Clinical trial NCT00791492: An Extension of Study Fx-005 Evaluating Long-Term Safety And Clinical Outcomes Of Fx-1006A In Patients With Transthyretin Amyloid Polyneuropathy
Official title: An Open-Label Extension Of Study Fx-005 Evaluating Long-Term Safety And Clinical Outcomes Of Fx-1006A In Patients With Transthyretin Amyloid Polyneuropathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Familial Amyloid Polyneuropathy
ATTR-PN
Keywords: FAP
Familial Amyloid Polyneuropathy
ATTR-PN
transthyretin
TTR
amyloid
polyneuropathy
familial
hereditary
amyloidosis
FoldRx
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2008-11-14
Enrollment: 86
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study is designed to determine the long-term safety and tolerability of Fx-1006A as well as the effects of Fx-1006A on clinical outcomes in patients with ATTR-PN.

All patients who enroll in this extension study will receive once-daily oral 20 mg Fx-1006A for 12 months; therefore, patients randomized to placebo in Study Fx-005 will cross over to active drug (Fx-1006A 20 mg) during this study. However, patients and their families as well as clinical Investigators and their clinical site staff will remain blinded to the original Fx-005 treatment assignment. It is intended that there will be no interruption in study medication administration between the two studies. The majority of safety and clinical outcomes assessments will be identical to those evaluated in Study Fx-005. Additional assessments for this open-label extension study include 24-hour Holter monitoring and skin biopsy for IENF; patients will be required to provide written informed consent to participate in this open-label extension study prior to having these additional procedures performed.

The values obtained from procedures and evaluations conducted during the Month 18 visit of Study Fx-005 will be used as the Baseline values for this open-label extension study. The Baseline assessments of IENF and Holter monitoring may be conducted at either day of the Month 18 visit days of Study Fx-005, but prior to the first Fx-1006A dose in this open-label extension study. Clinic Visits will be conducted at Week 6 (± 2 days), and Month 3 (± 1 week), Month 6 (± 2 weeks), and Month 12 (± 2 weeks). Monthly telephone contacts (± 1 week of the scheduled date) will be made during months in which no investigative site visits are scheduled (Months 2, 4, 5, 7, 8, 9, 10, and 11) for assessment of adverse events and concomitant medications.

Neurological evaluation by NIS-LL will be performed at Months 6 and 12. The NIS-LL will be assessed by utilizing the average of two successive NIS-LL clinical assessment scores obtained at least 24 hours apart within a one week period for each study visit. A dedicated neurologist will be required to perform NIS-LL scoring across all time-points for each individual patient enrolled in the study.

Quality of life utilizing the Norfolk QOL-DN will be assessed at Months 6 and 12 (based on the total score as well as the five individual domains of the questionnaire).

QST (utilizing CASE IV), NCS, HRDB, mBMI, and echocardiography will be conducted at Months 6 and 12. Holter monitoring will be conducted at Baseline and Months 6 and 12. Biopsies for IENF will be obtained at Baseline only. Assessments of troponin I and NT-pro-BNP levels will be made at each study visit.

Blood samples for pharmacokinetic assessments (Fx-1006A concentrations as well as calculated steady-state parameters) and pharmacodynamic assessments (TTR stabilization) will be collected at Week 6 and Months 6 and 12.

Safety and tolerability will be assessed throughout the study. Vital signs, 12-lead ECG, blood and urine samples for clinical laboratory tests (serum chemistry, hematology, coagulation panel, urinalysis, and urine pregnancy testing), adverse events, and concomitant medications will be assessed at each study visit. Eye examinations (including fundal photography) will be conducted at Months 6 and 12. Abbreviated physical examinations will be conducted at Week 6, and Months 3 and 6, and a complete physical examination will be conducted at Month 12.

All patients will be contacted by telephone 30 days (± 1 week) after the last dose of study medication for assessment of adverse events and concomitant medications.

