Trial Outcomes & Findings for A Study to Assess the Efficacy of Raltegravir (Isentress®), Administered in Combination With Other Antiretroviral Drugs as Treatment for Adults and Older Adults Infected With the Human Immunodeficiency Virus 1 (HIV-1)(MK-0518-145) (Wirksamkeit Von Isentress® Unter Praxisbedingungen) (NCT NCT01213316)

Last Updated: 2016-05-23

Results Overview

The percentage of participants with an HIV-1 viral load \<50 copies/mL of HIV-1 RNA after 48 weeks of raltegravir treatment was determined.

Recruitment status

COMPLETED

Target enrollment

451 participants

Primary outcome timeframe

Baseline and 48 weeks

Results posted on

2016-05-23

Participant Flow

The Initial Cohort included participants \>=18 years old to receive treatment for 96 weeks. With the amendment, participants in the initial cohort \>=50 years old could continue for an additional 48-weeks observation (Prolonged Cohort), and participants \>=50 years old were newly enrolled to receive treatment for 48 weeks (Amendment Cohort).

Participant milestones

Participant milestones
Measure	Overall Participants HIV-1 infected participants received raltegravir 400 mg tablet orally twice daily for 96 weeks (Initial Cohort), 144 weeks (Prolonged Cohort) or 48 weeks (Amendment Cohort) in combination with other antiretroviral drugs under conditions representative of standard of clinical practice for HIV-1 patients in Germany.
Overall Study STARTED	451
Overall Study Amendment Cohort: Prolonged Participants	48
Overall Study Amendment Cohort: Newly Enrolled	179
Overall Study Discontinued Treatment Before 48 Weeks	67
Overall Study Initial Cohort	272
Overall Study COMPLETED	451
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A Study to Assess the Efficacy of Raltegravir (Isentress®), Administered in Combination With Other Antiretroviral Drugs as Treatment for Adults and Older Adults Infected With the Human Immunodeficiency Virus 1 (HIV-1)(MK-0518-145) (Wirksamkeit Von Isentress® Unter Praxisbedingungen)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Overall Participants n=451 Participants HIV-1 infected participants received raltegravir 400 mg tablet orally twice daily for 96 weeks (Initial Cohort), 144 weeks (Prolonged Cohort) or 48 weeks (Amendment Cohort) in combination with other antiretroviral drugs under conditions representative of standard of clinical practice for HIV-1 patients in Germany.
Age, Continuous	50.8 Years STANDARD_DEVIATION 11.5 • n=5 Participants
Sex: Female, Male Female	69 Participants n=5 Participants
Sex: Female, Male Male	382 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and 48 weeks

Population: The analysis set included all participants who received at least one dose of raltegravir during the observation period.

The percentage of participants with an HIV-1 viral load \<50 copies/mL of HIV-1 RNA after 48 weeks of raltegravir treatment was determined.

Outcome measures

Outcome measures
Measure	Overall Participants n=451 Participants HIV-1 infected participants received raltegravir 400 mg tablet orally twice daily for 96 weeks (Initial Cohort), 144 weeks (Prolonged Cohort) or 48 weeks (Amendment Cohort) in combination with other antiretroviral drugs under conditions representative of standard of clinical practice for HIV-1 patients in Germany.
Percentage of Participants With an HIV-1 Viral Load <50 Copies/mL After 48 Weeks of Raltegravir Treatment Baseline	50.8 Percentage of participants Interval 46.1 to 55.5
Percentage of Participants With an HIV-1 Viral Load <50 Copies/mL After 48 Weeks of Raltegravir Treatment 48 weeks	74.7 Percentage of participants Interval 70.4 to 78.7

PRIMARY outcome

Timeframe: Baseline and 48 weeks

Population: The analysis set included aging participants (Prolonged Participants and Newly Enrolled Participants) who received at least one dose of raltegravir during the observation period.

The percentage of aging participants (\>=50 years old at initiation of raltegravir treatment) with an HIV-1 viral load \<50 copies/mL of HIV-1 RNA after 48 weeks of raltegravir treatment was determined.

