E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary immunodeficiency |
Primaire immuundeficientie |
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E.1.1.1 | Medical condition in easily understood language |
Primary immunodeficiency |
Primaire immuundeficientie |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to establish in CVID patients with depression the changing, i.e. increasing, effect of Tα1 on the naïve CD4/CD8 ratio. |
Evalueren van het effect van Thymalfasin op herstel van de verlaagde naive CD4/CD8 ratio in CVID patienten met depressie |
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E.2.2 | Secondary objectives of the trial |
-Changes in depression, anxiety, fatigue and quality of life scores -Changes in T lymphocyte subsets (such as Th1, Th2, Th17 and T regulatory cells) and T cell regulating cytokines (such as IL-7 and sCD25) -Changes in levels of markers of inflammation, such as the hCRP and IL-6 serum levels and the monocyte inflammatory gene expression. -Assessment of adverse events. -Changes in antibiotic usage
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-Veranderingen in depressive, vermoeidheid en kwaliteit van leven scores -Veranderingen in T lymfocyten patronen en cel regulerende cytokines -Veranderingen in niveaus van ontstekings markers zoals hCRP an Il-6 serum niveaus en de moncyte onsteking gen expressie. -In kaart brengen van bijwerkingen -Veranderingen in het gebruik van antibiotica |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Written informed consent must be obtained before any assessment is performed.Suffering from the following condition oCommon variable immunodeficiency (CVID), with an established diagnosis according to the diagnostic criteria from the European Society for Immunodeficiences (ESID) 2014, in accordance with the International Union of Immunological Societies (IUIS). -Stable and standard use of classical (tricyclic) or non-tricyclic antidepressant (SSRI, SNRI, MAOI, other), with or without mood stabilizer, in a stable dosing regimen for a duration of at least 4 weeks prior to inclusion in the clinical study -Presence of a depressive mood disorder as determined by the Hamilton Rating Scale for Depression (HAM-D) (above 12). -Age between 18 and 75.
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- Ondertekend troestemmingsformulier Lijdend aan onderstaande aandoening - Common variable immunodeficiency (CVID), met een diagnose gesteld op basis van de diagnostische criteria volgens de European Society for Immunodeficienices (ESID) 2014,in overeenstemming met de International Union of Immunological Societies (IUIS). - Stabiele en standard gebruik van klassieke (tricyclische) of niet-tricyclissche anntidepressiva (SSRI, SNRI, MAOI, anders), met of zonder stemmingsstabilisator, in stabiele dosering gedurende tenminste 4 weken voorafgaande aan inclusie in de studie - Aanwezigheid van een depressieve stemmingsstoornissen, vastgelegd met de Hamilton Rating Scale for Depression (HAM-D) (meer dan 12) - Leeftijd tussen 18 en 75 jaar |
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E.4 | Principal exclusion criteria |
- Active, concomitant autoimmune disease clinical manifestations - Renal insufficiency defined by a creatinine clearance of less than 30 ml/min (CKD-EPI or MDRD formula) - Hepatic impairment, i.e. unexplained persistent liver function abnormalities - Laboratory parameters at the pre-treatment visit showing any of the following abnormal results: transaminases > 2x the upper limit of normal (ULN) and/or bilirubin > 2x ULN - Severe cardiac (LVEF < 45%) and/or pulmonary disease (FVC <50%) - History of heart failure, symptomatic coronary artery disease, significant ventricular tachyarrhythmia, stent placement, coronary artery bypass surgery, and/or myocardial infarction - Use of other investigational drugs, within 5 half-lives of enrollment or within 30 days, whichever is longer - History of hypersensitivity to any of the study treatments or excipients or to drugs of similar chemical classes. - Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation. - Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 2 days after last dose of study medication. - History of malignancy within the last 5 years, except for resected basal or squamous cell carcinoma of the skin, treated cervical dysplasia, or treated in situ cervical cancer. - Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. - Any condition or treatment, which in the opinion of the investigator, places the subject at unacceptable risk as a patient in the trial. |
- Actieve gelijktijdige autoimmuunziekte met klinische verschijnselen -Nierfunctiestoornissen met een geschatte klaring van minder dan 30 ml/min (gebruikmakend van CKD-EPI of MDRD formule) -Levertestafwijkingen, i.e. ionverklaarde en persisterende leverfunctiestoornissen -Labratoriumafwijkingen op visite voor starten van behandeling met een of meer vand e volgende afwijkingen: transaminases >2x boven de maximale normaalwaarde en/of bilirubine >2x boven de maximale normaalwaarde -Cardiale dysfunctie (met linkerventrikelejectiefractie <45%) en/of longfunctiestoornissen met een FVC<50% van normal -Historie van hartfalen, symptomatisch coronairlijden, ventriculaire tachyaritmie, stentplaatsing, coronairarterie bypassoperatie en/of hartinfarct -Gebruik van andere geneesmiddelen in wetenschappelijk onderzoek voor starten van deze studie (minimal 5x halfwaardetijd of 30 dagen voorafgaande aan start onderzoek) -Voorgeschiedenis van overgevoeligheid voor de studiebehandeling of geneesmiddelen van dezelfde klasse -Zwangerschap of lactatie -Vrouwen in de vruchtbare leeftijd, tenzij er adequate anticonceptie wordt gebruikt, tijdens en tot 2 dagen na gebruik van de studiemedicatie -Maligniteit in de laatste 5 jaar voorafgaande aan stafrten van studie, behalve gereserceerde basal of plaveiselcelcarcinoom van de huid, behandelde cervicale dysplasia -Een psychologische, familiaire, sociologische of geografische situatie die mogelijke compliantaie aan de stude in de weg staat -Elke conditie of behandeling welke in de ogen van de hoofdponderzoeker een patient aan een onacceptable risico blootstelt |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint of this study will be the increase in the naïve CD4+/CD8+ ratio, measured after 8 weeks of treatment and 8 weeks after termination of the treatment period (i.e. 16 weeks after initiation of treatment) |
Primaire uitkomst van deze studie is de stijging van de naive CD4+/ CD8+ ratio, gemeten na 8 weken behandeling en 8 weken na beeindiging van de klinische studie/behandelperiode |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint will be evaluated 8 weeks after start treatment and 8 weeks after termination of the treatment. |
Het primaire eindpunt zal 8 weken na start studiebehandeling en 8 weken na beeindiging van de behandeling geevalueerd worden. |
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E.5.2 | Secondary end point(s) |
EFFICACY 1) Change in depression scores (Hamilton Depression Scale (HAM-D) scores) from baseline to week 8 and at 8 weeks after termination of the clinical study (i.e. 12 weeks after initiation of treatment).. 2) Change in fatigue scores (Fatigue Severity Scale (FSS)) from baseline to week 8 and at 8 weeks after termination of the clinical study (i.e. 12 weeks after initiation of treatment). 3) Change in health-related quality of life scores (SF36, CVID_QoL) from baseline to week 8 and at 8 weeks after termination of the treatment period (i.e. 12 weeks after initiation of treatment). 4) Increase/decrease in numbers of Th1, Th2 and Th17 cells 5) Alterations in the balance between naïve and memory T helper cells 6) Alterations in the balance between the Th17/T regulatory cells 7) Decrease in inflammatory gene expression (cluster 1 and 2 gene expression) in circulating monocytes 8) Decrease in circulating levels of hCRP, IL-6, sCD25, IL-7, BDNF SAFETY 9) Frequency and type of adverse events 10) Lab tests: mean change and frequency of values outside the normal range (hematology, liver and kidney biochemistry) 11) Changes in the antibiotic usage
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Effectiviteit 1) Verandering in depressie scores (Hamilton Depression Scale (HAM-D) scores) op baseline, na 8 weken behandeling en 8 weken na beeindiging van de klinische studie 2) Verandering in vermoeidheidsscores (Fatigue Severity Scale (FSS)) op baseline, na 8 weken behandeling en 8 weken na beeindiging van de klinische studie 3) Verandering in gezondheidsgerelateerde kwalitiet van leven scores (SF36, CVID, QoL) 4) Toename/afname in het totaal aantal Th1, Th2 en Th17 cellen 5) Verandering in de verhouding tussen naieve en geheugen T helper cellen 6) Verandering in de balans tussen de Th17/regulatoire T cellen 7) Afname in expressie van inflammatoire genen (cluster 1 en 2 gen expressie profielen) in circulerende leukocyten 8) Afname in circulerende levels hCRP, IL-6, CCL2, PTX-3, sCD25, SCF, BDNF Veiligheid 9) Frequentie en type bijwerkingen 10) Laboratoriumtesten: Gemiddelde verandering en frequentie van waarden buiten referentiewaarden 11) Veranderingen in het gebruik van antibiotica |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary endpoints will be evaluated 8 weeks after start treatment and 8 weeks after termination of study treatment. |
De secundaire eindpunten zullen 8 weken na start studiebehandeling en 8 weken na beeindiging van de behandeling geevalueerd worden. |
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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 | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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
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LVLS. The trial will end when the last subject completes the last visit discontinues form the trial or is lost to follow up |
LVLS. The studie zal eindigen als het laatste subject de laatste visite heft afgerond of niet meer deelneemt aan de trial of geen follow up kan ondergaan. |
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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 | |
E.8.9.1 | In the Member State concerned months | 31 |
E.8.9.1 | In the Member State concerned days | |