First Time in Human Study of GSK1223249 in Amyotrophic Lateral Sclerosis

• Register: ClinicalTrials.gov
• Last refreshed on: 16 December 2017
• Main ID: NCT00875446
• Date of registration: 02/04/2009
• Prospective Registration: Yes
• Primary sponsor: GlaxoSmithKline
• Public title: First Time in Human Study of GSK1223249 in Amyotrophic Lateral Sclerosis
• Scientific title: A Single and Repeat Dose Escalation Study of the Safety, Pharmacokinetics and Pharmacodynamics of GSK1223249 in ALS Patients
• Date of first enrolment: May 13, 2009
• Target sample size: 76
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT00875446
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: Double (Participant, Investigator).
• Phase: Phase 1

Countries of recruitment

France, Italy, United Kingdom, United States

Contacts

• Name: GSK Clinical Trials
• Affiliation: GlaxoSmithKline

Key inclusion & exclusion criteria

Inclusion Criteria:

- Patients with diagnosis of familial or sporadic ALS, defined as meeting the possible,
laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS
according to the revised World Federation of Neurology El Escorial criteria [Rix
Brooks 2000].

- Onset of muscle weakness within 60 months of study entry.

- Patients who have low Slow Inspiratory Vital Capacity (SVC) below that what is
predicted for age and sex can be included into the study at the discretion of the
investigator as long as they are NOT respiratory insufficient.

- If on any medication (including riluzole), these must have been stable within the
previous one month. (See also 'Concomitant Medications' - Section 8).

- Age 18 - 80 years inclusive.

- Male or Female of non-childbearing potential (NCBP) defined as follows:

Pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal
defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with
simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and oestradiol < 40 pg/ml (<140
pmol/L) is confirmatory]. Females on hormone replacement therapy (HRT) and whose menopausal
status is in doubt will be required to use one of the contraception methods in Section
7.1.1, if they wish to continue their HRT during the study. Otherwise, they must
discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment.
For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and
the blood draw; this interval depends on the type and dosage of HRT. Following confirmation
of their post-menopausal status, they can resume use of HRT during the study without use of
a contraceptive method.

- Male subjects must agree to use one of the contraception methods listed in Section
7.1.2. This criterion must be followed from the time of the first dose of study
medication until the last follow-up visit.

- QTcB < 500 msec or uncorrected QT <600msec (machine or manual overread). If subject
has bundle branch block then criteria is QTcB < 530 msec.

- A Body Mass Index that at the discretion of the investigator is acceptable for
inclusion into the study.

- Capable of giving written informed consent, which includes compliance with the
requirements and restrictions listed in the consent form.

Exclusion Criteria:

- Patients with other neuromuscular disorders (in addition to their ALS diagnosis),
unless the investigator determines that such additional disorder will not affect
safety or other measures in this study.

- Patients with evidence of dementia or psychiatric illness which, in the investigator's
opinion, is likely to prevent them from a full understanding of and/or compliance with
the study requirements and procedures.

- Patients with abnormalities detected during the screening evaluations which, in the
investigator's medical judgement, are sufficiently significant to exclude them from
participation in the study.

- Patients who have participated in a clinical trial involving receipt of a
biopharmaceutical product within 6 months prior to the first dosing day.

- Exposure to more than four new investigational products within 12 months prior to the
first dosing day.

- The subject has a positive drugs of abuse test at the screening or pre dose visit. A
minimum list of drugs that will be screened for include amphetamines, barbiturates,
cocaine, opiates and benzodiazepines. Subjects who are on any of these drugs by
prescription for medical reasons may be considered by the investigator for inclusion
if they fulfil other entry criteria.

- The subject has a positive alcohol test at the pre-dose visit. History of regular
excessive alcohol consumption within 6 months of the study defined as:

- For European sites: an average weekly intake of > 28 units for males or >21 units for
females. One unit is equivalent to 8g of alcohol: a half-pint (~240mL) of beer, 1
glass (125mL) of wine or 1 (25mL) measure of spirits.

- For North American sites: an average weekly intake of >21 drinks for males or >14
drinks for women. One drink is equivalent to 12 g alcohol: 12 ounces (360mL) of beer,
5 ounces (150mL) of wine or 1.5 ounces (45mL) of 80 proof distilled spirits.

- History of sensitivity to GSK1223249, or components thereof, or a history of drugs or
other allergies that, in the opinion of the investigator or GSK Medical Monitor,
contraindicates their participation.

- Where participation in the study would result in donation of blood or blood products
in excess of 500 mL within a 56 day period.

- Females of childbearing potential, pregnant females as determined by positive serum or
urine beta hCG test at screening or prior to dosing, or lactating females.

- Patients who have received any type of vaccination in the last 3 weeks before study
drug administration.

- Unwillingness or inability to follow the procedures outlined in the protocol

- Subjects who will undergo muscle biopsies (cohorts 3-optional 5, 6, 7 and 8 will not
be eligible for inclusion, if any of the following criteria apply:

Patients with wasted deltoids (MRC score = 2) and patients with normal deltoids (MRC score
5).

Patients who cannot achieve normal coagulation in the peri-operative period and those who
may otherwise be at higher risk of bleeding complications



Age minimum: 18 Years
Age maximum: 80 Years
Gender: All

Health Condition(s) or Problem(s) studied

Amyotrophic Lateral Sclerosis

Intervention(s)

Drug: PLACEBO

Drug: GSK1223249

Primary Outcome(s)

Adverse events, vital signs, standard physical examination, ECG and standard clinical laboratory tests (haematology and biochemistry). Evaluation of safety will include any adverse effects on Immunogenicity, ALSFRS-R, SVC, Muscle Strength and MUNE. [Time Frame: 12-16 Weeks]

Secondary Outcome(s)

Motor Unit Number Estimation (MUNE) [Time Frame: 12-16 Weeks]

Relationships between PK of GSK1223249 and relevant pharmacological endpoints [Time Frame: At least 16 weeks]

GSK1223249: Single dose PK (Part 1): AUC(0-8), AUC(0-t), AUC(0-Week 4), %AUCex, Cmax, tlast, CL, Vss, MRT, ?z and t½.Repeat dose PK (Part 2): GSK1223249 AUC(0-Week 4), Cmax and after the second dose, AUC(0-t), AUC(0-8),?z and t½. [Time Frame: 12-16 Weeks]

ALSFRS-R scores, Manual Muscle Strength test and Slow Inspirational Vital Capacity (SVC) [Time Frame: 12-16Weeks]

Presence of antibodies to GSK1223249 will be assessed in serum samples using immuno-electrochemiluminescent assay. [Time Frame: At least 16 weeks]

Muscle biopsies for protein analysis, Immunohistochemistry (IHC), Transcriptomics. Blood for protein analysis and other biomarkers. [Time Frame: At least 16 weeks]

Secondary ID(s)

111330

Source(s) of Monetary Support

Please refer to primary and secondary sponsors