Amyloidogenic Transthyretin (ATTR) AmyloidosisPhase 1NCT03336580
A Study of PRX004 in Subjects With Amyloid Transthyretin (ATTR) Amyloidosis
A Phase 1 study testing PRX004 in people with Amyloidogenic Transthyretin (ATTR) Amyloidosis, run by Prothena Biosciences Limited at 7 sites in 4 countries.
Trial summary
A Phase 1, open-label study of intravenous (IV) PRX004 as a single agent in subjects with hereditary amyloid transthyretin (hATTR) amyloidosis. The study will consist of 3 phases and will enroll up to a total of 36 subjects. A 3+3 dose escalation component to determine the safety, tolerability, PK, PD, and MTD. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Amyloidogenic Transthyretin (ATTR) Amyloidosis
- What is being tested?
- PRX004
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 21 participants
- Where
- 7 sitesin 4 countries
- Study dates
- 5 Apr 2018to 23 Jul 2020
- Phase
- Phase 1
- Are there results?
- None posted in the registry
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
- Age ≥18 years
- Ability to understand and willingness to sign an informed consent form prior to initiation of any study procedures
- Diagnosis of amyloidosis determined by polarizing light microscopy of green birefringent material in Congo Red-stained tissue specimens; and confirmed diagnosis of ATTR amyloidosis by immunohistochemistry, mass spectrometry, documentation of an ATTR mutation by gene sequencing, or 99m technetium-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scans and/or technetium pyrophosphate (PYP) SPECT cardiac imaging. If scintigraphy is used for diagnosis then the grade must be 2 or greater, indicative of transthyretin amyloidosis-cardiomyopathy (ATTR-CM) (Gillmore, 2016)
- Known TTR mutation
- [Inclusion Criterion 5 removed in Amendment 2]
- Patients receiving concomitant tafamidis or diflunisal may enroll in the study, providing the dose has been stable for the last 6 months
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- Karnofsky Performance Status (KPS) ≥60%
- Adequate organ function, including all of the following:
- Adequate bone marrow reserve, defined as the following: absolute neutrophil count ≥1.0 × 109/L; platelet count ≥100 × 109/L; hemoglobin ≥10 g/dL
- Hepatic: total bilirubin ≤ 2 times the upper limit of normal (× ULN), transaminases (aspartate aminotransferase and/or alanine aminotransferase) ≤3 × ULN; alkaline phosphatase ≤5 × ULN
- Renal: estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2
- If currently receiving a diuretic, must have been on a stable dose for at least 4 weeks prior to the first dose of study drug
- Systolic blood pressure ≥90 mmHg and ≤180 mmHg
- Subjects with cardiomyopathy must have an NT-proBNP ≥650 pg/mL and ≤5000 pg/mL (ie, ≥76.9 pmol/L and ≤591 pmol/L) or evidence of septal wall thickening >1.2 cm on echocardiogram
- Must have a biopsy unless data are available from a previous one. The biopsy may be taken from any tissue or organ affected by ATTR amyloidosis (eg, skin, lip, abdominal fat pad, salivary gland), at the Investigator's discretion. Nerve biopsies are not required.
- Women of childbearing potential must have 2 negative pregnancy tests during Screening, the second within 24 hours prior to the first administration of study drug, and must agree to use highly effective physician-approved contraception from Screening to 90 days following the last study drug administration
- Male subjects must be surgically sterile or must agree to use highly effective physician-approved contraception from Screening to 90 days following the last study drug administration
- Polyneuropathy Disability (PND) Score ≤IIIB
- Neuropathy Impairment Score (NIS) ≥5 and ≤130
Who cannot join
- Amyloid light chain or other non-ATTR amyloidosis
- Any past history of or present abuse of alcohol, diabetes, B12 or folate deficiencies, autoimmune diseases, hereditary disorders other than transthyretin (eg, Charcot-Marie-Tooth), uncontrolled hypothyroidism, or other etiologies for the peripheral neuropathy
- Received prior liver transplant
- Planned liver transplant during the study
- Modified body mass index (mBMI) ≤600 kg/m2 × g/L
- New York Heart Association (NYHA) Functional Class III-IV (Appendix 2)
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- LVEF ≤45%
- Uncontrolled symptomatic orthostatic hypotension
- Myocardial infarction, unstable or uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia, within 6 months prior to the first dose of study drug
- Any history of clinically significant sinus pauses on ECG
- Sinus pauses >3 seconds in the day or sinus pauses >5 seconds at night during the 48-hour pre-dose cardiac monitoring (ie, prior to first dose of study drug)
- Arrhythmia requiring treatment diagnosed during the 48-hour pre-dose cardiac monitoring (ie, prior to first dose of study drug). Note: subject could be reconsidered for entry into the study if appropriate treatment is obtained
- Hospitalized for heart failure within the 12 weeks prior to the first dose of study drug
- Uncontrolled infection, or active malignancy with the exception of the following:
- Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer
- Low risk prostate cancer with Gleason score <7 and prostate specific antigen <10 mg/mL
- Any other cancer from which the subject has been disease-free for ≥2 years
- Clinically significant pleural effusion per Investigator (e.g., presence of pleural effusion ≥30% in either hemithorax)
- History of Grade ≥3 hypersensitivity-associated AEs or hypersensitivities to other monoclonal antibodies or the excipients found in the PRX004 formulation
- Known HIV infection or known hepatitis B or C virus carrier
- Women who are pregnant or breastfeeding
- Treatment with an investigational agent within 30 days or 5 half-lives (whichever is longer) prior to Month 1-Day 1
- Any condition which could interfere with, or the treatment for which might interfere with, the conduct of the study or which would, in the opinion of the Medical Monitor or Investigator unacceptably increase the subject's risk by participating in the study
- Treatment with patisiran or inotersen within 90 days or 5 halflives (whichever is longer) prior to Month 1-Day 1
Trial locations and contacts
7 sites in 4 countries.
7 sites in 4 countries
United States4 sites
Tufts Medical Center
Boston, Massachusetts, 02111
Penn Presbyterian Medical Center
Philadelphia, Pennsylvania, 19104
Oregon Health and Science University
Portland, Oregon, 97239
Mayo Clinic Minnesota
Rochester, Minnesota, 55905
Spain1 site
Hospital Universitario Puerta de Hierro - Majadahonda
Majadahonda, Madrid, 28222
About this study
Official title: A Phase 1, Open-label, Dose Escalation Study of Intravenous PRX004 in Subjects With Amyloid Transthyretin (ATTR) Amyloidosis
A Phase 1, open-label study of intravenous (IV) PRX004 as a single agent in subjects with hereditary amyloid transthyretin (hATTR) amyloidosis. The study will consist of 3 phases and will enroll up to a total of 36 subjects. A 3+3 dose escalation component to determine the safety, tolerability, PK, PD, and MTD. An expansion component in anticipated PRX004 RP2D cohorts selected from the Dose Escalation Phase. An extended dosing component for eligible subjects from the Dose Escalation or Expansion phases.
Read the detailed description
This Phase 1, open-label consists of 3 phases. The Dose Escalation Phase is a 3+3 dose escalation component to determine the safety, tolerability, PK, PD, and MTD of IV PRX004 when given as a single agent in up to 36 evaluable subjects with hATTR amyloidosis. The Expansion Phase is an expansion component in anticipated PRX004 RP2D cohorts selected from the Dose Escalation Phase (this may occur in addition to cohorts in which additional subjects were added due to the observation of a dose-limiting [DLT] in the Escalation Phase). The Long-term Extension (LTE) Phase is an extended dosing component for eligible subjects from the Dose Escalation or Expansion phases.
