Trial Outcomes & Findings for CSP #512 - Options in Management With Anti-Retrovirals (NCT NCT00050089)

NCT ID: NCT00050089

Last Updated: 2015-04-23

Results Overview

New or recurrent AIDS event or Death were compared between Standard-ART (standard) and Mega-ART (intensification)

Recruitment status

COMPLETED

Study phase

Target enrollment

368 participants

Primary outcome timeframe

From date of randomization until onset of primary outcome or end of study follow-up (12/31/2007) whichever occured first, up to 6.5 years

Results posted on

2015-04-23

Participant Flow

A total of 368 participants were enrolled in the trial: 41 in Canada, 39 in the UK and 288 in the US-VA.

339 participants were randomized to factorial design(Canada=41;UK=10;US-VA=288). 29 participants in the UK were enrolled in a protocol-approved option, where they were allowed to select one of the factors and be randomized to the other. All 29 selected the ARDFP vs No ARDFP factor and were randomized to the Standard-ART vs Mega-ART factor.

Participant milestones

Participant milestones
Measure	No ARDFP+Standard-ART No Antiretroviral Drug-Free Period (No ARDFP) and Standard-ART Standard-ART: up to 4 anti-HIV drugs	No ARDFP+Mega-ART No Antiretroviral Drug-Free Period (No ARDFP) and Mega-ART Mega-ART: 5 or more anti-HIV drugs	ARDFP+Standard-ART Antiretroviral Drug-Free Period (ARDFP) and Standard-ART Intended duration of ARDFP: 12 week2 Standard-ART: up to 4 anti-HIV drugs	ARDFP+Mega-ART Antiretroviral Drug-Free Period (ARDFP) and Mega-ART Intended duration of ARDFP: 12 weeks Mega-ART: 5 or more anti-HIV drugs
Overall Study STARTED	106	98	86	78
Overall Study Baseline	91	84	86	78
Overall Study COMPLETED	106	98	86	78
Overall Study NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

