Trial Outcomes & Findings for Evaluating the Use of Pitavastatin to Reduce the Risk of Cardiovascular Disease in HIV-Infected Adults (NCT NCT02344290)

Last Updated: 2025-09-04

Results Overview

MACE is a composite of cardiovascular (CV) death, myocardial infarction, hospitalization for unstable angina, stroke, transient ischemic attack (TIA), peripheral arterial ischemia, coronary, carotid or peripheral arterial revascularization, or death from an undetermined cause. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Non-CV deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

7769 participants

Primary outcome timeframe

From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Results posted on

2025-09-04

Participant Flow

Participants were enrolled from March 26, 2015 to July 31, 2019.

4 inadvertent duplicate enrollments of the same person were excluded. The total enrollment number of 7769 represents unique participants enrolled.

Participant milestones

Participant milestones
Measure	Pitavastatin Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Overall Study STARTED	3888	3881
Overall Study Enrolled in Mechanistic Substudy	402	402
Overall Study Completed Mechanistic Substudy	349	350
Overall Study COMPLETED	3201	3201
Overall Study NOT COMPLETED	687	680

Reasons for withdrawal

Reasons for withdrawal
Measure	Pitavastatin Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Overall Study Withdrawal by Subject	315	324
Overall Study Lost to Follow-up	258	249
Overall Study Unable to get to clinic	69	60
Overall Study Physician Decision	25	25
Overall Study Site Closure	15	19
Overall Study Other	5	3

