Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Pilot Trial of Phenylbutyrate/Genistein Duotherapy in Delta F508-Homozygous Cystic Fibrosis Patients
Brief Summary: We are testing a new combination of medicines, to determine if they could be used to treat cystic fibrosis (CF). Subjects with CF who have two copies of the most common mutation (change) found in patients with CF called DF508. CF is caused by a lack of chloride movement in the nose, sinuses, lungs, intestines, pancreas and sweat glands. We are conducting this study to determine the safety of using a combination of two medicines, Phenylbutyrate and Genistein, to improve the ability of the cells lining the nose to regulate movement of salt (chloride) and water in people with CF.

Phenylbutyrate has been extensively used to treat patients with rare metabolic diseases (which are very different from CF), Phenylbutyrate is an investigational drug for the purpose of this study. Genistein is a naturally occurring substance that is found in food products such as soy and tofu, but is also an investigational drug for this study. Both drugs may be able to restore normal chloride movements in body organs and glands. We will be studying salt and water in the nose movement by a technique called nasal transepithelial potential difference (NPD).


Options:
A: Inclusion Criteria:

1. Male or female subject ≥ 18 years of age, on the day of signing the Informed Consent Form (ICF).
2. A confirmed clinical diagnosis of CF.
3. One F508del mutation on one allele in the CFTR gene, a gating (class III) mutation (one of the following: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) on the 2nd allele in the CFTR gene (documented in the subject's medical record or CF registry).
4. Weight ≥ 40 kg.
5. Stable concomitant treatment for at least 4 weeks (28 days) prior to baseline (including physician prescribed ivacaftor (Kalydeco®) 150 mg b.i.d.).
6. Forced expiratory volume in 1 second (FEV1) ≥ 40% of predicted normal for age, gender and height at screening (pre- or postbronchodilator).

Exclusion Criteria:

1. History of clinically meaningful unstable or uncontrolled chronic disease that makes the subject unsuitable for inclusion in the study in the opinion of the investigator.
2. Unstable pulmonary status or respiratory tract infection (including rhinosinusitis) requiring a change in therapy within 4 weeks of baseline.
3. Need for supplemental oxygen during the day, and \>2 liters per minute (LPM) while sleeping.
4. History of hepatic cirrhosis with portal hypertension (e.g., signs/symptoms of splenomegaly, esophageal varices, etc).
5. Abnormal liver function test at screening; defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) and/or alkaline phosphatase and/or total bilirubin (\>1.5 times ULN (CTCAE Grade 2) and/or gamma-glutamyl transferase (GGT) ≥ 3x the upper limit of normal (ULN), and/or total bilirubin (\>1.5 times ULN (CTCAE Grade 2).
6. Estimated creatinine clearance \< 60mL/min using the Cockroft-Gault formula at screening.
B: Inclusion Criteria:

1. Able to communicate with pertinent staff, able to understand and willing to comply with the requirements of the trial, and able and willing to give informed consent.
2. Willing to practice a reliable and study-accepted method of contraception during the study.
3. Diagnosis of cystic fibrosis consisting of both:

   1. clinical manifestations of cystic fibrosis and
   2. cystic fibrosis genotype homozygous for Delta F508 and sweat sodium or chloride \> 60 mEq/L
4. Oxyhemoglobin saturation greater than or equal to 92% while breathing room air

Exclusion Criteria:

1. Underlying diseases likely to limit life span and/or increase risk of complications:

   1. Cancer requiring treatment in the past 5 years, with the exception of cancers that have been cured, or in the opinion of the investigator, carry a good prognosis such as non-melanoma skin cancer, papillary thyroid carcinoma, and cervical cancer in situ.
   2. GI disease

   i. Inflammatory bowel disease requiring treatment in the past year ii. elevations in ALT or AST levels to greater than 3 times the upper limit of normal
2. Conditions or behaviors likely to affect the conduct of the study