CSP #512 - Options in Management With Anti-Retrovirals

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	No ARDFP + Standard ART n=91 Participants Standard Antiretroviral Treatment regimen	No ARDFP + Mega ART n=84 Participants Intensive Antiretroviral Treatment regimen	ARDFP + Standard ART n=86 Participants Antiretroviral Treatment Interruption and Standard ART	ARDFP + Mega ART n=78 Participants Antiretroviral Treatment Interruption and Intensive ART	Total n=339 Participants Total of all reporting groups
Age, Continuous	48.7 years STANDARD_DEVIATION 8.99 • n=5 Participants	48.3 years STANDARD_DEVIATION 7.92 • n=7 Participants	49.2 years STANDARD_DEVIATION 8.1 • n=5 Participants	48.2 years STANDARD_DEVIATION 8.58 • n=4 Participants	48.6 years STANDARD_DEVIATION 8.39 • n=21 Participants
Age, Customized 31-40 years	16 participants n=5 Participants	11 participants n=7 Participants	12 participants n=5 Participants	15 participants n=4 Participants	54 participants n=21 Participants
Age, Customized 41-50 years	35 participants n=5 Participants	41 participants n=7 Participants	36 participants n=5 Participants	30 participants n=4 Participants	142 participants n=21 Participants
Age, Customized 51-60 years	33 participants n=5 Participants	28 participants n=7 Participants	31 participants n=5 Participants	28 participants n=4 Participants	120 participants n=21 Participants
Age, Customized >60 years	7 participants n=5 Participants	4 participants n=7 Participants	7 participants n=5 Participants	5 participants n=4 Participants	23 participants n=21 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	2 Participants n=4 Participants	7 Participants n=21 Participants
Sex: Female, Male Male	90 Participants n=5 Participants	82 Participants n=7 Participants	84 Participants n=5 Participants	76 Participants n=4 Participants	332 Participants n=21 Participants
Race/Ethnicity, Customized White	42 participants n=5 Participants	45 participants n=7 Participants	38 participants n=5 Participants	35 participants n=4 Participants	160 participants n=21 Participants
Race/Ethnicity, Customized Black	41 participants n=5 Participants	30 participants n=7 Participants	36 participants n=5 Participants	31 participants n=4 Participants	138 participants n=21 Participants
Race/Ethnicity, Customized Asian	1 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	0 participants n=4 Participants	1 participants n=21 Participants
Race/Ethnicity, Customized Hispanic	6 participants n=5 Participants	9 participants n=7 Participants	9 participants n=5 Participants	12 participants n=4 Participants	36 participants n=21 Participants
Race/Ethnicity, Customized Aboriginal	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	0 participants n=4 Participants	2 participants n=21 Participants
Race/Ethnicity, Customized Other	0 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants	0 participants n=4 Participants	2 participants n=21 Participants
Region of Enrollment United States	77 participants n=5 Participants	71 participants n=7 Participants	73 participants n=5 Participants	67 participants n=4 Participants	288 participants n=21 Participants
Region of Enrollment United Kingdom	2 participants n=5 Participants	2 participants n=7 Participants	3 participants n=5 Participants	3 participants n=4 Participants	10 participants n=21 Participants
Region of Enrollment Canada	12 participants n=5 Participants	11 participants n=7 Participants	10 participants n=5 Participants	8 participants n=4 Participants	41 participants n=21 Participants
log10 Viral Load	4.76 log10 copies/mL STANDARD_DEVIATION 0.55 • n=5 Participants	4.75 log10 copies/mL STANDARD_DEVIATION 0.76 • n=7 Participants	4.64 log10 copies/mL STANDARD_DEVIATION 0.67 • n=5 Participants	4.7 log10 copies/mL STANDARD_DEVIATION 0.75 • n=4 Participants	4.71 log10 copies/mL STANDARD_DEVIATION 0.68 • n=21 Participants
CD4 cells/mm3	136 cells/mm^3 STANDARD_DEVIATION 112 • n=5 Participants	127 cells/mm^3 STANDARD_DEVIATION 107 • n=7 Participants	130 cells/mm^3 STANDARD_DEVIATION 106 • n=5 Participants	127 cells/mm^3 STANDARD_DEVIATION 106 • n=4 Participants	130 cells/mm^3 STANDARD_DEVIATION 108 • n=21 Participants
CD4 level CD4 <=100 cells/mm^3	38 participants n=5 Participants	38 participants n=7 Participants	36 participants n=5 Participants	33 participants n=4 Participants	145 participants n=21 Participants
CD4 level CD4 >100 cells/mm^3	53 participants n=5 Participants	46 participants n=7 Participants	50 participants n=5 Participants	45 participants n=4 Participants	194 participants n=21 Participants
Mode of HIV Infection Blood	12 participants n=5 Participants	7 participants n=7 Participants	8 participants n=5 Participants	7 participants n=4 Participants	34 participants n=21 Participants
Mode of HIV Infection Heterosexual	20 participants n=5 Participants	19 participants n=7 Participants	22 participants n=5 Participants	19 participants n=4 Participants	80 participants n=21 Participants
Mode of HIV Infection Intravenous Drug Use (IVDU)	11 participants n=5 Participants	16 participants n=7 Participants	15 participants n=5 Participants	9 participants n=4 Participants	51 participants n=21 Participants
Mode of HIV Infection Men who have Sex with Men (MSM)	42 participants n=5 Participants	37 participants n=7 Participants	37 participants n=5 Participants	39 participants n=4 Participants	155 participants n=21 Participants
Mode of HIV Infection Other	6 participants n=5 Participants	5 participants n=7 Participants	2 participants n=5 Participants	4 participants n=4 Participants	17 participants n=21 Participants
Mode of HIV Infection Unknown	0 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants	0 participants n=4 Participants	2 participants n=21 Participants
AIDS at entry Yes	59 participants n=5 Participants	46 participants n=7 Participants	44 participants n=5 Participants	51 participants n=4 Participants	200 participants n=21 Participants
AIDS at entry No	32 participants n=5 Participants	38 participants n=7 Participants	42 participants n=5 Participants	27 participants n=4 Participants	139 participants n=21 Participants
Hepatitis B (HBsAg) Yes	10 participants n=5 Participants	4 participants n=7 Participants	15 participants n=5 Participants	8 participants n=4 Participants	37 participants n=21 Participants
Hepatitis B (HBsAg) No	81 participants n=5 Participants	80 participants n=7 Participants	71 participants n=5 Participants	70 participants n=4 Participants	302 participants n=21 Participants
Hepatitis C (Hep C anti-HCV) Yes	17 participants n=5 Participants	21 participants n=7 Participants	27 participants n=5 Participants	12 participants n=4 Participants	77 participants n=21 Participants
Hepatitis C (Hep C anti-HCV) No	74 participants n=5 Participants	63 participants n=7 Participants	59 participants n=5 Participants	66 participants n=4 Participants	262 participants n=21 Participants
OI medications for prophylaxis Anti-PCP	75 participants n=5 Participants	67 participants n=7 Participants	71 participants n=5 Participants	62 participants n=4 Participants	275 participants n=21 Participants
OI medications for prophylaxis Anti-CMV	2 participants n=5 Participants	0 participants n=7 Participants	2 participants n=5 Participants	0 participants n=4 Participants	4 participants n=21 Participants
OI medications for prophylaxis Antibacterial	43 participants n=5 Participants	39 participants n=7 Participants	33 participants n=5 Participants	37 participants n=4 Participants	152 participants n=21 Participants
OI medications for prophylaxis Antifungal	22 participants n=5 Participants	23 participants n=7 Participants	22 participants n=5 Participants	19 participants n=4 Participants	86 participants n=21 Participants
Concomitant Medications Lipid Lowering	24 participants n=5 Participants	20 participants n=7 Participants	33 participants n=5 Participants	21 participants n=4 Participants	98 participants n=21 Participants
Concomitant Medications Other antiviral	43 participants n=5 Participants	30 participants n=7 Participants	30 participants n=5 Participants	33 participants n=4 Participants	136 participants n=21 Participants

