Primary* Evaluate the safety and tolerability of single- and multiple-ascending doses of ALN-GO1, respectively, in healthy adult subjects and in patients with PH1Secondary* Characterize the pharmacokinetics (PK) of ALN-GO1* Evaluate the…
ID
Source
Brief title
Condition
- Inborn errors of metabolism
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary
* The primary endpoint is the incidence of adverse events. Safety will also be
evaluated through vital signs, electrocardiograms, clinical laboratory
assessments, and physical examinations.
Secondary outcome
Secondary Endpoints for Part B
o PK parameters including, but not limited to, Cmax, tmax, AUC, t*, fe/F, and
CLR
o Urinary oxalate excretion (oxalate concentration in 24-hour urine collection)
o Urinary glycolate excretion (glycolate concentration in 24-hour urine
collection)
o Plasma glycolate concentration
o Calculated creatinine clearance
Background summary
Currently, there are no approved therapies for the treatment of PH1. Disease
management is based on supportive measures, including high fluid intake,
potassium citrate (to increase urinary oxalate solubility), Vitamin B6, and
treatment of complications such as urinary tract stones and infections.
Therefore, there is a high unmet medical need for additional treatments for
patients with PH1.
Study objective
Primary
* Evaluate the safety and tolerability of single- and
multiple-ascending doses of ALN-GO1, respectively,
in healthy adult subjects and in patients with PH1
Secondary
* Characterize the pharmacokinetics (PK) of ALN-GO1
* Evaluate the pharmacodynamics (PD) of ALN-GO1
Exploratory
* Characterize exploratory biomarkers of PH1
* Characterize the PK of metabolites of ALN-GO1
Study design
This is a randomized, single-blind, placebo-controlled study of subcutaneously
administered ALN-GO1. Subjects and patients will be randomized in a 3:1 ratio
to receive either ALN-GO1 or placebo. The study is designed to evaluate the
safety, tolerability, PK, and PD of single- and multiple-ascending doses of
ALN-GO1 and will be conducted in 2 parts:
* Part A: SAD part in healthy adult subjects
* Part B: MAD part in adult and pediatric patients with PH1
In Part A, subjects in each cohort will be randomized to receive 1 dose of
ALN-GO1 or placebo.
In Part B, patients will be enrolled in up to 6 sequential dose cohorts to
receive ALN-GO1 or placebo monthly or quarterly. Patients dosed monthly will
receive 3 doses of ALN-GO1 or placebo. After completion of the blinded portion
of the study, patients dosed monthly will be unblinded on or after Day 78.
Patients who initially received placebo will then receive 3 doses of open-label
ALN-GO1 dosed monthly at the same dose administered to the cohort into which
they were initially randomized and will follow the same assessment schedule.
Patients dosed quarterly will receive either ALN-GO1 or placebo on Day 1. All
patients in quarterly dosing cohorts, including those initially randomized to
placebo, will receive open-label ALN-GO1 on Day 85 at the same dose
administered to the cohort into which they were initially randomized. Up to 2
expansion cohorts in Part B may be enrolled based on available safety and PD
data; these patients will all receive open-label ALN-GO1, not placebo.
After the dosing period, patients will return to the clinical study center for
continued safety, tolerability, PK, and PD monitoring for at least 12 weeks (84
days) following the last dose of study drug. Following completion of the
12-week postdose follow-up period, patients will be invited to participate
in an open-label extension study.
For patients who do not enroll in the open-label extension study, safety and PD
follow up will continue until 24-hour urinary oxalate is >80% of baseline, and
plasma glycolate is <20% above baseline or = the ULN. If an investigator
wishes to discontinue follow-up after completion of the postdose follow-up
period and prior to oxalate and glycolate recovery, the Safety Review Committee
(SRC) must agree based upon consideration of emerging data on the safety of
ALN-GO1 knockdown and the individual patient*s safety and PD data.
A Safety Review Committee (SRC) will perform ongoing reviews of safety,
tolerability, and available PD data, with the primary purpose of protecting the
safety of subjects/patients participating in this clinical study.
Intervention
ALN-GO1 is a synthetic, double-stranded small interfering RNA oligonucleotide
directed against hydroxyacid oxidase 1 mRNA that is covalently linked to a
ligand containing 3 N-acetylgalactosamine residues. ALN-GO1 will be supplied as
a sterile solution for subcutaneous (SC) injection at a targeted concentration
of 200 mg/mL.
Study burden and risks
ALN-GO1 is designed to reduce hepatic production of oxalate. The potential
benefit of this treatment is the amelioration of the clinical course of PH1 in
patients across the spectrum of disease, irrespective of age and disease stage;
however, patients with PH1 in this study may not receive treatment for a
sufficient duration, or at an adequate dose, to experience clinical benefit.
The potential benefit to children enrolled in this study includes possible
reduction in oxalate production during the study period, which may have a
temporarily ameliorating effect on their disease. In addition, experience in
children with this disease under carefully controlled conditions will provide
data that may enhance the future development of this therapeutic.
Moreover, since evaluation of safety and PD effects in children will be
important in the design of future studies, it is considered important and
appropriate to enroll children in the current study.
Third Street 300
Cambridge 02142 MA
US
Third Street 300
Cambridge 02142 MA
US
Listed location countries
Age
Inclusion criteria
1. Male and female subjects aged 18-64 years (or age of legal consent,
whichever is older), inclusive (Part A) and 6-64 years, inclusive (Part B).
2. Women of child bearing potential must have a negative pregnancy
test, cannot be breastfeeding, and must be willing to use contraception.
3. Willing to provide written informed consent and to comply with study
requirements.
Additional Inclusion Criteria for Part B:
4. confirmation of PH1 disease.
5. 24-hour urinary oxalate excretion of >0.7 mmol/1.73m2/day.
6.Estimated GFR of >45 mL/min/1.73m2.
7. If taking Vitamin B6 (pyridoxine), must have been on stable regimen
for at least 90 days .
Exclusion criteria
1. Any uncontrolled or serious disease, or any medical or surgical
condition (with the exception of PH1 for patients in Part B) that may
either interfere with participation in the clinical study, and/or put the
subject at significant risk (according to the Investigator's judgment) if
he/she participates in the clinical study.
2. Mental illness, alcoholism, drug abuse, or heavy smokers and users of
nicotine
3. History of multiple drug allergies or intolerance to subcutaneous
injection
4. Received an investigational agent within 3 months before the first
dose of study drug or are in follow-up of another clinical study
5. Known history of allergic reaction to an oligonucleotide or GalNAc
6. History of intolerance to SC injection or relevant abdominal scarring
7. Women who are pregnant or breast feeding
Part B only
8. Echocardiography (ECHO) assessment of normal left ventricular systolic function, defined as left ventricular ejection fraction <55% at screening
9. Troponin I > the upper limit of normal (ULN) at screening
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-004407-23-NL |
| CCMO | NL58243.000.16 |