Randomized trial of nirmatrelvir/ritonavir versus placebo in adults with acute COVID-19 to prevent long COVID

The COVID-19 pandemic has had a global impact with more than 750 million confirmed cases and an estimated 6.9 million deaths [1]. Even though the number of COVID-19 hospitalizations is decreasing, a considerable burden of long-term complications, referred to as long COVID, has been reported after acute SARS-CoV-2 infection [2 –5]. The World Health Organization (WHO) classifies long COVID as the continuation of, or development of new symptoms 3 months after the initial SARS-CoV-2 infection, lasting for at least 2 months [6]. Long COVID appears to be a more common post-viral condition than illnesses after other viral infections [7]. Acute COVID-19 presenting with severe disease manifestations requiring hospitalization is particularly associated with long-term complications. Nevertheless, long COVID can occur in up to 30% of patients even after mild to moderate acute SARS-CoV-2 infection [2, 5, 8]. In line with this, the risk of developing long COVID after infection with an Omicron variant is similar to that after a Delta variant infection [9]. The duration of long COVID is unclear, but over 30% of sequelae persist at 2-year follow-up even in patients who had not been hospitalized during the initial infection [10]. The high prevalence of long-term persisting symptoms after COVID-19 may have a large public health impact [11]. The pathophysiology of long COVID is still unresolved, and there is still no cure for this condition [12]. Apart from avoiding infection, there are no definite treatment strategies for long COVID, although there is some evidence for the partial protective effect of leading a healthy lifestyle [13], vaccination [14, 15], and receiving antiviral treatment for acute COVID-19 [16]. Better preventive measures are needed. Early treatment with the novel antiviral combination nirmatrelvir/ritonavir (Paxlovid®) prevents hospitalization and death from COVID [17, 18]. In the current trial, we aim to assess whether treatment with nirmatrelvir/ritonavir for acute COVID-19 regardless of disease severity during the acute phase can prevent persistent symptoms or long COVID at 3-month follow-up and beyond.

PanoramicNOR is a two-arm 1:1 randomized clinical trial assessing whether adults (P—study population) treated with nirmatrelvir/ritonavir (I—intervention) for acute COVID-19 versus those treated with placebo (C—comparator) will have a reduced probability of suffering persistent symptoms at 3 months and beyond (O—outcome). This is a superiority study with parallel groups.

The main study site is the setting of municipal healthcare services in Bergen, Norway. Two additional inclusion sites are in Ålesund and Oslo, Norway. Follow-up of participants and assessment of adverse events are done by study personnel at the main study site in Bergen.

Patients testing positive for COVID-19 attending the study recruitment office will be screened for eligibility by study staff, consisting of nurses and a medical doctor, who will also obtain informed consent.

Eligible participants will be asked to physically attend the study site for enrolment in the study. Written informed consent is provided after discussion between a member of the trial team and the participant, where the risks and benefits of taking part and follow-up procedures will be explained. Prior to consent, written and summary versions of the patient information sheet (PIS) and informed consent form (ICF) will be available to participants detailing the exact nature of the trial and the known side effects and risks involved in taking part. Participants will be informed that they are free to withdraw from the study at any time without giving any reasons. Adequate time will be given to the participant to consider the information and to ask any questions about the trial before deciding whether to participate. For participants who are too unwell or unable to respond to surveys themselves, a study partner who they identify will be able to assist the participant in completing screening, baseline, and follow-up online forms and/or calls and provide information to them on their behalf when necessary.

After informed consent is signed, participants will enter online baseline information, including demographics, comorbidities, concomitant medication, allergies, COVID-19 vaccine history, and previous COVID-19, residual symptoms of past COVID-19 infection, and their contact details and those of a study partner. Identifying a study partner is not a requirement to participate in the study.

The trial team will use Norwegian health registries as source data for relevant medical information, including emergency hospitalization events (Norwegian Patient Registry—NPR), details concerning COVID-19-related hospital admissions (Norwegian Intensive Care and Pandemic Registry—NiPAR), mortality and cause of death (Norwegian Cause of Death Registry), contacts with primary care (Norwegian Registry for Primary Health Care—KPR), COVID-19 vaccine history (Norwegian Immunization Registry—SYSVAK), drug prescriptions (Norwegian Prescription Database—NorPD), and sick leave (The Sickness Absence Registry).

