E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
X-linked Chronic Granulomatous Disease |
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E.1.1.1 | Medical condition in easily understood language |
Chronic granulomatous disease is an inherited disorder in which immune system cells called phagocytes do not function properly. This results in ongoing and severe infections. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10008906 |
E.1.2 | Term | Chronic granulomatous disease |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
-Evaluation of safety
-Evaluation of biochemical and functional reconstitution in progeny of engrafted cells and transgene expression stability at 12 months |
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E.2.2 | Secondary objectives of the trial |
-Clinical efficacy and longitudinal evaluation of clinical effect in terms of augmented immunity against bacterial and fungal infection
-Transduction of CD34+ haematopoietic cells from X-CGD patients by ex vivo lentivirus-mediated gene transfer
-Evaluation of engraftment kinetics and stability |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male X-CGD patients > 6 months of age
-Molecular diagnosis confirmed by DNA sequencing and supported by laboratory evidence for absent or significantly reduced biochemical activity of the NADPH-oxidase
-At least one prior, ongoing or resistant severe infection and/or inflammatory complications requiring hospitalisation despite conventional therapy
- No HLA-matched donor available after 3 months search unless the risk of waiting for a potential match or for performing an allogeneic transplant is considered unacceptable
-No co-infection with Human Immunodeficiency Virus (HIV) or hepatitis B virus (HBsAg positive) or hepatitis C virus (HCV RNA positive)
-Written informed consent for adult patient
-Parental/guardian and where appropriate child’s signed consent/assent
- If applicable, patients must agree to use appropriate medically approved contraception during the trial and for 1 month afterwards |
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E.4 | Principal exclusion criteria |
-10/10 HLA identical (A,B,C,DR,DQ) family or unrelated or cord blood donor unless there is deemed to be an unacceptable risk associated with an allogeneic procedure
-Contraindication for leukapheresis (anaemia Hb <8g/dl, cardiovascular instability, severe coagulopathy)
-Contraindication for administration of conditioning medication and any component of the Investigational Medicinal Product (IMP) preparation
-Administration of gammainterferon within 30 days before the infusion of transduced autologous CD34+ cells
-Participation in another experimental therapeutic protocol within 6 months prior to baseline and during the study period
-Any other condition that, in the opinion of the Investigator, may compromise the safety or compliance of the patient or would preclude the patient from successful completion of the study
-Patient/Parent/Guardian unable or unwilling to comply with the protocol requirements |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Safety of the procedure as measured by the incidence of adverse events
- Restoration and stability over time of the NADPH functioning granulocytes assessed by a DHR test (≥ 5% of expressing cells at 12 months) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The assessment of the safety of the IMP by the measurement of the safety parameters, e.g. adverse events. This will include clinical adverse events, as well as any clinically significant laboratory abnormality which will have to be reported as an AE. Overall incidence of adverse events will be evaluated for the study as a whole. Similarly the incidence of serious adverse events will be monitored.
The determination of the efficacy of the IMP. It will be evaluated by the measurement of the percentage of oxidase positive granulocytes at month 12 by DHR test. |
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E.5.2 | Secondary end point(s) |
-Normalisation of nutritional status, growth, development (as measured by clinical evaluation), severe infection and/or inflammatory complication which recommended patient’s inclusion
-Percentage of transduced CD34+ haematopoietic cells infused and of blood cells over time (at month 1, 2, 3, 6, 9, 12, 18 and 24 months)
-Immunological reconstitution as measured by evidence of restored neutrophil functionality and immunity against bacterial and fungal infections over time |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
As a secondary efficacy endpoint, the evolution of the nutritional status, the growth and the development will be evaluated by the regular clinical examination during the study visit.
Similarly, the evolution of the severe infection and inflammation will be evaluated by the clinical exam but also by the imaging and the laboratory results.
For the immmunological reconstitution, the restoration of the neutrophil functionality and immunity will be measured by the NADPH oxidase activity (NBC and DHR) and the percentage of transduced CD34+ haematopoietic cells infused and of blood cells at month 1, 2, 3, 6, 9, 12, 18 and 24 to be validated with the Investigators). |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
France |
Germany |
Switzerland |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |