E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10070668 |
E.1.2 | Term | Huntington's disease |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020469 |
E.1.2 | Term | Huntington's chorea |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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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 |
• To assess the efficacy of 26-week oral daily dosing with PF-02545920 on motor function in subjects with HD. |
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E.2.2 | Secondary objectives of the trial |
• To assess the safety and tolerability of two oral doses (5 mg and 20 mg BID) of PF-02545920 in subjects with HD. • To assess the efficacy of 13 and 26-week oral daily dosing with PF-02545920 on chorea severity in subjects with HD. • To assess whether treatment with PF-02545920 can improve overall clinical impression in subjects with HD following multiple doses (13 and 26 weeks). |
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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 |
MRI study: A subset of subjects will be randomized into the MRI imaging cohort in which they will undergo a brain MRI session at Baseline Day 1 (V2) and at Week 26 (V9), in addition to other Baseline Day 1 (V2) procedures. Exploratory endpoints - functional: - Change from baseline in whole brain volume and in regional brain volume measured using structural magnetic resonance imaging (MRI) after 26 weeks of treatment - Change from baseline in white-matter microstructure measured using MRI/diffusion tensor imaging (DTI) after 26 weeks of treatment - Change from baseline in functional connectivity measured using resting state functional magnetic resonance imaging (rs-fMRI) after 26 weeks of treatment |
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E.3 | Principal inclusion criteria |
1. Evidence of a personally signed and dated informed consent(s) document(s) indicating that the subject has been informed of all pertinent aspects of the study. 2. Males or females between the age of 30 years and 65 years (inclusive) 3. Diagnosis of HD based on characteristic clinical findings, including presence of chorea, and genetic confirmation with the detection of an expansion of ≥ 36 CAG trinucleotide repeats in the huntingtin gene (Htt) 4. UHDRS Total Motor Score (TMS) equal or greater than 10 5. UHDRS total functional capacity (TFC) equal or greater than 7 6. Male and female subjects capable of having children and/or at risk for pregnancy must agree to use a highly effective method of contraception throughout the study and for at least 28 days (90 days for males) after the last dose of assigned treatment. A subject is capable of having children if, in the opinion of the investigator, he/she is sexually active and biologically capable. Female subjects who are not of childbearing potential (ie, meet at least 1 of the following criteria): • Have undergone a documented hysterectomy and/or bilateral oophorectomy; • Have medically confirmed ovarian failure; or • Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed by having a serum follicle stimulating hormone (FSH) level within the laboratory’s reference range for postmenopausal women. 7. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. The subset of subjects participating in the MRI imaging cohort must be willing and able to comply with scheduled MRI study procedures. |
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E.4 | Principal exclusion criteria |
1. Subjects who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Pfizer employees directly involved in the conduct of the study. 2. Evidence or history of: a. Clinically significant neurologic disorder other than Huntington’s disease. This also includes subjects with previous history of epilepsy or seizures (except childhood febrile seizures), stroke, head injury with significant neurologic sequelae. b. Other severe acute psychiatric condition, mania and/or psychosis. c. Attempted suicide or suicidal ideation with intention or plan, which required hospital admission and/or change of level of care within 12 months prior to Screening. For subjects who score ≥ 3 on the suicidal ideation item of the Problem Behaviors Assessment or answer “Yes” to the C-SSRS questions 4 or 5, a risk assessment should be done by a qualified mental health professional (a psychiatrist or licensed PhD level clinical psychologist) to assess whether it is safe for the subject to participate in the study (See Suicidality Risk Assessment). In addition, subjects deemed by the investigator to be at significant risk of suicidal or violent behavior should be excluded. 3. Evidence or history of any clinically significant conditions affecting one of the following systems: a. Hepatic: subject with evidence or history of significant hepatic disorder, including acute or chronic hepatitis B and acute hepatitis C, with liver function tests results higher than the normal limits. Subjects with positive hepatitis C antibody and normal (within the lab normal ranges) liver functions tests can be included in the study. b. Renal c. Endocrine (excluding adequately controlled hypothyroidism and hyperthyroidism and controlled type 2 diabetes with fasting blood glucose ≤ 180 mg/dl and hemoglobin A1c (HgA1c) ≤ 8 at Screening ) d. Pulmonary e. Hematological f. Gastrointestinal (including any condition possibly affecting drug absorption, eg, gastrectomy, gastric bypass) g. Immunological, including positivity for human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) h. Severe