A Study to Explore the Impact of Lumacaftor/Ivacaftor on Disease Progression in Subjects Aged 2 Through 5 Years With Cystic Fibrosis, Homozygous for F508del

• Sponsor: Vertex Pharmaceuticals Incorporated (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03625466
• Collaborator: (none)
• Enrollment: 51
• Locations: 5
• Arms: 3
• Actual Duration (Months): 37.9
• Patients Per Site: 10.2
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study will explore the impact of lumacaftor/ivacaftor (LUM/IVA) on disease progression in subjects aged 2 through 5 years with cystic fibrosis (CF), homozygous for F508del (F/F).

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis	Drug: LUM; Drug: LUM/IVA; Drug: IVA; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 51 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Double blinded in Part 1, and Open label in Part 2
• Primary Purpose: Treatment
• Official Title: An Exploratory Phase 2, 2-part, Randomized, Double-blind, Placebo-controlled Study With a Long-term, Open-label Period to Explore the Impact of Lumacaftor/Ivacaftor on Disease Progression in Subjects Aged 2 Through 5 Years With Cystic Fibrosis, Homozygous for F508del
• Actual Study Start Date: Aug 10, 2018
• Actual Primary Completion Date: Oct 9, 2020
• Actual Study Completion Date: Oct 7, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1: Placebo Participants received placebo matched to LUM/IVA in placebo-controlled period for 48 weeks.	Drug: Placebo; Placebo matched to LUM/IVA for oral administration.
Experimental: Part 1: LUM/IVA Participants weighing less than (<)14 kilograms (kg) at screening received LUM 100 milligrams (mg)/IVA 125 mg fixed-dose combination (FDC) every 12 hours (q12h) in placebo-controlled period for 48 weeks. Participants weighing greater than or equals to (>=)14 kg at screening received LUM 150 mg/IVA 188 mg FDC q12h in placebo-controlled period for 48 weeks.	Drug: LUM/IVA; FDC granules for oral administration.; Other Names: Lumacaftor/Ivacaftor VX-809/VX-770
Experimental: Part 2: Open Label Period Participants <6 years of age will receive LUM/IVA as FDC granules dependent upon weight at Day 1. Participants >=6 years of age at or after the Week 48 Visit will receive LUM 200 mg/IVA 250 mg tablets q12h.	Drug: LUM; FDC tablet or granule (LUM/IVA).; Other Names: Lumacaftor VX-809 ; Drug: IVA; FDC tablet or granule (LUM/IVA).; Other Names: Ivacaftor VX-770

Outcome Measures

Primary Outcome Measures

1. Part 1: Absolute Change From Baseline in MRI Global Chest Score at Week 48 [From Baseline at Week 48]

   MRI scans assessed semi-quantitatively via a standardized chest MRI scoring system. Each participant had 6 lobes scored using 7 scoring parameters:1) Bronchiectasis/wall thickening 2) Mucus plugging 3) Abscesses/sacculations 4) Consolidations 5) Special findings 6)Mosaic pattern 7) Perfusion abnormalities. For each of 7 parameter, there were scores of 6 lobes (score of each lobe : 0= normal value, 1 = <50% of lobe involved and 2 = >=50% of lobe involved). MRI global score was calculated as sum of parameters 1 to 7. MRI total score is ranged from 0-84. Higher score indicate more lobe involvement.

Secondary Outcome Measures

1. Part 1: Absolute Change in Lung Clearance Index2.5 (LCI2.5) Through Week 48 [From Baseline Through Week 48]

   LCI2.5 represents the number of lung turnovers required to reduce the end-tidal inert gas concentration to 1/40th of its starting value.

2. Part 1: Absolute Change in Weight-for-age Z-score at Week 48 [From Baseline at Week 48]

   The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.

3. Part 1: Absolute Change in Stature-for-age Z-score at Week 48 [From Baseline at Week 48]

   The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.

4. Part 1: Absolute Change in Body Mass Index (BMI)-For-age Z-score at Week 48 [From Baseline at Week 48]

   BMI was defined as weight in kilogram (kg) divided by squared height in meters (m^2). The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 5 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Subjects with confirmed diagnosis of CF.

• Homozygous for F508del (F/F).

• Subjects who weigh ≥8 kg without shoes and wearing light clothing at the Screening Visit.

Key Exclusion Criteria:

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

• Solid organ or hematological transplantation.

• History of any illness or comorbidity reviewed at the Screening Visit that, in the opinion of the investigator, might confound the results of the study.

Other protocol defined Inclusion/Exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Charite Paediatric Pulmonology Department	Berlin		Germany
2	Justus-Leibig-Universitat Zentrum fur Kinderheilkunde und Jugendmedizin	Giessen		Germany
3	Hannover Medical School	Hannover		Germany
4	Heidelberg Cystic Fibrosis Center	Heidelberg		Germany
5	Universitatsklinikum Schleswig-Holstein, Klinik für Kinder- und Jugendmedizin	Lubeck		Germany

Sponsors and Collaborators

• Vertex Pharmaceuticals Incorporated

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jul 24, 2019
• Statistical Analysis Plan - Oct 16, 2020

More Information

Publications

None provided.

• Responsible Party: Vertex Pharmaceuticals Incorporated
• ClinicalTrials.gov Identifier: NCT03625466
• Other Study ID Numbers: VX16-809-121; 2017-003761-99
• First Posted: Aug 10, 2018
• Last Update Posted: Dec 8, 2021
• Last Verified: Nov 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis; Disease Progression; Ivacaftor

Study Results

Participant Flow

Recruitment Details	This study was planned to have 2 parts: Parts 1 (Placebo-controlled Period) and 2 (Open-label Period). Part 1 has been completed while Part 2 is still ongoing. Primary completion was achieved based on Part 1 in October 2020. Therefore, only Part 1 results are reported. Complete results including Part 2 will be updated within 1 year of study completion date.
Pre-assignment Detail	This study was conducted in participants with cystic fibrosis (CF) aged 2 to 5 years.

Arm/Group Title	Part 1: Placebo	Part 1: LUM/IVA
Arm/Group Description	Participants received placebo matched to LUM/IVA in placebo-controlled period for 48 weeks.	Participants weighing less than (<)14 kilograms (kg) at screening received LUM 100 milligrams (mg)/IVA 125 mg fixed-dose combination (FDC) every 12 hours (q12h) in placebo-controlled period for 48 weeks. Participants weighing greater than or equals to (>=)14 kg at screening received LUM 150 mg/IVA 188 mg FDC q12h in placebo-controlled period for 48 weeks.
Period Title: Overall Study
STARTED	16	35
COMPLETED	16	33
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Part 1: Placebo	Part 1: LUM/IVA	Total
Arm/Group Description	Participants received placebo matched to LUM/IVA in placebo-controlled period for 48 weeks.	Participants weighing <14 kg at screening received LUM 100 mg/IVA 125 mg FDC q12h in placebo-controlled period for 48 weeks. Participants weighing >=14 kg at screening received LUM 150 mg/IVA 188 mg FDC q12h in placebo-controlled period for 48 weeks.	Total of all reporting groups
Overall Participants	16	35	51
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	4.2 (1.0)	4.2 (1.0)	4.2 (1.0)
Sex: Female, Male (Count of Participants)
Female	7 43.8%	11 31.4%	18 35.3%
Male	9 56.3%	24 68.6%	33 64.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	16 100%	35 100%	51 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	16 100%	35 100%	51 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Magnetic Resonance Imaging (MRI) Global Chest Score (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	21.4 (9.3)	17.6 (9.7)	18.8 (9.6)

Outcome Measures

1. Primary Outcome

Title	Part 1: Absolute Change From Baseline in MRI Global Chest Score at Week 48
Description	MRI scans assessed semi-quantitatively via a standardized chest MRI scoring system. Each participant had 6 lobes scored using 7 scoring parameters:1) Bronchiectasis/wall thickening 2) Mucus plugging 3) Abscesses/sacculations 4) Consolidations 5) Special findings 6)Mosaic pattern 7) Perfusion abnormalities. For each of 7 parameter, there were scores of 6 lobes (score of each lobe : 0= normal value, 1 = <50% of lobe involved and 2 = >=50% of lobe involved). MRI global score was calculated as sum of parameters 1 to 7. MRI total score is ranged from 0-84. Higher score indicate more lobe involvement.
Time Frame	From Baseline at Week 48

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) included all randomized participants who carried the intended CF transmembrane conductance regulator gene (CFTR) allele mutation and received at least 1 dose of study drug in Part 1. Here "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Part 1: Placebo	Part 1: LUM/IVA
Arm/Group Description	Participants received placebo matched to LUM/IVA in placebo-controlled period for 48 weeks.	Participants weighing <14 kg at screening received LUM 100 mg/IVA 125 mg FDC q12h in placebo-controlled period for 48 weeks. Participants weighing >=14 kg at screening received LUM 150 mg/IVA 188 mg FDC q12h in placebo-controlled period for 48 weeks.
Measure Participants	15	32
Mean (Standard Deviation) [score on a scale]	-0.3 (6.1)	-1.7 (6.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 1: Placebo, Part 1: LUM/IVA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference
	Estimated Value	-1.5
	Confidence Interval	(2-Sided) 95%; -5.5 to 2.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Part 1: Absolute Change in Lung Clearance Index2.5 (LCI2.5) Through Week 48
Description	LCI2.5 represents the number of lung turnovers required to reduce the end-tidal inert gas concentration to 1/40th of its starting value.
Time Frame	From Baseline Through Week 48

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	Part 1: Placebo	Part 1: LUM/IVA
Arm/Group Description	Participants received placebo matched to LUM/IVA in placebo-controlled period for 48 weeks.	Participants weighing <14 kg at screening received LUM 100 mg/IVA 125 mg FDC q12h in placebo-controlled period for 48 weeks. Participants weighing >=14 kg at screening received LUM 150 mg/IVA 188 mg FDC q12h in placebo-controlled period for 48 weeks.
Measure Participants	16	35
Mean (95% Confidence Interval) [lung clearance index]	0.32	-0.37

3. Secondary Outcome

Title	Part 1: Absolute Change in Weight-for-age Z-score at Week 48
Description	The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.
Time Frame	From Baseline at Week 48

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	Part 1: Placebo	Part 1: LUM/IVA
Arm/Group Description	Participants received placebo matched to LUM/IVA in placebo-controlled period for 48 weeks.	Participants weighing <14 kg at screening received LUM 100 mg/IVA 125 mg FDC q12h in placebo-controlled period for 48 weeks. Participants weighing >=14 kg at screening received LUM 150 mg/IVA 188 mg FDC q12h in placebo-controlled period for 48 weeks.
Measure Participants	16	35
Mean (95% Confidence Interval) [z-score]	-0.07	0.13

4. Secondary Outcome

Title	Part 1: Absolute Change in Stature-for-age Z-score at Week 48
Description	The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.
Time Frame	From Baseline at Week 48

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	Part 1: Placebo	Part 1: LUM/IVA
Arm/Group Description	Participants received placebo matched to LUM/IVA in placebo-controlled period for 48 weeks.	Participants weighing <14 kg at screening received LUM 100 mg/IVA 125 mg FDC q12h in placebo-controlled period for 48 weeks. Participants weighing >=14 kg at screening received LUM 150 mg/IVA 188 mg FDC q12h in placebo-controlled period for 48 weeks.
Measure Participants	16	35
Mean (95% Confidence Interval) [z-score]	0.10	0.09

5. Secondary Outcome

Title	Part 1: Absolute Change in Body Mass Index (BMI)-For-age Z-score at Week 48
Description	BMI was defined as weight in kilogram (kg) divided by squared height in meters (m^2). The z-score is a statistical measure to describe whether a value was above or below the standard. A z-score of 0 is equal to the standard. Lower numbers indicate values lower than the standard and higher numbers indicate values higher than the standard.
Time Frame	From Baseline at Week 48

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	Part 1: Placebo	Part 1: LUM/IVA
Arm/Group Description	Participants received placebo matched to LUM/IVA in placebo-controlled period for 48 weeks.	Participants weighing <14 kg at screening received LUM 100 mg/IVA 125 mg FDC q12h in placebo-controlled period for 48 weeks. Participants weighing >=14 kg at screening received LUM 150 mg/IVA 188 mg FDC q12h in placebo-controlled period for 48 weeks.
Measure Participants	16	35
Mean (95% Confidence Interval) [z-score]	-0.24	0.20

