Study of Ivacaftor in Cystic Fibrosis Subjects Aged 12 Years and Older Homozygous for the F508del-CFTR Mutation (DISCOVER)

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition:	Cystic Fibrosis
Interventions:	Drug: Ivacaftor; Drug: Placebo

  Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

	Description
Placebo – Part A	Placebo matched to ivacaftor tablet orally every 12 hours (q12h) for 16 weeks during Part A (double-blind treatment period).
Ivacaftor – Part A	Ivacaftor 150 milligram (mg) tablet orally q12h for 16 weeks during Part A (double-blind treatment period).
Placebo/Ivacaftor – Part B	Participants who received placebo during Part A, received ivacaftor 150 mg tablet orally q12h for 96 weeks during Part B (open-label extension period).
Ivacaftor/Ivacaftor – Part B	Participants who received ivacaftor during Part A, received ivacaftor 150 mg tablet orally q12h for 96 weeks during Part B (open-label extension period).

Participant Flow for 2 periods

Period 1:   Part A (16-Week Double-Blind Treatment)

	Placebo – Part A	Ivacaftor – Part A	Placebo/Ivacaftor – Part B	Ivacaftor/Ivacaftor – Part B
STARTED	28 [1]	112 [2]	0	0
COMPLETED	26 [3]	104 [4]	0	0
NOT COMPLETED	2	8	0	0
Adverse Event	2	3	0	0
Lost to Follow-up	0	1	0	0
Noncompliance with Study Requirements	0	2	0	0
Required Prohibited Medication	0	1	0	0
Sponsor Decision	0	1	0	0

[1]	All subjects who received at least 1 dose of study drug (placebo)
[2]	All subjects who received at least 1 dose of study drug (ivacaftor)
[3]	Only 5 participants continued in Part B.
[4]	Only 33 participants continued in Part B.

Period 2:   Part B (96-Week Open-Label Extension)

	Placebo – Part A	Ivacaftor – Part A	Placebo/Ivacaftor – Part B	Ivacaftor/Ivacaftor – Part B
STARTED	0	0	5	33
COMPLETED	0	0	0	0
NOT COMPLETED	0	0	5	33
Adverse Event	0	0	0	2
Noncompliance with Study Requirements	0	0	0	1
Required Prohibited Medication	0	0	0	1
Study Termination by Sponsor	0	0	4	25
Withdrawal by Subject	0	0	1	2
Other	0	0	0	2

  Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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Reporting Groups

	Description
Placebo – Part A	Placebo matched to ivacaftor tablet orally every 12 hours (q12h) for 16 weeks during Part A (double-blind treatment period).
Ivacaftor – Part A	Ivacaftor 150 milligram (mg) tablet orally q12h for 16 weeks during Part A (double-blind treatment period).
Total	Total of all reporting groups

Baseline Measures

	Placebo – Part A	Ivacaftor – Part A	Total
Overall Participants Analyzed; [Units: Participants]	28	112	140
Age; [Units: Years]; Mean (Standard Deviation)	25.0 (8.35)	22.8 (10.26)	23.2 (9.91)
Age, Customized; [Units: Participants]
12 to 17 Years	6	44	50
18 to 24 Years	10	32	42
25 to 39 Years	12	26	38
40 to 45 Years	0	5	5
> 45 Years	0	5	5
Gender; [Units: Participants]
Female	12	54	66
Male	16	58	74
Race/Ethnicity, Customized; [Units: Participants]
Hispanic or Latino	1	2	3
Not Hispanic or Latino	27	110	137
Race/Ethnicity, Customized; [Units: Participants]
Black or African American	0	1	1
White	28	111	139
Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1), Continuous [1]; [Units: Percent predicted of FEV1]; Mean (Standard Deviation)	74.8 (24.06)	79.7 (22.67)	78.7 (22.95)
[1] Percent predicted for age, gender, and height.
ppFEV1, Categorical [1]; [Units: Participants]
< 70%	15	38	53
≥ 70% to ≤ 90%	5	35	40
> 90%	8	39	47
[1] Percent predicted for age, gender, and height.
Weight; [Units: Kilograms]; Mean (Standard Deviation)	63.2 (14.96)	58.2 (13.49)	59.2 (13.89)
Body Mass Index; [Units: Kilogram per square meter]; Mean (Standard Deviation)	22.2 (4.48)	21.2 (3.25)	21.4 (3.54)
Sweat Chloride; [Units: Millimoles per liter]; Mean (Standard Deviation)	102.4 (7.91)	101.4 (10.28)	101.6 (9.83)

