Study to Evaluate Lumacaftor and Ivacaftor Combination Therapy in Subjects 12 Years and Older With Advanced Lung Disease

• Sponsor: Vertex Pharmaceuticals Incorporated (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02390219
• Collaborator: (none)
• Enrollment: 46
• Locations: 6
• Arm: 1
• Duration (Months): 19.1
• Patients Per Site: 7.7
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety and tolerability of LUM/IVA combination therapy in subjects 12 years and older with CF and advanced lung disease and who are homozygous for the F508del CFTR mutation

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis; Advanced Lung Disease	Drug: Lumacaftor; Drug: Ivacaftor	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3b, Open-Label Study to Evaluate Lumacaftor and Ivacaftor Combination Therapy in Subjects 12 Years and Older With Cystic Fibrosis and Advanced Lung Disease, Homozygous for the F508del-CFTR Mutation
• Study Start Date: Mar 1, 2015
• Actual Primary Completion Date: Oct 1, 2016
• Actual Study Completion Date: Oct 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lumacaftor/Ivacaftor combination Lumacaftor 400 milligram (mg) and ivacaftor 250 mg combination tablet orally twice daily for 24 weeks.	Drug: Lumacaftor; Other Names: VX-809 ; Drug: Ivacaftor; Other Names: VX-770

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) [Day 1 up to Week 28]

   AE: any untoward medical occurrence in a participant during the study; event does not necessarily have a causal relationship with treatment. This includes any newly occurring event/previous condition that has increased in severity/frequency after informed consent form is signed. AE includes serious as well as non-serious AEs. SAE (subset of AE): medical event, which falls into any of the following categories, regardless of its relationship to study drug: death, life threatening adverse experience, in-patient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. TEAEs: AEs that started/ worsened on/after the start of study drug through the Safety Follow up Visit (4 weeks after the last dose of study drug). Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification.

Secondary Outcome Measures

1. Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Up to Week 24 [Baseline, Up to Week 24]

   FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification.

2. Absolute Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Up to Week 24 [Baseline, Up to Week 24]

   FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate FEV1 (for age, gender, race, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification.

3. Duration For Which Participants Received Intravenous (IV) Antibiotics [Baseline through Week 24]

   The duration for which participants received IV antibiotics for sinopulmonary signs and symptoms were reported. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification.

4. Number of Hospitalizations [Baseline through Week 24]

   Number of hospitalizations (all causes) through Week 24 was summarized. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification.

5. Absolute Change From Baseline in Sweat Chloride at Average of Day 15 and Week 4 [Baseline, Day 15 and Week 4]

   Sweat samples were collected using an approved collection device. Baseline was defined as the average of the measurements at screening and on Day 1 pre-dose. The average absolute change from baseline in sweat chloride was derived as: (Average of Day 15 and Week 4 value) minus Baseline value. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification.

6. Absolute Change From Baseline in Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Domain Score Through Week 24 [Baseline, Through Week 24]

   The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), the scaled score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Homozygous for the F508del-CFTR mutation; historical genotype must be documented in the participant's source documents.

• Percent predicted FEV1 <40 of adjusted for age, sex, and height at Screening

Exclusion Criteria:

• Participant currently receiving invasive mechanical ventilation.

• History of any comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the participant

• Any clinically significant laboratory abnormalities at screening that would interfere with the study assessments or pose an undue risk for the subject

• A 12-lead electrocardiograms (ECG) demonstrating QTcF >450 msec at Screening

• History of solid organ or hematological transplantation

• History of alcohol or drug abuse in the past year

• Ongoing or prior participation in an investigational drug study (including studies investigating lumacaftor and/or ivacaftor) within 30 days of screening.

• Use of strong inhibitors, moderate inducers, or strong inducers of CYP3A

• Pregnant and nursing females: Females of childbearing potential must have a negative pregnancy test at Screening and Day 1.

• Sexually active subjects of reproductive potential who are not willing to follow the contraception requirements

• Use of beta blockers or the equivalent at Screening.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Denver	Colorado	United States
2		Tampa	Florida	United States
3		Chicago	Illinois	United States
4		Saint Louis	Missouri	United States
5		Pittsburgh	Pennsylvania	United States
6		Houston	Texas	United States

Sponsors and Collaborators

• Vertex Pharmaceuticals Incorporated

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Vertex Pharmaceuticals Incorporated
• ClinicalTrials.gov Identifier: NCT02390219
• Other Study ID Numbers: VX14-809-106
• First Posted: Mar 17, 2015
• Last Update Posted: Dec 6, 2017
• Last Verified: Oct 1, 2017

• Additional relevant MeSH terms: Cystic Fibrosis; Lung Diseases; Fibrosis; Ivacaftor

Study Results

Participant Flow

Pre-assignment Detail	A total of 46 participants were enrolled and treated in the study.

