Clinical Trials Register

Summary
EudraCT Number:	2014-001291-56
Sponsor's Protocol Code Number:	A8241021
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-07-21
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2014-001291-56

A.3

Full title of the trial

A PHASE 2, RANDOMIZED, PLACEBO CONTROLLED, DOUBLE BLIND PROOF-OF-CONCEPT STUDY OF THE EFFICACY AND SAFETY OF PF-02545920 IN SUBJECTS WITH HUNTINGTON’S DISEASE

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A PHASE 2, RANDOMIZED, PLACEBO CONTROLLED, DOUBLE BLIND PROOF-OF-CONCEPT STUDY OF THE EFFICACY AND SAFETY OF PF-02545920 IN SUBJECTS WITH HUNTINGTON’S DISEASE

A.4.1

Sponsor's protocol code number

A8241021

A.5.4

Other Identifiers

Name:

US IND Number

Number:

118,646

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Pfizer Inc., 235 East 42nd Street, New York, NY 10017
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Pfizer Inc., 235 East 42nd Street, New York, NY 10017
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Pfizer Inc.
B.5.2	Functional name of contact point	Clinical Trials.gov Call Center
B.5.3	Address:
B.5.3.1	Street Address	235 East 42nd Street
B.5.3.2	Town/ city	New York
B.5.3.3	Post code	NY 10017
B.5.3.4	Country	United States
B.5.4	Telephone number	+1800718 1021
B.5.5	Fax number	+1303739 1119
B.5.6	E-mail	ClinicalTrials.govcallcenter@pfizer.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	PF-02545920
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	not available
D.3.9.2	Current sponsor code	PF-02545920
D.3.9.3	Other descriptive name	PF-02545920
D.3.9.4	EV Substance Code	SUB26938
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

HUNTINGTON’S DISEASE

E.1.1.1

Medical condition in easily understood language

HUNTINGTON’S DISEASE

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	17.0
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

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
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

E.1.3

Condition being studied is a rare disease

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.

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).

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

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.

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.

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.

E.5.1.1

Timepoint(s) of evaluation of this end point

after 26 weeks

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.

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.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

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

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.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

250

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

130

F.4.2.2

In the whole clinical trial

260

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Subjects will have the opportunity to enter an open label extension study.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	CHDI Foundation, Inc.
G.4.3.4	Network Country	United States

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-08-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-04-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-10-04

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