PRIMARY outcome

Timeframe: From date of randomization until onset of primary outcome or end of study follow-up (12/31/2007) whichever occured first, up to 6.5 years

Population: This includes participants randomized to Standard-ART or Mega-ART (339 via the 2X2 factorial design and 29 via the UK Option Scheme)

New or recurrent AIDS event or Death were compared between Standard-ART (standard) and Mega-ART (intensification)

Outcome measures

Outcome measures
Measure	Standard-ART n=192 Participants This includes participants randomized to Standard-ART (No ARDFP+Standard-ART or ARDFP+Standard-ART)	Mega-ART n=176 Participants This includes participants randomized to Mega-ART (No ARDFP+Mega-ART or ARDFP+Mega-ART)	ARDFP + Standard ART Standard ART regimen following ART interruption	ARDFP + Mega ART Intensive ART following ART interruption
Number of Participants With New or Recurrent AIDS Event, or Death	83 participants	82 participants	—	—

PRIMARY outcome

Timeframe: From date of randomization until onset of primary outcome or end of study follow-up (12/31/2007) whichever occured first, up to 6.5 years

Population: This includes participants randomized to No ARDFP or ARDFP (339 via the 2X2 factorial design and 0 via the UK Option Scheme)

New or recurrent AIDS event or Death were compared between No ARDFP (continuation) and ARDFP (interruption)

Outcome measures

Outcome measures
Measure	Standard-ART n=164 Participants This includes participants randomized to Standard-ART (No ARDFP+Standard-ART or ARDFP+Standard-ART)	Mega-ART n=175 Participants This includes participants randomized to Mega-ART (No ARDFP+Mega-ART or ARDFP+Mega-ART)	ARDFP + Standard ART Standard ART regimen following ART interruption	ARDFP + Mega ART Intensive ART following ART interruption
Number of Participants With New or Recurrent AIDS Event, or Death	70 participants	87 participants	—	—

PRIMARY outcome

Timeframe: From date of randomization until onset of primary outcome or end of study follow-up (12/31/2007) whichever occured first, up to 6.5 years

Population: This includes participants randomized to one of the four interventions (339 via the 2X2 factorial design)

