Panhematin for Prevention of Acute Attacks of Porphyria

Safety and Efficacy of Panhematin™ for Prevention of Acute Attacks of Porphyria

The purpose of this study is to determine if Panhematin is safe and effective for prevention of acute attacks of porphyria.

The study aims to provide high quality evidence for the use on hemin for prevention of acute attacks of porphyria. High quality studies have not been done previously for treating or preventing acute attacks with hemin. The lack of strong evidence for efficacy of hemin for treatment and prevention of attacks limits its availability for patients with acute porphyrias. Funding source: FDA Office of Orphan Product Development (FDA OOPD) FD-R-03720

This is a double-blind, randomized, placebo-controlled, parallel group trial investigating the efficacy and safety of Panhematin™ for preventing acute attacks in at least 20 subjects with well-documented acute porphyria (acute intermittent porphyria, hereditary coproporphyria or variegate porphyria). Subjects will (1.) have had frequent attacks in the past, with symptoms such as abdominal, back and/or limb pain and diagnosed after exclusion of other causes, and (2.) be on hemin prophylaxis for prevention of frequent attacks. It is expected that they will have had 6 or more attacks in one year before starting hemin prophylaxis. This would be considered justification for a preventive regimen of hemin on clinical grounds. Double blind Panhematin™ or placebo will be given. The number of doses will correspond to the number of doses that a subject receives in approximately one week for their prophylactic regimen. An interim analysis will be carried out after completion of 10 subjects to assess progress and possibly adjust the sample size. The trial consists of the following visits:

• A screening visit to determine eligibility and obtain informed consent.
• A treatment visit for administration of double blind prophylactic doses of Panhematin™ or placebo corresponding to the number of doses the subject receives for their prophylactic regimen within approximately one week.
• Follow up visit at 1, 2, 3, and 4 weeks to assess response to the infusion of Panhematin™ or placebo. These visits will be in person or by telephone.
• Additional visits may be scheduled if needed, for example for treatment of symptoms.
• Follow-up visits 3 and 6 months after the end of treatment either in person or by telephone Subjects will have laboratory documentation of one of the acute porphyrias. Molecular documentation is also expected, although rarely a causative mutation cannot be detected. Upon entry into the study they will be given in a blinded fashion one or more preventive doses of either Panhematin™ (4 mg/kg) or placebo, the number of which will correspond to the number of prophylactic doses they have been receiving within approximately one week for prophylaxis. A recurrent attack within the next 1, 2, 3 and 4 weeks will represent treatment failures. Because at study entry most subjects are expected to be on weekly prophylactic hemin treatment, and hemin is a short-acting drug, emphasis in the analysis will be on attacks occurring within 1 week after study treatment.

Any attacks that occur during the study will be treated according to standard of care, which may include Panhematin™, either at the study site or at a subject's usual treatment location.

It is intended that 20 subjects will complete treatment with blinded treatment and at least 4 weeks of follow up. A completed subject is one who meets all entrance criteria, has no exclusion criteria and completes the single dosing and at least one week of follow up, or is withdrawn because of an adverse event.

Inclusion Criteria:

1. Male or female aged 18 years
2. Willing to provide written informed consent
3. A diagnosis of acute intermittent porphyria, hereditary coproporphyria or variegate porphyria confirmed by the following criteria, which are based on the criteria for enrollment in the Longitudinal Study of the Porphyrias Consortium. For each type of porphyria, the inclusion criteria are based on 1) clinical features, 2) biochemical findings, as documented by laboratory reports (or copies) of porphyria-specific testing, and 3) molecular studies to identify a mutation in a porphyria-related gene. Equivocal biochemical measurements may require confirmatory testing. Testing for a disease-causing mutation must be attempted, but an identified mutation is not essential for enrollment, since it is known that a mutation cannot be found in a small fraction (<5%) of biochemically proven cases of porphyria. Subjects will (1.) have had frequent attacks in the past, with symptoms such as abdominal, back and/or limb pain and diagnosed after exclusion of other causes, and (2.) be on hemin prophylaxis for prevention of frequent attacks. It is expected that they will have had 6 or more attacks in one year before starting hemin prophylaxis.

Exclusion Criteria:

1. Symptoms such as abdominal, back or limb pain are explained by another condition, as judged by the investigator
2. Known or suspected allergy to Panhematin™ or related products
3. A known or suspected allergy to human albumin
4. Any disease or condition that the investigator judges would lead to an unacceptable risk to the patient or interfere with the successful collection of data for the trial
5. Previous randomization in this trial