A phase 2a, randomized, placebo-controlled, dose-ranging study to evaluate the safety and efficacy of ptc518 in subjects with Huntington's disease
- Conditions
- brain diseaseHuntington's disease10029305
- Registration Number
- NL-OMON53484
- Lead Sponsor
- PTC Therapeutics, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- Not specified
- Target Recruitment
- 24
1. Ambulatory male or female patient aged 25 years and older, inclusive
2. Subject is willing and able to provide informed consent and comply with all
protocol requirements
3. Genetically confirmed HD diagnosis with a cytosine-adenine-guanine (CAG)
repeat length from 42 to 50, inclusive. CAG repeat length may be determined
analytically through amplification.
Eligibility for HD-ISS Stage 2 Group (Parts A, B, and C)
4. A UHDRS IS score of 100
5. A UHDRS Total Functional Capacity (TFC) score of 13
6. A score between 0.18 and 4.93 inclusive on the normed version of the HD
prognostic index (PINHD)
Eligibility for HD-ISS Mild Stage 3 Group (Parts D, E, and F)
9. A UHDRS TFC score of 11 or 12, or a UHDRS TFC score of 13 with an UHDRS IS
score of <100
7. Women of childbearing potential (WOCBP) must agree to use highly effective
methods of contraception during dosing and for 6 months after stopping the
study medication. Women of childbearing potential are defined as women who are
fertile, following menarche and until becoming postmenopausal unless
permanently sterile. Permanent sterilization methods include hysterectomy,
bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is
defined as no menses for 12 months without an alternative medical cause. A high
follicle-stimulating hormone (FSH) level in the postmenopausal range may be
used to confirm a postmenopausal state in women not using hormonal
contraception or hormonal replacement therapy. However, in the absence of 12
months of amenorrhea, a single FSH measurement is insufficient.
Female partners of enrolled males who are of childbearing potential should
consider use of highly effective methods of contraception while the enrolled
male is taking study drug and for 6 months after stopping study drug.
Highly effective contraception methods are defined as those that can achieve a
failure rate of less than 1% per year when used consistently and correctly and
include the following:
• Combined (estrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation:
* Oral
* Intravaginal
* Transdermal
• Progestogen-only hormonal contraception associated with inhibition of
ovulation:
* Oral
* Injectable
* Implantable
• Intrauterine device
• Intrauterine hormone-releasing system
• Bilateral tubal occlusion
• Vasectomized partner
• Sexual abstinence
In case of use of oral contraception, WOCBP should have been stable on the same
pill for a minimum of 3 months prior to Screening.
Abstinence is acceptable only as true abstinence when this is in line with the
preferred and usual lifestyle of the subject. Periodic abstinence (eg,
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are
not acceptable methods of contraception.
8. Sexually active and fertile males must use a condom during intercourse while
taking study drug and for 6 months after stopping study drug and should neither
father a child nor donate sperm in this period. A condom is required to be used
also by vasectomized men in order to prevent potential delivery of the drug via
seminal fluid.
1. Inability or unwillingness to swallow oral tablets
2. Receipt of an experimental agent within 90 days or 5 half-lives prior to
Screening or anytime over the duration of this study, including RNA- or
DNA-targeted HD-specific investigational agents, (such as antisense
oligonucleotides), cell transplantation, or any other experimental brain surgery
3. Any history of gene therapy exposure for the treatment of HD
4. Participation in an investigational study or investigational paradigm (such
as exercise/physical activity, cognitive therapy, brain stimulation, etc)
within 90 days prior to Screening or anytime over the duration of this study
5. Presence of an implanted deep brain stimulation device. Observational
studies (such as ENROLL-HD) are not exclusionary.
6. Family history of early onset cataracts or presence of significant cataracts
at Baseline. Visually significant cataract is defined as any Lens Opacity
Classification System II grading >=2, Best Corrected Visual Acuity <20/40,
cataract as the primary cause of vision impairment, and self-reported vision of
fair or worse.
7. Brain and spinal pathology that may interfere with CSF homeostasis and
circulation, increased intracranial pressure (including presence of a shunt for
the drainage of CSF or an implanted central nervous system catheter),
malformations, and/or tumors
8. Hospitalization for any major medical or surgical procedure involving
general anesthesia within 12 weeks of Screening or planned during the study
9. At significant risk of suicide as measured by the C-SSRS Baseline version
with a moderate risk rating or higher score
10. Risk of a major depressive episode, psychosis, confusional state, or
violent behavior as assessed by the investigator
11. Any medical history of brain or spinal disease that would interfere with
the lumbar puncture process or safety assessments
12. History of malignancy of any organ system (other than localized basal cell
carcinoma of the skin or in situ cervical cancer), treated or untreated, within
the past 5 years, regardless of whether there is evidence of local recurrence
or metastases
13. Any medical history or condition that would interfere with the ability to
complete the protocol-specified assessments (eg, implanted shunt, conditions
precluding magnetic resonance imaging scans)
14. Antidepressant, antipsychotic, or benzodiazepine use, unless receiving a
stable dose for at least 6 weeks prior to Screening and with a dose regimen
that is not anticipated to change during the study. Benzodiazepine use for
sedation for study-related procedures during the course of the study is
permitted.
15. History of illicit/illegal drug use, or alcohol use in the high-risk
category of risk drinking levels according to the World Health Organization for
a duration of 1 month or longer that in the opinion of the investigator could
compromise the interpretability of study results
16. Clinically significant medical condition, which in the opinion of the
investigator could adversely affect the safety of the subject or impair the
assessment of study results (eg, inability to fast or any known
hypersensitivity to PTC518 or its excipients)
17. Current significant renal impairment defined as estimated glomerular
filtration rate <60 mL/min/1.73 m2 at Screening
18. Current hepatic impairm
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Safety Endpoints:<br /><br>• Safety profile as characterized by treatment-emergent adverse events (TEAEs),<br /><br>laboratory abnormalities, neurofilament light chain (NfL) levels in plasma and<br /><br>CSF, electrocardiogram (ECG), vital signs, slit lamp eye examination, Total<br /><br>Neuropathy Score - Clinical (TNSc), Columbia Suicide Severity Rating Scale (C<br /><br>SSRS), and physical examination<br /><br><br /><br>Primary Efficacy Endpoint:<br /><br>• Change from Baseline in blood tHTT protein at Month 3 </p><br>
- Secondary Outcome Measures
Name Time Method <p>Secondary Endpoints:<br /><br>• Change from Baseline in caudate volume as assessed via vMRI at Month 12 (key<br /><br>secondary)<br /><br>• Change from Baseline in cUHDRS scores at Month 12<br /><br>• Change from Baseline in blood tHTT protein at Month 12<br /><br>• Change from Baseline in CSF mHTT protein at Month 12<br /><br>• Change from Baseline in blood mHTT protein at Month 12</p><br>