OPTIC-2L: A Study Comparing Ponatinib and Nilotinib in Participants With Chronic Myeloid Leukemia

• Sponsor: Ariad Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02627677
• Collaborator: (none)
• Enrollment: 44
• Location: 1
• Arms: 3
• Actual Duration (Months): 60.7
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The purpose of this study is to compare the efficacy and safety of 2 starting doses of ponatinib compared to nilotinib in participants with imatinib-resistant chronic myeloid leukemia (CML) in chronic phase (CP).

Condition or Disease	Intervention/Treatment	Phase
Chronic Phase Chronic Myeloid Leukemia	Drug: Ponatinib 30 mg QD; Drug: Ponatinib 15 mg QD; Drug: Nilotinib 400 mg BID	Phase 3

Detailed Description

This is a multi-center, randomized study to demonstrate the efficacy and safety of 2 starting doses of ponatinib as a treatment for CP-CML compared to nilotinib. Eligible participants must have chronic phase chronic myeloid leukemia (CP-CML), be resistant to first-line imatinib treatment and have received no other tyrosine kinase inhibitors (TKIs).

Study Design

• Study Type: Interventional
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-label Study of Ponatinib Versus Nilotinib in Patients With Chronic Myeloid Leukemia in Chronic Phase Following Resistance to Imatinib
• Actual Study Start Date: Dec 31, 2015
• Actual Primary Completion Date: Oct 29, 2020
• Actual Study Completion Date: Jan 20, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A: Ponatinib 30 mg Ponatinib 30 mg, tablets, orally, once daily (QD) until achievement of major molecular response (MMR) up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to 42 months.	Drug: Ponatinib 30 mg QD; Ponatinib 30 mg, taken orally once daily.; Other Names: Iclusig AP24534
Experimental: Cohort B: Ponatinib 15 mg Ponatinib 15 mg, tablets, orally, QD until achievement of MMR up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to 45 months.	Drug: Ponatinib 15 mg QD; Ponatinib 15 mg, taken orally once daily.; Other Names: Iclusig AP24534
Active Comparator: Cohort C: Nilotinib 400 mg Nilotinib 400 mg, tablets, orally, twice daily up to approximately 42 months.	Drug: Nilotinib 400 mg BID; Nilotinib 400 mg, taken orally twice daily.; Other Names: Tasigna AMN107

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Major Molecular Response (MMR) [Up to 12 months]

   MMR is defined as the percentage of participants achieving a ratio of ≤0.1% Breakpoint Cluster Region-Abelson (BCR ABL) to ABL transcripts on the international scale (≤0.1% BCR-ABL/ABL[IS]) at any time within 12 months after randomization.

Secondary Outcome Measures

1. Percentage of Participants With Major Cytogenetic Response (MCyR) [Up to 12 months]

   MCyR was the percentage of participants achieving Complete cytogenetic response (CCyR: defined as 0% Philadelphia chromosome-positive [Ph+] metaphases by cytogenetic analysis of bone marrow) or Partial Cytogenetic Response (PCyR: defined as >0% to 35% Ph+ metaphases by cytogenetic analysis of bone marrow) at any time within 12 months after randomization.

2. Percentage of Participants With Complete Cytogenetic Response (CCyR) [Up to 12 months]

   CCyR rate was defined as the percentage of participants achieving CCyR up to 12 months after randomization. CCyR is defined as 0% Philadelphia chromosome-positive [Ph+] metaphases by cytogenetic analysis of bone marrow.

3. Percentage of Participants With Molecular Response (MR) [From Month 3 to every 3 months up to 48 months]

   Molecular response rate is defined as percentage of participants achieving MR2: Molecular response with 2-log reduction (defined as ≤1% BCR-ABL[IS]), MMR: Major molecular responder, MR4 (defined as ≤0.01% BCR-ABL[IS]), and MR4.5 (defined as ≤0.0032% BCR-ABL[IS]) after randomization.

4. Percentage of Participants With MR1 [Month 3]

   MR1 was defined as the percentage of participants achieving a ratio of ≤10% BCR ABL to ABL transcripts on the international scale at 3 months.

5. Percentage of Participants With Treatment Emergent Arterial Occlusive Events (TE-AOEs), Treatment Emergent Venous Thromboembolic Events (TE-VTE), Adverse Events (AEs), and Serious AEs (SAEs) [From first dose up to 30 days post last dose (Up to approximately 46 months)]

   TE-AOE: arterial occlusive event with an initial onset date on or after first dose date and no later than 30 days after last dose date of study treatment or events starting after initial consent that worsen in severity on or after first dose date. TE-VTE: vascular occlusive event with an initial onset date on or after first dose date and no later than 30 days after last dose date of study treatment or events starting after initial consent that worsen in severity on or after first dose date. AE: any untoward medical occurrence in participant administered pharmaceutical product; untoward medical occurrence does not necessarily have causal relationship with this treatment. SAE: any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is congenital anomaly/birth defect/is medically important event.

6. Time to Response [Up to approximately 60 months]

   Time to MMR defined as the interval between the randomization date and the first date at which the criteria for response was met. MMR was defined as <=0.1% BCR-ABL.

7. Duration of Response [Up to approximately 60 months]

   Duration of response defined as the interval between the first assessment at which the criteria for response was met until the earliest date at which loss of response occurs, or the criteria for progression was met.

