Clinical trial: Gene Therapy Trial for Platelet Derived Factor VIII Production in Hemophilia A (NCT03818763)

Eligibility criteria:
Inclusion Criteria:

          -  Study population will include: adult males ≥18 years of age with a diagnosis of severe
             hemophilia A and currently active high titer FVIII inhibitors (>5 BU). Females will be
             excluded because hemophilia A is an X-linked disorder that is extremely rare in
             females.

               1. Confirmed diagnosis of severe hemophilia A by undetectable plasma factor VIII:C
                  by a one-stage PTT-based assay and coatest chromogenic factor VIII assay. Only
                  subjects with the presence of a high titer factor VIII inhibitor (>5 BU) will be
                  included for enrollment.

               2. Subject may be prescribed prophylactic therapy with factor VIII bypassing agents
                  or factor VIII mimetics prior to referral for inclusion in the study.

               3. Subjects who are treated on demand using factor VIII bypassing agents must have a
                  history of four or more bleeding episodes requiring treatment in the six-month
                  period prior to referral for inclusion in the study.

               4. Adequate bone marrow reserve as demonstrated by ANC >1.5/cu.mm; Hemoglobin
                  >9g/dL; Platelets >100,000/microliter.

               5. Adequate renal function, defined as creatinine clearance>60 ml/min
                  (Cockroft-Gault formula)

               6. Adequate liver function, defined as defined as total bilirubin ≤1.5 times the
                  upper limit of normal (ULN) (excluding Gilbert's syndrome), both AST and ALT ≤3
                  times ULN at the time of screening, and no clinical signs or known
                  laboratory/radiographic evidence consistent with cirrhosis.

               7. Subject must sign an informed consent after explanation of the study and having
                  questions answered.

               8. Subject must be willing and able to document type of bleeding episodes and
                  treatment in a paper or electronic diary during the study.

               9. Subject must be willing to return for regular follow-up visits during the 15-year
                  study.

        Exclusion Criteria:

          -  A potential subject who meets any of the following exclusion criteria is ineligible to
             participate in the study.

               1. Therapy with factor VIII with the intent of immune tolerance induction within 30
                  days prior to inclusion within the study.

               2. Enrollment in another interventional clinical trial within 60 days prior to study
                  inclusion.

               3. Medical contraindication to PBSC cytokine mobilization, use of GCSF, PBSC
                  apheresis procedure or conditioning regimen.

               4. Medically significant organ dysfunction that would prevent compliance with
                  conditioning or would severely limit the probability of survival based on
                  clinical status.

               5. Those with a known co-existing clinically significant thrombophilic disorder, or
                  as determined by the presence of any of the below identified on screening
                  laboratory assessments:

                    -  FV Leiden

                    -  Protein S deficiency

                    -  Protein C deficiency

                    -  Prothrombin mutation (G20210A)

                    -  D-dimer >3 x the upper limit of normal (ULN) at Screening All known patients
                       with the above and any patient with a personal or significant family history
                       of thrombotic events (DVT, PE, arterial clots) as deemed by the principal
                       investigator will be screened for the above disorders.

               6. Active invasive malignancy (Non-melanoma skin cancers and carcinoma in situ are
                  not excluded).

               7. Known bone marrow disorders or abnormal bone marrow cytogenetics.

               8. Fertile males who are unwilling to use contraceptive techniques during and for
                  the twelve months following treatment.

               9. Life expectancy severely limited by disease(s) other than hemophilia A.

              10. Patients with HIV, hepatitis B, hepatitis C (with an AST/ALT > 3 times the upper
                  limit of normal).

              11. Other active infectious disease that is a contraindicat ion for immunosuppressive
                  therapy.

              12. Patients who have elective surgery scheduled during the study period.
Male
No healthy subjects accepted to join the trial.
Subject must be at least 18 Years old.


Patient description (medical language): A 20-year-old man comes to the emergency due to bleeding after a tooth extraction.  The bleeding has persisted for approximately 30 minutes despite constant direct pressure.  He is a known case of Hemophilia type A treated with FVIII. Blood pressure is 95/60 mm Hg and pulse is 105/min. His weight is 70 Kg. Family history is positive for Hemophilia type A in his maternal uncle. He also has a lipoma on his left arm which he plans to remove surgically. His FVIII activity is 40%.

Patient description (patient's own words): I got my tooth extracted and I could not stop bleeding for 30 min. I'm a 20 yo dude but I have Hemophilia type A treated with FVIII. My blood pressure was 95/60 and my pulse 105/min. I'm 70 kg. My uncle on my mom's side also has type A hemophilia. I also have a fatty swelling on my left arm and I was supposed to remove it. My FVIII activity was 40%.

Does the patient match the trial criteria? Contradiction