  Outcome Measures

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1. Primary:

Part A : Absolute Change From Part A Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Week 16 [ Time Frame: Part A baseline through Week 16 ]

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2. Secondary:

Part A : Absolute Change From Part A Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 16 [ Time Frame: Part A baseline through Week 16 ]

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3. Secondary:

Part A : Absolute Change From Part A Baseline in Sweat Chloride Concentration Through Week 16 [ Time Frame: Part A baseline through Week 16 ]

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4. Secondary:

Part A : Rate of Change From Baseline in Weight Through Week 16 [ Time Frame: Part A baseline through Week 16 ]

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5. Secondary:

Part B : Absolute Change From Part A and Part B Baseline in ppFEV1 Through Week 64 [ Time Frame: Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64 ]

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6. Secondary:

Part B : Rate of Change From Part A Baseline in ppFEV1 Through Week 64 [ Time Frame: Part A baseline through Week 64 ]

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7. Secondary:

Part B : Rate of Change From Part B Baseline in ppFEV1 Through Week 64 [ Time Frame: Part B baseline through Week 64 ]

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8. Secondary:

Part B : Absolute Change From Part A and Part B Baseline in CFQ-R Respiratory Domain Score Through Week 64 [ Time Frame: Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64 ]

  Show Outcome Measure 8

9. Secondary:

Part B : Absolute Change From Part A and Part B Baseline in Sweat Chloride Concentration Through Week 64 [ Time Frame: Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64 ]

  Show Outcome Measure 9

10. Secondary:

Part B : Absolute Change From Part A and Part B Baseline in Weight Through Week 64 [ Time Frame: Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64 ]

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11. Secondary:

Part B : Number of Participants With Pulmonary Exacerbations [ Time Frame: Part B baseline through Week 64 ]

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12. Secondary:

Part B : Number of Pulmonary Exacerbation Events [ Time Frame: Part B baseline through Week 64 ]

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13. Secondary:

Part B : Number of Pulmonary Exacerbation Events Per Participant Per Year [ Time Frame: Part B baseline through Week 64 ]

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  Serious Adverse Events

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Time Frame	Adverse events (serious and non-serious) were collected from signing of informed consent through 2 years after last dose (in Part B) of study drug (median treatment duration: 112 days for Part A and 381 days for Part B)
Additional Description	No text entered.

Reporting Groups

	Description
Placebo – Part A	Placebo matched to ivacaftor tablet orally q12h for 16 weeks during Part A (double-blind treatment period).
Ivacaftor – Part A	Ivacaftor 150 milligram (mg) tablet orally q12h for 16 weeks during Part A (double-blind treatment period).
Placebo/Ivacaftor – Part B	Participants who received placebo during Part A, received ivacaftor 150 mg tablet orally q12h for 96 weeks during Part B (open-label extension period).
Ivacaftor/Ivacaftor – Part B	Participants who received ivacaftor during Part A, received ivacaftor 150 mg tablet orally q12h for 96 weeks during Part B (open-label extension period).