Arm/Group Title	LUM/IVA
Arm/Group Description	Participants received lumacaftor (LUM) 400 milligram (mg) in combination with ivacaftor (IVA) 250 mg as fixed-dose combination (FDC) tablet orally every 12 hours (q12h) for 24 weeks. A reduced initial dose of LUM 200 mg in combination with IVA 125 mg FDC tablet orally q12h was permitted.
Period Title: Overall Study
STARTED	46
COMPLETED	33
NOT COMPLETED	13

Baseline Characteristics

Arm/Group Title	LUM/IVA
Arm/Group Description	Participants received LUM 400 mg in combination with IVA 250 mg as FDC tablet orally q12h for 24 weeks. A reduced initial dose of LUM 200 mg in combination with IVA 125 mg FDC tablet orally q12h was permitted.
Overall Participants	46
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.1 (9)
Sex: Female, Male (Count of Participants)
Female	16 34.8%
Male	30 65.2%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)
Description	AE: any untoward medical occurrence in a participant during the study; event does not necessarily have a causal relationship with treatment. This includes any newly occurring event/previous condition that has increased in severity/frequency after informed consent form is signed. AE includes serious as well as non-serious AEs. SAE (subset of AE): medical event, which falls into any of the following categories, regardless of its relationship to study drug: death, life threatening adverse experience, in-patient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. TEAEs: AEs that started/ worsened on/after the start of study drug through the Safety Follow up Visit (4 weeks after the last dose of study drug). Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification.
Time Frame	Day 1 up to Week 28

Outcome Measure Data

Analysis Population Description

Safety Set included all participants who were exposed to any amount of study drug.

Arm/Group Title	LUM/IVA
Arm/Group Description	Participants received LUM 400 mg in combination with IVA 250 mg as FDC tablet orally q12h for 24 weeks. A reduced initial dose of LUM 200 mg in combination with IVA 125 mg FDC tablet orally q12h was permitted.
Measure Participants	46
Participants with AEs	43 93.5%
Participants with SAEs	18 39.1%

2. Secondary Outcome

Title	Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Up to Week 24
Description	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification.
Time Frame	Baseline, Up to Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) included all participants who were enrolled and administered any amount of study drug. Here, "Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	LUM/IVA
Arm/Group Description	Participants received LUM 400 mg in combination with IVA 250 mg as FDC tablet orally q12h for 24 weeks. A reduced initial dose of LUM 200 mg in combination with IVA 125 mg FDC tablet orally q12h was permitted.
Measure Participants	32
Least Squares Mean (Standard Error) [Percent predicted of FEV1]	-0.4 (0.7)

3. Secondary Outcome

Title	Absolute Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Up to Week 24
Description	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate FEV1 (for age, gender, race, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification.
Time Frame	Baseline, Up to Week 24

Outcome Measure Data

Analysis Population Description

FAS included all participants who were enrolled and administered any amount of study drug. Here, "Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	LUM/IVA
Arm/Group Description	Participants received LUM 400 mg in combination with IVA 250 mg as FDC tablet orally q12h for 24 weeks. A reduced initial dose of LUM 200 mg in combination with IVA 125 mg FDC tablet orally q12h was permitted.
Measure Participants	32
Least Squares Mean (Standard Error) [Liter (L)]	-0.02 (0.03)

4. Secondary Outcome

Title	Duration For Which Participants Received Intravenous (IV) Antibiotics
Description	The duration for which participants received IV antibiotics for sinopulmonary signs and symptoms were reported. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification.
Time Frame	Baseline through Week 24

Outcome Measure Data

Analysis Population Description

FAS included all participants who were enrolled and administered any amount of study drug. Here, "Number of Participants Analyzed" signifies those participants who received at least one IV antibiotic for sinopulmonary signs and symptoms.

Arm/Group Title	LUM/IVA
Arm/Group Description	Participants received LUM 400 mg in combination with IVA 250 mg as FDC tablet orally q12h for 24 weeks. A reduced initial dose of LUM 200 mg in combination with IVA 125 mg FDC tablet orally q12h was permitted.
Measure Participants	22
Mean (Standard Deviation) [Days]	11.38 (18.15)

5. Secondary Outcome

Title	Number of Hospitalizations
Description	Number of hospitalizations (all causes) through Week 24 was summarized. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification.
Time Frame	Baseline through Week 24

Outcome Measure Data

Analysis Population Description

FAS included all participants who were enrolled and administered any amount of study drug. Here, "Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	LUM/IVA
Arm/Group Description	Participants received LUM 400 mg in combination with IVA 250 mg as FDC tablet orally q12h for 24 weeks. A reduced initial dose of LUM 200 mg in combination with IVA 125 mg FDC tablet orally q12h was permitted.
Measure Participants	16
Number [Hospitalizations]	23

6. Secondary Outcome

Title	Absolute Change From Baseline in Sweat Chloride at Average of Day 15 and Week 4
Description	Sweat samples were collected using an approved collection device. Baseline was defined as the average of the measurements at screening and on Day 1 pre-dose. The average absolute change from baseline in sweat chloride was derived as: (Average of Day 15 and Week 4 value) minus Baseline value. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification.
Time Frame	Baseline, Day 15 and Week 4

Outcome Measure Data

Analysis Population Description

FAS included all participants who were enrolled and administered any amount of study drug. Here, "Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	LUM/IVA
Arm/Group Description	Participants received LUM 400 mg in combination with IVA 250 mg as FDC tablet orally q12h for 24 weeks. A reduced initial dose of LUM 200 mg in combination with IVA 125 mg FDC tablet orally q12h was permitted.
Measure Participants	41
Mean (Standard Error) [Millimoles per litre (mmol/L)]	-16.4 (1.3)

7. Secondary Outcome

Title	Absolute Change From Baseline in Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Domain Score Through Week 24
Description	The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), the scaled score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification.
Time Frame	Baseline, Through Week 24

Outcome Measure Data

Analysis Population Description

FAS included all participants who were enrolled and administered any amount of study drug. Here, "Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	LUM/IVA
Arm/Group Description	Participants received LUM 400 mg in combination with IVA 250 mg as FDC tablet orally q12h for 24 weeks. A reduced initial dose of LUM 200 mg in combination with IVA 125 mg FDC tablet orally q12h was permitted.
Measure Participants	44
Least Squares Mean (Standard Error) [Units on a scale]	2.5 (1.7)