8. Progression-free Survival (PFS) [Up to end of study (approximately 60 months)]

   Progression-free survival (PFS) defined as the interval between the first dose date of study treatment and the first date at which the criteria for progression was met (progression to AP- or BP CML), or death due to any cause, censored at the last response assessment.

9. Overall Survival [Up to end of study (approximately 60 months)]

   Overall survival (OS) defined as the interval between the first dose date of study treatment and date of death due to any cause, censored at the last contact date to be alive.

10. Percentage of Participants Who Achieved/Maintained Complete Hematologic Response (CHR) [3 months after the first dose of study treatment]

    CHR rate is defined as the percentage of participants achieving CHR at any time after initiation of study treatment. CHR is defined as achieving all of the following measurements: White blood cells (WBC) ≤ institutional upper limit of normal (ULN); Platelets <450 x 10^9/L; No blasts or promyelocytes in peripheral blood; <5% myelocytes plus metamyelocytes in peripheral blood; Basophils in peripheral blood <5%; No extramedullary involvement (including no hepatomegaly or splenomegaly).

11. Percentage of Participants With Treatment Emergent AEs Leading to Treatment Discontinuation, Dose Reduction and Dose Interruption [From first dose up to end of treatment (Up to approximately 45 months)]

    An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.

12. Percentage of Participants With Progression to Accelerated Phase (AP) or Blast Phase (BP)-CML [Up to end of study (Up to approximately 60 months)]

    Progression to AP is defined as: >=15% and <30% blasts in peripheral blood or bone marrow or >=20% basophils in peripheral blood or bone marrow or >=30% blasts + promyelocytes in peripheral blood or bone marrow (but <30% blasts) or <100*10^9 platelets/L in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP-CML is defined as: >=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Have CP-CML and are resistant to first-line imatinib treatment.

2. Be male or female ≥18 years old.

3. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

4. Have adequate renal function as defined by the following criterion:

• Serum creatinine ≤1.5 × upper limit of normal (ULN) for institution.

1. Have adequate hepatic function as defined by all of the following criteria:

• Total serum bilirubin ≤1.5 × ULN, unless due to Gilbert's syndrome

• Alanine aminotransferase (ALT) ≤2.5 × ULN or ≤5 × ULN if leukemic infiltration of the liver is present

• Aspartate aminotransferase (AST) ≤2.5 × ULN or ≤5 × ULN if leukemic infiltration of the liver is present.

1. Have normal pancreatic status as defined by the following criterion:

• Serum lipase and amylase ≤1.5 × ULN.

Exclusion Criteria:

1. Have previously been treated with any approved or investigational TKIs other than imatinib or treated with imatinib within 14 days prior to receiving study drug.

2. Have previously been treated with any anti-CML therapy other than hydroxyurea, including interferon, cytarabine, immunotherapy, or any cytotoxic chemotherapy, radiotherapy, or investigational therapy.

3. Underwent autologous or allogeneic stem cell transplant.

4. Are in CCyR or MMR.

5. Have clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:

• Any history of myocardial infarction (MI), unstable angina, cerebrovascular accident, or transient ischemic attack (TIA)

• Any history of peripheral vascular infarction, including visceral infarction

• Any history of a revascularization procedure, including vascular surgery or the placement of a stent

• History of venous thromboembolism, including deep venous thrombosis, superficial venous thrombosis, or pulmonary embolism, within 6 months prior to enrollment

• Congestive heart failure (New York Heart Association [NYHA] class III or IV) within 6 months prior to enrollment or left ventricular ejection fraction (LVEF) less than 45% or less than the institutional lower limit of normal (whichever is higher) within 6 months prior to enrollment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cliniques Universitaire Saint-Luc (Site 058)	Bruxelles		Belgium	1200

Sponsors and Collaborators

• Ariad Pharmaceuticals

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

• Study Protocol - Mar 10, 2017
• Statistical Analysis Plan - Jul 31, 2016

More Information

Publications

None provided.

• Responsible Party: Ariad Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02627677
• Other Study ID Numbers: AP24534-15-303; 2015-001318-92
• First Posted: Dec 11, 2015
• Last Update Posted: Nov 26, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Ariad Pharmaceuticals: CML; CP-CML; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Ponatinib

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 90 investigative sites in Austria, Canada, Czechia, France, Hungary, Italy, Korea, and Russia from 31 December 2015 to 20 January 2021
Pre-assignment Detail	Participants with a diagnosis of chronic phase-chronic myeloid leukemia were enrolled and randomised at a ratio of 1:2:1 to receive ponatinib 30 mg and ponatinib 15 mg compared with nilotinib 400 mg.

Arm/Group Title	Cohort A: Ponatinib 30 mg	Cohort B: Ponatinib 15 mg	Cohort C: Nilotinib 400 mg
Arm/Group Description	Ponatinib 30 mg, tablets, orally, once daily (QD) until achievement of major molecular response (MMR) up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 42 months.	Ponatinib 15 mg, tablets, orally, QD until achievement of MMR up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 45 months.	Nilotinib 400 mg, tablets, orally, twice daily up to approximately 42 months.
Period Title: Overall Study
STARTED	11	21	12
COMPLETED	0	0	0
NOT COMPLETED	11	21	12

Baseline Characteristics

Arm/Group Title	Cohort A: Ponatinib 30 mg	Cohort B: Ponatinib 15 mg	Cohort C: Nilotinib 400 mg	Total
Arm/Group Description	Ponatinib 30 mg, tablets, orally, once daily (QD) until achievement of major molecular response (MMR) up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 42 months.	Ponatinib 15 mg, tablets, orally, QD until achievement of MMR up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 45 months.	Nilotinib 400 mg, tablets, orally, twice daily up to approximately 42 months.	Total of all reporting groups
Overall Participants	10	21	12	43
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.7 (17.43)	44.7 (15.53)	54.3 (13.23)	47.16 (15.69)
Sex: Female, Male (Count of Participants)
Female	3 30%	11 52.4%	6 50%	20 46.5%
Male	7 70%	10 47.6%	6 50%	23 53.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	1 8.3%	1 2.3%
Not Hispanic or Latino	10 100%	21 100%	11 91.7%	42 97.7%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	2 20%	4 19%	1 8.3%	7 16.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	7 70%	16 76.2%	10 83.3%	33 76.7%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 10%	1 4.8%	1 8.3%	3 7%
Region of Enrollment (Count of Participants)
Austria	0 0%	1 4.8%	0 0%	1 2.3%
Canada	0 0%	0 0%	1 8.3%	1 2.3%
Czech Republic	0 0%	0 0%	2 16.7%	2 4.7%
France	1 10%	1 4.8%	1 8.3%	3 7%
Hungary	0 0%	1 4.8%	0 0%	1 2.3%
Italy	0 0%	0 0%	1 8.3%	1 2.3%
Korea, North	1 10%	2 9.5%	0 0%	3 7%
Russia	8 80%	16 76.2%	7 58.3%	31 72.1%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	172.9 (9.62)	169.4 (9.35)	168.8 (9.17)	170.1 (9.28)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	77.50 (18.335)	72.72 (15.213)	70.94 (14.711)	73.34 (15.65)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	25.90 (5.870)	25.35 (4.974)	25.18 (4.442)	25.44 (4.95)

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Major Molecular Response (MMR)
Description	MMR is defined as the percentage of participants achieving a ratio of ≤0.1% Breakpoint Cluster Region-Abelson (BCR ABL) to ABL transcripts on the international scale (≤0.1% BCR-ABL/ABL[IS]) at any time within 12 months after randomization.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who have received at least 1 dose of study drug, with data available for analysis.

Arm/Group Title	Cohort A: Ponatinib 30 mg	Cohort B: Ponatinib 15 mg	Cohort C: Nilotinib 400 mg
Arm/Group Description	Ponatinib 30 mg, tablets, orally, once daily (QD) until achievement of major molecular response (MMR) up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 42 months.	Ponatinib 15 mg, tablets, orally, QD until achievement of MMR up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 45 months.	Nilotinib 400 mg, tablets, orally, twice daily up to approximately 42 months.
Measure Participants	10	21	11
Number (95% Confidence Interval) [percentage of participants]	50.0 500%	33.3 158.6%	45.5 379.2%

2. Secondary Outcome

Title	Percentage of Participants With Major Cytogenetic Response (MCyR)
Description	MCyR was the percentage of participants achieving Complete cytogenetic response (CCyR: defined as 0% Philadelphia chromosome-positive [Ph+] metaphases by cytogenetic analysis of bone marrow) or Partial Cytogenetic Response (PCyR: defined as >0% to 35% Ph+ metaphases by cytogenetic analysis of bone marrow) at any time within 12 months after randomization.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who have received at least 1 dose of study drug, with data available for analysis.

Arm/Group Title	Cohort A: Ponatinib 30 mg	Cohort B: Ponatinib 15 mg	Cohort C: Nilotinib 400 mg
Arm/Group Description	Ponatinib 30 mg, tablets, orally, once daily (QD) until achievement of major molecular response (MMR) up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 42 months.	Ponatinib 15 mg, tablets, orally, QD until achievement of MMR up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 45 months.	Nilotinib 400 mg, tablets, orally, twice daily up to approximately 42 months.
Measure Participants	10	20	12
Number (95% Confidence Interval) [percentage of participants]	50.0 500%	60.0 285.7%	50.0 416.7%

3. Secondary Outcome

Title	Percentage of Participants With Complete Cytogenetic Response (CCyR)
Description	CCyR rate was defined as the percentage of participants achieving CCyR up to 12 months after randomization. CCyR is defined as 0% Philadelphia chromosome-positive [Ph+] metaphases by cytogenetic analysis of bone marrow.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who have received at least 1 dose of study drug, with data available for analysis.

Arm/Group Title	Cohort A: Ponatinib 30 mg	Cohort B: Ponatinib 15 mg	Cohort C: Nilotinib 400 mg
Arm/Group Description	Ponatinib 30 mg, tablets, orally, once daily (QD) until achievement of major molecular response (MMR) up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 42 months.	Ponatinib 15 mg, tablets, orally, QD until achievement of MMR up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 45 months.	Nilotinib 400 mg, tablets, orally, twice daily up to approximately 42 months.
Measure Participants	10	20	12
Number (95% Confidence Interval) [percentage of participants]	40.0 400%	55.0 261.9%	50.0 416.7%

4. Secondary Outcome

Title	Percentage of Participants With Molecular Response (MR)
Description	Molecular response rate is defined as percentage of participants achieving MR2: Molecular response with 2-log reduction (defined as ≤1% BCR-ABL[IS]), MMR: Major molecular responder, MR4 (defined as ≤0.01% BCR-ABL[IS]), and MR4.5 (defined as ≤0.0032% BCR-ABL[IS]) after randomization.
Time Frame	From Month 3 to every 3 months up to 48 months

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who have received at least 1 dose of study drug, with data available for analysis. Number analyzed are participants with data available for analyses at given timepoint.

