A Randomized, Double-Blind, Placebo-Controlled Study of Idelalisib in Combination With Rituximab for Previously Treated Chronic Lymphocytic Leukemia (CLL)

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ClinicalTrials.gov Identifier: NCT01539512

Recruitment Status : Completed

First Posted : February 27, 2012

Results First Posted : October 16, 2014

Last Update Posted : May 14, 2019

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Sponsor:

Information provided by (Responsible Party):

Gilead Sciences

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
Condition	Chronic Lymphocytic Leukemia
Interventions	Drug: Idelalisib Drug: Rituximab Drug: Placebo to match idelalisib
Enrollment	220

Participant Flow

Recruitment Details	Participants were enrolled at a total of 53 study sites in the United States and Europe. The first participant was screened on 03 April 2012. The last study visit occurred on 20 April 2014.
Pre-assignment Details


Arm/Group Title	Idelalisib + Rituximab	Placebo + Rituximab
Arm/Group Description	Idelalisib 150 mg tablet administer...	Placebo to match idelalisib adminis...
Arm/Group Description	Idelalisib 150 mg tablet administered orally twice daily plus rituximab (8 intravenous doses through Week 20: Day 1: 375 mg/m^2, and 500 mg/m^2 thereafter)	Placebo to match idelalisib administered orally twice daily plus rituximab (8 intravenous doses through Week 20: Day 1: 375 mg/m^2, and 500 mg/m^2 thereafter)
Period Title: Overall Study
Started	110	110
Completed	87 ^[1]	97 ^[1]
Not Completed	23	13
Reason Not Completed
Adverse Event	9	7
Physician Decision	1	1
Withdrawal by Subject	12	5
Richter's Transformation	1	0
[1] Completed=reached primary efficacy endpoint (progressive disease or death) or finished study period.

Baseline Characteristics

Arm/Group Title		Idelalisib + Rituximab	Placebo + Rituximab	Total
Arm/Group Description		Idelalisib 150 mg tablet administer...	Placebo to match idelalisib adminis...	Total of all reporting groups
Arm/Group Description		Idelalisib 150 mg tablet administered orally twice daily plus rituximab (8 intravenous doses through Week 20: Day 1: 375 mg/m^2, and 500 mg/m^2 thereafter)	Placebo to match idelalisib administered orally twice daily plus rituximab (8 intravenous doses through Week 20: Day 1: 375 mg/m^2, and 500 mg/m^2 thereafter)	Total of all reporting groups
Overall Number of Baseline Participants		110	110	220
Baseline Analysis Population Description		...
Baseline Analysis Population Description		ITT Analysis Set: randomized participants with treatment group designated according to initial randomization.
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	110 participants	110 participants	220 participants
		71 (7.7)	70 (8.1)	71 (7.9)
Age, Customized Measure Type: Number Unit of measure: Participants	Number Analyzed	110 participants	110 participants	220 participants
< 65 years		21	27	48
≥ 65 years		89	83	172
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	110 participants	110 participants	220 participants
	Female	34 30.9%	42 38.2%	76 34.5%
	Male	76 69.1%	68 61.8%	144 65.5%
Race/Ethnicity, Customized Measure Type: Number Unit of measure: Participants	Number Analyzed	110 participants	110 participants	220 participants
Hispanic or Latino		3	2	5
Not Hispanic or Latino		101	102	203
Not Permitted		6	6	12
Race/Ethnicity, Customized Measure Type: Number Unit of measure: Participants	Number Analyzed	110 participants	110 participants	220 participants
White		100	98	198
Black or African American		3	3	6
Other		2	2	4
Not Permitted		5	7	12
Region of Enrollment Measure Type: Number Unit of measure: Participants	Number Analyzed	110 participants	110 participants	220 participants
France		3	3	6
Germany		7	5	12
Italy		2	5	7
United Kingdom		18	14	32
United States		80	83	163
Karnofsky Performance Status ^[1] Measure Type: Number Unit of measure: Participants	Number Analyzed	110 participants	110 participants	220 participants
40		1	1	2
50		3	4	7
60		6	5	11
70		20	13	33
80		42	46	88
90		23	28	51
100		15	13	28
		[1] Measure Description: Classifies patients according to their functional impairment. Scores range from 0-100; the lower the score, the worse the survival for most serious illnesses.
Time Since Diagnosis Mean (Standard Deviation) Unit of measure: Months
	Number Analyzed	110 participants	110 participants	220 participants
		108.3 (62.28)	106.4 (52.73)	107.4 (57.58)
Rai Stage at Screening ^[1] Measure Type: Number Unit of measure: Participants	Number Analyzed	110 participants	110 participants	220 participants
Rai Stage 0		0	1	1
Rai Stage 1		18	19	37
Rai Stage 2		16	10	26
Rai Stage 3		22	18	40
Rai Stage 4		48	54	102
Missing		6	8	14
		[1] Measure Description: Rai staging categorizes the disease progression of chronic lymphocytic leukemia (CLL), with classifications of low- (Stage 0), intermediate- (Stage 1 and 2), and high-risk (Stages 3 and 4) categories. Rai Stage 0: high number of lymphocytes in the blood (lymphocytosis) only. Rai Stage 1: lymphocytosis with enlarged lymphoid tissues (lymphadenopathy). Rai Stage 2: lymphocytosis with enlarged liver (hepatomegaly) or spleen (splenomegaly). Rai Stage 3: lymphocytosis with low red blood cell count (anemia). Rai Stage 4: lymphocytosis with low number of blood platelets (thrombocytopenia).
Binet Stage at Screening ^[1] Measure Type: Number Unit of measure: Participants	Number Analyzed	110 participants	110 participants	220 participants
Binet Stage A		7	4	11
Binet Stage B		29	32	61
Binet Stage C		63	60	123
Missing		11	14	25
		[1] Measure Description: Binet staging classifies CLL according to the number of lymphoid tissues involved, as well as the presence of anemia or thrombocytopenia. Stage A: fewer than three areas of enlarged lymphoid tissue; enlarged lymph nodes of the neck, underarms, and groin, as well as the spleen, are each considered "one group" whether unilateral (one-sided) or bilateral (on both sides). Binet Stage B: more than three areas of enlarged lymphoid tissue. Binet Stage C: anemia plus thrombocytopenia.

