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Post-COVID-19 SyndromePhase 2PROLIFICNCT05823896

ImPROving Quality of LIFe in the Long COVID Patient

A Phase 2 study testing Nirmatrelvir/ritonavir in people with Post-COVID-19 Syndrome and Long COVID, run by Karolinska Institutet at 1 site in Sweden.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The purpose of this study is to investigate the efficacy of orally administered nirmatrelvir/ritonavir compared with placebo/ritonavir to improve quality of life in non-hospitalized adult participants suffering from post-acute COVID-19 syndrome. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Post-COVID-19 Syndrome, Long COVID, Long Covid19
What is being tested?
Nirmatrelvir/ritonavir
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
219 participants
Where
1 siteSweden
Study dates
1 May 2023to 28 Nov 2024
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • The subject has given written consent to participate in the study.
  • ≥18 years of age at the time of the Screening Visit.
  • Post-acute COVID-19 syndrome (PACS) according to the WHO definition.
  • EQ-5D-5L VAS ≤ 50
  • All fertile participants must agree to use a highly effective method of contraception for the duration of the study and 28 days after last intake of the IMP.

Who cannot join

  • General exclusion criteria
  • Other non-related conditions with PACS like symptoms.
  • Renal function eGFR eGFRCysC \< 60 mL/min/1.73 m2.
  • Not able to comply with the study protocol.
  • Previous Paxlovid treatment.
  • Pregnancy or breastfeeding.
Show all 31Show fewer
  • Drug-drug interaction with ongoing treatment, including concomitant use of any medications or substances that are strong inducers of CYP3A4 within 28 days prior to first dose of nirmatrelvir/ritonavir and during study treatment.
  • Participants who are planning or considering vaccination (including boosters) through Study Day 45.
  • Active COVID-19 infection as verified by SARS CoV-2 positive antigen test.
  • Self-reported medical conditions, including:
  • Type 1 or Type 2 diabetes mellitus.
  • Chronic kidney disease.
  • Neurodevelopmental disorders (e.g., cerebral palsy, Down's syndrome) or other conditions that confer medical complexity (e.g., genetic or metabolic syndromes and severe congenital anomalies).
  • Active cancer other than localized skin cancer, including those requiring treatment including palliative treatment), as long as the treatment is not among the prohibited medications that must be administered/continued during the trial period.
  • Immunosuppressive disease (e.g., bone marrow or organ transplantation or primary immune deficiencies) OR prolonged use of immune-weakening medications:
  • Has received corticosteroids equivalent to prednisone ≥20 mg daily for at least 14 consecutive days within 30 days prior to study entry.
  • Has received treatment with biologics (e.g., infliximab, ustekinumab, etc.), immunomodulators (e.g., methotrexate, 6MP, azathioprine, etc.), or cancer chemotherapy within 90 days prior to study entry.
  • HIV infection with CD4+ cell count \<200/mm3.
  • History of hospitalization for the medical treatment of acute COVID-19
  • Current need for hospitalization or anticipated need for hospitalization within 48 hours after randomization in the clinical opinion of the site investigator.
  • Prior/Concomitant Therapy:
  • Current or expected use of any medications or substances that are highly dependent on CYP3A4 for clearance, and for which elevated plasma concentrations may be associated with serious and/or life-threatening events during treatment and for 4 days after the last dose of nirmatrelvir/ritonavir. List of potential interactions provided by Pfizer provided in Appendix A.
  • Has received or is expected to receive monoclonal antibody treatment, antiviral treatment (e.g., molnupiravir), or convalescent COVID-19 plasma.
  • Prior/Concurrent Clinical Study Experience:
  • Is unwilling to abstain from participating in another interventional clinical study with an investigational compound or device, including those for post-COVID-19 therapeutics, through the long-term follow-up visit.
  • Previous administration with any investigational drug or vaccine within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer).
  • Known prior participation in this trial or other trial involving nirmatrelvir.
  • Diagnostic Assessments:
  • Known history of any of the following abnormalities in clinical laboratory tests (within past 6 months of the screening visit):
  • AST or ALT level ≥2.5 X ULN
  • Total bilirubin ≥2 X ULN (≥3 X ULN for Gilbert's syndrome)

Trial locations and contacts

1 site in 1 country.

