Clinical trial NCT05852873: PAxlovid loNg cOvid-19 pRevention triAl With recruitMent In the Community in Norway
Official title: PAxlovid loNg cOvid-19 pRevention triAl With recruitMent In the Community in Norway
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Post COVID-19 Condition, Unspecified
SARS-CoV2 Infection
COVID-19
Keywords: Nirmatrelvir ritonavir
Prevention
Lead sponsor: Haukeland University Hospital
Sponsor class: OTHER
Collaborators: name: University of Bergen
name: Oslo University Hospital
name: University of Oslo
name: St. Olavs Hospital
name: Norwegian University of Science and Technology
First posted: 2023-05-10
Enrollment: 2000
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double-blinded placebo-controlleded randomized clinical trial
Primary purpose: PREVENTION

Brief summary: The goal of this clinical trial is to compare treatment with oral Paxlovid (nirmatrelvir/ritonavir) and placebo for acute COVID-19 as an intervention to prevent long-COVID (post-COVID-19 condition) in adults aged 18-64 years old.

The main question it aims to answer is:

Does treatment with Paxlovid for acute COVID-19 reduce the prevalence of long-COVID compared to placebo.

Participants with acute COVID-19, documented with positive lateral flow test or PCR, within the last 5 days will be randomised to take either Paxlovid or placebo. All participants will receive standard of care in addition. Participants will respond to electronic questionnaires at 14 time points during follow-up. The primary outcome is presence of long-COVID symptoms at 3 months follow-up.

Researchers will compare participants who received Paxlovid and placebo to see if Paxlovid treatment can prevent the occurrence of long-COVID.

Detailed description: PAxlovid loNg cOvid-19 pRevention triAl with recruitMent In the Community in Norway

Background: Despite high uptake of vaccination against COVID-19, the disease remains prevalent in Norway and in many countries around the world, with many patients continuing to experience considerable morbidity and requiring hospital treatment. There is therefore an urgent need to identify treatments for COVID-19 for use in the community early on in the illness that speeds recovery and prevents the need for hospital admission. A considerable burden of long term complications has been reported after COVID (named long COVID) even after home isolation of mild cases, but are particularly associated with more severe disease, and an early therapeutic intervention could potentially also prevent this COVID-19 related morbidity.

Aims and objectives: The study hypothesis is that antiviral treatment for acute Covid can prevent occurrence of persisting symptoms at 3 months and beyond. The primary objective is to assess whether a 5-day course of nirmatrelvir/ritonavir (Paxlovid ®) treatment for patients with acute Covid verified by positive SARS-CoV-2 PCR test result or positive lateral flow test, can reduce the prevalence of persistent symptoms at 3 months compared to placebo. The overall aim of the research is to identify a tool to prevent long COVID, and reduce its burden on society.

Interventions: This is a randomized clinical trial assessing whether healthy adults (P) treated with Paxlovid (I) for acute Covid versus those treated with placebo (C) will have reduced probability of suffering persistent symptoms at 3 months and beyond (O). Participants will be randomized 1:1 to two arms of the trial. Participants in the intervention arm will receive a standard 5-day treatment course Paxlovid (nirmatrelvir plus ritonavir) in addition to standard of care. Participants in the control arm will receive a 5-day course of placebo tablets, with the same appearance and quantity, in addition to standard of care. Participants will be randomised to receive either the antiviral agent Paxlovid (nirmatrelvir plus ritonavir) in addition to standard of care or Placebo plus standard of care.

Eligibility: Participants who meet the following inclusion criteria may be eligible to take part in the trial:

* Symptoms attributable to COVID-19 starting within the past 5 days and ongoing
* A positive PCR SARS-CoV-2 test or a positive lateral flow test. Any positive PCR test or a lateral flow test taken between two days before symptom onset and randomisation qualifies
* Age ≥ 18 years and \<65 years
* Participant is able and willing to provide informed consent, and able to comply with all study visits
* Patient not currently admitted to hospital
* No comorbidity which constitutes an indication for active antiviral treatment with Paxlovid as judged by the investigator
* No chronic renal impairment
* No chronic liver disease or liver impairment
* No previous randomisation in the PANORAMIC Norway trial
* Not currently participating in a clinical trial of a therapeutic agent
* Not currently taking Paxlovid
* No known allergy to Paxlovid
* No use of concomitant medication contraindicated for the treatment of Paxlovid
* Not currently pregnant or lactating
* Willingness to take a pregnancy test prior to starting study treatment (Participants of childbearing potential)
* Willingness to use highly effective contraceptive until 7 days after completing Paxlovid (Participants of childbearing potential or have a partner of childbearing potential)

Outcomes: The primary endpoint will be presence of pre-defined symptoms of long COVID at 3 months from randomisation). The secondary outcome will be all-cause, non-elective hospitalisation or death within 28 days of randomisation. Secondary outcomes will further include time to self-reported recovery; participant reported illness severity; duration of symptoms and symptom recurrence; healthcare service use; participant reported household infection rate; safety outcomes and cost-effectiveness outcomes; symptoms and well-being at six months (with determination of proportion with Long Covid) from randomisation. See Table 1 for details of objectives and outcome measures.