Outcome Measures

1.Primary Outcome


Title	Progression-Free Survival
Description	Progression-free survival was defined as the interval from randomizati...
Description	Progression-free survival was defined as the interval from randomization to the earlier of the first documentation of definitive disease progression or death from any cause. Definitive disease progression was CLL progression based on standard criteria (other than lymphocytosis alone) as defined by the 2008 update of the International Workshop on CLL guidelines, ie, appearance of any new lesion; increase by ≥ 50% in the sum of the products of the perpendicular diameters of measured lymph nodes (SPD); new or ≥ 50% enlargement of liver or spleen; transformation to a more aggressive histology (eg, Richter's or prolymphocytic transformation); reduction in the number of blood cells (cytopenia) attributable to CLL.
Time Frame	Up to 17 months

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Analysis Set: randomized participants with treatment group designated according to initial randomization.


Arm/Group Title	Idelalisib + Rituximab	Placebo + Rituximab
Arm/Group Description:	Idelalisib 150 mg tablet administer...	Placebo to match idelalisib adminis...
Arm/Group Description:	Idelalisib 150 mg tablet administered orally twice daily plus rituximab (8 intravenous doses through Week 20: Day 1: 375 mg/m^2, and 500 mg/m^2 thereafter)	Placebo to match idelalisib administered orally twice daily plus rituximab (8 intravenous doses through Week 20: Day 1: 375 mg/m^2, and 500 mg/m^2 thereafter)
Overall Number of Participants Analyzed	110	110
Median (95% Confidence Interval) Unit of Measure: months
	NA ^[1] (10.7 to NA)	5.5 (3.8 to 7.1)

[1]