allergic diseases (excluding untreated, asymptomatic, seasonal and environmental allergies at time of dosing) i. Any history of malignant tumors and treatment within the previous year 4. Subjects with: a. WBC ≤ 3500/mm3 OR ANC ≤ 2000/mm3 b. History of neutropenia, including benign ethnic neutropenia, clozapine induced agranulocytosis or granulocytopenia c. History of myeloproliferative disorders (primary myelofibrosis, polycythemia vera, essential thrombocythemia, chronic eosinophilic leukemia/hypereosinophilic syndrome, systemic mastocytosis) 5. Evidence or history of clinically significant cardiovascular disease, including: a. Uncontrolled hypertension (sitting or supine diastolic blood pressure > 95 mmHg and/or sitting or supine systolic blood pressure > 170 mmHg with or without treatment) b. Evidence of orthostatic symptoms (eg. dizziness upon standing) or systolic blood pressure (BP) drop ≥20 mm Hg or diastolic BP drop ≥10 mmHg from supine to standing assessment at screening. c. Any 12-lead ECG with repeated demonstration of QTc >450 msec or a QRS interval >120 msec at Screening. d. Coronary bypass surgery e. History of myocardial infarction or ischemic heart disease f. Heart failure. g. Non clinically significant ECG findings including sinus bradycardia and tachycardia will not exclude subjects from the study 6. Subjects with screening laboratory test results that deviate from the upper or lower limits of the reference range, as assessed by the study specific laboratory and confirmed by a single repeat, if deemed necessary, except for non-clinically significant values, as determined by the investigator. a. AST or ALT must be ≤2 X upper limit of reference range b. Total bilirubin must be within 1.5 X of the upper limit of reference range at screening; subjects with a history of Gilbert's syndrome may have a direct bilirubin measured and would be eligible for this study provided the direct bilirubin is ≤ ULN. 7. Subjects with laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study. See exclusion criteria # 4 and #7. 8. History of febrile illness within 5 days prior to the Screening. 9. A confirmed positive urine drug screen at Screening not explained by subject’s stable medication regimen (see Laboratory Tests for minimum requirements) For a full list of the Exclusion criteria please see the protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Change from baseline in the Total Motor Score (TMS) assessment of the Unified Huntington Disease Rating Scale (UHDRS) after 26 weeks treatment. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Adverse events, weight, vital signs (pulse, blood pressure and body temperature), physical examination, neurological examination, electrocardiogram (ECG) and clinical laboratory findings (hematology, biochemistry and urinalysis). The endpoints are: • The number and proportion of subjects with adverse events. • Assessment of clinical laboratory parameters. • Assessment of vital signs. • Assessment of ECG parameters. • White blood count (WBC) and absolute neutrophil count (ANC) at each visit. • Abnormal laboratory findings from baseline. • Frequency and severity of adverse events related to extrapyramidal symptoms (EPS) including dystonia and akathisia, as assessed by the investigator. • C SSRS (suicide severity assessment). • Change from baseline in the Total Maximum Chorea (TMC) score of the UHDRS after 13 and 26 weeks of treatment. • Clinical Global Impression-Improvement score after 13 and 26 weeks of treatment. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Number and proportion of subjects with adverse events, clinical laboratory parameters: at each visit. • Assessment of vital signs, ECG parameters: v1, v2, v5, v7, v9 • White blood count (WBC) and absolute neutrophil count (ANC): at each visit. • Abnormal laboratory findings from baseline: at each visit. • Frequency and severity of adverse events related to extrapyramidal symptoms (EPS) including dystonia and akathisia, as assessed by the investigator: at each visit. • C SSRS: at each visit. • Change from baseline in the Total Maximum Chorea (TMC) score of the UHDRS: after 13 and 26 weeks of treatment. • Clinical Global Impression-Improvement score: after 13 and 26 weeks of treatment. |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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 | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
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.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 12 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 | No |
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 |
Canada |
Germany |
Poland |
United Kingdom |
United States |
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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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End of Trial in a MS of the EU is defined as the time at which it is deemed that sufficient subjects have been recruited and completed the study as stated in the regulatory application (ie, CTA) and ethics application in the MS. Poor recruitment (recruiting less than the anticipated number in the CTA) by a MS is not a reason for premature termination but is considered a normal conclusion to the study in that MS. End of Trial in all other participating countries is defined as the LSLV. |
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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 | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |