E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adults patients having non severe sporadic Hemophagocytosis Lymphohistiocytosis |
|
E.1.1.1 | Medical condition in easily understood language |
Adults patients having non severe sporadic Hemophagocytosis Lymphohistiocytosis |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
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 |
Overall response rate (RR) achievement of either a Complete (CR) or a Partial response (PR) at day 15 of ITACITINIB treatment on clinical and biological symptoms of primitive/refractory/relapses in non-severe adults HLHs:
• Primitive: HLH with no previous treatment or nor flare
• Refractory: persistent HLH despite corticoid treatment
• Relapse: new HLH flare despite or not continuous treatment |
|
E.2.2 | Secondary objectives of the trial |
1- Response rate of ITACITINIB treatment at D8 and D30 on clinical and biological symptoms of primitive/refractory/relapse adults HLHs without severity criteria
2- Efficacy at the day of etiologic treatment if they received at least 7 days of treatment (ITACITINIB taken until J15)
3- Toxicity of ITACITINIB
4- Rescue therapy
5- Reduction of plasma cytokines level between D0 and D15 and correlation to the therapeutic response to D15
6- Clinical, biological, associated diseases characteristics of patients having CR, PR, No Response.
7- Overall survival at 3 months
|
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
IFN gamma, Il-6, Il-1, IP-10, IP-9, TNF-alpha levels in patient’s plasma at day 0, 8, 15, 30 days of treatment by ITACITINIB. |
|
E.3 | Principal inclusion criteria |
1. Patients age >= 18 years, with front line or recurrent sporadic HLH, without or awaiting diagnosis of associated pathologies that may benefit from specific treatment, without severity criteria, without organ failure
2. Inclusion criteria were adapted from the revised Diagnostic Guidelines for Hemophagocytic lymphohistiocytosis. Are request to be included:
1 major and 2 minors criteria including hyperferritinemia or/and hypertriglyceridemia
or
3 minors criteria including hyper ferritinemia or/and hypertriglyceridemia
Major criteria:
a. Cytological features of hemophagocytosis
b. Fever
c. Splenomegaly
Minor criteria:
d. Adenopathies
e. Cytopenia> 2 lineages:
Haemoglobin < 9 g/dl,
Platelets < 100 000/mm3
Neutrophils < 1000/mm3
f. Hypertriglyceridemia > 3 mmol/l and/or hypofibrigenemia < 1.5 g/l
g. Ferritin>500 ng/l
3. Patient is willing to provide written informed consent prior to enrolment and agrees to follow the protocol
4. Patient known to have systemic juvenile idiopathic arthritis are classified as having HLH if they met the following criteria
Ferritin >684 ng/mL
And any 2 of the following:
Platelet count < 181 000/mm3
ASAT > 48 UI/ml
Triglyceride > 4 mmol/L
Fibrinogen 3.6 g/L
5. Be willing to avoid pregnancy or fathering children based on 1 of the following criteria:
a. Women of non-childbearing potential (ie, surgically sterile with a hysterectomy and/or
bilateral oophorectomy OR ≥ 12 months of amenorrhea).
b. Women of childbearing potential who has a negative serum pregnancy test at
screening and who agrees to take appropriate precautions to avoid pregnancy (with at
least 99% certainty) from screening through safety follow-up. Permitted methods that
are at least 99% effective in preventing pregnancy (see Appendix 4) should be
communicated to the subject and their understanding confirmed.
c. Man who agrees to take appropriate precautions to avoid fathering children (with at
least 99% certainty) from screening through safety follow-up. Permitted methods that
are at least 99% effective in preventing pregnancy (see Appendix 4) should be
communicated to the subject and their understanding confirmed.
6. Be either affiliated to, or a beneficiary of, a social security category
|
|
E.4 | Principal exclusion criteria |
1. Organ failure: Confusion, organic kidney failure KADIGO 2liver failure (Factor V < 50%), heart failure, respiratory failure.