Baseline Characteristics

Participants in the United States (including Puerto Rico) and Canada. Because the ethnicity definition is not applicable to other geographic regions, they were excluded from the measure analysis population.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food	Total n=7769 Participants Total of all reporting groups
Age, Continuous	50 years n=3888 Participants	50 years n=3881 Participants	50 years n=7769 Participants
Age, Customized 40-49 years	1842 Participants n=3888 Participants	1888 Participants n=3881 Participants	3730 Participants n=7769 Participants
Age, Customized 50-59 years	1712 Participants n=3888 Participants	1649 Participants n=3881 Participants	3361 Participants n=7769 Participants
Age, Customized ≥60 years	334 Participants n=3888 Participants	344 Participants n=3881 Participants	678 Participants n=7769 Participants
Sex/Gender, Customized Cisgender	3691 Participants n=3888 Participants	3683 Participants n=3881 Participants	7374 Participants n=7769 Participants
Sex/Gender, Customized Transgender	63 Participants n=3888 Participants	64 Participants n=3881 Participants	127 Participants n=7769 Participants
Sex/Gender, Customized Not reported	134 Participants n=3888 Participants	134 Participants n=3881 Participants	268 Participants n=7769 Participants
Sex: Female, Male Female	1211 Participants n=3888 Participants	1208 Participants n=3881 Participants	2419 Participants n=7769 Participants
Sex: Female, Male Male	2677 Participants n=3888 Participants	2673 Participants n=3881 Participants	5350 Participants n=7769 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	366 Participants n=1957 Participants • Participants in the United States (including Puerto Rico) and Canada. Because the ethnicity definition is not applicable to other geographic regions, they were excluded from the measure analysis population.	332 Participants n=1961 Participants • Participants in the United States (including Puerto Rico) and Canada. Because the ethnicity definition is not applicable to other geographic regions, they were excluded from the measure analysis population.	698 Participants n=3918 Participants • Participants in the United States (including Puerto Rico) and Canada. Because the ethnicity definition is not applicable to other geographic regions, they were excluded from the measure analysis population.
Ethnicity (NIH/OMB) Not Hispanic or Latino	1575 Participants n=1957 Participants • Participants in the United States (including Puerto Rico) and Canada. Because the ethnicity definition is not applicable to other geographic regions, they were excluded from the measure analysis population.	1611 Participants n=1961 Participants • Participants in the United States (including Puerto Rico) and Canada. Because the ethnicity definition is not applicable to other geographic regions, they were excluded from the measure analysis population.	3186 Participants n=3918 Participants • Participants in the United States (including Puerto Rico) and Canada. Because the ethnicity definition is not applicable to other geographic regions, they were excluded from the measure analysis population.
Ethnicity (NIH/OMB) Unknown or Not Reported	16 Participants n=1957 Participants • Participants in the United States (including Puerto Rico) and Canada. Because the ethnicity definition is not applicable to other geographic regions, they were excluded from the measure analysis population.	18 Participants n=1961 Participants • Participants in the United States (including Puerto Rico) and Canada. Because the ethnicity definition is not applicable to other geographic regions, they were excluded from the measure analysis population.	34 Participants n=3918 Participants • Participants in the United States (including Puerto Rico) and Canada. Because the ethnicity definition is not applicable to other geographic regions, they were excluded from the measure analysis population.
Race/Ethnicity, Customized Black	1569 Participants n=3888 Participants	1639 Participants n=3881 Participants	3208 Participants n=7769 Participants
Race/Ethnicity, Customized White	1364 Participants n=3888 Participants	1340 Participants n=3881 Participants	2704 Participants n=7769 Participants
Race/Ethnicity, Customized Asian	571 Participants n=3888 Participants	567 Participants n=3881 Participants	1138 Participants n=7769 Participants
Race/Ethnicity, Customized Other	384 Participants n=3888 Participants	335 Participants n=3881 Participants	719 Participants n=7769 Participants
Region of Enrollment Haiti	69 participants n=3888 Participants	71 participants n=3881 Participants	140 participants n=7769 Participants
Region of Enrollment United States	1897 participants n=3888 Participants	1890 participants n=3881 Participants	3787 participants n=7769 Participants
Region of Enrollment Thailand	304 participants n=3888 Participants	286 participants n=3881 Participants	590 participants n=7769 Participants
Region of Enrollment India	246 participants n=3888 Participants	258 participants n=3881 Participants	504 participants n=7769 Participants
Region of Enrollment Spain	106 participants n=3888 Participants	107 participants n=3881 Participants	213 participants n=7769 Participants
Region of Enrollment Canada	60 participants n=3888 Participants	71 participants n=3881 Participants	131 participants n=7769 Participants
Region of Enrollment Botswana	145 participants n=3888 Participants	136 participants n=3881 Participants	281 participants n=7769 Participants
Region of Enrollment Brazil	546 participants n=3888 Participants	553 participants n=3881 Participants	1099 participants n=7769 Participants
Region of Enrollment South Africa	282 participants n=3888 Participants	288 participants n=3881 Participants	570 participants n=7769 Participants
Region of Enrollment Uganda	96 participants n=3888 Participants	85 participants n=3881 Participants	181 participants n=7769 Participants
Region of Enrollment Zimbabwe	62 participants n=3888 Participants	63 participants n=3881 Participants	125 participants n=7769 Participants
Region of Enrollment Peru	75 participants n=3888 Participants	73 participants n=3881 Participants	148 participants n=7769 Participants
Global burden of disease (GBD) region High income	2044 Participants n=3888 Participants	2051 Participants n=3881 Participants	4095 Participants n=7769 Participants
Global burden of disease (GBD) region Latin America and Caribbean	709 Participants n=3888 Participants	714 Participants n=3881 Participants	1423 Participants n=7769 Participants
Global burden of disease (GBD) region Southeast or East Asia	304 Participants n=3888 Participants	286 Participants n=3881 Participants	590 Participants n=7769 Participants
Global burden of disease (GBD) region South Asia	246 Participants n=3888 Participants	258 Participants n=3881 Participants	504 Participants n=7769 Participants
Global burden of disease (GBD) region Sub-Saharan Africa	585 Participants n=3888 Participants	572 Participants n=3881 Participants	1157 Participants n=7769 Participants
Atherosclerotic Cardiovascular Disease (ASCVD) risk score 0 - <2.5%	1096 Participants n=3888 Participants	1060 Participants n=3881 Participants	2156 Participants n=7769 Participants
Atherosclerotic Cardiovascular Disease (ASCVD) risk score 2.5 - <5%	1030 Participants n=3888 Participants	1025 Participants n=3881 Participants	2055 Participants n=7769 Participants
Atherosclerotic Cardiovascular Disease (ASCVD) risk score 5 - <7.5%	934 Participants n=3888 Participants	960 Participants n=3881 Participants	1894 Participants n=7769 Participants
Atherosclerotic Cardiovascular Disease (ASCVD) risk score 7.5 - 10%	540 Participants n=3888 Participants	561 Participants n=3881 Participants	1101 Participants n=7769 Participants
Atherosclerotic Cardiovascular Disease (ASCVD) risk score ≥10%	288 Participants n=3888 Participants	275 Participants n=3881 Participants	563 Participants n=7769 Participants
Nadir CD4 cell count <200 cells/mm^3	1890 Participants n=3888 Participants	1911 Participants n=3881 Participants	3801 Participants n=7769 Participants
Nadir CD4 cell count 200 - 349 cells/mm^3	1019 Participants n=3888 Participants	1022 Participants n=3881 Participants	2041 Participants n=7769 Participants
Nadir CD4 cell count ≥350 cells/mm^3	839 Participants n=3888 Participants	825 Participants n=3881 Participants	1664 Participants n=7769 Participants
Nadir CD4 cell count Unknown	140 Participants n=3888 Participants	123 Participants n=3881 Participants	263 Participants n=7769 Participants
CD4 cell count ≤500 cells/mm^3	1257 Participants n=3888 Participants	1253 Participants n=3881 Participants	2510 Participants n=7769 Participants
CD4 cell count >500 cells/mm^3	2631 Participants n=3888 Participants	2628 Participants n=3881 Participants	5259 Participants n=7769 Participants
HIV-1 RNA <LLQ	2641 Participants n=3009 Participants • The level of HIV-1 RNA was collected if data were available through standard care.	2609 Participants n=2988 Participants • The level of HIV-1 RNA was collected if data were available through standard care.	5250 Participants n=5997 Participants • The level of HIV-1 RNA was collected if data were available through standard care.
HIV-1 RNA LLQ - <400 copies/mL	305 Participants n=3009 Participants • The level of HIV-1 RNA was collected if data were available through standard care.	312 Participants n=2988 Participants • The level of HIV-1 RNA was collected if data were available through standard care.	617 Participants n=5997 Participants • The level of HIV-1 RNA was collected if data were available through standard care.
HIV-1 RNA ≥400 copies/mL	63 Participants n=3009 Participants • The level of HIV-1 RNA was collected if data were available through standard care.	67 Participants n=2988 Participants • The level of HIV-1 RNA was collected if data were available through standard care.	130 Participants n=5997 Participants • The level of HIV-1 RNA was collected if data were available through standard care.
Pre-existing diabetes	24 Participants n=3888 Participants	14 Participants n=3881 Participants	38 Participants n=7769 Participants
Mechanistic Substudy: Presence of Non-calcified Plaque (NCP) NCP present	132 Participants n=321 Participants • Participants enrolled in the Mechanistic Substudy with paired CT scans (entry and year 2) and data on this measure available.	139 Participants n=323 Participants • Participants enrolled in the Mechanistic Substudy with paired CT scans (entry and year 2) and data on this measure available.	271 Participants n=644 Participants • Participants enrolled in the Mechanistic Substudy with paired CT scans (entry and year 2) and data on this measure available.
Mechanistic Substudy: Presence of Non-calcified Plaque (NCP) NCP not present	189 Participants n=321 Participants • Participants enrolled in the Mechanistic Substudy with paired CT scans (entry and year 2) and data on this measure available.	184 Participants n=323 Participants • Participants enrolled in the Mechanistic Substudy with paired CT scans (entry and year 2) and data on this measure available.	373 Participants n=644 Participants • Participants enrolled in the Mechanistic Substudy with paired CT scans (entry and year 2) and data on this measure available.
Mechanistic Substudy: NCP Volume	52.3 mm^3 STANDARD_DEVIATION 193.5 • n=290 Participants • Participants enrolled in the Mechanistic Substudy with paired CT scans (entry and year 2) and data on this measure available.	57.7 mm^3 STANDARD_DEVIATION 109.2 • n=297 Participants • Participants enrolled in the Mechanistic Substudy with paired CT scans (entry and year 2) and data on this measure available.	55.1 mm^3 STANDARD_DEVIATION 156.5 • n=587 Participants • Participants enrolled in the Mechanistic Substudy with paired CT scans (entry and year 2) and data on this measure available.
Mechanistic Substudy: Total Plaque Volume	65.6 mm^3 STANDARD_DEVIATION 211.7 • n=302 Participants • Participants enrolled in the Mechanistic Substudy with paired CT scans (entry and year 2) and data on this measure available.	72.2 mm^3 STANDARD_DEVIATION 135.9 • n=309 Participants • Participants enrolled in the Mechanistic Substudy with paired CT scans (entry and year 2) and data on this measure available.	69.0 mm^3 STANDARD_DEVIATION 176.8 • n=611 Participants • Participants enrolled in the Mechanistic Substudy with paired CT scans (entry and year 2) and data on this measure available.