NA = Not reached due to insufficient number of events

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Idelalisib + Rituximab, Placebo + Rituximab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	P-value is from stratified log-rank test, adjusted for randomization stratification factors.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.18
	Confidence Interval	(2-Sided) 95% 0.10 to 0.32
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Overall Response Rate
Description	Overall response rate was defined as the percentage of participants wh...
Description	Overall response rate was defined as the percentage of participants who achieved a best overall response of complete response or partial response. Complete response was defined as no lymphadenopathy, hepatomegaly, splenomegaly; normal complete blood count; confirmed by bone marrow aspirate & biopsy. Partial response was defined as >1 of the following criteria: a 50% decrease in peripheral blood lymphocytes, lymphadenopathy, liver size, spleen size; plus ≥ 1 of the following: ≥ 1500/μL absolute neutrophil count, > 100000/μL platelets, > 11.0 g/dL hemoglobin or 50% improvement for either of these parameters without transfusions or growth factors.
Time Frame	Up to 17 months

Outcome Measure Data

Analysis Population Description

ITT Analysis Set: randomized participants with treatment group designated according to initial randomization.


Arm/Group Title	Idelalisib + Rituximab	Placebo + Rituximab
Arm/Group Description:	Idelalisib 150 mg tablet administer...	Placebo to match idelalisib adminis...
Arm/Group Description:	Idelalisib 150 mg tablet administered orally twice daily plus rituximab (8 intravenous doses through Week 20: Day 1: 375 mg/m^2, and 500 mg/m^2 thereafter)	Placebo to match idelalisib administered orally twice daily plus rituximab (8 intravenous doses through Week 20: Day 1: 375 mg/m^2, and 500 mg/m^2 thereafter)
Overall Number of Participants Analyzed	110	110
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: percentage of participants
	74.5 (65.4 to 82.4)	14.5 (8.5 to 22.5)

3.Secondary Outcome


Title	Lymph Node Response Rate
Description	Lymph node response rate was defined as the percentage of participants...
Description	Lymph node response rate was defined as the percentage of participants who achieved a ≥ 50% decrease from baseline in the SPD of index lymph nodes.
Time Frame	Up to 17 months

Outcome Measure Data

Analysis Population Description

ITT Analysis Set: randomized participants with treatment group designated according to initial randomization


Arm/Group Title	Idelalisib + Rituximab	Placebo + Rituximab
Arm/Group Description:	Idelalisib 150 mg tablet administer...	Placebo to match idelalisib adminis...
Arm/Group Description:	Idelalisib 150 mg tablet administered orally twice daily plus rituximab (8 intravenous doses through Week 20: Day 1: 375 mg/m^2, and 500 mg/m^2 thereafter)	Placebo to match idelalisib administered orally twice daily plus rituximab (8 intravenous doses through Week 20: Day 1: 375 mg/m^2, and 500 mg/m^2 thereafter)
Overall Number of Participants Analyzed	110	110
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: percentage of participants
	92.2 (85.1 to 96.6)	5.9 (2.2 to 12.5)

4.Secondary Outcome


Title	Overall Survival
Description	Overall survival was defined as the interval from randomization to dea...
Description	Overall survival was defined as the interval from randomization to death from any cause.
Time Frame	Up to 17 months

Outcome Measure Data

Analysis Population Description

ITT Analysis Set: randomized participants with treatment group designated according to initial randomization.


Arm/Group Title	Idelalisib + Rituximab	Placebo + Rituximab
Arm/Group Description:	Idelalisib 150 mg tablet administer...	Placebo to match idelalisib adminis...
Arm/Group Description:	Idelalisib 150 mg tablet administered orally twice daily plus rituximab (8 intravenous doses through Week 20: Day 1: 375 mg/m^2, and 500 mg/m^2 thereafter)	Placebo to match idelalisib administered orally twice daily plus rituximab (8 intravenous doses through Week 20: Day 1: 375 mg/m^2, and 500 mg/m^2 thereafter)
Overall Number of Participants Analyzed	110	110
Median (95% Confidence Interval) Unit of Measure: months
	NA ^[1] (NA to NA)	NA ^[1] (12.8 to NA)

[1]

NA = Not reached due to insufficient number of events

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Idelalisib + Rituximab, Placebo + Rituximab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.28
	Confidence Interval	(2-Sided) 95% 0.11 to 0.69
	Estimation Comments	[Not Specified]

5.Secondary Outcome


Title	Complete Response Rate
Description	Complete response rate was defined as the percentage of participants w...
Description	Complete response rate was defined as the percentage of participants who achieved a complete response.
Time Frame	Up to 17 months

Outcome Measure Data

Analysis Population Description

ITT Analysis Set: randomized participants with treatment group designated according to initial randomization.


Arm/Group Title	Idelalisib + Rituximab	Placebo + Rituximab
Arm/Group Description:	Idelalisib 150 mg tablet administer...	Placebo to match idelalisib adminis...
Arm/Group Description:	Idelalisib 150 mg tablet administered orally twice daily plus rituximab (8 intravenous doses through Week 20: Day 1: 375 mg/m^2, and 500 mg/m^2 thereafter)	Placebo to match idelalisib administered orally twice daily plus rituximab (8 intravenous doses through Week 20: Day 1: 375 mg/m^2, and 500 mg/m^2 thereafter)
Overall Number of Participants Analyzed	110	110
Measure Type: Number Unit of Measure: percentage of participants
	0	0

Adverse Events

Time Frame	During study treatment plus 30 days (up to 2 years)
Adverse Event Reporting Description	Safety Analysis Set: randomized participants who received at least 1 dose of study drug, with treatment assignments designated according to the actual treatment received.

Arm/Group Title	Idelalisib + Rituximab	Placebo + Rituximab
Arm/Group Description	Idelalisib 150 mg tablet administer...	Placebo to match idelalisib adminis...
Arm/Group Description	Idelalisib 150 mg tablet administered orally twice daily plus rituximab (8 intravenous doses through Week 20: Day 1: 375 mg/m^2, and 500 mg/m^2 thereafter)	Placebo to match idelalisib administered orally twice daily plus rituximab (8 intravenous doses through Week 20: Day 1: 375 mg/m^2, and 500 mg/m^2 thereafter)
All-Cause Mortality
	Idelalisib + Rituximab	Placebo + Rituximab
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events Serious Adverse Events
	Idelalisib + Rituximab	Placebo + Rituximab
	Affected / at Risk (%)	Affected / at Risk (%)
Total	65/110 (59.09%)	43/108 (39.81%)
Blood and lymphatic system disorders
Anaemia ^† 1	1/110 (0.91%)	1/108 (0.93%)
Febrile neutropenia ^† 1	5/110 (4.55%)	6/108 (5.56%)
Haemolytic anaemia ^† 1	1/110 (0.91%)	0/108 (0.00%)
Neutropenia ^† 1	3/110 (2.73%)	0/108 (0.00%)
Pancytopenia ^† 1	0/110 (0.00%)	1/108 (0.93%)
Splenic infarction ^† 1	0/110 (0.00%)	1/108 (0.93%)
Thrombocytopenia ^† 1	1/110 (0.91%)	1/108 (0.93%)
Cardiac disorders
Acute myocardial infarction ^† 1	1/110 (0.91%)	0/108 (0.00%)
Cardiac failure ^† 1	0/110 (0.00%)	1/108 (0.93%)
Cardiac failure congestive ^† 1	1/110 (0.91%)	0/108 (0.00%)
Left ventricular failure ^† 1	0/110 (0.00%)	1/108 (0.93%)
Myocardial infarction ^† 1	0/110 (0.00%)	1/108 (0.93%)
Right ventricular failure ^† 1	1/110 (0.91%)	0/108 (0.00%)
Endocrine disorders
Inappropriate antidiuretic hormone secretion ^† 1	1/110 (0.91%)	0/108 (0.00%)
Eye disorders
Eye pain ^† 1	1/110 (0.91%)	0/108 (0.00%)
Gastrointestinal disorders
Abdominal pain ^† 1	1/110 (0.91%)	1/108 (0.93%)
Colitis ^† 1	4/110 (3.64%)	0/108 (0.00%)
Constipation ^† 1	1/110 (0.91%)	1/108 (0.93%)
Diarrhoea ^† 1	8/110 (7.27%)	0/108 (0.00%)
Gastric mucosa erythema ^† 1	1/110 (0.91%)	0/108 (0.00%)
Nausea ^† 1	1/110 (0.91%)	0/108 (0.00%)
Oral pain ^† 1	1/110 (0.91%)	0/108 (0.00%)
Vomiting ^† 1	1/110 (0.91%)	0/108 (0.00%)
General disorders
Asthenia ^† 1	2/110 (1.82%)	3/108 (2.78%)
Chest pain ^† 1	1/110 (0.91%)	0/108 (0.00%)
Chills ^† 1	0/110 (0.00%)	1/108 (0.93%)
Device dislocation ^† 1	1/110 (0.91%)	0/108 (0.00%)
Fatigue ^† 1	0/110 (0.00%)	1/108 (0.93%)
General physical health deterioration ^† 1	0/110 (0.00%)	1/108 (0.93%)
Multi-organ failure ^† 1	0/110 (0.00%)	1/108 (0.93%)
Non-cardiac chest pain ^† 1	1/110 (0.91%)	1/108 (0.93%)
Oedema peripheral ^† 1	0/110 (0.00%)	2/108 (1.85%)
Pyrexia ^† 1	10/110 (9.09%)	3/108 (2.78%)
Infections and infestations
Abscess limb ^† 1	0/110 (0.00%)	1/108 (0.93%)
Alpha haemolytic streptococcal infection ^† 1	1/110 (0.91%)	0/108 (0.00%)
Bacteraemia ^† 1	0/110 (0.00%)	1/108 (0.93%)
Bronchitis ^† 1	1/110 (0.91%)	1/108 (0.93%)
Bronchopulmonary aspergillosis ^† 1	1/110 (0.91%)	0/108 (0.00%)
Cellulitis ^† 1	1/110 (0.91%)	4/108 (3.70%)
Diverticulitis ^† 1	1/110 (0.91%)	0/108 (0.00%)
Epididymitis ^† 1	1/110 (0.91%)	0/108 (0.00%)
Fungal oesophagitis ^† 1	0/110 (0.00%)	1/108 (0.93%)
Gastroenteritis ^† 1	1/110 (0.91%)	1/108 (0.93%)
Herpes simplex ^† 1	0/110 (0.00%)	1/108 (0.93%)
Herpes zoster disseminated ^† 1	1/110 (0.91%)	0/108 (0.00%)
Infection ^† 1	1/110 (0.91%)	0/108 (0.00%)
Listeriosis ^† 1	0/110 (0.00%)	1/108 (0.93%)
Lower respiratory tract infection ^† 1	3/110 (2.73%)	1/108 (0.93%)
Lung infection ^† 1	3/110 (2.73%)	1/108 (0.93%)
Mucosal infection ^† 1	0/110 (0.00%)	1/108 (0.93%)
Neutropenic sepsis ^† 1	2/110 (1.82%)	0/108 (0.00%)
Oral herpes ^† 1	1/110 (0.91%)	0/108 (0.00%)
Pneumocystis jirovecii pneumonia ^† 1	4/110 (3.64%)	1/108 (0.93%)
Pneumonia ^† 1	13/110 (11.82%)	10/108 (9.26%)
Pneumonia fungal ^† 1	2/110 (1.82%)	0/108 (0.00%)
Pneumonia legionella ^† 1	0/110 (0.00%)	1/108 (0.93%)
Pneumonia pseudomonal ^† 1	1/110 (0.91%)	0/108 (0.00%)
Respiratory tract infection ^† 1	0/110 (0.00%)	1/108 (0.93%)
Sepsis ^† 1	7/110 (6.36%)	3/108 (2.78%)
Sepsis syndrome ^† 1	2/110 (1.82%)	0/108 (0.00%)
Septic shock ^† 1	0/110 (0.00%)	2/108 (1.85%)
Soft tissue infection ^† 1	0/110 (0.00%)	1/108 (0.93%)
Stenotrophomonas infection ^† 1	1/110 (0.91%)	0/108 (0.00%)
Upper respiratory tract infection ^† 1	1/110 (0.91%)	2/108 (1.85%)
Urinary tract infection ^† 1	1/110 (0.91%)	1/108 (0.93%)
Urosepsis ^† 1	1/110 (0.91%)	0/108 (0.00%)
Injury, poisoning and procedural complications
Femur fracture ^† 1	0/110 (0.00%)	1/108 (0.93%)
Hip fracture ^† 1	0/110 (0.00%)	1/108 (0.93%)
Infusion related reaction ^† 1	1/110 (0.91%)	2/108 (1.85%)
Investigations
Blood creatinine increased ^† 1	0/110 (0.00%)	2/108 (1.85%)
International normalised ratio increased ^† 1	0/110 (0.00%)	1/108 (0.93%)
Neutrophil count decreased ^† 1	1/110 (0.91%)	0/108 (0.00%)
Transaminases increased ^† 1	1/110 (0.91%)	0/108 (0.00%)
Metabolism and nutrition disorders
Dehydration ^† 1	3/110 (2.73%)	0/108 (0.00%)
Hypercalcaemia ^† 1	2/110 (1.82%)	2/108 (1.85%)
Hyperkalaemia ^† 1	0/110 (0.00%)	1/108 (0.93%)
Hypokalaemia ^† 1	1/110 (0.91%)	0/108 (0.00%)
Hypomagnesaemia ^† 1	1/110 (0.91%)	0/108 (0.00%)
Tumour lysis syndrome ^† 1	1/110 (0.91%)	1/108 (0.93%)
Musculoskeletal and connective tissue disorders
Back pain ^† 1	1/110 (0.91%)	0/108 (0.00%)
Joint effusion ^† 1	0/110 (0.00%)	1/108 (0.93%)
Myalgia ^† 1	0/110 (0.00%)	1/108 (0.93%)
Pain in jaw ^† 1	1/110 (0.91%)	0/108 (0.00%)
Pathological fracture ^† 1	0/110 (0.00%)	1/108 (0.93%)
Rhabdomyolysis ^† 1	1/110 (0.91%)	0/108 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bronchial carcinoma ^† 1	1/110 (0.91%)	0/108 (0.00%)
Laryngeal squamous cell carcinoma ^† 1	0/110 (0.00%)	1/108 (0.93%)
Squamous cell carcinoma ^† 1	1/110 (0.91%)	0/108 (0.00%)
Nervous system disorders
Amnesia ^† 1	1/110 (0.91%)	0/108 (0.00%)
Cerebrovascular accident ^† 1	1/110 (0.91%)	0/108 (0.00%)
Convulsion ^† 1	1/110 (0.91%)	0/108 (0.00%)
Headache ^† 1	0/110 (0.00%)	1/108 (0.93%)
Iiird nerve disorder ^† 1	0/110 (0.00%)	1/108 (0.93%)
Lethargy ^† 1	1/110 (0.91%)	0/108 (0.00%)
Post herpetic neuralgia ^† 1	1/110 (0.91%)	0/108 (0.00%)
Presyncope ^† 1	0/110 (0.00%)	1/108 (0.93%)
Syncope ^† 1	0/110 (0.00%)	1/108 (0.93%)
Transient ischaemic attack ^† 1	2/110 (1.82%)	0/108 (0.00%)
Psychiatric disorders
Agitation ^† 1	1/110 (0.91%)	0/108 (0.00%)
Anxiety ^† 1	1/110 (0.91%)	0/108 (0.00%)
Confusional state ^† 1	1/110 (0.91%)	0/108 (0.00%)
Mental status changes ^† 1	0/110 (0.00%)	1/108 (0.93%)
Renal and urinary disorders
Pollakiuria ^† 1	0/110 (0.00%)	1/108 (0.93%)
Renal failure acute ^† 1	1/110 (0.91%)	0/108 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure ^† 1	1/110 (0.91%)	1/108 (0.93%)
Chronic obstructive pulmonary disease ^† 1	1/110 (0.91%)	1/108 (0.93%)
Cough ^† 1	0/110 (0.00%)	1/108 (0.93%)
Dyspnoea ^† 1	2/110 (1.82%)	3/108 (2.78%)
Haemoptysis ^† 1	1/110 (0.91%)	0/108 (0.00%)
Hypoxia ^† 1	2/110 (1.82%)	1/108 (0.93%)
Pleural effusion ^† 1	2/110 (1.82%)	1/108 (0.93%)
Pneumonitis ^† 1	4/110 (3.64%)	1/108 (0.93%)
Pulmonary embolism ^† 1	1/110 (0.91%)	0/108 (0.00%)
Pulmonary mass ^† 1	1/110 (0.91%)	0/108 (0.00%)
Pulmonary oedema ^† 1	0/110 (0.00%)	2/108 (1.85%)
Skin and subcutaneous tissue disorders
Angioedema ^† 1	1/110 (0.91%)	0/108 (0.00%)
Dermatitis exfoliative ^† 1	1/110 (0.91%)	0/108 (0.00%)
Rash ^† 1	0/110 (0.00%)	1/108 (0.93%)
Rash macular ^† 1	0/110 (0.00%)	1/108 (0.93%)
Skin disorder ^† 1	1/110 (0.91%)	0/108 (0.00%)
Urticaria ^† 1	1/110 (0.91%)	0/108 (0.00%)
Vascular disorders
Deep vein thrombosis ^† 1	2/110 (1.82%)	0/108 (0.00%)
Embolism ^† 1	0/110 (0.00%)	1/108 (0.93%)
Hypotension ^† 1	2/110 (1.82%)	1/108 (0.93%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA (17.0)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Idelalisib + Rituximab	Placebo + Rituximab