Patients who complete the Month 12 visit of this open-label study may be allowed to continue receiving Fx-1006A under a compassionate use program.

Patients who discontinue from the study at any time after enrollment (i.e., early termination) will have final safety assessments performed at the time of discontinuation. Any patient discontinuing after the Month 6 visit will have all safety and clinical outcomes assessments scheduled for the Month 12 visit performed.


Eligibility criteria: Inclusion Criteria:

Male and non-pregnant female patients meeting all of the following criteria are eligible for enrollment in this study:

* Patient has completed the Month 18 visit of Study Fx-005.
* If female, patient is post-menopausal, surgically sterilized, or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide) throughout the study. (A condom alone is not considered an acceptable method of birth control.) If male with a female partner of childbearing potential, willing to use an acceptable method of birth control for the duration of the study. For both females and males, acceptable birth control must be used for at least 3 months after the last dose of study medication.
* Patient is, in the opinion of the investigator, willing and able to comply with the study medication regimen and all other study requirements.
* Patient agrees not to participate in another investigational drug or device study while participating in this open-label extension study.

Exclusion Criteria:

Patients meeting any of the exclusion criteria will not be enrolled in the study:

* Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs), defined as greater than 3-4 times/month (ibuprofen and nimesulide will be permitted).
* If female, patient is pregnant or breast feeding.
* Patient has liver function test abnormalities: alanine transaminases (ALT) and/or aspartate transaminases (AST) \>2 times upper limit of normal (ULN) that in the medical judgment of the investigator are due to reduced liver function or active liver disease.