Arm/Group Title	Cohort A: Ponatinib 30 mg	Cohort B: Ponatinib 15 mg	Cohort C: Nilotinib 400 mg
Arm/Group Description	Ponatinib 30 mg, tablets, orally, once daily (QD) until achievement of major molecular response (MMR) up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 42 months.	Ponatinib 15 mg, tablets, orally, QD until achievement of MMR up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 45 months.	Nilotinib 400 mg, tablets, orally, twice daily up to approximately 42 months.
Measure Participants	10	21	12
MR2 - Month 3	70.0 700%	38.1 181.4%	45.5 379.2%
MR2 - Month 6	60.0 600%	57.1 271.9%	54.5 454.2%
MR2 - Month 9	50.0 500%	52.4 249.5%	45.5 379.2%
MR2 - Month 12	50.0 500%	52.4 249.5%	54.5 454.2%
MR2 - Month 15	50.0 500%	52.4 249.5%	54.5 454.2%
MR2 - Month 18	50.0 500%	47.6 226.7%	54.5 454.2%
MR2 - Month 21	50.0 500%	52.4 249.5%	45.5 379.2%
MR2 - Month 24	50.0 500%	47.6 226.7%	54.5 454.2%
MR2 - Month 27	50.0 500%	42.9 204.3%	54.5 454.2%
MR2 - Month 30	50.0 500%	38.1 181.4%	45.5 379.2%
MR2 - Month 33	30.0 300%	33.3 158.6%	27.3 227.5%
MR2 - Month 36	50.0 500%	33.3 158.6%	36.4 303.3%
MR2 - Month 39	20.0 200%	14.3 68.1%	18.2 151.7%
MR2 - Month 42	10.0 100%	9.5 45.2%	9.1 75.8%
MR2 - Month 45	10.0 100%	14.3 68.1%	9.1 75.8%
MR2 - Month 48	10.0 100%	4.8 22.9%	9.1 75.8%
MR3/MMR - Month 3	30.0 300%	4.8 22.9%	18.2 151.7%
MR3/MMR - Month 6	30.0 300%	28.6 136.2%	36.4 303.3%
MR3/MMR - Month 9	30.0 300%	28.6 136.2%	45.5 379.2%
MR3/MMR - Month 12	40.0 400%	33.3 158.6%	45.5 379.2%
MR3/MMR - Month 15	40.0 400%	28.6 136.2%	45.5 379.2%
MR3/MMR - Month 18	40.0 400%	38.1 181.4%	45.5 379.2%
MR3/MMR - Month 21	40.0 400%	33.3 158.6%	45.5 379.2%
MR3/MMR - Month 24	40.0 400%	33.3 158.6%	45.5 379.2%
MR3/MMR - Month 27	40.0 400%	33.3 158.6%	45.5 379.2%
MR3/MMR - Month 30	40.0 400%	33.3 158.6%	45.5 379.2%
MR3/MMR - Month 33	20.0 200%	28.6 136.2%	27.3 227.5%
MR3/MMR - Month 36	40.0 400%	28.6 136.2%	36.4 303.3%
MR3/MMR - Month 39	20.0 200%	14.3 68.1%	18.2 151.7%
MR3/MMR - Month 42	10.0 100%	9.5 45.2%	9.1 75.8%
MR3/MMR - Month 45	10.0 100%	9.5 45.2%	9.1 75.8%
MR3/MMR - Month 48	10.0 100%	4.8 22.9%	9.1 75.8%
MR4 - Month 3	0.0 0%	0.0 0%	0.0 0%
MR4 - Month 6	20.0 200%	14.3 68.1%	9.1 75.8%
MR4 - Month 9	10.0 100%	9.5 45.2%	18.2 151.7%
MR4 - Month 12	10.0 100%	9.5 45.2%	27.3 227.5%
MR4 - Month 15	10.0 100%	19.0 90.5%	27.3 227.5%
MR4 - Month 18	20.0 200%	23.8 113.3%	27.3 227.5%
MR4 - Month 21	20.0 200%	9.5 45.2%	36.4 303.3%
MR4 - Month 24	10.0 100%	19.0 90.5%	36.4 303.3%
MR4 - Month 27	20.0 200%	19.0 90.5%	36.4 303.3%
MR4 - Month 30	20.0 200%	14.3 68.1%	36.4 303.3%
MR4 - Month 33	0.0 0%	14.3 68.1%	9.1 75.8%
MR4 - Month 36	10.0 100%	19.0 90.5%	27.3 227.5%
MR4 - Month 39	20.0 200%	4.8 22.9%	18.2 151.7%
MR4 - Month 42	10.0 100%	0.0 0%	9.1 75.8%
MR4 - Month 45	10.0 100%	4.8 22.9%	9.1 75.8%
MR4 - Month 48	10.0 100%	0.0 0%	9.1 75.8%
MR4.5 - Month 3	0.0 0%	0.0 0%	0.0 0%
MR4.5 - Month 6	20.0 200%	0.0 0%	0.0 0%
MR4.5 - Month 9	0.0 0%	4.8 22.9%	9.1 75.8%
MR4.5 - Month 12	0.0 0%	4.8 22.9%	18.2 151.7%
MR4.5 - Month 15	10.0 100%	4.8 22.9%	9.1 75.8%
MR4.5 - Month 18	10.0 100%	9.5 45.2%	9.1 75.8%
MR4.5 - Month 21	10.0 100%	9.5 45.2%	27.3 227.5%
MR4.5 - Month 24	10.0 100%	4.8 22.9%	18.2 151.7%
MR4.5 - Month 27	10.0 100%	14.3 68.1%	18.2 151.7%
MR4.5 - Month 30	10.0 100%	4.8 22.9%	27.3 227.5%
MR4.5 - Month 33	0.0 0%	4.8 22.9%	0.0 0%
MR4.5 - Month 36	10.0 100%	9.5 45.2%	18.2 151.7%
MR4.5 - Month 39	10.0 100%	4.8 22.9%	18.2 151.7%
MR4.5 - Month 42	10.0 100%	0.0 0%	9.1 75.8%
MR4.5 - Month 45	10.0 100%	0.0 0%	9.1 75.8%
MR4.5 - Month 48	0.0 0%	0.0 0%	9.1 75.8%

