Treatment of patients with Hemophilia A who have developed inhibitory antibodies to clotting Factor VIII and have failed Immune Tolerance Induction MedDRA version: 20.0 Level: LLT Classification code 10053751 Term: Hemophilia A with anti factor VIII System Organ Class: 100000004850
Conditions
Interventions
Product Name: ItolDC-028
Product Code: ItolDC-028
Pharmaceutical Form: Suspension for injection
Current Sponsor code: ItolDC-028
Other descriptive name: autologous tolerogenic dendritic cells loaded w
Sponsors
Idogen AB
Eligibility
Sex/Gender
Male
Inclusion criteria
Inclusion criteria: 1. Men, 18-60 years of age, diagnosed with congenital severe Hemophilia A (defined as 5, BU>1 at inclusion, confirmed loss of effect of FVIII and by the investigator judged not being able to be treated with FVIII to stop a bleed. 3.Confirmed failure with conventional immune tolerance induction (ITI) protocols (i.e. regular, longtime, daily/several times weekly administration of FVIII at high or low dose with or without concomitant immunosuppression) such as the Malmö protocol (Freiburghaus 1999), the high-dose Bonn-protocol (Brackmann 1996) or the low-dose Dutch protocol (Mauser-Bunschoten 1995, Ter Avest 2010). a) Definition of ITI failure: Inhibitor titer decline less than 20% over any 6-month period after the first 3 months of ITI or failure to achieve success or partial response after 33 months of ITI (DiMichele 2007). The subject should have failed at least 1 ITI. 4. By the investigator been judged not eligible for, or not possible to treat, with conventional immune tolerance induction (ITI) protocols (i.e. not available at site; patient fulfilling established “bad risk criteria” for ITI (Osooli & Berntorp, 2015) and thus assessed as not suitable for ITI; other non-immunological contraindications to ITI such as problematic venous access and/or not willing to undergo the burden of frequent injections) 5. Peripheral venous access suitable for leukapheresis. 6. Appropriate contraceptive measures for preventing pregnancy to occur during the trial in the subjects’ spouses (as per Clinical Trial facilitation Group [CTFG] guidance, 2014.) (Clinical Trial Facilitation Group (CTFG) 2014). 7. Written informed consent is obtained. The subject signing the research consent form is, in the investigator's judgement, deemed to have adequate decision-making capacity to do so. 8. Investigator’s judgement that the subject has the physical and mental capacity to participate and complete the trial. 9. Vaccinated against Covid-19. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 9 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Treatment with Feiba throughout the trial. (Since Feiba contains small amount of FVIII, it will challenge the subject and interfere with the design of the trial, which includes a FVIII challenge with 50 IU/Kg Kovaltry, octocog alfa at Week 20.) However, if a serious bleed not responding to treatment with NovoSeven occurs, Feiba may be considered. 2. Treatment with other experimental treatment within 6 months prior to trial start. 3. Active infection requiring antibiotics or anti-viral treatment at screening. 4. Laboratory test results that deviate more than ±3 standard deviations (SD) from the local site laboratory's normal reference range at screening 5. History of clinically significant allergy (anaphylactic shock or anaphylactoid symptoms). 6. Previous or concomitant autoimmunity. 7. Previous or concomitant malignancy. 8. All immunocompromised subjects as determined by the investigator including subjects on systemic immunosuppressant drugs within 12 weeks of enrolment, or planned use during the trial period. 9. Any other disease, metabolic dysfunction, physical examination or laboratory finding giving reasonable suspicion that it may impact the safety or efficacy evaluation or render the subject at risk. The absence of such concomitant disease is ensured by a thorough history and physical examination prior to inclusion. If necessary, relevant medical records are requested. 10. Systemic inflammation. 11. Planned surgery including tooth extraction during the trial period. 12. Vaccination within 4 weeks prior to enrollment or planning to be vaccinated during the trial period. 13. Contraindications for undergoing leukapheresis: • Abnormal vital parameters, abnormal blood pressure or pulse • Fever • Infectious laboratory parameters (human immunodeficiency virus [HIV] and syphilis). Regarding hepatitis, patients with antibodies against HBs or HBc can be accepted if they are HBsAg negative, and patients with antibodies against HCV (Hepatitis C-Virus) can be accepted if they are HCV RNA negative. Regarding HIV, patients treated with anti-viral treatment with a PCR level of 200 cells/µL (validated cell count method) can be accepted. • Angiotensin-Converting Enzyme (ACE) inhibitor
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective is to evaluate the safety and tolerability of ItolDC-028 administered in subjects with Hemophilia A having neutralizing antibodies towards FVIII and having failed ITI;Secondary Objective: The secondary objective is to evaluate preliminary therapeutic efficacy of 3 therapeutic dose levels of ItolDC-028 through immune response evaluation, titer of Bethesda units (BU) and FVIII recovery and FVIII half-life as response to a FVIII challenge (Kovaltry®, octocog alfa);Primary end point(s): Primary safety endpoint: Number of adverse events (AEs)/serious AEs (SAEs) from the first administration of ItolDC-028 to the end of trial visit at Week 26 ;Timepoint(s) of evaluation of this end point: End of trial, visit at week 26 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary safety endpoints: - Changes in clinical safety assessments (coagulation, hematology, chemistry) - Changes in inhibitor titer of Bethesda units (BU) - Changes in urinalysis including glucose, protein and blood measurements - Changes in vital sign recordings - Changes in physical examination findings - Changes in ECG (electrocardiogram) recordings - Changes in chest X-ray recordings Secondary efficacy endpoints: - Proportion of subjects with no increase of inhibitor titer in BU 6 weeks after a FVIII challenge - Proportion of subjects having FVIII inhibitors <0.6 BU 6 weeks after a FVIII challenge - Proportion of subjects with eradication of inhibitors defined as a FVIII recovery of at least 66% of expected values in non-inhibitor subjects after an FVIII challenge. - Proportion of subjects with eradication of inhibitors defined as a FVIII half-life of at least 66% of expected values in non-inhibitor subjects after an FVIII challenge. - Changes in neutralizing antibodies (measured in functional assay as BU) between pre-treatment and the end of trial visit at Week 26 - Changes in immunophenotyping measurements (regulatory T cells [Tregs]), regulatory B cells [Bregs]) and effector T cells [Teffs]) between pre-treatment and the end of trial visit at Week 26 - Number of bleeding episodes from administration of ItolDC-028 to the end of trial visit at Week 26 - Changes in quality of life (evaluated by Haem-A-QoL total score) from before administration of ItolDC-028 to the end of trial visit at Week 26 ;Timepoint(s) of evaluation of this end point: Secondary safety endpoints: - End of trial, visit at week 26 Secondary efficacy endpoints: - 6 weeks after FVIII challenge - End of trial, visit at week 26 | — |
Countries
Norway, Sweden
Contacts
Public ContactChief Medical Officer
Idogen
Outcome results
None listed