Acute Intermittent Porphyria Clinical Trial
Official title:
Phase I, Multicentre, Open Label, Single Dose, Dose-ranging Clinical Trial to Investigate the Safety and Tolerability of a Gene Therapy rAAV2/5-PBGD for the Treatment of Acute Intermittent Porphyria
This is a Phase I trial aimed to determine the safety of the investigational gene therapy
product (rAAV2/5-PBGD) for the treatment of Acute Intermittent Porphyria (AIP).
Up to eight patients fulfilling the eligibility criteria will participate in this
multicentre, open label, single dose, dose-ranging Phase I clinical trial.
The enrolled patients will be followed up to assess the safety profile of the
investigational gene therapy product and to establish the maximum therapeutic safe dose to
be administered in future confirmatory/pivotal clinical trial(s). In addition, the
biological and clinical response to the treatment with rAAV2/5-PBGD in AIP patients will be
assessed.
A complete evaluation of the clinical (symptoms and quality of life assessment) and
laboratory (blood and urine) data will be performed.
Acute Intermittent Porphyria (AIP) is inherited as an autosomal dominant disorder of the
heme biosynthesis pathway. AIP is caused by a genetic defect in porphobilinogen deaminase
(PBGD), a key enzyme for heme synthesis.
AIP is characterized by acute episodes and asymptomatic periods. Neuropathic symptoms are
predominantly in these attacks, which may be related to the toxic effect produced by the
precursors delta-aminolevulinic acid (ALA) and porphobilinogen (PBG), accumulated because
the enzyme deficiency. It occurs with very low prevalence (1 in 50,000), but figures for
prevalence based on clinical manifestations (i.e., acute attacks) greatly underestimate the
number of patients with latent AIP.
Abdominal pain is the most common symptom, sometimes with constipation. Paresthesia and
paralysis also occur, and death may result from respiratory paralysis. Other symptoms,
including seizures, psychotic episodes, and hypertension, develop during acute attacks. They
may be precipitated by porphyrogenic drugs such as barbiturates, progestogens and
sulfonamides, some of which are known to induce the first rate-controlling step in heme
synthesis, ALA synthesis. Other known precipitants are alcohol, infection, starvation, and
hormonal changes; attacks are more common in women. Acute attacks rarely occur before
puberty.
This is a Phase I clinical trial mainly aimed to evaluate the safety of a recombinant adeno
associated vector with a liver-specific promoter for the PBGD expression (rAAV2/5-PBGD), for
the treatment of Acute Intermittent Porphyria.
The patients will be enrolled in an adaptive dose-escalation, multicentre trial to assess
safety profile, and to establish the maximum therapeutic safe dose to be administrated to
patients in further confirmatory or pivotal clinical trial.
This clinical trial is preceded by an "Observational study of acute intermittent porphyria
patients" (DIG-API-2011-01). In this observational study, severe AIP patients have been
followed for 6 to up to a maximum 24 months. During this time, the clinical and laboratory
(blood and urine biochemistry) conditions of the patients were evaluated, in order establish
clinical and biological baseline and history to compare the future results of this clinical
trial.
During this clinical trial, the safety will be evaluated by the Adverse Events (AEs) and
Serious Adverse Events (SAEs) assessment. A complete evaluation of the clinical and
laboratory (blood and urine) data will be collected. The study will also investigate as
secondary endpoints the effect of this treatment to modify other aspects of the patient
condition.
Due to the heterogeneity of genetic mutations and inter-individual variation, clinical
symptomatology and ALA/PBG levels in AIP subjects showed an evident variability in urine
samples both during acute attacks and during remission; each subject will be its own
control, so this study will be an intra-individually controlled clinical trial. At the end
of the clinical trial the efficacy evaluation will be performed based on the clinical and
biochemical changes compared to the baseline established in the previous observational
study.
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Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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