E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heart Failure and Renal Insufficiency. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10038474 |
E.1.2 | Term | Renal insufficiency |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019279 |
E.1.2 | Term | Heart failure |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to assess the safety and tolerability of Tonapofylline administered to subjects with heart failure and renal insufficiency |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to assess the effect of Tonapofylline on the following in subjects with heart failure and renal insufficiency: • Quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) • Exercise capacity as measured by 6-minute walk distance • Renal function as assessed by serum creatinine and Cystatin-C • Concomitant medications used to treat heart failure |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
EXPLORATORY GENETIC TESTING SUB-STUDY IN ASSOCIATION WITH STUDY 161HF201 (OPTIONAL) The goal of the planned exploratory genetic analysis in this study is to gather data that may lead to the identification of genetic factors that may affect the safety and efficacy of Tonapofylline.
BIOMARKER ANALYSIS SUB-STUDY IN ASSOCIATION WITH STUDY 161HF201 (OPTIONAL) Serum samples collected during the study may be used for proteomic analysis. Proteomic measurements may be broad-based or targeted to drug (Tonapofylline)pathway- or disease (heart failure and/or renal deficiency) pathway-related proteins. |
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E.3 | Principal inclusion criteria |
1. Must give written informed consent and any authorizations required by local law (e.g., Protected Health Information). 2. Must be 18 years of age or older. 3. Must have a previous diagnosis of HF with symptoms of HF present at screening (i.e., subjects must be graded as NYHA Class II, III, or IV). 4. Must meet the following criteria (subjects graded as NYHA Class III or IV at screening must meet one of the following, while subjects graded as NYHA Class II at screening must meet both of the following): • history of hospitalization for HF >1 month and ≤12 months prior to the screening visit, or documented, unscheduled outpatient treatment with intravenous (IV) diuretics, IV vasodilators, or IV inotropic medications >1 month and ≤12 months prior to the screening visit • documented BNP ≥150 pg/mL, or NTproBNP ≥500 pg/mL, within the 12 months prior to Day 1. 5. Must have renal insufficiency as defined by a reduced estimated glomerular filtration rate (eGFR) at the time of screening ≥20 and ≤70 mL/min/1.73 m2, as determined by the Modification of Diet in Renal Disease (MDRD) equation (abbreviated version). 6. Must be on an oral loop diuretic for at least the 4 weeks prior to Day 1. Dose adjustments are allowed within the 4 weeks prior to Day 1, but the dose on Day 1 must be within 50% to 200% of the dose the subject was receiving at 4 weeks prior to Day 1. The introduction or withdrawal of any other class of diuretic (i.e., thiazide diuretics) is not allowed within the 4 weeks prior to Day 1 7. Subjects with a reduced LVEF (≤40%) documented during screening must be on a pharmacological treatment regimen for HF for at least the 4 weeks prior to Day 1. The HF regimen must include: • treatment with a beta-blocker, unless contraindicated due to intolerance, and • treatment with an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), unless contraindicated due to intolerance. Note: The dose of any of the HF medications listed above may be adjusted once within the 4 weeks prior to Day 1. This restriction also applies to subjects with LVEF >40% if they are receiving treatment with beta-blockers, ACE inhibitors, and/or ARBs. 8. Women of childbearing potential must practice effective contraception during the study and be willing and able to continue contraception for 2 months after their last dose of study treatment. For further details of contraceptive requirements for this study, please refer to Section 15.5.3. All female subjects of childbearing potential must have a negative pregnancy test on Screening Day and Day 1.
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E.4 | Principal exclusion criteria |
1. History of an allergic reaction to any xanthine-containing compound. 2. History of seizure within the past 10 years or use of any medication for the suppression of seizures within the past 5 years. 3. Within the past 2 years, history of head injury with loss of consciousness, stroke, or transient ischemic attack. 4. History of multiple sclerosis, Alzheimer’s disease, mental retardation, meningitis/encephalitis, brain surgery, or penetrating head trauma. 5. History of, or prior neuroimaging evidence of, intracranial pathology known to increase the risk of seizure such as brain tumors of any kind (including meningioma), arteriovenous malformation, cerebral cavernous malformation, hydrocephalus, or encephalomalacia. 6. History consistent with illicit use of drugs or alcohol abuse within 6 months prior to Day 1. 7. Hospitalization for HF within 30 days of Day 1. 8. Myocardial infarction (MI) within 30 days of Day 1. 9. Hemodynamically destabilizing arrhythmia (e.g., ventricular tachycardia or ventricular fibrillation) within 30 days of Day 1. 10. Cardiac surgery within 60 days prior to Day 1. 11. Uncorrected hemodynamically significant primary valvular disease. 12. Known obstructive or restrictive cardiomyopathy. 13. Currently receiving chronic renal replacement therapy (e.g., hemodialysis or peritoneal dialysis). 14. Receiving adenosine or xanthine-based agents (e.g., aminophylline, theophylline, pentoxifylline, or dyphylline). 15. Receiving clozapine or metronidazole within 5 days of screening, during the screening period, or anticipated use during study drug treatment. 16. Regular consumption of excessive amounts of caffeinated beverages (e.g., >72 ounces [2.13 liters or 9 cups] of coffee/day). 17. Initiation of cardiac resynchronization treatment within 30 days prior to Day 1. 18. Serious systemic infection (e.g., septicemia) or major surgical procedures within the 30 days prior to Day 1. 19. Fever, with body temperature >38oC, within the 48 hours prior to first dose. 20. Evidence of malignancy within 6 months prior to Day 1. Subjects with a history of stable prostate cancer, basal cell carcinomas, or fewer than 3 squamous cell carcinomas are eligible. 21. Likelihood, in the Investigator’s opinion, of undergoing cardiac transplantation, left ventricular assist device (LVAD) or other device implantation, or other cardiac surgerywithin next 3 months; or of requiring continuous IV inotropic treatment, or referral for hospice or end of life treatment. 22. Sustained systolic blood pressure >170 or <90 mmHg at Screening Day or Day 1. 23. Screening laboratory findings as follows (Screening laboratory tests should be performed at the central laboratory): • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3 times the upper limit of normal, or • Total bilirubin >2.0 mg/dL. 24. Nursing mothers, pregnant women, or women planning on becoming pregnant during the study. 25. Participation in any other investigational study of drugs or devices within 30 days prior to Day 1. 26. Unwillingness to comply with protocol-required procedures. 27. Presence of any clinically significant (as determined by the Investigator) endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, and/or other major disease that might interfere with optimal safe participation in this study. 28. Other unspecified reasons that, in the opinion of the Investigator or Biogen Idec, make the subject unsuitable for enrollment.
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E.5 End points |
E.5.1 | Primary end point(s) |
The safety and tolerability of Tonapofylline administered to subjects with stable heart failure and renal insufficiency. This objective will be evaluated by the incidence of AEs and SAEs, clinically abnormal physical examinations and vital signs, shifts to outside the normal ranges in laboratory parameters, and electrocardiogram results. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |