BASECOVID - Bevacizumab in post-acute sequelae of COVID-19 : Efficacy and Safety (Pilot Study)

The primary objective is to assess the efficacy of bevacizumab injection in long COVID patients with impaired diffusing capacity of the lungs for carbon monoxide (DLCO) (less than 75% of predicted value) within 3 months after the first bevacizumab injection. The positive criterion is defined as a 10% increase in DLCO at three months after the introduction of bevacizumab. This objective addresses the persistent respiratory impairment observed in patients with post-acute sequelae of COVID-19, specifically targeting those with compromised pulmonary gas exchange capacity.

The secondary objectives include:

• Modification of clinical evaluation at 1, 2, 3 and 7 months, particularly the clinical symptoms of dyspnea and fatigue or other related clinical parameters in long COVID patients.

• Evaluation at month 3 and month 7 of psychological, cognitive and autonomic functions.

• Modification of other respiratory function markers including forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, total lung capacity (TLC), residual volume (RV), and 6 minute walking distance at 1, 2, 3 and 7 months after the initiation of bevacizumab treatment. Modification of DLCO will also be evaluated at 1 and 2 months.

• Decrease of circulating biomarkers of angiogenesis disorders or endotheliopathy at 1, 2, 3 and 7 months after the initiation of bevacizumab treatment.

• Safety of bevacizumab in long COVID patients during the 7 months of follow-up.

The sponsor did not provide information regarding the total number of participants for this clinical trial. The study population consists of adult patients aged 18 to 70 years of both genders who present with persistent **dyspnea** lasting more than 3 months following acute **COVID-19 infection**. Participants are characterized by **long COVID** with a modified Medical Research Council (mMRC) dyspnea scale score of 2 or higher at inclusion and impaired **diffusing capacity of the lungs for carbon monoxide (DLCO)** of less than 75% of the predicted value. The trial population requires documented COVID-19 infection confirmed by polymerase chain reaction or computed tomography scan at least 3 months prior to enrollment. Participants must be affiliated with social security and demonstrate good understanding of the French language. The trial does not involve vulnerable populations.

This is a French academic monocentric pilot study, phase II trial evaluating the use of **bevacizumab** in adult patients with persistent **dyspnea** more than 3 months after acute **COVID-19** infection. The study aims to assess the efficacy of bevacizumab injection in long COVID patients with impaired **DLCO** (less than 75% of predicted value) within 3 months after the first bevacizumab injection. The positive criteria will be a 10% increase in DLCO at three months after the introduction of bevacizumab. The trial is designed to evaluate both the efficacy and safety of bevacizumab in patients with persistent respiratory disorders following COVID-19 infection.

The primary endpoint is defined as the rate of patients with 10% increase of impaired DLCO within the 3 months after the introduction of bevacizumab. Secondary endpoints include the description of clinical symptoms at 1, 2, 3 and 7 months after the initiation of bevacizumab treatment, particularly **mMRC Scale**, Borg Scale, STOP-BANG Questionnaire, WHODAS 2.0, and Epworth Sleepiness Scale, which assess fatigue severity in long-COVID patients. Additional assessments will be conducted to evaluate psychological, cognitive, and autonomic functions at 3 and 7 months using the Nijmegen Questionnaire, the Hospital Anxiety and Depression Scale, the Montreal Cognitive Assessment, the self-reported Ricci-Gagnon Physical Activity Questionnaire, and the Somatic Symptom Disorder Scale-12. Other parameters explored by **Pulmonary Function Test** will be evaluated at 1, 2, 3 and 7 months, including **FEV1**, **FVC**, FEV1/FVC ratio, **TLC**, **RV** and 6 minute walking distance. The study will also measure circulating angiogenic biomarkers levels and monitor the number of side effects related to bevacizumab and the proportion of patients with hospitalization or medical consultation during the 7 months after the start of the treatment.

Bevacizumab will be administered via **intravenous use** as a concentrate for solution for infusion. The maximum daily dose amount is 1300 mg and the maximum total dose amount is 6500 mg. The maximum treatment period is 2 months. Principal inclusion criteria include patients over 18 years and 70 years or younger, social security affiliation, good understanding of the French language, written informed consent, documented COVID-19 infection more than 3 months before inclusion, long COVID suspicion with dyspnea (mMRC≥2 at inclusion), and DLCO less than 75% of predicted value less than 3 months old on the day of screening or to be obtained before Day 1 if older than 3 months.

The estimated recruitment start date is September 15, 2025, and the estimated end date is April 15, 2028. Participants will undergo screening to confirm eligibility, followed by baseline assessments before the initiation of bevacizumab treatment. Study visits will be conducted at 1, 2, 3 and 7 months after treatment initiation to evaluate clinical symptoms, pulmonary function parameters, psychological and cognitive functions, and biomarker levels. The end-of-study visit will occur at 7 months after the start of treatment. The expected length of participant involvement is approximately 7 months from the initiation of bevacizumab treatment. The study protocol includes monitoring for adverse events and safety assessments throughout the trial duration.

The experimental medication investigated in this clinical trial is **bevacizumab**, administered as a **concentrate for solution for infusion**. Bevacizumab is delivered via **intravenous use**. The maximum daily dose is 1300 mg, with a maximum total dose of 6500 mg administered over the course of treatment. The maximum treatment period is 2 months. This investigational product serves as the test medication in the study evaluating its efficacy and safety in patients experiencing **post-acute sequelae of COVID-19**, specifically those presenting with impaired **diffusing capacity of the lungs for carbon monoxide** (DLCO) below 75% of the predicted value.

Participant compliance monitoring will be conducted throughout the study period to ensure adherence to the prescribed dosing schedule and administration protocol. The primary efficacy endpoint is assessed at three months following the first bevacizumab injection, measuring changes in DLCO values.

Efficacy will be assessed using the rate of patients achieving a 10% increase in impaired **DLCO** (diffusing capacity of the lungs for carbon monoxide) within 3 months after the introduction of **bevacizumab** as the primary endpoint. The positive criterion is defined as a 10% increase in DLCO at three months following treatment initiation. DLCO measurements must be less than 3 months old at screening or obtained before Day 1 if older than 3 months, with baseline values required to be less than 75% of the predicted value.

Secondary efficacy assessments include clinical symptom evaluation at 1, 2, 3, and 7 months after bevacizumab initiation using validated instruments such as the **mMRC Scale**, **Borg Scale**, **STOP-BANG Questionnaire**, **WHODAS 2.0**, and **Epworth Sleepiness Scale** to assess fatigue severity in long-COVID patients. Psychological, cognitive, and autonomic functions will be evaluated at 3 and 7 months using the **Nijmegen Questionnaire**, **Hospital Anxiety and Depression Scale**, **Montreal Cognitive Assessment**, **Ricci-Gagnon Physical Activity Questionnaire**, and **Somatic Symptom Disorder Scale-12 (SSD-12)**. Pulmonary function parameters other than DLCO, including **FEV1**, **FVC**, **FEV1/FVC ratio**, **TLC**, **RV**, and **6-minute walking distance**, will be assessed at 1, 2, 3, and 7 months, with differences from baseline calculated at each timepoint. Additionally, DLCO differences from baseline will be evaluated at 1 and 2 months. Circulating **angiogenic biomarker** levels will be measured at baseline and at 1, 2, 3, and 7 months after treatment initiation to assess changes over time.