	Affected / at Risk (%)	Affected / at Risk (%)
Total	103/110 (93.64%)	102/108 (94.44%)
Blood and lymphatic system disorders
Anaemia ^† 1	13/110 (11.82%)	11/108 (10.19%)
Neutropenia ^† 1	28/110 (25.45%)	21/108 (19.44%)
Thrombocytopenia ^† 1	8/110 (7.27%)	4/108 (3.70%)
Gastrointestinal disorders
Abdominal distension ^† 1	2/110 (1.82%)	6/108 (5.56%)
Abdominal pain ^† 1	9/110 (8.18%)	11/108 (10.19%)
Abdominal pain upper ^† 1	8/110 (7.27%)	3/108 (2.78%)
Colitis ^† 1	6/110 (5.45%)	1/108 (0.93%)
Constipation ^† 1	16/110 (14.55%)	15/108 (13.89%)
Diarrhoea ^† 1	31/110 (28.18%)	19/108 (17.59%)
Gastrooesophageal reflux disease ^† 1	11/110 (10.00%)	0/108 (0.00%)
Nausea ^† 1	30/110 (27.27%)	25/108 (23.15%)
Stomatitis ^† 1	7/110 (6.36%)	1/108 (0.93%)
Vomiting ^† 1	16/110 (14.55%)	9/108 (8.33%)
General disorders
Asthenia ^† 1	8/110 (7.27%)	8/108 (7.41%)
Chills ^† 1	27/110 (24.55%)	16/108 (14.81%)
Fatigue ^† 1	34/110 (30.91%)	35/108 (32.41%)
Oedema peripheral ^† 1	12/110 (10.91%)	10/108 (9.26%)
Pain ^† 1	8/110 (7.27%)	1/108 (0.93%)
Pyrexia ^† 1	40/110 (36.36%)	18/108 (16.67%)
Infections and infestations
Bronchitis ^† 1	7/110 (6.36%)	4/108 (3.70%)
Cellulitis ^† 1	7/110 (6.36%)	2/108 (1.85%)
Pneumonia ^† 1	4/110 (3.64%)	6/108 (5.56%)
Sinusitis ^† 1	9/110 (8.18%)	6/108 (5.56%)
Upper respiratory tract infection ^† 1	9/110 (8.18%)	13/108 (12.04%)
Urinary tract infection ^† 1	8/110 (7.27%)	4/108 (3.70%)
Injury, poisoning and procedural complications
Infusion related reaction ^† 1	21/110 (19.09%)	33/108 (30.56%)
Investigations
Alanine aminotransferase increased ^† 1	8/110 (7.27%)	0/108 (0.00%)
Aspartate aminotransferase increased ^† 1	8/110 (7.27%)	0/108 (0.00%)
Weight decreased ^† 1	11/110 (10.00%)	9/108 (8.33%)
Metabolism and nutrition disorders
Decreased appetite ^† 1	18/110 (16.36%)	12/108 (11.11%)
Hypokalaemia ^† 1	8/110 (7.27%)	6/108 (5.56%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	9/110 (8.18%)	4/108 (3.70%)
Back pain ^† 1	6/110 (5.45%)	4/108 (3.70%)
Muscle spasms ^† 1	8/110 (7.27%)	7/108 (6.48%)
Nervous system disorders
Dizziness ^† 1	7/110 (6.36%)	9/108 (8.33%)
Headache ^† 1	11/110 (10.00%)	9/108 (8.33%)
Psychiatric disorders
Anxiety ^† 1	3/110 (2.73%)	7/108 (6.48%)
Insomnia ^† 1	10/110 (9.09%)	7/108 (6.48%)
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	27/110 (24.55%)	34/108 (31.48%)
Dyspnoea ^† 1	17/110 (15.45%)	22/108 (20.37%)
Nasal congestion ^† 1	6/110 (5.45%)	4/108 (3.70%)
Oropharyngeal pain ^† 1	6/110 (5.45%)	6/108 (5.56%)
Productive cough ^† 1	6/110 (5.45%)	4/108 (3.70%)
Skin and subcutaneous tissue disorders
Night sweats ^† 1	12/110 (10.91%)	13/108 (12.04%)
Pruritus ^† 1	6/110 (5.45%)	5/108 (4.63%)
Rash ^† 1	16/110 (14.55%)	4/108 (3.70%)
Skin lesion ^† 1	3/110 (2.73%)	7/108 (6.48%)
Vascular disorders
Hypotension ^† 1	4/110 (3.64%)	7/108 (6.48%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA (17.0)

