Study of the effects of combined treatment with the CFTR corrector ivacaftor and IV antibiotics on infection in CF.

• Register: EUCTR
• Last refreshed on: 29 August 2016
• Main ID: EUCTR2016-001785-29-IE
• Date of registration: 10/05/2016
• Prospective Registration: Yes
• Primary sponsor: St. Vincent's University Hospital
• Public title: Study of the effects of combined treatment with the CFTR corrector ivacaftor and IV antibiotics on infection in CF.
• Scientific title: Combined Effect of CFTR Modifiers and Intensive Antibiotic Treatment
• Date of first enrolment: 15/08/2016
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-001785-29
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Ireland

Contacts

• Name: Dr Edward McKone
• Affiliation: St. Vincent's University Hospital

• Name: Dr Edward McKone
• Affiliation: St. Vincent's University Hospital

Key inclusion & exclusion criteria

Inclusion criteria:
1.1 Inclusion Criteria
• Adult, greater or equal to 18 years of age
• Documentation of a CF diagnosis with the R117H CFTR mutation on at least 1 allele and any known or unknown second mutation other than G551D. CF diagnosis is defined as evidenced by one or more clinical features consistent with the CF phenotype and one or more of the following criteria:

a. sweat chloride = 60 mEq/liter by quantitative pilocarpine iontophoresis test (QPIT)
b. two well-characterized mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene
c. Abnormal nasal potential difference (change in NPD in response to a low chloride solution and isoproteronol of less than -5 mV)
• Prior chronic Pa or Sa in the sputum as defined by > 50% of prior sputum cultures with each organism in the year prior to enrollment. Patients need a minimum of 2 prior cultures in the year.
• Able to expectorate sputum
• Be clinically stable at the time of initiation of ivacaftor (Visit 1)
• Be off chronic inhaled or oral antibiotics (other than azithromycin) for 2 weeks prior to free enrollment
• Patients must be able to tolerate planned antibiotic regimen (anti-Staphylococcal and anti-Pseudomonas aeruginosa regimens)
• Written informed consent and assent if indicated obtained from subject or subject’s legal representative, able to communicate with the Investigator and comply with the requirements of the protocol
• If female and of childbearing potential, must have a negative pregnancy test on Day 1(Start of Treatment) prior to receiving study drug
• If female and of childbearing potential, is willing to use adequate contraception for the duration of the study and for 1 month following the study, as determined by the investigator
• If male and able to father a child, is willing to use adequate contraception for the duration of the study and for 1 month following the study, as determined by the investigator

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 14
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
• Participation in the VX-770-105, VX-770-106, VX-770-108, VX-770-109, VX-770-110, VX-770-111, VX-770-112, or VX-770-113 study, VX-770 Extended Access Program, VX-661-108, or use of ivacaftor within 6 months prior to Visit 1.
• Any upper or lower respiratory symptoms requiring treatment with oral, inhaled or IV antibiotics within the 2 weeks prior to Visit 1.
• History of solid organ transplantation.
• Presence of a condition or abnormality that in the opinion of the investigator would compromise the safety of the patient or the quality of the data.
• History of massive hemoptysis (>240 mL) within 72 hours of Visit 3.
• Inability to produce sputum
• Females who have a positive pregnancy test at Visit 2, are lactating, or are not practicing (or willing to practice) a medically acceptable form of contraception (acceptable forms of contraception: hormonal birth control, intrauterine device, barrier method plus a spermicidal agent or abstinence) from Visit 2 through Visit 7 unless surgically sterilized or postmenopausal.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Cystic fibrosis

Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]

Intervention(s)

Trade Name: Kalydeco
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: IVACAFTOR
CAS Number: 873054-44-5
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 300-300

Trade Name: Ciprofloxacin
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Ciprofloxacin
CAS Number: 86393-32-0
Other descriptive name: CIPROFLOXACIN HYDROCHLORIDE MONOHYDRATE
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 1500-1500

Product Name: Flucloxicillin
Pharmaceutical Form: Powder for injection
INN or Proposed INN: FLUCLOXACILLIN SODIUM
CAS Number: 1847-24-1
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 4000-8000

Trade Name: Fortum
Pharmaceutical Form:
INN or Proposed INN: CEFTAZIDIME
CAS Number: 72558-82-8
Concentration unit: g gram(s)
Concentration type: range
Concentration number: 4-8

Product Name: Tobramycin
Pharmaceutical Form: Powder and solvent for solution for injection
INN or Proposed INN: TOBRAMYCIN SULFATE
CAS Number: 79645-27-5
Concentration unit: mg/kg milligram(s)/kilogram
Concentration type: range
Concentration number: 10-20

Trade Name: Meropenem
Pharmaceutical Form:
INN or Proposed INN: Meropenem
CAS Number: 96036-03-2
Other descriptive name: MEROPENEM
Concentration unit: g gram(s)
Concentration type: range
Concentration number: 3-8

Trade Name: Colistin
Pharmaceutical Form:
INN or Proposed INN: COLISTIMETHATE SODIUM
CAS Number: 8068-28-8
Concentration unit: Munit million units
Concentration type: range
Concentration number: 2-8

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Visit 1 (Day 1)
Visit 5 (Week 19 +/- 5 days)

Main Objective: The primary objectives of this study are:

(i) To determine if the addition of intensive antibiotic treatment produces marked declines in sputum bacterial counts using a sequential intervention study. Because this is a pilot study, no control arm has been added. Patients will serve as their own controls.

(ii) To determine if ivacaftor alone (prior to initiation of antibiotics) produces decreases in sputum P. aeruginosa density and lung function improvements in patients with R117H mutations and non-G551D gating mutations comparable to those seen in patients with G551D mutations.

(iii) To determine if ivacaftor alone (prior to initiation of antibiotics) produces decreases in sputum S. aureus density.

Primary end point(s): Primary Endpoint
Change in sputum P. aeruginosa (Pa) or Staphylococcus aureus (Sa) counts as measured by culture and P. aeruginosa and S. aureus -specific 16S ribosomal DNA between visit 1 and 5

Secondary Objective: The secondary objective of the study is to explore the effect of treatment with ivacaftor (between days 1 and 7), and ivacaftor and antibiotics (on days 7 onward), on various experimental outcome measures directly and indirectly relevant to CFTR modulation.

Secondary Outcome(s)

Secondary end point(s): 1.2 Secondary Endpoints
• Safety as measured by:
o The incidence of adverse events from baseline through Week 19 (Visit 5)
o The incidence of hospitalizations from baseline through Week 55 (Visit 8)
• The relative change in FEV1 (liters) between Day 7 to Week 19.

• The absolute change in FEV1 (liters) between Day 7 to Week 19.

• Change in the absolute in FEV1 % predicted between Day 7 to Week 19.

• Proportion of patients retreated for pulmonary exacerbation following completion of IV antibiotics based on protocol

• Change in exacerbation rate in the 2 years prior to Visit 1 and 2 years after Visit 1.

• Change in both oral and intravenous antibiotic use in the 2 years prior to Visit 1 and 2 years after Visit 1.

• Change in bacterial community indices (richness, evenness and diversity) between Visit 3 and Week 19.

• Change in sputum P. aeruginosa growth rate indices between Visit 0 and Visit 3.

• Change in the sputum bacterial density of other CF pathogens (e.g. Haemophilus influenzae, Burkholderia cepacia complex, Achromobacter xylosoxidans, S. maltophilia) based on quantitative cultures, PCR or DNA based analysis from between Day 7 to Week 19.

• Change in the microbiome parameters like relative abundance of individual bacterial genera between Day 7 to Week 19.

• Change in sweat chloride between Visit 1 and 3 and Visit 3 and Week 19.

• Change in body weight between Visit 3 and Week 19.

• Change in body mass index (BMI) between Visit 3 and Week 19

• Change in respiratory symptom scores as measured by the CF Respiratory Symptom Diary (CFRSD) Chronic Respiratory Infection Symptom Scale (CRISS) between Visit 3 and Week 19.

• Systemic (i.e. Blood) and sputum markers of inflammation (including calprotectin, high sensitivity c-reactive protein, serum amyloid levels in blood; and interleukin 8, neutrophil elastase, and other markers in sputum) during the duration of the study.

• Change in research outcomes (microbiome parameters, sweat chloride, exhaled breath condensate, nasal pH, pupillomerty) from Visit 1 to Visit 2.

Timepoint(s) of evaluation of this end point: Visit 1 (Day 1+/- 1)
Visit 2 (Day 3+/- 1)
Visit 3 (Day 7+/- 1)
Visit 4 (Day 21 +/- 1)
Visit 5 (Week 19 +/- 5 days)
Visit 6 (Week 31 +/- 7 days)
Visit 7 (Week 43 +/- 15 days)
Visit 8 (Week 55 +/- 15 days)

Secondary ID(s)

ARIS2

Source(s) of Monetary Support

Vertex Pharmaceuticals