   1. Current or anticipated participation in another intervention research project
   2. Recent (with 2 months) sinus surgery or nasal polypectomy
   3. Currently pregnant or less than 3 months post-partum
   4. Currently nursing or within 6 weeks of having completed nursing
   5. Unwilling to undergo pregnancy testing or to report possible or confirmed pregnancy promptly during the course of the study
   6. Unwilling to use a reliable contraceptive method for two months after the completion of the study.
   7. Major psychiatric disorder, which, in the opinion of the investigators, would impede conduct of the study, e.g., alcoholism
   8. Other condition, which, in the opinion of the investigators, would impede conduct of the study.
3. Glucocorticoids other than topical, ophthalmic, and inhaled preparations.
4. Conditions that would place the patient at an increased risk for complications:

   1. Pneumothorax within the last 12 months
   2. Uncontrolled diabetes
   3. Asthma or allergic bronchopulmonary aspergillosis requiring systemic glucocorticoid therapy within the last two months
   4. Sputum culture growing a pathogen that does not have in vitro sensitivity to at least two types of antibiotics which could be administered to the patient
   5. History of major hemoptysis: (Greater than 240 mL of blood within a 24-hour period within the last 12 months).
5. Medication use or conditions not specifically mentioned above, including severe or end stage CF lung disease, that may serve as criteria for exclusion at the discretion of the investigators.
6. History of significant cardiovascular disease, such as myocardial infarction, congestive heart failure, unstable arrhythmia, or uncontrolled hypertension.
C: Inclusion Criteria:

* Aged 12 years and older
* Male or female Non-pregnant women who are to remain non-pregnant for 3 months after the end of the study. Women of childbearing potential must use a reliable method of contraception. Reliable methods of contraception for female patients include the following:
* barrier type devices (e.g., female condom, diaphragm and contraceptive sponge) used ONLY in combination with a spermicide
* intrauterine devices
* oral contraceptive agent
* Depo-Provera™ (medroxyprogesterone acetate)
* levonorgestrel implants Abstention, the rhythm method or contraception by the partner alone are NOT reliable methods of contraception. A woman is considered to have child-bearing potential unless she meets at least one of the following criteria:
* 6 weeks post-surgical bilateral salpingo-oophorectomy or hysterectomy
* Premature ovarian failure confirmed by a specialist gynecologist
* Age \> 50 years and not treated with any kind of HRT for at least 2 years prior to screening, and with amenorrhea for at least 24 consecutive months prior to screening and a serum FSH level of \> 40 IU/L at screening.
* Age \> 55 years and treated with HRT prior to screening with an appropriate medical documentation of spontaneous amenorrhea for at least 24 months. For female patients in the pediatric age range, a reliable method of contraception must be considered, if appropriate.

  * Male patients accepting for the duration of the study and for 3 months thereafter to use a condom and not to procreate a child (not in case of azoospermia)
  * Cystic fibrosis patients homozygous for the F508del mutation as confirmed by genetic test
  * Signed informed consent prior to any study-mandated procedure

Exclusion Criteria:

* Any condition prohibiting the correct measurement of the NPD such as upper respiratory tract infection
* Acute upper respiratory tract or pulmonary exacerbation requiring antibiotic intervention within 2 weeks of screening
* Severe renal impairment (creatinine clearance \< 30 mL/min as per Cockroft and Gault)
* Female patients of childbearing potential who will not undergo a pregnancy test prior to enrollment into the study
* History of significant lactose intolerance
* History of neuropathy
* Presence of clinically significant diarrhea (\> 3 liquid stools per day for \> 7 days) without definable cause within 1 month prior to screening
* Any known factor or disease that might interfere with treatment compliance, study conduct or interpretation of the results such as drug or alcohol dependence or psychiatric disease
* FEV1 \< 25% of predicted normal
* Oxygen saturation at rest \< 88%
* Active or passive smoking as measured using the Smokelyzer®
* Hypersensitivity to miglustat or any excipients
* Planned treatment or treatment with another investigationaldrug or therapy (e.g., gene therapy) within 1 month prior to randomization
* Breast-feeding, pregnant women or women who plan to become pregnant during the course of the study.
D: Key Inclusion Criteria:

* Completed study drug treatment in parent study (VX18-445-104); or had study drug interruption(s) in parent study but completed study visits up to the last scheduled visit of the Treatment Period in the parent study

Key Exclusion Criteria:

* History of study drug intolerance in parent study

Other protocol defined Inclusion/Exclusion criteria may apply.

Answer: B