Homozygous Familial Hypercholesterolemia (HoFH)Phase 1/2NCT02651675
A Gene Therapy Study for Homozygous Familial Hypercholesterolemia (HoFH)
A Phase 1/2 study testing AAV directed hLDLR gene therapy in people with Homozygous Familial Hypercholesterolemia (HoFH), run by REGENXBIO Inc. at 9 sites in 4 countries.
Trial summary
This first-in-human study is intended to evaluate the safety and preliminary effectiveness of AAV (Adeno-associated virus)-based liver-directed gene therapy in the treatment of adults with Homozygous Familial Hypercholesterolemia (HoFH). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Homozygous Familial Hypercholesterolemia (HoFH)
- What is being tested?
- AAV directed hLDLR gene therapy
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 9 participants
- Where
- 9 sitesin 4 countries
- Study dates
- Mar 2016to 27 Nov 2020
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male or female ≥ 18 years of age.
- Untreated and/or treated LDL-C levels and clinical presentation consistent with the diagnosis of homozygous FH (Familial hypercholesterolemia)
- Molecularly defined LDLR mutations at both LDLR alleles.
- A baseline serum AAV8 NAb (Neutralizing antibody) titer ≤ 1:10.
Who cannot join
- Unwilling to wash out of the following lipid lowering therapies for the pre-specified time period:
- niacin > 250 mg/day: within 6 weeks of baseline
- fibrates: within 4 weeks of baseline
- lomitapide: within 8 weeks of baseline
- mipomersen: within 24 weeks of baseline
- History of cirrhosis or chronic liver disease based on documented histological evaluation or non-invasive imaging or testing.
- Abnormal liver function tests (LFTs) at screening (AST (Aspartate aminotransferase) or ALT (Alanine aminotransferase) > 2 × upper limit of normal (ULN) and/or Total Bilirubin of > 1.5 × ULN
Trial locations and contacts
9 sites in 4 countries.
9 sites in 4 countries
United States5 sites
Boca Raton location
Boca Raton, Florida, 33434
Kansas City Location
Kansas City, Kansas, 66160
Nashville location
Nashville, Tennessee, 37232
Philadelphia Location
Philadelphia, Pennsylvania, 19104
Portland location
Portland, Oregon, 97239
About this study
Official title: AAV8-mediated Low Density Lipoprotein Receptor (LDLR) Gene Replacement in Subjects With Homozygous Familial Hypercholesterolemia (HoFH)
This first-in-human study is intended to evaluate the safety and preliminary effectiveness of AAV (Adeno-associated virus)-based liver-directed gene therapy in the treatment of adults with Homozygous Familial Hypercholesterolemia (HoFH).
Read the detailed description
Homozygous Familial Hypercholesterolemia (HoFH) is a rare genetic metabolic disorder characterized by absent or severely reduced capacity to catabolize circulating LDL (Low density lipoprotein) particles by the hepatic LDL receptor. As a consequence, HoFH subjects present abnormal total plasma cholesterol (LDL-C) levels, resulting in severe atherosclerosis often leading to early onset of cardiovascular disease. Early initiation of aggressive treatment for these patients is therefore essential. Unfortunately, despite existing therapies, treated LDL-C (Low density lipoprotein cholesterol) levels could remain well above acceptable levels. Thus, the functional replacement of the defective LDLR via AAV-based liver-directed gene therapy may be a viable approach to treat this disease and improve response to current lipid-lowering treatments. This first-in-human study is intended to evaluate the safety of this gene therapy investigational product and assess preliminary evidence of efficacy using plasma LDL-C levels as a surrogate biomarker for human LDLR transgene expression.
Subjects may be asked to participate in an optional kinetics study to assess the metabolic mechanism by which LDL-C is reduced.
