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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Porphyria Centre Sweden
Centro de Investigacion Medica Aplicada de Navarra
UniQure N. V.
Nationales Centrum für Tumorerkrankungen
Information provided by (Responsible Party):
Digna Biotech S.L.
ClinicalTrials.gov Identifier:
NCT02082860
First received: February 28, 2014
Last updated: March 11, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention Phase
Acute Intermittent Porphyria
Genetic: rAAV2/5-PBGD vector dosage 1
Genetic: rAAV2/5-PBGD vector dosage 2
Genetic: rAAV2/5-PBGD vector dosage 3
Genetic: rAAV2/5-PBGD vector dosage 4
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Digna Biotech S.L.:

Primary Outcome Measures:
  • Number of patients with Adverse Events and Serious Adverse Events [ Time Frame: Up to 48 weeks ] [ Designated as safety issue: Yes ]
    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


Secondary Outcome Measures:
  • Effect of the treatment on porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) urinary level. [ Time Frame: Up to 48 weeks ] [ Designated as safety issue: No ]
  • Clinical evolution of acute intermittent porphyria. Frequency of hospitalizations [ Time Frame: Up to 48 weeks ] [ Designated as safety issue: No ]
  • Frequency of treatments for AIP symptoms [ Time Frame: Up to 48 weeks ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Health-related quality of life will be assessed through the SF-36v2 questionnaire

  • Frequency of AIP symptoms [ Time Frame: Up to 48 weeks ] [ Designated as safety issue: No ]
  • Pharmacokinetic parameters [ Time Frame: Selection visit, Days 1, 2 and 3, week 1, week 2, week 3 and week 4 ] [ Designated as safety issue: No ]

Enrollment: 8
Study Start Date: November 2012
Estimated Study Completion Date: October 2014
Estimated Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort A
rAAV2/5-PBGD vector dosage 1
Genetic: rAAV2/5-PBGD vector dosage 1
Intravenous injection of rAAV2/5-PBGD vector, single administration on Day 1.
Experimental: Cohort B
rAAV2/5-PBGD vector dosage 2
Genetic: rAAV2/5-PBGD vector dosage 2
Intravenous injection of rAAV2/5-PBGD vector, single administration on Day 1.
Experimental: Cohort C
rAAV2/5-PBGD vector dosage 3
Genetic: rAAV2/5-PBGD vector dosage 3
Intravenous injection of rAAV2/5-PBGD vector, single administration on Day 1.
Experimental: Cohort D
rAAV2/5-PBGD vector dosage 4
Genetic: rAAV2/5-PBGD vector dosage 4
Intravenous injection of rAAV2/5-PBGD vector, single administration on Day 1.

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years to 64 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patient's written Informed Consent
  • Age between 18 and 64 years, inclusively.
  • Patients with confirmed diagnosis of Acute Intermittent Porphyria(AIP), as confirmed by clinical, biochemical data and genetic confirmation of porphobilinogen deaminase (PBGD) gene mutation. The patient must have a severe AIP condition, with at least two hospitalizations during the previous year due to acute attacks (clinical manifestations of acute porphyria), or at least four hospitalizations during the previous year due to the requirement of hospital treatment administration (including day-hospital and home hospital program)
  • Previous participation in the "Observational study of acute intermittent porphyria patients" for at least six months.
  • Ability to follow instructions and cooperate during the study conduct

Exclusion Criteria:

  • Pregnant women, as confirmed by a positive urine pregnancy test, or with intention of becoming pregnant
  • Female subjects of childbearing potential who are not using barrier methods of contraception, at least during the study.
  • Male subjects with partners of child bearing potential who are not using barrier contraceptive methods, at least during the study
  • Acute or chronic liver disease of viral, autoimmune or metabolic causes
  • History of acute or chronic severe gastrointestinal dysfunction (different than those typical gastrointestinal symptoms associated with an acute attack of AIP), in the opinion of the principal investigator
  • Kidney disorder (renal impairment defined as plasma creatinine > 2 mg/dl (150 µmol/l)), severe respiratory disease, severe autoimmune disease or severe acute active infection
  • Evidence of active Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection as reflected by HBs antigen or HCV-antibodies positivity (in case of HCV-antibodies positivity a HCV-RNA test should be performed in order to confirm active viral replication)
  • Positive human immunodeficiency virus (HIV) serological test
  • History of drug use (cannabis, cocaine, amphetamines, barbiturates) or alcohol abuse or addiction, during the three months preceding the selection visit
  • Presence of neutralizing antibodies against adeno-associated serotype 5 (AAV5)
  • Current or previous (within the previous 12 months) participation in a gene therapy trial.
  • Previous participation (at any time) in a gene therapy trial using AAV vectors
  • Any other disease or condition that, in the opinion of the principal investigator, contraindicates the participation in the study because it can expose the patient to a risk or because it disqualifies the patient to complete the schedule of the study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02082860

Locations
Spain
Clinica Universidad de Navarra
Pamplona, Navarra, Spain, 31008
12 Octubre Hospital
Madrid, Spain, 28041
Sponsors and Collaborators
Digna Biotech S.L.
Porphyria Centre Sweden
Centro de Investigacion Medica Aplicada de Navarra
UniQure N. V.
Nationales Centrum für Tumorerkrankungen
Investigators
Study Chair: Juan Ruiz, MD Digna Biotech S.L.
Principal Investigator: Jesus Prieto, MD Clinica Universidad de Navarra
Principal Investigator: Rafael Enriquez de Salamanca, MD Hospital 12 de Octubre
  More Information

No publications provided

Responsible Party: Digna Biotech S.L.
ClinicalTrials.gov Identifier: NCT02082860     History of Changes
Other Study ID Numbers: AAVPBGD-AIP-001, 2011-005590-23
Study First Received: February 28, 2014
Last Updated: March 11, 2014
Health Authority: Spain: Agencia Española de Medicamentos y Productos Sanitarios

Keywords provided by Digna Biotech S.L.:
Porphyria
Gene therapy
AAV
Liver gene transfer

Additional relevant MeSH terms:
Porphyrias
Porphyria, Erythropoietic
Porphyria, Acute Intermittent
Porphyrias, Hepatic
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Skin Diseases, Metabolic
Skin Diseases
Metabolic Diseases
Skin Diseases, Genetic
Liver Diseases
Digestive System Diseases

ClinicalTrials.gov processed this record on August 01, 2014