The Dose Escalation Phase will follow a standard 3+3 design, in which cohorts of 3 to 6 subjects with hATTR amyloidosis will be enrolled at each dose level to receive IV PRX004 once every 28 days, based on scheduling from Month 1-Day 1 for up to 3 doses. Each subject will participate in only 1 dose escalation cohort. The starting dose of PRX004 will be 0.1 mg/kg.
Dose escalation will occur after the third evaluable subject in a cohort has completed the first 28 days following the first administration of PRX004. Up to 6 dose levels of PRX004 may be investigated (0.1, 0.3, 1, 3, 10, and 30 mg/kg) if tolerable. In the event the starting dose of 0.1 mg/kg is not tolerated, the dose escalationwill be halted and the study stopped.
Each subject will receive a maximum of 3 infusions of PRX004 in the Dose Escalation Phase. Subjects who complete the Month 3-Day 22 Visit in the Dose Escalation or Expansion phases may be eligible to receive up to 15 additional PRX004 infusions in the LTE Phase.
Each subject will receive a maximum of 3 infusions of PRX004 in the Dose Escalation Phase. Subjects who complete the Month 3-Day 22 Visit in the Dose Escalation or Expansion phases may be eligible to receive up to 15 additional PRX004 infusions in the LTE Phase.
Subjects who completed the EOS Visit in the Dose Escalation Phase prior to implementation of Protocol Amendment 2 may re-enter the study in the LTE Phase if they meet specific inclusion/exclusion criteria.
- Being tested
- PRX004
- Medical subject headings
- Amyloidosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PRX004Drug
PRX004 (0.1, 0.3, 1, 3, 10, and 30 mg/kg) IV every 28 days
PRX004 IV every 28 days at RP2D(s)
PRX004 IV every 28 days at RP2D(s)
| Study group | Role | What they receive |
|---|---|---|
| PRX004 | Experimental | Dose escalation in up to 6 dose levels
Expansion of previously studied cohort(s) from Dose Escalation
Extended dosing at RP2D Receives: Drug: PRX004 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum Tolerated Dose of PRX004
Maximum Tolerated Dose of PRX004
Measured: 28 days
Number of subjects with treatment-emergent adverse events and clinically significant changes in ECGs, echocardiograms, cardiac telemetry, vital signs, and laboratory evaluations
Number of subjects with treatment-emergent adverse events and clinically significant changes in ECGs, echocardiograms, cardiac telemetry, vital signs, and laboratory evaluations
Measured: 3 months
Secondary outcomes (6)
PRX004 pharmacokinetic parameters - Cmin
Minimum observed concentration (Cmin) of PRX004 in plasma
Measured: 3 months
PRX004 pharmacokinetic parameters -Cmax
Maximum observed concentration (Cmax) of PRX004 in plasma
Measured: 3 months
PRX004 pharmacokinetic parameters - T1/2
Terminal elimination half-life (T1/2) of PRX004 in plasma
Measured: 3 months
PRX004 pharmacokinetic parameters -AUClast
Area under the concentration-time curve from time zero to the last quantifiable concentration time-point (AUClast) of PRX004 in plasma
Measured: 3 months
PRX004 pharmacokinetic parameters -AUCtau
Area under the concentration-time curve over the dosing interval (AUCtau) of PRX004 in plasma
Measured: 3 months
Immunogenicity indicators
Immunogenicity indicators: Anti-drug antibodies (ADAs)
Measured: 3 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Nov 2017
- Study start5 Apr 2018
- Primary completion23 Jul 2020
- Study completion23 Jul 2020
Why it stopped: Because of the impact of COVID-19 pandemic
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Amyloidogenic Transthyretin (ATTR) AmyloidosisStudies 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
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Dose Escalation Study
- Masking
- None (open label)
- Enrolment
- 21 participants (actual)
Sponsor and investigators
- Lead sponsor
- Prothena Biosciences Limited
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03336580
- Sponsor's protocol ID
- PRX004-101
- Other IDs
- 2017-003521-15, 2017
- Status last verified
- Aug 2020
- First submitted
- 23 Oct 2017
- Last updated
- 20 Aug 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Capustin M, Frishman WH. Transthyretin Cardiac Amyloidosis and Novel Therapies to Treat This Not-so-rare Cause of Cardiomyopathy. Cardiol Rev. 2021 Sep-Oct 01;29(5):263-273. doi: 10.1097/CRD.0000000000000387.
PubMed 34397539
Study at a glance
From the registry record, last updated by the sponsor on 20 Aug 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1, Open-label, Dose Escalation Study of Intravenous PRX004 in Subjects With Amyloid Transthyretin (ATTR) Amyloidosis
- ClinicalTrials.gov ID
- NCT03336580
- Acronym / sponsor ID
- PRX004-101
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Because of the impact of COVID-19 pandemic
- Enrolment
- 21 participants (actual)
- Lead sponsor
- Prothena Biosciences LimitedIndustry (pharma, biotech, devices)
- Study start
- 5 Apr 2018 (actual)
- Primary completion
- 23 Jul 2020 (actual)
- Study completion
- 23 Jul 2020 (actual)
- First posted
- 8 Nov 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
A Phase 1, open-label study of intravenous (IV) PRX004 as a single agent in subjects with hereditary amyloid transthyretin (hATTR) amyloidosis. The study will consist of 3 phases and will enroll up to a total of 36 subjects. A 3+3 dose escalation component to determine the safety, tolerability, PK, PD, and MTD. An expansion component in anticipated PRX004 RP2D cohorts selected from the Dose Escalation Phase. An extended dosing component for eligible subjects from the Dose Escalation or Expansion phases.
Detailed description
This Phase 1, open-label consists of 3 phases. The Dose Escalation Phase is a 3+3 dose escalation component to determine the safety, tolerability, PK, PD, and MTD of IV PRX004 when given as a single agent in up to 36 evaluable subjects with hATTR amyloidosis. The Expansion Phase is an expansion component in anticipated PRX004 RP2D cohorts selected from the Dose Escalation Phase (this may occur in addition to cohorts in which additional subjects were added due to the observation of a dose-limiting [DLT] in the Escalation Phase). The Long-term Extension (LTE) Phase is an extended dosing component for eligible subjects from the Dose Escalation or Expansion phases.
The Dose Escalation Phase will follow a standard 3+3 design, in which cohorts of 3 to 6 subjects with hATTR amyloidosis will be enrolled at each dose level to receive IV PRX004 once every 28 days, based on scheduling from Month 1-Day 1 for up to 3 doses. Each subject will participate in only 1 dose escalation cohort. The starting dose of PRX004 will be 0.1 mg/kg.
Dose escalation will occur after the third evaluable subject in a cohort has completed the first 28 days following the first administration of PRX004. Up to 6 dose levels of PRX004 may be investigated (0.1, 0.3, 1, 3, 10, and 30 mg/kg) if tolerable. In the event the starting dose of 0.1 mg/kg is not tolerated, the dose escalationwill be halted and the study stopped.
Each subject will receive a maximum of 3 infusions of PRX004 in the Dose Escalation Phase. Subjects who complete the Month 3-Day 22 Visit in the Dose Escalation or Expansion phases may be eligible to receive up to 15 additional PRX004 infusions in the LTE Phase.
Each subject will receive a maximum of 3 infusions of PRX004 in the Dose Escalation Phase. Subjects who complete the Month 3-Day 22 Visit in the Dose Escalation or Expansion phases may be eligible to receive up to 15 additional PRX004 infusions in the LTE Phase.
