Open Sweden: imPROving Quality of LIFe In the Long COVID Patient (PROLIFIC) 2023 Brodin et al

mango

mango

Senior Member (Voting Rights)
imPROving Quality of LIFe In the Long COVID Patient (PROLIFIC)
https://clinicaltrials.gov/ct2/show/NCT05823896

Petter Brodin
Karolinska Institutet, Sweden

"Brief 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."

"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.

Patients meeting the WHO definition of severe PACS will be identified from a database of 988 patients cared for by the Karolinska University Hospital Post-COVID clinics since May 2020, and in whom extensive clinical and laboratory examinations have been performed. A total of 400 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)."
 
I literally started wincing when I saw that acronym, because the BPSers love stupid acronyms. We should quit using them altogether.

Aside from that, this study is promising to provide correct results due to its large size.
 
I'm very happy to see an anti-viral trial. But...

About ritonavir:
Ritonavir is a protease inhibitor used for the treatment of HIV/AIDS. It is seldom employed for its own antiviral activity but instead serves as a booster for other protease inhibitors. Although ritonavir was initially designed to inhibit HIV protease, studies have found that it also inhibits cytochrome P450-3A4. Because of its mechanism of action, ritonavir is currently under investigation for its use in treating some forms of cancer. In addition, it is used in combination with other medicines to treat Hepatitis C infection.
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Side effects:
Ritonavir has several constitutional side effects, including malaise, dizziness, and insomnia, gastrointestinal side effects including nausea, vomiting, abdominal pain, and diarrhea, and metabolic side effects such as hyperlipidemia, hypertriglyceridemia, transaminitis, and rhabdomyolysis.[2] Although there are reports of QT prolongation with the use of protease inhibitors, studies have not established them as independent culprits.[10]

Because of the metabolic side effects of ritonavir, lipid-lowering agents might also be indicated along with protease inhibitors to reduce cardiovascular disease risk. Other serious adverse effects are pancreatitis, diabetes mellitus, renal failure, hypersensitivity reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), hepatotoxicity, leukopenia, and neutropenia.[6]
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Therefore, the trial design seems odd. For one treatment you have something that might potentially be useful, and for the control you have something that probably won't be useful but has a significant risk of side effects (including vague 'malaise' and other symptoms that can be confused with the Long Covid symptoms). If things work as expected, that's going to exaggerate the benefits of Paxlovid. I would have thought, for an initial study, that there should be a control with placebo/placebo as well, or instead of, the placebo/ritonavir.
 
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