NCT05567952

A Study to Learn About a Repeat 5-Day Treatment With the Study Medicines (Called Nirmatrelvir/Ritonavir) in People 12 Years Old or Older With Return of COVID-19 Symptoms and SARS-CoV-2 Positivity After Finishing Treatment With Nirmatrelvir/Ritonavir

Completed Phase 2 Results posted Last updated 8 October 2024

What this trial tests

Phase 2 trial testing nirmatrelvir in COVID-19 in 436 participants. Completed in 9 February 2024.

Timeline

19 October 2022

Primary endpoint
27 September 2023

9 February 2024

Quick facts

Lead sponsor	Pfizer
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	triple
Primary purpose	treatment
Enrollment	436
Start date	19 October 2022
Primary completion	27 September 2023
Estimated completion	9 February 2024
Sites	84 locations across Italy, Greece, Taiwan, Canada, United States

Drugs / interventions tested

• nirmatrelvir (Nirmatrelvir) — full drug profile →
• ritonavir (ritonavir) — full drug profile →
• placebo for nirmatrelvir — full drug profile →

Conditions studied

• COVID-19 — all drugs for COVID-19 →

Sponsor

Pfizer — full company profile →

Who can join

12 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.

Change From Baseline to Day 5 in Viral Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Ribonucleic Acid (RNA) Level in Nasopharyngeal (NP) Swabs: mITT Population Primary · Baseline, Day 5

Baseline was defined as the latest measurement between Day -1 and Day 1, but post-dose samples that were collected within 1 hour post start of dosing were also treated as baseline. Samples with result "\< lower limit of quantification (LLOQ)" were imputed as 1.7 log10 copies/milliliter (mL), and samples with result "Not Detected" were imputed as 0.0 log10 copies/mL.

Group	Value	95% CI
Nirmatrelvir 300 mg + Ritonavir 100 mg	-3.871	± 0.129
Placebo + Ritonavir 100 mg	-3.166	± 0.171

Time to Two Consecutive Negative Rapid Antigen Test (RAT) Results At Least 24 Hours Apart Through Day 28: mITT Population Secondary · Day 1 of dosing maximum up to Day 28 or censoring date, whichever occurred first

The event of 2 consecutive negative RAT results obtained at least 24 (-2) hours apart through Day 28 was defined as achieving 2 consecutive non-missing RATs with negative results through Day 28, where the 2 tests were at least 22 hours and at most 7 days apart. For the event of 2 consecutive negative RAT results obtained at least 24 hours apart through Day 28, the date of the first negative RAT result was considered the first event date. Time to 2 consecutive negative RAT results obtained at least 24 hours apart defined as: for participant achieving event, time to event = (first event date) -(

Group	Value	95% CI
Nirmatrelvir 300 mg + Ritonavir 100 mg	4.000	4.000 – 5.000
Placebo + Ritonavir 100 mg	5.000	5.000 – 6.000

Time to Sustained Alleviation of All Targeted Signs and Symptoms Through Day 28: mITT Population Secondary · Day 1 of dosing maximum up to Day 28 or censoring date, whichever occurred first

Sustained alleviation of all targeted COVID-19 signs/symptoms was defined as the event occurring on the first of 2 consecutive days when all symptoms scored as moderate or severe at study entry are scored as mild or absent and all symptoms scored mild or absent at study entry are scored as absent. The first day of the 2 consecutive-day period was considered the first event date. The time to sustained symptom alleviation was defined as for a participant with sustained symptom alleviation, time to event was calculated as (First Event Date) - (First Dose Date) +1. For a participant that either co

Group	Value	95% CI
Nirmatrelvir 300 mg + Ritonavir 100 mg	8.000	7.000 – 10.000
Placebo + Ritonavir 100 mg	9.000	8.000 – 11.000

Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Events (AEs) Leading to Discontinuation From Study Secondary · Day 1 of dosing up to maximum Week 24 follow-up

An AE was any untoward medical occurrence in a participant temporally associated with the use of study intervention, whether or not considered related to the study intervention. SAE was any untoward medical occurrence at any dose that: resulted in death, was life threatening (risk of death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions), resulted in congenital anomaly/birth defect, was a suspected transmission via a Pfizer produc

AEs

Group	Value	95% CI
Nirmatrelvir 300 mg + Ritonavir 100 mg	148
Placebo + Ritonavir 100 mg	55

SAEs

Group	Value	95% CI
Nirmatrelvir 300 mg + Ritonavir 100 mg	3
Placebo + Ritonavir 100 mg	1

AEs leading to discontinuation from study

Group	Value	95% CI
Nirmatrelvir 300 mg + Ritonavir 100 mg	0
Placebo + Ritonavir 100 mg	0

Adverse events — posted to ClinicalTrials.gov

Time frame: Day 1 of dosing up to maximum Week 24 follow-up. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Nirmatrelvir 300 mg + Ritonavir 100 mg

Serious: 3/289 (1%)

Deaths: 0/289

Placebo + Ritonavir 100 mg

Serious: 1/144 (1%)

Deaths: 0/144

Serious adverse events (5 terms)

Reaction	System	Nirmatrelvir 300 mg + Rito…	Placebo + Ritonavir 100 mg
Gastrointestinal haemorrhage	Gastrointestinal disorders	—	—
Hypovolaemia	Metabolism and nutrition disorders	—	—
B-cell lymphoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Generalised anxiety disorder	Psychiatric disorders	—	—
Major depression	Psychiatric disorders	—	—

Other adverse events (1 terms — click to expand)

Reaction	System	Nirmatrelvir 300 mg + Rito…	Placebo + Ritonavir 100 mg
Dysgeusia	Nervous system disorders	—	—

Most-reported serious reactions: Gastrointestinal haemorrhage, Hypovolaemia, B-cell lymphoma, Generalised anxiety disorder, Major depression.

Data from ClinicalTrials.gov NCT05567952 adverse events section.

Sponsor's own description

The purpose of this study is to learn about the safety and effects of nirmatrelvir/ritonavir for the potential treatment of COVID-19 rebound.

The study is seeking participants who:

* Have completed treatment with nirmatrelvir/ritonavir
* Have a rebound in COVID-19 symptoms
* Are SARS-CoV-2 (COVID-19) positive

All study medications will be taken 2 times a day by mouth for 5 days. The first dose of study medication is taken at the study clinic and the rest at home.

We will examine the experiences of people receiving the study medicines to those who do not. This will help us determine if the study medicines are safe and effective.

People taking part will be in this study for about 24 weeks. Enrolled participants will need to visit the study clinic at least 8 times during the study.

Publications & conference data

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

1. SARS-CoV-2 Rebound With and Without Use of COVID-19 Oral Antivirals.
   Smith DJ, Lambrou A, Patel P. · · 2023 · cited 21× · PMID 38127665 · DOI 10.15585/mmwr.mm7251a1
2. Paxlovid (Nirmatrelvir and Ritonavir) Use in Pregnant and Lactating Woman: Current Evidence and Practice Guidelines-A Scoping Review.
   Chourasia P, Maringanti BS, Edwards-Fligner M, Gangu K, et al · · 2023 · cited 18× · PMID 36679952 · DOI 10.3390/vaccines11010107
3. Nirmatrelvir combined with ritonavir for preventing and treating COVID-19.
   Reis S, Metzendorf MI, Kuehn R, Popp M, et al · · 2023 · cited 16× · PMID 38032024 · DOI 10.1002/14651858.cd015395.pub3
4. Review: The Landscape of Antiviral Therapy for COVID-19 in the Era of Widespread Population Immunity and Omicron-Lineage Viruses.
   Meyerowitz EA, Li Y. · · 2024 · cited 13× · PMID 37949817 · DOI 10.1093/cid/ciad685
5. Treating Acute Covid-19 - Final Chapters Still Unwritten.
   Gandhi RT, Hirsch M. · · 2024 · cited 12× · PMID 38598581 · DOI 10.1056/nejme2402224
6. Modeling suggests SARS-CoV-2 rebound after nirmatrelvir-ritonavir treatment is driven by target cell preservation coupled with incomplete viral clearance.
   Phan T, Ribeiro RM, Edelstein GE, Boucau J, et al · · 2025 · cited 9× · PMID 39902924 · DOI 10.1128/jvi.01623-24
7. Rebound of COVID-19 With Nirmatrelvir-Ritonavir Antiviral Therapy.
   Cohen MS, Brown ER. · · 2023 · cited 9× · PMID 37956432 · DOI 10.7326/m23-2887
8. Integrated virologic analysis of resistance to nirmatrelvir/ritonavir in individuals across four phase 2/3 clinical studies for the treatment of COVID-19.
   Baniecki ML, Guan S, Rai DK, Yang Q, et al · · 2025 · cited 2× · PMID 40592258 · DOI 10.1016/j.ebiom.2025.105819