Acute Intermittent Porphyria
Conditions
Keywords
RNAi therapeutic, Porphyria, AIP, Heme/Haem Arginate
Brief summary
The purpose of this study is to determine the long-term safety, tolerability and pharmacokinetics of givosiran (ALN-AS1) in AIP patients who completed study ALN-AS1-001 (NCT02452372).
Interventions
DRUGGivosiran
Givosiran by subcutaneous (SC) injection.
Sponsors
Alnylam Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Completed participation in Part C of study ALN-AS1-001 (NCT02452372) * Not on a scheduled regimen of hemin * Women of child bearing potential must have a negative serum pregnancy test, not be nursing, and use acceptable contraception * Willing and able to comply with the study requirements and to provide written informed consent
Exclusion criteria
* Clinically significant abnormal laboratory results * Received an investigational agent (other than ALN-AS1) within 90 days before the first dose of study drug or are in follow-up of another clinical study * History of multiple drug allergies or intolerance to subcutaneous injection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adverse Events (AEs) | Through Month 49 | An AE is any untoward medical occurrence in a participant or clinical investigational patient administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Pharmacodynamic (PD) Effect of Givosiran on Urine Levels of Delta-aminolevulinic Acid (ALA) as Measured by Percent Decrease From Baseline | Baseline; Month 48 | The PD effect of givosiran was evaluated by spot urine ALA levels normalized to spot urine creatinine levels. |
| The Pharmacodynamic (PD) Effect of Givosiran on Urine Levels of Porphobilinogen (PBG) as Measured by Percent Decrease From Baseline | Baseline; Month 48 | The PD effect of givosiran was evaluated by spot urine PBG levels normalized to spot urine creatinine levels. |
| Annualized Rate of Composite Porphyria Attacks | Through Month 48 | Porphyria attacks were defined as meeting all of the following criteria: an acute episode of neurovisceral pain in the abdomen, back, chest, extremities and/or limbs, no other medically determined cause, and required treatment with intravenous (IV) dextrose or hemin, carbohydrates, or analgesics, or other medications such as antiemetics at a dose or frequency beyond the participant's usual daily porphyria management. Composite porphyria attacks included porphyria attacks that required hospitalization, urgent healthcare visit, or intravenous (IV) hemin administration at home. The annualized attack rate (AAR) was calculated as the number of composite porphyria attacks/total person-years. |
| Annualized Rate of Hemin Administration | Through Month 49 | The annualized rate of hemin administration was evaluated by annualized days of hemin use, which is calculated as the number of doses of hemin administered/total person-years. |
Countries
Sweden, United Kingdom, United States
Participant flow
Recruitment details
Patients with acute intermittent porphyria (AIP) were enrolled at five sites in Sweden, United Kingdom and the United States.
Pre-assignment details
Patients who completed parent study ALN-AS1-001 (NCT02452372) and met all eligibility criteria for this study (ALN-AS1-002) were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Givosiran At the beginning of this study, participants received either givosiran 2.5 mg/kg subcutaneous (SC) injection once monthly (QM), givosiran 5.0 mg/kg SC injection QM, or givosiran 5.0 mg/kg SC injection once every 3 months (Q3M). Within a year, all participants were transitioned to givosiran 2.5 mg/kg SC injection QM. | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Givosiran |
|---|---|
| Age, Continuous | 37.4 years STANDARD_DEVIATION 12 |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 15 Participants |
| Race/Ethnicity, Customized Not Reported | 1 Participants |
| Race/Ethnicity, Customized White | 13 Participants |
| Region of Enrollment Sweden | 6 Participants |
| Region of Enrollment United Kingdom | 1 Participants |
| Region of Enrollment United States of America | 9 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 16 |
| other Total, other adverse events | 16 / 16 |
| serious Total, serious adverse events | 7 / 16 |
Outcome results
Primary
Percentage of Participants With Adverse Events (AEs)
An AE is any untoward medical occurrence in a participant or clinical investigational patient administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.
Time frame: Through Month 49
Population: SAS: All patients who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Givosiran | Percentage of Participants With Adverse Events (AEs) | 100 percentage of participants |
Secondary
Annualized Rate of Composite Porphyria Attacks
Porphyria attacks were defined as meeting all of the following criteria: an acute episode of neurovisceral pain in the abdomen, back, chest, extremities and/or limbs, no other medically determined cause, and required treatment with intravenous (IV) dextrose or hemin, carbohydrates, or analgesics, or other medications such as antiemetics at a dose or frequency beyond the participant's usual daily porphyria management. Composite porphyria attacks included porphyria attacks that required hospitalization, urgent healthcare visit, or intravenous (IV) hemin administration at home. The annualized attack rate (AAR) was calculated as the number of composite porphyria attacks/total person-years.
Time frame: Through Month 48
Population: SAS: All patients who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Givosiran | Annualized Rate of Composite Porphyria Attacks | 0.4 composite attacks/total person-years |
Secondary
Annualized Rate of Hemin Administration
The annualized rate of hemin administration was evaluated by annualized days of hemin use, which is calculated as the number of doses of hemin administered/total person-years.
Time frame: Through Month 49
Population: SAS: All patients who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Givosiran | Annualized Rate of Hemin Administration | 0.9 hemin doses/total person-years |
Secondary
The Pharmacodynamic (PD) Effect of Givosiran on Urine Levels of Delta-aminolevulinic Acid (ALA) as Measured by Percent Decrease From Baseline
The PD effect of givosiran was evaluated by spot urine ALA levels normalized to spot urine creatinine levels.
Time frame: Baseline; Month 48
Population: Patients from the PD Analysis Set (all patients who received any amount of study drug and who had at least 1 post-dose blood sample for PD), who were treated with givosiran 2.5 mg/kg SC injection QM. Values that occurred during a porphyria attack were excluded as a means of controlling for potential confounding by hemin. Overall number of participants analyzed is the number of participants available at the given time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Givosiran | The Pharmacodynamic (PD) Effect of Givosiran on Urine Levels of Delta-aminolevulinic Acid (ALA) as Measured by Percent Decrease From Baseline | 92.531 percent decrease | Standard Error 1.879 |
Secondary
The Pharmacodynamic (PD) Effect of Givosiran on Urine Levels of Porphobilinogen (PBG) as Measured by Percent Decrease From Baseline
The PD effect of givosiran was evaluated by spot urine PBG levels normalized to spot urine creatinine levels.
Time frame: Baseline; Month 48
Population: Patients from the PD Analysis Set (all patients who received any amount of study drug and who had at least 1 post-dose blood sample for PD), who were treated with givosiran 2.5 mg/kg SC injection QM. Values that occurred during a porphyria attack were excluded as a means of controlling for potential confounding by hemin. Overall number of participants analyzed is the number of participants available at the given time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Givosiran | The Pharmacodynamic (PD) Effect of Givosiran on Urine Levels of Porphobilinogen (PBG) as Measured by Percent Decrease From Baseline | 94.194 percent decrease | Standard Error 2.617 |