Sweden1 site
  • Karolinska Institutet

    Stockholm, SE171 77

Other trials in Sweden

About this study

Official title: An Interventional, Double-Blinded, 2-Arm Study to Investigate the Efficacy of Orally Administered Nirmatrelvir/Ritonavir Compared with Placebo/Ritonavir in Non-hospitalized Adult Participants Suffering from Post-COVID

The purpose of this study is to investigate the efficacy of orally administered nirmatrelvir/ritonavir compared with placebo/ritonavir to improve quality of life in non-hospitalized adult participants suffering from post-acute COVID-19 syndrome.

Read the detailed description

At present there is no curative treatment for post-acute COVID-19 syndrome (PACS). Treatment is focused on symptom management and individualized rehabilitation. There is data indicating SARS-CoV-2 viral persistence and chronic immune system activation in PACS. We are proposing an interventional, randomized and placebo-controlled clinical intervention trial of nirmatrelvir/ritonavir (300/100 mg) or placebo/ritonavir (100mg), twice daily for 15 days, in patients suffering from severe PACS and meeting the WHO definition of severe PACS. A total of 180 patients will be enrolled in this study and these will be randomized in a 2:1 ratio to receive either nirmatrelvir/ritonavir or placebo/ritonavir. The study will include deep exploratory systems-level analyses of the immune system in PACS patients, including changes induced by nirmatrelvir/ritonavir (Paxlovid®) treatment. The purpose of this study is to evaluate the efficacy of nirmatrelvir/ritonavir for its potential ability to provide sustained improvement in quality of life, in non-hospitalized patients with post-COVID, a patient group with high unmet medical needs.

Hypothesis: Nirmatrelvir/ritonavir (Paxlovid®) improves health-related quality of life measured using the EQ-5D-5L VAS scale, as compared to placebo/ritonavir, in objective and pre-defined clinical phenotypes: postural orthostatic tachycardia syndrome (POTS), microvascular dysfunction, inappropriate sinus tachycardia, persistent fever, post exertional malaise (PEM), fatigue, brain fog, dyspnea, dysfunctional breathing patterns or inflammatory phenotypes (increased plasma D-dimer, CRP, ESR and ferritin).

Being tested
Nirmatrelvir/ritonavir, Placebo/ritonavir
Medical subject headings
Post-Acute COVID-19 Syndrome, COVID-19, Postural Orthostatic Tachycardia Syndrome, Post-Infectious Disorders

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Nirmatrelvir/ritonavirDrug

    Also called Paxlovid

    300/100 mg tablet twice daily (q12h) administered orally for 15 days

  • Placebo/ritonavirDrug

    Also called Placebo

    100mg tablet twice daily (q12h) administered orally for 15 days

Study groups in NCT05823896
Study groupRoleWhat they receive
Nirmatrelvir/ritonavirActive comparatorOral nirmatrelvir/ritonavir (Paxlovid) 300/100 mg twice daily for 15 days
Receives: Drug: Nirmatrelvir/ritonavir
Placebo/ritonavirPlacebo comparatorOral placebo/ritonavir 100 mg twice daily for 15 days
Receives: Drug: Placebo/ritonavir

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change from baseline in quality of life over time

    The effect of oral administration of nirmatrelvir/ritonavir on quality of life measured as change from baseline using the EQ-5D-5L VAS scale.

    Measured: Baseline and day 16

Secondary outcomes (16)
  1. Change from baseline in quality of life over time

    The effect of oral administration of nirmatrelvir/ritonavir on quality of life measured as change from baseline using the EQ-5D-5L VAS scale.

    Measured: Baseline and days 45 and 90

  2. Change from baseline in hemodynamic response over time

    The effect of oral administration of nirmatrelvir/ritonavir on hemodynamic response (only patients diagnosed with postural orthostatic tachycardia syndrome, POTS). Change from baseline in delta maximum heart rate during active standing test.

    Measured: Baseline and days 45 and 90

  3. Change from baseline in dysautonomia over time

    The effect of oral administration of nirmatrelvir/ritonavir on dysautonomia symptoms. Change from baseline as measured using the Composite Autonomic Symptom Score (Compass31) questionnaire.