Adverse Events

Time Frame	Part 1: Day 1 up to Week 48
Arm/Group Title	Part 1: Placebo		Part 1: LUM/IVA
Arm/Group Description	Participants received placebo matched to LUM/IVA in placebo-controlled period for 48 weeks.		Participants weighing <14 kg at screening received LUM 100 mg/IVA 125 mg FDC q12h in placebo-controlled period for 48 weeks. Participants weighing >=14 kg at screening received LUM 150 mg/IVA 188 mg FDC q12h in placebo-controlled period for 48 weeks.
All Cause Mortality
	Part 1: Placebo		Part 1: LUM/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/35 (0%)
Serious Adverse Events
	Part 1: Placebo		Part 1: LUM/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/16 (12.5%)		7/35 (20%)
Gastrointestinal disorders
Constipation	0/16 (0%)		1/35 (2.9%)
Haematemesis	0/16 (0%)		1/35 (2.9%)
Intussusception	0/16 (0%)		1/35 (2.9%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	1/16 (6.3%)		3/35 (8.6%)
Pneumonia	0/16 (0%)		1/35 (2.9%)
Respiratory, thoracic and mediastinal disorders
Lung infiltration	1/16 (6.3%)		0/35 (0%)
Other (Not Including Serious) Adverse Events
	Part 1: Placebo		Part 1: LUM/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/16 (100%)		33/35 (94.3%)
Cardiac disorders
Tachycardia	1/16 (6.3%)		0/35 (0%)
Ear and labyrinth disorders
Otorrhoea	1/16 (6.3%)		0/35 (0%)
Eye disorders
Astigmatism	0/16 (0%)		2/35 (5.7%)
Blepharospasm	1/16 (6.3%)		0/35 (0%)
Gastrointestinal disorders
Abdominal pain	2/16 (12.5%)		7/35 (20%)
Abdominal pain upper	2/16 (12.5%)		1/35 (2.9%)
Abnormal faeces	1/16 (6.3%)		0/35 (0%)
Constipation	0/16 (0%)		4/35 (11.4%)
Diarrhoea	1/16 (6.3%)		4/35 (11.4%)
Faeces pale	2/16 (12.5%)		0/35 (0%)
Frequent bowel movements	1/16 (6.3%)		1/35 (2.9%)
Post-tussive vomiting	1/16 (6.3%)		1/35 (2.9%)
Vomiting	2/16 (12.5%)		2/35 (5.7%)
General disorders
Peripheral swelling	1/16 (6.3%)		0/35 (0%)
Pyrexia	3/16 (18.8%)		6/35 (17.1%)
Infections and infestations
Bacterial disease carrier	2/16 (12.5%)		0/35 (0%)
Bronchitis	1/16 (6.3%)		2/35 (5.7%)
Conjunctivitis	1/16 (6.3%)		1/35 (2.9%)
Diarrhoea infectious	1/16 (6.3%)		0/35 (0%)
Enterobiasis	1/16 (6.3%)		0/35 (0%)
Febrile infection	1/16 (6.3%)		0/35 (0%)
Gastroenteritis	2/16 (12.5%)		3/35 (8.6%)
Infective pulmonary exacerbation of cystic fibrosis	9/16 (56.3%)		15/35 (42.9%)
Nasopharyngitis	8/16 (50%)		22/35 (62.9%)
Otitis media	1/16 (6.3%)		3/35 (8.6%)
Otitis media acute	1/16 (6.3%)		0/35 (0%)
Pharyngitis streptococcal	1/16 (6.3%)		0/35 (0%)
Pneumonia	0/16 (0%)		2/35 (5.7%)
Pneumonia pseudomonal	1/16 (6.3%)		1/35 (2.9%)
Rhinitis	6/16 (37.5%)		9/35 (25.7%)
Sinusitis	1/16 (6.3%)		1/35 (2.9%)
Tonsillitis	1/16 (6.3%)		1/35 (2.9%)
Upper respiratory tract infection	3/16 (18.8%)		1/35 (2.9%)
Viral infection	1/16 (6.3%)		0/35 (0%)
Injury, poisoning and procedural complications
Skin abrasion	1/16 (6.3%)		0/35 (0%)
Skin laceration	1/16 (6.3%)		2/35 (5.7%)
Traumatic haematoma	1/16 (6.3%)		0/35 (0%)
Investigations
Alanine aminotransferase increased	0/16 (0%)		3/35 (8.6%)
Aspartate aminotransferase increased	0/16 (0%)		2/35 (5.7%)
Pseudomonas test positive	2/16 (12.5%)		1/35 (2.9%)
Staphylococcus test positive	1/16 (6.3%)		1/35 (2.9%)
Musculoskeletal and connective tissue disorders
Pain in extremity	1/16 (6.3%)		0/35 (0%)
Nervous system disorders
Headache	2/16 (12.5%)		3/35 (8.6%)
Respiratory, thoracic and mediastinal disorders
Cough	5/16 (31.3%)		10/35 (28.6%)
Dyspnoea	2/16 (12.5%)		1/35 (2.9%)
Epistaxis	2/16 (12.5%)		2/35 (5.7%)
Lung infiltration	1/16 (6.3%)		0/35 (0%)
Nasal congestion	4/16 (25%)		0/35 (0%)
Nasal obstruction	1/16 (6.3%)		0/35 (0%)
Nasal polyps	2/16 (12.5%)		1/35 (2.9%)
Oropharyngeal pain	0/16 (0%)		3/35 (8.6%)
Productive cough	2/16 (12.5%)		0/35 (0%)
Rhinorrhoea	1/16 (6.3%)		0/35 (0%)
Wheezing	1/16 (6.3%)		0/35 (0%)
Skin and subcutaneous tissue disorders
Dry skin	0/16 (0%)		2/35 (5.7%)
Rash	1/16 (6.3%)		3/35 (8.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.