Outcome measures

Outcome measures
Measure	Overall Participants n=227 Participants HIV-1 infected participants received raltegravir 400 mg tablet orally twice daily for 96 weeks (Initial Cohort), 144 weeks (Prolonged Cohort) or 48 weeks (Amendment Cohort) in combination with other antiretroviral drugs under conditions representative of standard of clinical practice for HIV-1 patients in Germany.
Percentage of Aging Participants With an HIV-1 Viral Load <50 Copies/mL After 48 Weeks of Raltegravir Treatment Baseline	62.1 Percentage of participants Interval 55.5 to 68.4
Percentage of Aging Participants With an HIV-1 Viral Load <50 Copies/mL After 48 Weeks of Raltegravir Treatment 48 weeks	77.5 Percentage of participants Interval 71.5 to 82.8

SECONDARY outcome

Timeframe: Baseline and 96 weeks

Population: The analysis set included participants in the Initial Cohort who received at least one dose of raltegravir during the observation period.

The percentage of participants with an HIV-1 viral load \<50 copies/mL of HIV-1 RNA after 96 weeks of raltegravir treatment was determined.

Outcome measures

Outcome measures
Measure	Overall Participants n=272 Participants HIV-1 infected participants received raltegravir 400 mg tablet orally twice daily for 96 weeks (Initial Cohort), 144 weeks (Prolonged Cohort) or 48 weeks (Amendment Cohort) in combination with other antiretroviral drugs under conditions representative of standard of clinical practice for HIV-1 patients in Germany.
Percentage of Participants With an HIV-1 Viral Load <50 Copies/mL After 96 Weeks of Raltegravir Treatment Baseline	43.8 Percentage of participants Interval 37.8 to 49.9
Percentage of Participants With an HIV-1 Viral Load <50 Copies/mL After 96 Weeks of Raltegravir Treatment 96 weeks	68.0 Percentage of participants Interval 62.1 to 73.5

SECONDARY outcome

Timeframe: Baseline and 96 weeks

Population: The analysis set included participants in the Initial Cohort who received at least one dose of raltegravir during the observation period.

The HIV-1 viral load (log10 copies/mL of HIV-1 RNA) was determined at Baseline and after 96 weeks of raltegravir treatment.

Outcome measures

Outcome measures
Measure	Overall Participants n=272 Participants HIV-1 infected participants received raltegravir 400 mg tablet orally twice daily for 96 weeks (Initial Cohort), 144 weeks (Prolonged Cohort) or 48 weeks (Amendment Cohort) in combination with other antiretroviral drugs under conditions representative of standard of clinical practice for HIV-1 patients in Germany.
HIV-1 Viral Load After 96 Weeks of Raltegravir Treatment Baseline	2.90 Log10 Copies/mL Standard Deviation 1.65 • Interval 62.1 to 73.5
HIV-1 Viral Load After 96 Weeks of Raltegravir Treatment 96 weeks	1.52 Log10 Copies/mL Standard Deviation 0.43

SECONDARY outcome

Timeframe: Baseline and 96 weeks

Population: The analysis set included participants in the Initial Cohort who received at least one dose of raltegravir during the observation period.

Mean CD4+ T-cell counts were determined at baseline and after 96 weeks of raltegravir treatment. A positive change from baseline indicates an increase in CD4+ T-cell count.

Outcome measures

Outcome measures
Measure	Overall Participants n=272 Participants HIV-1 infected participants received raltegravir 400 mg tablet orally twice daily for 96 weeks (Initial Cohort), 144 weeks (Prolonged Cohort) or 48 weeks (Amendment Cohort) in combination with other antiretroviral drugs under conditions representative of standard of clinical practice for HIV-1 patients in Germany.
Change From Baseline in CD4+ T-cell Counts After 96 Weeks of Raltegravir Treatment Baseline	461.9 CD4+ T-cells/µL Standard Deviation 286.35 • Interval 131.4 to 192.1
Change From Baseline in CD4+ T-cell Counts After 96 Weeks of Raltegravir Treatment Change from Baseline at 96 weeks: n=216	161.7 CD4+ T-cells/µL Standard Deviation 225.98 • Interval 131.4 to 192.1

SECONDARY outcome

Timeframe: Baseline and 48 weeks

Population: The analysis set included aging participants (Prolonged Participants and Newly Enrolled Participants) who received at least one dose of raltegravir during the observation period.

The HIV-1 viral load (log10 copies/mL of HIV-1 RNA) was determined in aging participants (\>=50 years old at initiation of raltegravir treatment) at Baseline and after 48 weeks of raltegravir treatment.

Outcome measures

Outcome measures
Measure	Overall Participants n=227 Participants HIV-1 infected participants received raltegravir 400 mg tablet orally twice daily for 96 weeks (Initial Cohort), 144 weeks (Prolonged Cohort) or 48 weeks (Amendment Cohort) in combination with other antiretroviral drugs under conditions representative of standard of clinical practice for HIV-1 patients in Germany.
HIV-1 Viral Load in Aging Participants After 48 Weeks of Raltegravir Treatment Baseline	2.28 Log10 Copies/mL Standard Deviation 1.43 • Interval 62.1 to 73.5
HIV-1 Viral Load in Aging Participants After 48 Weeks of Raltegravir Treatment 48 weeks	1.50 Log10 Copies/mL Standard Deviation 0.45

SECONDARY outcome

Timeframe: Baseline and 48 weeks

Population: The analysis set included aging participants (Prolonged Participants and Newly Enrolled Participants) who received at least one dose of raltegravir during the observation period.

Mean CD4+ T-cell counts were determined in aging participants (\>=50 years old at initiation of raltegravir treatment) at baseline and after 48 weeks of raltegravir treatment was determined. A positive change from baseline indicates an increase in CD4+ T-cell count.

Outcome measures

Outcome measures
Measure	Overall Participants n=227 Participants HIV-1 infected participants received raltegravir 400 mg tablet orally twice daily for 96 weeks (Initial Cohort), 144 weeks (Prolonged Cohort) or 48 weeks (Amendment Cohort) in combination with other antiretroviral drugs under conditions representative of standard of clinical practice for HIV-1 patients in Germany.
Change From Baseline in CD4+ T-cell Counts in Aging Participants After 48 Weeks of Raltegravir Treatment Change from Baseline at 48 weeks: n=202	63.2 CD4+ T-cells/µL Standard Deviation 183.43
Change From Baseline in CD4+ T-cell Counts in Aging Participants After 48 Weeks of Raltegravir Treatment Baseline	534.4 CD4+ T-cells/µL Standard Deviation 297.48 • Interval 37.7 to 88.6

SECONDARY outcome

Timeframe: Baseline and 48 weeks

Population: The analysis set included aging participants (Prolonged Participants and Newly Enrolled Participants) who received at least one dose of raltegravir during the observation period and had evaluable results.

Mean Framingham Risk for 10-year cardiovascular risk was determined in aging participants (\>=50 years old at initiation of raltegravir treatment). Points were allotted for each of following 8 risk factors : sex, age, systolic blood pressure, treatment for hypertension, smoking, diabetes, total cholesterol, and high-density lipoprotein. The sum of the points for each participant was assigned a percent 10-year cardiovascular risk on a lookup table, and could range from 0% to 100%. The mean Framingham Risk for 10-year cardiovascular risk was then calculated for the analysis population. The change from baseline was calculated as Baseline minus Week 48; a positive change indicates reduced risk. This Outcome Measure was added with Amendment 1 and applies only to aging participants.

Outcome measures

Outcome measures
Measure	Overall Participants n=105 Participants HIV-1 infected participants received raltegravir 400 mg tablet orally twice daily for 96 weeks (Initial Cohort), 144 weeks (Prolonged Cohort) or 48 weeks (Amendment Cohort) in combination with other antiretroviral drugs under conditions representative of standard of clinical practice for HIV-1 patients in Germany.
Change From Baseline in Mean Framingham Risk Score for the 10-Year Cardiovascular Risk in Aging Participants After 48 Weeks of Raltegravir Treatment Score at Baseline	24.1 Percentage risk Standard Deviation 17.5 • Interval 37.7 to 88.6
Change From Baseline in Mean Framingham Risk Score for the 10-Year Cardiovascular Risk in Aging Participants After 48 Weeks of Raltegravir Treatment Change from Baseline at 48 weeks: n=65	1.1 Percentage risk Standard Deviation 10.9

SECONDARY outcome

Timeframe: Baseline and 48 weeks

Mean Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Risk Score for 5-year cardiovascular risk was determined in aging participants (\>=50 years old at initiation of raltegravir treatment) at Baseline and after 48 weeks of raltegravir treatment. The score included the following 8 risk factors: sex, age, systolic blood pressure, family cardiovascular disease history, current smoking, previous cigarette smoker, diabetes, total cholesterol, high-density lipoprotein, currently on indinavir, currently on lopinavir, currently on abacavir, duration and current use of indinavir and duration and current use of lopinavir. The D:A:D Risk Score is interpreted as low: \<1%; moderate: 1-5%; high: 5-10%; and very high: \>10%. The change from baseline was calculated as Week 48 minus Baseline; a positive change indicates increased risk. This Outcome Measure was added with Amendment 1 and applies only to aging participants.

Outcome measures

Outcome measures
Measure	Overall Participants n=91 Participants HIV-1 infected participants received raltegravir 400 mg tablet orally twice daily for 96 weeks (Initial Cohort), 144 weeks (Prolonged Cohort) or 48 weeks (Amendment Cohort) in combination with other antiretroviral drugs under conditions representative of standard of clinical practice for HIV-1 patients in Germany.
Change From Baseline in Mean D:A:D Risk Score for the 5-Year Cardiovascular Risk in Aging Participants After 48 Weeks of Raltegravir Treatment Score at Baseline	9.4 Percentage risk Standard Deviation 8.7 • Interval 37.7 to 88.6
Change From Baseline in Mean D:A:D Risk Score for the 5-Year Cardiovascular Risk in Aging Participants After 48 Weeks of Raltegravir Treatment Change from Baseline at 48 weeks: n=57	4.2 Percentage risk Standard Deviation 9.5

SECONDARY outcome

Timeframe: Baseline

Population: The analysis set included aging participants (Prolonged Participants and Newly Enrolled Participants) who received at least one dose of raltegravir during the observation period.

The percentage of aging participants with Baseline comorbidities was reported. This Outcome Measure was added with Amendment 1 and applies only to aging participants.

Outcome measures

Outcome measures
Measure	Overall Participants n=227 Participants HIV-1 infected participants received raltegravir 400 mg tablet orally twice daily for 96 weeks (Initial Cohort), 144 weeks (Prolonged Cohort) or 48 weeks (Amendment Cohort) in combination with other antiretroviral drugs under conditions representative of standard of clinical practice for HIV-1 patients in Germany.
Percentage of Aging Participants With Concomitant Diseases at Baseline	93.8 Percentage of participants

SECONDARY outcome

Timeframe: Baseline

Population: The analysis set included aging participants (Prolonged Participants and Newly Enrolled Participants) who received at least one dose of raltegravir during the observation period.

The percentage of aging participants taking concomitant medication in addition to their other antiretroviral therapy was reported. This Outcome Measure was added with Amendment 1 and applies only to aging participants.

Outcome measures

Outcome measures
Measure	Overall Participants n=227 Participants HIV-1 infected participants received raltegravir 400 mg tablet orally twice daily for 96 weeks (Initial Cohort), 144 weeks (Prolonged Cohort) or 48 weeks (Amendment Cohort) in combination with other antiretroviral drugs under conditions representative of standard of clinical practice for HIV-1 patients in Germany.
Percentage of Aging Participants Taking Concomitant Medications at Baseline	74.9 Percentage of participants

Adverse Events

Overall Participants

Serious events: 34 serious events

Other events: 0 other events

Deaths: 0 deaths

Initial Cohort Participants

Serious events: 25 serious events

Other events: 0 other events

Deaths: 0 deaths

Aging Participants

Serious events: 17 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Adverse event data not reported

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp.

Phone: 1-800-672-6372

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The results of this study will be published by the sponsor according to the current guidelines for publication. The Contract Research Organization will assist the sponsor with initial publication. Further details will be laid down in the financial agreement between the sponsor and the Contract Research Organization.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Overall Participants n=451 participants at risk HIV-1 infected participants received raltegravir 400 mg tablet orally twice daily for 96 weeks (Initial Cohort), 144 weeks (Prolonged Cohort) or 48 weeks (Amendment Cohort) in combination with other antiretroviral drugs under conditions representative of standard of clinical practice for HIV-1 patients in Germany.	Initial Cohort Participants n=272 participants at risk HIV-1 infected participants received raltegravir 400 mg tablet orally twice daily for 96 weeks in combination with other antiretroviral drugs under conditions representative of standard of clinical practice for HIV-1 patients in Germany.	Aging Participants n=227 participants at risk HIV-1 infected participants \>=50 years old received raltegravir 400 mg tablet orally twice daily for 144 weeks (Prolonged Cohort) or 48 weeks (Amendment Cohort) in combination with other antiretroviral drugs under conditions representative of standard of clinical practice for HIV-1 patients in Germany.
Blood and lymphatic system disorders Anaemia megaloblastic	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Cardiac disorders Angina pectoris	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.37% 1/272 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/227 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Cardiac disorders Arrhythmia	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Cardiac disorders Cardiogenic shock	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.37% 1/272 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/227 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
General disorders Chest pain	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Cardiac disorders Myocardial infarction	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.37% 1/272 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/227 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Gastrointestinal disorders Anal fistula	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.37% 1/272 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/227 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Gastrointestinal disorders Diarrhoea	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.37% 1/272 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/227 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Infections and infestations Gastroenteritis	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Gastrointestinal disorders Pancreatitis acute	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.37% 1/272 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/227 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
General disorders Asthenia	0.22% 1/451 • Number of events 2 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 2 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
General disorders Fatigue	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Hepatobiliary disorders Hepatic failure	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.37% 1/272 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/227 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Immune system disorders Hypersensitivity	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.37% 1/272 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/227 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Infections and infestations Pyelonephritis	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Infections and infestations Spirochaetal infection	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Investigations Blood triglycerides increased	0.22% 1/451 • Number of events 2 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 2 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Investigations C-reactive protein increased	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Investigations Electrocardiogram Q wave abnormal	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Investigations Heart rate increased	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Investigations Lipase increased	0.44% 2/451 • Number of events 2 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.74% 2/272 • Number of events 2 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.88% 2/227 • Number of events 2 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Investigations Transaminases increased	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.37% 1/272 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/227 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Investigations Weight increased	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Metabolism and nutrition disorders Decreased appetite	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Metabolism and nutrition disorders Dehydration	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.37% 1/272 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/227 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Musculoskeletal and connective tissue disorders Osteonecrosis	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.37% 1/272 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/227 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Diffuse large B-cell lymphoma	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Glioblastoma	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Kaposi's sarcoma	0.44% 2/451 • Number of events 2 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.37% 1/272 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-Hodgkin's lymphoma recurrent	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.37% 1/272 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/227 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Salivary gland cancer	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm malignant	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.37% 1/272 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/227 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Nervous system disorders Dizziness	0.67% 3/451 • Number of events 3 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	1.3% 3/227 • Number of events 3 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Psychiatric disorders Depressed mood	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Psychiatric disorders Depression	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Psychiatric disorders Panic attack	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Psychiatric disorders Suicide attempt	0.44% 2/451 • Number of events 2 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.74% 2/272 • Number of events 2 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/227 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.22% 1/451 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.00% 0/272 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.	0.44% 1/227 • Number of events 1 • Overall Participants: up to 48 weeks; Initial Cohort Participants: up to 96 weeks; Aging Participants: up to 48 weeks. Overall Participants and Aging Participants: MedDRA version 17.1; Initial Cohort Participants: MedDRA version 14.1.