Subjects who completed the EOS Visit in the Dose Escalation Phase prior to implementation of Protocol Amendment 2 may re-enter the study in the LTE Phase if they meet specific inclusion/exclusion criteria.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Dose Escalation Study
| Arm | Type | Receives |
|---|---|---|
| PRX004 | Experimental | Drug: PRX004Dose escalation in up to 6 dose levels Expansion of previously studied cohort(s) from Dose Escalation Extended dosing at RP2D |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (19 listed)
- Age ≥18 years
- Ability to understand and willingness to sign an informed consent form prior to initiation of any study procedures
- Diagnosis of amyloidosis determined by polarizing light microscopy of green birefringent material in Congo Red-stained tissue specimens; and confirmed diagnosis of ATTR amyloidosis by immunohistochemistry, mass spectrometry, documentation of an ATTR mutation by gene sequencing, or 99m technetium-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scans and/or technetium pyrophosphate (PYP) SPECT cardiac imaging. If scintigraphy is used for diagnosis then the grade must be 2 or greater, indicative of transthyretin amyloidosis-cardiomyopathy (ATTR-CM) (Gillmore, 2016)
- Known TTR mutation
- [Inclusion Criterion 5 removed in Amendment 2]
Key exclusion criteria (24 listed)
- Amyloid light chain or other non-ATTR amyloidosis
- Any past history of or present abuse of alcohol, diabetes, B12 or folate deficiencies, autoimmune diseases, hereditary disorders other than transthyretin (eg, Charcot-Marie-Tooth), uncontrolled hypothyroidism, or other etiologies for the peripheral neuropathy
- Received prior liver transplant
- Planned liver transplant during the study
- Modified body mass index (mBMI) ≤600 kg/m2 × g/L
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 |
|---|---|---|
| PRX004PRX004 (0.1, 0.3, 1, 3, 10, and 30 mg/kg) IV every 28 days PRX004 IV every 28 days at RP2D(s) PRX004 IV every 28 days at RP2D(s) | Drug | PRX004 |
Primary outcome
Maximum Tolerated Dose of PRX004
Time frame: 28 days
Maximum Tolerated Dose of PRX004
Number of subjects with treatment-emergent adverse events and clinically significant changes in ECGs, echocardiograms, cardiac telemetry, vital signs, and laboratory evaluations
Time frame: 3 months
Number of subjects with treatment-emergent adverse events and clinically significant changes in ECGs, echocardiograms, cardiac telemetry, vital signs, and laboratory evaluations
6 secondary outcomes
PRX004 pharmacokinetic parameters - Cmin
Time frame: 3 months
PRX004 pharmacokinetic parameters -Cmax
Time frame: 3 months
PRX004 pharmacokinetic parameters - T1/2
Time frame: 3 months
PRX004 pharmacokinetic parameters -AUClast
Time frame: 3 months
PRX004 pharmacokinetic parameters -AUCtau
Time frame: 3 months
Immunogenicity indicators
Time frame: 3 months
Results and safety
The study was stopped early (reason given: Because of the impact of COVID-19 pandemic). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Aug 2020.
- Derived from this study: PubMed 34397539Capustin M, Frishman WH. Transthyretin Cardiac Amyloidosis and Novel Therapies to Treat This Not-so-rare Cause of Cardiomyopathy. Cardiol Rev. 2021 Sep-Oct 01;29(5):263-273. doi: 10.1097/CRD.0000000000000387.
- Individual participant dataSharing planned: No
Related trials for Amyloidogenic Transthyretin (ATTR) Amyloidosis
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Amyloidogenic Transthyretin (ATTR) Amyloidosis, Cardiac Amyloidosis
Not yet recruitingPhase 3
To Evaluate the Long-term Safety and Tolerability of Acoramidis in Participants With Newly Diagnosed ATTR-CM (ACT-EARLY OLE)
Amyloidosis in Transthyretin (TTR), Amyloidosis, Familial
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.
7 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing PRX004 in people with Amyloidogenic Transthyretin (ATTR) Amyloidosis, run by Prothena Biosciences Limited at 7 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 19 inclusion and 24 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 20 Aug 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in United States, Portugal, Spain, Sweden. 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 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.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Because of the impact of COVID-19 pandemic). Results are not available in the source record.
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?
Maximum Tolerated Dose of PRX004 (time frame: 28 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03336580, which also lists 1 linked publication.
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 20 Aug 2020.