Bioavailability and Pharmacokinetics of Calcium Dobesilate (Doxium®) in the Nasal Mucosal Tissue, Saliva and Blood of Treated Patients (CaDoBio)

CaDoBio (Calcium Dobesilate Bioavailability): a Bioavailability and Pharmacokinetics Research Project to Measure the Concentrations of Calcium Dobesilate (Doxium®) in the Nasal Mucosal Tissue, Saliva and Blood of Treated Patients

Calcium dobesilate (CaD) has been shown to have potential antiviral effects, mediated via its interaction with the heparansulfate (HS) binding site of the viral SARS-CoV-2 spike protein (direct action), necessary for interation with the ACE-2 receptor on human cells. Preliminary pre-clinical results using viral pseudotyped particles demonstrated that CaD reduces the uptake of SARS-CoV-2 spike protein in cultured endothelial cells by more than 50%.

Moreover, CaD is a well-established vasoactive and angioprotective drug improving endothelial dysfunction with a good tolerability profile. CaD strengthens vessels integrity and improves blood flow by acting on multiple parameters, like cytokines levels and signaling by FGF and VEGF. All these parameters may be dysregulated at some stage of Covid-19 pathological evolution, and acting on these could potentially reduce the progression toward severe disease. Based on these data, we hypothesize that CaD could be used as an early treatment for SARS-CoV-2 positive outpatients.

However, bioavailability data and pharmacokinetics of CaD are not well known, outside of old data on animal models. Being able to show that the drug is present in nasal mucosae and saliva, where the virus is likely to start the infection of the host, would be a first step before studying a possible effect on the disease course on infected patients.

Therefore this project plans to include between 6 and 10 patients, treated with CaD, for whom different nasal, saliva and blood sample will be taken at different timepoints before and after the daily dose of the treatment. Samples will be then analysed to detect and quantify the presence of CaD.

Study Overview

• Status: Active, not recruiting
• Conditions: Biological Availability
• Intervention / Treatment: Drug: Calcium Dobesilate

• Study Type: Observational
• Enrollment (Actual): 14

Contacts and Locations

Study Locations

• Switzerland
  • Geneva, Switzerland, 1205
    • HUG

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients already on CaD treatment according to the approved indication of treatment, or patients meeting conditions for CaD treatment

Description

Inclusion Criteria:

1. Patients treated with calcium dobesilate (1000-2000mg/day), at any time on treatment or for whom initiation of treatment has been prescribed, for one of its Swiss indications:

   • Microangiopathies, in particular diabetic retinopathy.
   • Clinical symptoms of chronic venous insufficiency of the legs (pains, cramps, paraesthesia, oedemas, stasis dermatitis), superficial thrombophlebitis in adjuvant treatment.
   • Haemorrhoidal syndrome, post-thrombotic syndrome, microcirculatory disorders of arteriovenous origin.
2. Male or female
3. Aged ≥18 years
4. Subject has provided the appropriate written informed consent. Subject must provide written informed consent before any study-specific procedures are performed

Exclusion Criteria:

1. Known sensitivity to calcium dobesilate
2. Currently suffering from or treated for a nasal condition, e.g., a runny, congested nose, nasal infection, or an oral condition, e.g., oral infection, including suspected SARS-CoV-2 infection
3. Currently treated with a nasal or an oral product, or any treatment with the same active substance as in CaD (e.g., doxiproct, dicynone)
4. Current participation in any other investigational drug study
5. Only for patients already on CaD treatment: treatment with CaD initiated within last 7 days only
6. Only for patients starting CaD treatment: treatment with CaD within last 30 days

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Ongoing; Patients already on calcium dobesilate treatment	Drug: Calcium Dobesilate; Dosage of calcium dobesilate in different tissues; Other Names: Biological samples
New; Patients with approved indication for calcium dobesilate treatment but not already on treatment	Drug: Calcium Dobesilate; Dosage of calcium dobesilate in different tissues; Other Names: Biological samples

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CaD presence and concentration in nasal mucosa	Nasal mucosa tissue of calcium dobesilate for patients on treatment as assessed by tandem mass spectrometry in ug/ml	Day 0
CaD presence and concentration in saliva	Saliva concentrations of calcium dobesilate for patients on treatment as assessed by tandem mass spectrometry in ug/ml	Day 0

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmakokinetic of CaD in plasma for patients on treatment	Calcium dobesilate plasma concentrations in ug/ml for patients on treatment	Day 0 - before the morning dose
Pharmakokinetic of CaD in plasma for patients on treatment	Calcium dobesilate plasma concentrations in ug/ml for patients on treatment	Day 0 - 4 hours after the morning dose
Pharmakokinetic of CaD in plasma for patients on treatment	Calcium dobesilate plasma concentrations in ug/ml for patients on treatment	Day 0 - 8 hours after the morning dose
Pharmakokinetic of CaD in plasma for patients starting treatment	Calcium dobesilate plasma concentrations in ug/ml for patients starting treatment	Day 0 - before the morning dose
Pharmakokinetic of CaD in plasma for patients starting treatment	Calcium dobesilate plasma concentrations in ug/ml for patients starting treatment	Day 0- 4 hours after the morning dose
Pharmakokinetic of CaD in plasma for patients starting treatment	Calcium dobesilate plasma concentrations in ug/ml for patients starting treatment	Day 0 - 8 hours after the morning dose
Pharmakokinetic of CaD in plasma for patients starting treatment	Calcium dobesilate plasma concentrations in ug/ml for patients starting treatment	Day 1 - before the morning dose
Pharmakokinetic of CaD in plasma for patients starting treatment	Calcium dobesilate plasma concentrations in ug/ml for patients starting treatment	Day 1 - 4 hours after the morning dose
Pharmakokinetic of CaD in plasma for patients starting treatment	Calcium dobesilate plasma concentrations in ug/ml for patients starting treatment	Day 1- 8 hours after the morning dose
Pharmakokinetic of CaD in plasma for patients starting treatment	Calcium dobesilate plasma concentrations in ug/ml for patients starting treatment	Day 3- before the morning dose
Pharmakokinetic of CaD in plasma for patients starting treatment	Calcium dobesilate plasma concentrations in ug/ml for patients starting treatment	Day 3 - 4 hours after the morning dose
Pharmakokinetic of CaD in plasma for patients starting treatment	Calcium dobesilate plasma concentrations in ug/ml for patients starting treatment	Day 3- 8 hours after the morning dose
Pharmakokinetic of CaD in plasma for patients starting treatment	Calcium dobesilate plasma concentrations in ug/ml for patients starting treatment	Day 7- before the morning dose
Pharmakokinetic of CaD in plasma for patients starting treatment	Calcium dobesilate plasma concentrations in ug/ml for patients starting treatment	Day 7 - 4 hours after the morning dose
Pharmakokinetic of CaD in plasma for patients starting treatment	Calcium dobesilate plasma concentrations in ug/ml for patients starting treatment	Day 7- 8 hours after the morning dose
Correlation between nasal mucosal tissue and plasma concentration for patients on treatment	Ratio in %	Day 0
Correlation between oral tissue and plasma concentration for patients on treatment	Ratio in %	Day 0

Collaborators and Investigators

• Sponsor: University Hospital, Geneva

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2021
• Primary Completion (Actual): May 26, 2021
• Study Completion (Anticipated): August 1, 2021

Study Registration Dates

• First Submitted: June 3, 2021
• First Submitted That Met QC Criteria: June 10, 2021
• First Posted (Actual): June 11, 2021

Study Record Updates

• Last Update Posted (Actual): June 11, 2021
• Last Update Submitted That Met QC Criteria: June 10, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Biological Availability; Calcium dobesilate
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Calcium-Regulating Hormones and Agents; Hemostatics; Coagulants; Calcium; Calcium Dobesilate
• Other Study ID Numbers: 2020-03050

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: Pharmacokinetic data Individual concentrations

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No