- Being tested
- AAV directed hLDLR gene therapy
- Keywords
- LDL Receptors, Gene therapy, Metabolic Diseases, Rare diseases, Genetic Diseases, Atherosclerosis, cardiovascular disease
- Medical subject headings
- Homozygous Familial Hypercholesterolemia, Hyperlipoproteinemia Type II, Metabolic Diseases, Rare Diseases, Genetic Diseases, Inborn, Atherosclerosis, Cardiovascular Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AAV directed hLDLR gene therapyGenetic
AAV directed hLDLR gene therapy is a novel adeno-associated viral (AAV8) vector with human low-density lipoprotein receptor (hLDLR) gene
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1 | Experimental | 2.5E12 (genome copies)/kg (kilogram) body weight (E means the exponential constant) Receives: Genetic: AAV directed hLDLR gene therapy |
| Cohort 2 | Experimental | 7.5E12 GC/kg body weight Receives: Genetic: AAV directed hLDLR gene therapy |
| Cohort 2 Expansion | Experimental | 7.5E12 GC/kg body weight
DSMB (Data Safety Monitoring Board) approved expansion of Dose 2 cohort, 3 additional subjects enrolled and received prophylactic corticosteroids Receives: Genetic: AAV directed hLDLR gene therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With IP (Investigational Product) Related Adverse Events
Physical examinations; Clinical laboratory parameters; and adverse event reporting
Measured: Up to 24 weeks
Secondary outcomes (5)
Percent Change in LDL-C
Percent change in LDL-C compared to baseline
Measured: 18 weeks, 12 weeks for cohort 1 only, compared to baseline
Percent Change in Lipid Parameters Compared to Baseline Values
total cholesterol (TC); non-high density lipoprotein cholesterol (non-HDL-C); HDL-C; fasting triglycerides (TG); overflow density lipoprotein cholesterol (VLDL-C); lipoprotein(a) (Lp(a)); apolipoprotein B (apoB) and apolipoprotein A-I (apo A-I)
Measured: 18 weeks, 12 weeks for cohort 1 only, compared to baseline
Number of Participants With IP Related Adverse Events
Physical examinations; Clinical laboratory parameters; and adverse event reporting
Measured: up to 104 weeks
Amount of Vector Shedding, Urine
Amount of virus secreted in urine
Measured: up to 104 weeks
Amount of Vector Shedding, Plasma
Amount of virus secreted in plasma
Measured: up to 104 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Jan 2016 (estimated)
- Study startMar 2016
- Primary completion27 Nov 2020
- Study completion27 Nov 2020
Why it stopped: Terminated by Sponsor for Business Reasons
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Homozygous Familial Hypercholesterolemia (HoFH)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Model description
- dose escalation
- Masking
- None (open label)
- Enrolment
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- REGENXBIO Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02651675
- Sponsor's protocol ID
- FHGT002
- Other IDs
- P01HL059407
- Status last verified
- Jun 2023
- First submitted
- 4 Jan 2016
- Last updated
- 13 Jul 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 13 Jul 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- AAV8-mediated Low Density Lipoprotein Receptor (LDLR) Gene Replacement in Subjects With Homozygous Familial Hypercholesterolemia (HoFH)
- ClinicalTrials.gov ID
- NCT02651675
- Acronym / sponsor ID
- FHGT002
- Keywords
- LDL Receptors, Gene therapy, Metabolic Diseases, Rare diseases, Genetic Diseases, Atherosclerosis, cardiovascular disease
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Terminated by Sponsor for Business Reasons
- Enrolment
- 9 participants (actual)
- Lead sponsor
- REGENXBIO Inc.Industry (pharma, biotech, devices)
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Study start
- Mar 2016 (actual)
- Primary completion
- 27 Nov 2020 (actual)
- Study completion
- 27 Nov 2020 (actual)
- First posted
- 11 Jan 2016 (estimated)
- Results
- Posted 13 Jul 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This first-in-human study is intended to evaluate the safety and preliminary effectiveness of AAV (Adeno-associated virus)-based liver-directed gene therapy in the treatment of adults with Homozygous Familial Hypercholesterolemia (HoFH).
