. 
 
Outcome Measures: 
 
Change in Fev1 
 
Participant Selection 
Inclusion Criteria: 
1. Evidence of singed and dated informed consent/assent documents indicating that the subject has 
been informed of all pertinent aspects of the trial 
2. Age 18 years or older 
3. Body weight > 16 kg. 

 
 
 
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4. Diagnosis of CF and documentation of the presence of a nonsense mutation of the CFTR gene, 
as determined by historical genotyping 
5. Ability to perform a valid reproducible spirometry with FEV1 > 30% and < 90% predicted for 
age, gender, and height 
6. If the subject is sexually active, willingness to abstain from sexual intercourse of employ a barrier 
or method of contraception during the study drug administration 
7. Willingness and ability to comply with all study procedures and assessments. 
 
Exclusion Criteria: 
1. Any changes in a chronic treatment regimen for CF or for CF-related conditions within two 
weeks prior to screening 
2. Evidence of pulmonary exacerbation or acute upper or lower respiratory tract infection within 
two weeks prior to screening. 
3. Ongoing tobramycin immunosuppressive, warfarin, phenytoin, or tolbutamide therapy 
4. History of solid organ or hematological transplantation. 
5. A history of positive hepatitis B surface antigen test, hepatitis C antibody test, or human 
immunodeficiency 
6. Major complications of lung disease within four weeks prior to screening 
7. pregnancy or breast feeding 
8. Current smoker or a smoking history of > 10 pack years 
9. Prior or ongoing medical condition, medical history, physical findings, ECG, or laboratory 
abnormality that in the investigators opinion could adversely affect the safety of the subject, 
makes it unlikely that the course of treatment or follow-up would be completed or could impair 
the assessments of the study results 
 
Recruitment Methods 
Eligible participants will be recruited from the Principal Investigators Cystic Fibrosis specialty Care 
clinic the University of Alabama at Birmingham. 
 
Study Methods:  
This study will be an open-label, single-center study, where up to 5 CF patients homozygous for 
W1282X CFTR or W1282X mutation in-trans with other minimal function mutations will initiate 
Symdeko for 28 days followed by Ivacaftor for 28 days OR Ivacaftor for 28 days followed by a 28 day 
off period. 
 

 
 
 
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This assigned alternation will occur for 168 days for 9 study visits across a 6-month period. 
 
Subjects may continue to receive existing therapy/prophylaxis for treatment of CF or CF-related 
conditions. The two treatment intervals will be summarized and evaluated for inter-individual and 
between treatment group analyses.  
 
 
Statistical Analysis 
Results will also be compared to historical run-in data already collected. Clinical efficacy of Symdeko 
as compared to baseline CFTR modulator therapy will be evaluated by lung function (spirometry). 
 
Costs 
The experimental procedure will be done at no cost to the subject or his/her insurance company. If any 
complications arise, they will be billed to the subject’s insurance company.  
 
Biostatistical Analysis  
The within-subject change in FEV1 over baseline CFTR modulator therapy will be the primary 
efficacy outcome measure. Based on the design, the primary analysis will be a descriptive analysis of 
within-subject changes in outcome measures from week 1 to 24 of CFTR function.  These data also 
will be used to test the null hypothesis of no change using the non-parametric Wilcoxon signed-rank 
test (due to small numbers). Change with washout (if conducted; this can be omitted for safety 
considerations) also will be informative.  AE reporting will be conducted via listing tables and 
classified according to causality, per protocol. All statistical tests will be two-sided and will use 
α=0.05.  
 
 
Risk and Discomforts 
CFQR Questionnaire: 
There is a possible risk of loss of confidentiality in questionnaires due to medical history not remaining 
private. This potential risk is guarded against by maintaining completed questionnaires in a locked 
filing system in a locked room at the Child Health Research Center and in password-protected 
computers located at the center. 
 
Blood Draw 
Drawing blood from the arm may cause pain, bruising, light-headedness, and, on rare occasions, 
infection. 
 
Spirometry: 
Some people may have some light-headedness or chest soreness from the hard blowing. The chest 
soreness usually goes away by itself. It can also be helped with non-prescription pain-relievers. 
 
Sweat Test: 

 
 
 
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The Macroduct System is a frequently used system in hospitals and clinics worldwide. This is 
considered to be a very safe painless procedure, but rare small burns have been reported at the site of 
the electrode even though the participant showed no discomfort during the test.   
 
 
Nasal Potential Difference Test: 
Local irritation of the skin where the needle is placed and local infection at the site are possible but 
unlikely.  Nasal irritation, tearing and sneezing may occur because of the tubing placement in the nose.  
Nose bleeding is possible, but very unlikely.  Infusion of amiloride, isoproterenol and ATP into the 
nose will have no foreseeable risks or discomforts. 
 
 
HNE Collection: 
The brushings and/or scrapes inside the nose can be mildly painful and may be associated with a small 
amount of bleeding.  The risk of infection at the site of the brushing and/or scrape is very small. 
 
Rectal Biopsy:  
The rectal biopsy will be mucosal and not transmural, acquiring approximately 2-3 mm of 
tissue 
per biopsy from the very distal rectum (5 cm cephalad). Risks associated with the sub-study 
procedures include: 
• Potential discomfort related to saline enema 
• Potential risks of sedation- Conscious sedation will include use of intravenous midazolam 
and/or morphine as determined by the Gastroenterologist and based on UAB policies regarding 
conscious sedation (attached). Both medications may cause serious or life-threatening breathing 
problems such as shallow, slowed, or temporarily stopped breathing. This GI will monitor heart 
and lungs and to provide life-saving medical treatment quickly if needed.  
• Potential risks of local bleeding and infection 
• Very small risk of bowel perforation 
 
Bleeding would be predicted to be self-limited and infection would be treatable with 
antibiotics. 
Bowel perforation would be treated with antibiotics, repeat endoscopy and, in severe cases, 
with 
surgical intervention. These risks are minimized by performing biopsies under direct 
visualization, not including subjects with diseased tissue in the distal rectum, and are small 
relative to the potential future benefits of developing new CF therapeutics to address patient 
specific CFTR mutation defects. 
 
Risks of optional conscious sedation: 
Nausea and vomiting, although very uncommon, may occur. 
Slight risk of respiratory slowing and respiratory arrest 
 
Risk will be minimized through continuous monitoring throughout participation in the study, including 
comprehensive laboratory assessments, and physical exams. Participants will undergo blood tests 
during this study to look for any possible changes in liver function > than 3X upper limit of normal and 
creatinine kinase. 

 
 
 
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Potential Benefits  
There may be no direct medical benefits to the study participants. data acquired during the study may 
help inform how to treat people with cystic fibrosis in the future. 
 
Monitoring and Quality Assurance 
Dr. Rowe is Principal Investigators at the UAB study site and will be directly responsible for 
the conduct of all study-related procedures performed at UAB. Dr. Rowe will be responsible for 
ensuring patient safety and will directly perform or supervise the performance of the study procedures 
described per protocol. Dr. Rowe has weekly meetings with his research team in which all facets of the 
protocol will be discussed and reviewed. Dr. Rowe is also responsible for reporting any unexpected or 
adverse events to the UAB IRB within the required time frame according to guidelines.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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