PRIMARY outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of Major Adverse Cardiovascular Event (MACE)	4.95 events per 1000 person-years Interval 4.07 to 6.03	7.77 events per 1000 person-years Interval 6.64 to 9.08

SECONDARY outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

Cardiac ischemia or myocardial infarction component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of Cardiac Ischemia or Myocardial Infarction	1.48 events per 1000 person-years Interval 1.03 to 2.11	2.65 events per 1000 person-years Interval 2.03 to 3.46

SECONDARY outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

Cerebrovascular event (stroke or TIA) component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of Cerebrovascular Event (Stroke or TIA)	1.53 events per 1000 person-years Interval 1.07 to 2.17	2.46 events per 1000 person-years Interval 1.86 to 3.24

SECONDARY outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

Peripheral arterial ischemia component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of Peripheral Arterial Ischemia	0.10 events per 1000 person-years Interval 0.02 to 0.39	0.15 events per 1000 person-years Interval 0.05 to 0.45

SECONDARY outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

CV death component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Non-CV deaths and deaths from undetermined causes were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of Death From CV Causes	0.69 events per 1000 person-years Interval 0.41 to 1.16	0.98 events per 1000 person-years Interval 0.63 to 1.51

SECONDARY outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

CV or undetermined death component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Non-CV deaths were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of Death From CV or Undetermined Causes	1.72 events per 1000 person-years Interval 1.23 to 2.39	2.54 events per 1000 person-years Interval 1.94 to 3.33

SECONDARY outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

Cardiac cardiac catheterization or revascularization component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of Cardiac Catheterization or Revascularization	1.08 events per 1000 person-years Interval 0.71 to 1.64	1.77 events per 1000 person-years Interval 1.27 to 2.45

SECONDARY outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

Carotid or cerebrovascular revascularization component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of Carotid or Cerebrovascular Revascularization	0 events per 1000 person-years No events were observed in the pitavastatin group. Confidence interval could not be estimated.	0 events per 1000 person-years No events were observed in the placebo group. Confidence interval could not be estimated.

SECONDARY outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

Peripheral arterial revascularization component of the primary composite MACE outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of Peripheral Arterial Revascularization	0 events per 1000 person-years No events were observed in the pitavastatin group. Confidence interval could not be estimated.	0.29 events per 1000 person-years Interval 0.13 to 0.65

SECONDARY outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

A composite outcome including MACE and death from any cause. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of MACE or Death	9.31 events per 1000 person-years Interval 8.07 to 10.75	12.02 events per 1000 person-years Interval 10.6 to 13.63

SECONDARY outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

Death from any cause. The incidence rates were estimated based on time to event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of Death (All-cause)	6.18 events per 1000 person-years Interval 5.19 to 7.36	6.99 events per 1000 person-years Interval 5.93 to 8.23

SECONDARY outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

A composite of non-CV clinical diagnoses including: non-AIDS-defining cancers (excluding basal cell and squamous cell carcinomas of the skin), AIDS-defining events (based on Centers for Disease Control and Prevention \[CDC\] 2014 classification), end-stage renal disease, and end-stage liver disease. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of Non-CV Clinical Diagnoses	9.17 events per 1000 person-years Interval 7.93 to 10.59	9.90 events per 1000 person-years Interval 8.61 to 11.38

SECONDARY outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

Non-AIDS-defining cancer (excluding basal cell and squamous cell carcinomas of the skin) component of the composite non-CV clinical diagnoses outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of Non-AIDS-defining Cancer	5.25 events per 1000 person-years Interval 4.34 to 6.36	5.68 events per 1000 person-years Interval 4.74 to 6.83

SECONDARY outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

AIDS-defining event component of the composite non-CV clinical diagnoses outcome. Events were captured based on the Centers for Disease Control and Prevention \[CDC\] 2014 classification. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of AIDS-defining Event	3.36 events per 1000 person-years Interval 2.65 to 4.27	3.55 events per 1000 person-years Interval 2.82 to 4.47

SECONDARY outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

End-stage renal disease (defined as initiation of dialysis or renal transplantation) component of the composite non-CV clinical diagnoses outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of End-Stage Renal Disease	0.15 events per 1000 person-years Interval 0.05 to 0.46	0.24 events per 1000 person-years Interval 0.1 to 0.59

SECONDARY outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

End-stage liver disease (defined as cirrhosis or hepatic decompensation requiring hospitalization) component of the composite non-CV clinical diagnoses outcome. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated via cause-specific relative hazard (i.e. hazard ratio) of prescribed pitavastatin compared to placebo from Cox proportional hazards models, stratified by screening CD4 count and sex. Deaths (without preceding event of interest) were treated as competing events and censored. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of End-Stage Liver Disease	0.59 events per 1000 person-years Interval 0.33 to 1.04	0.64 events per 1000 person-years Interval 0.37 to 1.1

SECONDARY outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

Safety analysis outcome measure of non-fatal serious adverse event was defined by International Conference on Harmonisation (ICH) criteria. Fatal events were excluded as deaths were a secondary efficacy outcome (see outcome measure: incidence rate of death (all-cause)). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo), adjusted for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of Non-fatal Serious Adverse Event	4.17 events per 100 person-years Interval 3.88 to 4.48	4.18 events per 100 person-years Interval 3.89 to 4.49

SECONDARY outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: Participants without pre-existing diabetes at baseline, according to the randomized treatment group.

Safety analysis outcome measure of diabetes was defined as new diagnosis of diabetes with initiation of anti-diabetic agent. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo), adjusted for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3864 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3867 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of Diabetes	1.18 events per 100 person-years Interval 1.04 to 1.34	0.91 events per 100 person-years Interval 0.79 to 1.06

SECONDARY outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

Safety analysis outcome measure of myalgia, muscle weakness or myopathy which were grade 3 or higher or treatment-limiting. Grade 3 or higher includes grade 3 and 4 events, where grade 3 refers to severe and grade 4 to life-threatening according to DAIDS AE Grading Table (version 2.1). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo), adjusted for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of Myalgia, Muscle Weakness or Myopathy	0.46 events per 100 person-years Interval 0.38 to 0.56	0.29 events per 100 person-years Interval 0.23 to 0.38

SECONDARY outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

Safety analysis outcome measure of rhabdomyolysis which was grade 3 or higher or treatment-limiting. Grade 3 or higher includes grade 3 and 4 events, where grade 3 refers to severe and grade 4 to life-threatening, according to DAIDS AE Grading Table (version 2.1). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo). Due to small number of events, there was no adjustment for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of Rhabdomyolysis	0.015 events per 100 person-years Interval 0.005 to 0.046	0.020 events per 100 person-years Interval 0.007 to 0.052

SECONDARY outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

Safety analysis outcome measure of Grade 3 or higher alanine transaminase (ALT). Grade 3 or higher includes grade 3 and 4 events, where grade 3 refers to severe and grade 4 to life-threatening, according to DAIDS AE Grading Table (version 2.1). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo). Due to small number of events, there was no adjustment for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of Grade 3 or Higher ALT	0.059 events per 100 person-years Interval 0.033 to 0.1	0.044 events per 100 person-years Interval 0.023 to 0.085

SECONDARY outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

Safety analysis outcome measure of any AE. AE collection included events of grade ≥3, those that were serious (defined by International Conference on Harmonisation (ICH) criteria) or treatment-limiting, and targeted diagnosis of diabetes. Grade ≥3 includes events that were grade 3 (serious) or grade 4 (life-threatening) per DAIDS AE Grading Table (version 2.1). Fatal events were excluded as deaths were a secondary efficacy outcome (see outcome measure: incidence rate of death (all-cause)). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo), adjusted for screening CD4 and sex. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of Adverse Event (AE)	8.83 events per 100 person-years Interval 8.38 to 9.31	8.49 events per 100 person-years Interval 8.05 to 8.95

SECONDARY outcome

Timeframe: At entry and months 12, 24, 36, 48, 60, 72, 84. Participants' follow-up time on study varied, depending on their time of enrollment.

Population: All participants enrolled according to the randomized treatment group. The number of participants with fasting LDL-C available is shown at each timepoint.

LDL-C level was derived as LDL-C calculated according to the Friedewald formula at triglycerides ≤400 mg/dL, and direct LDL-C at triglycerides \>400 to \<500 mg/dL. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Fasting Low-density Lipoprotein Cholesterol (LDL-C) Entry: LDL-C	107 mg/dL Interval 87.0 to 129.0	106 mg/dL Interval 86.0 to 127.0
Fasting Low-density Lipoprotein Cholesterol (LDL-C) Month 12: LDL-C	74 mg/dL Interval 58.0 to 92.0	105 mg/dL Interval 85.0 to 126.0
Fasting Low-density Lipoprotein Cholesterol (LDL-C) Month 24: LDL-C	75 mg/dL Interval 59.0 to 93.0	104 mg/dL Interval 84.0 to 126.0
Fasting Low-density Lipoprotein Cholesterol (LDL-C) Month 36: LDL-C	73 mg/dL Interval 57.0 to 92.0	104 mg/dL Interval 83.0 to 126.0
Fasting Low-density Lipoprotein Cholesterol (LDL-C) Month 48: LDL-C	73 mg/dL Interval 56.0 to 92.0	103 mg/dL Interval 83.0 to 124.0
Fasting Low-density Lipoprotein Cholesterol (LDL-C) Month 60: LDL-C	73 mg/dL Interval 56.0 to 93.0	103 mg/dL Interval 82.0 to 125.0
Fasting Low-density Lipoprotein Cholesterol (LDL-C) Month 72: LDL-C	74 mg/dL Interval 57.0 to 95.0	101 mg/dL Interval 82.0 to 122.0
Fasting Low-density Lipoprotein Cholesterol (LDL-C) Month 84: LDL-C	75 mg/dL Interval 59.0 to 98.0	98 mg/dL Interval 81.0 to 121.0

SECONDARY outcome

Timeframe: At entry and months 12, 24, 36, 48, 60, 72, 84. Participants' follow-up time on study varied, depending on their time of enrollment.

Population: All participants enrolled according to the randomized treatment group. The number of participants with fasting non-HDL-C available is shown at each timepoint.

Non-HDL cholesterol levels were calculated as total cholesterol minus HDL cholesterol. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) Entry: non-HDL-C	133 mg/dL Interval 110.0 to 158.0	132 mg/dL Interval 108.0 to 157.0
Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) Month 12: non-HDL-C	97 mg/dL Interval 80.0 to 118.0	131 mg/dL Interval 108.0 to 156.0
Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) Month 24: non-HDL-C	98 mg/dL Interval 80.0 to 121.0	131 mg/dL Interval 108.0 to 156.0
Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) Month 36: non-HDL-C	97 mg/dL Interval 78.0 to 118.0	130 mg/dL Interval 107.0 to 154.0
Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) Month 48: non-HDL-C	96 mg/dL Interval 77.0 to 119.0	128 mg/dL Interval 106.0 to 154.0
Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) Month 60: non-HDL-C	96 mg/dL Interval 78.0 to 120.0	127 mg/dL Interval 104.0 to 153.0
Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) Month 72: non-HDL-C	95 mg/dL Interval 78.0 to 121.0	124 mg/dL Interval 104.0 to 150.0
Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) Month 84: non-HDL-C	99 mg/dL Interval 80.0 to 124.0	123 mg/dL Interval 101.0 to 151.0

SECONDARY outcome

Timeframe: From January 1, 2020 through end of study; the median follow-up time was 3.3 years.

Population: Participants who remained in REPRIEVE follow-up at the start of the COVID-19 pandemic (defined as January 1, 2020), according to the randomized treatment group.

Serious COVID-19 was defined as COVID-19 that resulted in hospitalization or death or was life-threatening as per the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Guideline E2A definition. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios from Poisson regression models (prescribed pitavastatin compared to placebo), adjusted for GBD region to account for regional differences. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3451 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3454 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of Serious COVID-19	0.45 events per 100 person-years Interval 0.34 to 0.59	0.60 events per 100 person-years Interval 0.48 to 0.77

SECONDARY outcome

Timeframe: From January 1, 2020 through end of study; the median follow-up time was 3.3 years.

Population: Participants who remained in REPRIEVE follow-up at the start of the COVID-19 pandemic (defined as January 1, 2020), according to the randomized treatment group.

COVID-19 was defined as COVID-19 clinical diagnosis or positive test result (SARS-CoV-2 PCR or rapid antigen tests). The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The treatment effect was estimated using incidence rate ratios (prescribed pitavastatin compared to placebo) from Poisson regression models, adjusted for GBD region to account for regional differences. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=3451 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3454 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of COVID-19	8.79 events per 100 person-years Interval 8.22 to 9.39	8.35 events per 100 person-years Interval 7.8 to 8.93

SECONDARY outcome

Timeframe: Entry and Year 2.

Population: Participants enrolled in the Mechanistic Substudy, with complete case outcome data (paired entry and year 2).

NCP was defined as plaque voxels with attenuation of \<350. Change in NCP is expressed as absolute change from baseline (calculated as NCP volume at 2 years minus NCP volume at entry), based on quantitative read of the CT scan, whenever available. Participants without a quantitative read and no evidence of NCP based on the corresponding qualitative read were assigned a value of zero for the change. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=290 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=297 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
For Mechanistic Substudy: Change in Non-Calcified Plaque (NCP) Volume From Baseline to Year 2	-1.70 mm^3 Standard Deviation 25.2	2.62 mm^3 Standard Deviation 27.1

SECONDARY outcome

Timeframe: Entry and year 2.

Population: Participants enrolled in the Mechanistic Substudy, with complete case outcome data (paired entry and year 2).

Progression at Year 2 was defined as any progression/increase in NCP volume in participants with evidence of NCP at entry, or incident NCP in participants without evidence of NCP at entry. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=302 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=309 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
For Mechanistic Substudy: Number of Participants With Progression of NCP From Baseline to Year 2	53 Participants	85 Participants

SECONDARY outcome

Timeframe: Entry and year 2.

Population: Participants enrolled in the Mechanistic Substudy, with complete case outcome data (paired entry and year 2).

Total plaque includes all plaque voxels (noncalcified + calcified). Change in total plaque volume is expressed as absolute change from baseline (calculated as volume at 2 years minus volume at entry). Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=302 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=309 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
For Mechanistic Substudy: Change in Total Plaque Volume From Baseline to Year 2	2.34 mm^3 Standard Deviation 28.7	6.89 mm^3 Standard Deviation 32.3

SECONDARY outcome

Timeframe: Entry and month 24.

Population: Participants enrolled in the Mechanistic Substudy with biomarker results available.

Level of inflammatory biomarker lipoprotein-associated phospholipase A2 (LpPLA2). Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=402 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=402 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
For Mechanistic Substudy: LpPLA2 Level Entry	126 ng/mL Interval 94.8 to 169.0	131 ng/mL Interval 89.6 to 163.0
For Mechanistic Substudy: LpPLA2 Level Month 24	119 ng/mL Interval 84.0 to 160.0	143 ng/mL Interval 105.0 to 186.0

SECONDARY outcome

Timeframe: Entry and month 24.

Population: Participants enrolled in the Mechanistic Substudy with biomarker results available at entry and month 24.

Change in inflammatory biomarker LpPLA2 from baseline calculated as value at month 24 minus value at entry. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=335 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=333 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
For Mechanistic Substudy: Change in LpPLA2 From Baseline	-9.77 ng/mL Interval -33.6 to 16.8	19.9 ng/mL Interval -5.6 to 43.0

SECONDARY outcome

Timeframe: Entry and month 24.

Population: Participants enrolled in the Mechanistic Substudy with biomarker results available.

Level of inflammatory marker high-sensitivity C-reactive protein (HsCRP). Censored values below or above the assay limit were imputed. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=402 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=402 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
For Mechanistic Substudy: HsCRP Level Entry	0.18 mg/dL Interval 0.08 to 0.39	0.18 mg/dL Interval 0.09 to 0.33
For Mechanistic Substudy: HsCRP Level Month 24	0.17 mg/dL Interval 0.07 to 0.36	0.19 mg/dL Interval 0.1 to 0.4

SECONDARY outcome

Timeframe: Entry and month 24.

Population: Participants enrolled in the Mechanistic Substudy with biomarker results available at entry and month 24.

Change in inflammatory biomarker hsCRP from baseline calculated as value at month 24 minus value at entry. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=343 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=335 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
For Mechanistic Substudy: Change in HsCRP From Baseline	-0.01 mg/mL Interval -0.1 to 0.08	0.01 mg/mL Interval -0.09 to 0.11

SECONDARY outcome

Timeframe: Entry and month 24.

Population: Participants enrolled in the Mechanistic Substudy with biomarker results available.

Level of immune biomarker soluble CD163. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=402 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=402 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
For Mechanistic Substudy: Soluble CD163 Level Entry	849 ng/mL Interval 651.0 to 1163.0	845 ng/mL Interval 613.0 to 1074.0
For Mechanistic Substudy: Soluble CD163 Level Month 24	1013 ng/mL Interval 728.0 to 1419.0	1003 ng/mL Interval 745.0 to 1384.0

SECONDARY outcome

Timeframe: Entry and month 24.

Population: Participants enrolled in the Mechanistic Substudy with biomarker results available at entry and month 24.

Change in immune biomarker soluble CD163 from baseline calculated as value at month 24 minus value at entry. Treatment discontinuation was ignored, including the initiation of statin therapy as part of clinical care (intention to treat policy).

Outcome measures

Outcome measures
Measure	Pitavastatin n=335 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=330 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
For Mechanistic Substudy: Change in Soluble CD163 From Baseline	149 ng/mL Interval -60.8 to 420.0	143 ng/mL Interval -46.0 to 453.0

OTHER_PRE_SPECIFIED outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

Subgroup analysis of the primary composite MACE outcome measure (as described above) by sex. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The Cox proportional hazards models described for the primary outcome above were expanded to include sex and interaction of sex and treatment, to evaluate modification of statin effect.

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of MACE by Sex Among females	3.9 events per 1000 person-years Interval 2.7 to 5.8	6.2 events per 1000 person-years Interval 4.6 to 8.4
Incidence Rate of MACE by Sex Among males	5.5 events per 1000 person-years Interval 4.4 to 6.9	8.5 events per 1000 person-years Interval 7.1 to 10.2

OTHER_PRE_SPECIFIED outcome

Timeframe: From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years).

Population: All participants enrolled according to the randomized treatment group.

Subgroup analysis of the primary composite MACE outcome measure (as described above) by race. The incidence rates were estimated based on time to the first event using Poisson distribution, with follow-up time censored at last contact. The Cox proportional hazards models described for the primary outcome above were expanded to include race and interaction of race and treatment, to evaluate modification of statin effect.

Outcome measures

Outcome measures
Measure	Pitavastatin n=3888 Participants Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 Participants Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Incidence Rate of MACE by Race Among Asians	1.6 events per 1000 person-years Interval 0.7 to 3.7	7.0 events per 1000 person-years Interval 4.6 to 10.6
Incidence Rate of MACE by Race Among Blacks	5.8 events per 1000 person-years Interval 4.3 to 7.7	8.7 events per 1000 person-years Interval 6.9 to 10.9
Incidence Rate of MACE by Race Among Whites	5.6 events per 1000 person-years Interval 4.1 to 7.7	7.5 events per 1000 person-years Interval 5.7 to 9.9
Incidence Rate of MACE by Race Among Other	5.0 events per 1000 person-years Interval 2.7 to 9.4	5.7 events per 1000 person-years Interval 3.1 to 10.6

Adverse Events

Pitavastatin

Serious events: 750 serious events

Other events: 488 other events

Deaths: 126 deaths

Placebo

Serious events: 755 serious events

Other events: 420 other events

Deaths: 143 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Pitavastatin n=3888 participants at risk Participants received pitavastatin once a day for the entire time they were in study follow-up. Pitavastatin: One tablet (4 mg) taken once daily, orally with or without food	Placebo n=3881 participants at risk Participants received placebo for pitavastatin once a day for the entire time they were in study follow-up. Placebo: One tablet taken once daily, orally with or without food
Investigations Physical examination procedures and organ system status	1.6% 62/3888 • From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). AE collection included events of grade ≥3, those that were serious (per ICH criteria) or treatment-limiting, and all new diagnoses of diabetes. Grade ≥3 includes events that were grade 3 (serious) or grade 4 (life-threatening) per DAIDS AE Grading Table (version 2.1). Targeted clinical events for pitavastatin efficacy evaluation (MACE, death, COVID-19, heart failure) were not considered AEs. MedDRA High Level Term (HLT) grouped by System Organ Class is presented in the summary tables.	1.7% 65/3881 • From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). AE collection included events of grade ≥3, those that were serious (per ICH criteria) or treatment-limiting, and all new diagnoses of diabetes. Grade ≥3 includes events that were grade 3 (serious) or grade 4 (life-threatening) per DAIDS AE Grading Table (version 2.1). Targeted clinical events for pitavastatin efficacy evaluation (MACE, death, COVID-19, heart failure) were not considered AEs. MedDRA High Level Term (HLT) grouped by System Organ Class is presented in the summary tables.
Investigations Renal function analyses	3.2% 125/3888 • From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). AE collection included events of grade ≥3, those that were serious (per ICH criteria) or treatment-limiting, and all new diagnoses of diabetes. Grade ≥3 includes events that were grade 3 (serious) or grade 4 (life-threatening) per DAIDS AE Grading Table (version 2.1). Targeted clinical events for pitavastatin efficacy evaluation (MACE, death, COVID-19, heart failure) were not considered AEs. MedDRA High Level Term (HLT) grouped by System Organ Class is presented in the summary tables.	3.1% 122/3881 • From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). AE collection included events of grade ≥3, those that were serious (per ICH criteria) or treatment-limiting, and all new diagnoses of diabetes. Grade ≥3 includes events that were grade 3 (serious) or grade 4 (life-threatening) per DAIDS AE Grading Table (version 2.1). Targeted clinical events for pitavastatin efficacy evaluation (MACE, death, COVID-19, heart failure) were not considered AEs. MedDRA High Level Term (HLT) grouped by System Organ Class is presented in the summary tables.
Metabolism and nutrition disorders Diabetes mellitus (incl subtypes)	6.1% 238/3888 • From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). AE collection included events of grade ≥3, those that were serious (per ICH criteria) or treatment-limiting, and all new diagnoses of diabetes. Grade ≥3 includes events that were grade 3 (serious) or grade 4 (life-threatening) per DAIDS AE Grading Table (version 2.1). Targeted clinical events for pitavastatin efficacy evaluation (MACE, death, COVID-19, heart failure) were not considered AEs. MedDRA High Level Term (HLT) grouped by System Organ Class is presented in the summary tables.	4.7% 184/3881 • From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). AE collection included events of grade ≥3, those that were serious (per ICH criteria) or treatment-limiting, and all new diagnoses of diabetes. Grade ≥3 includes events that were grade 3 (serious) or grade 4 (life-threatening) per DAIDS AE Grading Table (version 2.1). Targeted clinical events for pitavastatin efficacy evaluation (MACE, death, COVID-19, heart failure) were not considered AEs. MedDRA High Level Term (HLT) grouped by System Organ Class is presented in the summary tables.
Metabolism and nutrition disorders General nutritional disorders NEC	1.7% 66/3888 • From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). AE collection included events of grade ≥3, those that were serious (per ICH criteria) or treatment-limiting, and all new diagnoses of diabetes. Grade ≥3 includes events that were grade 3 (serious) or grade 4 (life-threatening) per DAIDS AE Grading Table (version 2.1). Targeted clinical events for pitavastatin efficacy evaluation (MACE, death, COVID-19, heart failure) were not considered AEs. MedDRA High Level Term (HLT) grouped by System Organ Class is presented in the summary tables.	1.1% 44/3881 • From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). AE collection included events of grade ≥3, those that were serious (per ICH criteria) or treatment-limiting, and all new diagnoses of diabetes. Grade ≥3 includes events that were grade 3 (serious) or grade 4 (life-threatening) per DAIDS AE Grading Table (version 2.1). Targeted clinical events for pitavastatin efficacy evaluation (MACE, death, COVID-19, heart failure) were not considered AEs. MedDRA High Level Term (HLT) grouped by System Organ Class is presented in the summary tables.
Musculoskeletal and connective tissue disorders Muscle pains	2.0% 77/3888 • From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). AE collection included events of grade ≥3, those that were serious (per ICH criteria) or treatment-limiting, and all new diagnoses of diabetes. Grade ≥3 includes events that were grade 3 (serious) or grade 4 (life-threatening) per DAIDS AE Grading Table (version 2.1). Targeted clinical events for pitavastatin efficacy evaluation (MACE, death, COVID-19, heart failure) were not considered AEs. MedDRA High Level Term (HLT) grouped by System Organ Class is presented in the summary tables.	1.1% 44/3881 • From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). AE collection included events of grade ≥3, those that were serious (per ICH criteria) or treatment-limiting, and all new diagnoses of diabetes. Grade ≥3 includes events that were grade 3 (serious) or grade 4 (life-threatening) per DAIDS AE Grading Table (version 2.1). Targeted clinical events for pitavastatin efficacy evaluation (MACE, death, COVID-19, heart failure) were not considered AEs. MedDRA High Level Term (HLT) grouped by System Organ Class is presented in the summary tables.
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue pain and discomfort	1.0% 40/3888 • From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). AE collection included events of grade ≥3, those that were serious (per ICH criteria) or treatment-limiting, and all new diagnoses of diabetes. Grade ≥3 includes events that were grade 3 (serious) or grade 4 (life-threatening) per DAIDS AE Grading Table (version 2.1). Targeted clinical events for pitavastatin efficacy evaluation (MACE, death, COVID-19, heart failure) were not considered AEs. MedDRA High Level Term (HLT) grouped by System Organ Class is presented in the summary tables.	1.1% 43/3881 • From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). AE collection included events of grade ≥3, those that were serious (per ICH criteria) or treatment-limiting, and all new diagnoses of diabetes. Grade ≥3 includes events that were grade 3 (serious) or grade 4 (life-threatening) per DAIDS AE Grading Table (version 2.1). Targeted clinical events for pitavastatin efficacy evaluation (MACE, death, COVID-19, heart failure) were not considered AEs. MedDRA High Level Term (HLT) grouped by System Organ Class is presented in the summary tables.
Vascular disorders Vascular hypertensive disorders NEC	0.95% 37/3888 • From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). AE collection included events of grade ≥3, those that were serious (per ICH criteria) or treatment-limiting, and all new diagnoses of diabetes. Grade ≥3 includes events that were grade 3 (serious) or grade 4 (life-threatening) per DAIDS AE Grading Table (version 2.1). Targeted clinical events for pitavastatin efficacy evaluation (MACE, death, COVID-19, heart failure) were not considered AEs. MedDRA High Level Term (HLT) grouped by System Organ Class is presented in the summary tables.	1.3% 50/3881 • From entry through end of study. Follow-up time varied depending on time of enrollment (the median follow-up time was 5.6 years). AE collection included events of grade ≥3, those that were serious (per ICH criteria) or treatment-limiting, and all new diagnoses of diabetes. Grade ≥3 includes events that were grade 3 (serious) or grade 4 (life-threatening) per DAIDS AE Grading Table (version 2.1). Targeted clinical events for pitavastatin efficacy evaluation (MACE, death, COVID-19, heart failure) were not considered AEs. MedDRA High Level Term (HLT) grouped by System Organ Class is presented in the summary tables.

Additional Information

REPRIEVE Project Manager

REPRIEVE Clinical Coordinating Center

Phone: 617-724-9109

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60