Study of Safety, Efficacy, Tolerability, Pharmacokinetics and Pharmacodynamics of LNP023 in in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)

June 10, 2024 updated by: Novartis Pharmaceuticals

An Open Label, Single Arm, Multiple Dose Study to Assess Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of LNP023 When Administered in Addition to Standard of Care (SoC) in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) With Signs of Active Hemolysis

This was a Phase 2, open label, single arm, multiple dose study to assess efficacy, safety, pharmacokinetics and pharmacodynamics of iptacopan when administered in addition to Standard of care (SoC) in patients with paroxysmal nocturnal hemoglobinuria (PNH) with signs of active hemolysis.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

LNP023 is a novel oral small molecular weight compound that inhibits factor B (FB) of the alternative pathway (AP). Blockade of the AP with oral LNP023 has the potential to prevent both intra - and extravascular hemolysis.

This two-cohort study consisted of a screening period of up to 68 days, a baseline visit, and Treatment periods Part 1 and Part 2. The planned duration of Treatment Part 1 was 13 weeks; the planned duration of Treatment Part 2 (treatment extension for patients who benefit from LNP023 treatment in Part 1 of the study based on reduced hemolytic parameters) was between approximately 2 to 3 years.

Cohort 1: Orally administered iptacopan 200 mg b.i.d. in Part 1 and Part 2 in addition to SoC.

Cohort 2: Orally administered iptacopan 50 mg b.i.d. for a minimum of 2 weeks in addition to SoC; this could be increased to iptacopan 200 mg b.i.d. at study day 15 or at any time later in the study if LDH was not within limit of normal or reduced by at least 60% as compared to baseline values.

End of Study (EoS) visit happened 2 weeks after last LNP023 administration for patients not joining the roll over extension program (REP).

A safety follow-up call was conducted 30 days after last administration of study treatment (applicable only for patients not joining the REP).

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
16

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Paris Cedex 10, France, 75475
        • Novartis Investigative Site
  • Germany
      • Essen, Germany, 45147
        • Novartis Investigative Site
  • Italy
      • Napoli, Italy, 80131
        • Novartis Investigative Site

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Male and female patients between the age of 18-80 (inclusive) at Baseline with a diagnosis of PNH based on documented clone size of ≥10% by RBCs and/or granulocytes, measured by glycosylphosphatidylinositol (GPI)-deficiency on flow cytometry (screening or medical history data acceptable).
  2. For Cohort 1 only: LDH values ≥1.5 × Upper limit of normal (ULN) range for at least 3 pre-SoC dosing measurements taken in relation to 3 different SoC dosing dates over a maximum of 10 weeks prior to Day 1 (Screening, Baseline, or medical history data acceptable). All other Screening pre-SoC LDH values must be >1 × ULN range (for pre-SoC samples collected at the same day as SoC administration).
  3. For Cohort 2 only: LDH values ≥1.25 × ULN range for at least 3 pre-SoC dosing measurements taken in relation to 3 different SoC dosing dates over a maximum of 10 weeks prior to Day 1 (Screening, Baseline, or medical history data acceptable). All other Screening pre-SoC LDH values must be >1 × ULN range (for pre-SoC samples collected at the same day as SoC administration).
  4. For Cohort 2 only: Hemoglobin level <10.5 g/dL at Baseline.
  5. PNH patients on stable regimen of SoC complement blockade (monoclonal antibody with anti C5 activity) for at least 3 months prior to first treatment with iptacopan.
  6. Previous vaccination against N. meningitidis types A, C, Y and W-135 is required at least 4 weeks prior to first dosing with iptacopan. Vaccination against N. meningitidis type B should be conducted if available and acceptable by local regulations, at least 4 weeks prior to first dosing with iptacopan. If iptacopan treatment must start earlier than 4 weeks post vaccination, prophylactic antibiotic treatment must be initiated.
  7. Previous vaccination for the prevention of S. pneumoniae and H. influenzae at least 4 weeks prior to first dosing with iptacopan. If iptacopan treatment must start earlier than 4 weeks post vaccination, prophylactic antibiotic treatment must be initiated.

Exclusion Criteria:

  1. Known or suspected hereditary complement deficiency at Screening.
  2. History of hematopoietic stem cell transplantation as verified both at Screening and at Baseline (unless baseline was skipped).
  3. Patients with laboratory evidence of bone marrow failure.
  4. A positive Human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C test result at Screening.
  5. Presence or suspicion (based on judgment of the Investigator) of active infection within 2 weeks prior to first dose of iptacopan, or history of severe recurrent bacterial infections.
  6. History of recurrent meningitis, history of meningococcal infections despite vaccination as verified both at Screening and at Baseline (unless Baseline was skipped).
  7. Patients on immunosuppressive agents such as (but not limited to) cyclosporine, mycophenolate mofetil, tacrolimus, cyclophosphamide, methotrexate less than 8 weeks prior to first treatment with iptacopan unless on a stable regimen for at least 3 months prior to first iptacopan dose.
  8. Systemic corticosteroids administered at the dose of ≥10 mg per day prednisone equivalent within less than 4 weeks prior to first treatment with iptacopan.
  9. Severe concurrent co-morbidities; e.g., patients with severe kidney disease (dialysis), advanced cardiac disease (New York Heart disease Association (NYHA) class IV), severe pulmonary arterial hypertension (World Health Organization (WHO) class IV), unstable thrombotic event not amenable to active treatment as judged by the Investigator both at Screening and at Baseline (unless Baseline was skipped).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Cohort 1: LNP023 200mg bid + SoC
Orally administered iptacopan 200 mg b.i.d. in Part 1 and Part 2
Drug: iptacopan
iptacopan bid orally administered
Other Names:
  • LNP023
Combination product: Standard of Care
Standard of Care (SoC) is defined as an antibody with anti C5 activity. At the time of study start, eculizumab was the only available SoC; eculizumab will be hereafter referred to as SoC.
Experimental: Cohort 2: LNP023 50mg/200mg bid + SoC
Orally administered iptacopan 50 mg b.i.d. for a minimum of 2 weeks in addition to SoC; this could be increased to iptacopan 200 mg b.i.d. at study day 15 or at any time later in the study if LDH was not within limit of normal or reduced by at least 60% as compared to baseline values.
Drug: iptacopan
iptacopan bid orally administered
Other Names:
  • LNP023
Combination product: Standard of Care
Standard of Care (SoC) is defined as an antibody with anti C5 activity. At the time of study start, eculizumab was the only available SoC; eculizumab will be hereafter referred to as SoC.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Percent Change From Baseline in Lactate Dehydrogenase (LDH) Level at Day 92
Time Frame: Baseline and Day 92

Serum LDH was used as an intravascular hemolysis marker to assess the effect of iptacopan on the reduction of chronic hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) patients when administered in addition to SoC (monoclonal antibody with anti C5 activity)

Baseline is defined as the mean of the last 3 measurements prior to dose administration.
Baseline and Day 92

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Absolute Change From Baseline in Lactate Dehydrogenase (LDH) Level
Time Frame: Baseline, day 8, 15, 29, 57 and 92

Serum LDH was used as an intravascular hemolysis marker to assess the effect of iptacopan on the reduction of chronic hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) patients when administered in addition to SoC (monoclonal antibody with anti C5 activity)

Baseline is defined as the mean of the last 3 measurements prior to dose administration.
Baseline, day 8, 15, 29, 57 and 92
Absolute Change From Baseline in Hemoglobin
Time Frame: Baseline; day 1, 2, 8, 15, 22, 29, 36, 43, 57, 71, 85, 92, 113, 127, 141, 155, 169, 197, 225, 253, 281, 309, 337, 393, 449, 505, 561, 617, 673, 729, 785, 841, 897, 953, 1009, 1065, 1121, 1177, 1233

Hemoglobin was used as a marker of intra and extravascular hemolysis when administered in addition to SoC (monoclonal antibody with anti C5 activity) to assess the effect of iptacopan.

Baseline is defined as the mean of all pre-dose measurements.
Baseline; day 1, 2, 8, 15, 22, 29, 36, 43, 57, 71, 85, 92, 113, 127, 141, 155, 169, 197, 225, 253, 281, 309, 337, 393, 449, 505, 561, 617, 673, 729, 785, 841, 897, 953, 1009, 1065, 1121, 1177, 1233
Absolute Change From Baseline in Free Hemoglobin
Time Frame: Baseline; day 1, 2, 8, 15, 22, 29, 36, 43, 57, 71, 85, 92, 113, 127, 141, 155, 169, 197, 225, 253, 281, 309, 337, 393, 449, 505, 561, 617, 673, 729, 785, 841, 897, 953, 1009, 1065, 1121, 1177, 1233

Free hemoglobin was used as a marker of intra and extravascular hemolysis when administered in addition to SoC (monoclonal antibody with anti C5 activity) to assess the effect of iptacopan.

Baseline is defined as the mean of all pre-dose measurements.
Baseline; day 1, 2, 8, 15, 22, 29, 36, 43, 57, 71, 85, 92, 113, 127, 141, 155, 169, 197, 225, 253, 281, 309, 337, 393, 449, 505, 561, 617, 673, 729, 785, 841, 897, 953, 1009, 1065, 1121, 1177, 1233
Absolute Change From Baseline in Reticulocytes Count
Time Frame: Baseline; day 1, 2, 8, 15, 22, 29, 36, 43, 57, 71, 85, 92, 113, 127, 141, 155, 169, 197, 225, 253, 281, 309, 337, 393, 449, 505, 561, 617, 673, 729, 785, 841, 897, 953, 1009, 1065, 1121, 1177, 1233

Reticulocytes count was used as a marker of intra and extravascular hemolysis when administered in addition to SoC (monoclonal antibody with anti C5 activity) to assess the effect of iptacopan.

Baseline is defined as the mean of all pre-dose measurements.
Baseline; day 1, 2, 8, 15, 22, 29, 36, 43, 57, 71, 85, 92, 113, 127, 141, 155, 169, 197, 225, 253, 281, 309, 337, 393, 449, 505, 561, 617, 673, 729, 785, 841, 897, 953, 1009, 1065, 1121, 1177, 1233
Absolute Change From Baseline in C3 Fragment Deposition on PNH RBC
Time Frame: Day 1 pre dose, day 8, 22, 29, 57, 92, 113, 141, 169, 253, 337, 505, 673, 785, 953, 1121, 1233

C3 fragment deposition on PNH Red blood cell (RBC) was used as a marker of intra and extravascular hemolysis when administered in addition to SoC (monoclonal antibody with anti C5 activity) to assess the effect of iptacopan.

Baseline is defined as Day 1 pre-dose measurement.
Day 1 pre dose, day 8, 22, 29, 57, 92, 113, 141, 169, 253, 337, 505, 673, 785, 953, 1121, 1233
Mean PNH Clone Size
Time Frame: Day 1 pre dose, day 8, 22, 29, 57, 92, 113, 141, 169, 253, 337, 505, 673, 785, 953, 1121, 1233

Mean PNH clone size on Red Blood Cells (RBC) was used as a marker of intra and extravascular hemolysis when administered in addition to SoC (monoclonal antibody with anti C5 activity) to assess the effect of iptacopan.

Baseline is defined as the mean of all pre-dose measurements.
Day 1 pre dose, day 8, 22, 29, 57, 92, 113, 141, 169, 253, 337, 505, 673, 785, 953, 1121, 1233
Mean Haptoglobin Levels
Time Frame: Day 2, 8, 15, 22, 29, 36, 43, 57, 71, 85, 92, 113, 127, 141, 155, 169, 197, 225, 253, 281, 309, 337, 393, 449, 505, 561, 617, 673, 729, 785, 841, 897, 953, 1009, 1065, 1121, 1177, 1233

Haptoglobin level was used as a marker of intra and extravascular hemolysis when administered in addition to SoC (monoclonal antibody with anti C5 activity) to assess the effect of iptacopan.

Baseline is defined as the mean of all pre-dose measurements.
Day 2, 8, 15, 22, 29, 36, 43, 57, 71, 85, 92, 113, 127, 141, 155, 169, 197, 225, 253, 281, 309, 337, 393, 449, 505, 561, 617, 673, 729, 785, 841, 897, 953, 1009, 1065, 1121, 1177, 1233
Absolute Change From Baseline in Total Bilirubin
Time Frame: Baseline; day 1, 2, 8, 15, 22, 29, 36, 43, 57, 71, 85, 92, 113, 127, 141, 155, 169, 197, 225, 253, 281, 309, 337, 393, 449, 505, 561, 617, 673, 729, 785, 841, 897, 953, 1009, 1065, 1121, 1177, 1233

Bilirubin was used as a marker of intra and extravascular hemolysis when administered in addition to SoC (monoclonal antibody with anti C5 activity) to assess the effect of iptacopan.