Limitations and Caveats

Following a recommendation by an independent Data Monitoring Committee (DMC), the study was stopped early due to highly statistically significant results for the primary efficacy endpoint of progression-free survival.

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.

After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met:

The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or
The study has been completed at all study sites for at least 2 years

Results Point of Contact

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Name/Title:	Clinical Trial Disclosures
Organization:	Gilead Sciences, Inc.
EMail:	ClinicalTrialDisclosures@gilead.com

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

Barrientos JC, Hillmen P, Salles G, Sharman J, Stilgenbauer S, Gurtovaya O, Xing G, Ruzicka B, Bhargava P, Ghia P, Pagel JM. No increased bleeding events in patients with relapsed chronic lymphocytic leukemia and indolent non-Hodgkin lymphoma treated with idelalisib. Leuk Lymphoma. 2021 Apr;62(4):837-845. doi: 10.1080/10428194.2020.1845339. Epub 2020 Dec 10.

Gordon MJ, Huang J, Chan RJ, Bhargava P, Danilov AV. Medical comorbidities in patients with chronic lymphocytic leukaemia treated with idelalisib: analysis of two large randomised clinical trials. Br J Haematol. 2021 Feb;192(4):720-728. doi: 10.1111/bjh.16879. Epub 2020 Jun 29.

Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn I, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Stilgenbauer S, Cramer P, Aiello M, Johnson DM, Miller LL, Li D, Jahn TM, Dansey RD, Hallek M, O'Brien SM. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014 Mar 13;370(11):997-1007. doi: 10.1056/NEJMoa1315226. Epub 2014 Jan 22.

Layout table for additonal information

Responsible Party:	Gilead Sciences
ClinicalTrials.gov Identifier:	NCT01539512
Other Study ID Numbers:	GS-US-312-0116 2011-005180-24 ( EudraCT Number )
First Submitted:	February 12, 2012
First Posted:	February 27, 2012
Results First Submitted:	October 9, 2014
Results First Posted:	October 16, 2014
Last Update Posted:	May 14, 2019

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