5. Secondary Outcome

Title	Percentage of Participants With MR1
Description	MR1 was defined as the percentage of participants achieving a ratio of ≤10% BCR ABL to ABL transcripts on the international scale at 3 months.
Time Frame	Month 3

Outcome Measure Data

Analysis Population Description

Safety Population includes all participants who have received at least 1 dose of study drug, with data available for analysis.

Arm/Group Title	Cohort A: Ponatinib 30 mg	Cohort B: Ponatinib 15 mg	Cohort C: Nilotinib 400 mg
Arm/Group Description	Ponatinib 30 mg, tablets, orally, once daily (QD) until achievement of major molecular response (MMR) up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 42 months.	Ponatinib 15 mg, tablets, orally, QD until achievement of MMR up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 45 months.	Nilotinib 400 mg, tablets, orally, twice daily up to approximately 42 months.
Measure Participants	10	21	11
Number [percentage of participants]	70.0 700%	66.7 317.6%	63.6 530%

6. Secondary Outcome

Title	Percentage of Participants With Treatment Emergent Arterial Occlusive Events (TE-AOEs), Treatment Emergent Venous Thromboembolic Events (TE-VTE), Adverse Events (AEs), and Serious AEs (SAEs)
Description	TE-AOE: arterial occlusive event with an initial onset date on or after first dose date and no later than 30 days after last dose date of study treatment or events starting after initial consent that worsen in severity on or after first dose date. TE-VTE: vascular occlusive event with an initial onset date on or after first dose date and no later than 30 days after last dose date of study treatment or events starting after initial consent that worsen in severity on or after first dose date. AE: any untoward medical occurrence in participant administered pharmaceutical product; untoward medical occurrence does not necessarily have causal relationship with this treatment. SAE: any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is congenital anomaly/birth defect/is medically important event.
Time Frame	From first dose up to 30 days post last dose (Up to approximately 46 months)

Outcome Measure Data

Analysis Population Description

Safety Population includes all participants who have received at least 1 dose of study drug.

Arm/Group Title	Cohort A: Ponatinib 30 mg	Cohort B: Ponatinib 15 mg	Cohort C: Nilotinib 400 mg
Arm/Group Description	Ponatinib 30 mg, tablets, orally, once daily (QD) until achievement of major molecular response (MMR) up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 42 months.	Ponatinib 15 mg, tablets, orally, QD until achievement of MMR up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 45 months.	Nilotinib 400 mg, tablets, orally, twice daily up to approximately 42 months.
Measure Participants	10	21	12
TE-AOE	0 0%	4.8 22.9%	8.3 69.2%
TE-VOEs	0 0%	0 0%	0 0%
AEs	100 1000%	95.2 453.3%	100 833.3%
SAEs	40.0 400%	14.3 68.1%	16.7 139.2%

7. Secondary Outcome

Title	Time to Response
Description	Time to MMR defined as the interval between the randomization date and the first date at which the criteria for response was met. MMR was defined as <=0.1% BCR-ABL.
Time Frame	Up to approximately 60 months

Outcome Measure Data

Analysis Population Description

Safety Population includes all participants who have received at least 1 dose of study drug. Only responders were analyzed for this outcome measure.

Arm/Group Title	Cohort A: Ponatinib 30 mg	Cohort B: Ponatinib 15 mg	Cohort C: Nilotinib 400 mg
Arm/Group Description	Ponatinib 30 mg, tablets, orally, once daily (QD) until achievement of major molecular response (MMR) up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 42 months.	Ponatinib 15 mg, tablets, orally, QD until achievement of MMR up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 45 months.	Nilotinib 400 mg, tablets, orally, twice daily up to approximately 42 months.
Measure Participants	5	9	5
Median (95% Confidence Interval) [months]	3.07	6.29	6.07

8. Secondary Outcome

Title	Duration of Response
Description	Duration of response defined as the interval between the first assessment at which the criteria for response was met until the earliest date at which loss of response occurs, or the criteria for progression was met.
Time Frame	Up to approximately 60 months

Outcome Measure Data

Analysis Population Description

Safety Population includes all participants who have received at least 1 dose of study drug. Only responders were analyzed for this outcome measure.

Arm/Group Title	Cohort A: Ponatinib 30 mg	Cohort B: Ponatinib 15 mg	Cohort C: Nilotinib 400 mg
Arm/Group Description	Ponatinib 30 mg, tablets, orally, once daily (QD) until achievement of major molecular response (MMR) up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 42 months.	Ponatinib 15 mg, tablets, orally, QD until achievement of MMR up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 45 months.	Nilotinib 400 mg, tablets, orally, twice daily up to approximately 42 months.
Measure Participants	5	9	5
Median (95% Confidence Interval) [months]	NA	NA	NA

9. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	Progression-free survival (PFS) defined as the interval between the first dose date of study treatment and the first date at which the criteria for progression was met (progression to AP- or BP CML), or death due to any cause, censored at the last response assessment.
Time Frame	Up to end of study (approximately 60 months)

Outcome Measure Data

Analysis Population Description

Safety Population includes all participants who have received at least 1 dose of study drug.

Arm/Group Title	Cohort A: Ponatinib 30 mg	Cohort B: Ponatinib 15 mg	Cohort C: Nilotinib 400 mg
Arm/Group Description	Ponatinib 30 mg, tablets, orally, once daily (QD) until achievement of major molecular response (MMR) up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 42 months.	Ponatinib 15 mg, tablets, orally, QD until achievement of MMR up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 45 months.	Nilotinib 400 mg, tablets, orally, twice daily up to approximately 42 months.
Measure Participants	10	21	12
Median (95% Confidence Interval) [months]	NA	NA	NA

10. Secondary Outcome

Title	Overall Survival
Description	Overall survival (OS) defined as the interval between the first dose date of study treatment and date of death due to any cause, censored at the last contact date to be alive.
Time Frame	Up to end of study (approximately 60 months)

Outcome Measure Data

Analysis Population Description

Safety Population includes all participants who have received at least 1 dose of study drug.

Arm/Group Title	Cohort A: Ponatinib 30 mg	Cohort B: Ponatinib 15 mg	Cohort C: Nilotinib 400 mg
Arm/Group Description	Ponatinib 30 mg, tablets, orally, once daily (QD) until achievement of major molecular response (MMR) up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 42 months.	Ponatinib 15 mg, tablets, orally, QD until achievement of MMR up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 45months.	Nilotinib 400 mg, tablets, orally, twice daily up to approximately 42 months.
Measure Participants	10	21	12
Median (95% Confidence Interval) [months]	NA	NA	NA

11. Secondary Outcome

Title	Percentage of Participants Who Achieved/Maintained Complete Hematologic Response (CHR)
Description	CHR rate is defined as the percentage of participants achieving CHR at any time after initiation of study treatment. CHR is defined as achieving all of the following measurements: White blood cells (WBC) ≤ institutional upper limit of normal (ULN); Platelets <450 x 10^9/L; No blasts or promyelocytes in peripheral blood; <5% myelocytes plus metamyelocytes in peripheral blood; Basophils in peripheral blood <5%; No extramedullary involvement (including no hepatomegaly or splenomegaly).
Time Frame	3 months after the first dose of study treatment

Outcome Measure Data

Analysis Population Description

Safety Population includes all participants who have received at least 1 dose of study drug.

Arm/Group Title	Cohort A: Ponatinib 30 mg	Cohort B: Ponatinib 15 mg	Cohort C: Nilotinib 400 mg
Arm/Group Description	Ponatinib 30 mg, tablets, orally, once daily (QD) until achievement of major molecular response (MMR) up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 42 months.	Ponatinib 15 mg, tablets, orally, QD until achievement of MMR up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 45 months.	Nilotinib 400 mg, tablets, orally, twice daily up to approximately 42 months.
Measure Participants	10	21	12
Number (95% Confidence Interval) [percentage of participants]	60.0 600%	81.0 385.7%	50.0 416.7%

12. Secondary Outcome

Title	Percentage of Participants With Treatment Emergent AEs Leading to Treatment Discontinuation, Dose Reduction and Dose Interruption
Description	An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.
Time Frame	From first dose up to end of treatment (Up to approximately 45 months)

Outcome Measure Data

Analysis Population Description

Safety Population includes all participants who have received at least 1 dose of study drug.

Arm/Group Title	Cohort A: Ponatinib 30 mg	Cohort B: Ponatinib 15 mg	Cohort C: Nilotinib 400 mg
Arm/Group Description	Ponatinib 30 mg, tablets, orally, once daily (QD) until achievement of major molecular response (MMR) up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 42 months.	Ponatinib 15 mg, tablets, orally, QD until achievement of MMR up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 45 months.	Nilotinib 400 mg, tablets, orally, twice daily up to approximately 42 months.
Measure Participants	10	21	12
TEAEs Leading to Treatment Discontinuation	10.0 100%	23.8 113.3%	25.0 208.3%
TEAEs Leading to Dose Reduction	40.0 400%	19.0 90.5%	33.3 277.5%
TEAEs Leading to Dose Interruption	70.0 700%	38.1 181.4%	41.7 347.5%

13. Secondary Outcome

Title	Percentage of Participants With Progression to Accelerated Phase (AP) or Blast Phase (BP)-CML
Description	Progression to AP is defined as: >=15% and <30% blasts in peripheral blood or bone marrow or >=20% basophils in peripheral blood or bone marrow or >=30% blasts + promyelocytes in peripheral blood or bone marrow (but <30% blasts) or <100*10^9 platelets/L in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP-CML is defined as: >=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.
Time Frame	Up to end of study (Up to approximately 60 months)

Outcome Measure Data

Analysis Population Description

As the study was terminated, data was not collected and analyzed for this outcome measure.

