NCT04372628: TREATNOW

Trial of Early Therapies During Non-hospitalized Outpatient Window for COVID-19

Completed Phase 2 Results posted Last updated 28 February 2024

What this trial tests

Phase 2 trial testing Lopinavir/Ritonavir 400 mg/100 mg in COVID-19 in 452 participants. Completed in 18 January 2022.

Timeline

1 June 2020

Primary endpoint
16 December 2021

18 January 2022

Quick facts

Lead sponsor	Vanderbilt University Medical Center
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	sequential
Masking	triple
Primary purpose	treatment
Enrollment	452
Start date	1 June 2020
Primary completion	16 December 2021
Estimated completion	18 January 2022
Sites	6 locations across United States

Drugs / interventions tested

• Lopinavir/Ritonavir 400 mg/100 mg — full drug profile →
• Placebo

Conditions studied

• COVID-19 — all drugs for COVID-19 →

Sponsor

Vanderbilt University Medical Center

Who can join

18 and older, any sex, with COVID-19. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Modified COVID Ordinal Outcomes Scale: Study Day 15 (Group 2 and Placebo Control Group) Primary · Day 1 to Day 15

Improvement of clinical condition of the participant defined by the Modified COVID Ordinal Outcomes Scale (Modified from the COVID-19 WHO ordinal Outcomes score to fit the outpatient setting). This scale reflects a range of participants from dead to not hospitalized and with no limitations to activities of daily living. A score of 1 is "death", 2 is "Hospitalized on mechanical ventilation or extracorporeal membrane oxygenator (ECMO)", 3 is "Hospitalized on supplemental oxygen", 4 is "Hospitalized not on supplemental oxygen", 5 is "Not hospitalized with symptoms and limitation in activity", 6 i

Group	Value	95% CI
Group 2 - Lopinavir/Ritonavir	0
Placebo Control Group	0
Group 2 - Lopinavir/Ritonavir	1
Placebo Control Group	0
Group 2 - Lopinavir/Ritonavir	5
Placebo Control Group	4
Group 2 - Lopinavir/Ritonavir	1
Placebo Control Group	2

Modified COVID Ordinal Outcome Scale: Study Day 8 (Group 2 and Placebo Control Group) Secondary · on or at Day 8

Improvement of clinical condition of the participant defined by the Modified COVID Ordinal Outcomes Scale (Modified from the COVID-19 WHO ordinal Outcomes score to fit the outpatient setting). This scale reflects a range of participants from dead to not hospitalized and with no limitations to activities of daily living. A score of 1 is "death", 2 is "Hospitalized on mechanical ventilation or extracorporeal membrane oxygenator (ECMO)", 3 is "Hospitalized on supplemental oxygen", 4 is "Hospitalized not on supplemental oxygen", 5 is "Not hospitalized with symptoms and limitation in activity", 6 i

Group	Value	95% CI
Group 2 - Lopinavir/Ritonavir	0
Placebo Control Group	0
Group 2 - Lopinavir/Ritonavir	1
Placebo Control Group	0
Group 2 - Lopinavir/Ritonavir	2
Placebo Control Group	1
Group 2 - Lopinavir/Ritonavir	0
Placebo Control Group	0

Modified COVID Ordinal Outcome Scale: Study Day 29 (Group 2 and Placebo Control Group) Secondary · on or at Day 29

Improvement of clinical condition of the participant defined by the Modified COVID Ordinal Outcomes Scale (Modified from the COVID-19 WHO ordinal Outcomes score to fit the outpatient setting). This scale reflects a range of participants from dead to not hospitalized and with no limitations to activities of daily living. A score of 1 is "death", 2 is "Hospitalized on mechanical ventilation or extracorporeal membrane oxygenator (ECMO)", 3 is "Hospitalized on supplemental oxygen", 4 is "Hospitalized not on supplemental oxygen", 5 is "Not hospitalized with symptoms and limitation in activity", 6 i