Baseline is defined as the mean of all pre-dose measurements.
Baseline; day 1, 2, 8, 15, 22, 29, 36, 43, 57, 71, 85, 92, 113, 127, 141, 155, 169, 197, 225, 253, 281, 309, 337, 393, 449, 505, 561, 617, 673, 729, 785, 841, 897, 953, 1009, 1065, 1121, 1177, 1233
Number of Participants With on Study Transfusions From Packed RBC Units
Time Frame: Up to 46 months
Number of participants with on study transfusions from packed RBC units was collected.
Up to 46 months
Pharmacokinetics Profile: Maximum Plasma Concentration (Cmax)
Time Frame: Day 1, 29, 169, 337

Cmax is the maximum (peak) observed plasma drug concentration after single dose administration (mass x volume-1).

PK assessment parameters were determined using the actual recorded sampling times and non-compartmental methods.

In Cohort 2, patients were supposed to be orally administered iptacopan 50 mg b.i.d. in addition to SoC; this was increased to iptacopan 200 mg b.i.d. at study day 15 or at any time later in the study if LDH was not within limit of normal or reduced by at least 60% as compared to baseline values. One patient in Cohort 2 was orally administered iptacopan 25 mg at day 1 due to a dosing error.
Day 1, 29, 169, 337
Pharmacokinetics Profile: Area Under the Curve (AUC) Tau
Time Frame: day 1, 29, 169, 337

The AUCtau is the area under the plasma concentration-time curve calculated to the end of a dosing interval (tau) at steady-state.

PK assessment parameters were determined using the actual recorded sampling times and non-compartmental methods.

In Cohort 2, patients were supposed to be orally administered iptacopan 50 mg b.i.d. in addition to SoC; this was increased to iptacopan 200 mg b.i.d. at study day 15 or at any time later in the study if LDH was not within limit of normal or reduced by at least 60% as compared to baseline values. One patient in Cohort 2 was orally administered iptacopan 25 mg at day 1 due to a dosing error.
day 1, 29, 169, 337
Pharmacokinetics Profile: Time to Reach Maximum Plasma Concentration (Tmax)
Time Frame: Day 1, 29, 169, 337

Tmax is the time to reach maximum (peak) plasma drug concentration after single dose administration (time).

PK assessment parameters were determined using the actual recorded sampling times and non-compartmental methods.

In Cohort 2, patients were supposed to be orally administered iptacopan 50 mg b.i.d. in addition to SoC; this was increased to iptacopan 200 mg b.i.d. at study day 15 or at any time later in the study if LDH was not within limit of normal or reduced by at least 60% as compared to baseline values. One patient in Cohort 2 was orally administered iptacopan 25 mg at day 1 due to a dosing error.
Day 1, 29, 169, 337
Red Blood Cell Count: Mean Erythrocytes Levels
Time Frame: Screening, Baseline, Day 2,8,15,22,29,36,43,57,71,85,92,113,127,141,155,169,197,225,253,281,309,337,393,449,505,561,617,673,729,729,785,841,897,953,1009,1065,1121,1177,1233
Erythrocytes levels were used as a marker of intra and extravascular hemolysis when administered in addition to SoC (monoclonal antibody with anti C5 activity) to assess the effect of iptacopan.
Screening, Baseline, Day 2,8,15,22,29,36,43,57,71,85,92,113,127,141,155,169,197,225,253,281,309,337,393,449,505,561,617,673,729,729,785,841,897,953,1009,1065,1121,1177,1233

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Novartis Pharmaceuticals

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 9, 2018

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
April 22, 2020

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
February 28, 2022

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
February 14, 2018

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 14, 2018

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
February 20, 2018

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
June 12, 2024

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 10, 2024

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
June 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • CLNP023X2201
  • 2017-000888-33 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Paroxysmal Nocturnal Hemoglobinuria (PNH) With Signs of Active Hemolysis

Clinical Trials on iptacopan

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Cookie Settings

We use cookies to ensure that we give you the best experience on our website. For more details carefully read our Privacy and Cookies Policy. ...>>>You can change your preferences or withdraw your consent at any time by deleting the cookies from your website or computer as described in the policy. Please accept it and choose your preferences by ticking the corresponding boxes in the "Manage Settings" section below. Please carefully read our Terms of Service before you proceed with using any part of this website.
«Manage Settings