Serious Adverse Events

	Placebo – Part A	Ivacaftor – Part A	Placebo/Ivacaftor – Part B	Ivacaftor/Ivacaftor – Part B
Total, Serious Adverse Events
# participants affected / at risk	6/28 (21.43%)	15/112 (13.39%)	2/5 (40.00%)	14/33 (42.42%)
Congenital, familial and genetic disorders
Cystic fibrosis lung † 1 [3]
# participants affected / at risk	5/28 (17.86%)	10/112 (8.93%)	2/5 (40.00%)	13/33 (39.39%)
# events	6	12	4	20
Gastrointestinal disorders
Abdominal pain † 1
# participants affected / at risk	0/28 (0.00%)	1/112 (0.89%)	0/5 (0.00%)	0/33 (0.00%)
# events	0	2	0	0
General disorders
Fatigue † 1
# participants affected / at risk	0/28 (0.00%)	1/112 (0.89%)	0/5 (0.00%)	0/33 (0.00%)
# events	0	1	0	0
Infections and infestations
Bronchopneumonia † 1
# participants affected / at risk	1/28 (3.57%)	0/112 (0.00%)	0/5 (0.00%)	0/33 (0.00%)
# events	1	0	0	0
Central line infection † 1
# participants affected / at risk	0/28 (0.00%)	0/112 (0.00%)	0/5 (0.00%)	1/33 (3.03%)
# events	0	0	0	1
Lung infection † 1
# participants affected / at risk	0/28 (0.00%)	0/112 (0.00%)	0/5 (0.00%)	1/33 (3.03%)
# events	0	0	0	1
Injury, poisoning and procedural complications
Ankle fracture † 1
# participants affected / at risk	0/28 (0.00%)	0/112 (0.00%)	0/5 (0.00%)	1/33 (3.03%)
# events	0	0	0	1
Pelvic fracture † 1
# participants affected / at risk	0/28 (0.00%)	0/112 (0.00%)	0/5 (0.00%)	1/33 (3.03%)
# events	0	0	0	1
Traumatic brain injury † 1
# participants affected / at risk	0/28 (0.00%)	0/112 (0.00%)	0/5 (0.00%)	1/33 (3.03%)
# events	0	0	0	1
Musculoskeletal and connective tissue disorders
Myopathy † 1
# participants affected / at risk	0/28 (0.00%)	1/112 (0.89%)	0/5 (0.00%)	0/33 (0.00%)
# events	0	1	0	0
Nervous system disorders
Cognitive disorder † 1
# participants affected / at risk	1/28 (3.57%)	0/112 (0.00%)	0/5 (0.00%)	0/33 (0.00%)
# events	1	0	0	0
Psychiatric disorders
Anxiety † 1
# participants affected / at risk	0/28 (0.00%)	0/112 (0.00%)	0/5 (0.00%)	1/33 (3.03%)
# events	0	0	0	1
Depression † 1
# participants affected / at risk	0/28 (0.00%)	1/112 (0.89%)	0/5 (0.00%)	1/33 (3.03%)
# events	0	1	0	1
Suicidal ideation † 1
# participants affected / at risk	0/28 (0.00%)	1/112 (0.89%)	0/5 (0.00%)	0/33 (0.00%)
# events	0	1	0	0
Respiratory, thoracic and mediastinal disorders
Haemoptysis † 1
# participants affected / at risk	0/28 (0.00%)	1/112 (0.89%)	0/5 (0.00%)	1/33 (3.03%)
# events	0	1	0	3
Hypoxia † 1
# participants affected / at risk	0/28 (0.00%)	1/112 (0.89%)	0/5 (0.00%)	0/33 (0.00%)
# events	0	1	0	0
Nasal polyps † 1
# participants affected / at risk	0/28 (0.00%)	1/112 (0.89%)	0/5 (0.00%)	0/33 (0.00%)
# events	0	1	0	0
Vascular disorders
Venous thrombosis † 1
# participants affected / at risk	1/28 (3.57%)	0/112 (0.00%)	0/5 (0.00%)	0/33 (0.00%)
# events	1	0	0	0

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA (12.0)
[3]	CF exacerbations were coded as "cystic fibrosis lung."

  Other Adverse Events

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  Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
In Part B, the treatment duration was 96 weeks; however, due to early study termination all analysis were performed up to Week 64, as planned.

  More Information

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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.

The agreement is: The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo. The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo. Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.

Results Point of Contact:  

Name/Title: Medical Monitor
Organization: Vertex
phone: 617-444-6777
e-mail: medicalinfo@vrtx.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Flume PA, Liou TG, Borowitz DS, Li H, Yen K, Ordoñez CL, Geller DE; VX 08-770-104 Study Group. Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest. 2012 Sep;142(3):718-724. doi: 10.1378/chest.11-2672.

Responsible Party:	Vertex Pharmaceuticals Incorporated
ClinicalTrials.gov Identifier:	NCT00953706 History of Changes
Other Study ID Numbers:	VX08-770-104; 2009-010261-23 ( EudraCT Number )
First Submitted:	August 4, 2009
First Posted:	August 6, 2009
Results First Submitted:	February 27, 2012
Results First Posted:	August 21, 2012
Last Update Posted:	September 11, 2015