Group	Value	95% CI
Group 2 - Lopinavir/Ritonavir	1
Placebo Control Group	0
Group 2 - Lopinavir/Ritonavir	1
Placebo Control Group	0
Group 2 - Lopinavir/Ritonavir	1
Placebo Control Group	1
Group 2 - Lopinavir/Ritonavir	9
Placebo Control Group	11

Number of Patients Hospitalized: Day 1 to 29 (Group 2 and Placebo Control Group) Secondary · Day 1 to Day 29

Number of patients hospitalized from Day 1 to 29 (Group 2 and Placebo Control Group)

Group	Value	95% CI
Group 2 - Lopinavir/Ritonavir	7
Placebo Control Group	6
Group 2 - Lopinavir/Ritonavir	214
Placebo Control Group	221

Time to Hospitalization Day 1 to Day 29 (Group 2 and Placebo Control Group) Secondary · Day 1 to Day 29

Number of days from enrollment to hospitalization (Group 2 and Placebo Control Group)

Group	Value	95% CI
Group 2 - Lopinavir/Ritonavir	6	2 – 11
Placebo Control Group	7	3 – 13

Time to Symptom Resolution: Day 1 to Day 29 (Group 2 and Placebo Control Group) Secondary · Day 1 to Day 29

Number of days from enrollment to resolution of COVID-19 symptoms (Group 2 and Placebo Control Group)

Group	Value	95% CI
Group 2 - Lopinavir/Ritonavir	11	8 – 29
Placebo Control Group	11	7 – 29

All-cause, All-location Mortality: Day 1 to Day 29 (Group 2 and Placebo Control Group) Secondary · Day 1 to Day 29

Survival status (All-cause, all-location mortality) from Day 1 to Day 29 (Group 2 and Placebo Control Group)

Group	Value	95% CI
Group 2 - Lopinavir/Ritonavir	1
Placebo Control Group	0
Group 2 - Lopinavir/Ritonavir	173
Placebo Control Group	195
Group 2 - Lopinavir/Ritonavir	47
Placebo Control Group	32

Oxygen-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group) Secondary · Day 1 to Day 29

Number of Days without oxygen Day 1 to Day 29 (Group 2 and Placebo Control Group)

Group	Value	95% CI
Group 2 - Lopinavir/Ritonavir	17	17 – 17
Placebo Control Group	17	17 – 17

Fever-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group) Secondary · Day 1 to Day 29

Number of days without fever from Day 1 to Day 29 (Group 2 and Placebo Control Group)

Group	Value	95% CI
Group 2 - Lopinavir/Ritonavir	16	14 – 17
Placebo Control Group	17	15 – 17

Ventilator-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group) Secondary · Day 1 to Day 29

Number of days without ventilator use from Day 1 to Day 29 (Group 2 and Placebo Control Group)

Group	Value	95% CI
Group 2 - Lopinavir/Ritonavir	17	17 – 17
Placebo Control Group	17	17 – 17

ICU-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group) Secondary · Day 1 to Day 29

Number of days outside the ICU from Day 1 to Day 29 (Group 2 and Placebo Control Group)

Group	Value	95% CI
Group 2 - Lopinavir/Ritonavir	17	17 – 17
Placebo Control Group	17	17 – 17

Hospital-free Days: Day 1 to Day 29 (Group 2 and Placebo Control Group) Secondary · Day 1 to Day 29

Number of days outside the hospital from Day 1 to Day 29 (Group 2 and Placebo Control Group)

Group	Value	95% CI
Group 2 - Lopinavir/Ritonavir	17	17 – 17
Placebo Control Group	17	17 – 17

Adverse events — posted to ClinicalTrials.gov

Time frame: Enrollment - Study Day 16 (or 48 hours after completion of the study drug administration) Deaths were observed through day 29 per the secondary outcome Measure 7 specification, but AEs were only collected as AEs through study Day 16.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Group 1- Hydroxychloroquine

Serious: 0/4 (0%)

Deaths: 0/4

Group 2 - Lopinavir/Ritonavir

Serious: 2/221 (1%)

Deaths: 1/221

Placebo Control Group

Serious: 1/227 (0%)

Deaths: 0/227

Serious adverse events (6 terms)

Reaction	System	Group 1- Hydroxychloroquine	Group 2 - Lopinavir/Ritona…	Placebo Control Group
Lung Infection	Infections and infestations	—	—	—
Sepsis	Infections and infestations	—	—	—
Adult Respiratory Distress Syndrome (ARDS)	Respiratory, thoracic and mediastinal disorders	—	—	—
Cardiac Arrest	Cardiac disorders	—	—	—
Multi-Organ Failure	General disorders	—	—	—
Acute Kidney Injury	Renal and urinary disorders	—	—	—

Other adverse events (5 terms — click to expand)

Reaction	System	Group 1- Hydroxychloroquine	Group 2 - Lopinavir/Ritona…	Placebo Control Group
Diarrhea	Gastrointestinal disorders	—	—	—
Nausea	General disorders	—	—	—
Abdominal Pain	Gastrointestinal disorders	—	—	—
Chest Pain	Cardiac disorders	—	—	—
Fever	General disorders	—	—	—

Most-reported serious reactions: Lung Infection, Sepsis, Adult Respiratory Distress Syndrome (ARDS), Cardiac Arrest, Multi-Organ Failure, Acute Kidney Injury.

Data from ClinicalTrials.gov NCT04372628 adverse events section.

Sponsor's own description

Blinded, multicenter, placebo-controlled, randomized clinical trial evaluating lopinavir/ritonavir vs placebo in early outpatient treatment of adults with COVID-19

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Drug repurposing approach to fight COVID-19.
   Singh TU, Parida S, Lingaraju MC, Kesavan M, et al · · 2020 · cited 299× · PMID 32889701 · DOI 10.1007/s43440-020-00155-6
2. COVID-19: Characteristics and Therapeutics.
   Chilamakuri R, Agarwal S. · · 2021 · cited 192× · PMID 33494237 · DOI 10.3390/cells10020206
3. The emergence of COVID-19 as a global pandemic: Understanding the epidemiology, immune response and potential therapeutic targets of SARS-CoV-2.
   Muralidar S, Ambi SV, Sekaran S, Krishnan UM. · · 2020 · cited 184× · PMID 32971147 · DOI 10.1016/j.biochi.2020.09.018
4. Post-COVID-19 syndrome. SARS-CoV-2 RNA detection in plasma, stool, and urine in patients with persistent symptoms after COVID-19.
   Tejerina F, Catalan P, Rodriguez-Grande C, Adan J, et al · · 2022 · cited 88× · PMID 35240997 · DOI 10.1186/s12879-022-07153-4
5. Multicenter Interim Guidance on Use of Antivirals for Children With Coronavirus Disease 2019/Severe Acute Respiratory Syndrome Coronavirus 2.
   Chiotos K, Hayes M, Kimberlin DW, Jones SB, et al · · 2021 · cited 74× · PMID 32918548 · DOI 10.1093/jpids/piaa115
6. Role of Lopinavir/Ritonavir in the Treatment of Covid-19: A Review of Current Evidence, Guideline Recommendations, and Perspectives.
   Meini S, Pagotto A, Longo B, Vendramin I, et al · · 2020 · cited 52× · PMID 32629768 · DOI 10.3390/jcm9072050
7. Pharmacological Modulators of Autophagy as a Potential Strategy for the Treatment of COVID-19.
   Pereira GJDS, Leão AHFF, Erustes AG, Morais IBM, et al · · 2021 · cited 36× · PMID 33920748 · DOI 10.3390/ijms22084067
8. Chemotherapy vs. Immunotherapy in combating nCOVID19: An update.
   Choudhury A, Mukherjee G, Mukherjee S. · · 2021 · cited 28× · PMID 34020832 · DOI 10.1016/j.humimm.2021.05.001