Clinical Trial: Phase I Gene Therapy Clinical Trial Using the Vector rAAV2/5-PBGD for the Treatment of Acute Intermittent Porphyria

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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 In

Brief Summary:

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.


Detailed Summary:

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
Sponsor: Digna Biotech S.L.

Current Primary Outcome: Number of patients with Adverse Events and Serious Adverse Events [ Time Frame: Up to 48 weeks ]

To assess the safety and determine the maximum therapeutic safe dose of the investigational gene therapy (GT) product rAAV2/5-PBGD for the treatment of AIP, registering and evaluating the occurrence of Adverse Events and/or Serious Adverse Events at the dose identified will be performed


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Effect of the treatment on porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) urinary level. [ Time Frame: Up to 48 weeks ]
  • Clinical evolution of acute intermittent porphyria. Frequency of hospitalizations [ Time Frame: Up to 48 weeks ]
  • Frequency of treatments for AIP symptoms [ Time Frame: Up to 48 weeks ]
    The information regarding the requirement of specific treatments for symptoms control (analgesics, hemin and glucose endovenous solutions) will be collected.
  • Psychological evaluation of AIP patients [ Time Frame: Up to 48 weeks ]
    Anxiety and depression will be assessed by using the Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) rating scales.
  • Health related quality of life of AIP patients [ Time Frame: Up to 48 weeks ]
    Health-related quality of life will be assessed through the SF-36v2 questionnaire
  • Frequency of AIP symptoms [ Time Frame: Up to 48 weeks ]
  • Pharmacokinetic parameters [ Time Frame: Selection visit, Days 1, 2 and 3, week 1, week 2, week 3 and week 4 ]


Original Secondary Outcome: Same as current

Information By: Digna Biotech S.L.

Dates:
Date Received: February 28, 2014
Date Started: November 2012
Date Completion:
Last Updated: December 17, 2014
Last Verified: December 2014