Acute Porphyrias
Conditions
Keywords
Acute porphyria, Hemin
Brief summary
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)
Interventions
BIOLOGICALPanhematin
Glucose loading
OTHERGlucose
Glucose is administered to both groups as routine care.
Sponsors
The University of Texas Medical Branch, Galveston
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in NRS Pain Score Between Baseline and 12 Hours | Baseline and 12 hours | The difference in the pre-infusion NRS pain scores and NRS pain score 12 hours from the infusion start time. To define this variable, all blinded study treatment infusion times were compared with the pain score survey times. The pain score closest to but prior to the infusion time was the pre-infusion pain score. Numeric rating scale for pain (0-10; 0=no pain, 10=most severe pain). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Biochemical Effects of Panhematin In Participants Treated Early For Attacks of Porphyria | Day 1 (baseline), Day 2, Day 3 and Day 4 | Difference in the panhematin and placebo arm for the change in urinary ALA, (PBG), and total porphyrins between baseline and subsequent time points. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Effects of Clinical Features on Response to Panhematin | 4 days | Age, sex, exacerbating factors |
| Effects of Genetic Features on Response to Panhematin | 4 days | Types of mutations |
| Use of Reconstitution of Panhematin With Albumin | 4 days | Frequency of side effects or adverse events |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Panhematin Panhematin plus glucose
Panhematin: Glucose loading
Glucose: Glucose is administered to both groups as routine care. | 10 |
| Placebo Placebo (saline) plus glucose
Glucose: Glucose is administered to both groups as routine care. | 10 |
| Total | 20 |
Baseline characteristics
| Characteristic | Placebo | Total | Panhematin |
|---|---|---|---|
| Age, Continuous | 36.7 years STANDARD_DEVIATION 11.2 | 36.7 years STANDARD_DEVIATION 8.8 | 36.6 years STANDARD_DEVIATION 6.2 |
| Race/Ethnicity, Customized Hispanic | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Non-Hispanic American Indian or Alaskan native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Non-Hispanic Asian | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Non-Hispanic Black or African American | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Non-Hispanic White | 6 Participants | 15 Participants | 9 Participants |
| Sex: Female, Male Female | 10 Participants | 20 Participants | 10 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 0 / 10 | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 |
Outcome results
Primary
Difference in NRS Pain Score Between Baseline and 12 Hours
The difference in the pre-infusion NRS pain scores and NRS pain score 12 hours from the infusion start time. To define this variable, all blinded study treatment infusion times were compared with the pain score survey times. The pain score closest to but prior to the infusion time was the pre-infusion pain score. Numeric rating scale for pain (0-10; 0=no pain, 10=most severe pain).
Time frame: Baseline and 12 hours
Population: One participant was randomized incorrectly and didn't meet inclusion criteria. Therefore, this analysis was done without one participant, making this analysis done under modified intent-to-treat protocol, not true intent-to-treat protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Panhematin | Difference in NRS Pain Score Between Baseline and 12 Hours | -0.2 score on a scale | Standard Deviation 2.2 |
| Placebo | Difference in NRS Pain Score Between Baseline and 12 Hours | -0.2 score on a scale | Standard Deviation 1.9 |
Secondary
Biochemical Effects of Panhematin In Participants Treated Early For Attacks of Porphyria
Difference in the panhematin and placebo arm for the change in urinary ALA, (PBG), and total porphyrins between baseline and subsequent time points.
Time frame: Day 1 (baseline), Day 2, Day 3 and Day 4
Population: One participant was randomized incorrectly and didn't meet inclusion criteria. Therefore, this analysis was done without one participant, making this analysis done under modified intent-to-treat protocol, not true intent-to-treat protocol.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Panhematin | Biochemical Effects of Panhematin In Participants Treated Early For Attacks of Porphyria | PBG Day 1 vs Day 4 | 20.16 mean difference of mg/g creatinine | Standard Deviation 18.63 |
| Panhematin | Biochemical Effects of Panhematin In Participants Treated Early For Attacks of Porphyria | Total Porphyrins Day 1 vs Day 2 | 297.60 mean difference of mg/g creatinine | Standard Deviation 948.9 |
| Panhematin | Biochemical Effects of Panhematin In Participants Treated Early For Attacks of Porphyria | ALA Day 1 vs Day 2 | 8.47 mean difference of mg/g creatinine | Standard Deviation 8.97 |
| Panhematin | Biochemical Effects of Panhematin In Participants Treated Early For Attacks of Porphyria | ALA Day 1 vs Day 3 | 13.27 mean difference of mg/g creatinine | Standard Deviation 11.45 |
| Panhematin | Biochemical Effects of Panhematin In Participants Treated Early For Attacks of Porphyria | ALA Day 1 vs Day 4 | 14.90 mean difference of mg/g creatinine | Standard Deviation 11.85 |
| Panhematin | Biochemical Effects of Panhematin In Participants Treated Early For Attacks of Porphyria | PBG Day 1 vs Day 2 | 6.56 mean difference of mg/g creatinine | Standard Deviation 11.69 |
| Panhematin | Biochemical Effects of Panhematin In Participants Treated Early For Attacks of Porphyria | PBG Day 1 vs Day 3 | 15.56 mean difference of mg/g creatinine | Standard Deviation 17.88 |
| Panhematin | Biochemical Effects of Panhematin In Participants Treated Early For Attacks of Porphyria | Total Porphyrins Day 1 vs Day 3 | 594.00 mean difference of mg/g creatinine | Standard Deviation 1173.48 |
| Panhematin | Biochemical Effects of Panhematin In Participants Treated Early For Attacks of Porphyria | Total Porphyrins Day 1 vs Day 4 | 606.11 mean difference of mg/g creatinine | Standard Deviation 1238.87 |
| Placebo | Biochemical Effects of Panhematin In Participants Treated Early For Attacks of Porphyria | Total Porphyrins Day 1 vs Day 4 | 331.33 mean difference of mg/g creatinine | Standard Deviation 836.59 |
| Placebo | Biochemical Effects of Panhematin In Participants Treated Early For Attacks of Porphyria | PBG Day 1 vs Day 4 | -5.83 mean difference of mg/g creatinine | Standard Deviation 20 |
| Placebo | Biochemical Effects of Panhematin In Participants Treated Early For Attacks of Porphyria | PBG Day 1 vs Day 2 | -2.94 mean difference of mg/g creatinine | Standard Deviation 12.85 |
| Placebo | Biochemical Effects of Panhematin In Participants Treated Early For Attacks of Porphyria | Total Porphyrins Day 1 vs Day 3 | 165.00 mean difference of mg/g creatinine | Standard Deviation 678.41 |
| Placebo | Biochemical Effects of Panhematin In Participants Treated Early For Attacks of Porphyria | ALA Day 1 vs Day 2 | 2.31 mean difference of mg/g creatinine | Standard Deviation 5.5 |
| Placebo | Biochemical Effects of Panhematin In Participants Treated Early For Attacks of Porphyria | PBG Day 1 vs Day 3 | -7.08 mean difference of mg/g creatinine | Standard Deviation 10.76 |
| Placebo | Biochemical Effects of Panhematin In Participants Treated Early For Attacks of Porphyria | ALA Day 1 vs Day 3 | -0.57 mean difference of mg/g creatinine | Standard Deviation 6.01 |
| Placebo | Biochemical Effects of Panhematin In Participants Treated Early For Attacks of Porphyria | Total Porphyrins Day 1 vs Day 2 | 317.00 mean difference of mg/g creatinine | Standard Deviation 682.93 |
| Placebo | Biochemical Effects of Panhematin In Participants Treated Early For Attacks of Porphyria | ALA Day 1 vs Day 4 | 1.99 mean difference of mg/g creatinine | Standard Deviation 10.73 |
Comparison: ALA Day 1 vs Day 2p-value: 0.043495% CI: [2.14, 13.37]ANCOVA
Comparison: ALA Day 1 vs Day 3p-value: 0.000395% CI: [11.32, 21.25]ANCOVA
Comparison: ALA Day 1 vs Day 4p-value: 0.019895% CI: [6.7, 25.26]ANCOVA
Comparison: PBG Day 1 vs Day 2p-value: 0.15895% CI: [-1.67, 22.49]ANCOVA
Comparison: PGB Day 1 vs Day 3p-value: 0.012795% CI: [11.3, 37.74]ANCOVA
Comparison: PBG Day 1 vs Day 4p-value: 0.032895% CI: [9.64, 47.27]ANCOVA
Comparison: Total Porphyrins Day 1 vs Day 2p-value: 0.999395% CI: [-465.4, 489.8]ANCOVA
Comparison: Total Porphyrins Day 1 vs Day 3p-value: 0.291595% CI: [-200.87, 1109.86]ANCOVA
Comparison: Total Porphyrins Day 1 vs Day 4p-value: 0.438295% CI: [-292, 944.25]ANCOVA
Other Pre-specified
Effects of Clinical Features on Response to Panhematin
Age, sex, exacerbating factors
Time frame: 4 days
Other Pre-specified
Effects of Genetic Features on Response to Panhematin
Types of mutations
Time frame: 4 days
Other Pre-specified
Use of Reconstitution of Panhematin With Albumin
Frequency of side effects or adverse events
Time frame: 4 days