Data collected will include participant identifiable information and will be accessed at Haukeland University Hospital according to Primary Care Clinical Trials Unit (PC-CTU) Information Governance policies and Norwegian General Data Protection Regulations (GDPR). Data will only be held for the duration it is required; this will be reviewed annually. All documents will be stored safely and confidentially. On all study-specific documents, other than the signed consent, the participant will be referred to by the study participant number/code, not by name.

A subgroup of up to 500 patients will be asked to attend a face-to-face visit and/or to donate a microbiological or blood sample for the purpose of the study, at 3, 6, and 12 months after inclusion. A subset of 100 patients, with and without symptoms at 3 months, will be included in a study to characterize any effects on the brain by neurocognitive assessment, electroencephalography (EEG), and magnetic resonance imaging (MRI) investigations. The two subgroups of participants will have additional consent forms specific to the respective sub-studies.

At the initiation of the study, nirmatrelvir/ritonavir was the only antiviral drug on the market approved to treat COVID-19 in an outpatient setting in Norway. Currently, neither nirmatrelvir/ritonavir nor any other pharmacological agents have proven efficacy in preventing long COVID. Therefore, we have chosen to compare nirmatrelvir/ritonavir with placebo.

Participants in the intervention arm will receive a standard 5-day treatment course of nirmatrelvir/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. An independent professor at the University of Bergen, who was not part of the trial team, made a randomization list of 2000 numbers with 1:1, non-stratified randomization to interventional product or placebo. The company preparing placebo products coated both the interventional products and the placebos with identical coating and identical labelling of the package apart from the unique study number. Participants are consecutively allocated according to the pre-made randomization list to receive either the antiviral agent nirmatrelvir/ritonavir in addition to standard of care or placebo plus standard of care. They will receive the study medication in two containers marked "nirmatrelvir/placebo" and "ritonavir/placebo," both with their study number on the box, and be given both oral and written instructions on how to take the study medication. The study medication will be taken at home at the same dosage as is recommended for nirmatrelvir/ritonavir, one dose (two tablets nirmatrelvir/placebo and one tablet ritonavir/placebo) morning and evening for 5 days. The study nurse or study doctor will call the participant between day 1 and day 3 to check if the participants are taking the study medication as prescribed and whether they have experienced any adverse reactions. After 5 days of taking the oral study medication, there are no further medical interventions in the study.

Each participant has the right to withdraw from the study at any time without giving reasons or justification. In addition, the investigator team may discontinue a participant from the study at any time if the investigator team considers it necessary for any reason, including ineligibility (either arising during the study or retrospectively) or withdrawal of consent. Data that has already been collected about the participant will be kept and included in the analyses of the trial. Withdrawn participants will not be replaced. Although withdrawals, in principle, may reduce the power of the study, we do not expect the attrition to be sufficient to make this a serious concern. If serious adverse events occur, study medication will be stopped, but the patient will be followed up and data collected. Only the standard dose of nirmatrelvir/ritonavir is used in this study, as per the manufacturer's instructions.

A safety call will be made to all participants between days 1 and 3 to ensure compliance and that the medication is used as prescribed. Moreover, medication adherence will be captured daily in the electronic diaries or in phone calls with the patient. The research team will call participants/study partners who have not completed their diary for at least 2 days before day 7. No more than two contact attempts will be made at each of these follow-up points. Deviation(s) from the prescribed dosage regimen will be recorded. The participants not completing the intervention will be asked to return any unused intervention drugs to the research center for destruction.

The study doctor will check relevant interactions between participants' regular medicines and nirmatrelvir/ritonavir to ensure there are no serious known interactions before the participant is enrolled in the trial. Concomitant medications that are contraindicated for the treatment of nirmatrelvir/ritonavir include the following (supplemental information):Medicinal products that are highly dependent on the enzyme 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.Nirmatrelvir/ritonavir cannot be started immediately after discontinuation of any of the medicinal products listed specifically in the protocol due to the delayed offset of the recently discontinued CYP3A inducer.Medicinal products that are contraindicated with nirmatrelvir/ritonavir according to the SmPC: https://www.ema.europa.eu/en/medicines/human/EPAR/paxlovid↗.

The study doctor on site will make a judgement and may adjust the patient's regular medication for the intervention period (5 days of treatment + 7 days of residual effect of nirmatrelvir/ritonavir) to avoid drug–drug interactions, if this is deemed safe and the patient finds it acceptable.

Patients are insured in accordance with the Product Liability Act in the Drug Insurance and the Patient Injuries Act.

