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

NCT02082860 | Completed Phase 1 DMC

• 2 other identifiers: AAVPBGD-AIP-0012011-005590-23
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 2

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.

Conditions

Acute Intermittent Porphyria

Keywords

Porphyria; Gene therapy; AAV; Liver gene transfer

Outcome Measures

Primary Outcomes (1)

• Number of patients with Adverse Events and Serious Adverse Events

  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

  Up to 48 weeks

Secondary Outcomes (7)

• Effect of the treatment on porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) urinary level.

  Up to 48 weeks

• Clinical evolution of acute intermittent porphyria. Frequency of hospitalizations

  Up to 48 weeks

• Frequency of treatments for AIP symptoms

  Up to 48 weeks

• Psychological evaluation of AIP patients

  Up to 48 weeks

• Health related quality of life of AIP patients

  Up to 48 weeks

Study Arms (4)

Cohort A

EXPERIMENTAL

rAAV2/5-PBGD vector dosage 1

Genetic: rAAV2/5-PBGD vector dosage 1

Cohort B

EXPERIMENTAL

rAAV2/5-PBGD vector dosage 2

Genetic: rAAV2/5-PBGD vector dosage 2

Cohort C

EXPERIMENTAL

rAAV2/5-PBGD vector dosage 3

Genetic: rAAV2/5-PBGD vector dosage 3

Cohort D

EXPERIMENTAL

rAAV2/5-PBGD vector dosage 4

Genetic: rAAV2/5-PBGD vector dosage 4

Interventions

rAAV2/5-PBGD vector dosage 1 GENETIC

Intravenous injection of rAAV2/5-PBGD vector, single administration on Day 1.

Cohort A

rAAV2/5-PBGD vector dosage 2 GENETIC

Intravenous injection of rAAV2/5-PBGD vector, single administration on Day 1.

Cohort B

rAAV2/5-PBGD vector dosage 3 GENETIC

Intravenous injection of rAAV2/5-PBGD vector, single administration on Day 1.

Cohort C

rAAV2/5-PBGD vector dosage 4 GENETIC

Intravenous injection of rAAV2/5-PBGD vector, single administration on Day 1.

Cohort D

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Digna Biotech S.L.: lead
• Porphyria Centre Sweden: collaborator
• University of Navarra: collaborator
• UniQure N.V.: collaborator
• Nationales Centrum für Tumorerkrankungen: collaborator

Study Sites (2)

12 Octubre Hospital

Madrid, Madrid, 28041, Spain

Location

Clinica Universidad de Navarra

Pamplona, Navarre, 31008, Spain

Location

Related Publications (1)

• D'Avola D, Lopez-Franco E, Sangro B, Paneda A, Grossios N, Gil-Farina I, Benito A, Twisk J, Paz M, Ruiz J, Schmidt M, Petry H, Harper P, de Salamanca RE, Fontanellas A, Prieto J, Gonzalez-Aseguinolaza G. Phase I open label liver-directed gene therapy clinical trial for acute intermittent porphyria. J Hepatol. 2016 Oct;65(4):776-783. doi: 10.1016/j.jhep.2016.05.012. Epub 2016 May 17.

  PMID: 27212246 DERIVED

MeSH Terms

Conditions

Porphyria, Acute Intermittent; Porphyrias

Condition Hierarchy (Ancestors)

Porphyrias, Hepatic; Liver Diseases; Digestive System Diseases; Skin Diseases, Genetic; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin Diseases; Skin and Connective Tissue Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Juan Ruiz, MD

  Digna Biotech S.L.

  STUDY CHAIR

• Jesus Prieto, MD

  Clinica Universidad de Navarra

  PRINCIPAL INVESTIGATOR

• Rafael Enriquez de Salamanca, MD

  Hospital 12 de Octubre

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 28, 2014
• First Posted: March 10, 2014
• Study Start: November 1, 2012
• Primary Completion: July 1, 2014
• Study Completion: November 1, 2014
• Last Updated: December 18, 2014

Record last verified: 2014-12

Locations

ES (2)