    Measured: Baseline and days 45 and 90

  4. Change from baseline in fever in patients with POTS over time

    The effect of oral administration of nirmatrelvir/ritonavir on fever (only patients diagnosed with POTS). Change from baseline in POTS-specific symptoms as measured by using the Malmo POTS score, MAPS.

    Measured: Baseline and days 45 and 90

  5. Change from baseline in endothelial function over time

    The effect of oral administration of nirmatrelvir/ritonavir on reactive hyperemia index. Change from baseline in endothelial function measured using the EndoPat® device.

    Measured: Baseline and day 45

  6. Change from baseline in heart rate over time

    The effect of oral administration of nirmatrelvir/ritonavir on 24-h average heart rate. Change from baseline in heart rate using ECG monitoring device.

    Measured: Baseline and days 45 and 90

  7. Change from baseline in fever over time

    The effect of oral administration of nirmatrelvir/ritonavir on fever. Change from baseline in body temperature.

    Measured: Baseline and days 16, 45 and 90

  8. Change from baseline in physical capacity over time

    The effect of oral administration of nirmatrelvir/ritonavir on physical capacity. Change from baseline as measured by 6-minute walk test.

    Measured: Baseline and days 16, 45 and 90

  9. Change from baseline in handgrip strength over time

    The effect of oral administration of nirmatrelvir/ritonavir on handgrip strength. Change from baseline as measured by JAMAR hand dynamometer.

    Measured: Baseline and days 16, 45 and 90

  10. Change from baseline in physical activity over time

    The effect of oral administration of nirmatrelvir/ritonavir on physical activity. Change from baseline as measured by accelerometer.

    Measured: Baseline and days 16, 45 and 90

  11. Change from baseline in post-exertional malaise over time

    The effect of oral administration of nirmatrelvir/ritonavir on post-exertional malaise. Change from baseline in total score as measured by the Post-Exertional Malaise (PEM) short form.

    Measured: Baseline and day 90

  12. Change from baseline in fatigue over time

    The effect of oral administration of nirmatrelvir/ritonavir on fatigue. Change from baseline as measured by the fatigue severity scale (FSS) and mental fatigue scale (MFS).

    Measured: Baseline and days 16, 45 and 90

  13. Change from baseline in cognitive dysfunction over time

    The effect of oral administration of nirmatrelvir/ritonavir on cognitive dysfunction. Change from baseline over time as measured by the Montreal Cognitive Assessment (MoCA) test.

    Measured: Baseline and days 16, 45 and 90

  14. Change from baseline in dyspnea over time

    The effect of oral administration of nirmatrelvir/ritonavir on dyspnea measured as change from baseline in respiratory symptoms using the Chronic obstructive disease assessment (CAT) and Modified Medical Research Council (mMRC) tests.

    Measured: Baseline and days 16, 45 and 90

  15. Change from baseline in plasma biomarkers over time

    The effect of oral administration of nirmatrelvir/ritonavir on plasma biomarkers. Change from baseline in the following plasma biomarkers: D-dimer, CRP, ESR, ferritin, NTproBNP and LD.

    Measured: Baseline and days 16, 45 and 90

  16. Change from baseline in dysfunctional breathing patterns over time

    The effect of oral administration of nirmatrelvir/ritonavir on dysfunctional breathing patterns. Change from baseline in Njimegen questionnaire.

    Measured: Baseline and days 16, 45 and 90

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Apr 2023
  2. Study start1 May 2023
  3. Primary completion28 Nov 2024
  4. Study completion28 Nov 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
This is a phase II, interventional, randomized, parallel group, double-blind, placebo-controlled, single-center study of nirmatrelvir/ritonavir (300/100 mg) or placebo/ritonavir (100mg), administered orally twice daily for 15 days in non-hospitalized patients with post- COVID conditions.
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
219 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05823896
Sponsor's protocol ID
KI-PROLIFIC-2023
Other IDs
2022-003855-32
Acronym
PROLIFIC
Status last verified
Sep 2024
First submitted
20 Apr 2023
Last updated
4 Dec 2024
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Caruso D, Guido G, Zerunian M, Polidori T, Lucertini E, Pucciarelli F, Polici M, Rucci C, Bracci B, Nicolai M, Cremona A, De Dominicis C, Laghi A. Post-Acute Sequelae of COVID-19 Pneumonia: Six-month Chest CT Follow-up. Radiology. 2021 Nov;301(2):E396-E405. doi: 10.1148/radiol.2021210834. Epub 2021 Jul 27.