An independent scientist prepared a randomization list from 1 to 2000, assigning each number to treatment with nirmatrelvir/ritonavir or placebo using fixed equal allocation ratios. Upon inclusion in the study, participants are consecutively assigned to the next randomization number on the list and given the corresponding package of study product (either nirmatrelvir/ritonavir or placebo).

PanoramicNOR is a double-blinded placebo-controlled trial. If unblinding or code breaking is required, as requested by the protocol or the Data and Safety Monitoring Board (DSMB), this will be made available to the DSMB. However, those managing the data will be blinded to participant allocation. The trial team and recruiting clinicians will be blinded to the results of interim analyses. During the course of the trial, only the unblinding statisticians and the independent members of the DSMB will have access to the unblinded interim results.

As described under outcomes above, a total of 13 symptoms will be recorded, and the primary outcome is a dichotomous variable for the presence of any of the three most important long COVID symptoms: (i) fatigue, (ii) dyspnea, and (iii) cognitive symptoms (defined as memory and/or concentration problems). In addition, data on nine secondary outcomes will be collected, as described above. The data collection forms can be found at the end of the protocol.

The participants will receive a text message with the questionnaire on each day they are supposed to answer a new form (daily: days 0–7, weekly: weeks 2–4, at 3, 6, 12, and 24 months). If they have not answered during the day, they will get a reminder in the evening to fill out the questionnaire. If the participant still has not answered the next day, the study team can make up to two phone calls to the participant to remind them to fill out the questionnaire form. After this, no further attempts to contact participants regarding the specific questionnaire form will be made, and missing data points will remain as such.

For the purpose of obtaining blood samples, the subgroup participants will be contacted in due time to schedule an appointment at the study center for follow-up blood tests. This will also be the case for the MRI group participants. In addition, all participants will get a phone call between days 1 and 3 to ensure they are taking nirmatrelvir/ritonavir or placebo correctly and answer any new questions that may have arisen since they were included.

The following summarizes the study's data management plan.

Data with identifying variables will be stored on firewall-protected secure servers, separately from non-identifiable information such as clinical and microbiological data. Consent forms from participants will be safely stored separately from the collected data in a locked cabinet.

Blood will be sampled at inclusion from the willing participants at the study sites. The blood will be sampled in 10-mL collecting tubes (2 × serum, 2 × EDTA, 4 × sodium heparin, and 1 × tempus blood RNA tube) using standard venipuncture technique. After collection, the blood samples will be handled in accordance with the blood sample SOP 1; further details can be found there. The serum and EDTA tubes will be frozen at minus 80 °C and the tempus blood RNA tube at minus 20 °C. The sodium heparin tubes will be used for whole blood preservation in cytodelics whole blood stabilizer solution and for peripheral blood mononuclear cells isolation; these procedures are described in blood sample SOP 2. We will also collect separate samples for CRP, D-dimer, and fibrinogen at inclusion and send these to the clinical laboratory at Haukeland University Hospital for storage and analysis. Blood to be sampled at 3-, 6-, and 12-month follow-up is detailed in blood sample SOP 3. Throat PCR swabs of all participants will be collected upon inclusion and frozen at minus 80 °C for later use.

The primary outcome, i.e., the effect of intervention on a binary variable for the presence of any of three key long COVID symptoms, will be analyzed with an appropriate logistic regression model. Depending on whether we obtain a good balance of prognostic factors between the randomized groups, we may consider adjustment for prognostic factors in the analyses. We will report an odds ratio with 95% confidence intervals and a p-value from this analysis.

The primary analysis will be an "intention-to-treat" analysis performed on all patients who were randomized. In addition, a per-protocol analysis will be performed for patients who reported having adhered to the ingestion of the study product (antiviral or placebo) and on other subgroups of the study population. If adherence is incomplete, we will attempt to estimate the biological effect of the medication by using instrumental variable analysis [20].

In the analysis of follow-up data up to 24 months, we will use appropriate mixed models to account for the correlation of symptoms over time. We will estimate the main effect of treatment and test whether the effect is uniform over time.

Secondary outcomes will be analyzed with appropriate regression models depending on the type of outcome variable. For binary outcomes, we will use logistic regression. For the number of symptom counts, we will consider negative binomial regression, and for score outcomes, we will attempt ordinal logistic regression and quantile regression. Using quantile regression models, we will estimate the effect of the intervention also in the tails of the score distribution.

