Alipogene Tiparvovec for the Treatment of LPLD Patients

Study Overview
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Brief Summary
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The aim of the study is to provide further confirmatory evidence of clinical benefit in LPLD patients treated with alipogene tiparvovec by assessing both the clinical response (as defined by a range of parameters), and the metabolic response (postprandial CM metabolism) in LPLD patients with and without an immunosuppressant regimen.

Detailed Description
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This is a prospective, interventional, randomised, open-label, parallel group study evaluating the clinical response as well as the dynamics of postprandial chylomicron metabolism in patients treated with alipogene tiparvovec with and without immunosuppressants. The study will be conducted in 12 LPLD patients who will be randomised into the Immuno+ (cyclosporin and mycophenolate mofetil) or the Immuno- group.

Official Title
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An Open Label, Multi-centre Trial of Alipogene Tiparvovec for the Treatment of LPLD Patients

Conditions
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LPL Deficiency

Intervention / Treatment
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* Drug: alipogene tiparvovec
* Drug: Prednisolone
* Drug: Cyclosporins
* Drug: Mycophenolate mofetil


Participation Criteria
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Eligibility Criteria
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Main inclusion criteria are: Patients with a history of severe or multiple pancreatitis attacks despite dietary fat restriction. Genetically confirmed diagnosis of LPLD Post-heparin plasma LPL protein mass > 5% of normal LPL activity ≤20% of normal (in post- heparin plasma) Fasting plasma TG concentration >10 mmol/L. Main exclusion criteria are: Females with a positive pregnancy test or who are breastfeeding, or on contraceptive use. Patients with a positive HIV, Hepatitis B, Hepatitis C or being positive for tuberculosis. Patients under treatment with antiplatelet or other anti-coagulants. Patient allergic to or having a condition that prohibits the use of immunosuppressants.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: alipogene tiparvovec with IS<br>Patients in the Immuno+ group will receive an immunosuppressant regimen to be initiated three days prior to alipogene tiparvovec administration. The regimen is to be continued for 12 weeks: Cyclosporins (3 mg/kg/day) and mycophenolate mofetil (2 x 1 g/day). Patients will receive IV bolus of 1mg/kg of methyl Prednisolone half an hour prior to IMP administration. | Drug: alipogene tiparvovec<br>* A dose of 1x10(*12) gc/kg alipogene tiparvovec (Glybera) of body weight administered as a single set of intramuscular injections at multiple sites in multiple muscles of both upper legs and if necessary, the lower legs.<br>* Other names: Glybera;Drug: Prednisolone<br>* IV bolus methylprednisolone 1mg/kg half hour prior to administration<br>Drug: Cyclosporins<br>* Immuno + group will receive cyclosporine (3 mg/kg/day) from three days prior to until 12 weeks following IMP administration<br>Drug: Mycophenolate mofetil<br>* Immuno + group will receive Mycophenolate mofetil (2x 1 g/day) from three days prior to until 12 weeks following IMP administration<br>|
| Other: alipogene tiparvovec without IS<br>Patients in the Immuno- group will not receive an immunosuppressant regimen during 12 weeks. Patients will receive IV bolus of 1mg/kg of methyl Prednisolone half an hour prior to IMP administration. | Drug: alipogene tiparvovec<br>* A dose of 1x10(*12) gc/kg alipogene tiparvovec (Glybera) of body weight administered as a single set of intramuscular injections at multiple sites in multiple muscles of both upper legs and if necessary, the lower legs.<br>* Other names: Glybera;Drug: Prednisolone<br>* IV bolus methylprednisolone 1mg/kg half hour prior to administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Clinical Response of alipogene tiparvovec in LPLD patients | The overall clinical response of alipogene tiparvovec in LPLD patients will be assessed compared to baseline, by a combination of measurements, of which each gives relevant information to obtain enough and solid evidence in a small trial. Each of these outcome measures will be evaluated in combination with the results of other measures (to get an overall conclusion relating the clinical response). Descriptive methods will be used (so no formal statistical analyses will be performed), due to the specific nature and the small sample size of a rare disease trial. | 2 years | 
| The long term effect of alipogene tiparvovec on post prandial metabolism of chylomicrons (ppCM) in LPLD patients. | CM [3H]-activity will be assessed during ppCM testing pre- and post-dose, compared to baseline. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effect of alipogene tiparvovec on postprandial metabolism of chylomicrons (ppCM) in LPLD patients with and without immunosuppression treatment, at 14 weeks post-administration. | CM [3H]-activity will be assessed during ppCM testing pre- and post-dose, compared to baseline. | Baseline, 14 weeks | 
| Immuno response of alipogene tiparvovec by analysis of antibody formation | The immuno response of alipogene tiparvovec will be assessed by measuring the antibody formation compared to baseline. | Baseline, 1 and 2 years post dose | 
| Immuno response of alipogene tiparvovec by analysis of T-cell response | T-cell responses against alipogene tiparvovec will be assessed by measuring the T-cell response compared to baseline. | Baseline, 1 and 2 years post dose |