Arm/Group Title	Cohort A: Ponatinib 30 mg	Cohort B: Ponatinib 15 mg	Cohort C: Nilotinib 400 mg
Arm/Group Description	Ponatinib 30 mg, tablets, orally, once daily (QD) until achievement of major molecular response (MMR) up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 42 months.	Ponatinib 15 mg, tablets, orally, QD until achievement of MMR up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 45 months.	Nilotinib 400 mg, tablets, orally, twice daily up to approximately 42 months.
Measure Participants	0	0	0

Adverse Events

Time Frame	All-cause mortality: From first dose up to end of study (Up to approximately 60 months); for serious and other adverse events: from first dose up to 30 days post last dose (Up to approximately 46 months)
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population includes all participants who have received at least 1 dose of study drug.
Arm/Group Title	Cohort A: Ponatinib 30 mg		Cohort B: Ponatinib 15 mg		Cohort C: Nilotinib 400 mg
Arm/Group Description	Ponatinib 30 mg, tablets, orally, once daily (QD) until achievement of major molecular response (MMR) up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 42 months.		Ponatinib 15 mg, tablets, orally, QD until achievement of MMR up to 12 months. Once MMR was achieved, participants received reduced dose of ponatinib 15 mg orally once daily up to approximately 45 months.		Nilotinib 400 mg, tablets, orally, twice daily up to approximately 42 months.
All Cause Mortality
	Cohort A: Ponatinib 30 mg		Cohort B: Ponatinib 15 mg		Cohort C: Nilotinib 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/10 (10%)		1/21 (4.8%)		0/12 (0%)
Serious Adverse Events
	Cohort A: Ponatinib 30 mg		Cohort B: Ponatinib 15 mg		Cohort C: Nilotinib 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/10 (40%)		3/21 (14.3%)		2/12 (16.7%)
Blood and lymphatic system disorders
Thrombocytopenia	0/10 (0%)		1/21 (4.8%)		0/12 (0%)
Neutropenia	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Cardiac disorders
Atrial flutter	0/10 (0%)		1/21 (4.8%)		0/12 (0%)
Gastrointestinal disorders
Pancreatitis acute	0/10 (0%)		1/21 (4.8%)		0/12 (0%)
Intestinal obstruction	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Infections and infestations
Pneumonia	2/10 (20%)		0/21 (0%)		0/12 (0%)
Sepsis	0/10 (0%)		1/21 (4.8%)		0/12 (0%)
Septic shock	0/10 (0%)		1/21 (4.8%)		0/12 (0%)
Injury, poisoning and procedural complications
Femoral neck fracture	1/10 (10%)		0/21 (0%)		0/12 (0%)
Investigations
Platelet count decreased	2/10 (20%)		0/21 (0%)		0/12 (0%)
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	0/10 (0%)		1/21 (4.8%)		0/12 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumonia aspiration	0/10 (0%)		1/21 (4.8%)		0/12 (0%)
Vascular disorders
Peripheral arterial occlusive disease	0/10 (0%)		1/21 (4.8%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Cohort A: Ponatinib 30 mg		Cohort B: Ponatinib 15 mg		Cohort C: Nilotinib 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/10 (100%)		20/21 (95.2%)		12/12 (100%)
Blood and lymphatic system disorders
Thrombocytopenia	5/10 (50%)		5/21 (23.8%)		2/12 (16.7%)
Anaemia	2/10 (20%)		3/21 (14.3%)		0/12 (0%)
Neutropenia	1/10 (10%)		3/21 (14.3%)		2/12 (16.7%)
Anaemia folate deficiency	1/10 (10%)		0/21 (0%)		0/12 (0%)
Splenic lesion	1/10 (10%)		0/21 (0%)		0/12 (0%)
Thrombocytosis	0/10 (0%)		1/21 (4.8%)		1/12 (8.3%)
Cardiac disorders
Sinus tachycardia	0/10 (0%)		2/21 (9.5%)		0/12 (0%)
Left ventricular hypertrophy	1/10 (10%)		0/21 (0%)		0/12 (0%)
Pericardial effusion	1/10 (10%)		0/21 (0%)		1/12 (8.3%)
Sinus arrhythmia	1/10 (10%)		0/21 (0%)		0/12 (0%)
Arrhythmia supraventricular	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Atrial fibrillation	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Dilatation atrial	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Right atrial hypertrophy	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Right ventricular dilatation	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Tachycardia	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Tricuspid valve incompetence	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Eye disorders
Retinal vascular disorder	1/10 (10%)		1/21 (4.8%)		0/12 (0%)
Cataract	1/10 (10%)		0/21 (0%)		0/12 (0%)
Periorbital oedema	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Gastrointestinal disorders
Abdominal pain	1/10 (10%)		1/21 (4.8%)		0/12 (0%)
Nausea	0/10 (0%)		2/21 (9.5%)		1/12 (8.3%)
Vomiting	2/10 (20%)		0/21 (0%)		1/12 (8.3%)
Constipation	1/10 (10%)		0/21 (0%)		0/12 (0%)
Dental caries	1/10 (10%)		0/21 (0%)		0/12 (0%)
Gastritis	1/10 (10%)		0/21 (0%)		0/12 (0%)
Pancreatitis	1/10 (10%)		0/21 (0%)		0/12 (0%)
Inguinal hernia	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Hypertriglyceridaemia	1/10 (10%)		2/21 (9.5%)		0/12 (0%)
Hyperglycaemia	1/10 (10%)		1/21 (4.8%)		0/12 (0%)
Diabetes mellitus	1/10 (10%)		0/21 (0%)		0/12 (0%)
Hyperlipidaemia	1/10 (10%)		0/21 (0%)		0/12 (0%)
Hypophosphataemia	0/10 (0%)		1/21 (4.8%)		1/12 (8.3%)
Hypophosphataemia	0/10 (0%)		0/21 (0%)		2/12 (16.7%)
General disorders
Fatigue	0/10 (0%)		1/21 (4.8%)		3/12 (25%)
Pyrexia	1/10 (10%)		0/21 (0%)		0/12 (0%)
Asthenia	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Influenza like illness	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Hepatobiliary disorders
Hepatitis toxic	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Hyperbilirubinaemia	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Ocular icterus	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Infections and infestations
Conjunctivitis	1/10 (10%)		0/21 (0%)		0/12 (0%)
Hepatitis viral	1/10 (10%)		0/21 (0%)		0/12 (0%)
Infection	1/10 (10%)		0/21 (0%)		0/12 (0%)
Pharyngitis	1/10 (10%)		0/21 (0%)		0/12 (0%)
Ear infection	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Nasopharyngitis	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Respiratory tract infection	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Injury, poisoning and procedural complications
Procedural pain	1/10 (10%)		1/21 (4.8%)		0/12 (0%)
Contusion	0/10 (0%)		1/21 (4.8%)		1/12 (8.3%)
Paternal exposure timing unspecified	1/10 (10%)		0/21 (0%)		0/12 (0%)
Thermal burn	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Investigations
Alanine aminotransferase increased	3/10 (30%)		1/21 (4.8%)		2/12 (16.7%)
Blood cholesterol increased	2/10 (20%)		2/21 (9.5%)		3/12 (25%)
Platelet count decreased	2/10 (20%)		2/21 (9.5%)		0/12 (0%)
Aspartate aminotransferase increased	2/10 (20%)		0/21 (0%)		2/12 (16.7%)
Lipase increased	1/10 (10%)		1/21 (4.8%)		2/12 (16.7%)
Neutrophil count decreased	1/10 (10%)		1/21 (4.8%)		0/12 (0%)
Platelet count increased	1/10 (10%)		1/21 (4.8%)		0/12 (0%)
Weight increased	1/10 (10%)		1/21 (4.8%)		0/12 (0%)
Blood alkaline phosphatase increased	1/10 (10%)		0/21 (0%)		0/12 (0%)
Blood bilirubin increased	1/10 (10%)		0/21 (0%)		1/12 (8.3%)
Blood magnesium decreased	1/10 (10%)		0/21 (0%)		0/12 (0%)
Blood phosphorus decreased	1/10 (10%)		0/21 (0%)		0/12 (0%)
Blood triglycerides increased	1/10 (10%)		0/21 (0%)		0/12 (0%)
Lymphocyte count decreased	1/10 (10%)		0/21 (0%)		0/12 (0%)
White blood cell count decreased	1/10 (10%)		0/21 (0%)		0/12 (0%)
Gamma-glutamyltransferase increased	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
N-terminal prohormone brain natriuretic peptide increased	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Weight decreased	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Musculoskeletal and connective tissue disorders
Myalgia	1/10 (10%)		4/21 (19%)		1/12 (8.3%)
Arthralgia	0/10 (0%)		4/21 (19%)		2/12 (16.7%)
Pain in extremity	1/10 (10%)		3/21 (14.3%)		1/12 (8.3%)
Musculoskeletal pain	0/10 (0%)		1/21 (4.8%)		1/12 (8.3%)
Musculoskeletal chest pain	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Spinal pain	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Nervous system disorders
Dizziness	0/10 (0%)		2/21 (9.5%)		0/12 (0%)
Headache	0/10 (0%)		1/21 (4.8%)		1/12 (8.3%)
Psychiatric disorders
Anxiety	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Respiratory, thoracic and mediastinal disorders
Bronchial obstruction	1/10 (10%)		0/21 (0%)		0/12 (0%)
Epistaxis	1/10 (10%)		0/21 (0%)		0/12 (0%)
Cough	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Pulmonary artery dilatation	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Pulmonary hypertension	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Throat irritation	0/10 (0%)		0/21 (0%)		1/12 (8.3%)
Skin and subcutaneous tissue disorders
Dry skin	0/10 (0%)		2/21 (9.5%)		0/12 (0%)
Rash	0/10 (0%)		2/21 (9.5%)		0/12 (0%)
Rash maculo-papular	0/10 (0%)		2/21 (9.5%)		0/12 (0%)
Dermatitis	1/10 (10%)		0/21 (0%)		0/12 (0%)
Rash papular	0/10 (0%)		1/21 (4.8%)		2/12 (16.7%)
Vascular disorders
Hypertension	2/10 (20%)		2/21 (9.5%)		1/12 (8.3%)
Essential hypertension	1/10 (10%)		0/21 (0%)		0/12 (0%)
Peripheral artery stenosis	0/10 (0%)		0/21 (0%)		1/12 (8.3%)

Limitations/Caveats

This study was terminated due to operational feasibility and not due to any safety concerns.

More Information

Certain Agreements

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

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.