Participating sites
A total of twenty-three hospitals across all four Regional Health Authorities in Norway took part in the NOR-Solidarity trial, showcasing a national effort to address the challenges posed by the COVID-19 pandemic.
Inclusion criteria
The primary inclusion criteria mandated that participants be adult patients aged 18 and older, who had a confirmed diagnosis of SARS-CoV-2 infection via PCR testing. Eligible patients were those admitted to either a hospital ward or an intensive care unit (ICU). Prior to their participation in the study, patients or their legally authorized representatives were required to provide informed consent. Furthermore, patients must not have anticipated a transfer to a non-study hospital within 72 hours from the time of enrollment.
Exclusion criteria
The exclusion criteria were comprehensive, focusing primarily on patients with severe co-morbidities that could significantly impact their life expectancy, particularly those with conditions five times the upper limit of normal. Additional exclusion factors included experiencing acute medical issues such as myocardial infarction in the week preceding enrollment, known intolerance to the study medications, as well as pregnancy or breastfeeding. Other reasons cited by investigators that could disqualify a patient included participation in any other confounding clinical trials, a prolonged QT interval exceeding 470 ms, and prior receipt of any investigational drugs. Moreover, patients already taking any prohibited medications—including haloperidol, carbamazepine, and phenobarbital—were also excluded from the study.
Informed consent
During this study involving seriously ill COVID-19 patients, there were protocols for obtaining informed consent from the patients or their legally authorized representatives. Comprehensive efforts were taken to ensure that direct consent was secured from patients themselves, although in cases where a patient was incapacitated, their representative—designated by the hospital—was permitted to provide consent on their behalf. Furthermore, patients were given the opportunity to affirm their consent as soon as they were able to do so during their recovery process. The research adhered strictly to the ethical principles delineated in the Declaration of Helsinki.
Procedures
In the initial phase of the trial, participants were randomly allocated to either the standard care regimen of their local hospital or to the standard care enhanced with remdesivir or hydroxychloroquine (HCQ). As facts emerged suggesting hydroxychloroquine’s ineffectiveness against COVID-19, recommendations by the World Health Organization shifted the focus, with patients subsequently randomized only to either standard care or to standard care combined with remdesivir. The study took an approach that combined patients assigned to standard care or those additionally receiving hydroxychloroquine into a single control cohort, referred to as SoC ± HCQ. For further information on NOR-Solidarity’s procedures, protocol, and analysis plan, see the primary publication and consult the supplementary information for more detailed intervention data.
Outcomes
The initial study aimed to determine whether patients receiving standard care in conjunction with remdesivir experienced any medical advantages over a control group receiving only standard care. However, it was concluded that remdesivir-treated patients did not exhibit any benefits compared to their counterparts. Despite these findings, a further investigation was warranted to assess any potential long-term benefits of remdesivir treatment against the control group. Three primary endpoints were established, focusing on self-reported symptoms of (i) fatigue, (ii) shortness of breath, and (iii) coughing three months post-randomization, measured using the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT). These endpoints were specifically selected for their relevance to post-acute sequelae of SARS-CoV-2 infection (commonly referred to as long COVID), which has been reported to affect a significant proportion of patients.
The study further outlined secondary endpoints, including assessments of the three primary endpoints after a one-month period, along with the comprehensive CAT score across all questions taken at both one month and three months, the EQ-5D-5L index score after three months, and evaluations based on the RAND 36-item health survey after the same three-month interval.
Details regarding the primary and secondary endpoints, along with references to the methodology, can be located within the statistical analysis plan presented in the supplementary information.
Questionnaires
This study utilized three distinct questionnaires to gather outcome data reported by patients. First was the chronic obstructive pulmonary disease (COPD) Assessment Test (CAT), originally devised to assess quality of life in COPD patients; while not validated for COVID-19, it remains a robust tool for quantifying fatigue, breathlessness, and coughing symptoms on a scale ranging from 0 (no symptom) to 5 (symptom present at all times). This test comprises eight questions that yielded a cumulative score ranging from 0 to 40, administered at both one month and three months to track changes in respiratory symptoms over time.
The final survey implemented was the SF-36, a comprehensive 36-item assessment covering eight health-related dimensions, both physical and psychological. Patients were instructed to complete this survey independently, free from caregiver intervention, with assessments conducted at the three-month post-enrollment mark to capture relevant health data.
Statistics
In the primary analysis, there were no evaluations of the necessary sample size. Prior to any comparative analyses regarding the outcomes, a patient-reported outcome measure-specific statistical analysis plan was created and received approval. Regardless of these supplementary analyses, there were no adjustments made for multiple testing, and therefore all significant findings should be interpreted with caution. Efficacy comparisons of remdesivir were made against concurrent control groups randomized to either standard care alone or in combination with hydroxychloroquine.
All analyses were executed using randomly selected patients who had at least one observation recorded post-randomization. These analyses employed two-sample t-tests, presenting estimated differences between the groups alongside 95% confidence intervals. Missing data arising from patient mortality were treated by imputing the worst outcome, while other types of missing data were addressed with multiple imputation using chained equations (MICE). Certain variables, including age, sex, hospital duration, and baseline clinical progression, were included in the imputation model to provide conservative estimates absent any treatments. Sensitivity analyses also explored various scenarios, while subgroup analyses were conducted based on primary endpoints categorized by baseline indicators.
Ethical statement
The research conducted in the NOR-Solidarity trial garnered approval from the regional ethics committee and the Norwegian Medicines Agency, and is cataloged with clinicaltrials.gov and EudraCT. It was conducted under strict adherence to established ethical guidelines and regulations as outlined in the Declaration of Helsinki and ICH E6 (R2) Good Clinical Practice.
Reporting summary
**Interview with Dr. Elin Krogstad – Lead Researcher of the NOR-Solidarity Trial**
**Interviewer:** Thank you for joining us today, Dr. Krogstad. Can you start by explaining the significance of the NOR-Solidarity trial in the context of the COVID-19 pandemic?
**Dr. Krogstad:** Thank you for having me. The NOR-Solidarity trial represents a nationwide collaboration among 23 hospitals across all four Regional Health Authorities in Norway. It aimed to address the urgent challenges presented by COVID-19 by investigating the effectiveness of treatments like remdesivir and hydroxychloroquine in hospitalized patients.
**Interviewer:** What were the primary criteria for participant inclusion in the trial?
**Dr. Krogstad:** Participants had to be adults, 18 years or older, with a confirmed SARS-CoV-2 infection via PCR testing. They needed to be admitted to either a hospital ward or an ICU and had to provide informed consent before enrollment. Importantly, we required assurance that they wouldn’t be transferred to a non-study hospital within 72 hours of joining the trial.
**Interviewer:** You mentioned informed consent. Can you elaborate on how that process worked, especially considering that some patients were critically ill?
**Dr. Krogstad:** Certainly. Informed consent was a top priority. We ensured that consent was obtained directly from patients whenever possible. However, in cases where a patient was incapacitated, their legally authorized representative could provide consent. If a patient recovered and became able to give their consent later, they had the opportunity to do so.
**Interviewer:** There were strict exclusion criteria as well. Could you highlight some of the key factors that disqualified potential participants?
**Dr. Krogstad:** Yes, the exclusion criteria were indeed comprehensive. Patients with severe co-morbidities, recent acute medical issues, known drug intolerances, or who were pregnant or breastfeeding were excluded. Additionally, anyone involved in other conflicting clinical trials or those on prohibited medications could not participate.
**Interviewer:** How did the trial evolve during its course, particularly concerning the use of hydroxychloroquine?
**Dr. Krogstad:** Initially, participants were randomized to either a standard care regimen or standard care enhanced with hydroxychloroquine or remdesivir. However, due to emerging evidence about hydroxychloroquine’s ineffectiveness, the World Health Organization revised its recommendations. Consequently, we shifted our focus, randomizing participants solely to standard care or standard care plus remdesivir.
**Interviewer:** What were the study’s outcomes, especially regarding the effectiveness of remdesivir?
**Dr. Krogstad:** The initial findings indicated that patients treated with remdesivir did not show significant medical advantages compared to those receiving standard care alone. However, this prompted further analysis, particularly regarding long-term outcomes. We established primary endpoints focusing on symptoms like fatigue, shortness of breath, and coughing three months post-randomization.
**Interviewer:** Lastly, could you discuss the tools used to gather data on patient outcomes in this trial?
**Dr. Krogstad:** We employed several questionnaires, including the COPD Assessment Test (CAT) and the SF-36 health survey. These tools allowed us to quantify respiratory symptoms and assess overall health-related quality of life at both one-month and three-month intervals after enrollment.
**Interviewer:** Thank you, Dr. Krogstad, for your insights about the NOR-Solidarity trial. It’s fascinating to see how this research is contributing to our understanding of COVID-19 treatments.
**Dr. Krogstad:** Thank you! It’s essential work, and we remain committed to analyzing the data and hopefully improving outcomes for those affected by COVID-19.