Further analysis plans include cost-efficacy analyses and explorative analyses. We will estimate the resource inputs associated with providing the antiviral treatment in routine clinical practice. Societal costs will be estimated using data on primary care encounters, hospital inpatient/day case admissions, outpatient visits, and accident and emergency attendances. Loss of quality-adjusted life year (QALY) will be estimated. Unit costs will be valued using national reference tariffs. Compound total health care cost per trial participant over the trial time horizon will be estimated. Secondary expressions of cost-effectiveness will include incremental cost per hospitalization and/or death prevented over 28 and 60 days. Relevant data may be obtained from abovementioned registries, including NPR, NIPaR, the Norwegian Cause of Death Registry, KPR, NorPD, SYSVAK, and the Sickness Absence Registry. Cost-effectiveness will be expressed in terms of incremental cost per QALY gained. Bivariate regression of costs and measures of health consequence, with multiple imputation of missing data, will be conducted to generate within-trial estimates of incremental cost-effectiveness. Sensitivity analyses will assess the impact of areas of uncertainty surrounding components of the economic evaluation. The probability of cost-effectiveness at alternative thresholds will be measured. Cost-effectiveness threshold values will be informed by guidance from government departments on the value placed by decision-makers on an additional QALY and on a statistical life.

Interim analyses will be performed when 1000 patients have reached 28 days follow-up, assessing any deaths and hospitalizations occurring in the study population, or at the request of the DSMB. The study will be stopped if the proportion of deaths at 28-day follow-up is higher in one of the groups by a significance of p < 0.02 and an effect size of odds ratio > 4. Severe adverse events will be reported consecutively to the DSMB. The DSMB will evaluate this independently of the interim analysis.

Any deviations from the protocol will be documented in a protocol deviation form and filed in the study master file. The Norwegian Clinical Research Infrastructure Network (NorCRIN) SOP is used to identify noncompliances, escalation to the central team, and assessment of whether a noncompliance/deviation may be a potential serious breach. Missing data for both binary and continuous variables will, in the main analyses, be handled as nonresponses. Depending on the degree of missingness, we may perform supplementary analyses with multiple imputation of missing values to assess the possibility that the missing data may introduce bias.

The R code for the statistical analyses will be published alongside the articles from the study. Anonymous data from the study may be made available upon reasonable request.

The Trial Steering Committee (TSC) will ensure the rights, safety, and wellbeing of the trial participants. They will make recommendations about how the study is operating, any ethical or safety issues, and any data being produced from other relevant studies that might impact the trial. Composition and roles and responsibilities of the TSC are detailed in the TSC charter. The TSC advises the Trial Management Group (TMG) about the conduct of the study and stopping randomization to study arms (based on recommendations received from the DSMB and/or relevant information external to the trial). If national recommendations in standard of care change during the study period, the TSC will make recommendations to the TMG regarding potential new risks or benefits. The Statistical Analysis Committee (SAC) will perform interim analyses and report these to the DSMB. The TMG will remain blind to these interim analyses until a recommendation is received from the TSC about stopping randomization or safety concerns. TMG will be responsible for the day-to-day running of the trial, including monitoring all aspects of the trial and ensuring that the protocol is being adhered to. It will include co-investigators and will meet weekly in the first instance. Composition, roles, and responsibilities of the TMG are detailed in the TMG charter. A core project team (PT) from within the TMG will meet weekly or as required for operational decision-making.

The DSMB will review the data received from the SAC at each interim analysis, as described in the statistical analysis section, in order to ensure that the process is working correctly and to review and monitor the accruing data to ensure the rights, safety, and wellbeing of the trial participants. The composition, roles, and responsibilities of the DSMB are detailed in the DSMB charter. The DSMB reviews data from interim analyses and makes recommendations to the TSC if safety concerns have emerged.

The following summarizes the handling of potential adverse events (AE). The detailed plan can be found in the study protocol.

The first monitoring at each site will be scheduled after the inclusion of the first 10 study subjects. The sites will be monitored on-site every other month in the first half of the year and then yearly according to the number of trial subjects included in the study. Additional monitoring will be done if requested by the DSMB. If needed or in case of concerns, monitoring of patients at St. Olav Hospital may occur. The monitoring plan will be updated if applicable. At the monitor visit, source data verification (SDV) will be performed for the following data.

Any substantial amendments to the protocol will be submitted to the relevant medical research ethical committee.

Findings on the primary outcome will be published as soon as possible after the completion of the study in a high-rank peer-reviewed journal with open access. Publications on secondary outcomes will be published in due time.

The study protocol is version 2.3, dated 23rd March 2023. The first patient was recruited on the 12th of May 2023. The study is ongoing, and recruitment is estimated to be complete in December 2025.