Transthyretin AmyloidosisPhase 2NCT01171859
Safety, Efficacy and Pharmacokinetics of Doxycycline Plus Tauroursodeoxycholic Acid in Transthyretin Amyloidosis
A Phase 2 study testing Doxycycline + Tauroursodeoxycholic acid in people with Transthyretin Amyloidosis, run by Fondazione IRCCS Policlinico San Matteo di Pavia at 1 site in Italy.
Trial summary
This study is being conducted to explore the potential benefits of a twelve-month doxycycline (at the best tolerated dose of 200 mg/day) and tauroursodeoxycholic acid (750 mg/day) treatment on disease progression in patients affected by transthyretin amyloidosis, including: 1) patients not eligible for liver… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Transthyretin Amyloidosis
- What is being tested?
- Doxycycline + Tauroursodeoxycholic acid
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- 1 siteItaly
- Study dates
- Jul 2010to Oct 2015
- Phase
- Phase 2
- 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
- Histochemical diagnosis of amyloidosis as based on detection by polarizing microscopy of green birefringent material in Congo red-stained tissue specimens;
- Molecular definition of the transthyretin (TTR) mutation or immunohistochemical staining of amyloid fibrils with anti-TTR antibody;
- ECOG performance status (PS) 0, 1, 2;
- New York Heart Association (NYHA) class ≤III
- Systolic blood pressure ≥100 mmHg (standing)
- Must have symptomatic organ involvement with amyloid to justify therapy; must have evidence of neuropathy and/or cardiomyopathy progression after liver transplantation performed since at least one year.
- Contraception for women of childbearing potential. Medically approved contraception could include abstinence. A negative serum pregnancy test is required prior to initiation of treatment with study medication.
Who cannot join
- Liver transplantation in the previous 12 months or liver transplantation anticipated in less than 6 months;
- ALT and/or AST ≥ 2 x Upper Normal Limit (UNL);
- Alkaline phosphatase ≥ 2 x UNL;
- Creatinine clearance < 30 ml/min;
- Any other lab values that in the opinion of the investigator might place the subject at unacceptable risk for participation in the study;
- Echocardiographic ejection fraction < 50%;
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- Other neuropathies, due to vitamin B12 deficiency, alcoholism, hypothyroidism, uremia, diabetes mellitus, vasculitides;
- History of poor compliance;
- History of hypersensitivity to any of the ingredients of the study therapies;
- Use of any investigational drug, device (or biologic) within 4 weeks prior to study entry or during the study.
Trial locations and contacts
1 site in 1 country.
Italy1 site
Amyloid Research and Treatment Centre, Biotechnology Research Laboratories
Pavia, Pavia, 27100
About this study
Official title: A Single Center, Twelve-month, Open-label, Prospective Study Followed by a Six-month Withdrawal Period to Evaluate the Efficacy, Tolerability, Safety and Pharmacokinetics of Doxycycline in Combination With Tauroursodeoxycholic Acid in Transthyretin Amyloidosis
This study is being conducted to explore the potential benefits of a twelve-month doxycycline (at the best tolerated dose of 200 mg/day) and tauroursodeoxycholic acid (750 mg/day) treatment on disease progression in patients affected by transthyretin amyloidosis, including: 1) patients not eligible for liver transplantation; 2) patients eligible for liver transplantation, as a "bridge" therapy between the time of diagnosis and surgery, with the aim of stabilizing the disease; 3) patients showing disease progression after liver transplantation performed since at least 1 year.
It is a phase II, therapeutic exploratory, two-part, 18-month, single centre, prospective study.
Part I is a 12-month, open label treatment period in which doxycycline (200 mg/day, continuously) and tauroursodeoxycholic acid (750 mg/day continuously) are administered to 40 consenting subjects with transthyretin amyloidosis. Part II is a withdrawal period in which subjects will be monitored for disease progression. During part I, subjects will be evaluated at baseline (study Day 0), and then after 3, 6, 9 and 12 months of doxycycline plus tauroursodeoxycholic acid treatment or at premature treatment discontinuation; during part II, they will be assessed at months 15 and 18. Monthly phone contacts and blood tests will be performed to monitor potential adverse events.
- Conditions
- Transthyretin Amyloidosis
- Being tested
- Doxycycline + Tauroursodeoxycholic acid
- Keywords
- amyloidosis, transthyretin, doxycycline, Tauroursodeoxycholic acid
- Medical subject headings
- Amyloidosis, Hereditary, Transthyretin-Related, Amyloidosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Doxycycline + Tauroursodeoxycholic acidDrug
doxycycline 100 mg twice a day for 12 months; tauroursodeoxycholic acid 250 mg three times a day for 12 months
| Study group | Role | What they receive |
|---|---|---|
| Doxycycline + Tauroursodeoxycholic acid | Experimental | Not described Receives: Drug: Doxycycline + Tauroursodeoxycholic acid |
What is being measured
The primary outcome is the main question the study is designed to answer.