Primary outcomes:
measure: Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 6
timeFrame: Month 6
measure: Percentage of Participants With Response to Treatment as Measured by Neuropathy Impairment Score - Lower Limb (NIS-LL) at Month 12
timeFrame: Month 12
measure: Change From Baseline in Norfolk Quality of Life- Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 6
timeFrame: Baseline, Month 6
measure: Change From Baseline in Norfolk Quality of Life- Diabetic Neuropathy (QOL-DN) Total Quality of Life (TQOL) Score at Month 12
timeFrame: Baseline, Month 12
Secondary outcomes:
measure: Change From Baseline in Neuropathy Impairment Score - Lower Limb (NIS-LL) Score at Month 6 and 12
timeFrame: Baseline, Month 6, 12
measure: Change From Baseline in Norfolk Quality of Life - Diabetic Neuropathy (QOL-DN) Domain Scores at Month 6 and 12
timeFrame: Baseline, Month 6, 12
measure: Change From Baseline in Summated 7 Score for Large Nerve Fiber Function at Month 6 and 12
timeFrame: Baseline, Month 6, 12
measure: Change From Baseline in Summated 3 Score for Small Nerve Fiber Function at Month 6 and 12
timeFrame: Baseline, Month 6, 12
measure: Change From Baseline in Modified Body Mass Index (mBMI) at Month 6 and 12
timeFrame: Baseline, Month 6, 12
measure: Change From Baseline in Troponin I Concentration at Week 6, Month 3, 6 and 12
timeFrame: Baseline, Week 6, Month 3, 6, 12
measure: Change From Baseline in N-Terminal Prohormone Brain Natriuretic Peptide (NT-proBNP) Concentration at Week 6, Month 3, 6 and 12
timeFrame: Baseline, Week 6, Month 3, 6, 12
measure: Intraepidermal Nerve Fiber (IENF) Density
timeFrame: Baseline
measure: Percentage of Participants With Stabilized Transthyretin (TTR) Tetramer
timeFrame: Month 6, 12
Other outcomes:
measure: Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)
timeFrame: Baseline up to 30 days after last dose of study medication
measure: Number of Participants With Treatment-emergent Adverse Events Greater Than or Equal to Grade 3
timeFrame: Baseline up to 30 days after last dose of study medication
measure: Number of Participants With Clinically Significant Treatment-emergent Echocardiography (ECHO) Findings
timeFrame: Baseline, Day 1 up to Month 12 (anytime on-treatment)
measure: Number of Participants With Clinically Significant Treatment-emergent Electrocardiogram (ECG) Findings
timeFrame: Baseline, Day 1 up to Month 12 (anytime on-treatment)
measure: Number of Participants With Clinically Significant Treatment-emergent Holter Monitor Findings
timeFrame: Baseline, Day 1 up to Month 12 (anytime on-treatment)
measure: Number of Participants Who Discontinued Due to Clinical or Laboratory Adverse Events
timeFrame: Baseline up to Month 12
Locations:
city: Buenos Aires
country: Argentina
facility: FLENI Departamento de Hepatología y Transplante de Organos
city: Ciudad de Buenos Aires
country: Argentina
facility: FLENI-Hepatology and Organ Transplant Dept.
city: Rio de Janeiro
country: Brazil
facility: Hospital Universitario Clementino Fraga Filho
city: Paris
country: France
facility: Service de Neurologie, CHU Henri Mondor
city: Munster
country: Germany
facility: Universitatsklinikum Munster, Transplant Hepatology
city: Lisboa
country: Portugal
facility: Serviço de Neurologia-Hospital de Santa Maria
city: Lisbon
country: Portugal
facility: Servicio de Neurologica Piso 7, Hospital de Santa Maria
city: Porto
country: Portugal
facility: Unidade Clinica de Paramiloidose-Hospital Santo Antonio
city: Porto
country: Portugal
facility: Unidade Clinica de Paramiloidose, Hospital Geral de Santo Antonio, Largo Prof Abdel Salazar
city: Umea
country: Sweden
facility: Umea University Hospital
city: Umea
country: Sweden
facility: FAP-Teamet Familjar Amyloids, Norrlands universitetssjukhus
Study officials:
affiliation: FoldRx Pharmaceuticals, Inc.
name: Jeff Packman
role: STUDY_DIRECTOR
References:
citation: Merlini G, Coelho T, Waddington Cruz M, Li H, Stewart M, Ebede B. Evaluation of Mortality During Long-Term Treatment with Tafamidis for Transthyretin Amyloidosis with Polyneuropathy: Clinical Trial Results up to 8.5 Years. Neurol Ther. 2020 Jun;9(1):105-115. doi: 10.1007/s40120-020-00180-w. Epub 2020 Feb 27.
citation: Huber P, Flynn A, Sultan MB, Li H, Rill D, Ebede B, Gundapaneni B, Schwartz JH. A comprehensive safety profile of tafamidis in patients with transthyretin amyloid polyneuropathy. Amyloid. 2019 Dec;26(4):203-209. doi: 10.1080/13506129.2019.1643714. Epub 2019 Jul 27.
citation: Amass L, Li H, Gundapaneni BK, Schwartz JH, Keohane DJ. Influence of baseline neurologic severity on disease progression and the associated disease-modifying effects of tafamidis in patients with transthyretin amyloid polyneuropathy. Orphanet J Rare Dis. 2018 Dec 17;13(1):225. doi: 10.1186/s13023-018-0947-7.
citation: Waddington Cruz M, Amass L, Keohane D, Schwartz J, Li H, Gundapaneni B. Early intervention with tafamidis provides long-term (5.5-year) delay of neurologic progression in transthyretin hereditary amyloid polyneuropathy. Amyloid. 2016 Sep;23(3):178-183. doi: 10.1080/13506129.2016.1207163. Epub 2016 Aug 5.
citation: Coelho T, Maia LF, da Silva AM, Cruz MW, Plante-Bordeneuve V, Suhr OB, Conceicao I, Schmidt HH, Trigo P, Kelly JW, Labaudiniere R, Chan J, Packman J, Grogan DR. Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy. J Neurol. 2013 Nov;260(11):2802-14. doi: 10.1007/s00415-013-7051-7. Epub 2013 Aug 22.