Detailed description
Homozygous Familial Hypercholesterolemia (HoFH) is a rare genetic metabolic disorder characterized by absent or severely reduced capacity to catabolize circulating LDL (Low density lipoprotein) particles by the hepatic LDL receptor. As a consequence, HoFH subjects present abnormal total plasma cholesterol (LDL-C) levels, resulting in severe atherosclerosis often leading to early onset of cardiovascular disease. Early initiation of aggressive treatment for these patients is therefore essential. Unfortunately, despite existing therapies, treated LDL-C (Low density lipoprotein cholesterol) levels could remain well above acceptable levels. Thus, the functional replacement of the defective LDLR via AAV-based liver-directed gene therapy may be a viable approach to treat this disease and improve response to current lipid-lowering treatments. This first-in-human study is intended to evaluate the safety of this gene therapy investigational product and assess preliminary evidence of efficacy using plasma LDL-C levels as a surrogate biomarker for human LDLR transgene expression.
Subjects may be asked to participate in an optional kinetics study to assess the metabolic mechanism by which LDL-C is reduced.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- dose escalation
| Arm | Type | Receives |
|---|---|---|
| Cohort 1 | Experimental | Genetic: AAV directed hLDLR gene therapy2.5E12 (genome copies)/kg (kilogram) body weight (E means the exponential constant) |
| Cohort 2 | Experimental | Genetic: AAV directed hLDLR gene therapy7.5E12 GC/kg body weight |
| Cohort 2 Expansion | Experimental | Genetic: AAV directed hLDLR gene therapy7.5E12 GC/kg body weight DSMB (Data Safety Monitoring Board) approved expansion of Dose 2 cohort, 3 additional subjects enrolled and received prophylactic corticosteroids |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Male or female ≥ 18 years of age.
- Untreated and/or treated LDL-C levels and clinical presentation consistent with the diagnosis of homozygous FH (Familial hypercholesterolemia)
- Molecularly defined LDLR mutations at both LDLR alleles.
- A baseline serum AAV8 NAb (Neutralizing antibody) titer ≤ 1:10.
Key exclusion criteria (7 listed)
- Unwilling to wash out of the following lipid lowering therapies for the pre-specified time period:
- History of cirrhosis or chronic liver disease based on documented histological evaluation or non-invasive imaging or testing.
- Abnormal liver function tests (LFTs) at screening (AST (Aspartate aminotransferase) or ALT (Alanine aminotransferase) > 2 × upper limit of normal (ULN) and/or Total Bilirubin of > 1.5 × ULN
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AAV directed hLDLR gene therapyAAV directed hLDLR gene therapy is a novel adeno-associated viral (AAV8) vector with human low-density lipoprotein receptor (hLDLR) gene | Genetic | Cohort 1, Cohort 2, Cohort 2 Expansion |
Primary outcome
Number of Participants With IP (Investigational Product) Related Adverse Events
Time frame: Up to 24 weeks
Physical examinations; Clinical laboratory parameters; and adverse event reporting
5 secondary outcomes
Percent Change in LDL-C
Time frame: 18 weeks, 12 weeks for cohort 1 only, compared to baseline
Percent Change in Lipid Parameters Compared to Baseline Values
Time frame: 18 weeks, 12 weeks for cohort 1 only, compared to baseline
Number of Participants With IP Related Adverse Events
Time frame: up to 104 weeks
Amount of Vector Shedding, Urine
Time frame: up to 104 weeks
Amount of Vector Shedding, Plasma
Time frame: up to 104 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Jul 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
9 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing AAV directed hLDLR gene therapy in people with Homozygous Familial Hypercholesterolemia (HoFH), run by REGENXBIO Inc. at 9 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 13 Jul 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 9 sites in United States, Italy, Canada, Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 13 Jul 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With IP (Investigational Product) Related Adverse Events (time frame: Up to 24 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Jul 2023.