Response rate to doxycycline + tauroursodeoxycholic acid treatment
A responder is a subject with:
- a modified body mass index (mBMI) reduction of less than 10% and a change in the Neurologic Impairment Score-Lower Limbs (NIS-LL) <2 (in subjects with peripheral neuropathy);
- a modified body mass index (mBMI) reduction of less than 10% and an increase in N-terminal natriuretic peptide type B (NT-proBNP) concentration of less than 30% or < 300 pg/mL (in subjects with isolated cardiomyopathy).
Measured: One year
Secondary outcomes (6)
Number of patients experiencing treatment-emergent adverse events
Measured: One year
Change in quality of life
SF-36 scale
Measured: Every six months
doxycycline pharmacokinetics (PK)
Measured: Every three months
response in autonomic dysfunction, sensory-motor peripheral neuropathy and visceral organ involvement
response assessed according to the Kumamoto Scale score
Measured: One year
neurologic response
response assessed by motor and sensory nerves conduction studies
Measured: One year
Incidence of patients discontinuing from the study because of clinical or laboratory adverse events
Measured: One year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Jul 2010 (estimated)
- Study startJul 2010
- Primary completionApr 2015
- Study completionOct 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Transthyretin AmyloidosisStudies of the same condition, open and under way.
- More trials run by Fondazione IRCCS Policlinico San Matteo di PaviaThe sponsor's other registered studies.
- 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 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- Fondazione IRCCS Policlinico San Matteo di Pavia
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Giampaolo Merlini, Fondazione IRCCS Policlinico San Matteo di Pavia
- Investigators
- Giampaolo Merlini, MD, Principal investigator, IRCCS Policlinico San Matteo
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01171859
- Sponsor's protocol ID
- DOXYTUDCA2010
- Other IDs
- 2010-020422-17
- Status last verified
- Feb 2016
- First submitted
- 27 Jul 2010
- Last updated
- 25 Feb 2016
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Cardoso I, Saraiva MJ. Doxycycline disrupts transthyretin amyloid: evidence from studies in a FAP transgenic mice model. FASEB J. 2006 Feb;20(2):234-9. doi: 10.1096/fj.05-4509com.
PubMed 16449795Macedo B, Batista AR, Ferreira N, Almeida MR, Saraiva MJ. Anti-apoptotic treatment reduces transthyretin deposition in a transgenic mouse model of Familial Amyloidotic Polyneuropathy. Biochim Biophys Acta. 2008 Sep;1782(9):517-22. doi: 10.1016/j.bbadis.2008.05.005. Epub 2008 Jun 3.
PubMed 18572024Cardoso I, Martins D, Ribeiro T, Merlini G, Saraiva MJ. Synergy of combined doxycycline/TUDCA treatment in lowering Transthyretin deposition and associated biomarkers: studies in FAP mouse models. J Transl Med. 2010 Jul 30;8:74. doi: 10.1186/1479-5876-8-74.
PubMed 20673327
Study at a glance
From the registry record, last updated by the sponsor on 25 Feb 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Single Center, Twelve-month, Open-label, Prospective Study Followed by a Six-month Withdrawal Period to Evaluate the Efficacy, Tolerability, Safety and Pharmacokinetics of Doxycycline in Combination With Tauroursodeoxycholic Acid in Transthyretin Amyloidosis
- ClinicalTrials.gov ID
- NCT01171859
- Acronym / sponsor ID
- DOXYTUDCA2010
- Conditions
- Transthyretin Amyloidosis
- Keywords
- amyloidosis, transthyretin, doxycycline, Tauroursodeoxycholic acid
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- Fondazione IRCCS Policlinico San Matteo di PaviaUniversity, hospital or other
- Study start
- Jul 2010
- Primary completion
- Apr 2015 (actual)
- Study completion
- Oct 2015 (actual)
- First posted
- 29 Jul 2010 (estimated)
- 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.
This study is being conducted to explore the potential benefits of a twelve-month doxycycline (at the best tolerated dose of 200 mg/day) and tauroursodeoxycholic acid (750 mg/day) treatment on disease progression in patients affected by transthyretin amyloidosis, including: 1) patients not eligible for liver transplantation; 2) patients eligible for liver transplantation, as a "bridge" therapy between the time of diagnosis and surgery, with the aim of stabilizing the disease; 3) patients showing disease progression after liver transplantation performed since at least 1 year.