Adverse Events

Time Frame	Day 1 up to Week 28
Adverse Event Reporting Description	AEs were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification.
Arm/Group Title	LUM/IVA
Arm/Group Description	Participants received LUM 400 mg in combination with IVA 250 mg as FDC tablet orally q12h for 24 weeks. A reduced initial dose of LUM 200 mg in combination with IVA 125 mg FDC tablet orally q12h was permitted.
All Cause Mortality
	LUM/IVA
	Affected / at Risk (%)	# Events
Total	1/46 (2.2%)
Serious Adverse Events
	LUM/IVA
	Affected / at Risk (%)	# Events
Total	18/46 (39.1%)
General disorders
Pyrexia	1/46 (2.2%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	16/46 (34.8%)
Bacteraemia	1/46 (2.2%)
Influenza	1/46 (2.2%)
Pneumonia	1/46 (2.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/46 (2.2%)
Nervous system disorders
Neuralgia	1/46 (2.2%)
Respiratory, thoracic and mediastinal disorders
Cough	1/46 (2.2%)
Haemoptysis	1/46 (2.2%)
Respiration abnormal	1/46 (2.2%)
Other (Not Including Serious) Adverse Events
	LUM/IVA
	Affected / at Risk (%)	# Events
Total	43/46 (93.5%)
Cardiac disorders
Palpitations	1/46 (2.2%)
Tachycardia	1/46 (2.2%)
Ear and labyrinth disorders
Vertigo	1/46 (2.2%)
Eye disorders
Lacrimation increased	1/46 (2.2%)
Gastrointestinal disorders
Diarrhoea	5/46 (10.9%)
Nausea	5/46 (10.9%)
Abdominal pain	3/46 (6.5%)
Abdominal pain upper	3/46 (6.5%)
Constipation	3/46 (6.5%)
Flatulence	2/46 (4.3%)
Abdominal discomfort	1/46 (2.2%)
Dyspepsia	1/46 (2.2%)
Dysphagia	1/46 (2.2%)
Gastrointestinal tract mucosal discolouration	1/46 (2.2%)
Gastrooesophageal reflux disease	1/46 (2.2%)
Toothache	1/46 (2.2%)
Vomiting	1/46 (2.2%)
General disorders
Fatigue	7/46 (15.2%)
Chest pain	4/46 (8.7%)
Pain	3/46 (6.5%)
Pyrexia	3/46 (6.5%)
Asthenia	1/46 (2.2%)
Immune system disorders
Seasonal allergy	2/46 (4.3%)
Drug hypersensitivity	1/46 (2.2%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	20/46 (43.5%)
Nasopharyngitis	3/46 (6.5%)
Gastroenteritis viral	2/46 (4.3%)
Vulvovaginal mycotic infection	2/46 (4.3%)
Chronic sinusitis	1/46 (2.2%)
Clostridium difficile colitis	1/46 (2.2%)
Clostridium difficile infection	1/46 (2.2%)
Conjunctivitis	1/46 (2.2%)
Influenza	1/46 (2.2%)
Labyrinthitis	1/46 (2.2%)
Oral candidiasis	1/46 (2.2%)
Sinusitis	1/46 (2.2%)
Sinusitis bacterial	1/46 (2.2%)
Tooth abscess	1/46 (2.2%)
Upper respiratory tract infection	1/46 (2.2%)
Investigations
Alanine aminotransferase increased	3/46 (6.5%)
Aspartate aminotransferase increased	3/46 (6.5%)
Pulmonary function test decreased	3/46 (6.5%)
Blood glucose increased	2/46 (4.3%)
Gamma-glutamyltransferase increased	2/46 (4.3%)
Blood creatine phosphokinase increased	1/46 (2.2%)
Blood glucose decreased	1/46 (2.2%)
Blood immunoglobulin E increased	1/46 (2.2%)
Blood phosphorus decreased	1/46 (2.2%)
Blood pressure diastolic increased	1/46 (2.2%)
Forced expiratory volume decreased	1/46 (2.2%)
Fungal test positive	1/46 (2.2%)
Oxygen consumption increased	1/46 (2.2%)
Prostatic specific antigen increased	1/46 (2.2%)
Sputum abnormal	1/46 (2.2%)
Weight decreased	1/46 (2.2%)
Weight increased	1/46 (2.2%)
White blood cell count increased	1/46 (2.2%)
Metabolism and nutrition disorders
Decreased appetite	5/46 (10.9%)
Dehydration	1/46 (2.2%)
Musculoskeletal and connective tissue disorders
Back pain	2/46 (4.3%)
Muscle spasms	2/46 (4.3%)
Arthralgia	1/46 (2.2%)
Musculoskeletal chest pain	1/46 (2.2%)
Musculoskeletal discomfort	1/46 (2.2%)
Myalgia	1/46 (2.2%)
Nervous system disorders
Headache	7/46 (15.2%)
Lethargy	4/46 (8.7%)
Dizziness	2/46 (4.3%)
Transient ischaemic attack	1/46 (2.2%)
Psychiatric disorders
Insomnia	4/46 (8.7%)
Affect lability	1/46 (2.2%)
Anxiety	1/46 (2.2%)
Depression	1/46 (2.2%)
Irritability	1/46 (2.2%)
Renal and urinary disorders
Nephrocalcinosis	1/46 (2.2%)
Reproductive system and breast disorders
Breast pain	1/46 (2.2%)
Menorrhagia	1/46 (2.2%)
Respiratory, thoracic and mediastinal disorders
Respiration abnormal	25/46 (54.3%)
Cough	21/46 (45.7%)
Dyspnoea	20/46 (43.5%)
Sputum increased	13/46 (28.3%)
Oropharyngeal pain	9/46 (19.6%)
Haemoptysis	7/46 (15.2%)
Nasal congestion	5/46 (10.9%)
Wheezing	5/46 (10.9%)
Respiratory tract congestion	3/46 (6.5%)
Upper respiratory tract congestion	3/46 (6.5%)
Productive cough	2/46 (4.3%)
Rhinorrhoea	2/46 (4.3%)
Asthma	1/46 (2.2%)
Dyspnoea exertional	1/46 (2.2%)
Epistaxis	1/46 (2.2%)
Increased viscosity of bronchial secretion	1/46 (2.2%)
Lower respiratory tract congestion	1/46 (2.2%)
Painful respiration	1/46 (2.2%)
Paranasal sinus discomfort	1/46 (2.2%)
Paranasal sinus hypersecretion	1/46 (2.2%)
Pneumothorax spontaneous	1/46 (2.2%)
Sinus congestion	1/46 (2.2%)
Sputum retention	1/46 (2.2%)
Upper-airway cough syndrome	1/46 (2.2%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	3/46 (6.5%)
Rash	3/46 (6.5%)
Pruritus	2/46 (4.3%)
Acne	1/46 (2.2%)
Alopecia	1/46 (2.2%)
Eczema	1/46 (2.2%)
Night sweats	1/46 (2.2%)
Rash macular	1/46 (2.2%)
Urticaria	1/46 (2.2%)
Vascular disorders
Hot flush	1/46 (2.2%)
Hypertension	1/46 (2.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Restriction Description: PI is free to publish results of the study after (1)first multi-center publication, (2)if sponsor elects not to publish the results, or (3)18 months after close of the study, whichever occurs first. Proposed publications are to be submitted to the sponsor for review and comment for a period of at least 45 days(which may be extended under certain circumstances related to protection of intellectual property); the sponsor cannot require changes to the proposed publications.