Study design: This is a two-arm 1:1 randomized double-blinded placebo-controlled clinical trial. The study is designed to assess whether healthy adults (P) treated with Paxlovid (I) for acute Covid versus those treated with placebo (C) will have reduced probability of suffering persistent symptoms at 3 months and beyond (O). An external statistician will produce a randomization list prior to the start of the trial. At the time of inclusion in the study, study personnel will blindly allocate participants to receive active ingredient or placebo according to the randomization list. All enrolment (screening, eligibility review, informed consent and baseline data) will be conducted by the trial team, with follow-up procedures (electronic diary) conducted remotely with participants or their chosen support person (Study Partner) using the trial website or a telephone call with the trial team. Any hospitalisations and deaths will be recorded.

Recruitment: A central trial team will recruit and allocate participants to the next medication/Placebo number. A participant pack containing Paxlovid or Placebo will be given to the participant or their Study Partner, which is a person appointed by the participant to act on their behalf, for instance to collect study medication at the central study site. During the study period, further recruitment sites and PraksisNett collaboration will be considered.

Data to be recorded: Demographic features including age, gender, comorbidity, allergies, medication history and present medication, COVID vaccine history and previous COVID-19 will be captured at baseline. In the online diary (completed each day for 7 days, weekly for 28 days, and at 3 and 6 months) and during telephone calls, participants or their Study Partners will rate the severity of symptoms including how well they are feeling, record contacts with the health services (including hospital admission), record study medication use, resource use, sick leave, and new infections in the household. Follow-up beyond 28 days after randomisation will be by accessing medical registries and by participant questionnaire for information relevant to the longer-term consequences of COVID-19 at three and six months from randomisation. To investigate the impact of trial interventions on the longer-term effects of COVID-19, we will also remotely follow-up participants, for up to 1 year.

Exploratory subprojects: 1. A subgroup of up to 500 patients will be asked to attend a face-to-face visit or to donate a microbiological or blood sample for the purpose of the study, at 3, 6 and 12 months after inclusion. 2. A smaller group of 100 patients, with and without symptoms at 3 months will be included in a study on brain damage, including neurocognitive, EEG and MRI investigations.

Numbers to be randomised: An estimated maximum of approximately 1000 participants per arm will be required to provide approximately 90% power for detecting a 20% relative reduction in long COVID symptoms in an experimental arm relative to Placebo, based on the assumption of an underlying 30% prevalence of long COVID at 3 months in the placebo arm, and an intervention lowering the long COVID rate to 22%.

Eligibility criteria: Inclusion Criteria:

* Symptoms attributable to COVID-19 started within the past 5 days and ongoing
* Positive PCR or lateral flow SARS-CoV-2 test. Any positive PCR test or a lateral flow test taken between two days before symptom onset and randomisation qualifies.
* Age between 18 and 65 years
* Participant is able and willing to provide informed consent
* Willingness to take a pregnancy test prior to starting study treatment (Participants of childbearing potential)

Exclusion Criteria:

* Patients that are not able to comply with all study visits
* Patient currently inpatient at hospital
* Comorbidity which requires active antiviral treatment as judged by the investigator
* Any chronic renal impairment
* Any chronic liver disease or liver impairment
* Previous randomisation in the PANORAMIC Norway trial
* Currently participating in a clinical trial of a therapeutic agent
* Currently taking Paxlovid
* Known allergy to Paxlovid
* Use of concomitant medication contraindicated for the treatment of Paxlovid\*
* Pregnant and lactating women
* Participants of childbearing potential (participants who are anatomically and physiologically capable of becoming pregnant), or have a partner of childbearing potential, not willing to use highly effective contraceptive until 7 days after completing Paxlovid.

  \* Concomitant medications that are contraindicated for the treatment of Paxlovid
* Medicinal products that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions.
* Medicinal products that are potent CYP3A inducers where significantly reduced nirmatrelvir/ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance. Paxlovid cannot be started immediately after discontinuation of such medicinal products due to the delayed offset of the recently discontinued CYP3A inducer.

More information is available in the study protocol on medicinal products that are contraindicated with concomitant use of Paxlovid.

Primary outcomes:
measure: Symptoms of long-COVID
timeFrame: Change in symptoms from baseline to 3, 6 and 12 months follow-up
Secondary outcomes:
measure: Symptoms individually and grouped by organ system
timeFrame: Change in symptoms from baseline to 3, 6, 12 and 24 months follow-up
measure: Graded responses for symptoms and symptom constellations
timeFrame: Change in symptoms from baseline to 3, 6, 12 and 24 months follow-up
measure: Risk factors for long-COVID
timeFrame: Up to 24 months
measure: Severity of acute disease
timeFrame: 28 days
measure: Hospitalisation
timeFrame: 28 days
measure: Severe adverse events
timeFrame: Up to 24 months
measure: Absence from work
timeFrame: Up to 24 months
measure: Societal costs
timeFrame: Up to 24 months
measure: Symptoms of long-COVID
timeFrame: Change in symptoms from baseline to 3, 6 and 12 months follow-up
Other outcomes:
Locations:
city: Bergen
country: Norway
facility: Haukeland University Hospital
state: Vestland
Study officials:
affiliation: Haukeland University Hospital
name: Nina Langeland, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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