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Tysabri in PNS


- candidate number23738
- NTR NumberNTR5745
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR7-feb-2016
- Secondary IDsNL48712.078.14 2014-000675-13
- Public TitleTysabri in PNS
- Scientific TitleNatalizumab (Tysabri®) for the treatment of anti-Hu associated paraneoplastic neurological syndromes
- ACRONYMna
- hypothesisParaneoplastic neurological syndromes (PNS) are ‘remote effects’ of cancer. It is thought that expression of Hu antigens by the tumor provokes an autoimmune response not only directed against the tumor but also against nervous tissues. PNS disorders are rapidly progressive over weeks to months leaving the patient severely debilitated. At the time of neurological presentation, 70% is not yet known with cancer which often makes the diagnosis difficult 1-4. The most frequent PNS is associated with anti-Hu autoantibodies (Hu-PNS). Hu-PNS is a monophasic, severe, Th1 mediated organ specific autoimmune disease.5, 6 Plasma exchange, corticosteroids, cyclophosphamide and intravenous immunoglobulins (IVIG) are generally considered not effective in the treatment of Hu-PNS and immunosuppressive or immunomodulating treatment is at present not recommended.9 Other than anti-tumor therapy after the detection of the tumor, no effective treatment for Hu-PNS is available. Functional improvement rarely occurs (<10%) and most of the patients ultimately die from the severe neurological disorder and not from the underlying malignancy.1, 2, 4 Better treatment modalities for PNS are a highly unmet medical need. Natalizumab may contribute to reduced activation of T cells already present in the CNS, leading to apoptosis and strongly inhibits migration of activated T cells to the CNS and consequently lowers damage done to the CNS by these cells during Hu-PNS.
- Healt Condition(s) or Problem(s) studiedParaneoplastic neurological syndromes
- Inclusion criteria- PEM/PSN associated with high titer (≥400) anti-Hu antibodies in serum or plasma
- The neurological symptoms must still be progressing defined as neurological deterioration over the last 4 weeks
- Score mRS ≥ 2
- Absolute CD4+ cell count ≥400 x 109 cells per liter
- Patients aged  18 years
- Patients who receive or will receive anti-tumor therapy are allowed to participate
- Patients who have given written informed consent
- Exclusion criteria- Patients who are unwilling to undergo lumbar puncture
- Known hypersensitivity to natalizumab or one of the additives
- Progressive multifocal leukoencephalopathy (PML)
- Immune compromised patients (patients using immunosuppressive medications other than short course (<2 weeks) of steroids)
- Liver enzymes (ASAT, ALAT, -GT, Alk. Phosphatase) higher than 5x upper limit of normal value (ULN)
- Chronic HBV infection (HBsAg positive)
- Renal failure (GFR < 30 ml/min)
- Active infection for which antibiotics are indicated
- Active viral infection for which antiviral medication is indicated
- Known current pregnancy or lactating (NB: women of childbearing potential should take adequate contraceptive precautions).
- No history of active melanoma in the past 5 years; no history of T cell lymphoma or primary CNS lymphoma
- mec approval receivedyes
- multicenter trialno
- randomisedno
- group[default]
- TypeSingle arm
- Studytypeintervention
- planned startdate 15-feb-2016
- planned closingdate1-jan-2020
- Target number of participants20
- InterventionsEvery 4 weeks, 300 mg natalizumab (Tysabri) will be i.v. infused over 1 hour, for a total of 3 infusions.
Natalizumab is used as monotherapy.
Concomitant immunotherapy will not be allowed with the exception of short courses of steroids.
Concomitant chemotherapy for an underlying malignancy will be allowed. PI will pay special attention to potential interaction with the study drug.
- Primary outcomeFunctional improvement with one point or more on the modified Rankin scale after the 12th week of natalizumab (compared to baseline).
- Secondary outcomeNeurological improvement and safety. Neurological improvement is defined as a positive score (>0) in the EFIT overall evaluation and improvement on the AMC linear disability scale, Barthel index and PNS neurological scale after three natalizumab infusions (the 12th week of natalizumab), compared to baseline. Safety is assessed by CTC AE 4.0 criteria, from date of registration until 28 days after last study drug administration.
- TimepointsSee primary and secondary outcomes
- Trial web site
- statusplanned
- CONTACT FOR PUBLIC QUERIESProf.dr. P.A.E. Sillevis Smitt
- CONTACT for SCIENTIFIC QUERIESProf.dr. P.A.E. Sillevis Smitt
- Sponsor/Initiator Erasmus Medical Center
- Funding
(Source(s) of Monetary or Material Support)
Erasmus Medical Center, Biogen Nederland
- Publications
- Brief summaryRationale: Paraneoplastic neurological syndromes (PNS) are ‘remote effects’ of cancer. It is thought that expression of Hu antigens by the tumor provokes an autoimmune response not only directed against the tumor but also against nervous tissues. PNS disorders are rapidly progressive over weeks to months leaving the patient severely debilitated. At the time of neurological presentation, 70% is not yet known with cancer which often makes the diagnosis difficult 1-4. The most frequent PNS is associated with anti-Hu autoantibodies (Hu-PNS). Hu-PNS is a monophasic, severe, Th1 mediated organ specific autoimmune disease.5, 6 Plasma exchange, corticosteroids, cyclophosphamide and intravenous immunoglobulins (IVIG) are generally considered not effective in the treatment of Hu-PNS and immunosuppressive or immunomodulating treatment is at present not recommended.9 Other than anti-tumor therapy after the detection of the tumor, no effective treatment for Hu-PNS is available. Functional improvement rarely occurs (<10%) and most of the patients ultimately die from the severe neurological disorder and not from the underlying malignancy.1, 2, 4 Better treatment modalities for PNS are a highly unmet medical need. Natalizumab may contribute to reduced activation of T cells already present in the CNS, leading to apoptosis and strongly inhibits migration of activated T cells to the CNS and consequently lowers damage done to the CNS by these cells during Hu-PNS.

Objectives: Primary Objective: functional improvement with one point or more on the modified Rankin scale after the 12th week of natalizumab (compared to baseline).
Secondary Objectives: neurological improvement and safety. Neurological improvement is defined as a positive score (>0) in the EFIT overall evaluation and improvement on the AMC linear disability scale, Barthel index and PNS neurological scale after three natalizumab infusions (the 12th week of natalizumab), compared to baseline. Safety is assessed by CTC AE 4.0 criteria, from date of registration until 28 days after last study drug administration.

Study design: This is an uncontrolled single center phase II study testing 3 monthly infusions of natalizumab in 20 patients.

Study population: 20 patients with Hu-PNS; expected median age 60-65 years.

Intervention: Natalizumab 300 mg, intravenous infusions q 4 weeks for a maximum of 3 infusions over 12 weeks. Main study endpoint: The primary endpoint is the functional improvement with one point or more on the modified Rankin scale after the 12th week of natalizumab (compared to baseline).

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The direct side effects of the 3 (maximum) natalizumab infusions are mild and manageable. Potential serious side effects include PML and induction of tumor growth. However, the risk of these serious side effects is considered very low, as discussed in sections 1.2.6 and 13.1 of the protocol. The main burden for the patients are a short admission (1-2 nights); 3 natalizumab infusions (1 during admission; 2 in daycare); 2 additional outpatient visits, all at Erasmus MC department of Neurology. In addition, 2 lumbar punctures and 4 venapunctures are performed. During all 5 (maximum) visits, general physical and neurological examinations will be performed; 2 questionnaires (Barthel and AMC linear disability scale), nine hole peg test, ten metre walking test, Williams delayed recall test and Boston aphasia severity scale will be taken.
- Main changes (audit trail)
- RECORD7-feb-2016 - 22-mei-2016


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