Controlled Trial of Panhematin in Treatment of Acute Attacks of Porphyria

A Double-blind, Randomized, Placebo-controlled, Parallel Group Trial on the Efficacy and Safety of PanhematinTM in the Treatment of Acute Attacks of Porphyria

This study aims to provide high quality evidence for the effectiveness and safety of hemin (PanhematinTM , Recordati) for treatment of acute attacks of porphyria. These types of studies have not been done before with either PanhematinTM or the hemin preparation available in Europe (NormosangTM, Orphan Europe).

There are two treatment groups in this study. One group will be treated with PanhematinTM plus glucose, and the other group will be treated with glucose plus an inactive salt solution (called a "placebo"). To avoid prejudice, the treatment given to each participant will be blinded (meaning the participants and most of the hospital staff will not know which treatment the participant will receive) and randomized (meaning participants will have an equal chance of receiving either treatment, like the flip of a coin). A placebo-controlled, randomized study is the standard method used to prove treatments are effective and safe. PanhematinTM and glucose will be given in the same manner as is usual for treating an attack of porphyria. For participants who are chosen to receive the placebo, their treatment will be switched to real PanhematinTM at any time if their symptoms do not improve. This is called "rescue" treatment, and assures that they study is safe and patients who need hemin will receive it. Treatment with hemin will be for 4 days, or longer if needed. Since the study treatment is started as soon as possible after symptoms appear, there will be very little delay in providing hemin to those who need it. Funding Source - Office of Orphan Products Development (FDA OOPD)

Inclusion Criteria:

• Male or female aged 18 years
• Willing to provide written informed consent
• Acute symptoms (7 days duration or less to time of enrollment) such as abdominal, back and/or limb pain, diagnosed by the investigator as caused by porphyria after initial evaluation has excluded other causes.
• Diagnosis of acute porphyria documented by a substantial increase in urinary or serum porphobilinogen (PBG).
• Type of acute porphyria confirmed by additional testing (in addition to increased PBG), which may be completed before or after treatment begins using pretreatment samples:
• For acute intermittent porphyria (AIP): Normal or only slight increases in plasma and fecal porphyrins. Most (~90 percent) will have deficient activity of erythrocyte porphobilinogen deaminase (PBGD), and almost all (>95 percent) will have a demonstrable disease-causing PBGD mutation.
• For hereditary coproporphyria (HCP): Substantial increases in fecal porphyrins (almost entirely coproporphyrin III). In the absence of skin photosensitivity, most will have normal or only slight increases in plasma porphyrins. Almost all (>95 percent) will have a demonstrable disease-causing coproporphyrinogen oxidase (CPO) mutation.
• For variegate porphyria (VP): Substantial increases in fecal porphyrins (mostly coproporphyrin III and protoporphyrin), increased plasma total porphyrins and a fluorescence emission maximum of diluted plasma at neutral pH near 626 nm. Almost all (~95 percent) will have a demonstrable disease-causing protoporphyrinogen oxidase (PPO) mutation.

Exclusion Criteria:

• Symptoms such as abdominal, back or limb pain are explained by another condition, as judged by the investigator
• Therapy with hemin within 7 days prior to enrollment in this study
• Known or suspected allergy to Panhematin™ or related products
• Preexisting coagulation defect or concurrent treatment with an anticoagulant
• Previously documented renal impairment defined as a serum creatinine above 1.7 mg/dL or 150 mmol/L.
• A diagnosis of diabetes mellitus, which might increase the risk of glucose infusion.
• Heart failure, significant chronic anemia or any disease or condition that the investigator judges would lead to an unacceptable risk to the patient or interfere with the successful collection of date for the trial
• Previous randomization in this trial