It is a phase II, therapeutic exploratory, two-part, 18-month, single centre, prospective study.
Part I is a 12-month, open label treatment period in which doxycycline (200 mg/day, continuously) and tauroursodeoxycholic acid (750 mg/day continuously) are administered to 40 consenting subjects with transthyretin amyloidosis. Part II is a withdrawal period in which subjects will be monitored for disease progression. During part I, subjects will be evaluated at baseline (study Day 0), and then after 3, 6, 9 and 12 months of doxycycline plus tauroursodeoxycholic acid treatment or at premature treatment discontinuation; during part II, they will be assessed at months 15 and 18. Monthly phone contacts and blood tests will be performed to monitor potential adverse events.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Doxycycline + Tauroursodeoxycholic acid | Experimental | Drug: Doxycycline + Tauroursodeoxycholic acid |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Histochemical diagnosis of amyloidosis as based on detection by polarizing microscopy of green birefringent material in Congo red-stained tissue specimens;
- Molecular definition of the transthyretin (TTR) mutation or immunohistochemical staining of amyloid fibrils with anti-TTR antibody;
- ECOG performance status (PS) 0, 1, 2;
- New York Heart Association (NYHA) class ≤III
- Systolic blood pressure ≥100 mmHg (standing)
Key exclusion criteria (10 listed)
- Liver transplantation in the previous 12 months or liver transplantation anticipated in less than 6 months;
- ALT and/or AST ≥ 2 x Upper Normal Limit (UNL);
- Alkaline phosphatase ≥ 2 x UNL;
- Creatinine clearance < 30 ml/min;
- Any other lab values that in the opinion of the investigator might place the subject at unacceptable risk for participation in the study;
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 |
|---|---|---|
| Doxycycline + Tauroursodeoxycholic aciddoxycycline 100 mg twice a day for 12 months; tauroursodeoxycholic acid 250 mg three times a day for 12 months | Drug | Doxycycline + Tauroursodeoxycholic acid |
Primary outcome
Response rate to doxycycline + tauroursodeoxycholic acid treatment
Time frame: One year
A responder is a subject with: * a modified body mass index (mBMI) reduction of less than 10% and a change in the Neurologic Impairment Score-Lower Limbs (NIS-LL) <2 (in subjects with peripheral neuropathy); * a modified body mass index (mBMI) reduction of less than 10% and an increase in N-terminal natriuretic peptide type B (NT-proBNP) concentration of less than 30% or < 300 pg/mL (in subjects with isolated cardiomyopathy).
6 secondary outcomes
Number of patients experiencing treatment-emergent adverse events
Time frame: One year
Change in quality of life
Time frame: Every six months
doxycycline pharmacokinetics (PK)
Time frame: Every three months
response in autonomic dysfunction, sensory-motor peripheral neuropathy and visceral organ involvement
Time frame: One year
neurologic response
Time frame: One year
Incidence of patients discontinuing from the study because of clinical or laboratory adverse events
Time frame: One year
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Feb 2016.
- Background: PubMed 16449795Cardoso I, Saraiva MJ. Doxycycline disrupts transthyretin amyloid: evidence from studies in a FAP transgenic mice model. FASEB J. 2006 Feb;20(2):234-9. doi: 10.1096/fj.05-4509com.
- Background: PubMed 18572024Macedo B, Batista AR, Ferreira N, Almeida MR, Saraiva MJ. Anti-apoptotic treatment reduces transthyretin deposition in a transgenic mouse model of Familial Amyloidotic Polyneuropathy. Biochim Biophys Acta. 2008 Sep;1782(9):517-22. doi: 10.1016/j.bbadis.2008.05.005. Epub 2008 Jun 3.
- Background: PubMed 20673327Cardoso I, Martins D, Ribeiro T, Merlini G, Saraiva MJ. Synergy of combined doxycycline/TUDCA treatment in lowering Transthyretin deposition and associated biomarkers: studies in FAP mouse models. J Transl Med. 2010 Jul 30;8:74. doi: 10.1186/1479-5876-8-74.
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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.
Giampaolo Merlini, MD principal investigator
IRCCS Policlinico San Matteo
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Doxycycline + Tauroursodeoxycholic acid in people with Transthyretin Amyloidosis, run by Fondazione IRCCS Policlinico San Matteo di Pavia at 1 site in Italy.
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 7 inclusion and 10 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: finished, as of the sponsor's last update on 25 Feb 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. 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 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Response rate to doxycycline + tauroursodeoxycholic acid treatment (time frame: One year). 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 NCT01171859, which also lists 3 linked publications.
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 25 Feb 2016.