Sample Data and Safety Monitoring Plan

Study Title: A Multi-Center, Double-Blind, Randomized, Placebo-Controlled, Parallel Group Trial, Investigating the Efficacy and Safety of PorphozymÔ (Recombinant Human Porphobilinogen Deaminase) in the Treatment of Acute Attacks in AIP

Key personnel:
Principal Investigator: Karl E. Anderson, M.D.
Co-Investigator: Chul Lee, Ph.D.
Study Coordinator: Csilla K. Hallberg, M.D.
Primary Study Contact: Karl E. Anderson, M.D.; kanderso@utmb.edu; 772-4661 (voice); 409-772-6287 (fax); 409-643-2814 (page)

Protocol Identification Numbers:
IRB#: 03-070
CRC#: 617
IND #: IND 10863-Porphyzymeä(rhPBGD)

Study Summary: Acute intermittent porphyria (AIP) is a genetic (autosomal dominant) disease due to a deficiency of porphobilinogen deaminase (PBGD). Excess porphobilinogen and other heme biosynthetic pathway intermediates accumulate in liver and plasma and are excreted in urine. Symptoms occur mostly as acute attacks due to effects on the nervous system. Standard therapies include intravenous glucose and hemin (hematin, heme albumin or heme arginate), but these are not always effective. The primary objective of this multi-center, double-blind, randomized, placebo-controlled, parallel group, Phase II-III trial is to investigate the biochemical efficacy of Porphozym™ (recombinant human porphobilinogen deaminase, rhPBGD) on plasma porphobilinogen in subjects with acute intermittent porphyria (AIP) during an attack. Secondary objectives include assessments of clinical efficacy and pharmacokinetics of rhPBGD in plasma. At least 36 subjects will be enrolled in the trial, both in Europe and the U.S., including up to 12 at UTMB. Potential patients who are likely to have recurrent attacks are informed of the study in advance and encouraged to come to the hospital early in an attack. After a screening period that is as short as possible (£4 hours) subjects enrolled in the trial will be randomized to treatment with either Porphozym™ or placebo, as well as glucose. If the symptoms of porphyria become worse during treatment the trial drug may be discontinued and the patient treated with hemin. Treatment with trial drug is given over 48 hours, after which standard treatment, including hemin, may be given if clinically indicated. Follow-up visits will occur up to 6 months after end of treatment.

Level of risk: There have been no adverse effects in human studies to date. The level of risk for this study is considered moderate because it involves an investigational drug and requires multiple blood drawings. All known risks have been described in the protocol, consent form and investigator brochure.

Plan for safety monitoring and review: At UTMB, the Principal Investigator, Karl E. Anderson, M.D., is responsible for ensuring that appropriate medical care and medical coverage is provided to all subjects participating in this study on the CRC or elsewhere in UTMB Hospital. This responsibility may be delegated to a qualified physician, fellow, or resident who possesses the requisite clinical expertise and patient care privileges.

The Principal Investigator is responsible for monitoring procedures during the conduct of the study in each patient, including enrollment, data and sample collection and subject safety and well-being.

During the course of the trial, the sponsor's clinical study monitor will visit the trial site at regular intervals and must be available for discussions by telephone. The purposes of these visits are to verify: that the rights and well-being off trial subjects are protected, that the reported trial data are accurate, complete, and verifiable from source documents and that the conduct of the trial is in compliance with the currently approved protocol and amendments, with GCP, and with the applicable regulatory requirements.

An external Safety Monitoring Committee (SMC) has been convened by the sponsor, and meets at 3 month intervals.

Documents describing the organization, responsibilities, and operation of these monitoring entities have been provided to the IRB and the CRC Research Subject Advocate. The results of these reviews will be distributed to the CRC Research Subject Advocate through the IRB.

Plan for adverse event reporting: At UTMB, monitoring for and documentation of adverse events on the CRC, whether anticipated or unanticipated, is the responsibility of the Principal Investigator who will maintain oversight but may delegate collection of information related to this function to Csilla K. Hallberg, M.D.

Reporting requirements for adverse events are detailed in the protocol, and the scale used to assess severity is the Common Toxicity Criteria Scale. All Serious Adverse Experiences, whether deemed drug-related or expected, must be documented on the Case Report Form, reported by the Principal Investigator to the sponsor immediately or within 24 hours by telephone.

In addition, the Principal Investigator will follow the reporting requirements for serious and unexpected adverse events outlined in the UTMB IRB Adverse Event Policy. All unanticipated, serious, fatal and/or life-threatening adverse events will be reported to the UTMB IRB, CRC Program Director and Research Subject Advocate, and the sponsor within 24 hours of occurrence or recognition. Aggregate reports of adverse events will be prepared on an annual basis and forwarded to the IRB and CRC at annual review.

Plan for data management: Case report forms (CRFs) will be used for each subject. To protect the participant's right of privacy, the Patient Identification Number (PID) will identify subjects and the sponsor will provide Study Identification Number (SID). Site monitors will visit participating clinical research sites to review the individual subject records, including consent forms, CRFs, supporting data, laboratory specimen records, and medical records (physicians' progress notes, nurses' notes, individuals' hospital charts), to ensure protection of study subjects, compliance with the protocol, and accuracy and completeness of records. The monitor must be given direct access to source documents (original documents, data and records). Direct access includes permission to examine, analyze, verify and reproduce any records and reports that are important to the evaluation of the clinical trial. Any copies made of records to be removed from the site will not include identifying information other than PID or SID. Items required for review are listed in the study protocol. The monitor will ensure that the CRFs are collected. Further management of the data will be the responsibility of the sponsor.