    PubMed 34313468
  • Han X, Fan Y, Alwalid O, Li N, Jia X, Yuan M, Li Y, Cao Y, Gu J, Wu H, Shi H. Six-month Follow-up Chest CT Findings after Severe COVID-19 Pneumonia. Radiology. 2021 Apr;299(1):E177-E186. doi: 10.1148/radiol.2021203153. Epub 2021 Jan 26.

    PubMed 33497317
  • Ceban F, Ling S, Lui LMW, Lee Y, Gill H, Teopiz KM, Rodrigues NB, Subramaniapillai M, Di Vincenzo JD, Cao B, Lin K, Mansur RB, Ho RC, Rosenblat JD, Miskowiak KW, Vinberg M, Maletic V, McIntyre RS. Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis. Brain Behav Immun. 2022 Mar;101:93-135. doi: 10.1016/j.bbi.2021.12.020. Epub 2021 Dec 29.

    PubMed 34973396
  • Goh D, Lim JCT, Fernaindez SB, Joseph CR, Edwards SG, Neo ZW, Lee JN, Caballero SG, Lau MC, Yeong JPS. Case report: Persistence of residual antigen and RNA of the SARS-CoV-2 virus in tissues of two patients with long COVID. Front Immunol. 2022 Sep 5;13:939989. doi: 10.3389/fimmu.2022.939989. eCollection 2022.

    PubMed 36131932
  • Visvabharathy L, Orban ZS, Koralnik IJ. Case report: Treatment of long COVID with a SARS-CoV-2 antiviral and IL-6 blockade in a patient with rheumatoid arthritis and SARS-CoV-2 antigen persistence. Front Med (Lausanne). 2022 Sep 23;9:1003103. doi: 10.3389/fmed.2022.1003103. eCollection 2022.

    PubMed 36213654
  • Hammond J, Leister-Tebbe H, Gardner A, Abreu P, Bao W, Wisemandle W, Baniecki M, Hendrick VM, Damle B, Simon-Campos A, Pypstra R, Rusnak JM; EPIC-HR Investigators. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med. 2022 Apr 14;386(15):1397-1408. doi: 10.1056/NEJMoa2118542. Epub 2022 Feb 16.

    PubMed 35172054
  • Toussi SS, Neutel JM, Navarro J, Preston RA, Shi H, Kavetska O, LaBadie RR, Binks M, Chan PLS, Demers N, Corrigan B, Damle B. Pharmacokinetics of Oral Nirmatrelvir/Ritonavir, a Protease Inhibitor for Treatment of COVID-19, in Subjects With Renal Impairment. Clin Pharmacol Ther. 2022 Oct;112(4):892-900. doi: 10.1002/cpt.2688. Epub 2022 Jul 5.

    PubMed 35712797
  • Sundaram A, Vaughan B, Kost K, Bankole A, Finer L, Singh S, Trussell J. Contraceptive Failure in the United States: Estimates from the 2006-2010 National Survey of Family Growth. Perspect Sex Reprod Health. 2017 Mar;49(1):7-16. doi: 10.1363/psrh.12017. Epub 2017 Feb 28.

    PubMed 28245088
  • Swank Z, Senussi Y, Manickas-Hill Z, Yu XG, Li JZ, Alter G, Walt DR. Persistent Circulating Severe Acute Respiratory Syndrome Coronavirus 2 Spike Is Associated With Post-acute Coronavirus Disease 2019 Sequelae. Clin Infect Dis. 2023 Feb 8;76(3):e487-e490. doi: 10.1093/cid/ciac722.

    PubMed 36052466

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Nirmatrelvir/ritonavir in people with Post-COVID-19 Syndrome and Long COVID, run by Karolinska Institutet at 1 site in Sweden.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 31 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 4 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Sweden. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change from baseline in quality of life over time (time frame: Baseline and day 16). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05823896, which also lists 9 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Dec 2024.

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