2. Fibrinogenemia < 0.5 g/dl or platelets < 20G/L
3. Indication to intensive care unit transfer on an organ failure requiring assistance (dialysis, Ventilation (assisted or VNI), shock regardless of the origin
4. Participation in another interventional study involving human
5. Breastfeeding women
6. Women with a positive pregnancy test or not willing to take contraceptive measures
7. Known allergies, hypersensitivity, or intolerance to any of the ITACITINIB or excipients, or similar compounds
8. Current or history of recurrent infections, including HBV, HCV
9. Participants with active HBV or HCV infection that requires treatment or who are at risk for HBV reactivation (ie Positive HBs Ag serology)
10. Candidates positive for HCV antibody and positive PCR RNA HCV
11. HIV infection with positive viral charge
12. Protected adults (including individual under guardianship by court order) |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Overall Response Rate: achievement of either a Complete (CR) or a Partial Response (PR) to ITACITINIB treatment for HLHs in adults without any sign of severity at D15 of treatment evaluated at D15 of treatment on the major and minor diagnostic criteria of HLH.
Major diagnostic criteria:
- Fever
- Organomegaly (not related to etiology)
Minor diagnostic criteria:
- Cytopenias: hemoglobin, platelets, neutrophils
- Hypertriglyceridemia
- Hypofibrinogenemia
- Ferritin
• COMPLETE RESPONSE is defined at D15 of treatment, by:
No HLH progression: none of those criteria, 1 to 7
1- No decrease of Hb level>2 gr/dL if <10 gr/dL
2- No decrease of Pq<25000 if <100 000/mm3.
3- No decrease of PNN > 50% if PNN <1000/mm3.
4- No decrease of more than 1 gr/l if fibrinogen<2.5 gr/l
5- No increase of ferritinemia more than 25% of basal value
6- No worsening of fever more than 1 degree Celsius
7- No severity criteria
• PARTIAL RESPONSE is defined at D15 of treatment by: no Complete Response and no Progression and no gravity criteria
• PROGRESSION is defined at day 15 of treatment by presence of at least one severity criteria:
1- Presence of 6/6 of the following criteria:
1- Decrease of Hb level>2 gr/dL if <10 gr/dL
2- Decrease of Pq<25000 if <100 000/mm3
3- Decrease of PNN > 50% if PNN <1000/mm3
4- Decrease of more than 1 gr/l if fibrinogen<2.5 gr/l
5- Increase of ferritinemia more than 25% of basal value
6- Worsening of fever more than 1 degree Celsius
2- Organ failure (at least one of those criteria): confusion, organic kidney failure (< 60 ml/min), liver failure (Factor V < 50%), heart failure, respiratory failure, fibrinogen < 0.5 g/l, platelets < 20G/L
3- Indication to intensive care unit transfer or an organ failure requiring assistance (dialysis, Ventilation (assisted or NIV), shock regardless of the origin)
4- HLH specific treatment: VP 16, cyclosporine, biotherapies(s)
In this case, ITACITINIB will be stopped and patient will be considered in failure. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
1. Response rate at D8, and D30 of treatment.
2. Response rate to ITACITINIB treatment for HLHs in adults without any sign of severity at the day of etiologic treatment if patients have been treated by ITACITINIB at least during seven days. Response to ITACITINIB is evaluated at the day of etiologic treatment on the major and minor diagnostic criteria of HLHs
3. Toxicity of ITACITINIB not related to evolution of HLHs (cytopenia, worsening of hepatic balance, secondary infections)
4. Rescue therapy
5. Range of decrease in plasma rate of IFN gamma IP-10, Il-1, Il-6, IL-10, TNF alfa between D0 and D15 of ITACITINIB treatment in each patient group: response and progression
6. Clinical, biological, associated diseases and evolutions characteristics of patients in each response group
7. Overall survival at 3 months |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Day 0, Day 8, Day 15, Day 30 and Day 90 |
|
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 | No |
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) | No |
E.7.1.1 | First administration to humans | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 13 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |