Carglumic Acid in Methylmalonic Acidemia and Propionic Acidemia

Study Overview
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Brief Summary
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A Phase IIIb (Three b), Randomized Multicentre Comparative Trial to Evaluate the Long Term Effectiveness & Safety of the use of Carglumic Acid (Carbaglu®) in Patients with Propionic Acidemia (PA) or Methylmalonic Acidemia (MMA). Carbaglu® clinical experience in Organic Acidemia (OA) is limited to a non-comparative retrospective collection of data from patients who had received Carbaglu® for 1 to 15 days. There is no current evidence supporting the use of carglumic acid for the chronic management of patients with OA. The investigators are proposing a randomized multicentre prospective clinical trial to evaluate long-term effects of the use of Carbaglu® (50mg/kg/day) combined with standard chronic therapy in patients with PA and MMA compared to standard chronic therapy alone.

Official Title
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Randomized Multicentre Comparative Trial to Evaluate the Long Term Effectiveness of the Use of Carbaglu® in Patients With Propionic Acidemia (PA) or Methylmalonic Acidemia (MMA)

Conditions
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Methylmalonic Acidemia, Propionic Acidemia

Intervention / Treatment
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* Drug: Carglumic Acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female Children of 15 years old or less Parent or legal guardian agree to participate and to sign the (Institutional Review Board) IRB approved Informed Consent Form (assent forms will be waived due to the mental disability of those children) Not participating in any other clinical trial in the previous 30 days PA or MMA confirmed using the following criteria: PA confirmed by the measurement of acylcarnitine profile, urine organic acid, measurement of propionyl Co-A carboxylase in leukocytes or cultured fibroblasts or by DNA molecular testing of PCCA (Propionyl CoA Carboxylase, Alpha Polypeptide) or PCCB (propionyl CoA carboxylase, beta polypeptide) gene MMA confirmed by the measurement of acylcarnitine profile, urine organic acid, measurement of methymalonyl Co-A mutase in culture fibroblasts or DNA molecular testing of mutgene. Expected survival of at least 6 months, for the purpose of this study Survival expectance will be defined as patient not admitted to the Pediatric Intensive Care Unit (PICU) due to hyperammonemia more than 2 times per year or asymptomatic patients diagnosed by newborn screening program or stable chronic patients who are followed up at outpatient clinic. Exclusion Criteria: Patients with other organic acidemia or any other cause of hyperammonemia Patient receiving other investigational therapy for PA or MMA Past history of hypersensitivity or drug allergy to Carbaglu® Patient with PA or MMA and other inherited genetic conditions or congenital anomalies

Ages Eligible for Study
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Maximum Age: 15 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 |
| --- | --- |
| No Intervention: Methylmalonic Acidemia Control Arm<br>patients with Methylmalonic Acidemia will receive standard therapy only (protein restricted diet, L-carnitine, metronidazole and vitamin B12) | |
| Experimental: Methylmalonic Acidemia Active arm<br>patients with Methylmalonic Acidemia will receive Carglumic Acid in addition to standard therapy (protein restricted diet, L-carnitine, metronidazole and vitamin B12) | Drug: Carglumic Acid<br>* Carglumic Acid 50 mg/kg/day (twice daily)<br>* Other names: Carbaglu;|
| No Intervention: Propionic Acidemia Control Arm<br>patients with Propionic Acidemia will receive standard therapy only (protein restricted diet, L-carnitine, metronidazole and biotin) | |
| Experimental: Propionic Acidemia Active arm<br>patients with Propionic Acidemia will receive Carglumic Acid in addition to standard therapy (protein restricted diet, L-carnitine, metronidazole and biotin) | Drug: Carglumic Acid<br>* Carglumic Acid 50 mg/kg/day (twice daily)<br>* Other names: Carbaglu;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of emergency visits due to hyperammonemia within 24 months period |  | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first visit to the ER due to hyperammonemia from starting the treatment. |  | 24 months | 
| Plasma ammonia levels over the study treatment period. |  | 24 months | 
| Number of days of hospitalization |  | 24 months | 
| Acylcarnitine level for all patients |  | once on screening visit | 
| Measuring urine organic acid levels for both diseases. |  | 24 months | 
| Measuring Plasma aminoacids' levels for both diseases |  | 24 months |