New or recurrent AIDS event or Death were compared between No ARDFP (continuation)+Standard-ART (standard), No ARDFP (continuation)+Mega-ART (intensification), ARDFP (interruption)+Standard-ART (standard) and ARDFP (interruption)+Mega-ART (intensification)

Outcome measures

Outcome measures
Measure	Standard-ART n=91 Participants This includes participants randomized to Standard-ART (No ARDFP+Standard-ART or ARDFP+Standard-ART)	Mega-ART n=84 Participants This includes participants randomized to Mega-ART (No ARDFP+Mega-ART or ARDFP+Mega-ART)	ARDFP + Standard ART n=86 Participants Standard ART regimen following ART interruption	ARDFP + Mega ART n=78 Participants Intensive ART following ART interruption
Number of Participants With New or Recurrent AIDS Event, or Death	46 participants	41 participants	35 participants	35 participants

SECONDARY outcome

Timeframe: From date of randomization until onset of secondary outcome or end of study follow-up (12/31/2007) whichever occured first, up to 6.5 years

New, on-study non-HIV related Serious Adverse events were compared between Standard-ART (standard) and Mega-ART (intensification)

Outcome measures

Outcome measures
Measure	Standard-ART n=192 Participants This includes participants randomized to Standard-ART (No ARDFP+Standard-ART or ARDFP+Standard-ART)	Mega-ART n=176 Participants This includes participants randomized to Mega-ART (No ARDFP+Mega-ART or ARDFP+Mega-ART)	ARDFP + Standard ART Standard ART regimen following ART interruption	ARDFP + Mega ART Intensive ART following ART interruption
Number of Participants With a New, Non-HIV Related Serious Adverse Event	97 participants	88 participants	—	—

SECONDARY outcome

Timeframe: From date of randomization until onset of secondary outcome or end of study follow-up (12/31/2007) whichever occured first, up to 6.5 years

New, on-study non-HIV related Serious Adverse events were compared between ARDFP (interruption) and No ARDFP (continuation)

Outcome measures

Outcome measures
Measure	Standard-ART n=164 Participants This includes participants randomized to Standard-ART (No ARDFP+Standard-ART or ARDFP+Standard-ART)	Mega-ART n=175 Participants This includes participants randomized to Mega-ART (No ARDFP+Mega-ART or ARDFP+Mega-ART)	ARDFP + Standard ART Standard ART regimen following ART interruption	ARDFP + Mega ART Intensive ART following ART interruption
Number of Participants With New, Non-HIV Related Serious Adverse Event	84 participants	92 participants	—	—

Adverse Events

No ARDFP + Standard ART

Serious events: 55 serious events

Other events: 0 other events

Deaths: 0 deaths

No ARDFP + Mega ART

Serious events: 56 serious events

Other events: 0 other events

Deaths: 0 deaths

ARDFP + Standard ART

Serious events: 54 serious events

Other events: 0 other events

Deaths: 0 deaths

ARDFP + Mega ART

Serious events: 49 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Adverse event data not reported

Additional Information

Dr. Sheldon Brown

VAMC Bronx

Phone: (718) 584-9000

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	No ARDFP + Standard ART n=106 participants at risk；n=91 participants at risk Standard Antiretroviral Treatment regimen	No ARDFP + Mega ART n=98 participants at risk；n=84 participants at risk Intensive Antiretroviral Treatment regimen	ARDFP + Standard ART n=86 participants at risk Antiretroviral Treatment Interruption and Standard ART	ARDFP + Mega ART n=78 participants at risk Antiretroviral Treatment Interruption and Intensive ART
Infections and infestations Meningitis	0.00% 0/91 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/86 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/78 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Infections and infestations Viral rash NOS	1.1% 1/91 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/78 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Infections and infestations Meningitis bacterial NOS	1.1% 1/91 • Number of events 2 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/78 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Infections and infestations Meningitis cryptococcal	1.1% 1/91 • Number of events 2 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/84 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.3% 1/78 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Infections and infestations Oesophageal candidiasis	2.2% 2/91 • Number of events 3 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	3.6% 3/84 • Number of events 7 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/86 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.3% 1/78 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Infections and infestations Otitis media acute NOS	1.1% 1/91 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/78 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Infections and infestations Parvovirus infection	1.1% 1/91 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.3% 1/78 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Infections and infestations Pneumonia staphylococcal	0.00% 0/91 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/86 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.3% 1/78 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Infections and infestations Systemic candida	1.1% 1/91 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/78 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Metabolism and nutrition disorders Dehydration	2.2% 2/91 • Number of events 3 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	3.6% 3/84 • Number of events 4 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.3% 1/78 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Metabolism and nutrition disorders Diabetes mellitus NOS	1.1% 1/91 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/84 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	2.6% 2/78 • Number of events 2 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Skin and subcutaneous tissue disorders Psoriasis	0.00% 0/91 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/86 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/78 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Skin and subcutaneous tissue disorders Rash NOS	1.1% 1/91 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.3% 1/78 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Skin and subcutaneous tissue disorders Rash pruritic	0.00% 0/91 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/84 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/78 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Blood and lymphatic system disorders Acquired methaemoglobinaemia	0.00% 0/91 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/86 • Number of events 2 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/78 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Blood and lymphatic system disorders Anaemia NOS	5.5% 5/91 • Number of events 7 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	6.0% 5/84 • Number of events 6 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	7.0% 6/86 • Number of events 10 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	6.4% 5/78 • Number of events 6 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Blood and lymphatic system disorders Anaemia of chronic disease	0.00% 0/91 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/84 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.3% 1/78 • Number of events 2 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Blood and lymphatic system disorders Bone marrow depression NOS	0.00% 0/91 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/84 • Number of events 2 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/78 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Blood and lymphatic system disorders Febrile neutropenia	2.2% 2/91 • Number of events 2 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/84 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/86 • Number of events 2 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.3% 1/78 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Blood and lymphatic system disorders Leukocytosis	1.1% 1/91 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/78 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Blood and lymphatic system disorders Neutropenia	2.2% 2/91 • Number of events 2 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/84 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/78 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Blood and lymphatic system disorders Pancytopenia	1.1% 1/91 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/86 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/78 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Blood and lymphatic system disorders Secondary anaemia	2.2% 2/91 • Number of events 2 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/78 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/91 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/84 • Number of events 3 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/86 • Number of events 2 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.3% 1/78 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Cardiac disorders Acute coronary syndrome	1.1% 1/91 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/78 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Cardiac disorders Acute myocardial infarction	0.00% 0/91 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/86 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/78 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Cardiac disorders Atrial tachycardia	0.00% 0/91 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.3% 1/78 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Cardiac disorders Bradycardia NOS	0.00% 0/91 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/84 • Number of events 2 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/78 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Cardiac disorders Cardiac aneurysm	0.00% 0/91 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.3% 1/78 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Cardiac disorders Cardiac arrest	0.00% 0/91 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/86 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/78 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Cardiac disorders Cardiac disorder NOS	0.00% 0/91 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/84 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/78 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Cardiac disorders Cardiac failure NOS	0.00% 0/91 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/84 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.3% 1/78 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Cardiac disorders Cardiac failure congestive	2.2% 2/91 • Number of events 3 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	3.6% 3/84 • Number of events 3 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.3% 1/78 • Number of events 2 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Cardiac disorders Cardio-respiratory arrest	0.00% 0/91 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/84 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.3% 1/78 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Cardiac disorders Cardiomyopathy NOS	0.00% 0/91 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/86 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/78 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Cardiac disorders Cardiovascular disorder NOS	1.1% 1/91 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/78 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Cardiac disorders Coronary artery atherosclerosis	0.00% 0/91 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.3% 1/78 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Cardiac disorders Coronary artery disease NOS	0.00% 0/91 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.2% 1/84 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/78 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Cardiac disorders Diastolic dysfunction	0.00% 0/91 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.3% 1/78 • Number of events 2 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.
Cardiac disorders Endocarditis NOS	0.00% 0/91 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/84 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	0.00% 0/86 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.	1.3% 1/78 • Number of events 1 MedDRA was used to code SAE of participants randomized to the 2x2 factorial design (n=339).Hence the number at risk for the four arms reflects only participants enrolled in the 2x2 factorial. Not Serious Adverse events were not coded using MedDRA.